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Validation of Cleaning Processes (7/93)  

GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).

 

I. INTRODUCTION

 

Validation of cleaning procedures has generated considerable discussion since agency documents, including the Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.

 

This guide is designed to establish inspection consistency and uniformity by discussing practices that have been found acceptable (or unacceptable). Simultaneously, one must recognize that for cleaning validation, as with validation of other processes, there may be more than one way to validate a process. In the end, the test of any validation process is whether scientific data shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.

 

This guide is intended to cover equipment cleaning for chemical residues only.

 

II. BACKGROUND

 

For FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shall be maintained in a clean and orderly manner ***." A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to prevent contamination or adulteration of drug products. Historically, FDA investigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipment and/or poor dust control systems. Also, historically speaking, FDA was more concerned about the contamination of nonpenicillin drug products with penicillins or the cross-contamination of drug products with potent steroids or hormones. A number of products have been recalled over the past decade due to actual or potential penicillin cross-contamination.

 

One event which increased FDA awareness of the potential for cross contamination due to inadequate procedures was the 1988 recall of a finished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become contaminated with low levels of intermediates and degradants from the production of agricultural pesticides. The cross-contamination in that case is believed to have been due to the reuse of recovered solvents. The recovered solvents had been contaminated because of a lack of control over the reuse of solvent drums. Drums that had been used to store recovered solvents from a pesticide production process were later used to store recovered solvents used for the resin manufacturing process. The firm did not have adequate controls over these solvent drums, did not do adequate testing of drummed solvents, and did not have validated cleaning procedures for the drums.

 

Some shipments of this pesticide contaminated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This resulted in the contamination of the bags used in that facility's fluid bed dryers with pesticide contamination. This in turn led to cross contamination of lots produced at that site, a site where no pesticides were normally produced.

 

FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical manufacturer which manufactured potent steroid products as well as non-steroidal products using common equipment. This firm was a multi-use bulk pharmaceutical facility. FDA considered the potential for cross-contamination to be significant and to pose a serious health risk to the public. The firm had only recently started a cleaning validation program at the time of the inspection and it was considered inadequate by FDA. One of the reasons it was considered inadequate was that the firm was only looking for evidence of the absence of the previous compound. The firm had evidence, from TLC tests on the rinse water, of the presence of residues of reaction byproducts and degradants from the previous process.

 

III. GENERAL REQUIREMENTS

 

FDA expects firms to have written procedures (SOP's) detailing the cleaning processes used for various pieces of equipment. If firms have one cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, we expect the written procedures to address these different scenario. Similarly, if firms have one process for removing water soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is to be followed. Bulk pharmaceutical firms may decide to dedicate certain equipment for certain chemical manufacturing process steps that produce tarry or gummy residues that are difficult to remove from the equipment. Fluid bed dryer bags are another example of equipment that is difficult to clean and is often dedicated to a specific product. Any residues from the cleaning process itself (detergents, solvents, etc.) also have to be removed from the equipment.

 

FDA expects firms to have written general procedures on how cleaning processes will be validated.

 

FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.

 

FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.

 

FDA expects firms to conduct the validation studies in accordance with the protocols and to document the results of studies.

 

FDA expects a final validation report which is approved by management and which states whether or not the cleaning process is valid. The data should support a conclusion that residues have been reduced to an "acceptable level."

 

IV. EVALUATION OF CLEANING VALIDATION

 

The first step is to focus on the objective of the validation process, and we have seen that some companies have failed to develop such objectives. It is not unusual to see manufacturers use extensive sampling and testing programs following the cleaning process without ever really evaluating the effectiveness of the steps used to clean the equipment. Several questions need to be addressed when evaluating the cleaning process. For example, at what point does a piece of equipment or system become clean? Does it have to be scrubbed by hand? What is accomplished by hand scrubbing rather than just a solvent wash? How variable are manual cleaning processes from batch to batch and product to product? The answers to these questions are obviously important to the inspection and evaluation of the cleaning process since one must determine the overall effectiveness of the process. Answers to these questions may also identify steps that can be eliminated for more effective measures and result in resource savings for the company.

 

Determine the number of cleaning processes for each piece of equipment. Ideally, a piece of equipment or system will have one process for cleaning, however this will depend on the products being produced and whether the cleanup occurs between batches of the same product (as in a large campaign) or between batches of different products. When the cleaning process is used only between batches of the same product (or different lots of the same intermediate in a bulk process) the firm need only meet a criteria of, "visibly clean" for the equipment. Such between batch cleaning processes do not require validation.

 

1. Equipment Design

 

Examine the design of equipment, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represent significant concern. For example, sanitary type piping without ball valves should be used. When such nonsanitary ball valves are used, as is common in the bulk drug industry, the cleaning process is more difficult.

 

When such systems are identified, it is important that operators performing cleaning operations be aware of problems and have special training in cleaning these systems and valves. Determine whether the cleaning operators have knowledge of these systems and the level of training and experience in cleaning these systems. Also check the written and validated cleaning process to determine if these systems have been properly identified and validated.

 

In larger systems, such as those employing long transfer lines or piping, check the flow charts and piping diagrams for the identification of valves and written cleaning procedures. Piping and valves should be tagged and easily identifiable by the operator performing the cleaning function. Sometimes, inadequately identified valves, both on prints and physically, have led to incorrect cleaning practices.

 

Always check for the presence of an often critical element in the documentation of the cleaning processes; identifying and controlling the length of time between the end of processing and each cleaning step. This is especially important for topicals, suspensions, and bulk drug operations. In such operations, the drying of residues will directly affect the efficiency of a cleaning process.

 

Whether or not CIP systems are used for cleaning of processing equipment, microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred. There should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation. For example, equipment should be dried before storage, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.

 

Subsequent to the cleaning process, equipment may be subjected to sterilization or sanitization procedures where such equipment is used for sterile processing, or for nonsterile processing where the products may support microbial growth. While such sterilization or sanitization procedures are beyond the scope of this guide, it is important to note that control of the bioburden through adequate cleaning and storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility. This is also particularly important from the standpoint of the control of pyrogens in sterile processing since equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens.

 

2. Cleaning Process Written

 

Procedure and Documentation

 

Examine the detail and specificity of the procedure for the (cleaning) process being validated, and the amount of documentation required. We have seen general SOPs, while others use a batch record or log sheet system that requires some type of specific

documentation for performing each step. Depending upon the complexity of the system and cleaning process and the ability and training of operators, the amount of documentation necessary for executing various cleaning steps or procedures will vary.

 

When more complex cleaning procedures are required, it is important to document the critical cleaning steps (for example certain bulk drug synthesis processes). In this regard, specific documentation on the equipment itself which includes information about who cleaned it and when is valuable. However, for relatively simple cleaning operations, the mere documentation that the overall cleaning process was performed might be sufficient.

 

Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may also dictate the amount of documentation required. For example, when variable residue levels are detected following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness of the process and operator performance. Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required.

 

3. Analytical Methods

 

Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. With advances in analytical technology, residues from the manufacturing and cleaning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique (see below).

 

4. Sampling

 

There are two general types of sampling that have been found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions.

 

a. Direct Surface Sampling - Determine the type of sampling material used and its impact on the test data since the sampling material may interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of samples. Therefore, early in the validation program, it is important to assure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.

 

Advantages of direct sampling are that areas hardest to clean and which are reasonably accessible can be evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are "dried out" or are insoluble can be sampled by physical removal.

 

b. Rinse Samples - Two advantages of using rinse samples are that a larger surface area may be sampled, and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated.

 

A disadvantage of rinse samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment. An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the pot.

 

Check to see that a direct measurement of the residue or contaminant has been made for the rinse water when it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.

 

c. Routine Production In-Process Control

 

Monitoring - Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a cleaning process has been validated. This would be particularly true for the bulk drug substance manufacturer where reactors and centrifuges and piping between such large equipment can be sampled only using rinse solution samples. Any indirect test method must have been shown to correlate with the condition of the equipment. During validation, the firm should document that testing the uncleaned equipment gives a not acceptable result for the indirect test.

 

V. ESTABLISHMENT OF LIMITS

 

FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the bulk and finished dosage form industries. The firm's rationale for the residue limits established should be logical based on the manufacturer's knowledge of the materials involved and be practical, achievable, and verifiable. It is important to define the sensitivity of the analytical methods in order to set reasonable limits. Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue.

 

Check the manner in which limits are established. Unlike finished pharmaceuticals where the chemical identity of residuals are known (i.e., from actives, inactives, detergents) bulk processes may have partial reactants and unwanted by-products which may never have been chemically identified. In establishing residual limits, it may not be adequate to focus only on the principal reactant since other chemical variations may be more difficult to remove. There are circumstances where TLC screening, in addition to chemical analyses, may be needed. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if equipment is not dedicated. The objective of the inspection is to ensure that the basis for any limits is scientifically justifiable.

 

VI. OTHER ISSUES

 

a. Placebo Product

 

In order to evaluate and validate cleaning processes some manufacturers have processed a placebo batch in the equipment under essentially the same operating parameters used for processing product. A sample of the placebo batch is then tested for residual contamination. However, we have documented several significant issues that need to be addressed when using placebo product to validate cleaning processes.

 

One cannot assure that the contaminate will be uniformly distributed throughout the system. For example, if the discharge valve or chute of a blender are contaminated, the

contaminant would probably not be uniformly dispersed in the placebo; it would most likely be concentrated in the initial discharge portion of the batch. Additionally, if the contaminant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo.

 

Some firms have made the assumption that a residual contaminant would be worn off the equipment surface uniformly; this is also an invalid conclusion. Finally, the analytical power may be greatly reduced by dilution of the contaminate. Because of such problems, rinse and/or swab samples should be used in conjunction with the placebo method.

 

b. Detergent

 

If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues. A common problem associated with detergent use is its composition. Many detergent suppliers will not provide specific composition, which makes it difficult for the user to evaluate residues. As with product residues, it is important and it is expected that the manufacturer evaluate the efficiency of the cleaning process for the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily removable. Otherwise, a different detergent should be selected.

 

c. Test Until Clean

 

Examine and evaluate the level of testing and the retest results since testing until clean is a concept utilized by some manufacturers. They test, resample, and retest equipment or systems until an "acceptable" residue level is attained. For the system or equipment with a validated cleaning process, this practice of resampling should not be utilized and is acceptable only in rare cases. Constant retesting and resampling can show that the cleaning process is not validated since these retests actually document the presence of unacceptable residue and contaminants from an ineffective cleaning process.

 

VII. REFERENCES

 

1) J. Rodehamel, "Cleaning and Maintenance," Pgs 82-87, University of Wisconsin's Control Procedures in Drug Production Seminar, July 17-22, 1966, William Blockstein, Editor, Published by the University of Wisconsin, L.O.C.#66-64234.

 

2) J.A. Constance, "Why Some Dust Control Exhaust Systems Don't Work," Pharm. Eng., January-February, 24-26 (1983).

 

3) S.W. Harder, "The Validation of Cleaning Procedures," Pharm. Technol. 8 (5), 29-34 (1984)

 

4) W.J. Mead, "Maintenance: Its Interrelationship with Drug Quality," Pharm. Eng. 7(3), 29-33 (1987).

 

5) J.A. Smith, "A Modified Swabbing Technique for Validation of Detergent Residues in Clean-in-Place Systems," Pharm. Technol. 16(1), 60-66 (1992).

 

6) Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations," Pharm. Technol. 17(4), 54-60 (1993).

 

7) McCormick, P.Y. and Cullen, L.F., in Pharmaceutical Process Validation, 2nd Ed., edited by I.R. Berry and R.A. Nash, 319-349 (1993)

Bulk Pharmaceutical Chemicals (7/91)  

GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS

 

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights,

privileges, benefits, or immunities for or on any person(s).

 

This guide, originally published in April 1984, was first revised in February 1987, and again in September 1991. This May 1994 printing is the same as the 1991 revision except for a few editorial changes.

 

CONTENTS

 

PART I GENERAL GUIDANCE

 

Subject ..............................................................................Page

 

Introduction ..........................................................................11

 

Status of Bulk Pharmaceutical Chemicals ...............................22

 

Scope ...................................................................................33

 

General Guidance - Bulk GMPs ............................................34

 

Inspectional Approach ..........................................................45

 

Registration ...........................................................................56

 

Product of Foreign Origin ......................................................57

 

Relationship to Dosage Forms/Dosage Form Approval ..........68

 

PART II SPECIFIC INTERPRETATIONS FOR

 

BPC OPERATIONS

 

General ..................................................................................69

 

Buildings and Facilities.............................................................610

 

Equipment ..............................................................................911

 

Raw Materials ........................................................................1012

 

Containers, Closures, and Packaging Components ..................1113

 

Production and Process Controls ............................................1114

 

In-Process Testing ..................................................................1315

 

Packaging and Labeling of Finished BPC ................................1316

 

Expiration Dating or Re-evaluation Dating ...............................1317

 

Laboratory Controls ...............................................................1418

 

Stability Testing ......................................................................1419

 

Reserve Samples ....................................................................1520

 

Batch Production Records ......................................................1521

 

APPENDIX22

 

A. Impurities ..........................................................................2315

 

B. References.........................................................................2416

 

PART I - GENERAL GUIDANCE

 

 

Introduction

 

This document is intended to aid agency personnel in determining whether the methods used in, and the facilities and manufacturing controls used for, the production of Bulk Pharmaceutical Chemicals (BPCs) are adequate to assure that they have the quality and purity which they purport or are represented to possess.

 

There are basic differences between the processes used for the production of BPCs and the processes used for the production of finished products. BPCs usually are made by chemical synthesis, by recombinant DNA technology, fermentation, enzymatic reactions, recovery from natural materials, or combinations of these processes. On the other hand, finished drug products are usually the result of a formulation from bulk materials whose quality can be measured against fixed specifications.

 

In almost every case in the production of BPCs, the starting materials, or derivatives of the starting materials, undergo some significant chemical change. Impurities,

contaminants, carriers, vehicles, inerts, diluents, and/or unwanted crystalline or molecular forms which may be present in the raw materials are largely removed by various treatments in the production process. Purification is the ultimate objective and is effected by various chemical, physical, and/or biological processing steps. The effectiveness of these steps is in turn confirmed by various chemical, biological, and physical tests of the BPC.

 

In contrast, in finished drug product production, the quality of the drug ingredients (the components), and the care exercised in handling them, somewhat predetermines the purity of the finished drug product. Purification steps usually are not involved.

 

The use of precision automated, mechanical, or electronic control and recording equipment and of automated processing equipment is even more likely to be found in a BPC plant than in a finished drug product plant. Use of such equipment is appropriate when adequate inspection, calibration, and maintenance procedures are utilized.

 

Production equipment and operations will vary widely depending on the type of BPC in production, the scale of production, and the type of operation (batch vs. continuous). In general, the environmental conditions, equipment, and operational techniques employed are those associated with the chemical industry rather than the finished drug product industry. Chemical processes frequently are performed in closed systems, which tends to provide protection against contamination, even when the reaction vessels are not enclosed in buildings. However, this does not preclude the introduction of contaminants from equipment, materials used to protect equipment, corrosion, cleaning, and personnel.

 

In evaluating the adequacy of measures taken to preclude contamination of, or by, materials in the process, it is appropriate to consider the type of system (open or closed), form of the material (wet or dry), stage of processing and use of the equipment and/or area (multi-purpose or dedicated). "Closed" systems in chemical plants are often not closed when they are being charged and/or when the final product is being emptied. Also, the same reaction vessels are frequently used for different reactants.

 

Other factors that an investigator must consider in evaluating a BPC plant are:

 

(a) Degree of exposure of the material to adverse environmental conditions;

 

(b) Potential for cross-contamination from any source;

 

(c) Relative ease and thoroughness of clean-up;

 

(d) Sterile vs. non-sterile operations.

 

In the production of BPCs, the recycling of process liquors and recovery from waste streams which have been tested and meet appropriate standards often are necessary for quality, economic, and environmental reasons. In addition, the production of some BPCs involves processes in which chemical and biochemical mechanisms have not been fully understood and scientifically documented. Therefore, the methods and procedures for materials accountability will often differ from those applicable to the manufacture of dosage form drug products.

 

The producer of BPCs must recognize the need for appropriate evaluation, using appropriate standards and/or test procedures, of raw materials before their introduction into the process. In addition, as chemical processing proceeds, a chain of documentation should be established which at the minimum includes a written process and appropriate production records, records of raw materials used, records of initial and subsequent batch numbers, records of the critical processing steps accomplished, and intermediate test results with meaningful standards. It should be recognized that all intermediates need not be tested. A firm should, however, be able to identify critical or key points in the process where sampling and testing selective intermediates is necessary in order to monitor the performance of the process. As the end of the process is approached, the completeness of the records should increase, and the latter finishing steps should be thoroughly documented and conducted under appropriate conditions to avoid contamination and mixups.

 

 

Status of Bulk Pharmaceutical Chemicals

 

BPCs are components of drug products. The manufacture of BPCs should be carried out in accordance with concepts of good manufacturing practice (GMP) consistent with this guide whether or not the manufacturers are required to register under 21 CFR 207. The manufacturers of inactive ingredients may not be required to register with FDA, but they are not exempt from complying with GMP concepts, and they are not exempt from inspection. Whether or not this type of firm will be inspected on a surveillance basis is

generally discretionary. However, such a firm is always subject to "for cause" inspection.

 

The question of when an industrial chemical becomes a BPC can be complex, and there is no satisfactory answer. However, criteria such as the following can be used to identify a chemical as a BPC:

 

(a) When there is no recognized non-drug commercial use for the chemical.

 

(b) When it reaches the point in its isolation and purification where it is intended that the substances will be used in a drug product.

 

(c) When the manufacturer sells the product or offers it for sale to a pharmaceutical firm for use in a drug product.

 

Many elements and simple compounds that will ultimately comprise the molecule of BPC originate from botanicals, mines, oil wells, and sea water. It would be unrealistic to expect drug product GMP concepts to apply to the production of these progenitors. As a general rule, however, it is reasonable to expect GMP concepts to start to become applicable at that point where a starting material enters a biological or chemical synthesis or series of processing steps, where it is known that the end product will be a BPC.

 

 

Scope

 

This guide is applicable to all BPCs produced in the United States. It is also applicable to BPCs produced in foreign countries intended to be exported to the United States or to be delivered to a U.S. overseas base. This guide applies to: a) human drugs; b) veterinary drugs; and c) biologics.

 

The guide applies when the BPC is: a) a drug of animal, botanical, synthetic or biological origin, including those produced with rDNA technology; b) an inactive

ingredient (although inspections will only be conducted by special assignment, or for cause); c) a component not appearing in the finished drug product; and d) a bulk intended for use in placebos.

 

Excluded from consideration are medical gases and bulk-packaged drug products (final dosage forms), which are subject to other requirements and full CGMPs.

 

 

General Guidance - Bulk GMPs

 

Although the GMP regulations under 21 CFR, Parts 210 and 211, apply only to finished dosage form drugs, Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act requires that all drugs be manufactured, processed, packed, and held in accordance with current good manufacturing practice (CGMP). No distinction is made between BPCs and finished pharmaceuticals, and failure of either to comply with CGMP constitutes a failure to comply with the requirements of the Act. There are many cases where GMPs for dosage form drugs and BPCs are parallel. For this reason, the requirements under Part 211 will be used as guidelines for inspection of BPC manufacturers, as interpreted in this document. This document does not supersede the GMP regulations, rather it provides general guidance to inspectional personnel as to the extent and point of application of some of the concepts of Parts 210 and 211 to BPC production.

 

Although strict observance of GMPs, approaching or equaling those expected for finished drug products, may be expected in some types of bulk processes, in most others it is neither feasible nor required to apply rigid controls during the early processing steps. In all processes of this type, however, the requirements should be increasingly tightened according to some reasonable rationale. At some logical processing step, usually well before the final finishing operation, appropriate GMPs should be imposed and maintained throughout the remainder of the process.

 

Good judgement and a thorough knowledge of the process are required to permit sound evaluation of the processing step at which imposition of GMPs should take place. A detailed process flow diagram should be available for the processes used. This diagram should identify the unit operations, equipment used, stages at which various substances are added, key steps in the process, critical parameters (time, temperature, pressure, etc.) and monitoring points. As briefly discussed in the introduction, the documentation system required for the early steps in the process must provide a chain of documentation but need not necessarily be as comprehensive as in the later parts of the process. Complete documentation should, at a minimum, be initiated where:

 

(a) The bulk pharmaceutical chemical can be identified and quantified for those processes where the molecule is produced during the course of the process (e.g., fermentation, synthesis, or recombinant DNA technology). In this regard, a theoretical yield should be established with appropriate limits, and there should be an investigation if the actual yield falls outside the limits.

 

(b) A contaminant, impurity, or other substance likely to adversely affect the purity, potency, or form of the molecule, is first identified and subsequent attempts are made to remove it (e.g., removal of crystalline occlusion, etc.).

 

(c) An attempt is initiated to separate a mixture of different forms of the same molecule and isolate a desired form of the molecule for pharmacological or other reasons (e.g., separation of racemic mixtures).

 

The complete documentation should be continued throughout the remainder of the process, including the application of full GMP concepts, for all significant processing steps until the BPC is packaged into a bulk container, or is transported without containerization to a location for subsequent manufacture into drug products.

 

Significant processing steps can involve a number of unit operations or unit processes. Unit operations include those processing steps wherein the material is treated by physical means and/or the transfer and change of energy, but no chemical change of the molecule occurs; unit processes include those processing steps wherein the molecule undergoes a chemical change.

 

Significant processing steps can include: a) phase changes involving either the desired molecule or the solvent, inert carrier or vehicle, e.g., dissolution, crystallization, evaporation, sublimation, distillation or absorption; b) a phase separation such as filtration or centrifugation; c) any chemical change involving the desired molecule, e.g., removal or addition of water of hydration, acetylization, formation of the salt; d) an adjustment of the solution containing the molecule such as adjustment of pH or pO2; e) a precision measurement of contained or added BPC components, in-process solutions, recycled materials is performed, i.e., weighing, volumetric measuring, optical rotation, spectrophotometric determinations, etc.; and f) changes occur in surface area, particle size, or lot uniformity, e.g., milling, agglomeration, blending.

 

In order to promote uniformity in inspectional GMP coverage for a BPC, the following minimal criteria should be applied:

 

The lot of BPC to be released and/or certified is the essential element. A unique lot number should be assigned to this quantity of material. The firm should be prepared to demonstrate that this lot:

 

(a) Has been prepared under GMP conditions from the processing point as described above.

 

(b) Has a batch record (as described later in this document).

 

(c) Is homogenous.

 

(d) Is not intermingled with material from other lots for the purpose of hiding or diluting an adulterated substance while completing the processing through packaging.

 

(e) Has been sampled in accordance with a sampling plan which assures that the sample truly represents the lot.

 

(f) Has been analyzed using scientifically sound tests and methods designed to assure that the product meets established standards and specifications for quality, identity, and purity.

 

(g) Has stability data to support the intended period of use.

 

 

Inspectional Approach

 

The inspectional approach for coverage of a BPC operation should be the same whether or not that BPC is referenced as active ingredient in a pending application. The purpose, operational limitations and validation of the critical processing steps of a production process should be examined to determine that the firm adequately controls such steps to assure that the process works consistently. Overall, the inspection must determine the BPC manufacturer's capability to deliver a product that consistently meets the specifications of the bulk drug substance that the finished dosage form manufacturer listed in the application and/or the product needed for research purposes.

 

BPC manufacturing plants often produce laboratory scale or "pilot" batches. Scale-up to commercial full-scale (routine) production may involve several stages and data should be reviewed to demonstrate the adequacy of the scale-up process. Such scale-ups to commercial size production may produce significant problems in consistency among batches. Pilot batches serve as the basis for establishing in-process and finished product purity specifications. Typically, manufacturers will generate reports that discuss the development and limitation of the manufacturing process. Summaries of such reports should be reviewed to determine if the plant is capable of producing adequately the bulk substance. The reports serve as the basis for the validation of the manufacturing and control process and the basic documentation that the process works consistently.

 

Drug Master Files (DMFs) are a valuable source of detailed information regarding the process and controls for BPCs. Although DMFs are not mandatory, most firms, particularly foreign manufacturers, have submitted them to FDA. A review of a process flow chart is helpful in understanding the various processing stages. Then, in conjunction with the review of the processing records, the critical stages should be identified, typically those where in-process samples are collected. The information expected from in-process testing should be determined along with the action to be taken by the firm should these specification limits be exceeded. For example, an in-process test result may show the presence of some unreacted material which may indicate that the process time should be extended.

 

A good starting point for the BPC inspection is a review of product failures evidenced by the rejection of a batch that did not meet specifications, return of a product by a customer, or recall of the product. The cause of the failure should have been determined by the manufacture, a report of the investigation prepared, and subsequent corrective action initiated and documented. Such records and documents should be reviewed to ensure that such product failures are not the result of a process that has been poorly developed or one that does not perform consistently.

 

Complaint files should also be reviewed since customers may report some aspects of product attributes that are not entirely suitable for their use. These may be caused by impurities or inconsistencies in the BPC manufacturing process. Also, storage areas in

the warehouse may hold rejected product. In addition, a review of change control logs, material review board documents, and master formula and batch production records showing frequent revisions may reveal problems in the BPC production process.

 

In the analytical laboratory, specifications for the presence of unreacted intermediates and solvent residues in the finished BPC should be reviewed. These ranges should be at or near irreducible levels.

 

An inspectional team consisting of investigators and engineers, laboratory analysts or computer experts should participate in the inspection, as appropriate, when resources permit.

 

 

Registration

 

Domestic manufacturers of bulk pharmaceutical chemicals are required to register (and list their products) in accordance with section 510 of the Act if they meet the definition of a "bulk drug substance" under 21 CFR 207.3(a)(4), i.e., a substance that is represented as a drug and, when used, becomes an active ingredient or finished dosage form of such drug. Specifically excluded from registration are manufacturers of intermediates (21 CFR 207.3(a)(4)) and inactive ingredients which are excipients, colorings, etc. (21 CFR 207.10(e)).

 

 

Products of Foreign Origin

 

The results of inspections of foreign manufacturers of BPCs directly affect the status of these products when offered for entry into this country. BPC's may be sampled, detained, and/or refused entry into the United States if an inspection of the foreign manufacturer reveals that the firm is not complying with GMPs. This would also be the case if the products demonstrate actual adulteration or misbranding.

 

Although foreign firms are not required to register in accordance with section 510 of the Act, they are required to list all of their products (21 CFR 207.40(a)). Products not listed are subject to detention and/or refusal of entry.

 

 

Relationship to Dosage Forms and Dosage Form Approval

 

The finished product formulator is highly dependent on the BPC manufacturer to provide bulk substances uniform in chemical and physical characteristics. This is particularly important in the context of the product approval process where bioequivalency comparisons are made between clinical production or biobatches and commercial batches. The BPC used to manufacture commercial batches must not significantly differ from that used on these test batches to provide adequate assurance of product performance. Where significant differences occur, additional testing by the dose form manufacturer to establish the equivalence of the finished product may be required. This remains equally important post-approval for subsequent commercial batches to assure that marketed products are not adversely affected over time.

 

Manufacturers holding DMFs covering production of BPCs (21 CFR 314.420) must update such DMFs with any changes. The DMF holders must also notify each dose form manufacturer referencing the DMF of any such changes to the DMF.

 

In general, BPCs are used as purchased, with no further refining or purification taking place. Consequently, impurities present in the BPC will be present in the finished dosage form.

 

While dosage form manufacturers may have limited control over BPC quality (obtaining certificates of analysis and testing representative samples), the BPC manufacturer has ultimate control over physical characteristics, quality, and the presence of trace-level impurities in the BPC.

 

Many bulk substances are used in different types of dosage forms including oral, topical and parenteral products where physical characteristics, particularly particle size, may be important. While it is primarily the dosage form manufacturer's responsibility to identify the particular physical characteristics needed, it is the responsibility of the BPC manufacturer to adequately control processes to consistently provide BPCs complying with physical specifications.

 

The end use of the BPC should be identified and kept in mind during inspections of BPC manufacturers. A particularly important distinction involves whether or not the BPC will be used in the preparation of a sterile dosage form and whether or not it is represented as pyrogen free. The BPC manufacturer is responsible for ensuring that BPCs are pyrogen free if they make such a representation in specifications, labeling, or applications, including DMFs. In addition, any manipulation of sterile BPCs post-sterilization must be performed as a validated aseptic process. This is particularly important for those BPCs which are not further sterilized prior to packaging into final containers (e.g., bulk antibiotic powders).

 

In some instances, the USP monograph may specify that the BPCs not meeting parenteral grade standards be labeled as not suitable for use in the preparation of injectable products.

 

PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS

 

 

General

 

The following sections will discuss those specific points of the CGMPs which are clearly different in a BPC operation in contrast to a finished product operation. Points not separately discussed here should be viewed as appropriate to BPC manufacturing operations using finished product GMPs for guidance.

 

 

Buildings and Facilities

 

(a) Contamination/Cross Contamination

 

Cross contamination is not permitted under any circumstances. However, the fact that a BPC plant is, or can be, used for manufacturing multiple drugs, even simultaneously, is not in itself objectionable with only a few exceptions. There must be separate facilities

and completely separate air handling systems for the production of penicillin as the CGMP regulations require for dosage form drug products. It is also encouraged that separate facilities and air handling systems be used for the production of certain steroids, alkaloids, cephalosporins, certain hazardous or toxic drugs, pesticides, chemicals, and/or starting materials.

 

NOTE: Containment via closed system is considered a separate facility. The intent is to require isolation of penicillin production operations from operations for non-penicillin products. Separation can be achieved in a facility, building, or plant by effectively isolating and sealing off from one another these two types of operations. Isolation of facilities does not necessarily mean separation by geographical distance or the placement of these operations in separate buildings. Effective means can almost certainly be developed to separate activities from one another to prevent cross-contamination problems within a single building. Containment in a fermentor would meet this criterion and they are applicable to both dry and liquid state penicillin production.

 

Even though penicillin production may take place in the same building as non-penicillin production, air handling systems must at all times be completely separate. This includes fermentation procedures. This is the only means by which cross-contamination can be prevented through air facilities.

 

The point at which the final BPC product is initially recovered (usually as a moist cake from a centrifuge or filter press) should be in a clean environment and not exposed to airborne contaminants such as dust from other drugs or industrial chemicals. Typically, the damp product will be unloaded into clean, covered containers and transported elsewhere for drying and other manipulations. These subsequent operations should be performed in separate areas because, once dry, the BPC is more likely to contaminate its environment; this in turn makes it likely that other products in the same area might become contaminated. The primary consideration is that the building and facilities should not contribute to an actual or potential contamination of the BPC.

 

Air handling systems for BPC plants should be designed to prevent cross-contamination. For economic reasons, it is a common practice to recycle a portion of the exhaust air back into the same area. For dedicated areas processing the same BPC, this is not objectionable. The adequacy of such a system of operation for multi-use areas, especially if several products are processed simultaneously, should be carefully analyzed. In multi-use areas where several products are completely confined in closed vessels and piping systems, the extent of filtration of the supply air (combined fresh make-up air and recycled air) is not a problem (although other regulatory agencies or company policy may impose restrictions) except when the closed system must be opened (charging). In those areas where the BPCs are in a damp or moistened form

(such as filter or centrifuge cake) and may be exposed to the room air environment, filter efficiencies on the supply air system as low as 85% may be perfectly adequate. In those areas wherein one or more of the products is being processed in a dry form, even total filtration of the entire supply air flow with HEPA filters may not be adequate. In all cases, the firm should be able to demonstrate adequacy of their air handling system with data and (in case of doubt) the investigator should consider collection of product samples for analysis for cross-contamination.

 

Process wastes and unusable residues should be removed and disposed of in a manner that will insure that they do not interfere with subsequent steps of the process or adulterate the product.

 

Adequate sanitation of buildings and areas for BPCs requires considerable judgement. Many starting materials, particularly botanicals, may have some unavoidable contamination with rodent or other animal filth or be infested with insects. In such cases, it is not realistic to expect high standards in storage areas for starting materials and perhaps in the limited area of the plant wherein the initial steps of processing are conducted.

 

The control methods utilized by the firm to prevent an increase of such contamination or infestation in holding areas, or its spread to other areas of the plant, are of primary importance.

 

(b) Water Systems/Water Quality

 

Water used in the production of BPCs in many instances (e.g., fermentation of antibiotics) may be potable water obtained from wells or surface sources. This is acceptable provided that water quality standards are established that are consistent with compendial or other regulatory requirements for source drinking water. Although it is not expected that potable water be routinely tested as a component, sufficient data from periodic testing should be available to show compliance with standards from both chemical and microbiological standpoints, including freedom from pathogenic organisms. Where adequate data are available from municipal water authorities, it need not be generated by the manufacturer.

 

Purified water is widely used in the manufacture of BPCs. Because of the well recognized potential for microbial growth in deionizers and ultrafiltration (UF) or reverse osmosis (RO) systems used to produce purified water, such systems must be

properly validated and controlled. Proper control methods include the establishment of water quality specifications and corresponding action levels, remedial action when microbial levels are exceeded, and adequate maintenance procedures such as regeneration and sanitation/sterilization. Appropriate specifications for chemical and microbial quality should be established and periodic testing conducted. Such specifications will vary depending on the process and the point in the process where the water is used. For example, if the water is used in later processing steps such as for a final wash of the filter cake, or if the BPC is crystallized from an aqueous system, the water quality standards should be higher than normally specified for purified water. This is particularly important where the BPC is intended for use in parenteral dosage forms. The frequency of microbial and chemical testing of purified water is dependent upon a variety of factors including the test results and the point in the process (e.g., final wash in centrifuge) at which such water is used.

 

The USP includes suggested microbial action guidelines for source drinking water and purified water in the General Chapter on Water for Pharmaceutical Purposes and includes standards for specific types of water in monographs (e.g. Purified Water, USP). If the firm specifies a water of compendial quality in an application, the water should meet the standards given in the compendium.

 

Similar principles to those discussed above for purified water apply to Water For Injection (WFI) utilized in sterile and pyrogen-free BPC processing. The WFI system must be monitored for microorganisms and the validation data and reports of monitoring should be reviewed as is required for the production of finished dosage forms.

 

Most purified and WFI water systems, including RO and UF systems, have the potential for the development of endotoxins. If the final BPC is purported to be pyrogen free or sterile, or will be used in preparing parenteral products, routine testing of the process water for endotoxins (preferably by the LAL method) is indicated. However, end point testing alone is not adequate and validation of the system to control endotoxin development should be conducted.

 

(c) Aseptic/Sterile Processing

 

One of the more difficult processes is the manufacture of a sterile BPC. The aseptic crystallization and subsequent processing (drying, milling, and blending) present unique challenges. Since the operators are the primary source of contamination in an aseptic operation, processes are being designed to eliminate direct operator contact. However, some aseptic bulk operations still utilize considerable operator involvement which

requires adequate controls. Major potential problem areas include aseptic removal of the BPC from the centrifuge, manual transfer to drying trays and mills, and the inability to sterilize the dryer.

 

Unfortunately, not all equipment currently in use can be sterilized. The BPC manufacturer must have data to document the sanitizing of critical processing equipment such as centrifuges and dryers.

 

Sterilization by use of ethylene oxide is sometimes attempted for powders. In this operation, the powders are spread in a thin layer and exposed to the gas. Typically, however, ethylene oxide does not penetrate the BPC in this powdered form. The manufacturer should validate that the ethylene oxide exposure does, in fact, produce a sterile product.

 

The Sterile Drug Process Inspections Compliance Program (CP 7356.002A) provides detailed inspectional guidance for coverage of the manufacture of sterile BPCs. Also, the Aseptic Processing Guidelines, although intended for coverage of dosage forms, includes principles that are also applicable to aseptic processing of sterile bulks. Both documents should be reviewed in association with any inspections of the manufacture of sterile BPCs.

 

 

Equipment

 

(a) Multipurpose Equipment

 

As is the case with buildings, many BPCs are produced using multipurpose equipment. Fermentation tanks, reactors, centrifuges, and other pieces of equipment are readily used or adapted for a variety of products. With few exceptions, such multiple usage is satisfactory provided that the equipment is cleanable and is in fact cleaned according to written procedures. The cleaning program should take into consideration the need for different procedures depending on what product or intermediate was produced. Equipment that contains tarry or gummy residues that cannot be removed readily should be dedicated for use only with limited portions of a synthesis.

 

Where temperature control is important, temperature recording devices should be utilized, with recording charts retained as part of the batch record. For example, reactors may require narrow temperature ranges for consistent operation, and when recorders are absent, the manufacturer should justify their absence.

 

(b) Equipment Cleaning and Use Log

 

Where multipurpose equipment is in use, it is important to be able to determine previous usage as an aid in investigating cross-contamination or the possibility thereof.

 

An equipment cleaning and use log, while desirable and even preferable, is not the only method of determining prior use. Generally speaking, any documentation system that clearly identifies the previous batch and shows that the equipment was in fact cleaned is acceptable.

 

(c) Equipment Located Outdoors

 

Some fermentation tanks, reaction vessels, and other equipment are not situated within buildings; thus a considerable amount of processing occurs out-of-doors. Such processing is unobjectionable provided that it occurs in a closed system.

 

(d) Protected Environment

 

Isolation of intermediates or products may require the use of a protected environment to avoid microbial contamination or degradation caused by exposure to air or light. The degree of protection required may vary depending on the stage of the process. Equipment should be designed to minimize the possibility of contamination when used by the operator. Often, direct contact is involved in the unloading of centrifuge bags, transfer hoses (particularly those used to transfer powders), drying equipment and pumps.

 

Also, the sanitary design of transfer equipment such as pumps should be evaluated. Those with moving parts should be assessed in regard to the integrity of seals and other packing materials to avoid product contamination.

 

Processes requiring special environments to assure product quality (inert atmosphere, protection from light, etc.) should be carefully scrutinized for any lapses in the special environment. If any such lapses are found in the production process, adequate evidence and appropriate rationales must be shown that such lapses have not compromised the quality of the BPC. Such environmental concerns become more important after the purification of the BPC has been completed. The area where the BPC may be exposed, and especially those used to manufacture parenteral substances, should have environmental quality similar to that used for the manufacture of dosage forms. For example, controlled areas may need to be established along with appropriate air quality classifications. Such areas should be serviced by suitable air handling systems and there should be adequate environmental monitoring programs. Any manipulation of sterile BPCs post-sterilization must be performed as an aseptic process, including the utilization of Class 100 air and other aseptic controls.

 

(e) Cleaning of Product Contact Surfaces

 

Cleaning of multiple use equipment is an area where validation must be carried out. The manufacturer should have determined the degree of effectiveness of the cleaning procedure for each BPC or intermediate used in that particular piece of equipment.

 

Validation data should verify that the cleaning process will remove residues to an acceptable level. However, it may not be possible to remove absolutely every trace of material, even with a reasonable number of cleaning cycles.

 

Specific inspectional coverage for cleaning should include:

 

1. Detailed Cleaning Procedure:

 

There should be a written equipment cleaning procedure that provides details of what should be done and materials to be utilized. Some manufacturers list the specific solvent for each BPC and intermediate.

 

For stationary vessels, often clean-in-place (CIP) apparatus may be encountered. For evaluation of these systems, diagrams will be necessary, along with identification of specific valves.

 

2. Sampling Plan:

 

After cleaning, there should be some periodic testing to assure that the surface has been cleaned to the validated level. One common method is the analysis of the final rinse water or solvent for the presence of the substance last used in that piece of equipment. There should always be a specific analytical determination for such a residual substance.

 

3. Analytical Method/Cleaning Limits:

 

Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?" The sensitivity of modern analytical apparatus has lowered some detection thresholds past parts per million, down to parts per billion.

 

The residue limits established for each piece of apparatus should be practical, achievable, and verifiable. When reviewing these limits, ascertain the rationale for establishment at that level. The manufacturer should be able to document, by means of data, that the residual level permitted is scientifically sound.

 

Another factor to consider is the possible non-uniformity of the residue. If residue is found, it may not necessarily be at the maximum detectable level due to the random sampling, such as taking a swab from a limited area on that piece of equipment.

 

 

Raw Materials

 

(a) Raw materials, especially those received in large quantities (hundreds of bags or in bulk), should not be physically moved from a quarantine area to a released area prior to quality control acceptance. However, such raw materials may remain in the quarantine

area after release. The important consideration is that an unreleased material should not be used prior to quality control acceptance. Effective quarantine can be established with suitable identifying labels or signs, sound and valid documentation systems, etc. With increasing frequency, it is noted that such quarantine and documentation is widely being accomplished internally with a computer system in lieu of a physical stock control system. This is acceptable provided that system controls are adequate to prevent use of unreleased material.

 

(b) Film-wrapped palletized bags may not be individually identified by information normally applied to every container in a lot. To insist otherwise would destroy many of the advantages of film wrapped pallets. This is acceptable provided the pallet load itself is adequately identified. If issued individually, bags should be identified with the necessary information at the time of issuance.

 

(c) Some raw materials are stored in silos or other large containers, making precise separation of lots difficult. Considering that such materials are usually nutrients or are inactive, such storage is acceptable. It should be possible, via inventory or other records, to show usage of such materials with reasonable accuracy.

 

(d) Solvents used in BPC production are frequently stored in large tanks. Often, fresh and recovered solvents are commingled so that precise lot identity is missing. This is satisfactory provided incoming solvents are identified and tested prior to being mixed with recovered solvents and if the latter are tested for contaminates from the process in which they were used previously. The quality of the solvent mixture must also be monitored at suitable intervals.

 

(e) Some raw materials are stored out-of-doors; e.g., acids, other corrosive substances, explosive materials, etc. Such storage conditions are satisfactory provided the containers give suitable protection to their contents, identifying labels remain legible, and containers are adequately cleaned prior to opening and use.

 

(f) Some raw materials may not be acceptance tested by the firm because of the hazards involved; e.g., phosphorus pentachloride, sodium azide, etc. This is acceptable where there is a reason based on safety or other valid considerations. In such a circumstance, assay certification from the vendor should be on file. There should always be some evidence of an attempt by the BPC manufacturer to establish identity even if it is only a visual examination of containers, examination of labels, and recording of lot numbers from the labels.

 

 

Containers, Closures, and Packaging

 

Components

 

A system for BPC containers, closures, and packaging components should include the following features at a minimum:

 

(a) Suitable written specifications, examina- tion or testing methods, and cleaning procedures where so indicated.

 

(b) Determination that the container-closure system is not reactive, additive, or absorptive so as to alter the quality of the BPC beyond its established specifications and that it provides adequate protection against deterioration and contamination.

 

(c) Storage and handling in a manner to protect containers and closures from contamination and deterioration and to avoid mixups (e.g., between containers that have different specifications but are similar in appearance).

 

(d) Use of bulk shipping containers in which bulk pharmaceutical components were received should be avoided for BPC storage or shipment unless a suitable polymer lining or inner bag is used.

 

 

Production and Process Controls

 

(a) Mother Liquors

 

Mother liquors containing recoverable amounts of BPCs are frequently re-used. Such re-use may consist of employing the mother liquor to dissolve the reactants in the next

run of that step in the synthesis. Re-use may also consist of a separate reaction to obtain a "second crop" of final product. Finally, since crystallizations are sometimes slow, some second crops are obtained simply by allowing the second crystallization to continue for long periods after the first crop is removed. These secondary recovery procedures are acceptable providing the isolated BPC meets its original, or other suitable, specifications. The recovery procedures should be indicated in batch production records.

 

Similarly, mother liquors may contain unreacted starting materials or intermediates that are not recoverable. Secondary recovery procedures for these materials are acceptable provided that the materials meet suitable specifications.

 

(b) In Process Blending/Mixing

 

Deliberate in-process blending, or mixing, is that blending required in the process for a variety of reasons and is carried out with reasonable reproducibility from run to run during the process. Examples include: 1) Collection of multiple fermentation batches in a single holding tank (with a new batch number); 2) Recycling solution from one batch for further use in a succeeding batch; 3) Repeated crystallizations of the same mother liquor for better yield of crystals; and 4) Collecting several centrifuge loads in a single dryer/blender. Such in-process blending is acceptable provided it is adequately documented in batch production records.

 

Incidental carryover is another type of in-process mixing that occurs frequently. Examples include: 1) Residue adhering to the wall of a micronizer used for milling the finished BPC; 2) Residual layer of damp crystals remaining in a centrifuge bowl after discharge of the bulk of the crystals from a prior batch; and 3) Incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. These practices are usually acceptable since we do not normally require complete cleanup between successive batches of the same drug during a production campaign. However, in the case of non-dedicated production units, complete cleaning procedures designed to prevent contamination that would alter the quality of the substance must be employed when changing from one BPC to another. The effectiveness of these cleaning procedures may require the use of analytical testing for the substances involved.

 

In contrast to in-process blending and incidental carryover discussed above, the process intent should be directed toward achieving homogeneity of the batch of finished BPC to the maximum extent feasible. Three areas in the processing of finished batches of BPCs should be examined carefully and critically. These are: 1) The final blending operation

that will constitute the finished batch; 2) The point in the process at which the lot number is assigned; 3) The sampling procedure used to obtain the sample is intended to be representative of the batch.

 

Note: Blending of batches or lots that individually do not conform to specifications with other lots that do conform (to salvage adulterated material) is not acceptable practice.

 

(c) Validation of Process and Control

 

Procedures

 

An important factor in the assurance of product quality includes the adequate design and control of the manufacturing process. Routine end product testing alone is not necessarily sufficient because of limited sensitivity of such testing to reveal all variations that may occur and affect the chemical, physical, and microbial characteristics of the product. Each step of the manufacturing process must be controlled to the extent necessary to assure that the product meets established specifications. The concept of process validation is a key element in assuring that these quality assurance goals are met.

 

Process validation is required in general and specific terms by the CGMP regulations for finished dosage forms (21 CFR Parts 210 and 211). More specific guidance on process validation is provided in guidelines (See References). Many of these concepts are applicable to BPCs to assure that such BPCs are manufacturered in accordance with CGMPs as required by the Act under Section 501 (a)(2)(B).

 

BPC manufacturers are expected to adequately determine and document that significant manufacturing processes perform consistently. The type of BPC, the range of specifications and other factors determine the extent of the process development and documentation required. However, most bulk manufacturing processes and control procedures can be validated with less arduous procedures than would be required for finished dosage forms.

 

Many firms already possess the data necessary to prepare an evaluation of the process and demonstrate that it works consistently. For example, limitations of a reaction and/or purification steps are usually identified in the development phase. Impurities with

acceptable levels and tests used to determine them are established at this phase. The report describing the process reactions and purifications, impurities, and key tests needed for process control provide the basis for validation. Thus, when the process is scaled up to production batch sizes, a comparison can be made with development batches. Scale-up and development reports, along with purity profiles would constitute such a validation report.

 

While validation can be applied to any process, greater emphasis should be placed on validation of the BPC production at the stage(s) in the synthesis and purification steps used for the bulk substance and/or the removal of impurities.

 

(d) Reprocessing

 

Where reprocessing occurs during the synthesis of a BPC, there should be written documentation covering the reason for the failure, the procedures involved in the reprocessing, and changes made to eliminate a recurrence of the problem. Merely relying on final testing of the reprocessed BPC as a means of demonstrating compliance with specifications, and neglecting the investigation and evaluation of the manufacturing process, is unacceptable.

 

Equivalence of the quality of reworked material to the original material must also be evaluated and documented to insure that the reprocessed batches will conform with all established standards, specifications, and characteristics. Obviously, if the product failure results from a human error, it will not reflect on the process, but may reflect on other aspects such as adequacy of training. However, there should be sufficient investigation, evaluation, and documentation to show that reprocessed product is at least equivalent to other acceptable product and that the failure did not result from an inadequate process.

 

(e) Process Change

 

Manufacturers should have a formal process change system in place with standard operating procedures covering such changes. Management of the change system should be assigned to an independent quality unit having responsibility and authority for final approval of process changes.

 

(f) Impurities

 

Characterization and control of impurities in a BPC are important because of the adverse effects that such impurities may have on dosage form stability, safety and efficacy. Consequently, it is important that manufacturers identify and set appropriate limits for impurities and adequately control manufacturing processes so that the impurities consistently meet established specifications.

 

The attached Appendix A (Impurities) includes a more detailed discussion of impurities and should be reviewed prior to conducting inspections.

 

 

In-process Testing

 

BPCs are normally subjected to various in-process tests to show that a synthesis or fermentation is proceeding satisfactorily. Such tests are often performed by production personnel in production laboratory facilities. Approval to continue with the synthesis (process) is often issued within the production department. The important considerations are that specified tests are performed, recorded, and results are within specified limits. In addition, instruments should be calibrated at appropriate intervals.

 

It is important that a firm utilize a quality control unit independent from production that has the responsibility and authority to reject in-process materials not meeting specifications. Such responsibility and authority should also extend beyond testing to include overall quality assurance activities such as procedure approvals, investigation of product failures, process change approvals, and product record reviews.

 

 

Packaging and Labeling of Finished BPC

 

(a) Sound procedures must be employed to protect the quality and purity of the BPC when it is packaged and to assure that the correct label is applied to containers. A good system of packaging and labeling should have the following features at a minimum:

 

(1) A file of master labels. A responsible individual reviews incoming labels against the appropriate master labels.

 

(2) Storage of labels in separate containers, or compartments, to prevent mixups.

 

(3) Formal issuance by requisition or other document.

 

(4) Issuance of an exact number of labels sufficient for the number of containers to be labeled, retention copies, and calculated excesses, if any.

 

(5) The employment of a lot number from which the complete batch history can be determined.

 

(6) Avoidance of labeling more than one batch at a time without adequate separation and controls.

 

(7) Reconciliation of the number of labels issued with the number of units packaged, together with the destruction of excess labels bearing lot numbers.

 

(b) If returnable BPC containers are re-used, all previous labeling should be removed or defaced. If the containers are repetitively used solely for the same BPC, all previous lot numbers, or the entire label, should be removed or completely obliterated.

 

(c) Labeling for containers of BPCs is subject to all applicable provisions of 21 CFR, Parts 200 and 201. In case questionable labeling is encountered, collect samples of the labeling for submission to the appropriate Center(s) for review.

 

 

Expiration Dating or Re-evaluation Dating

 

(a) With few exceptions, expiration dates are not presently considered to be a general requirement for all BPCs. Thus the absence of an expiration date may not be objectionable. The chief exception is antibiotic BPCs where expiration dates are required by the antibiotics regulations.

 

(b) Where expiration or re-evaluation dates are used on BPCs either because of a regulatory requirement or voluntarily, they must be derived from appropriate stability testing.

 

(c) Where stability testing reveals a limited shelf life, e.g., less than two years, the label should declare a supportable expiration date or indicate the need for re-evaluation testing at an appropriate interval to assure quality at time of use.

 

 

Laboratory Controls

 

(a) Raw materials are usually subjected to an identity test and additional testing to determine if they meet appropriate specifications. Such specifications will vary in depth, sophistication, and the amount of testing required to show conformance. This in turn will depend on various factors such as the critical nature of the raw material, its function in the process, the stage of the synthesis, etc. Raw material specifications should be written documents, even if only minimal requirements are required/requested. The specifications should be organized to separate those tests that are routine from those that are performed infrequently or for new suppliers.

 

(b) Laboratory controls should include a comprehensive set of meaningful analytical procedures designed to substantiate that each batch of finished BPC meets established specifications for quality, purity, identity, and assay. Data derived from manufacturing processes and from in-process controls also provide some assurance that a batch may be acceptable.

 

(c) Many BPCs are extracted from, or purified by, the use of organic solvents in the later (final) stages of recovery. The solvents are normally removed by drying the moist BPC. In view of the varying (and sometimes unknown) toxicity of solvents, it is important that BPC specifications include tests and limits for residues of solvents and

other reactants. Refer to the attached Appendix A for further information about impurities, including volatile organic impurities.

 

(d) Appropriate analytical methods should be validated.

 

 

Stability Testing

 

Most BPC manufacturers conduct stability testing programs for their products; however, such programs may be less comprehensive than the programs now required for finished pharmaceuticals.

 

Undetected changes in raw materials specifications, or subtle changes in manufacturing procedures, may affect the stability of BPCs. This, together with the generally widespread existence of stability testing programs, make it reasonable to require such programs for BPCs.

 

(a) A stability testing program for BPCs should contain the following features:

 

(1) The program should be formalized in writing.

 

(2) Stability samples should be stored in containers that approximate the market container. For example, where the product is marketed in polylined drums, it is acceptable to keep stability samples in the same container material/closure system within mini-fiber drums. Such samples may be stored in glass or other suitable containers only if there are data developed by the firm or others to show that results are comparable.

 

(3) The program should include samples from the first three commercial size batches.

 

(4) Thereafter, a minimum of one batch a year, if there is one, should be entered in the program.

 

NOTE: Lower levels of sampling may be acceptable if previous stability studies have shown the BPC to be stable for extended periods and the normal period between production and ultimate use of the BPC is relatively short.

 

(5) The samples should be stored under conditions specified on the label for the marketed product.

 

(6) It is recommended that additional samples be stored under stressful conditions (e.g., elevated temperature, light, humidity or freezing) if such conditions can be reasonably anticipated.

 

(7) Stability indicating methods should be used.

 

(b) Conducting a stability testing program does not usually lead to a requirement to employ expiration dates. If testing does not indicate a reasonable shelf life, e.g., two years or more, under anticipated storage conditions, then the BPC can be labeled with an expiration date or should be re-evaluated at appropriate intervals. If the need for special storage conditions exists, e.g., protection from light, such restrictions should be placed on the labeling.

 

 

Reserve Samples

 

Reserve samples of the released BPCs should be retained for one year after distribution is complete or for one year after expiration or re-evaluation date.

 

 

Batch Production Records

 

Documentation of the BPC manufacturing process should include a written description of the process and production records similar to those required for dosage form production. However, it is likely that computer systems will be associated with BPC production. Computer systems are increasingly used to initiate, monitor, adjust, and otherwise control both fermentations and syntheses. These operations may be accompanied by recording charts that show key parameters (e.g., temperature) at suitable intervals, or even continuously throughout the process. In other cases, key measurements (e.g., pH) may be displayed on a television screen for that moment in time but are not available in hard copy.

 

In both cases, conventional hard-copy batch production records may be missing. In other words, records showing addition of ingredients, actual performance of operations by identifiable individuals, and other information usually seen in conventional records may be missing. As a practical matter, when computers and other sophisticated equipment are employed, the emphasis must change from conventional, hand-written records to:

 

(a) Systems and procedures that show the equipment is in fact performing as intended;

 

(b) Checking and calibration of the equipment at appropriate intervals;

 

(c) Retention of suitable backup systems such as copies of the program, duplicate tapes, or microfilm;

 

(d) Assurance that changes in the program are made only by authorized personnel and that they are clearly documented.

 

 

APPENDIX A

 

 

Impurities

 

The United States Pharmacopeia (USP) defines an impurity as any component of a drug substance (excluding water) that is not the chemical entity defined as the drug substance.

 

It has been demonstrated that impurities in a finished drug product can cause degradation and lead to stability problems. Further, some adverse reactions in patients have been traced to impurities in the active ingredient. Therefore, the presence or absence of impurities at the time of clinical trial and stability testing is a very important element of drug testing and development, and the appearance of an impurity in scaled up product that was not present during test stages presents serious questions about the stability of the product and its impact on safety and efficacy.

 

We expect the manufacturer to establish an appropriate impurity profile for each BPC based on adequate consideration of the process and test results. Because different manufacturers synthesize drug substances by different processes and, therefore, will probably have different impurities, the USP has developed the Ordinary Impurities Test in an effort to establish some specification. Also, in order to protect proprietary information, tests for specific impurities and even solvents are typically not listed in the compendia.

 

The USP also notes that the impurity profile of a drug substance is a description of the impurities present in a typical lot of drug substance produced by a given manufacturing process. Such impurities should not only be detected and quanitated, but should also be identified and characterized when this is possible with reasonable effort. Individual limits should be established for all major impurities.

 

During the inspection, compare the impurity profile for the pilot batch material to that of the commercial size BPC batches to determine if the profile has significant changes. In some cases, drug manufacturers have submitted purity profiles in filings. Yet, when covered in some detail in an inspection, it became apparent that additional impurity data obtained by other methods (gradient HPLC) had become available but not yet filed. Thus, manufacturers should be asked specifically for current complete purity profiles, and these profiles should include the levels of solvents normally found in the purified drug substance along with acceptable specifications. Determine if the current impurity profile is reported to dose form manufacturers, especially if it has changed. Also, determine if the DMF (or AADA for bulk antibiotics) is current.

 

The USP provides extensive coverage of impurities in the following three sections:

 

(a) USP Section 1086 - Impurities In Official Articles

 

This section defines five different types of impurities, both known and unknown including foreign substances, toxic impurities, con- comitant components (such as isomers or racemates), signal impurities (which are process related), and ordinary impurities. The USP notes that when a specific test and limit is specified for a known impurity, generally a reference standard for that impurity is required.

 

Two of the impurities are singled out for in-depth coverage, ordinary impurities and organic or volatile impurities.

 

(b) USP Section 466 - Ordinary Impurities

 

These are generally specified for each BPC in the individual monograph. The method of detection involves comparison with a USP reference standard, on a thin layer chromatographic (TLC) plate, with a review for spots other than the principal spot. The ordinary impurity total should not exceed 2% as a general limit.

 

Be sure to review the extensive USP coverage of 8 factors that should be considered in setting limits for impurity levels.

 

Related substances are defined as those structurally related to a drug substance such as a degradation product or impurities arising from a manufacturing process or during storage of the BPC.

 

Process contaminants are substances including reagents, inorganics (e.g., heavy metals, chloride, or sulfate), raw materials, and solvents. The USP notes that these substances may be introduced during manufacturing or handling procedures.

 

The third and most recent USP section regarding impurities is one that appears in the USP-NF XXII third supplement:

 

(c) USP Section 467 - Organic Volative

 

Impurities

 

Several gas chromatography (GC) methods are given for the detection of specific toxic solvents and the determination involves use of a standard solution of solvents. There are limits for specified organic volatile impurities present in the BPC unless otherwise noted in the individual monograph.

 

As the USP notes, the setting of limits on impurities in a BPC for use in an approved new drug may be much lower than those levels encountered when the substance was initially synthesized.

 

Further, additional purity data may be obtained by other methods such as gradient high performance liquid chromatography (HPLC). Be sure to ask for complete impurity profiles.

 

In preparation for a BPC inspection, these sections of the USP should be given a detailed review.

 

APPENDIX B

 

 

References

 

1. CP 7356.002A - Sterile Drug Process Inspections.

 

2. CP 7356.002F - Bulk Pharmaceutical Chemicals (BPCs).

 

3. Guideline on General Principles of Process Validation, May, 1987.

 

4. Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacturer of Drug Substances, Feb. 1987.

 

5. Guideline on Sterile Drug Products Produced by Aseptic Processing, June 1987.

 

6. Code of Federal Regulations, Title 21 Part 210 and 211, Drugs: Current Good Manufacturing Practice

 

314.420 - Drug Master Files

 

201.122 - Drugs for Processing, Repacking, or Manufacturing (bulk labeling requirements)

 

7. United States Pharmacopeia, Current Revision, and Supplements.

 

High Purity Water Systems (7/93)  

GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS

 

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights,

privileges, benefits, or immunities for or on any person(s).

 

This guide discusses, primarily from a microbiological aspect, the review and evaluation of high purity water systems that are used for the manufacture of drug

products and drug substances. It also includes a review of the design of the various types of systems and some of the problems that have been associated with these systems. As with other guides, it is not all-inclusive, but provides background and guidance for the review and evaluation of high purity water systems. The Guide To Inspections of Microbiological Pharmaceutical Quality Control Laboratories (May, 1993) provides additional guidance.

 

I. SYSTEM DESIGN

 

One of the basic considerations in the design of a system is the type of product that is to be manufactured. For parenteral products where there is a concern for pyrogens, it is expected that Water for Injection will be used. This applies to the formulation of products, as well as to the final washing of components and equipment used in their manufacture. Distillation and Reverse Osmosis (RO) filtration are the only acceptable methods listed in the USP for producing Water for Injection. However, in the bulk Pharmaceutical and Biotechnology industries and some foreign companies, Ultra Filtration (UF) is employed to minimize endotoxins in those drug substances that are administered parenterally.

 

For some ophthalmic products, such as the ophthalmic irrigating solution, and some inhalation products, such as Sterile Water for Inhalation, where there are pyrogen specifications, it is expected that Water for Injection be used in their formulation. However, for most inhalation and ophthalmic products, purified water is used in their formulation. This also applies to topicals, cosmetics and oral products.

 

Another design consideration is the temperature of the system. It is recognized that hot (65 - 80oC) systems are self sanitizing. While the cost of other systems may be less expensive for a company, the cost of maintenance, testing and potential problems may be greater than the cost of energy saved. Whether a system is circulating or one-way is also an important design consideration. Obviously, water in constant motion is less liable to have high levels of contaminant. A one-way water system is basically a "dead-leg".

 

Finally, and possibly the most important consideration, is the risk assessment or level of quality that is desired. It should be recognized that different products require different quality waters. Parenterals require very pure water with no endotoxins. Topical and oral products require less pure water and do not have a requirement for endotoxins. Even with topical and oral products there are factors that dictate different qualities for water. For example, preservatives in antacids are marginally effective, so more stringent microbial limits have to be set. The quality control department should assess each

product manufactured with the water from their system and determine the microbial action limits based on the most microbial sensitive product. In lieu of stringent water action limits in the system the manufacturer can add a microbial reduction step in the manufacturing process for the sensitive drug product(s).

 

II. SYSTEM VALIDATION

 

A basic reference used for the validation of high purity water systems is the Parenteral Drug Association Technical Report No. 4 titled, "Design Concepts for the Validation of a Water for Injection System."

 

The introduction provides guidance and states that, "Validation often involves the use of an appropriate challenge. In this situation, it would be undesirable to introduce microorganisms into an on-line system; therefore, reliance is placed on periodic testing for microbiological quality and on the installation of monitoring equipment at specific checkpoints to ensure that the total system is operating properly and continuously fulfilling its intended function."

 

In the review of a validation report, or in the validation of a high purity water system, there are several aspects that should be considered. Documentation should include a description of the system along with a print. The drawing needs to show all equipment in the system from the water feed to points of use. It should also show all sampling points and their designations. If a system has no print, it is usually considered an objectionable condition. The thinking is if there is no print, then how can the system be validated? How can a quality control manager or microbiologist know where to sample? In those facilities observed without updated prints, serious problems were identified in these systems. The print should be compared to the actual system annually to insure its accuracy, to detect unreported changes and confirm reported changes to the system.

 

After all the equipment and piping has been verified as installed correctly and working as specified, the initial phase of the water system validation can begin. During this phase the operational parameters and the cleaning/ sanitization procedures and frequencies will be developed. Sampling should be daily after each step in the purification process and at each point of use for two to four weeks. The sampling procedure for point of use sampling should reflect how the water is to be drawn e.g. if a hose is usually attached the sample should be taken at the end of the hose. If the SOP calls for the line to be flushed before use of the water from that point, then the sample is taken after the flush. At the end of the two to four week time period the firm should have developed its SOPs for operation of the water system.

 

The second phase of the system validation is to demonstrate that the system will consistently produce the desired water quality when operated in conformance with the SOPs. The sampling is performed as in the initial phase and for the same time period. At the end of this phase the data should demonstrate that the system will consistently produce the desired quality of water.

 

The third phase of validation is designed to demonstrate that when the water system is operated in accordance with the SOPs over a long period of time it will consistently produce water of the desired quality. Any variations in the quality of the feedwater that could affect the operation and ultimately the water quality will be picked up during this phase of the validation. Sampling is performed according to routine procedures and frequencies. For Water for Injection systems the samples should be taken daily from a minimum of one point of use, with all points of use tested weekly. The validation of the water system is completed when the firm has a full years worth of data.

 

While the above validation scheme is not the only way a system can be validated, it contains the necessary elements for validation of a water system. First, there must be data to support the SOPs. Second, there must be data demonstrating that the SOPs are valid and that the system is capable of consistently producing water that meets the desired specifications. Finally, there must be data to demonstrate that seasonal variations in the feedwater do not adversely affect the operation of the system or the water quality.

 

The last part of the validation is the compilation of the data, with any conclusions into the final report. The final validation report must be signed by the appropriate people responsible for operation and quality assurance of the water system.

 

A typical problem that occurs is the failure of operating procedures to preclude contamination of the system with non-sterile air remaining in a pipe after drainage. In a system illustrated as in Figure 1, (below) a typical problem occurs when a washer or hose connection is flushed and then drained at the end of the operation. After draining, this valve (the second off of the system) is closed. If on the next day or start-up of the operation the primary valve off of the circulating system is opened, then the non-sterile air remaining in the pipe after drainage would contaminate the system. The solution is to pro-vide for operational procedures that provide for opening the secondary valve before the primary valve to flush the pipe prior to use.

 

 

 

 

Another major consideration in the validation of high purity water systems is the acceptance criteria. Consistent results throughout the system over a period of time constitute the primary element.

 

III. MICROBIAL LIMITS

 

Water For Injection Systems

 

Regarding microbiological results, for Water For Injection, it is expected that they be essentially sterile. Since sampling frequently is performed in non-sterile areas and is not truly aseptic, occasional low level counts due to sampling errors may occur. Agency

policy, is that less than 10 CFU/100ml is an acceptable action limit. None of the limits for water are pass/fail limits. All limits are action limits. When action limits are exceeded the firm must investigate the cause of the problem, take action to correct the problem and assess the impact of the microbial contamination on products manufactured with the water and document the results of their investigation.

 

With regard to sample size, 100 - 300 mL is preferred when sampling Water for Injection systems. Sample volumes less than 100 mL are unacceptable.

 

The real concern in WFI is endotoxins. Because WFI can pass the LAL endotoxin test and still fail the above microbial action limit, it is important to monitor WFI systems for both endotoxins and microorganisms.

 

Purified Water Systems

 

For purified water systems, microbiological specifications are not as clear. USP XXII specifications, that it complies with federal Environmental Protection Agency regulations for drinking water, are recognized as being minimal specifications. There have been attempts by some to establish meaningful microbiological specifications for purified water. The CFTA proposed a specification of not more than 500 organisms per ml. The USP XXII has an action guideline of not greater than 100 organisms per ml. Although microbiological specifications have been discussed, none (other than EPA standards) have been established. Agency policy is that any action limit over 100 CFU/mL for a purified water system is unacceptable.

 

The purpose of establishing any action limit or level is to assure that the water system is under control. Any action limit established will depend upon the overall purified water system and further processing of the finished product and its use. For example, purified water used to manufacture drug products by cold processing should be free of objectionable organisms. We have defined "objectionable organisms" as any organisms that can cause infections when the drug product is used as directed or any organism capable of growth in the drug product. As pointed out in the Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories, the specific contaminant, rather than the number is generally more significant.

 

Organisms exist in a water system either as free floating in the water or attached to the walls of the pipes and tanks. When they are attached to the walls they are known as biofilm, which continuously slough off organisms. Thus, contamination is not uniformly

distributed in a system and the sample may not be representative of the type and level of contamination. A count of 10 CFU/mL in one sample and 100 or even 1000 CFU/mL in a subsequent sample would not be unrealistic.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Thus, in establishing the level of contamination allowed in a high purity water system used in the manufacture of a non-sterile product requires an understanding of the use of the product, the formulation (preservative system) and manufacturing process. For example, antacids, which do not have an effective preservative system, require an action limit below the 100 CFU/mL maximum.

 

The USP gives some guidance in their monograph on Microbiological Attributes of Non-Sterile Products. It points out that, "The significance of microorganisms in non-sterile pharmaceutical products should be evaluated in terms of the use of the product, the nature of the product, and the potential harm to the user." Thus, not just the indicator organisms listed in some of the specific monographs present problems. It is up to each manufacturer to evaluate their product, the way it is manufactured, and establish am acceptable action level of contamination, not to exceed the maximum, for the water system, based on the highest risk product manufactured with the water.

 

IV. WATER FOR INJECTION SYSTEMS

 

In the review and evaluation of Water For Injection systems, there are several concerns.

 

Pretreatment of feedwater is recommended by most manufacturers of distillation equipment and is definitely required for RO units. The incoming feedwater quality may fluctuate during the life of the system depending upon seasonal variations and other external factors beyond the control of the pharmaceutical facility. For example, in the spring (at least in the N.E.), increases in gram negative organisms have been known. Also, new construction or fires can cause a depletion of water stores in old mains which can cause an influx of heavily contaminated water of a different flora.

 

A water system should be designed to operate within these anticipated extremes. Obviously, the only way to know the extremes is to periodically monitor feedwater. If the feedwater is from a municipal water system, reports from the municipality testing can be used in lieu of in-house testing.

 

V. STILL

 

Figures 3-5 represent a typical basic diagram of a WFI system. Most of the new systems now use multi-effect stills. In some of the facilities, there has been evidence of endotoxin contamination. In one system this occurred, due to malfunction of the feedwater valve and level control in the still which resulted in droplets of feedwater being carried over in the distillate.

 

Figure 31 Figure 4 2 Figure 53

In another system with endotoxin problems, it was noted that there was approximately 50 liters of WFI in the condenser at the start-up. Since this water could lie in the condenser for up to several days (i.e., over the weekend), it was believed that this was the reason for unacceptable levels of endotoxins.

 

More common, however, is the failure to adequately treat feedwater to reduce levels of endotoxins. Many of the still fabricators will only guarantee a 2.5 log to 3 log reduction

in the endotoxin content. Therefore, it is not surprising that in systems where the feedwater occasionally spikes to 250 EU/ml, unacceptable levels of endotoxins may occasionally appear in the distillate (WFI). For example, recently three new stills, including two multi-effect, were found to be periodically yielding WFI with levels greater than .25 EU/ml. Pretreatment systems for the stills included only deionization systems with no UF, RO or distillation. Unless a firm has a satisfactory pretreatment system, it would be extremely difficult for them to demonstrate that the system is validated.

 

The above examples of problems with distillation units used to produce WFI, point to problems with maintenance of the equipment or improper operation of the system indicating that the system has not been properly validated or that the initial validation is no longer valid. If you see these types of problems you should look very closely at the system design, any changes that have been made to the system, the validation report and the routine test data to determine if the system is operating in a state of control.

 

Typically, conductivity meters are used on water systems to monitor chemical quality and have no meaning regarding microbiological quality.

 

Figures 3-5 also show petcocks or small sampling ports between each piece of equipment, such as after the still and before the holding tank. These are in the system to isolate major pieces of equipment. This is necessary for the qualification of the equipment and for the investigation of any problems which might occur.

 

VI. HEAT EXCHANGERS

 

One principal component of the still is the heat exchanger. Because of the similar ionic quality of distilled and deionized water, conductivity meters cannot be used to monitor microbiological quality. Positive pressure such as in vapor compression or double tubesheet design should be employed to prevent possible feedwater to distillate contamination in a leaky heat exchanger.

 

An FDA Inspectors Technical Guide with the subject of "Heat Exchangers to Avoid Contamination" discusses the design and potential problems associated with heat exchangers. The guide points out that there are two methods for preventing contamination by leakage. One is to provide gauges to constantly monitor pressure differentials to ensure that the higher pressure is always on the clean fluid side. The other is to utilize the double-tubesheet type of heat exchanger.

 

In some systems, heat exchangers are utilized to cool water at use points. For the most part, cooling water is not circulated through them when not in use. In a few situations, pinholes formed in the tubing after they were drained (on the cooling water side) and not in use. It was determined that a small amount of moisture remaining in the tubes when combined with air caused a corrosion of the stainless steel tubes on the cooling water side. Thus, it is recommended that when not in use, heat exchangers not be drained of the cooling water.

 

VII. HOLDING TANK

 

In hot systems, temperature is usually maintained by applying heat to a jacketed holding tank or by placing a heat exchanger in the line prior to an insulated holding tank.

 

The one component of the holding tank that generates the most discussion is the vent filter. It is expected that there be some program for integrity testing this filter to assure that it is intact. Typically, filters are now jacketed to prevent condensate or water from blocking the hydrophobic vent filter. If this occurs (the vent filter becomes blocked), possibly either the filter will rupture or the tank will collapse. There are methods for integrity testing of vent filters in place.

 

It is expected, therefore, that the vent filter be located in a position on the holding tank where it is readily accessible.

 

Just because a WFI system is relatively new and distillation is employed, it is not problem-free. In an inspection of a manufacturer of parenterals, a system fabricated in 1984 was observed. Refer to Figure 6.4 While the system may appear somewhat complex on the initial review, it was found to be relatively simple. Figure 7 5is a schematic of the system. The observations at the conclusion of the inspection of this manufacturer included, "Operational procedures for the Water For Injection system failed to provide for periodic complete flushing or draining. The system was also open to the atmosphere and room environment. Compounding equipment consisted of non-sealed, open tanks with lids. The Water for Injection holding tank was also not sealed and was never sampled for endotoxins." Because of these and other comments, the firm recalled several products and discontinued operations.

 

VIII. PUMPS

 

Pumps burn out and parts wear. Also, if pumps are static and not continuously in operation, their reservoir can be a static area where water will lie. For example, in an inspection, it was noted that a firm had to install a drain from the low point in a pump housing. Pseudomonas sp. contamination was periodically found in their water system which was attributed in part to a pump which only periodically is operational.

 

IX. PIPING

 

Piping in WFI systems usually consist of a high polished stainless steel. In a few cases, manufacturers have begun to utilize PVDF (polyvinylidene fluoride) piping. It is purported that this piping can tolerate heat with no extractables being leached. A major problem with PVDF tubing is that it requires considerable support. When this tubing is heated, it tends to sag and may stress the weld (fusion) connection and result in leakage. Additionally, initially at least, fluoride levels are high. This piping is of benefit in product delivery systems where low level metal contamination may accelerate the degradation of drug product, such as in the Biotech industry.

 

One common problem with piping is that of "dead-legs". The proposed LVP Regulations defined dead-legs as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use. It should be pointed out that this was developed for hot 75 - 80o circulating systems. With colder systems (65 - 75oC), any drops or unused portion of any length of piping has the potential for the formation of a biofilm and should be eliminated if possible or have special sanitizing procedures. There should be n o threaded fittings in a pharmaceutical water system. All pipe joints must utilize sanitary fittings or be butt welded. Sanitary fittings will usually be used where the piping meets valves, tanks and other equipment that must be removed for maintenance or replacement. Therefore, the firm's procedures for sanitization, as well as the actual piping, should be reviewed and evaluated during the inspection.

 

X. REVERSE OSMOSIS

 

Another acceptable method for manufacturing Water for Injection is Reverse Osmosis (RO). However, because these systems are cold, and because RO filters are not absolute, microbiological contamination is not unusual. Figure 86 shows a system that was in use several years ago. There are five RO units in this system which are in parallel. Since RO filters are not absolute, the filter manufacturers recommend that at least two be in series. The drawing also illustrates an Ultraviolet (UV) light in the

system downstream from the RO units. The light was needed to control microbiological contamination.

 

Also in this system were ball valves. These valves are not considered sanitary valves since the center of the valve can have water in it when the valve is closed. This is a stagnant pool of water that can harbor microorganisms and provide a starting point for a biofilm.

 

As an additional comment on RO systems, with the recognition of microbiological problems, some manufacturers have installed heat exchangers immediately after the RO filters to heat the water to 75 - 80oC to minimize microbiological contamination.

 

With the development of biotechnology products, many small companies are utilizing RO and UF systems to produce high purity water. For example, Figure 97 illustrates a wall mounted system that is fed by a single pass RO unit.

 

As illustrated, most of these systems employ PVC or some type of plastic tubing. Because the systems are typically cold, the many joints in the system are subject to contamination. Another potential problem with PVC tubing is extractables. Looking at the WFI from a system to assure that it meets USP requirements without some assurance that there are no extractables would not be acceptable.

 

The systems also contain 0.2 micron point of use filters which can mask the level of microbiological contamination in the system. While it is recognized that endotoxins are the primary concern in such a system, a filter will reduce microbiological contamination, but not necessarily endotoxin contamination. If filters are used in a water system there should be a stated purpose for the filter, i.e., particulate removal or microbial reduction, and an SOP stating the frequency with which the filter is to be changed which is based on data generated during the validation of the system.

 

As previously discussed, because of the volume of water actually tested (.1ml for endotoxins vs. 100ml for WFI), the microbiological test offers a good index of the level of contamination in a system. Therefore, unless the water is sampled prior to the final 0.2 micron filter, microbiological testing will have little meaning.

 

At a reinspection of this facility, it was noted that they corrected the deficient water system with a circulating stainless steel piping system that was fed by four RO units in series. Because this manufacturer did not have a need for a large amount of water (the total system capacity was about 30 gallons), they attempted to let the system sit for approximately one day. Figure 98 shows that at zero time (at 9 AM on 3/10), there were no detectable levels of microorganisms and of endotoxins. After one day, this static non-circulating system was found to be contaminated. The four consecutive one hour samples also illustrate the variability among samples taken from a system. After the last sample at 12 PM was collected, the system was resanitized with 0.5% peroxide solution, flushed, recirculated and resampled. No levels of microbiological contamination were found on daily samples after the system was put back in operation. This is the reason the agency has recommended that non-recirculating water systems be drained daily and water not be allowed to sit in the system.

 

XI. PURIFIED WATER SYSTEMS

 

Many of the comments regarding equipment for WFI systems are applicable to Purified Water Systems. One type system that has been used to control microbiological contamination utilizes ozone. Figure 109 illustrates a typical system. Although the system has purported to be relatively inexpensive, there are some problems associated with it. For optimum effectiveness, it is required that dissolved ozone residual remain in the system. This presents both employee safety problems and use problems when drugs are formulated.

 

Published data for Vicks Greensboro, NC facility showed that their system was recontaminated in two to three days after the ozone generator was turned off. In an inspection of another manufacturer, it was noted that a firm was experiencing a contamination problem with Pseudomonas sp. Because of potential problems with employee safety, ozone was removed from the water prior to placing it in their recirculating system. It has been reported that dissolved ozone at a level of 0.45 mg/liter will remain in a system for a maximum of five to six hours.

 

Another manufacturer, as part of their daily sanitization, removes all drops off of their ozonated water system and disinfects them in filter sterilized 70% isopropyl alcohol. This manufacturer has reported excellent microbiological results. However, sampling is only performed immediately after sanitization and not at the end of operations. Thus, the results are not that meaningful.

 

Figure 1110 and Figure1211 illustrate another purified water system which had some problems. Unlike most of the other systems discussed, this is a one-way and not

recirculating system. A heat exchanger is used to heat the water on a weekly basis and sanitize the system. Actually, the entire system is a "dead-leg."

 

Figure 11 also shows a 0.2 micron in line filter used to sanitize the purified water on a daily basis. In addition to the filter housing providing a good environment for microbiological contamination, a typical problem is water hammer that can cause "ballooning" of the filter. If a valve downstream from the filter is shut too fast, the water pressure will reverse and can cause "ballooning". Pipe vibration is a typical visible sign of high back pressure while passage of upstream contaminants on the filter face is a real problem. This system also contains several vertical drops at use points. During sanitization, it is important to "crack" the terminal valves so that all of the elbows and bends in the piping are full of water and thus, get complete exposure to the sanitizing agent.

 

It should be pointed out that simply because this is a one-way system, it is not inadequate. With good Standard Operational Procedures, based on validation data, and routine hot flushings of this system, it could be acceptable. A very long system (over 200 yards) with over 50 outlets was found acceptable. This system employed a daily flushing of all outlets with 80oC water.

 

The last system to be discussed is a system that was found to be objectionable. Pseudomonas sp. found as a contaminant in the system (after FDA testing) was also found in a topical steroid product (after FDA testing). Product recall and issuance of a Warning Letter resulted. This system (Figure 13)12 is also one-way that employs a UV light to control microbiological contamination. The light is turned on only when water is needed. Thus, there are times when water is allowed to remain in the system. This system also contains a flexible hose which is very difficult to sanitize. UV lights must be properly maintained to work. The glass sleeves around the bulb(s) must be kept clean or their effectiveness will decrease. In multibulb units there must be a system to determine that each bulb is functioning. It must be remembered that at best UV light will only kill 90% of the organisms entering the unit.

 

XIII. PROCESS WATER

 

Currently, the USP, pg. 4, in the General Notices Section, allows drug substances to be manufactured from Potable Water. It comments that any dosage form must be manufactured from Purified Water, Water For Injection, or one of the forms of Sterile Water. There is some inconsistency in these two statements, since Purified Water has to be used for the granulation of tablets, yet Potable Water can be used for the final purification of the drug substance.

 

The FDA Guide to Inspection of Bulk Pharmaceutical Chemicals comments on the concern for the quality of the water used for the manufacture of drug substances, particularly those drug substances used in parenteral manufacture. Excessive levels of microbiological and/or endotoxin contamination have been found in drug substances, with the source of contamination being the water used in purification. At this time, Water For Injection does not have to be used in the finishing steps of synthesis/purification of drug substances for parenteral use. However, such water systems used in the final stages of processing of drug substances for parenteral use should be validated to assure minimal endotoxin/ microbiological contamination.

 

In the bulk drug substance industry, particularly for parenteral grade substances, it is common to see Ultrafiltration (UF) and Reverse Osmosis (RO) systems in use in water systems. While ultrafiltration may not be as efficient at reducing pyrogens, they will reduce the high molecular weight endotoxins that are a contaminant in water systems. As with RO, UF is not absolute, but it will reduce numbers. Additionally, as previously discussed with other cold systems, there is considerable maintenance required to maintain the system.

 

For the manufacture of drug substances that are not for parenteral use, there is still a microbiological concern, although not to the degree as for parenteral grade drug substances. In some areas of the world, Potable (chlorinated) water may not present a microbiological problem. However, there may be other issues. For example, chlorinated water will generally increase chloride levels. In some areas, process water may be obtained directly from neutral sources.

 

In one inspection, a manufacturer was obtaining process water from a river located in a farming region. At one point, they had a problem with high levels of pesticides which was a run-off from farms in the areas. The manufacturing process and analytical methodology was not designed to remove and identify trace pesticide contaminants. Therefore, it would seem that this process water when used in the purification of drug substances would be unacceptable.

 

XIV. INSPECTION STRATEGY

 

Manufacturers typically will have periodic printouts or tabulations of results for their purified water systems. These printouts or data summaries should be reviewed. Additionally, investigation reports, when values exceed limits, should be reviewed.

 

Since microbiological test results from a water system are not usually obtained until after the drug product is manufactured, results exceeding limits should be reviewed with regard to the drug product formulated from such water. Consideration with regard to the further processing or release of such a product will be dependent upon the specific contaminant, the process and the end use of the product. Such situations are usually evaluated on a case-by-case basis. It is a good practice for such situations to include an investigation report with the logic for release/rejection discussed in the firm's report. End product microbiological testing, while providing some information should not be relied upon as the sole justification for the release of the drug product. The limitations of microbiological sampling and testing should be recognized.

 

Manufacturers should also have maintenance records or logs for equipment, such as the still. These logs should also be reviewed so that problems with the system and equipment can be evaluated.

 

In addition to reviewing test results, summary data, investigation reports and other data, the print of the system should be reviewed when conducting the actual physical inspection. As pointed out, an accurate description and print of the system is needed in order to demonstrate that the system is validated.

Lyophilization of Parenterals (7/93)  

GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS

 

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights,

privileges, benefits, or immunities for or on any person(s).

 

INTRODUCTION

 

Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The process consists of three separate, unique, and interdependent processes; freezing, primary drying (sublimation), and secondary drying (desorption).

 

The advantages of lyophilization include:

 

Ease of processing a liquid, which simplifies aseptic handling

 

Enhanced stability of a dry powder

 

Removal of water without excessive heating of the product

 

Enhanced product stability in a dry state

 

Rapid and easy dissolution of reconstituted product

 

Disadvantages of lyophilization include:

 

Increased handling and processing time

 

Need for sterile diluent upon reconstitution

 

Cost and complexity of equipment

 

The lyophilization process generally includes the following steps:

 

o Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI).

 

o Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter.

 

o Filling into individual sterile containers and partially stoppering the containers under aseptic conditions.

 

o Transporting the partially stoppered containers to the lyophilizer and loading into the chamber under aseptic conditions.

 

o Freezing the solution by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or pre-freezing in another chamber.

 

o Applying a vacuum to the chamber and heating the shelves in order to evaporate the water from the frozen state.

 

o Complete stoppering of the vials usually by hydraulic or screw rod stoppering mechanisms installed in the lyophilizers.

 

There are many new parenteral products, including anti-infectives, biotechnology derived products, and in-vitro diagnostics which are manufactured as lyophilized products. Additionally, inspections have disclosed potency, sterility and stability problems associated with the manufacture and control of lyophilized products. In order to provide guidance and information to investigators, some industry procedures and deficiencies associated with lyophilized products are identified in this Inspection Guide.

 

It is recognized that there is complex technology associated with the manufacture and control of a lyophilized pharmaceutical dosage form. Some of the important aspects of these operations include: the formulation of solutions; filling of vials and validation of the filling operation; sterilization and engineering aspects of the lyophilizer; scale-up and validation of the lyophilization cycle; and testing of the end product. This discussion will address some of the problems associated with the manufacture and control of a lyophilized dosage form.

 

PRODUCT TYPE/FORMULATION

 

Products are manufactured in the lyophilized form due to their instability when in solution. Many of the antibiotics, such as some of the semi-synthetic penicillins, cephalosporins, and also some of the salts of erythromycin, doxycycline and chloramphenicol are made by the lyophilization process. Because they are antibiotics, low bioburden of these formulations would be expected at the time of batching. However, some of the other dosage forms that are lyophilized, such as hydrocortisone sodium succinate, methylprednisolone sodium succinate and many of the biotechnology derived products, have no antibacterial effect when in solution.

 

For these types of products, bioburden should be minimal and the bioburden should be determined prior to sterilization of these bulk solutions prior to filling. Obviously, the batching or compounding of these bulk solutions should be controlled in order to prevent any potential increase in microbiological levels that may occur up to the time that the bulk solutions are filtered (sterilized). The concern with any microbiological level is the possible increase in endotoxins that may develop. Good practice for the compounding of lyophilized products would also include batching in a controlled environment and in sealed tanks, particularly if the solution is to be held for any length of time prior to sterilization.

 

In some cases, manufacturers have performed bioburden testing on bulk solutions after prefiltration and prior to final filtration. While the testing of such solutions may be meaningful in determining the bioburden for sterilization, it does not provide any information regarding the potential formation or presence of endotoxins. While the testing of 0.1 ml samples by LAL methods of bulk solution for endotoxins is of value, testing of at least 100 ml size samples prior to prefiltration, particularly for the presence of gram negative organisms, would be of greater value in evaluating the process. For example, the presence of Pseudomonas sp. in the bioburden of a bulk solution has been identified as an objectionable condition.

 

FILLING

 

The filling of vials that are to be lyophilized has some problems that are somewhat unique. The stopper is placed on top of the vial and is ultimately seated in the lyophilizer. As a result the contents of the vial are subject to contamination until they are actually sealed.

 

Validation of filling operations should include media fills and the sampling of critical surfaces and air during active filling (dynamic conditions).

 

Because of the active involvement of people in filling and aseptic manipulations, an environmental program should also include an evaluation of microbiological levels on people working in aseptic processing areas. One method of evaluation of the training of operators working in aseptic processing facilities includes the surface monitoring of gloves and/or gowns on a daily basis. Manufacturers are actively sampling the surfaces of personnel working in aseptic processing areas. A reference which provides for this type of monitoring is the USP XXII discussion of the Interpretation of Sterility Test Results. It states under the heading of "Interpretation of Quality Control Tests" that review consideration should be paid to environmental control data, including...microbial monitoring, records of operators, gowns, gloves, and garbing practices. In those situations in which manufacturers have failed to perform some type of personnel monitoring, or monitoring has shown unacceptable levels of contamination, regulatory situations have resulted.

 

Typically, vials to be lyophilized are partially stoppered by machine. However, some filling lines have been noted which utilize an operator to place each stopper on top of the vial by hand. At this time, it would seem that it would be difficult for a manufacturer to justify a hand-stoppering operation, even if sterile forceps are employed, in any type of operation other than filling a clinical batch or very small number of units. Significant regulatory situations have resulted when some manufacturers have hand-stoppered vials. Again, the concern is the immediate avenue of contamination offered by the operator. It is well recognized that people are the major source of contamination in an aseptic processing filling operation. The longer a person works in an aseptic operation, the more microorganisms will be shed and the greater the probability of contamination.

 

Once filled and partially stoppered, vials are transported and loaded into the lyophilizer. The transfer and handling, such as loading of the lyophilizer, should take place under primary barriers, such as the laminar flow hoods under which the vials were filled. Validation of this handling should also include the use media fills.

 

Regarding the filling of sterile media, there are some manufacturers who carry out a partial lyophilization cycle and freeze the media. While this could seem to greater mimic the process, the freezing of media could reduce microbial levels of some contaminants. Since the purpose of the media fill is to evaluate and justify the aseptic capabilities of the process, the people and the system, the possible reduction of microbiological levels after aseptic manipulation by freezing would not be warranted. The purpose of a media fill is not to determine the lethality of freezing and its effect on any microbial contaminants that might be present.

 

In an effort to identify the particular sections of filling and aseptic manipulation that might introduce contamination, several manufacturers have resorted to expanded media fills. That is, they have filled approximately 9000 vials during a media fill and segmented the fill into three stages. One stage has included filling of 3000 vials and stoppering on line; another stage included filling 3000 vials, transportation to the lyophilizer and then stoppering; a third stage included the filling of 3000 vials, loading in the lyophilizer, and exposure to a portion of the nitrogen flush and then stoppering. Since lyophilizer sterilization and sterilization of the nitrogen system used to backfill require separate validation, media fills should primarily validate the filling, transportation and loading aseptic operations.

 

The question of the number of units needed for media fills when the capacity of the process is less than 3000 units is frequently asked, particularly for clinical products. Again, the purpose of the media fill is to assure that product can be aseptically processed without contamination under operating conditions. It would seem, therefore, that the maximum number of units of media filled be equivalent to the maximum batch size if it is less than 3000 units.

 

After filling, dosage units are transported to the lyophilizer by metal trays. Usually, the bottom of the trays are removed after the dosage units are loaded into the lyophilizer. Thus, the dosage units lie directly on the lyophilizer shelf. There have been some situations in which manufacturers have loaded the dosage units on metal trays which were not removed. Unfortunately, at one manufacturer, the trays warped which caused a moisture problem in some dosage units in a batch.

 

In the transport of vials to the lyophilizer, since they are not sealed, there is concern for the potential for contamination. During inspections and in the review of new facilities, the failure to provide laminar flow coverage or a primary barrier for the transport and loading areas of a lyophilizer has been regarded as an objectionable condition. One manufacturer as a means of correction developed a laminar flow cart to transport the vials from the filling line to the lyophilizer. Other manufacturers building new facilities have located the filling line close to the lyophilizer and have provided a primary barrier extending from the filling line to the lyophilizer.

 

In order to correct this type of problem, another manufacturer installed a vertical laminar flow hood between the filling line and lyophilizer. Initially, high velocities with inadequate return caused a contamination problem in a media fill. It was speculated that new air currents resulted in rebound contamination off the floor. Fortunately, media fills and smoke studies provided enough meaningful information that the problem could be corrected prior to the manufacture of product. Typically, the lyophilization process includes the stoppering of vials in the chamber.

 

Another major concern with the filling operation is assurance of fill volumes. Obviously, a low fill would represent a subpotency in the vial. Unlike a powder or liquid fill, a low fill would not be readily apparent after lyophilization particularly for a biopharmaceutical drug product where the active ingredient may be only a milligram. Because of the clinical significance, sub-potency in a vial potentially can be a very serious situation.

 

For example, in the inspection of a lyophilization filling operation, it was noted that the firm was having a filling problem. The gate on the filling line was not coordinated with the filling syringes, and splashing and partial filling was occurring. It was also observed that some of the partially filled vials were loaded into the lyophilizer. This resulted in rejection of the batch.

 

On occasion, it has been seen that production operators monitoring fill volumes record these fill volumes only after adjustments are made. Therefore, good practice and a good quality assurance program would include the frequent monitoring of the volume of fill, such as every 15 minutes. Good practice would also include provisions for the isolation of particular sections of filling operations when low or high fills are encountered.

 

There are some atypical filling operations which have not been discussed. For example, there have also been some situations in which lyophilization is performed on trays of solution rather than in vials. Based on the current technology available, it would seem that for a sterile product, it would be difficult to justify this procedure.

 

The dual chamber vial also presents additional requirements for aseptic manipulations. Media fills should include the filling of media in both chambers. Also, the diluent in these vials should contain a preservative. (Without a preservative, the filling of diluent would be analogous to the filling of media. In such cases, a 0% level of contamination would be expected.)

 

LYOPHILIZATION CYCLE AND CONTROLS

 

After sterilization of the lyophilizer and aseptic loading, the initial step is freezing the solution. In some cycles, the shelves are at the temperature needed for freezing, while for other cycles, the product is loaded and then the shelves are taken to the freezing temperature necessary for product freeze. In those cycles in which the shelves are

precooled prior to loading, there is concern for any ice formation on shelves prior to loading. Ice on shelves prior to loading can cause partial or complete stoppering of vials prior to lyophilization of the product. A recent field complaint of a product in solution and not lyophilized was attributed to preliminary stoppering of a few vials prior to exposure to the lyophilization cycle. Unfortunately, the firm's 100% vial inspection failed to identify the defective vial.

 

Typically, the product is frozen at a temperature well below the eutectic point.

 

The scale-up and change of lyophilization cycles, including the freezing procedures, have presented some problems. Studies have shown the rate and manner of freezing may affect the quality of the lyophilized product. For example, slow freezing leads to the formation of larger ice crystals. This results in relatively large voids, which aid in the escape of water vapor during sublimation. On the other hand, slow freezing can increase concentration shifts of components. Also, the rate and manner of freezing has been shown to have an affect on the physical form (polymorph) of the drug substance.

 

It is desirable after freezing and during primary drying to hold the drying temperature (in the product) at least 4-5o below the eutectic point. Obviously, the manufacturer should know the eutectic point and have the necessary instrumentation to assure the uniformity of product temperatures. The lyophilizer should also have the necessary instrumentation to control and record the key process parameters. These include: shelf temperature, product temperature, condenser temperature, chamber pressure and condenser pressure. The manufacturing directions should provide for time, temperature and pressure limits necessary for a lyophilization cycle for a product. The monitoring of product temperature is particularly important for those cycles for which there are atypical operating procedures, such as power failures or equipment breakdown.

 

Electromechanical control of a lyophilization cycle has utilized cam-type recorder-controllers. However, newer units provide for microcomputer control of the freeze drying process. A very basic requirement for a computer controlled process is a flow chart or logic. Typically, operator involvement in a computer controlled lyophilization cycle primarily occurs at the beginning. It consists of loading the chamber, inserting temperature probes in product vials, and entering cycle parameters such as shelf temperature for freezing, product freeze temperature, freezing soak time, primary drying shelf temperature and cabinet pressure, product temperature for establishment of fill vacuum, secondary drying shelf temperature, and secondary drying time.

 

In some cases, manufacturers have had to continuously make adjustments in cycles as they were being run. In these situations, the lyophilization process was found to be non-validated.

 

Validation of the software program of a lyophilizer follows the same criteria as that for other processes. Basic concerns include software development, modifications and security. The Guide to Inspection of Computerized Systems in Drug Processing contains a discussion on potential problem areas relating to computer systems. A Guide to the Inspection of Software Development Activities is a reference that provides a more detailed review of software requirements.

 

Leakage into a lyophilizer may originate from various sources. As in any vacuum chamber, leakage can occur from the atmosphere into the vessel itself. Other sources are media employed within the system to perform the lyophilizing task. These would be the thermal fluid circulated through the shelves for product heating and cooling, the refrigerant employed inside the vapor condenser cooling surface and oil vapors that may migrate back from the vacuum pumping system.

 

Any one, or a combination of all, can contribute to the leakage of gases and vapors into the system. It is necessary to monitor the leak rate periodically to maintain the integrity of the system. It is also necessary, should the leak rate exceed specified limits, to determine the actual leak site for purposes of repair.

 

Thus, it would be beneficial to perform a leak test at some time after sterilization, possibly at the beginning of the cycle or prior to stoppering. The time and frequency for performing the leak test will vary and will depend on the data developed during the cycle validation. The pressure rise found acceptable at validation should be used to determine the acceptable pressure rise during production. A limit and what action is to be taken if excessive leakage is found should be addressed in some type of operating document.

 

In order to minimize oil vapor migration, some lyophilizers are designed with a tortuous path between the vacuum pump and chamber. For example, one fabricator installed an oil trap in the line between the vacuum pump and chamber in a lyophilizer with an internal condenser. Leakage can also be identified by sampling surfaces in the chamber after lyophilization for contaminants. One could conclude that if contamination is found on a chamber surface after lyophilization, then dosage units in the chamber could also be contaminated. It is a good practice as part of the validation of cleaning of the lyophilization chamber to sample the surfaces both before and after cleaning.

 

Because of the lengthy cycle runs and strain on machinery, it is not unusual to see equipment malfunction or fail during a lyophilization cycle. There should be provisions in place for the corrective action to be taken when these atypical situations occur. In addition to documentation of the malfunction, there should be an evaluation of the possible effects on the product (e.g., partial or complete meltback. Refer to subsequent discussion). Merely testing samples after the lyophilization cycle is concluded may be insufficient to justify the release of the remaining units. For example, the leakage of chamber shelf fluid into the chamber or a break in sterility would be cause for rejection of the batch.

 

The review of Preventive Maintenance Logs, as well as Quality Assurance Alert Notices, Discrepancy Reports, and Investigation Reports will help to identify problem batches when there are equipment malfunctions or power failures. It is recommended that these records be reviewed early in the inspection.

 

CYCLE VALIDATION

 

Many manufacturers file (in applications) their normal lyophilization cycles and validate the lyophilization process based on these cycles. Unfortunately, such data would be of little value to substantiate shorter or abnormal cycles. In some cases, manufacturers are unaware of the eutectic point. It would be difficult for a manufacturer to evaluate partial or abnormal cycles without knowing the eutectic point and the cycle parameters needed to facilitate primary drying.

 

Scale-up for the lyophilized product requires a knowledge of the many variables that may have an effect on the product. Some of the variables would include freezing rate and temperature ramping rate. As with the scale-up of other drug products, there should be a development report that discusses the process and logic for the cycle. Probably more so than any other product, scale-up of the lyophilization cycle is very difficult.

 

There are some manufacturers that market multiple strengths, vial sizes and have different batch sizes. It is conceivable and probable that each will have its own cycle parameters. A manufacturer that has one cycle for multiple strengths of the same product probably has done a poor job of developing the cycle and probably has not adequately validated their process. Investigators should review the reports and data that support the filed lyophilization cycle.

 

LYOPHILIZER STERILIZATION/DESIGN

 

The sterilization of the lyophilizer is one of the more frequently encountered problems noted during inspections. Some of the older lyophilizers cannot tolerate steam under pressure, and sterilization is marginal at best. These lyophilizers can only have their inside surfaces wiped with a chemical agent that may be a sterilant but usually has been found to be a sanitizing agent. Unfortunately, piping such as that for the administration of inert gas (usually nitrogen) and sterile air for backfill or vacuum break is often inaccessible to such surface "sterilization" or treatment. It would seem very difficult for a manufacturer to be able to demonstrate satisfactory validation of sterilization of a lyophilizer by chemical "treatment".

 

Another method of sterilization that has been practiced is the use of gaseous ethylene oxide. As with any ethylene oxide treatment, humidification is necessary. Providing a method for introducing the sterile moisture with uniformity has been found to be difficult.

 

A manufacturer has been observed employing Water For Injection as a final wash or rinse of the lyophilizer. While the chamber was wet, it was then ethylene oxide gas sterilized. As discussed above, this may be satisfactory for the chamber but inadequate for associated plumbing.

 

Another problem associated with ethylene oxide is the residue. One manufacturer had a common ethylene oxide/nitrogen supply line to a number of lyophilizers connected in parallel to the system. Thus, there could be some ethylene oxide in the nitrogen supply line during the backfilling step. Obviously, this type of system is objectionable.

 

A generally recognized acceptable method of sterilizing the lyophilizer is through the use of moist steam under pressure. Sterilization procedures should parallel that of an autoclave, and a typical system should include two independent temperature sensing systems. One would be used to control and record temperatures of the cycle as with sterilizers, and the other would be in the cold spot of the chamber. As with autoclaves, lyophilizers should have drains with atmospheric breaks to prevent back siphonage.

 

As discussed, there should also be provisions for sterilizing the inert gas or air and the supply lines. Some manufacturers have chosen to locate the sterilizing filters in a port of the chamber. The port is steam sterilized when the chamber is sterilized, and then the sterilizing filter, previously sterilized, is aseptically connected to the chamber. Some

manufacturers have chosen to sterilize the filter and downstream piping to the chamber in place. Typical sterilization-in-place of filters may require steaming of both to obtain sufficient temperatures. In this type of system, there should be provisions for removing and/or draining condensate. The failure to sterilize nitrogen and air filters and the piping downstream leading into the chamber has been identified as a problem on a number of inspections.

 

Since these filters are used to sterilize inert gas and/or air, there should be some assurance of their integrity. Some inspections have disclosed a lack of integrity testing of the inert gas and/or air filter. The question is frequently asked how often should the vent filter be tested for integrity? As with many decisions made by manufacturers, there is a level of risk associated with the operation, process or system, which only the manufacturer can decide. If the sterilizing filter is found to pass the integrity test after several uses or batches, then one could claim its integrity for the previous batches. However, if it is only tested after several batches have been processed and if found to fail the integrity test, then one could question the sterility of all of the previous batches processed. In an effort to minimize this risk, some manufacturers have resorted to redundant filtration.

 

For most cycles, stoppering occurs within the lyophilizer. Typically, the lyophilizer has some type of rod or rods (ram) which enter the immediate chamber at the time of stoppering. Once the rod enters the chamber, there is the potential for contamination of the chamber. However, since the vials are stoppered, there is no avenue for contamination of the vials in the chamber which are now stoppered. Generally, lyophilizers should be sterilized after each cycle because of the potential for contamination of the shelf support rods. Additionally, the physical act of removing vials and cleaning the chamber can increase levels of contamination.

 

In some of the larger units, the shelves are collapsed after sterilization to facilitate loading. Obviously, the portions of the ram entering the chamber to collapse the shelves enters from a non-sterile area. Attempts to minimize contamination have included wiping the ram with a sanitizing agent prior to loading. Control aspects have included testing the ram for microbiological contamination, testing it for residues of hydraulic fluid, and testing the fluid for its bacteriostatic effectiveness. One lyophilizer fabricator has proposed developing a flexible "skirt" to cover the ram.

 

In addition to microbiological concerns with hydraulic fluid, there is also the concern with product contamination.

 

During steam sterilization of the chamber, there should be space between shelves that permit passage of free flowing steam. Some manufacturers have placed "spacers" between shelves to prevent their total collapse. Others have resorted to a two phase sterilization of the chamber. The initial phase provides for sterilization of the shelves when they are separated. The second phase provides for sterilization of the chamber and piston with the shelves collapsed.

 

Typically, biological indicators are used in lyophilizers to validate the steam sterilization cycle. One manufacturer of a Biopharmaceutical product was found to have a positive biological indicator after sterilization at 121oC for 45 minutes. During the chamber sterilization, trays used to transport vials from the filling line to the chamber were also sterilized. The trays were sterilized in an inverted position on shelves in the chamber. It is believed that the positive biological indicator is the result of poor steam penetration under these trays.

 

The sterilization of condensers is also a major issue that warrants discussion. Most of the newer units provide for the capability of sterilization of the condenser along with the chamber, even if the condenser is external to the chamber. This provides a greater assurance of sterility, particularly in those situations in which there is some equipment malfunction and the vacuum in the chamber is deeper than in the condenser.

 

Malfunctions that can occur, which would indicate that sterilization of the condenser is warranted, include vacuum pump breakdown, refrigeration system failures and the potential for contamination by the large valve between the condenser and chamber. This is particularly true for those units that have separate vacuum pumps for both the condenser and chamber. When there are problems with the systems in the lyophilizer, contamination could migrate from the condenser back to the chamber. It is recognized that the condenser is not able to be sterilized in many of the older units, and this represents a major problem, particularly in those cycles in which there is some equipment and/or operator failure.

 

As referenced above, leakage during a lyophilization cycle can occur, and the door seal or gasket presents an avenue of entry for contaminants. For example, in an inspection, it was noted that during steam sterilization of a lyophilizer, steam was leaking from the unit. If steam could leak from a unit during sterilization, air could possibly enter the chamber during lyophilization.

 

Some of the newer lyophilizers have double doors - one for loading and the other for unloading. The typical single door lyophilizer opens in the clean area only, and contamination between loads would be minimal. This clean area, previously discussed,

represents a critical processing area for a product made by aseptic processing. In most units, only the piston raising/lowering shelves is the source of contamination. For a double door system unloading the lyophilizer in a non-sterile environment, other problems may occur. The non-sterile environment presents a direct avenue of contamination of the chamber when unloading, and door controls similar to double door sterilizers should be in place.

 

Obviously, the lyophilizer chamber is to be sterilized between batches because of the direct means of contamination. A problem which may be significant is that of leakage through the door seal. For the single door unit, leakage prior to stoppering around the door seal is not a major problem from a sterility concern, because single door units only open into sterile areas. However, leakage from a door gasket or seal from a non-sterile area would present a significant microbiological problem. In order to minimize the potential for contamination, it is recommended that the lyophilizers be unloaded in a clean room area to minimize contamination. For example, in an inspection of a new manufacturing facility, it was noted that the unloading area for double door units was a clean room, with the condenser located below the chamber on a lower level.

 

After steam sterilization, there is often some condensate remaining on the floor of the chamber. Some manufacturers remove this condensate through the drain line while the chamber is still pressurized after sterilization. Unfortunately, some manufacturers have allowed the chamber to come to and remain at atmospheric pressure with the drain line open. Thus, non-sterile air could contaminate the chamber through the drain line. Some manufacturers have attempted to dry the chamber by blowing sterile nitrogen gas through the chamber at a pressure above atmospheric pressure.

 

In an inspection of a biopharmaceutical drug product, a Pseudomonas problem probably attributed to condensate after sterilization was noted. On a routine surface sample taken from a chamber shelf after sterilization and processing, a high count of Pseudomonas sp. was obtained. After sterilization and cooling when the chamber door was opened, condensate routinely spilled onto the floor from the door. A surface sample taken from the floor below the door also revealed Pseudomonas sp. contamination. Since the company believed the condensate remained in the chamber after sterilization, they repiped the chamber drain and added a line to a water seal vacuum pump.

 

FINISHED PRODUCT TESTING FOR

 

LYOPHILIZED PRODUCTS

 

There are several aspects of finished product testing which are of concern to the lyophilized dosage form. These include dose uniformity testing, moisture and stability testing, and sterility testing.

 

(a) Dose Uniformity

 

The USP includes two types of dose uniformity testing: content uniformity and weight variation. It states that weight variation may be applied to solids, with or without added substances, that have been prepared from true solutions and freeze-dried in final containers. However, when other excipients or other additives are present, weight variation may be applied, provided there is correlation with the sample weight and potency results. For example, in the determination of potency, it is sometimes common to reconstitute and assay the entire contents of a vial without knowing the weight of the sample. Performing the assay in this manner will provide information on the label claim of a product, but without knowing the sample weight will provide no information about dose uniformity. One should correlate the potency result obtained form the assay with the weight of the sample tested.

 

(b) Stability Testing

 

An obvious concern with the lyophilized product is the amount of moisture present in vials. The manufacturer's data for the establishment of moisture specifications for both product release and stability should be reviewed. As with other dosage forms, the expiration date and moisture limit should be established based on worst case data. That is, a manufacturer should have data that demonstrates adequate stability at the moisture specification.

 

As with immediate release potency testing, stability testing should be performed on vials with a known weight of sample. For example, testing a vial (sample) which had a higher fill weight (volume) than the average fill volume of the batch would provide a higher potency results and not represent the potency of the batch. Also, the expiration date and stability should be based on those batches with the higher moisture content. Such data should also be considered in the establishment of a moisture specification.

 

For products showing a loss of potency due to aging, there are generally two potency specifications. There is a higher limit for the dosage form at the time of release. This limit is generally higher than the official USP or filed specification which is official

throughout the entire expiration date period of the dosage form. The USP points out that compendial standards apply at any time in the life of the article.

 

Stability testing should also include provisions for the assay of aged samples and subsequent reconstitution of these aged samples for the maximum amount of time specified in the labeling. On some occasions, manufacturers have established expiration dates without performing label claim reconstitution potency assays at the various test intervals and particularly the expiration date test interval. Additionally, this stability testing of reconstituted solutions should include the most concentrated and the least concentrated reconstituted solutions. The most concentrated reconstituted solution will usually exhibit degradation at a faster rate than less concentrated solutions.

 

(c) Sterility Testing

 

With respect to sterility testing of lyophilized products, there is concern with the solution used to reconstitute the lyophilized product. Although products may be labeled for reconstitution with Bacteriostatic Water For Injection, Sterile Water For Injection (WFI) should be used to reconstitute products. Because of the potential toxicities associated with Bacteriostatic Water For Injection, many hospitals only utilize WFI. Bacteriostatic Water For Injection may kill some of the vegetative cells if present as contaminants, and thus mask the true level of contamination in the dosage form.

 

As with other sterile products, sterility test results which show contamination on the initial test should be identified and reviewed.

 

FINISHED PRODUCT INSPECTION - MELTBACK

 

The USP points out that it is good pharmaceutical practice to perform 100% inspection of parenteral products. This includes sterile lyophilized powders. Critical aspects would include the presence of correct volume of cake and the cake appearance. With regard to cake appearance, one of the major concerns is meltback.

 

Meltback is a form of cake collapse and is caused by the change from the solid to liquid state. That is, there is incomplete sublimation (change from the solid to vapor state) in the vial. Associated with this problem is a change in the physical form of the drug

substance and/or a pocket of moisture. These may result in greater instability and increased product degradation.

 

Another problem may be poor solubility. Increased time for reconstitution at the user stage may result in partial loss of potency if the drug is not completely dissolved, since it is common to use in-line filters during administration to the patient.

 

Manufacturers should be aware of the stability of lyophilized products which exhibit partial or complete meltback. Literature shows that for some products, such as the cephalosporins, that the crystalline form is more stable than the amorphous form of lyophilized product. The amorphous form may exist in the "meltback" portion of the cake where there is incomplete sublimation.

 

GLOSSARY

 

ATMOSPHERE, THE EARTH

 

The envelope of gases surrounding the earth, exerting under gravity a pressure at the earth's surface, which includes by volume 78% nitrogen, 21% oxygen, small quantities of hydrogen, carbon dioxide, noble gases, water vapor, pollutants and dust.

 

ATMOSPHERIC PRESSURE

 

The pressure exerted at the earth's surface by the atmosphere. For reference purposes a standard atmosphere is defined as 760 torr or millimeters of mercury, or 760,000 microns.

 

BACKSTREAMING

 

A process that occurs at low chamber pressures where hydrocarbon vapors from the vacuum system can enter the product chamber.

 

BLANK-OFF PRESSURE

 

This is the ultimate pressure the pump or system can attain.

 

BLOWER (see Mechanical Booster Pump)

 

This pump is positioned between the mechanical pump and the chamber. It operates by means of two lobes turning at a high rate of speed. It is used to reduce the chamber pressure to less than 20 microns.

 

BREAKING VACUUM

 

Admitting air or a selected gas to an evacuated chamber, while isolated from a vacuum pump, to raise the pressure towards, or up to, atmospheric.

 

CIRCULATION PUMP

 

A pump for conveying the heat transfer fluid.

 

CONDENSER (Cold trap)

 

In terms of the lyophilization process, this is the vessel that collects the moisture on plates and holds it in the frozen state. Protects the vacuum pump from water vapor contaminating the vacuum pump oil.

 

CONDENSER/RECEIVER

 

In terms of refrigeration, this unit condenses (changes) the hot refrigerant gas into a liquid and stores it under pressure to be reused by the system.

 

COOLING

 

The lowering of the temperature in any part of the temperature scale.

 

CONAX CONNECTION

 

A device to pass thermocouple wires through and maintain a vacuum tight vessel.

 

CONTAMINATION

 

ln the vacuum system, the introduction of water vapor into the oil in the vacuum pump, which then causes the pump to lose its ability to attain its ultimate pressure.

 

DEFROSTING

 

The removal of ice from a condenser by melting or mechanical means.

 

DEGREE OF CRYSTALLIZATION

 

The ratio of the energy released during the freezing of a solution to that of an equal volume of water.

 

DEGREE OF SUPERCOOLING

 

The number of degrees below the equilibrium freezing temperature where ice first starts to form.

 

DESICCANT

 

A drying agent.

 

DRY

 

Free from liquid, and/or moisture.

 

DRYING

 

The removal of moisture and other liquids by evaporation.

 

EQUILIBRIUM FREEZING TEMPERATURES

 

The temperature where ice will form in the absence of supercooling.

 

EUTECTIC TEMPERATURE

 

A point of a phase diagram where all phases are present and the temperature and composition of the liquid phase cannot be altered without one of the phases disappearing.

 

EXPANSION TANK

 

This tank is located in the circulation system and is used as a holding and expansion tank for the transfer liquid.

 

FILTER OR FILTER/DRIER

 

There are two systems that have their systems filtered or filter/dried. They are the circulation and refrigeration systems. In the newer dryers this filter or filter/dryer is the same, and can be replaced with a new core.

 

FREE WATER

 

The free water in a product is that water that is absorbed on the surfaces of the product and must be removed to limit further biological and chemical reactions.

 

FREEZING

 

This is the absence of heat. A controlled change of the product temperature as a function of time, during the freezing process, so as to ensure a completely frozen form.

 

GAS BALLAST

 

Used in the vacuum system on the vacuum pump to decontaminate small amounts of moisture in the vacuum pump oil.

 

GAS BLEED (Vacuum control)

 

To control the pressure in the chamber during the cycle to help the drying process. In freeze-drying the purpose is to improve heat-transfer to the product.

 

HEAT EXCHANGER

 

This exchanger is located in the circulation and refrigeration systems and transfers the heat from the circulation system to the refrigeration system.

 

HEAT TRANSFER FLUID

 

A liquid of suitable vapor pressure and viscosity range for transferring heat to or from a component, for example, a shelf or condenser in a freeze-dryer. The choice of such a fluid may depend on safety considerations. Diathermic fluid.

 

HOT GAS BYPASS

 

This is a refrigeration system. To control the suction pressure of the BIG FOUR (20-30 Hp) compressors during the refrigeration operation.

 

HOT GAS DEFROST

 

This is a refrigeration system. To defrost the condenser plates after the lyophilization cycle is complete.

 

ICE

 

The solid, crystalline form of water.

 

INERT GAS

 

Any gas of a group including helium, radon and nitrogen, formerly considered chemically inactive.

 

INTERSTAGE

 

In a two stage compressor system, this is the cross over piping on top of the compressor that connects the low side to the high side. One could also think of it as low side, intermediate, and high side.

 

INTERSTAGE PRESSURE REGULATING VALVE

 

This valve controls the interstage pressure from exceeding 80 - 90 PSI. This valve opens to suction as the interstage pressure rises above 80 - 90 PSI.

 

LEXSOL

 

A heat transfer fluid (high grade kerosene).

 

LIQUID SUB-COOLER HEAT EXCHANGER (see Sub-cooled Liquid)

 

The liquid refrigerant leaving the condenser/receiver at cooling water temperature is sub-cooled to a temperature of +15oF (-10oC) to -15oF (-25oC).

 

LYOPHILIZATION

 

A process in which the product is first frozen and then, while still in the frozen state, the major portion of the water and solvent system is reduced by sublimation and desorption so as to limit biological and chemical reactions at the designated storage temperature,

 

MAIN VACUUM VALVE (see Vapor Valve)

 

This valve is between the chamber and external condenser to isolate the two vessels after the process is finished. This is the valve that protects the finished product.

 

MATRIX

 

A matrix, in terms of the lyophilization process, is a system of ice crystals and solids that is distributed throughout the product.

 

MECHANICAL BOOSTER PUMP (see Blower)

 

A roots pump with a high displacement for its size but a low compression ratio. When backed by an oil-seal rotary pump the combination is an economical alternative to a two-stage oil-sealed rotary pump, with the advantage of obtaining a high vacuum.

 

MECHANICAL VACUUM PUMP

 

The mechanical pumping system that lowers the pressure in the chamber to below atmospheric pressure so that sublimation can occur.

 

MELTING TEMPERATURE (Melt-back)

 

That temperature where mobile water first becomes evident in a frozen system.

 

MICRON (see Torr)

 

A unit of pressure used in the lyophilization process. One micron = one Mtorr or 25,400 microns = 1" Hg., or 760,000 microns = one atmosphere.

 

NONCONDENSABLES

 

A mixture of gases such as nitrogen, hydrogen, chlorine, and hydrocarbons. They may be drawn into the system through leaks when part of the system is under a vacuum. Their presence reduces the operating efficiency of the system by increasing the condensing pressure.

 

NUCLEATION

 

The formation of ice crystals on foreign surfaces or as a result of the growth of water clusters.

 

OIL-MIST FILTER

 

In vacuum terminology a filter attached to the discharge (exhaust) of an oil-sealed rotary pump to eliminate most of the "smoke" of suspended fine droplets of oil which would be discharged into the environment.

 

OIL SEALED ROTARY PUMP

 

A standard type of mechanical vacuum pump used in freeze-drying with a high compression ratio but having a relatively low displacement (speed) for its size. A two-stage pump is effectively two such pumps in series and can obtain an ultimate vacuum.

 

OIL SEPARATOR

 

Separates the oil from the compressor discharge gas and returns the oil through the oil float trap and piping to the compressor crankcase.

 

REAL LEAK

 

A real leak is a source of atmospheric gases resulting from a penetration through the chamber.

 

RECONSTITUTE

 

The dissolving of the dried product into a solvent or diluent.

 

RELIEF VALVE

 

Used for safety purposes to prevent damage in case excessive pressure is encountered.

 

ROTARY VANE PUMP

 

A mechanical pumping system with sliding vanes as the mechanical seal. Can be single or two stages.

 

SHELF COMPRESSOR (Controlling Compressor)

 

Used for controlling the shelf temperature, either cooling or from overheating.

 

SELF LIQUID HEAT EXCHANGER

 

The transfer of heat from the shelf fluid to the refrigeration system through tubes in the exchanger causing compressor suction gas to warm.

 

SHELVES

 

In terms of the lyophilization process, they are a form of heat exchanger, within the chamber, that have a serpentine liquid flow through them, entering one side and flowing to the other side. They are located in the circulation system.

 

SINGLE STAGE COMPRESSOR

 

This is a normal type compressor used in refrigeration. In the lyophilization process it is used to control the shelf temperature, both for cooling and keeping the shelf temperature from overheating using a temperature controller.

 

SILICONE OIL

 

A heat transfer fluid.

 

STERILIZATION

 

The use of steam and pressure to kill any bacteria that may be able to contaminate that environment or vessel.

 

SUBLIMATION

 

The conversion of a material from a solid phase directly to a vapor phase, without passing through the liquid phase. This is referred to as the primary drying stage.

 

SUB-COOLED LIQUID (See Liquid Sub-cooler Heat Exchanger)

 

The liquid refrigerant is cooled through an exchanger so that it increases the refrigerating effect as well as reduces the volume of gas flashed from the liquid refrigerant in passage through the expansion valve.

 

SUCTION LINE ACCUMULATOR

 

To provide adequate refrigerant liquid slug protection (droplets of liquid refrigerant) from returning to the compressor, and causing damage to the compressor.

 

TCE

 

Trichloroethylene - A heat transfer fluid.

 

TEMPERATURE

 

The degree of hotness or coldness of a body.

 

THERMOCOUPLE

 

A metal-to-metal contact between two dissimilar metals that produces a small voltage across the free ends of the wire.

 

THERMOSTATIC EXPANSION VALVE

 

An automatic variable device controlling the flow of liquid refrigerant.

 

TORR (See Micron)

 

A unit of measure equivalent to the amount of pressure in 1000 microns.

 

TWO STAGE COMPRESSOR (see Interstage)

 

This is a specially built compressor. Its function is to be able to attain low temperatures by being able to operate at low pressures. It is two compressors built into one. A low stage connected internally and a high stage connected externally with piping, called interstage.

 

UNLOADING VALVE

 

This valve connects the interstage with suction to equalize both pressures during pump-down.

 

VACUUM

 

Strictly speaking, a space in which the total pressure is less than atmospheric.

 

VACUUM CONTROL (Gas Bleed)

 

To assist in the rate of sublimation, by controlling the pressure in the lyophilizer.

 

VACUUM PUMP

 

A mechanical way of reducing the pressure in a vessel below atmospheric pressure to where sublimation can occur. There are three types of pumps, rotary vane, rotary piston and mechanical booster.

 

VAPOR BAFFLE

 

A target shaped object placed in the condenser to direct vapor flow and to promote an even distribution of condensate.

 

VACUUM VALVES

 

The vacuum valves used are of a ball or disk type that can seal without leaking. The balI types are used for services to the chamber and condenser. They are also used for drains and isolation applications. The disk types are used in the vacuum line system and are connected to the vacuum pump, chamber and condenser.

 

VAPOR VALVE (See Main Vacuum Valve)

 

The vacuum valve between the chamber and external condenser. When this valve is closed the chamber is isolated from the external condenser. Also known as the main vapor valve.

 

VIAL

 

A small glass bottle with a flat bottom, short neck and flat flange designed for stoppering.

 

VIRTUAL LEAK

 

In the vacuum system a virtual leak is the passage of gas into the chamber from a source that is located internally in the chambe

Microbiological Pharmaceutical Quality Control Labs (7/93)  

GUIDE TO INSPECTIONS OF MICROBIOLOGICAL PHARMACEUTICAL QUALITY CONTROL LABORATORIES

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does not confer any rights,

privileges, benefits, or immunities for or on any person(s).

I. INTRODUCTION

 

The Guide to the Inspection of Pharmaceutical Quality Control Laboratories provided very limited guidance on the matter of inspection of microbiological laboratories. While that guide addresses many of the issues associated with the chemical aspect of laboratory analysis of pharmaceuticals, this document will serve as a guide to the inspection of the microbiology analytical process. As with any laboratory inspection, it is recommended that an analyst (microbiologist) who is familiar with the tests being inspected participate in these inspections.

 

II. MICROBIOLOGICAL TESTING OF NON-STERILE PRODUCTS

 

For a variety of reasons, we have seen a number of problems associated with the microbiological contamination of topical drug products, nasal solutions and inhalation products. The USP Microbiological Attributes Chapter <1111> provides little specific guidance other than "The significance of microorganisms in non-sterile pharmaceutical products should be evaluated in terms of the use of the product, the nature of the product, and the potential hazard to the user." The USP recommends that certain categories be routinely tested for total counts and specified indicator microbial contaminants. For example natural plant, animal and some mineral products for Salmonella, oral liquids for E. Coli, topicals for P. aeruginosa and S. Aureus, and articles intended for rectal, urethral, or vaginal administration for yeasts and molds. A number of specific monographs also include definitive microbial limits.

 

As a general guide for acceptable levels and types of microbiological contamination in products, Dr. Dunnigan of the Bureau of Medicine of the FDA commented on the health hazard. In 1970, he said that topical preparations contaminated with gram negative organisms are a probable moderate to serious health hazard. Through the literature and through our investigations, it has been shown that a variety of infections have been traced to the gram negative contamination of topical products. The classical example being the Pseudomonas cepacia contamination of Povidone Iodine products reported by a hospital in Massachusetts several years ago.

 

Therefore, each company is expected to develop microbial specifications for their non-sterile products. Likewise, the USP Microbial Limits Chapter <61> provides methodology for selected indicator organisms, but not all objectionable organisms. For example, it is widely recognized that Pseudomonas cepacia is objectionable if found in a topical product or nasal solution in high numbers; yet, there are no test methods provided in the USP that will enable the identification of the presence of this microorganism.

 

A relevant example of this problem is the recall of Metaproterenol Sulfate Inhalation Solution. The USP XXII monograph requires no microbial testing for this product. The agency classified this as a Class I recall because the product was contaminated with Pseudomonas gladioli/cepacia. The health hazard evaluation commented that the risk of pulmonary infection is especially serious and potentially life-threatening to patients with chronic obstructive airway disease, cystic fibrosis, and immuno-compromised patients. Additionally, these organisms would not have been identified by testing procedures delineated in the general Microbial Limits section of the Compendia.

 

The USP currently provides for retests in the Microbial Limits section <61> however there is a current proposal to remove the retest provision. As with any other test, the results of initial test should be reviewed and investigated. Microbiological contamination is not evenly dispersed throughout a lot or sample of product and finding a contaminant in one sample and not in another does not discount the findings of the initial sample results. Retest results should be reviewed and evaluated, and particular emphasis should be placed on the logic and rationale for conducting the retest.

 

In order to isolate specific microbial contaminants, FDA laboratories, as well as many in the industry, employ some type of enrichment media containing inactivators, such as Tween or lecithin. This is essential to inactivate preservatives usually present in these types of product and provides a better medium for damaged or slow growing cells. Other growth parameters include a lower temperature and longer incubation time (at least 5 days) that provide a better survival condition for damaged or slow-growing cells.

 

For example, FDA laboratories use the test procedures for cosmetics in the Bacteriological Analytical Manual (BAM), 6th Edition, to identify contamination in non-sterile drug products. This testing includes an enrichment of a sample in modified letheen broth. After incubation, further identification is carried out on Blood Agar Plates and MacConkey Agar Plates. Isolated colonies are then identified. This procedure allows FDA microbiologists to optimize the recovery of all potential pathogens and to quantitate and speciate all recovered organisms. Another important aspect of procedures used by FDA analysts is to determine growth promotion characteristics for all of the media used.

 

The selection of the appropriate neutralizing agents are largely dependent upon the preservative and formulation of the product under evaluation. If there is growth in the enrichment broth, transfer to more selective agar media or suitable enrichment agar may be necessary for subsequent identification.

 

Microbiological testing may include an identification of colonies found during the Total Aerobic Plate Count test. Again, the identification should not merely be limited to the USP indicator organisms.

 

The importance of identifying all isolates from either or both Total Plate Count testing and enrichment testing will depend upon the product and its intended use. Obviously, if an oral solid dosage form such as a tablet is tested, it may be acceptable to identify isolates when testing shows high levels. However, for other products such as topicals, inhalants or nasal solutions where there is a major concern for microbiological contamination, isolates from plate counts, as well as enrichment testing, should be identified.

 

III. FACILITIES, EQUIPMENT, AND

 

MEDIA

 

Begin the inspection with a review of analyses being conducted and inspect the plates and tubes of media being incubated (caution should be exercised not to inadvertently contaminate plates or tubes of media on test). Be particularly alert for retests that have not been documented and "special projects" in which investigations of contamination problems have been identified. This can be evaluated by reviewing the ongoing analyses (product or environmental) for positive test results. Request to review the previous day's plates and media, if available and compare your observations to the recorded entries in

the logs. Inspect the autoclaves used for the sterilization of media. Autoclaves may lack the ability to displace steam with sterile filtered air. For sealed bottles of media, this would not present a problem. However, for non-sealed bottles or flasks of media, non-sterile air has led to the contamination of media. In addition, autoclaving less than the required time will also allow media associated contaminants to grow and cause a false positive result. These problems may be more prevalent in laboratories with a heavy workload.

 

Check the temperature of the autoclave since overheating can denature and even char necessary nutrients. This allows for a less than optimal recovery of already stressed microorganisms. The obvious problem with potential false positives is the inability to differentiate between inadvertent medium contamination and true contamination directly associated with the sample tested.

 

IV. STERILITY TESTING

 

On 10/11/91, the Agency published a proposed rule regarding the manufacture of drug products by aseptic processing and terminal sterilization. A list of contaminated or potentially contaminated drug products made by aseptic processing and later recalled was also made available. Many of the investigations/inspections of the recalled products started with a list of initial sterility test failures. FDA review of the manufacturer's production, controls, investigations and their inadequacies, coupled with the evidence of product failure (initial sterility test failure) ultimately led to the action.

 

The USP points out that the facilities used to conduct sterility tests should be similar to those used for manufacturing product. The USP states, "The facility for sterility testing should be such as to offer no greater a microbial challenge to the articles being tested than that of an aseptic processing production facility". Proper design would, therefore, include a gowning area and pass-through airlock. Environmental monitoring and gowning should be equivalent to that used for manufacturing product.

 

Since a number of product and media manipulations are involved in conducting a sterility test, it is recommended that the inspection include actual observation of the sterility test even though some companies have tried to discourage inspection on the grounds that it may make the firm's analyst nervous. The inspection team is expected to be sensitive to this concern and make the observations in a manner that will create the least amount of disruption in the normal operating environment. Nevertheless, such concerns are not sufficient cause for you to suspend this portion of the inspection.

 

One of the most important aspects of the inspection of a sterility analytical program is to review records of initial positive sterility test results. Request lists of test failures to facilitate review of production and control records and investigation reports. Particularly, for the high risk aseptically filled product, initial positive sterility test results and investigations should be reviewed. It is difficult for the manufacturer to justify the release of a product filled aseptically that fails an initial sterility test without identifying specific problems associated with the controls used for the sterility test.

 

Examine the use of negative controls. They are particularly important to a high quality sterility test. Good practice for such testing includes the use of known terminally sterilized or irradiated samples as a system control. Alternatively, vials or ampules filled during media fills have also been used.

 

Be especially concerned about the case where a manufacturer of aseptically filled products has never found an initial positive sterility test. While such situations may occur, they are rare. In one case, a manufacturer's records showed that they had never found a positive result; their records had been falsified. Also, the absence of initial positives may indicate that the test has not been validated to demonstrate that there is no carryover of inhibition from the product or preservative.

 

Inspect robotic systems or isolation technology, such as La Calhene units used for sterility testing. These units allow product withdrawal in the absence of people. If an initial test failure is noted in a sample tested in such a system, it could be very difficult to justify release based on a retest, particularly if test controls are negative.

 

Evaluate the time period used for sterility test sample incubation. This issue has been recently clarified. The USP states that samples are to be incubated for at least 7 days, and a proposal has been made to change the USP to require a period of 14 days incubation. You are expected to evaluate the specific analytical procedure and the product for the proper incubation period. Seven days may be insufficient, particularly when slow growing organisms have been identified. Media fill, environmental, sterility test results and other data should be reviewed to assure the absence of slow growing organisms. Also, you should compare the methods being used for incubation to determine if they conform to those listed in approved or pending applications.

 

V. METHODOLOGY AND

 

VALIDATION OF TEST

 

PROCEDURES

 

Determine the source of test procedures. Manufacturers derive test procedures from several sources, including the USP, BAM and other microbiological references. It would be virtually impossible to completely validate test procedures for every organism that may be objectionable. However, it is a good practice to assure that inhibitory substances in samples are neutralized.

 

During inspections, including pre-approval inspections, evaluate the methodology for microbiological testing. For example, we expect test methods to identify the presence of organisms such as Pseudomonas cepacia or other Pseudomonas species that may be objectional or present a hazard to the user. Where pre-approval inspections are being conducted, compare the method being used against the one submitted in the application. Also verify that the laboratory has the equipment necessary to perform the tests and that the equipment was available and in good operating condition on the dates of critical testing.

 

The USP states that an alternate method may be substituted for compendial tests, provided it has been properly validated as giving equivalent or better results.

 

You may find that dehydrated media are being used for the preparation of media. Good practice includes the periodic challenge of prepared media with low levels of organisms. This includes USP indicator organisms as well as normal flora. The capability of the media to promote the growth of organisms may be affected by the media preparation process, sterilization (overheating) and storage. These represent important considerations in any inspection and in the good management of a microbiology laboratory.

 

VI. DATA STORAGE

 

Evaluate the test results that have been entered in either logbooks or on loose analytical sheets. While some manufacturers may be reluctant to provide tabulations, summaries, or printouts of microbiological test results, this data should be reviewed for the identification of potential microbial problems in processing. When summaries of this data are not available the inspection team is expected to review enough data to construct their own summary of the laboratory test results and quality control program.

 

Some laboratories utilize preprinted forms only for recording test data. Some laboratories have also pointed out that the only way microbiological test data could be reviewed during inspections would be to review individual batch records. However, in most cases, preprinted forms are in multiple copies with a second or third copy in a central file. Some companies use log-books for recording data. These logbooks should also be reviewed.

 

Additionally, many manufacturers are equipped with an automated microbial system for the identification of microorganisms. Logs of such testing, along with the identification of the source of the sample, are also of value in the identification of potential microbial problems in processing.

 

The utilization of automated systems for the identification of microorganisms is relatively common in the parenteral manufacturer where isolates from the environment, water systems, validation and people are routinely identified.

 

Microbiologists in our Baltimore District are expert on the use of automated microbic analytical systems. They were the first FDA laboratory to use such equipment and have considerable experience in validating methods for these pieces of equipment. Contact the Baltimore District laboratory for information or questions about these systems. Plants with heavy utilization of these pieces of equipment should be inspected by individuals from the Baltimore District laboratory.

 

VII. MANAGEMENT REVIEW

 

Microbiological test results represent one of the more difficult areas for the evaluation and interpretation of data. These evaluations require extensive training and experience in microbiology. Understanding the methodology, and more importantly, understanding the limitations of the test present the more difficult issues. For example, a manufacturer found high counts of Enterobacter cloacae in their oral dosage form product derived from a natural substance. Since they did not isolate E. coli, they released the product. FDA analysis found E. cloacae in most samples from the batch and even E. coli in one sample. In this case management failed to recognize that microbiological contamination might not be uniform, that other organisms may mask the presence of certain organisms when identification procedures are performed, and that microbiological testing is far from absolute. The inspection must consider the relationship between the organisms found in the samples and the potential for the existence of other objectionable conditions. For example, it is logical to assume that if the process would allow E.

cloacae to be present, it could also allow the presence of the objectionable indicator organism. The microbiologist should evaluate this potential by considering such factors as methodology, and the growth conditions of the sample as well as other fundamental factors associated with microbiological analysis.

 

Evaluate management's program to audit the quality of the laboratory work performed by outside contractors.

 

VIII. CONTRACT TESTING

 

LABORATORIES

 

Many manufacturers contract with private or independent testing laboratories to analyze their products. Since, these laboratories will conduct only the tests that the manufacturer requests, determine the specific instructions given to the contractor. Evaluate these instructions to assure that necessary testing will be completed. For example, in a recent inspection of a topical manufacturer, total plate count and testing for the USP indicator organisms were requested. The control laboratory performed this testing only and did not look for other organisms that would be objectionable based on the product's intended use.

 

Analytical results, particularly for those articles in which additional or retesting is conducted, should be reviewed. Test reports should be provided to the manufacturer for tests conducted. It is not unusual to see contract laboratories fail to provide complete results, with both failing as well as passing results.

 

Bacteriostasis/fungiostasis testing must be performed either by the contract lab or the manufacturer. These test results must be negative otherwise any sterility test results obtained by the contractor on the product may not be valid.

 

Pharmaceutical Quality Control Labs (7/93) 

GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROL LABORATORIES

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).

 

 

1. INTRODUCTION

 

The pharmaceutical quality control laboratory serves one of the most important functions in pharmaceutical production and control. A significant portion of the CGMP regulations (21 CFR 211) pertain to the quality control laboratory and product testing. Similar concepts apply to bulk drugs.

 

This inspection guide supplements other inspectional information contained in other agency inspectional guidance documents. For example, Compliance Program 7346.832 requiring pre-approval NDA/ANDA inspections contains general instructions to conduct product specific NDA/ANDA inspection audits to measure compliance with the applications and CGMP requirements. This includes pharmaceutical laboratories used for in-process and finished product testing.

 

2. OBJECTIVE

 

The specific objective will be spelled out prior to the inspection. The laboratory inspection may be limited to specific issues, or the inspection may encompass a comprehensive evaluation of the laboratory's compliance with CGMP's. As a minimum, each pharmaceutical quality control laboratory should receive a comprehensive GMP evaluation each two years as part of the statutory inspection obligation.

 

In general these inspections may include

 

-- the specific methodology which will be used to test a new product

 

-- a complete assessment of laboratory's conformance with GMP's

 

-- a specific aspect of laboratory operations

 

3. INSPECTION PREPARATION

 

FDA Inspection Guides are based on the team inspection approach and our inspection of a laboratory is consistent with this concept. As part of our effort to achieve uniformity and consistency in laboratory inspections, we expect that complex, highly technical and specialized testing equipment, procedures and data manipulations, as well as scientific laboratory operations will be evaluated by an experienced laboratory analyst with specialized knowledge in such matters.

 

District management makes the final decision regarding the assignment of personnel to inspections. Nevertheless, we expect investigators, analysts and others to work as teams and to advise management when additional expertise is required to complete a meaningful inspection.

 

Team members participating in a pre-approval inspection must read and be familiar with Compliance Program 7346.832, Pre-Approval Inspections/Investigations. Relevant sections of the NDA or ANDA should be reviewed prior to the inspection; but if the application is not available from any other source, this review will have to be conducted using the company's copy of the application.

 

Team members should meet, if possible, prior to the inspection to discuss the approach to the inspection, to define the roles of the team members, and to establish goals for completion of the assignment. Responsibilities for development of all reports should also be established prior to the inspection. This includes the preparation of the FDA 483.

 

The Center for Drug Evaluation and Research (CDER) may have issued deficiency letters listing problems that the sponsor must correct prior to the approval of NDA/ANDA's and supplements. The inspection team is expected to review such letters on file at the district office, and they are expected to ask the plant for access to such letters. The team should evaluate the replies to these letters to assure that the data are

accurate and authentic. Complete the inspection even though there has been no response to these letters or when the response is judged inadequate.

 

4. INSPECTION APPROACH

 

A. General

 

In addition to the general approach utilized in a drug CGMP inspection, the inspection of a laboratory requires the use of observations of the laboratory in operation and of the raw laboratory data to evaluate compliance with CGMP's and to specifically carry out the commitments in an application or DMF. When conducting a comprehensive inspection of a laboratory, all aspects of the laboratory operations will be evaluated.

 

Laboratory records and logs represent a vital source of information that allows a complete overview of the technical ability of the staff and of overall quality control procedures. SOPs should be complete and adequate and the operations of the laboratories should conform to the written procedures. Specifications and analytical procedures should be suitable and, as applicable, in conformance with application commitments and compendial requirements.

 

Evaluate raw laboratory data, laboratory procedures and methods, laboratory equipment,including maintenance and calibration, and methods validation data to determine the overall quality of the laboratory operation and the ability to comply with CGMP regulations.

 

Examine chromatograms and spectra for evidence of impurities, poor technique, or lack of instrument calibration.

 

Most manufacturers use systems that provide for the investigation of laboratory test failures. These are generally recorded in some type of log. Ask to see results of analyses for lots of product that have failed to meet specifications and review the analysis of lots that have been retested, rejected, or reworked. Evaluate the decision to release lots of product when the laboratory results indicate that the lot failed to meet specifications and determine who released them.

 

B. Pre-Approval

 

Documents relating to the formulation of the product, synthesis of the bulk drug substance, product specifications, analysis of the product, and others are examined during the review process in headquarters. However, these reviews and evaluations depend on accurate and authentic data that truly represents the product.

 

Pre-approval inspections are designed to determine if the data submitted in an application are authentic and accurate and if the procedures listed in the application were actually used to produce the data contained in the application. Additionally, they are designed to confirm that plants (including the quality control laboratory) are in compliance with CGMP regulations.

 

The analytical sections of drug applications usually contain only test results and the methods used to obtain them. Sponsors are not required to file all the test data because such action would require voluminous submissions and would often result in filing redundant information. Sponsors may deliberately or unintentionally select and report data showing that a drug is safe and effective and deserves to be approved. The inspection team must decide if there is valid and scientific justification for the failure to report data which demonstrates the product failed to meet its predetermined specifications.

 

Coordination between headquarters and the field is essential for a complete review of the application and the plant. Experienced investigators and analysts may contact the review chemist (with appropriate supervisory concurrence) when questions concerning specifications and standards arise.

 

Inspections should compare the results of analyses submitted with results of analysis of other batches that may have been produced. Evaluate the methods and note any exceptions to the procedures or equipment actually used from those listed in the application and confirm that it is the same method listed in the application. The analyst is expected to evaluate raw laboratory data for tests performed on the test batches (biobatches and clinical batches) and to compare this raw data to the data filed in the application.

 

5. FAILURE (OUT-OF-

 

SPECIFICATION) LABORATORY

 

RESULTS

 

Evaluate the company's system to investigate laboratory test failures. These investigations represent a key issue in deciding whether a product may be released or rejected and form the basis for retesting, and resampling.

 

In a recent court decision the judge used the term "out-of-specification" (OOS) laboratory result rather than the term "product failure" which is more common to FDA investigators and analysts. He ruled that an OOS result identified as a laboratory error by a failure investigation or an outlier test. The court provided explicit limitations on the use of outlier tests and these are discussed in a later segment of this document., or overcome by retesting. The court ruled on the use of retesting which is covered in a later segment of this document. is not a product failure. OOS results fall into three categories:

 

-- laboratory error

 

-- non-process related or operator error

 

-- process related or manufacturing process error

 

A. LABORATORY ERRORS

 

Laboratory errors occur when analysts make mistakes in following the method of analysis, use incorrect standards, and/or simply miscalculate the data. Laboratory errors must be determined through a failure investigation to identify the cause of the OOS. Once the nature of the OOS result has been identified it can be classified into one of the three categories above. The inquiry may vary with the object under investigation.

 

B. LABORATORY INVESTIGATIONS

 

The exact cause of analyst error or mistake can be difficult to determine specifically and it is unrealistic to expect that analyst error will always be determined and documented. Nevertheless, a laboratory investigation consists of more than a retest. The inability to identify an error's cause with confidence affects retesting procedures, not the investigation inquiry required for the initial OOS result.

 

The firm's analyst should follow a written procedure, checking off each step as it is completed during the analytical procedure. We expect laboratory test data to be recorded directly in notebooks; use of scrap paper and loose paper must be avoided. These common sense measures enhance the accuracy and integrity of data.

 

Review and evaluate the laboratory SOP for product failure investigations. Specific procedures must be followed when single and multiple OOS results are investigated. For the single OOS result the investigation should include the following steps and these inquiries must be conducted before there is a retest of the sample:

 

o the analyst conducting the test should report the OOS result to the supervisor

 

o the analyst and the supervisor should conduct an informal laboratory investigation which addresses the following areas:

 

1. discuss the testing procedure

 

2. discuss the calculation

 

3. examine the instruments

 

4. review the notebooks containing the OOS result

 

An alternative means to invalidate an initial OOS result, provided the failure investigation proves inconclusive, is the "outlier" test. However, specific restrictions must be placed on the use of this test.

 

1. Firms cannot frequently reject results on this basis.

 

2. The USP standards govern its use in specific cases only.

 

3. The test cannot be used for chemical testing results. An initial content uniformity test was OOS followed by a passing retest. The initial OOS result was claimed the result of analyst error based on a statistical evaluation of the data. The court ruled that the use of an outlier test is inappropriate in this case..

 

4. It is never appropriate to utilize outlier tests for a statistically based test, i.e., content uniformity and dissolution.

 

Determine if the firm uses an outlier test and evaluate the SOP.

 

Determine that a full scale inquiry has been made for multiple OOS results. This inquiry involves quality control and quality assurance personnel in addition to laboratory workers to identify exact process or non process related errors.

 

When the laboratory investigation is inconclusive (reason for the error is not identified) the firm:

 

1. Cannot conduct 2 retests and base release on average of three tests

 

2. Cannot use outlier test in chemical tests

 

3. Cannot use a re-sample to assume a sampling or preparation error

 

4. Can conduct a retest of different tablets from the same sample when a retest is considered appropriate (see criteria elsewhere)

 

C. FORMAL INVESTIGATIONS

 

Formal investigations extending beyond the laboratory must follow an outline with particular attention to corrective action. The company must:

 

1. State the reason for the investigation

 

2. Provide summation of the process sequences that may have caused the problem

 

3. Outline corrective actions necessary to save the batch and prevent similar recurrence

 

4. List other batches and products possibly affected, the results of investigation of these batches and products, and any corrective action. Specifically:

 

o examine other batches of product made by the errant employee or machine

 

o examine other products produced by the errant process or operation

 

5. Preserve the comments and signatures of all production and quality control personnel who conducted the investigation and approved any reprocessed material after additional testing

 

D. INVESTIGATION DOCUMENTATION

 

Analyst's mistakes, such as undetected calculation errors, should be specified with particularity and supported by evidence. Investigations along with conclusions reached must be preserved with written documentation that enumerates each step of the investigation. The evaluation, conclusion and corrective action, if any, should be preserved in an investigation or failure report and placed into a central file.

 

E. INVESTIGATION TIME FRAMES

 

All failure investigations should be performed within 20 business days of the problem's occurrence and recorded and written into a failure or investigation report.

 

6. PRODUCT FAILURES

 

An OOS laboratory result can be overcome (invalidated) when laboratory error has been documented. However, non-process and process related errors resulting from operators making mistakes, equipment (other than laboratory equipment) malfunctions, or a manufacturing process that is fundamentally deficient, such as an improper mixing time, represent product failures.

 

Examine the results of investigations using the guidance in section 5 above and evaluate the decision to release, retest, or rework products.

 

7. RETESTING

 

Evaluate the company's retesting SOP for compliance with scientifically sound and appropriate procedures. A very important ruling in one recent court decision sets forth a procedure to govern the retesting program. This district court ruling provides an excellent guide to use in evaluating some aspects of a pharmaceutical laboratory, but should not be considered as law, regulation or binding legal precedent. The court ruled that a firm should have a predetermined testing procedure and it should consider a point at which testing ends and the product is evaluated. If results are not satisfactory, the product is rejected.

 

Additionally, the company should consider all retest results in the context of the overall record of the product. This includes the history of the product. The court ordered a recall of one batch of product on the basis of an initial content uniformity failure and no basis to invalidate the test result and on a history of content uniformity problems with the product., type of test performed, and in-process test results. Failing assay results cannot be disregarded simply on the basis of acceptable content uniformity results.

 

The number of retests performed before a firm concludes that an unexplained OOS result is invalid or that a product is unacceptable is a matter of scientific judgment. The goal of retesting is to isolate OOS results but retesting cannot continue ad infinitum.

 

In the case of nonprocess and process-related errors, retesting is suspect. Because the initial tests are genuine, in these circumstances, additional testing alone cannot contribute to product quality. The court acknowledged that some retesting may precede a finding of nonprocess or process-based errors. Once this determination is made, however, additional retesting for purposes of testing a product into compliance is not acceptable.

 

For example, in the case of content uniformity testing designed to detect variability in the blend or tablets, failing and non-failing results are not inherently inconsistent and passing results on limited retesting do not rule out the possibility that the batch is not uniform. As part of the investigation firms should consider the record of previous batches, since similar or related failures on different batches would be a cause of concern.

 

Retesting following an OOS result is ruled appropriate only after the failure investigation is underway and the failure investigation determines in part whether retesting is appropriate. It is appropriate when analyst error is documented or the review of analyst's work is "inconclusive" , but it is not appropriate for known and undisputed non-process or process related errors.

 

The court ruled that retesting:

 

o must be done on the same, not a different sample

 

o may be done on a second aliquot from the same portion of the sample that was the source of the first aliquot

 

o may be done on a portion of the same larger sample previously collected for laboratory purposes

 

8. RESAMPLING

 

Firms cannot rely on resampling. The court ordered the recall of one batch of product after having concluded that a successful resample result alone cannot invalidate an initial OOS result. to release a product that has failed testing and retesting unless the failure investigation discloses evidence that the original sample is not representative or was improperly prepared.

 

Evaluate each resampling activity for compliance with this guidance.

 

9. AVERAGING RESULTS OF

 

ANALYSIS

 

Averaging can be a rational and valid approach when the object under consideration is total product assay, but as a general rule this practice should be avoided. The court ruled that the firm must recall a batch that was released for content uniformity on the basis of averaged test results. because averages hide the variability among individual test results. This phenomenon is particularly troubling if testing generates both OOS and passing individual results which when averaged are within specification. Here, relying on the average figure without examining and explaining the individual OOS results is highly misleading and unacceptable.

 

Content uniformity and dissolution results never should be averaged to obtain a passing value.

 

In the case of microbiological turbidimetric and plate assays an average is preferred by the USP. In this case, it is good practice to include OOS results in the average unless an outlier test (microbiological assays) suggests the OOS is an anomaly.

 

10. BLEND SAMPLING AND

 

TESTING

 

The laboratory serves a vital function in blend testing which is necessary to increase the likelihood of detecting inferior batches. Blend uniformity testing cannot be waived in favor of total reliance on finished product testing because finished product testing is limited.

 

One court has ruled that sample size influences ultimate blend test results and that the sample size should resemble the dosage size. Any other practice would blur differences in portions of the blend and defeat the object of the test. If a sample larger than the unit must be taken initially, aliquots which resemble the dosage size should be carefully removed for the test, retests, and reserve samples. Obviously, the initial larger sample should not be subjected to any additional mixing or manipulation prior to removing test aliquots as this may obscure non-homogeneity.

 

Multiple individual blend uniformity samples taken from different areas cannot be composited. However when variation testing is not the object of assay testing, compositing is permitted.

 

If firms sample product from sites other than the blender, they must demonstrate through validation that their sampling technique is representative of all portions and concentrations of the blend. This means that the samples must be representative of those sites that might be problems; e.g. weak or hot spots in the blend.

 

11. MICROBIOLOGICAL

 

The review of microbiological data on applicable dosage forms is best performed by the microbiologist (analyst). Data that should be reviewed include preservative

effectiveness testing, bioburden data, and product specific microbiological testing and methods.

 

Review bioburden (before filtration and/or sterilization) from both an endotoxin and sterility perspective. For drug substance labs evaluate methods validation and raw data for sterility, endotoxin testing, environmental monitoring, and filter and filtration validation. Also, evaluate the methods used to test and establish bioburdens.

 

Refer to the Microbiological Inspection Guide for additional information concerning the inspection of microbiological laboratories.

 

12. SAMPLING

 

Samples will be collected on pre-approval inspections. Follow the sampling guidelines in CP 7346.832, Part III, pages 5 and 6.

 

13. LABORATORY RECORDS AND

 

DOCUMENTATION

 

Review personal analytical notebooks kept by the analysts in the laboratory and compare them with the worksheets and general lab notebooks and records. Be prepared to examine all records and worksheets for accuracy and authenticity and to verify that raw data are retained to support the conclusions found in laboratory results.

 

Review laboratory logs for the sequence of analysis versus the sequence of manufacturing dates. Test dates should correspond to the dates when the sample should have been in the laboratory. If there is a computer data base, determine the protocols for making changes to the data. There should be an audit trail for changes to data.

 

We expect raw laboratory data to be maintained in bound, (not loose or scrap sheets of paper), books or on analytical sheets for which there is accountability, such as

prenumbered sheets. For most of those manufacturers which had duplicate sets of records or "raw data", non-numbered loose sheets of paper were employed. Some companies use discs or tapes as raw data and for the storage of data. Such systems have also been accepted provided they have been defined (with raw data identified) and validated.

 

Carefully examine and evaluate laboratory logs, worksheets and other records containing the raw data such as weighings, dilutions, the condition of instruments, and calculations. Note whether raw data are missing, if records have been rewritten, or if correction fluid has been used to conceal errors. Results should not be changed without explanation. Cross reference the data that has been corrected to authenticate it. Products cannot be "tested into compliance" by arbitrarily labeling out-of-specification lab results as "laboratory errors" without an investigation resulting in scientifically valid criteria.

 

Test results should not have been transcribed without retention of the original records, nor should test results be recorded selectively. For example, investigations have uncovered the use of loose sheets of paper with subsequent selective transcriptions of good data to analyst worksheets and/or workbooks. Absorbance values and calculations have even been found on desk calendars.

 

Cut charts with injections missing, deletion of files in direct data entry systems, indirect data entry without verification, and changes to computerized programs to override program features should be carefully examined. These practices raise questions about the overall quality of data.

 

The firm should have a written explanation when injections, particularly from a series are missing from the official work-sheets or from files and are included among the raw data. Multiple injections recorded should be in consecutive files with consecutive injection times recorded. Expect to see written justification for the deletion of all files.

 

Determine the adequacy of the firm's procedures to ensure that all valid laboratory data are considered by the firm in their determination of acceptability of components, in-process, finished product, and retained stability samples. Laboratory logs and documents when cross referenced may show that data has been discarded by company officials who decided to release the product without a satisfactory explanation of the results showing the product fails to meet the specifications. Evaluate the justification for disregarding test results that show the product failed to meet specifications.

 

14. LABORATORY STANDARD

 

SOLUTIONS

 

Ascertain that suitable standards are being used (i.e. in-date, stored properly). Check for the reuse of stock solutions without assuring their stability. Stock solutions are frequently stored in the laboratory refrigerator. Examine the laboratory refrigerators for these solutions and when found check for appropriate identification. Review records of standard solution preparation to assure complete and accurate documentation. It is highly unlikely that a firm can "accurately and consistently weigh" to the same microgram. Therefore data showing this level of standardization or pattern is suspect and should be carefully investigated.

 

15. METHODS VALIDATION

 

Information regarding the validation of methods should be carefully evaluated for completeness, accuracy and reliability. In particular, if a compendial method exists, but the firm chooses to use an alternate method instead, they must compare the two and demonstrate that the in-house method is equivalent or superior to the official procedure. For compendial methods firms must demonstrate that the method works under the actual conditions of use.

 

Methods can be validated in a number of ways. Methods appearing in the USP are considered validated and they are considered validated if part of an approved ANDA. Also a company can conduct a validation study on their method. System suitability data alone is insufficient for and does not constitute method validation.

 

In the review of method validation data, it is expected that data for repetitive testing be consistent and that the varying concentrations of test solutions provide linear results. Many assay and impurity tests are now HPLC, and it is expected that the precision of these assays be equal or less than the RSD's for system suitability testing. The analytical performance parameters listed in the USP XXII, <1225>, under the heading of Validation of Compendial Methods, can be used as a guide for determining the analytical parameters (e.g., accuracy, precision, linearity, ruggedness, etc.) needed to validate the method.

 

16. EQUIPMENT

 

Laboratory equipment usage, maintenance, calibration logs, repair records, and maintenance SOPs also should be examined. The existence of the equipment specified in the analytical methods should be confirmed and its condition noted. Verify that the equipment was present and in good working order at the time the batches were analyzed. Determine whether equipment is being used properly.

 

In addition, verify that the equipment in any application was in good working order when it was listed as used to produce clinical or biobatches. One would have to suspect the data that are generated from a piece of equipment that is known to be defective. Therefore, continuing to use and release product on the basis of such equipment represents a serious violation of CGMP's.

 

17. RAW MATERIAL TESTING

 

Some inspections include the coverage of the manufacturer of the drug substance. The safety and efficacy of the finished dosage form is largely dependent on the purity and quality of the bulk active drug substance. Examine the raw data reflecting the analysis of the drug substance including purity tests, charts, etc.

 

Check the impurity profiles of the BPC used in the biobatch and clinical production batches to determine if it is the same as that being used to manufacture full scale production batches. Determine if the manufacturer has a program to audit the certificate of analysis of the BPC, and, if so, check the results of these tests. Report findings where there is substantial difference in impurity profiles and other test results.

 

Some older compendial methods may not be capable of detecting impurities as necessary to enable the control of the manufacturing process, and newer methods have been developed to test these products. Such methods must be validated to ensure that they are adequate for analytical purposes in the control and validation of the BPC manufacturing process. The drug substance manufacturer must have complete knowledge of the manufacturing process and the potential impurities that may appear in the drug substance. These impurities cannot be evaluated without a suitable method and one that has been validated.

 

Physical tests such as particle size for raw materials, adhesion tests for patches, and extrusion tests for syringes are essential tests to assure consistent operation of the production and control system and to assure quality and efficacy. Some of these tests are filed in applications and others may be established by the protocols used to manufacture the product. The validation of methods for such tests are as important as the test for chemical attributes.

 

Physical properties tests often require the use of unique equipment and protocols. These tests may not be reproducible in other laboratories, therefore, on site evaluation is essential.

 

18. IN PROCESS CONTROLS AND

 

SPECIFICATIONS

 

Evaluate the test results from in-process tests performed in the production areas or laboratory for conformance with established sampling and testing protocols, analytical methods, and specifications. For example, evaluate the tests for weight variation, hardness, and friability. These tests may be performed every fifteen or thirty minutes during tableting or encapsulating procedures. All testing must comply with CGMP's.

 

The drug application may contain some of the in-process testing plan, including methods and specifications. The inspection must confirm that the in-process tests were done, as described in the plan, and ascertain that the results were within specifications. The laboratory work for the lengthier tests should also be reviewed.

 

The methods used for in-process testing may differ from those used for release testings. Usually, whether the methods are the same or different, the specifications may be tighter for the in-process tests. A product with a 90.0%-110.0% assay release specification may have a limit of 95.%-105.0% for the in-process blend. Some of the tests done may differ from those done at release. For example, a firm may perform disintegration testing as an in-process test but dissolution testing as a release test.

 

Expect to see consistent in-process test results within batches and between batches of the same formulation/process (including development or exhibit batches). If this is not the case, expect to see scientific data to justify the variation.

 

19. STABILITY

 

A stability-indicating method must be used to test the samples of the batch. If there is no stability-indicating assay additional assay procedures such as TLC should be used to supplement the general assay method. Evidence that the method is stability indicating must be presented, even for compendial methods.

 

Manufacturers may be required to accelerate or force degradation of a product to demonstrate that the test is stability indicating. In some cases the sponsor of ANDA's may be able to search the literature and find background data for the specificity of a particular method. This information may also be obtained from the supplier of the drug substance. Validation would then be relatively straightforward, with the typical parameters listed in the USP in chapter <1225> on validation of compendial methods addressed as applicable.

 

Evaluate the manufacturer's validation report for their stability testing. Again, review the raw laboratory data and the results of testing at the various stations to determine if the data actually reported matches the data found in on site records.

 

Evaluate the raw data used to generate the data filed documenting that the method is stability indicating and the level of impurities.

 

20. COMPUTERIZED LABORATORY

 

DATA ACQUISITION SYSTEMS

 

The use of computerized laboratory data acquisition systems is not new and is addressed in the following CGMP guidance documents:

 

o Compliance Policy Guide 7132a.07 Computerized Drug Processing: Input/Output Checking.

 

o Compliance Policy Guide 7132a.08 Computerized Drug Processing: Identification of "Persons" on Batch Production and Control Records.

 

o Compliance Policy Guide 7132a.11 Computerized Drug Processing: CGMP Applicability to Hardware and Software

 

o Compliance Policy Guide 7132a.12 Computerized Drug Processing: Vendor Responsibility

 

o Compliance Policy Guide 7132a.15 Computerized Drug Processing: Source Code for Process Control Application Programs

 

o Guide to Inspection of Computerized Systems in Drug Processing.

 

It is important, for computerized and non computerized systems, to define the universe of data that will be collected, the procedures to collect it, and the means to verify its accuracy. Equally important are the procedure to audit data and programs and the process for correcting errors. Several issues must be addressed when evaluating computerized laboratory systems. These include data collection, processing, data integrity, and security.

 

Procedures should only be judged adequate when data are secure, raw data are not accidentally lost, and data cannot be tampered with. The system must assure that raw data are stored and actually processed.

 

The agency has provided some basic guidance on security and authenticity issues for computerized systems:

 

o Provision must be made so that only authorized individuals can make data entries.

 

o Data entries may not be deleted. Changes must be made in the form of amendments.

 

o The data base must be made as tamperproof as possible.

 

o The Standard Operating Procedures must describe the procedures for ensuring the validity of the data.

 

One basic aspect of validation of laboratory computerized data acquisition requires a comparison of data from the specific instrument with that same data electronically transmitted through the system and emanating on a printer. Periodic data comparisons would be sufficient only when such comparisons have been made over a sufficient period of time to assure that the computerized system produces consistent and valid results.

 

21. LABORATORY MANAGEMENT

 

Overall management of the laboratory work, its staff, and the evaluation of the results of analysis are important elements in the evaluation of a control laboratory. Span of supervisory control, personnel qualifications, turnover of analysts, and scope of the laboratory's responsibility are important issues to examine when determining the quality of overall management and supervision of work. Individually or collectively, these factors are the basis for an objection only when they are shown to result in inadequate performance of responsibilities required by the CGMPs.

 

Review laboratory logs for the sequence of analysis and the sequence of manufacturing dates. Examine laboratory records and logs for vital information about the technical competence of the staff and the quality control procedures used in the laboratory.

 

Observe analysts performing the operations described in the application. There is no substitute for actually seeing the work performed and noting whether good technique is used. You should not stand over the analysts, but watch from a distance and evaluate their actions.

 

Sometimes the company's employees have insufficient training or time to recognize situations that require further investigation and explanation. Instead they accept unexplained peaks in chromatograms with no effort to identify them. They may accept stability test results showing an apparent increase in the assay of the drug with the passage of time with no apparent question about the result. Also, diminishing reproducibility in HPLC chromatograms appearing several hours after system suitability is established is accepted without question.

 

Good manufacturing practice regulations require an active training program and the documented evaluation of the training of analysts.

 

The authority to delete files and override computer systems should be thoroughly examined. Evaluate the history of changes to programs used for calculations. Certain changes may require management to re-examine the data for products already released.

Dosage Form Drug Manufacturers cGMPs (10/93)  

GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURER'S - CGMPR'S

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).

 

I. INTRODUCTION

 

This document is intended to be a general guide to inspections of drug manufacturers to determine their compliance with the drug CGMPR's. This guide should be used with instructions in the IOM, other drug inspection guides, and compliance programs. A list of the inspection guides is referenced in Chapter 10 of the IOM. Some of these guides are:

 

o Guide to Inspections of Bulk Pharmaceutical Chemicals.

 

o Guide to Inspections of High Purity Water Systems.

 

o Guide to Inspections of Pharmaceutical Quality Control Laboratories.

 

o Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories.

 

o Guide to Inspections of Lyophilization of Parenterals.

 

o Guide to Inspections of Validation of Cleaning Processes.

 

o Guide to Inspections of Computerized Systems in Drug Processing.

 

o Guideline on General Principles of Process Validation.

 

II. CURRENT GOOD

 

MANUFACTURING PRACTICE

 

REGULATIONS

 

Prescription vs. Non-prescription

 

All drugs must be manufactured in accordance with the current good manufacturing practice regulations otherwise they are considered to be adulterated within the meaning of the FD&C Act, Section 501(a)(2)(B). Records relating to prescription drugs must be readily available for review in accordance with Sec. 704(a)(1)(B) of the FD&C Act. If the product is an OTC drug which is covered by an NDA or ANDA, FDA may review, copy and verify the records under Sec. 505(k)(2) of the FD&C Act. However, if the

product is an OTC drug for which there is no application filed with FDA, the firm is not legally required to show these records to the investigator during an inspection being conducted under Section 704 of the FD&C Act. Nonetheless, all manufacturers of prescription and OTC drugs must comply with the drug CGMPR requirements, including those involving records. The investigator should review these records as part of the inspection in determining the firm's compliance with the CGMP regulations. On rare occasions, a firm may refuse to allow review of OTC records stating they are not legally required to. While the firm may be under no legal obligation to permit review of such records, this does not relieve the firm of its statutory requirement to comply with the good manufacturing practices under section 501(a)(2)(B) of the Food Drug and Cosmetic Act, including the requirements for maintaining records.

 

If a firm refuses review of OTC records, the investigator should determine by other inspectional means the extent of the firm's compliance with CGMPR's. Inspectional observations and findings that CGMPR's are not being followed are to be cited on a List of Inspectional Observations, FDA-483, for both prescription and non-prescription drugs.

 

Organization and Personnel [21 CFR 211 Subpart B]

 

The firm must have a quality control department that has the responsibility and authority as described in the referenced CFR. The quality control department must maintain its independence from the production department, and its responsibilities must be in writing.

 

Obtain the name, title and individual responsibilities of corporate officers and other key employees as indicated in the IOM.

 

In the drug industry, an employee's education and training for their position has a significant impact on the production of a quality product. Report whether the firm has a formalized training program, and describe the type of training received. The training received by an employee should be documented.

 

Quality control must do product annual review on each drug manufactured, and have written annual review procedures. Review these reports in detail. This report will quickly let you know if the manufacturing process is under control. The report should provide a summary all lots that failed in-process or finished product testing, and other critical factors. Investigate any failures.

 

Quality control must validate the manufacturing process for each drug manufactured. Review and evaluate this data.

 

Buildings and Facilities [21 CFR 211 Subpart C]

 

Review the construction, size, and location of plant in relation to surroundings. There must be adequate lighting, ventilation, screening, and proper physical barriers for all operations including dust, temperature, humidity, and bacteriological controls. There must be adequate blueprints which describe the high purity water, HEPA, and compressed air systems. The site must have adequate locker, toilet, and hand washing facilities.

 

The firm must provide adequate space for the placement of equipment and materials to prevent mix-ups in the following operations:

 

o receiving, sampling, and storage of raw materials;

 

o manufacturing or processing;

 

o packaging and labeling;

 

o storage for containers, packaging materials, labeling, and finished products;

 

o production and control laboratories.

 

Equipment [21 CFR 211 Subpart D]

 

Review the design, capacity, construction, and location of equipment used in the manufacturing, processing, packaging, labeling, and laboratories. Describe the manufacturing equipment including brief descriptions of operating principles. Consider the use of photographs, flow charts, and diagrams to supplement written descriptions.

 

New equipment must be properly installed, and operate as designed. Determine if the equipment change would require FDA pre-approval and/or revalidation of the manufacturing process. The equipment must be cleaned before use according to written procedures. The cleaning must be documented and validated.

 

The equipment should not adversely effect the identity, strength, quality, or purity of the drug. The material used to manufacture the equipment must not react with the drug. Also, lubricants or coolants must not contaminate the drug.

 

The equipment should be constructed and located to ease cleaning, adjustments, and maintenance. Also, it should prevent contamination from other or previous manufacturing operations. Equipment must be identified as to its cleaning status and content. The cleaning and maintenance of the equipment are usually documented in a log book maintained in the immediate area. Determine if the equipment is of suitable capacity and accuracy for use in measuring, weighing, or mixing operations. If the equipment requires calibration, they must have a written procedure for calibrating the equipment and document the calibration.

 

Components and Product Containers [21 CFR 211 Subpart E]

 

Inspect the warehouse and determine how components, drug product containers, and closures are received, identified, stored, handled, sampled, tested, and approved or rejected. They must have written procedures which describe how these operations are done. Challenge the system to decide if it is functioning correctly. If the handling and storage of components are computer controlled, the program must be validated.

 

The receiving records must provide traceability to the component manufacturer and supplier. The receiving records for components should contain the name of the component, manufacturer, supplier if different from the manufacturer, and carrier. In addition, it should include the receiving date, manufacturer's lot number, quantity received, and control number assigned by the firm.

 

Check sanitary conditions in the storage area, stock rotation practices, retest dates, and special storage conditions (protection from light, moisture, temperature, air, etc.). Inspect glandular and botanical components for insect infestation.

 

Components or finished product adulterated by rodents, insects, or chemicals must be documented and submitted for seizure.

 

Collect the evidence even if the firm plans to voluntarily destroy the product. Be alert for components, colors, and food additives that may be new drug substances, appear to have no use in the plant or appear to be from an unknown supplier. Check the colors against the Color Additives Status List in the IOM Determine if the color is approved for its intended use, and required statements are declared on the drug label.

 

Components might be received at more than one location. Components must be handled in accordance with the drug CGMP's including components used in the research and development lab. Determine how components are identified after receipt and quarantined until released. Components must be identified so the status (quarantine, approved, or rejected) is known. Review the criteria for removing components from quarantine and challenge the system. Determine what records are maintained in the storage area to document the movement of components to other areas, and how rejected components handled. The component container has an identification code affixed to it. This unique code provides traceability from the component manufacturer to its use in the finished product.

 

Review the sampling and testing procedures for components, and the process by which approved materials are released for use. Decide if these practices are adequate and followed.

 

Determine the validity, and accuracy of the firm's inventory system for drug components, containers, closures and labeling. Challenge the component inventory records by weighing a lot and comparing the results against the quantity remaining on the inventory record. Significant discrepancies in these records should be investigated.

 

Evaluate the following to determine whether the firm has shown that the containers and closures are compatible with the product, will provide adequate protection for the drug against deterioration or contamination, are not additive or absorptive, and are suitable for use:

 

o Specifications for containers, closures, cotton filler, and desiccant, etc.

 

o What tests or checks are made (cracks, glass particles, durability of material, metal particles in ointment tubes, compliance with compendium specifications, etc.).

 

o Cleaning procedures and how containers are stored.

 

o Handling of preprinted containers. Are these controlled as labeling, or as containers? The firm must review the labeling for accuracy.

 

Production and Process Controls [21 CFR Subpart F]

 

1. Critical Manufacturing Steps [21 CFR 211.101]

 

Each critical step in the manufacturing process shall be done by a responsible individual and checked by a second responsible individual. If such steps in the processing are controlled by automatic mechanical or electronic equipment, its performance should be verified.

 

Critical manufacturing steps include the selection, weighing, measuring and identifying of components, and addition of components during processing. It includes the recording of deviations from the batch record, mixing time and testing of in-process material, and the determination of actual yield and percent of theoretical yield. These manufacturing steps are documented when done, and not before or after the fact.

 

2. Equipment Identification [21 CFR 211.105]

 

All containers and equipment used in to manufacture a drug should be labeled at all times. The label should identify the contents of the container or equipment including the

batch number, and stage of processing. Previous identification labels should be removed. The batch should be handled and stored to prevent mixups or contamination.

 

3. In-Line and Bulk Testing [21 CFR 211.110]

 

To ensure the uniformity and integrity of products, there shall be adequate in-process controls, such as checking the weights and disintegration time of tablets, the fill of liquids, the adequacy of mixing, the homogeneity of suspensions, and the clarity of solutions.

 

Determine if in-process test equipment is on site and the specified tests are done. Be alert for prerecording of test results such as tablet weight determinations.

 

The bulk drug is usually held in quarantine until all tests are completed before it is released to the packaging and labeling department. However, the testing might be done after packaging. product.

 

4. Actual Yield [21 CFR 211.103]

 

Determine if personnel check the actual against the theoretical yield of each batch of drug manufactured. In the event of any significant unexplained discrepancies, determine if there is a procedure to prevent distribution of the batch in question, and related batches.

 

5. Personnel Habits

 

Observe the work habits of plant personnel. Determine:

 

Their attitudes and actions involving the jobs they perform. (Careless, lackadaisical, disgruntled, etc.).

 

Their dress. (Clean dresses, coats, shirts and pants, head coverings, etc.

 

If proper equipment is used for a given job or whether short cuts are taken (i.e. use of hands and arms to mix or empty trays of drug components).

 

If there are significant written or verbal language barriers that could affect their job performance.

 

Tablet and Capsule Products

 

Become familiar with the type of equipment and its location in the tableting operation. The equipment may include rotary tableting machines, coating and polishing pans, punches and dies, etc. The equipment should be constructed and located to facilitate maintenance and cleaning at the end of each batch or at suitable intervals in the case of a continuous batch operation. If possible, observe the cleaning and determine if the cleaning procedure is followed.

 

The ingredients in a tablet are the active ingredient, binders, disintegrators, bases, and lubricants. The binder is added to the batch to keep the tablet together. Excess binder will make the tablet too hard for use. The disintegrator is used to help disintegration of the tablet after administration. The base should be an inert substance which is compatible with the active ingredient and is added to provide size and weight. The lubricant helps in the flow of granulated material, prevents adhesion of the tablet material to the surface of punches and dies, and helps in tablet ejection from the machine.

 

Tablets and capsules are susceptible to airborne contamination because of the manipulation of large quantities of dry ingredients. To prevent cross-contamination in the tableting department, pay close attention to the maintenance, cleaning, and location of equipment, and the storage of granulations and tablets. To prevent cross-contamination, the mixing, granulation, drying and/or tableting operation should be segregated in enclosed areas with its own air handling system. Determine what precautions are taken to prevent cross-contamination. When cross-contamination is suspect, investigate the problem and collect in-line samples(INV) and official samples of the suspect product. Determine what temperature, humidity, and dust collecting controls are used by the firm in manufacturing operations. Lack of temperature and humidity controls can affect the quality of the tablet.

 

Observe the actual operation of the equipment and determine whether powders or granulations are processed according to the firm's specifications. The mixing process must be validated. The drying ovens should have their own air handling system which will prevent cross-contamination. Does the firm record drying time/temperature and maintain recording charts including loss on drying test results? Review the in-line tests performed by production and/or quality control. Some in-process tests are tablet weight, thickness, hardness, disintegration , and friability. Evaluate the disposition of in-process samples.

 

Capsules may be either hard, or soft type. They are filled with powder, beads, or liquid by machine. The manufacturing operation of powders for capsules should follow the same practice as for tablets. Determine manufacturing controls used, in-line testing, and basis for evaluating test results for the filling operations.

 

Sterile Products

 

Typically, a sterile drug contains no viable microorganisms and is non-pyrogenic. Drugs for intravenous injection, irrigation, and as ophthalmic preparations, etc., meet this criteria. In addition, other dosage forms might be labeled as sterile. For instance, an ointment applied to a puncture wound or skin abrasion.

 

Parenteral drugs must be non-pyrogenic, because the presence of pyrogens can cause a febrile reaction in human beings. Pyrogens are the products of the growth of microorganisms. Therefore, any condition that permits bacterial growth should be avoided in the manufacturing process. Pyrogens may develop in water located in stills, storage tanks, dead legs, and piping, or from surface contamination of containers, closures, or other equipment. Parenterals may also contain chemical contaminants that will produce a pyretic response in humans or animals although there are no pyrogens present.

 

There are many excellent reference materials which should be reviewed before the inspection. Some of these are the "Guideline on Sterile Drug Products Produced by Aseptic Processing," and chapter 84 on pyrogens in the Remington's Pharmaceutical Sciences.

 

Determine and evaluate the procedures used to minimize the hazard of contamination with microorganisms and particulates of sterile drugs.

 

o Personnel

 

Review the training program to ensure that personnel performing production and control procedures have experience and training commensurate with their intended duties. It is important that personnel be trained in aseptic procedures. The employees must be properly gowned and use good aseptic techniques.

 

o Buildings

 

The non-sterile preparation areas for sterile drugs should be controlled. Refer to Subpart C of the proposed CGMPR's for LVP's; however, deviations from these proposed regulations are not necessarily deviations from the CGMPR's. Evaluate the air cleanliness classification of the area. For guidance in this area, review Federal Standard #209E entitled "Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones." Observe the formulation practices or procedures used in the preparation areas. Be alert for routes of contamination. Determine how the firm minimizes traffic and unnecessary activity in the preparation area. Determine if filling rooms and other aseptic areas are constructed to eliminate possible areas for microbiological/particulate contamination. For instance, dust-collecting ledges, porous surfaces, etc. Determine how aseptic areas are cleaned and maintained.

 

1. Air

 

Air supplied to the non-sterile preparation or formulation area for manufacturing solutions prior to sterilization should be filtered as necessary to control particulates. Air being supplied to product exposure areas where sterile drugs are processed and handled should be high efficiency particulate air (HEPA) filtered under positive pressure.

 

Review the firm's system for HEPA filters, determine if they are certified and/or Dioctyl Phthalate (DOP) tested and frequency of testing.

 

Review the compressed air system and determine if it is filtered at the point of use to control particulates. Diagrams of the HEPA filtered and compressed air systems should be reviewed and evaluated.

 

2. Environmental Controls

 

Specifications for viable and non-viable particulates must be established. Specifications for viable particulates must include provisions for both air and surface sampling of aseptic processing areas and equipment. Review the firm's environmental control program, specifications, and test data. Determine if the firm follows its procedure for reviewing out-of-limit test results. Also, determine if review of environmental test data is included as a part of the firm's release procedures.

 

Note: In the preparation of media for environmental air and surface sampling, suitable inactivating agents should be added. For example, the addition of penicillinase to media used for monitoring sterile penicillin operations and cephalosporin products.

 

o Equipment

 

Determine how the equipment operates including the cleaning and maintenance practices. Determine how equipment used in the filling room is sterilized, and if the sterilization cycle has been validated. Determine the practice of re-sterilizing equipment if sterility has been compromised.

 

Determine the type of filters used. Determine the purpose of the filters, how they are assembled, cleaned, and inspected for damage. Determine if a microbial retentive filter, and integrity testing is required.

 

o Water for Injection

 

Water used in the production of sterile drugs must be controlled to assure that it meets U.S.P. specifications. Review the firm's water for injection production, storage, and delivery system. Determine that the stills, filters, storage tanks, and pipes are installed and operated in a manner that will not contaminate the water. Evaluate the firm's

procedures and specifications that assure the quality of the water for injection. As reference material, review the "FDA Guide to Inspecteons of High Purity Water Systems" before initiating an inspection.

 

o Containers and Closures

 

Determine how containers and closures are handled and stored. Decide if the cleaning, sterilization, and depyrogenization are adequate, and have been validated.

 

o Sterilization

 

1. Methods

 

Determine what method of sterilization is used. A good source of reference material on validation of various sterilization processes is the Parenteral Drug Association Technical Reports. For instance, Technical Report #1 covers "Validation of Steam Sterilization Cycles." Review and evaluate the validation data whatever the method employed.

 

If steam under pressure is used, an essential control is a mercury thermometer and a recording thermometer installed in the exhaust line. The time required to heat the center of the largest container to the desired temperature must be known. Steam must expel all air from the sterilizer chamber to eliminate cold spots. The drain lines should be connected to the sewer by means of an air break to prevent back siphoning. The use of paper layers or liners and other practices which might block the flow of steam should be avoided. Charts of time, temperature, and pressure should be filed for each sterilizer load.

 

If sterile filtration is used, determine the firm's criteria for selecting the filter and the frequency of changing. Review the filter validation data. Determine if the firm knows the bioburden of the drug, and examine their procedures for filter integrity testing. Filters might not be changed after each batch is sterilized. Determine if there is data to justify the integrity of the filters for the time used and that "grow through" has not occurred.

 

If ethylene oxide sterilization is used, determine what tests are made for residues and degradation. Review the ETO sterilization cycle including preconditioning of the product, ETO concentration, gas exposure time, chamber and product temperature, and chamber humidity.

 

2. Indicators

 

Determine the type of indicator used to assure sterility. Such as, lag thermometers, peak controls, Steam Klox, test cultures, biological indicators, etc.

 

Caution: When spore test strips are used to test the effectiveness of ethylene oxide sterilization, be aware that refrigeration may cause condensation on removal to room temperature. Moisture on the strips converts the spore to the more susceptible vegetative forms of the organism which may affect the reliability of the sterilization test. The spore strips should not be stored where they could be exposed to low levels of ethylene oxide.

 

If biological indicators are used, review the current U.S.P. on sterilization and biological indicators. In some cases, testing biological indicators may become all or part of the sterility testing.

 

Biological indicators are of two forms, each of which incorporates a viable culture of a single species of microorganism. In one form, the culture is added to representative units of the lot to be sterilized or to a simulated product that offers no less resistance to sterilization than the product to be sterilized. The second form is used when the first form is not practical as in the case of solids. In the second form, the culture is added to disks or strips of filter paper, or metal, glass, or plastic beads.

 

During the inspection of a firm which relies on biological indicators, review background data complied by the firm to include:

 

o Surveys of the types and numbers of organisms in the product before sterilization.

 

o Data on the resistance of the organism to the specific sterilization process.

 

o Data used for selecting the most resistant organism and its form (spore or vegetative cell).

 

o Studies of the stability and resistance of the selected organism to the specific sterilization process.

 

o Studies on the recovery of the organism used to inoculate the product.

 

o If a simulated product or surface similar to the solid product is used, validation of the simulation or similarity. The simulated product or similar surface must not affect the recovery of the numbers of indicator organisms applied.

 

o Validation of the number of organisms used to inoculate the product, simulated product, or similar surface, to include stability of the inoculum during the sterilization process.

 

Since qualified personnel are crucial to the selection and application of these indicators, review their qualifications including experience dealing with the process, expected contaminants, testing of resistance of organisms, and technique.

 

Review the firm's instructions regarding use, control and testing, of the biological indicator by product including a description of the method used to demonstrate presence or absence of viable indicator in or on the product.

 

Review the data used to support the use of the indicator each time it is used. Include the counts of the inoculum used; recovery data to control the method used to demonstrate the sterilization of the indicator organism; counts on unprocessed, inoculated material to

 

indicate the stability of the inoculum for the process time; and

 

results of sterility testing specifically designed to demonstrate the presence or absence of the indicator organism for each batch or filling operation.

 

In using indicators, you must assure yourself that the organisms are handled so they don't contaminate the drug manufacturing area and product.

 

3. Filled Containers

 

Evaluate how the filled vials or ampules leave the filling room. Is the capping or sealing done in the sterile fill area? If not, how is sterility maintained until capped?

 

Review the tests done on finished vials, ampules, or other containers, to assure proper fill and seal. For instance, leak and torque tests.

 

Review examinations made for particulcte contamination. You can quickly check for suspected particulate matter by using a polariscope. Employees doing visual examinations on line must be properly trained. If particle counts are done by machine, this operation must be validated.

 

4. Personnel Practices

 

Check how the employees sterilize and operate the equipment used in the filling area.

 

Observe filling room personnel practices. Are the employees properly dressed in sterile gowns, masks, caps, and shoe coverings? Observe and evaluate the gowning procedures, and determine if good aseptic technique is maintained in the dressing and filling rooms.

 

Check on the practices after lunch and other absences. Is fresh sterile garb supplied, or are soiled garments reused?

 

Determine if the dressing room is next to the filling area and how employees and supplies enter the sterile area.

 

o Laboratory Controls

 

For guidance on how to inspect micro and chemistry labs, review the "FDA Guide to Inspections of Pharmaceutical Quality Control Laboratories" and "FDA Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories."

 

1. Retesting for Sterility

 

See the USP for guidance on sterility testing. Sterility retesting is acceptable provided the cause of the initial non-sterility is known, and thereby invalidates the original results. It cannot be assumed that the initial sterility test failure is a false positive. This conclusion must be justified by sufficient documented investigation. Additionally, spotty or low level contamination may not be identified by repeated sampling and testing.

 

Review sterility test failures and determine the incidence, procedures for handling, and final disposition of the batches involved.

 

2. Retesting for Pyrogens

 

As with sterility, pyrogen retesting can be performed provided it is known that the test system was compromised. It cannot be assumed that the failure is a false positive without documented justification.

 

Review any initial pyrogen test failures and determine the firm's justification for retesting.

 

3. Particulate Matter Testing

 

Particulate matter consists of extraneous, mobile, undissolved substances, other than gas bubbles, unintentionally present in parenteral solutions.

 

Cleanliness specifications or levels of non-viable particulate contamination must be established. Limits are usually based on the history of the process. The particulate matter test procedure and limits for LVP's in the U.S.P. can be used as a general guideline. However, the levels of particulate contamination in sterile powders are generally greater than in LVP's. LVP solutions are filtered during the filling operation. However, sterile powders, except powders lyophilized in vials, cannot include filtration as a part of the filling operation. Considerable particulate contamination is also present in sterile powders which are spray dried due to charring during the process.

 

Review the particulate matter test procedure and release criteria. Review production and control records of any batches for which complaints of particulate matter have been received.

 

o Production Records

 

Production records should be similar to those for other dosage forms. Critical steps, such as integrity testing of filters, should be signed and dated by a second responsible person.

 

Review production records to ensure that directions for significant manufacturing steps are included and reflect a complete history of production.

 

Ointments, Liquids, and Lotions

 

Major factors in the preparation of these drugs are the selection of raw materials, manufacturing practices, equipment, controls, and laboratory testing.

 

Following the basic drug inspection fundamentals, fully evaluate the production procedures. In addition, evaluate specific information regarding:

 

o The selection and compatibility of ingredients.

 

o Whether the drug is a homogeneous preparation free of extraneous matter.

 

o The possibility of decomposition, separation, or crystallization of ingredients.

 

o The adequacy of ultimate containers to hold and dispense contents.

 

o Procedure for cleaning the containers before filling.

 

o Maintenance of homogeneity during manufacturing and filling operations.

 

The most common problem associated with the production of these dosage forms is microbiological contamination caused by faulty design and/or control of purified water systems. During inspections, evaluate the adequacy of the water system. Review and evaluate the micro/chemistry test results on the routine monitoring of the water system including validation of the water system. Review any microbiological tests done on the finished drug including in-process testing.

 

Some of these drugs have preservatives added which protect them from microbial contamination. The preservatives are used primarily in multiple-dose containers to inhibit the growth of microorganisms introduced inadvertently during or after manufacturing. Evaluate the adequacy of preservative system. Preservative effectiveness testing for these products should be reviewed. For additional information, review the "Antimicrobial Preservatives-Effectiveness" section of the U.S.P..

 

Equipment employed for manufacturing topical drugs is sometimes difficult to clean. This is especially true for those which contain insoluble active ingredients, such as the sulfa drugs. The firm's equipment cleaning procedures including cleaning validation data should be reviewed and evaluated.

 

Packaging and Labeling [21 CFR Subpart G]

 

Packaging and labeling operations must be controlled so only those drugs which meet the specifications established in the master formula records are distributed. Review in detail the packaging and labeling operations to decide if the system will prevent drug and label mix-ups. Approximately 25% of all drug recalls originate in this area.

 

Evaluate what controls or procedures the firm has to provide positive assurance that all labels are correct. Determine if packaging and labeling operations include:

 

o Adequate physical separation of labeling and packaging operations from manufacturing process.

 

o Review of:

 

1. Label copy before delivery to the printer.

 

2. Printer's copy.

 

3. Whether firm's representative inspects the printer.

 

4. Whether or not gang printing is prohibited.

 

5. Whether labels are checked against the master label before released to stock. Determine who is responsible for label review prior to release of the labels to production. Also, whether the labels are identical to the labeling specified in the batch production records.

 

o Separate storage of each label (including package inserts) to avoid mixups.

 

o Inventory of label stocks. Determine if the printer's count is accepted or if labels are counted upon receipt.

 

o Designation of one individual to be responsible for storage and issuance of all labels.

 

o Receipt by the packaging and labeling department of a batch record, or other record, showing the quantity of labels needed for a batch. Determine if the batch record is retained by the packaging supervisor or accompanies the labels to the actual packaging and labeling line.

 

o Adequate controls of the quantities of labeling issued, used, and returned. Determine if excess labels are accounted for and if excess labels bearing specific control codes, and obsolete or changed labels are destroyed.

 

o Inspection of the facilities before labeling to ensure that all previously used labeling and drugs have been removed.

 

o Assurance that batch identification is maintained during packaging.

 

o Control procedures to follow if a significant unexplained discrepancy occurs between quantity of drug packaged and the quantity of labeling issued.

 

o Segregated facilities for labeling one batch of the drug at a time. If this is not practiced, determine what steps are taken to prevent mix-ups.

 

o Methods for checking similar type labels of different drugs or potencies to prevent mixing.

 

o Quarantine of finished packaged products to permit adequate examination or testing of a representative sample to safeguard against errors. Also, to prevent distribution of any batch until all specified tests have been met.

 

o An individual who makes the final decision that the drug should go to the warehouse, or the shipping department.

 

o Utilization of any outside firms, such as contract packers, and what controls are exercised over such operations.

 

Special attention should be devoted to firms using "rolls" of pressure sensitive labels. Investigators have found instances where:

 

o Paper chips cut from label backing to help running the labels through a coder interfered with the code printer causing digits in the lot number to be blocked out.

 

o Some rolls contained spliced sections resulting in label changes in the roll.

 

o Some labels shifted on the roll when the labels were printed resulting in omitting required information.

 

The use of cut labels can cause a significant problem and should be evaluated in detail. Most firms are replacing their cut labels with roll labels.

 

Review prescription drugs for which full disclosure information may be lacking. If such products are found, submit labels and other labeling as exhibits with the EIR See 21 CFR 201.56 for the recommended sequence in which full disclosure information should be presented.

 

Review labels of OTC products for warnings required by 21 CFR 369.

 

A control code must be used to identify the finished product with a lot, or control number that permits determination of the complete history of the manufacture and control of the batch.

 

Determine:

 

o The complete key (breakdown) to the code.

 

o Whether the batch number is the same as the control number on the finished package. If not, determine how the finished package control number relates, and how it is used to find the identity of the original batch.

 

Beginning August 3, 1994 the following new requirements will become effective:

 

o Use of gang-printed labels will be prohibited unless they are adequately differentiated by size, shape or color. (211.122(f))

 

o If cut labels are used one of the following special control procedures shall be used (211.122(g)):

 

(1) Dedication of packaging lines.

 

(2) Use of electronic or electromechanical equipment to conduct a 100-percent examination of finished product.

 

(3) Use of visual inspection to examine 100-percent of the finished product for hand applied labeling. The visual examination will be conducted by one person and independently verified by a second person.

 

o Labeling reconciliation required by 211.125 is waived for cut or roll labeling if a 100-percent examination is performed according to 211.22(g)(2).

 

Holding and Distribution [21 CFR subpart H]

 

Check the finished product storage and shipping areas for sanitary condition, stock rotation, and special storage conditions needed for specific drugs. Evaluate any drugs that have been rejected, or are on hold for other than routine reasons.

 

Laboratory Controls [21 CFR Subpart I]

 

Laboratory controls should include adequate specifications and test procedures to assure that components, in-process and finished products conform to appropriate standards of identity, strength, quality, and purity.

 

In order to permit proper evaluation of the firm's laboratory controls, determine:

 

o Whether the firm has established a master file of specifications for all raw materials used in drug manufacture. This master file should include sampling procedures, sample size, number of containers to be sampled, manner in which samples will be identified, tests to be performed, and retest dates for components subject to deterioration.

 

o The firm's policies about protocols of assay. These reports are often furnished by raw material suppliers; however, the manufacturer is responsible for verifying the validity of the protocols by periodically performing their own complete testing and routinely conducting identity tests on all raw materials received.

 

o Laboratory procedure for releasing raw materials, finished bulk drugs or packaged drugs from quarantine. Determine who is responsible for this decision. Raw material specifications should include approved suppliers. For NDA or ANDA drugs, the approved suppliers listed in their specifications should be the same as those approved in the NDA or ANDA.

 

o If the laboratory is staffed and equipped to do all raw material, in-process, and finished product testing that is claimed.

 

o Whether drug preparations are tested during processing. If so, determine what type of tests are made and whether a representative sample is obtained from various stages of processing.

 

o Specifications and description of laboratory testing procedures for finished products.

 

o Procedures for checking the identity and strength of all active ingredients including pyrogen and sterility testing, if applicable.

 

o If the laboratory conducts pyrogen tests, safety tests, or bioassays; determine the number of laboratory animals and if they are adequately fed and housed. Determine what care is provided on weekends and holidays.

 

o Sterility testing procedures.

 

Entries should be permanently recorded and show all results, both positive and negative. Examine representative samples being tested and their records. When checking the sterility testing procedures, determine:

 

1. Physical conditions of testing room. The facility used to conduct sterility testing should be similar to those used for manufacturing products.

 

2. Laboratory procedures for handling sterile sample.

 

3. Use of ultra-violet lights.

 

4. Number of units tested per batch.

 

5. Procedure for identifying test media with specific batches.

 

6. Test media's ability to support growth of organisms.

 

7. Length of incubation period.

 

8. Procedure for diluting products to offset the effects of bacteriostatic agents.

 

o Pyrogen testing procedures

 

Determine if animals involved in positive pyrogen tests are withdrawn from use for the required period.

 

If the L.A.L. Test is used, review the FDA "Guideline on Validation of the Limulus Amebocyte Lysate Test ***."

 

o If any tests are made by outside laboratories, report the names of the laboratories and the tests they perform. Determine what precautions the firm takes to insure that the laboratories' work is bona fide.

 

o Methods used to check the reliability, accuracy, and precision of laboratory test procedures and instrumentation.

 

o How final acceptance or rejection of raw materials, intermediates, and finished products is determined. Review recent rejections and disposition of affected items.

 

o The provisions for complete records of all data concerning laboratory tests performed, including dates and endorsements of individuals performing the tests, and traceability.

 

o For components and finished product, the reserve sample program and procedures should be evaluated. Challenge the system and determine if the samples are maintained and can be retrieved. The storage container must maintain the integrity of the product.

 

o Whether stability tests are performed on:

 

1. The drug product in the container and closure system in which marketed.

 

2. Solutions prepared as directed in the labeling at the time of dispensing. Determine if expiration dates, based on appropriate stability studies, are placed on labels.

 

o If penicillin and non-penicillin products are manufactured on the same premises, whether non-penicillin products are tested for penicillin contamination.

 

Obtain copies of laboratory records, batch records, and any other documents that show errors or other deficiencies.

 

Control Records [21 CFR Subpart J]

 

1. Master Production and Control Records [21 CFR 211.186]

 

The various master production and control records are important because all phases of production and control are governed by them. Master records, if erroneous, may adversely affect the product. These records must be prepared according to the drug CGMPR's outlined in 21 CFR 211.186. These records might not be in one location, but should be readily available for review.

 

2. Batch Production and Control Records [21 CFR 211.188]

 

The batch production and control records must document each significant step in the manufacture, labeling, packaging, and control of specific batches of drugs. 21 CFR 211.188 provides the basic information the batch records must provide. A complete production and control record may consist of several separate records which should be readily available to the investigator.

 

Routinely check the batch record calculations against the master formula record. Give special attention to those products on which there have been complaints.

 

Be alert for transcription errors from the master formula record to the batch record. Be alert for transcription or photocopying errors involving misinterpretation of symbols, abbreviations, and decimal points, etc.

 

It is important that batch production records be specific in terms of equipment (v-blender vs. ribbon blender) and processing times (mixing time and speed). The equipment should have its own unique identification number. The manufacturing process for these products must be standardized, controlled, and validated.

 

3. Distribution [21 CFR 211.196]

 

Complete distribution records should be maintained per 21 CFR 211.196. Be alert for suspicious shipments of products subject to abuse or which have been targeted for high priority investigation by the agency. These include steroids, counterfeits, diverted drugs (i.e.; physician samples, clinical packs, etc.).

 

Determine and evaluate if the firm checks on the authenticity of orders received. What references are used, e.g. current editions of the AMA Directory, Hays Directory, etc.

 

4. Complaint Files [21 CFR 211.198]

 

21 CFR 211.198 requires that records of all written and oral complaints be maintained. Although FDA has no authority to require a drug firm, except for prescription drugs, to open its complaint files, attempt to review the firm's files.

 

The complaint files should be readily available for review. Do a follow-up investigation on all applicable consumer complaints in the firm's district factory jacket. Review and evaluate the firm's procedures for handling complaints. Determine if all complaints are handled as complaints and not inappropriately excluded.

 

Review the complaints and determine if they were fully investigated. Evaluate the firm's conclusions of the investigation, and determine if appropriate corrective action was taken. Determine if the product should be recalled, or warrant a comprehensive investigation by FDA

 

Returned Drug Products [21 CFR Subpart K]

 

Returned drugs often serve as an indication that products may have decomposed during storage, are being recalled or discontinued.

 

Determine how returned drug items are handled. For example, are they quarantined, destroyed after credit, or returned to storage?

 

If an abnormally large amount of a specific drug item is on hand, determine why. Check if returned drug items are examined in the laboratory, and who makes the ultimate decision as to the use of the returned drugs.

 

Note: Dumping salvage drugs in the trash is a potentially dangerous practice. Advise management to properly dispose of the drugs to preclude salvage. Drugs should be disposed of in accordance with E.P.A. regulations.

Oral Solid Dosage Forms Pre/Post Approval Issues (1/94) 

GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATION

January, 1994

 

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).

 

I INTRODUCTION

 

This inspection guide provides information regarding the inspection and evaluation of the manufacturing and control processes used to manufacture solid oral dosage form pharmaceutical products. This document provides guidance for the FDA investigator and promotes uniformity and consistency during the inspection and evaluation of the validation of the solid oral dosage form manufacturing and control processes. It covers three phases of the validation process; product development, design of the validation protocol, and demonstration runs (validation) of the equipment and process in the manufacture of full scale commercial production batches.

 

Although this document it is not all inclusive, it addresses many of the issues and examples of validation problems of oral solid dosage forms which investigators and analysts may encounter. The inspection team is expected to review other agency documents in preparation for these inspections.

 

The Validation Guideline issued by the agency in 1987 defines process validation as establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.

 

The three components of this definition include documented evidence, consistency, and predetermined specifications. Documented evidence includes the experiments, data and analytical results that support the master formula, the in-process and finished product specifications, and the filed manufacturing process.

 

With regard to consistency, several batches would have to be manufactured, using the full scale batch size, to demonstrate that a process meets the consistency test. At least three batches are needed to demonstrate consistency.

 

The development of a product and its manufacturing process and specifications, the design of the validation protocol, and the demonstration (validation) runs of the full scale manufacturing process requires scientific judgement based on good scientific data. We expect that in-process control and product specifications will be established during the product development process, with the test batch serving as the critical batch used for the establishment of specifications.

 

Specifications, such as hardness and particle size, should be established prior to validation of the process; these specifications should be included in the validation protocol. The use of product development runs of the process to establish both specifications and demonstrate that the system is validated often causes problems. In these cases, more in-depth inspection and evaluation will be required; some of these process runs often produce failing product because the product specifications have not been fully established and tested.

 

The inspection team should observe facilities, equipment and processes to put data review in proper context. It is also important that raw data, including validation and laboratory logbooks be audited or reviewed to verify accuracy and authenticity.

 

II BACKGROUND

 

Two common complaints regarding validation issues frequently have been raised. The first concerns the misconception that the 1987 validation guide represents a new requirement. The second concerns the lack of specificity in the agency's guides. In 1978, the Current Good Manufacturing Practice Regulations were revised and provided for process validation. Therefore this guideline does not represent a new requirement. The regulation is nearly 15 years old.

 

Both the agency and the industry have recognized the need to establish general guidance for the validation of manufacturing processes, and the agency published a draft guideline in March, 1983. However this draft guideline was a very general document addressing general principles and was applicable to sterile and non-sterile drugs and devices. In March, 1984, it was reissued as a draft guideline, and was finalized in May, 1987.

 

The 1987 validation guideline merely points out the need to adequately develop and control manufacturing processes. It discusses microbiological issues and provides few specific an practical applications for the validation of manufacturing processes for a marketed solid oral dosage form.

 

The issue of retrospective validation, and its application to marketed products, is frequently encountered. This concept of using historical data (test results), along with process control and process specificity was of value until more scientific methods for demonstrating process validation evolved. It should be pointed out that retrospective validation is not merely the review of test results. It also requires that the manufacturing process be specific and the same each time a batch is manufactured. Thus, specific raw material specifications (including particle size when necessary), in-process specifications (tablet hardness, etc.), and specific manufacturing directions are required. Obviously, any failing batches attributed to the process would necessitate the conclusion that the process is not validated and is inadequate.

 

Prospective process validation is required, particularly for those products introduced in the last 7 to 8 years, or those for which manufacturing changes have been made. However, in some cases where older products have been on the market without sufficient pre-market process validation, it may be possible to validate, in some measure, the adequacy of the process by examination of accumulated test data on the product and records of the manufacturing procedures used.

 

III PRODUCT DEVELOPMENT

 

A. PRODUCT DEVELOPMENT REPORTS

 

There is no statute or regulation that specifically requires a product development report, although companies are required to produce scientific data which justifies the formulation and the manufacturing and control processes. Most companies have used product development reports, technology transfer reports, and others to summarize the scientific data that justifies the product and process. The product development report should satisfy the needs of the company. Therefore, there is no specific format for the contents of the report.

 

It is suggested that the company develop a product development SOP which describes the development process, the documentation requirements, and the individuals

responsible for approving the filed process. This SOP can be brief and again there is no legal requirement that companies produce such an SOP.

 

Investigators must not list the absence and or the poor quality of a product development report on the FDA 483. The investigators should list or include the inadequacy of data to support the filed process and specific Master Formula filed. It is not a GMP deficiency nor is it a filing requirement to have a formal Development Report. Investigators should review product development reports since they will reduce the time required to inspect the process.

 

The development data found in these reports should include the following:

 

 

 

1. Drug Substance Characterization

 

Characterization of the chemical and physical properties of the drug substance is one of the most important steps in the development of a solid dosage form. Chemical properties especially the identification of impurities are very important. In addition, the physical properties of the BPC such as solubility, polymorphism, hygroscopicity, particle size, density, etc. must be addressed.

 

The literature, and actual experience demonstrates, that the physical quality, e.g., particle size of raw materials, can sometimes produce a significant impact on the availability and clinical effect of a dosage form drug. Therefore, it is appropriate that the physical characteristics of a drug substance be characterized, that the impact of the physical characteristics be determined and that a specification for the bulk drug product be established if necessary.

 

Development data will vary between new drugs and generics. Characterization and establishment of specifications for the drug substance is one example. In most cases the manufacturing process for a new drug substance (new chemical entity) is developed and scaled-up before the dosage form. In early development stages very little information is available regarding polymorphic forms, solubility, etc. Consequently, changes to the manufacturing process for the drug substance may change the purity profile or physical characteristics and thus cause problems with the finished dosage form. Although these

types of problems are expected, the firm must investigate and document batch failures for the BPC and dosage form product.

 

On the other hand the generic manufacturer usually purchases the drug substance from a BPC manufacturer who may not be willing to supply information regarding the synthesis or analysis of the drug substance. Therefore, the finished dosage form manufacturer must perform the appropriate test to characterize the drug substance chemically and physically and establish appropriate specifications. This may require developing analytical methods to identify impurities. In some cases this information can be obtained from literature searches.

 

In either case it is important that the firm compare the drug substance used to manufacturer the bio-batch or clinical batch(es) and the drug substance used for the commercial batches. Therefore, review the specifications, analytical methods, and test results for the lots of the drug substance used to manufacture these batches. Remember that the safety of the drug may be based upon the type and level of impurities and different physical characteristics may affect dissolution or content uniformity.

 

Inspectional coverage should be given to the physical characteristics of raw materials, especially bulk drug substances, since they frequently affect the performance of the dosage form in which they are incorporated. This is particularly important for those drug substances that are poorly soluble in water.

 

For those products on which biostudies were conducted, the physical characteristics of the drug substance used for the study should serve as the basis for the physical specifications.

 

It is widely recognized that when discussing in-vivo release rates and drug absorption rates, fast, immediate release is not always best. For some "immediate" release drug products, such as carbamazepine tablets, a slower release is desired. Therefore, it is frequently desirable to have minimum and maximum particle size specifications to control the release rate. For example, micronizing or milling a drug substance and providing greater surface area of the substance may also result in faster dissolution and possibly faster absorption and higher blood levels. Such changes to "improve" the dissolution may not always be desired.

 

In addition to release or dissolution, variation in particle size, particle shape, and/or bulk density can also have an effect on the uniformity of dosage forms, particularly those manufactured by direct compression or direct encapsulation.

 

Particulate solids, once mixed, have a tendency to segregate by virtue of differences in the shape, size and density (other variables are also important) of the particles of which they are composed. This process of separation occurs during mixing, as well as during subsequent handling of the completed mix. Generally, large differences in particle size, density or shape within the mixture result in instability in the mixture. The segregation process normally requires energy input and can be reduced following mixing by careful handling.

 

Some manufacturers have established wide ranges for specifications. Investigators should review these specifications from a GMP and validation perspective. Even though a wide range for a physical specification, such as particle size or surface area may be established in a filing, it is expected that such ranges be verified in the validation of the process. In a recent court decision the judge ruled that companies cannot hide behind the approval of processes listed in an application when these processes do not work. In other words the approval of the filing has no impact on processes that do not perform consistently.

 

For example, in a filed process it was determined that particle size would have no effect on drug absorption and dissolution and a wide range particle size specification was established. However, in the GMP review, it was found that variation in particle size had a major effect on content uniformity. Therefore, a tighter particle size specification had to be established.

 

Control of the physical characteristics of the excipient is also important because variations in such characteristics may also affect the performance of the dosage form. Changes in particle size of some excipients, for example, may affect content uniformity. In other cases, a change in the supplier of an excipient or lubricant may affect dissolution or bioavailability. In fact, the release of the active ingredients in some products is "timed" by varying lubricant blending time and concentration. The literature contains many examples of lubricant processing causing major changes. Such changes in excipients illustrate the deficiencies with the utilization of retrospective validation because, for such validation to be satisfactory, control of all parameters and key steps in the process are necessary.

 

The control of mixing times and physical characteristics of all ingredients is critical to successful validation of all formulations and processes. A major question that must be

addressed is the need for testing physical characteristics (particle size) for each batch of excipient. For many single source excipients, particle size is a supplier specification and is usually tightly controlled. Having established a specification and not testing each lot of excipient upon receipt may be satisfactory in such cases. However, for some multi-source excipients and where the dosage formulator expects to shift sources of supply, there may be differences in physical characteristics (particle size) that may have an effect on dose uniformity and dissolution. Examine the practices with respect to the source of supply of the key excipients and determine if there is justification for the lack of testing lots of excipient for physical characteristics.

 

2. Manufacturing Procedures

 

Procedures used to manufacture development batches must be specific and well documented. This is necessary for scale-up and subsequent comparison to the commercial process.

 

This is another area where you will see differences between NDA/NADA and ANDA/ANADA products. In the case of the NDA/NADA you will see several clinical and/or test batches manufactured over a period of time and you would expect to see changes in the process as more is learned about the drug and the process. The level of documentation should increase as the process becomes more defined and the firm begins phase II and III studies.

 

The generic product focus is on the biobatch. Again the process used to manufacturer the biobatch must be well defined and well documented. Also the firm should have worked with the process by means of test batches so they can reproduce the biobatch. Therefore you would expect to see more than one batch made at this stage of the development process.

 

 

 

3. In-process Testing

 

Specific specifications required to control the manufacturing process must be established and justified. This will require granulation studies which would include

blend uniformity, sieve analysis, and moisture. Read the section under, "Demonstration Runs of the Process (Validation of Process)" for more information.

 

4. Finished Product Testing

 

Testing for the monograph standards such as content uniformity (when a specification applies), assay, hardness, friability, dissolution, and others are essential.

 

5. Dissolution Profile

 

The dissolution profiles for the biobatch or pivotal clinical batches should be evaluated in the product development report. There should be good correlation to the dissolution specifications and test results for the biobatch/clinical test batches and the full scale commercial process.

 

6. Stability

 

The Center for Drugs conducts an evaluation of the stability data and approves the expiration date. The product development report should contain an evaluation of the stability data that has been obtained.

 

During post-approval inspections stability data is reviewed by the field. Therefore, the investigator must audit underlying raw data and analytical worksheets to assure the accuracy and authenticity of stability data contained in summary reports.

 

B. PRE-APPROVAL INSPECTIONS

 

Validation of three full size commercial lots is not required for approval of the application, however the firm must have data that justifies the full scale commercial process filed in the NDA/ANDA or NADA/ANADA application. In other words, the firm should have sufficient research on the test batches to establish specifications for the manufacturing and control procedures listed in the application. These data and

specifications form the basis for the validation protocol which may be developed following approval of the application. The final step in the process is the demonstration (validation) runs proving that the process will perform consistently. Firms should validate the process using the specifications listed in the filing.

 

To evaluate the proposed manufacturing process the following areas must be covered during the pre-approval inspection:

 

1. Master Formula

 

This document must include specific manufacturing directions for the full scale commercial process including in-process and finished product specifications.

 

Compare the process filed in the application to the process used to manufacturer the bio/clinical batch. In some cases the process may be different after scale-up. This is acceptable if the firm has data showing the product produced by this process will be equivalent. Data such as granulation studies, finished product test results, and dissolution profiles are used to document that the two processes are equivalent.

 

2. History Section of the Application

 

This section of the application is used to identify the biobatch or batches used for pivotal clinical studies. It is also useful for review of the correspondence between the firm and CDER/CVM. One of the basic objectives of our review is to identify the biobatch. Also, any batches in which in-vivo studies were carried out, and particularly those which in-vivo studies showed inequivalency should be reviewed.

 

3. Development Data (Product Development Report)

 

The firm cannot logically proceed to the validation step without some prior evaluation of the process. During the development phase the critical process parameters must be identified and specifications established. These predetermined specifications must be established during the development of the process, with the biobatch or pivotal clinical batch serving as the reference batch.

 

Development of a solid dosage form will vary from firm to firm and will be dependent upon the specific product and process. However, the formula ranges, physical and chemical specifications of the drug substance and excipients, in-process variables, interaction effects of the dosage form ingredients under normal and stress aging conditions, should be confirmed by limited challenge in pilot-scale and production-size batches.

 

This development data serves as the foundation for the manufacturing procedures, specifications and validation of the commercial process. In some cases, manufacturers have attempted to establish specifications such as hardness and particle size during validation. However, as the validation definition states, specifications must be determined prior to validation of the process.

 

When a manufacturer files a manufacturing process in an application, we expect that the process will yield a product which is equivalent to the product on which the biostudy or pivotal clinical study was conducted. Therefore, it is important that the development and scale-up of the process be well documented so that a link between the bio/clinical batches and the commercial process can be established. The firm should have data such as granulation studies, finished product test results, and dissolution profiles which may be used to document that the two processes are equivalent.

 

In most cases in vitro data alone will not be sufficient to document equivalency. Determine if an equivalency evaluation has been made. This bioequivalency evaluation must be made by qualified individuals, and the firm should have a signed statement documenting that the processes are equivalent. Therefore, in many cases you may see an in-vivo bioequivalency study performed. Obviously, the firm cannot provide this type of data if the have not manufactured pilot or test batches using the types of equipment an controls specified in the proposed master formula.

 

 

 

4. Inspection of the Facilities

 

It is important that you physically inspect the facility to assure that the area and the ancillary equipment such as air handling and water systems are suitable for the proposed manufacturing process. Construction of new walls, installation of new equipment, and

other significant changes must be evaluated for their impact on the overall compliance with GMP requirements. This includes facilities used for development batches and to be used for full-scale production batches.

 

5. Raw Materials

 

Review the information contained in the Raw Material section under Product Development Report above. Inventory records are a good source for the identification of batches used for product development and biostudies.

 

6. Laboratory

 

The inspection of a laboratory requires the use of observations of the laboratory in operation and of the raw laboratory data to evaluate compliance with GMP's and to specifically carry out the commitments in an application or DMF.

 

Evaluate raw laboratory data, laboratory procedures and methods, laboratory equipment, and methods validation data to determine the overall quality of the laboratory operation and the ability to comply with GMP regulations. (Refer to the Laboratory Inspection Guide for additional discussion).

 

Many of our inspection have identified foreign peaks and impurities not filed or discussed in applications. Also, many of our inspections have shown laboratory test methods not to be validated. The transfer of laboratory methods and technology from the Research and Development Department to the Quality Control Department should be reviewed.

 

7. Equipment

 

At the time of the pre-approval inspection we expect that the equipment is in place and qualified. New products, particularly potent drug products, can present cleaning problems in existing equipment. Manufacturers must validate their cleaning processes for the new drug/dosage form. (Refer to the Cleaning Validation Inspection Guide for additional discussion).

 

IV VALIDATION PROTOCOLS

 

Validation protocols are developed from the information obtained during product development research. These protocols list the specific manufacturing process and specifications that will be tested during the demonstration runs. Validation protocols are not required for the Pre-Approval Inspection but are required for Post-Approval Inspections.

 

Key processes and control specifications should have been established during product development research and should be carefully listed in the validation protocol.

 

V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS)

 

A. TEST BATCH RELATIONSHIPS

 

A "validated" process should produce a dosage form that is directly related to the dosage form on which equivalency and/or efficacy an safety were determined. This is usually the test batch. Therefore, compare the process used to make the test batch with the process that is used for routine full scale production batches. These processes and specifications must be equivalent. Therefore, the importance and the need for good control of the manufacturing process used to produce the test and clinical batches cannot be overemphasized. Typically the control of test batches includes, among others, drug substance characterization, granulation analyses, and dose uniformity and dissolution profiles.

 

The validation report should compare the manufacturing processes and specifications for the test batches to the full scale batches. However, such a finding may be contained in other documents. Request any evaluation that has been conducted on the equivalency of these batches and processes and review any tabulated data that shows the processing equivalency between the biobatch and validation batches.

 

B. Post-Approval Prospective Validation Inspections

 

Inspection team members must reread the sections under Part I Product Development which will not be restated under this section. Those sections contain information that is key to the evaluation of the validation process.

 

In the post-approval, pre-marketing phase, we review the Validation Protocol and the Validation Report. Obviously, a Validation Protocol that lists all of the variables and parameters that should be controlled when the process is validated cannot be written until the variables are identified in the development phase.

 

In many of our post-approval, pre-marketing inspections, validation (and consistency) could not be established. Failures of production size batches included dissolution, content uniformity and potency. Validation reports on batch scale-ups may also reflect selective reporting of data. Only through inspection and review of the facilities and raw data were the problems identified.

 

Several parameters must be considered when evaluating the validation of an oral solid dosage form manufacturing process. For example there are at least eight major areas that must be included:

 

o Biobatch Relationship

 

o Raw Materials

 

o Manufacturing Procedures and Equipment

 

o Granulation/Mix Analysis

 

o In-Process Controls

 

o Test Results with Validated Methods

 

o Investigations/Product Failures

 

o Site Review

 

1. Raw Materials

 

Physical characteristics of raw materials can vary among manufacturers of drug substances and, on occasion, have varied from lot to lot from the same manufacturer. Upon examination of retain samples of the lots of raw material, obvious physical differences between the two lots may be observed.

 

Review the raw material inventory records to evaluate the use of the drug substance in biobatch, clinical, and/or test batches. Pay attention to the quantities and source of materials used and the testing performed.

 

Inspections should cover the firm's data for the establishment of their physical specifications for drug substances. If the firm has no specification, or a very vague specification, they should be able to provide data to demonstrate that dissolution profiles and content uniformity will be satisfactory over a wide range of particle sizes. For example, a manufacturer may establish a specification of 90% of the particles must be less than 300 microns. For validation of this process, one would expect the use of micronized as well as material with particles close to 300 microns in size.

 

2. Manufacturing Procedures and Equipment

 

Regardless of the nature of the specificity of the manufacturing directions contained in the application, a detailed master formula with specific manufacturing directions and specifications must have been developed before any validation protocol is prepared and before the validation process begins. The basic premise of validation of a process is that a detailed process already exists which hopefully will be shown to perform consistently and produces products in compliance with predetermined specifications. Therefore, detailed manufacturing directions, specifying equipment and operating parameters must be specified in the master formula.

 

The importance of specific written directions and specifications cannot be overemphasized. For example, problem areas may include:

 

o the failure to specify the amount of granulating solution, resulting in overwetting and dissolution failures of aged batches

 

o the failure to specify the encapsulation machine and operating parameters, such as dosing discs, resulting in weight variation failures

 

o the failure to specify the compression machine(s) and operating parameters, resulting in content uniformity failures

 

In addition to the concern about specific manufacturing directions, equipment presents its own set of unique problems which have to be considered in the control of the manufacturing and the validation processes. The following is a brief description of some issues associated with equipment:

 

a. Blenders

 

Many solid oral dosage forms are made by direct compression. There are generally two types of mixers - low energy and high energy. The low energy mixers represent the classical type of slow mixers, such as ribbon blenders, tumblers, and planetary pony pan. The high energy mixers include some basic features of the low energy mixer but also contain some type of high speed blade, commonly termed an intensifier bar or chopper.

 

1. Pony Pan Type This mixer has historically been used for the manufacture of wet granulations. Because of its open pan or pot, granulating agents, such as starch paste, could be added while mixing. Since it is usually open at the top to allow the mixing blades to penetrate the powder, mixing operations are usually dusty and can lead to potential cross-contamination problems.

 

The usefulness of these mixers is limited to wet granulating. With this type of mixer, there is good horizontal (side to side) blending. However, vertical (top to bottom)

mixing does not occur. Powder placed in the mixer first will be poorly mixed. Segregation or unmixing is also a recognized problem. To minimize this problem, some manufacturers have emptied the pan contents half-way through the mixing cycle in an attempt to turn the powder over at the bottom of the mixer. To alleviate the problem of the lack of mixing along the sides or walls of the pan, manufacturers have utilized a hand-held steel paddle at various times during mixing. This type of mixing is difficult to control and reproduce. Thus, it would be difficult to validate.

 

The potential for segregation and poor mixing along the sides and particularly the bottom of the pony blender makes this type of blender less desirable for the dry blending of granulations of drug products. Consequently, whenever such dry blending is encountered, the investigator should be alert to potential problems with blending validation and content uniformity. Whenever in-process samples of the granulation are collected as part of an investigation or inspection, the formula card along with the weight of the dosage unit to be manufactured is needed for calculations.

 

2. Ribbon Blender In the ribbon blender, powder is mixed both horizontally and vertically. Loading operations can be dusty. However, during the actual blending, it is enclosed, thereby limiting the amount of dust generated to the environment.

 

The major and potentially the most serious problem with the ribbon blender is that there is a "dead-spot" or zone at the discharge valve in some of these blenders. To compensate for this "dead-spot", manufacturers have to recycle the powder from this area at some point during the mixing process. Obviously, there should be adequate and very specific directions and procedures for assuring this critical step is performed. Verify that this step is included in the directions.

 

Another concern with this mixer is the poor mixing at the ends of the center horizontal mixing bar and at the shell wall because of blade clearance. The level of powder placed in this mixer is normally at the top of the outer ribbon blade, and as with other mixers, care must be taken not to overfill the mixer.

 

Cleaning problems, particularly at the ends of the ribbon blender where the horizontal bar enters the blender, have been identified. If manufacturers do not disassemble and clean the seals/packing between batches, they should have data to demonstrate the absence of foreign contaminants between batches of different products processed in the blender.

 

3. Tumbler Blender Common mixers of this type include the twin-shell and double cone. These mixers exert a gentle mixing action. Because of this mild action, lumps of powder will not be broken up and mixed. Powders may also clump due to static charges and segregation can occur. Low humidity can contribute to this problem. Blending under very dry conditions has been found to lead to charge build-up and segregation, while blending of some products under humid conditions has led to lumping. More so than with other mixers, powder charge levels should not exceed 60 to 65% of the total volume of the mixer.

 

Fabricators of tumbler type blenders identify the volume as the actual working capacity and not the actual volume of the blender. It is important to correlate the bulk density of the granulation with the working capacity of the blender.

 

4. High Shear (high energy) Mixers There are several fabricators of these mixers that include GRAL, Diosna and Lodige or Littleford. These mixers are highly efficient and ideally suited for wet granulations. End point of wet granulations can be determined by a measurement on a gauge of the work needed to agitate the blend. The mixing vessel is enclosed, and dust only enters the environment when loading.

 

One of the problems associated with these mixers is the transfer or conversion of products blended in the older types of mixers to these blenders. Mixing times are going to be different, and the physical characteristics of the blend may also be different.

 

These mixers are very efficient. For wet granulations, it is important to control the rate and amount of addition of the solvent. Because of their efficiency, drug substance may partially dissolve and recrystallize upon drying as a different physical form.

 

The presence of an intensifier bar in the center of the blender which rotates at very high speeds breaks down smaller, harder agglomerates. A major disadvantage of this type of blender is that the extremely high speed of the intensifier bar generates considerable heat that can sometimes result in charring of some sugar base granulations. It should be pointed out that these same comments are applicable to other high energy mixers which also rely on high speed choppers to disperse powders. Also, cleaning of the blender requires disassembly of the intensifier bar between products.

 

5. Plastic Bag Any discussion of mixers would not be complete without addressing the plastic bag. Firms have resorted to the blending or manufacture of a trituration in a plastic bag. Obviously, it is very difficult to reproduce such a process, and there is the

potential for loss of powder as a result of breakage or handling. The use of a plastic bag cannot be justified in the manufacture of a pharmaceutical product.

 

When the plastic bag has been used, directions are usually not specific, and one would not know by reading the directions that a plastic bag was employed. In a recent inspection, a firm was noted to manufacture a small 5 kg. size batch of a tranquilizer. Because all of the firm's blenders were of much larger capacity, an inquiry was made as to the mixer employed. Although the processing records indicated a large blender was employed, it was later determined that the batch was actually blended in a plastic bag.

 

b) Dryers

 

There are two basic types of dryers. One is the oven dryer where the wet granulation is spread on trays and dried in an oven. The second dryer is the fluid bed dryer in which the wet granulation is "fluidized" or suspended in air. Generally, the fluid bed dryer yields a more uniform granulation with spherical particles. However, this may result in compression problems that may require additional compression force. It is not unusual to see manufacturers change from an oven dryer to the fluid bed dryer. However, such a change should be examined for equivalency with in-vitro testing such as hardness, disintegration and comparative dissolution and stability testing conducted.

 

Other issues of concern with drying include moisture uniformity and cross contamination. Tray dryers present more moisture uniformity problems than fluid bed dryers. Obviously, a dryer should be qualified for heat uniformity and a program developed to assure moisture uniformity in granulations at the end point of drying. With respect to fluid bed dryers, moisture problems can occur if the granulation is not completely fluidized.

 

Regarding cross contamination, oven dryers, particularly those in which air is recirculated, present cross contamination problems because air recirculates through a common filter and duct. For fluid bed dryers, the bag filters present cross contamination problems. In order to minimize problems, manufacturers use product dedicated bags.

 

 

 

c) Tablet and Capsule Equipment

 

Another important variable in the manufacturing process is the tablet press or encapsulating machine. The newer dosage form equipment requires granulations with good flow characteristics and good uniformity. The newer tablet presses control weight variation by compression force and require a uniform granulation to function correctly. Setup of the microprocessor controlled tablet press usually includes some type of challenge to the system. For example, a short punch is sometimes placed among the other punches. If the press is operating correctly, it will alarm when the lower or high weight tablet is compressed.

 

Different tablet compression equipment can cause dose uniformity, weight uniformity and hardness problems. For example, vibrations during tablet compression can cause segregation of the granulation in the feed hopper. Speed of the machine can affect fill of the die and tablet weight. Therefore, as previously discussed, it is important to have specific operating directions.

 

Many unit operations now provide for blending in totes with discharge of the tote directly into tablet compression equipment. Because of segregation problems at the end of discharge, tablets from the end of compression should be tested for content uniformity. The use of inserts in totes has been shown to minimize segregation.

 

With regard to the newer computer controlled tablet compression equipment, buckets of tablets are often rejected because of potential weight variation problems. The disposition of these tablets, as well as the granulation and tablets used to set up the press, should be investigated. Reworking processes must be validated.

 

With regard to encapsulation operations, the hygroscopic nature of gelatin capsules and some of the granulations, requires humidity controls for storage of the empty capsules and their subsequent filling. Scale-up of capsule products has also presented some problems because of the different types of encapsulation equipment. Older equipment that operated on gravity fill, such as the Lilly and Parke Davis machines, was commonly used for manufacturing capsules in clinical manufacturing areas. When formulations were scaled-up to high speed encapsulation equipment, flow problems and poor weight variation resulted. Additionally, some of the newer equipment provides for the formation of a slug which could impact on dissolution.

 

As previously discussed, set-up and review of operating directions should be covered in inspections. The investigation by firms of weight variation problems should also be covered. Many firms, in order to recondition (rework) batches, pass those particular

batches through a sorter, such as the Mocon Vericap. This machine works on the principal of current (dielectric constant), and moisture variation in the filled capsules can cause inaccurate results. Check the data used to qualify equipment and investigate the equipment log for this sorting machines to identify batches with weight problems that were processed in it. The data supporting the accuracy of equipment to reject low or high weight capsules should be reviewed.

 

d) Coating Equipment

 

Many tablets are now coated with an aqueous film coat that is usually very soluble. Current technology provides for fixed sprays of the coating solution. The volume of coating solution, rate and temperature can be controlled by some of the more highly automated operations. However, many sugar coated, enteric coated and delayed release products exist where some portions of the coating process are not highly soluble and are performed manually. Generally, the shellac undercoat used for sugar coated tablets has presented disintegration/dissolution problems, particularly in aged samples.

 

With respect to poor disintegration, Ferrous Sulfate tablets probably represents the classical example. Over the years, there have been many recalls from many different manufacturers for poor disintegration of coated Ferrous Sulfate tablets. Likewise, there have been many problems with poor dissolution attributed to the coating process. Again, the shellac undercoat hardens, and even sometimes cracks, resulting in poor dissolution.

 

There have been many occasions when the coating process was not validated. The number of applications of coats, volume of coating solution in a specific application, and temperature of the solution during application are all parameters that need to be addressed. For example, the temperature of application and even heat during drying have been found to cause dissolution failures in aged tablets.

 

Another problem associated with the coating process concerns the heat applied to products that are sensitive to heat. For example, it has been shown that estrogen tablets are heat sensitive and have exhibited stability problems. Thus, it is important to control this phase of the process.

 

There are a few products, such as some of the antihistamine tablets, in which the drug substance is applied during the coating process. Other products require the active drug substance to be applied as a dust on tacky tablets as part of the coating process. For

these products, it is particularly important to apply the drug in the coating solution in many controlled applications.

 

Examine processing records for specificity in the identification of critical steps in the coating process. Review the firm's data demonstrating that critical steps are consistent and reproducible.

 

Again, it is important as part of the validation of these processes to demonstrate dose uniformity and dissolution and to control the parameters of the coating process.

 

3. Granulation/Mix Analysis

 

A critical step in the manufacture of an oral solid dosage form is the blending of the final granulation. If uniformity is not achieved at this stage, then one could assume that some dosage units would not comply with uniformity requirements. The major advantage of blend analysis (from a uniformity perspective) is that specific areas of the blender which have the greatest potential to be non-uniform can be sampled. This is particularly true of the ribbon type blender and planetary or pony type mixers.

 

In some cases, such as for large or tumbler type blenders, it is impractical to sample from the blender directly. In such cases, granulations or blends could be sampled at the time of blender discharge or directly from drums. If sampling from drums, samples from the top, middle and bottom of each drum should be collected.

 

In most cases sampling thieves are readily available for sampling the small quantities that need to be taken from key areas of the blender or the drums. If samples larger than one dosage unit must be collected, however, adequate provisions must be made to prevent excessive handling manipulation between the time of sampling and the time of analysis. A sampling device for sampling dosage unit weights is also available in Cincinnati District for use by investigators.

 

Good science and logic would seem to dictate that sample sizes of the approximate equivalent weight of the dosage unit should be sampled in order to test for uniformity. Many industrial pharmacy and engineering texts confirm this approach. Large granulation sample sizes, such as one ounce will provide little information with respect

to uniformity. Generally, further mixing after sampling and prior to analysis occurs which yields misleading results.

 

The acceptance criteria for granulation dose uniformity testing needs to be evaluated. Although many firms evaluate dose uniformity using the compendial dose uniformity specifications (85-115% with an RSD of 6 to 7.8), such specifications should be tighter where supported by the firm's historical data on the level of blend uniformity with its equipment for a given product. In many cases compendial assay limits for the finished product (90 to 110% of label claim) are broad enough for this purpose, and most firms should be able to demonstrate blend assay results well within these limits. If larger sample sizes are taken for assay to evaluate total composite assay, then the specific USP or filed criteria for assay should be used. This key issue needs to be examined during the inspection.

 

In addition to analysis of blends for dose uniformity and potency, blends are tested for physical characteristics. A major physical parameter used to demonstrate equivalence between batches is the particle size profile. This is particularly important for the comparison of the biobatch with production batches and also, when processes are modified or changed. The particle size profile will provide useful information for demonstrating comparability.

 

Particle size profiles are particularly important for the tablet made by a wet granulation process. The size and even the type of granule can affect the pore size in a tablet and have an effect on dissolution. For example, a recent dissolution failure was attributed to a change in the milling screen size, yielding a granulation with larger granules. Since it was a coated tablet, larger pores permitted increased penetration into the tablet by the coating solution, resulting in slower dissolution.

 

Another test which is typically performed on the granulation, particularly when the wet granulation process is used, is loss-on-drying (LOD) and/or moisture content. If organic solvents are employed, then residual solvent residues are also tested. In the validation of a drying process, LOD levels are determined prior to, during and after drying in order to demonstrate times and levels. As with processing variables, levels (specifications) are established in the development phase with the validation phase used to confirm the adequacy of the process. As with other specifications and processes, the investigator should review the data used to support the drying process and determine the significance (if any) of variable drying times and levels.

 

4. In-Process Testing

 

For the purpose of this document, in-process testing is the testing performed on dosage forms during their compression/encapsulation stages to assure consistency throughout these operations. For tablets, individual tablet weights, moisture, hardness (compression force) and disintegration are performed. For capsules, individual weights and moisture are performed.

 

In many of the validation reports reviewed, manufacturers have neglected to supply individual (not composite) dosage unit weights performed throughout compression/encapsulation. This is particularly important for capsule products which may exhibit weight variation problems. If not part of validation reports, the individual dosage unit weights should be reviewed.

 

With regard to individual capsule weights, a major question that arises concerns acceptable levels. Since most USP assay limits are 90 to 110%, it would seem reasonable that each unit manufactured comply with these specifications. It should be pointed out that 85 to 115% limits are established by the USP for variability in both blending and compression or encapsulation operations.

 

Since hardness and disintegration specifications are established during development and biobatch production, testing is performed to demonstrate both equivalency (comparability) and consistency.

 

With regard to moisture, some tablets have set up upon aging as a result of poor moisture control and inadequate specifications. For example, this has been shown to be a major problem with Carbamazepine tablets.

 

5. Test Results

 

Finished product testing, particularly assay, content uniformity and dissolution, should be reviewed. With regard to dissolution, it is important to review dissolution profiles. Validation batches with dissolution profiles not comparable to biobatches indicate non-equivalency of the manufacturing process. Depending on the discriminating nature of the dissolution test, it may also indicate lack of equivalence of the dosage forms made during validation with the biobatch.

 

In the review of dissolution test results, it is important to eventually see results very close to 100% dissolution. In some cases, manufacturers will profile the dissolution results only to the specification. However, if lower, but still acceptable results are obtained (such as 85%), it is important to continue the test. This can be performed by increasing the speed of the apparatus. If a product completely dissolves, yet only results in a value of 85%, it may indicate some problem with the test. Likewise, high dissolution results (115%) also indicate some problem with the test. Obviously, unusual or atypical results should be explained in the validation report.

 

6. Investigations/Product Failures

 

In any process validation exercise, a basic objective is to prove that a process is satisfactory. Unfortunately, some processes are unsatisfactory and may sometimes yield unacceptable results. It is important, therefore, that when the final validation report is reviewed, all results, including failing results, be discussed and evaluated. For example, review of a manufacturing process showed that one of every eight batches manufactured failed content uniformity. Members of the company recognized that the process was unsatisfactory and not validated, but failed to draw this conclusion in the written validation report.

 

When reviewing a validation report, the basis for concluding that a process is satisfactory, particularly those with failing results, should be evaluated.

 

7. Site Review

 

A major aspect and possibly the most critical phase of the inspection of process validation is the review of data at the manufacturer. Manufacturers have presented validation reports which appeared to be very complete, however, when data was actually reviewed, failing batches were omitted without justification.

 

Additionally, review the raw data, including analytical raw data, for accuracy. Only through on-site audit or review of data could such situations be identified. Thus, even though a pre-approval inspection is performed, a post-approval inspection providing for a review of validation data is warranted, particularly in those cases in which deficiencies in validation data have been identified.

 

Note: This document does not bind FDA, and does not confer any rights, privileges, benefits, or immunities for or on any person(s).

Sterile Drug Substance Manufacturers (7/94) 

GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).

 

One of the more difficult processes to inspect and one which has presented considerable problems over the years is that of the manufacture of sterile bulk drug substances. Within the past several years, there have been a number of batches of sterile bulk drug substances from different manufacturers which exhibited microbiological contamination. One manufacturer had approximately 100 batches contaminated in a 6 month time period. Another had approximately 25 batches contaminated in a similar period. Other manufacturers have had recalls due to the lack of assurance of sterility. Although the Inspection Guide for Bulk Drug Substances provides some direction for the inspection of the sterile bulk drug substance, it does not provide the detailed direction needed.

 

I. INTRODUCTION

 

In the manufacture of the sterile bulk powders, it is important to recognize that there is no further processing of the finished sterile bulk powder to remove contaminants or impurities such as particulates, endotoxins and degradants.

 

As with other inspections, any rejected batches, along with the various reasons for rejection, should be identified early in the inspection to provide direction for the investigator. For example, lists of batches rejected and/or retested over a period of time should be obtained from the manufacturer to provide direction for coverage to be given to specific processes or systems. Because some of the actual sterile bulk operations may not be seen, and because of the complexity of the process, it is particularly important to review reports and summaries, such as validation studies, reject lists, Environmental Monitoring Summary Reports, QA Investigation Logs, etc. These systems and others

are discussed in the Basic Inspection Guide. This is particularly important for the foreign sterile bulk drug substance manufacturer where time is limited.

 

In the preparation for a sterile bulk drug substance inspection, a flow chart with the major processing steps should be obtained. Generally, the manufacture of a sterile bulk substance usually includes the following steps:

 

1. Conversion of the non-sterile drug substance to the sterile form by dissolving in a solvent, sterilization of the solution by filtration and collection in a sterilized reactor (crystallizer).

 

2. Aseptic precipitation or crystallization of the sterile drug substance in the sterile reactor.

 

3. Aseptic isolation of the sterile substance by centrifugation or filtration.

 

4. Aseptic drying, milling and blending of the sterile substance.

 

5. Aseptic sampling and packaging the drug substance.

 

These operations should be performed in closed systems, with minimal operator handling. Any aseptic operations performed by an operator(s) other than in a closed system should be identified and carefully reviewed.

 

II. COMPONENTS

 

In addition to the impurity concerns for the manufacture of bulk drug substances, there is a concern with endotoxins in the manufacture of the sterile bulk drug substances. The validation report, which demonstrates the removal, if present, of endotoxins to acceptable levels, should be reviewed. Some manufacturers have commented that since an organic solvent is typically used for the conversion of the non-sterile bulk drug substance to the sterile bulk drug substance, that endotoxins will be reduced at this

stage. As with any operation, this may or may not be correct. For example, in an inspection of a manufacturer who conducted extensive studies of the conversion (crystallization) of the non-sterile substance to the sterile drug substance, they found no change from the initial endotoxin level. Organic solvents were used in this conversion. Thus, it is important to review and assess this aspect of the validation report.

 

In the validation of this conversion (non-sterile to sterile) from an endotoxin perspective, challenge studies can be carried out on a laboratory or pilot scale to determine the efficiency of the step. Once it is established that the process will result in acceptable endotoxin levels, some monitoring of the production batches would be appropriate. As with any validation process, the purpose and efficiency of each step should be evaluated. For example, if the conversion (crystallization) from the non-sterile to the sterile substance is to reduce endotoxins by one log, then data should support this step.

 

Since endotoxins may not be uniformly distributed, it is also important to monitor the bioburden of the non-sterile substance(s) being sterilized. For example, gram negative contaminats in a non-sterile bulk drug substance prior to sterilization are of concern, particularly if the sterilization (filtration) and crystallization steps do not reduce the endotoxins to acceptable levels. Therefore, microbiological, as well as endotoxin data on the critical components and operational steps should be reviewed.

 

III. FACILITY

 

Facility design for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. These would include temperature, humidity and pressure control. Because sterile bulk aseptic facilities are usually larger, problems with pressure differentials and sanitization have been encountered. For example, a manufacturer was found to have the gowning area under greater pressure than the adjacent aseptic areas. The need to remove solvent vapors may also impact on area pressurization.

 

Unnecessary equipment and/or equipment that cannot be adequately sanitized, such as wooden skids and forklift trucks, should be identified. Inquire about the movement of large quantities of sterile drug substance and the location of pass-through areas between the sterile core and non-sterile areas. Observe these areas, review environmental monitoring results and sanitization procedures.

 

The CGMP Regulations prohibit the use of asbestos filters in the final filtration of solutions. At present, it would be difficult for a manufacturer to justify the use of asbestos filters for filtration of air or solutions. Inquire about the use of asbestos filters.

 

Facilities used for the charge or addition of non-sterile components, such as the non-sterile drug substance, should be similar to those used for the compounding of parenteral solutions prior to sterilization. The concern is soluble extraneous contaminants, including endotoxins, that may be carried through the process. Observe this area and review the environmental controls and specifications to determine the viable and non-viable particulate levels allowed in this area.

 

IV. PROCESSING

 

Sterile powders are usually produced by dissolving the non-sterile substance or reactants in an organic solvent and then filtering the solution through a sterilizing filter. After filtration, the sterile bulk material is separated from the solvent by crystallization or precipitation. Other methods include dissolution in an aqueous solution, filtration sterilization and separation by crystallization/filtration. Aqueous solutions can also be sterile filtered and spray dried or lyophilized.

 

In the handling of aqueous solutions, prior to solvent evaporation (either by spray drying or lyophilization), check the adequacy of the system and controls to minimize endotoxin contamination. In some instances, piping systems for aqueous solutions have been shown to be the source of endotoxin contamination in sterile powders. There should be a print available of the piping system. Trace the actual piping, compare it with the print and assure that there are no "dead legs" in the system.

 

The validation data for the filtration (sterilization) process should also be reviewed. Determine the firm's criteria for selection of the filter and the frequency of changing filters. Determine if the firm knows the bioburden and examine their procedures for integrity testing filters.

 

Filters might not be changed after each batch is sterilized. Determine if there is data to justify the integrity of the filters for the time periods utilized and that "grow through" has not occurred.

 

In the spray drying of sterile powders, there are some concerns. These include the sterilization of the spray dryer, the source of air and its quality, the chamber temperatures and the particle residence or contact time. In some cases, charring and product degradation have been found for small portions of a batch.

 

With regard to bulk lyophilization, concerns include air classification and aseptic barriers for loading and unloading the unit, partial meltback, uneven freezing and heat transfer throughout the powder bed, and the additional aseptic manipulations required to break up the large cake. For bulk lyophilization, unlike other sterile bulk operations, media challenges can be performed. At this point in time, with today's level of technology, it would seem that it would be difficult to justify the bulk lyophilization of sterile powders (from a microbiological aspect). Refer to the Guide for the Inspection of a Lyophilization Process for additional direction regarding this process.

 

Seek to determine the number and frequency of process changes made to a specific process or step. This can be an indicator of a problem experienced in a number of batches. A number of changes in a short period of time can be an indicator that the firm is experiencing problems. Review the Process Change SOP and the log for process changes, including the reason for such changes.

 

V. EQUIPMENT

 

Equipment used in the processing of sterile bulk drug substances should be sterile and capable of being sterilized. This includes the crystallizer, centrifuge and dryer. The sanitization, rather than sterilization of this equipment, is unacceptable. Sterilization procedures and the validation of the sterilization of suspect pieces of equipment and transfer lines should be reviewed.

 

The method of choice for the sterilization of equipment and transfer lines is saturated clean steam under pressure. In the validation of the sterilization of equipment and of transfer systems, Biological Indicators (BIs), as well as temperature sensors (Thermocouple (TC) or Resistance Thermal Device (RTD)) should be strategically located in cold spots where condensate may accumulate. These include the point of steam injection and steam discharge, as well as cold spots, which are usually low spots. For example, in a recent inspection, a manufacturer utilized a Sterilize-In-Place (SIP) system and only monitored the temperature at the point of discharge and not in low spots in the system where condensate can accumulate.

 

The use of formaldehyde is a much less desirable method of sterilization of equipment. It is not used in the United States, primarily because of residue levels in both the environment and in the product. A major problem with formaldehyde is its removal from piping and surfaces. In the inspection of a facility utilizing formaldehyde as a sterilant, pay particular attention to the validation of the cleaning process. The indirect testing of product or drug substance to demonstrate the absence of formaldehyde levels in a system is unacceptable. As discussed in the Cleaning Validation Guide, there should be some direct measure or determination of the absence of formaldehyde. Since contamination in a system and in a substance is not going to be uniform, merely testing the substance as a means of validating the absence of formaldehyde is unacceptable. Key surfaces should be sampled directly for residual formaldehyde.

 

One large foreign drug substance manufacturer, after formaldehyde sterilization of the system, had to reject the initial batches coming through the system because of formaldehyde contamination. Unfortunately, they relied on end product testing of the product and not on direct sampling to determine the absence of formaldehyde residues on equipment.

 

SIP systems for the bulk drug substance industry require considerable maintenance, and their malfunction has directly led to considerable product contamination and recall. The corrosive nature of the sterilant, whether it is clean steam, formaldehyde, peroxide or ethylene oxide, has caused problems with gaskets and seals. In two cases, inadequate operating procedures have led to even weld failure. For example, tower or pond water was inadvertently allowed to remain in a jacket and was valved shut. Clean steam applied to the tank resulted in pressure as high as 1,000 lbs., causing pinhole formation and contamination. Review the equipment maintenance logs. Review non-schedule equipment maintenance and the possible impact on product quality. Identify those suspect batches manufactured and released prior to the repair of the equipment.

 

Another potential problem with SIP systems is condensate removal from the environment. Condensate and excessive moisture can result in increased humidity and increases in levels of microorganisms on surfaces of equipment. Therefore, it is particularly important to review environmental monitoring after sterilization of the system.

 

The sterile bulk industry, as the non-sterile bulk industry, typically manufactures batches on a campaign basis. While this may be efficient with regard to system sterilization, it can present problems when a batch is found contaminated in the middle of a campaign. Frequently, all batches processed in a campaign in which a contaminated batch is identified are suspect. Review the failure investigation reports and the logic for the release of any batches in a campaign. Some of the more significant recalls have

occurred because of the failure of a manufacturer to conclusively identify and isolate the source of a contaminant.

 

VI. ENVIRONMENTAL

 

MONITORING

 

The environmental monitoring program for the sterile bulk drug substance manufacturer should be similar to the programs employed by the SVP industry. This includes the daily use of surface plates and the monitoring of personnel. As with the SVP industry, alert or action limits should be established and appropriate follow-up action taken when they are reached.

 

There are some bulk drug substance manufacturers that utilize UV lights in operating areas. Such lights are of limited value. They may mask a contaminant on a settling or aerobic plate. They may even contribute to the generation of a resistant (flora) organism. Thus, the use of Rodac or surface plates will provide more information on levels of contamination.

 

There are some manufacturers that set alert/action levels on averages of plates. For the sampling of critical surfaces, such as operators' gloves, the average of results on plates is unacceptable. The primary concern is any incidence of objectionable levels of contamination that may result in a non-sterile product.

 

As previously discussed, it is not unusual to see the highest level of contamination on the surfaces of equipment shortly after systems are steamed. If this occurs, the cause is usually the inadequate removal of condensate.

 

Since processing of the sterile bulk drug substance usually occurs around the clock, monitoring surfaces and personnel during the second and third shifts should be routine.

 

In the management of a sterile bulk operation, periodic (weekly/monthly/quarterly) summary reports of environmental monitoring are generated. Review these reports to obtain those situations in which alert/action limits were exceeded. Review the firm's

investigation report and the disposition of batches processed when objectionable environmental conditions existed.

 

VII. VALIDATION

 

The validation of the sterilization of some of the equipment and delivery systems and the validation of the process from an endotoxin perspective have been discussed.

 

In addition to these parameters, demonstration of the adequacy of the process to control other physicochemical aspects should also be addressed in a validation report. Depending upon the particular substance, these include potency, impurities, particulate matter, particle size, solvent residues, moisture content, and blend uniformity. For example, if the bulk substance is a blend of two active substances or an active substance and excipient, then there should be some discussion/evaluation of the process for assuring uniformity. The process validation report for such a blend would include documentation for the evaluation and assurance of uniformity. A list of validation reports and process variables evaluated should be reviewed.

 

As with a non-sterile bulk drug substance, there should be an impurity profile and specific, validated analytical methods. Those should also be reviewed.

 

Manufacturers are expected to validate the aseptic processing of sterile BPCs. Such validation must encompass all parts, phases, steps, and activities of any process where components, fluid pathways, in-process fluids, etc., are expected to remain sterile. Furthermore, such validation must include all probable potentials for loss of sterility as a result of processing. Validation must also account for all potential avenues of microbial ingress associated with the routine use of the process.

 

The validation procedure should approximate as closely as possible all those processing steps, activities, conditions, and characteristics that may have a bearing on the possibility of microbial ingress into the system during routine production. In this regard, it is essential that validation runs are as representative aspossible of routine production to ensure that the results obtained from validation are generalizable to routine production.

 

Validation must include the 100% assessment of sterility of an appropriate material that is subjected to the validation procedure. Culture media is the material of choice. whenever feasible. Where not feasible, non-media alternatives would be acceptable. Where necessary, different materials can be used in series for different phases of a composite aseptic process incapable of accommodating a single material. In any event, some material simulating the sterile BPC, or the sterile BPC itself, must pass through the entire system that is intended to be sterile. Any material used for process validation must be microbiologically inert.

 

Environmental and personnel monitoring must be performed during validation, in a manner and amount sufficient to establish appropriate monitoring limits for routine production.

 

At least three consecutive, successful validation runs are necessary before an aseptic process can be considered to be validated.

 

Alternative proposals for the validation of the aseptic processing of bulk pharmaceuticals will be considered by FDA on a case-by-case basis. For example, it may be acceptable to exclude from the aseptic processing validation procedure certain stages of the post-sterilization bulk process that take place in a totally closed system. Such closed systems should be sterilized in place by a validated procedure, integrity tested for each lot, and should not be subject to any intrusions whereby there may be the likelihood of microbial ingress. Suitable continuous system pressurization would be considered an appropriate means for ensuring system integrity.

 

VIII. WATER FOR INJECTION

 

Although water may not be a component of the sterile drug substance, water that comes in contact with the equipment or that enters into the reaction can be a source of impurities (e.g., endotoxins). Therefore, only water for injection should be utilized.

 

Some manufacturers have attempted to utilize marginal systems, such as single pass Reverse Osmosis (RO) systems. For example, a foreign drug substance manufacturer was using a single pass RO system with post RO sterilizing filters to minimize microbiological contamination. This system was found to be unacceptable. RO filters are not absolute and should therefore be in series. Also, the use of sterilizing filters in a Water for Injection system to mask a microbiological (endotoxin) problem has also been unacceptable. As with environmental monitoring, periodic reports should be reviewed.

 

If any questionable conditions are found, refer to the Inspection Guide for High Purity Water Systems.

 

IX. TERMINAL STERILIZATION

 

There are some manufacturers who sterilize bulk powders after processing, by the use of ethylene oxide or dry heat. Some sterile bulk powders can withstand the lengthy times and high temperatures necessary for dry heat sterilization. In the process validation for a dry heat cycle for a sterile powder, important aspects that should be reviewed include: heat penetration and heat distribution, times, temperatures, stability (in relation to the amount of heat received), and particulates.

 

With regard to ethylene oxide, a substantial part of the sterile bulk drug industry has discontinued the use of ethylene oxide as a "sterilizing" agent. Because of employee safety considerations, ethylene oxide residues in product and the inability to validate ethylene oxide sterilization, its use is on the decline. As a primary means of sterilization, its utilization is questionable because of lack of assurance of penetration into the crystal core of a sterile powder.

 

Ethylene oxide has also been utilized in the treatment of sterile powders. Its principal use has been for surface sterilization of powders as a precaution against potential microbiological contamination of the sterile powder during aseptic handling.

 

There are some manufacturers of ophthalmics that continue to use it as a sterilant for the drug used in the formulation of sterile ophthalmic ointments and suspensions. If used as a primary sterilant, validation data should be reviewed. Refer to the Inspection Guide for Topical Products for further discussion.

 

X. REWORK/REPROCESSING/

 

RECLAMATION

 

As with the principal manufacturing process, reprocessing procedures should also be validated. Additionally, these procedures must be approved in filings.

 

Review reprocessed batches and data that were used to validate the process. Detailed investigation reports, including the description, cause, and corrective action should be available for the batch to be reprocessed.

 

XI. LABORATORY TESTING

 

AND SPECIFICATIONS

 

The sterility testing of sterile bulk substances should be observed. Additionally, any examples of initial sterility test failures should be investigated. The release of a batch, particularly of a sterile bulk drug substance, which fails an initial sterility test and passes a retest is very difficult to justify. Refer to the Microbiological Guide and Laboratory Guide for additional direction.

 

Particulate matter is another major concern with sterile powders. Specifications for particulate matter should be tighter than the compendial limits established for sterile dosage forms. The subsequent handling, transfer and filling of sterile powders increases the level of particulates. It is also important to identify particulates so that their source can be determined. Review the firm's program for performing particulate matter testing. If there are no official limits established, review their release criteria for particulates, and the basis of their limit.

 

With regard to residues, since some sterile powders are crystallized out of organic solvents, low levels of these solvents may be unavoidable. In addition to evaluation of the process to assure that minimal levels are established, data used by the firm to establish a residue level should be reviewed. Obviously, each batch should be tested for conformance with the residue specification. Refer to the Inspection Guide for Bulk Drug Substances for additional direction regarding limits for impurities.

 

XII. PACKAGING

 

Sterile bulk drug substances are filled into different type containers which include sterile plastic bags and sterile cans. With regard to sterile bags, sterilization by irradiation is the method of choice because of the absence of residues. There are some manufacturers, particularly foreign, which utilize formaldehyde. A major disadvantage is that formaldehyde residues may and frequently do appear in the sterile drug substance. Consequently, we have reservations about the acceptability of the use of formaldehyde for, container sterilization because of the possibility of product contamination with formaldehyde residues.

 

If multiple sterile bags are used, operations should be performed in aseptic processing areas. Since the dosage form manufacturer expects all inner bags to be sterile, outer bags should be applied over the primary bag containing the sterile drug in an aseptic processing area. One large manufacturer of a sterile powder only applied the immediate or primary bag in an aseptic processing area. Thus, the outer portion of this primary bag was contaminated when the other bags were applied over this bag in non-sterile processing areas.

 

With regard to sterile cans, a concern is particulates, which can be generated due to banging and movement. Because of some with trace quantities of aluminum, companies have moved to stainless steel cans.

 

The firm's validation data for the packaging system should be reviewed. Important aspects of the sterile bag system include residues, pinholes, foreign matter (particulates), sterility and endotoxins. Important aspects of the rigid container systems include moisture, particulates and sterility.

Topical Drug Products (7/94) 

GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).

 

I. PURPOSE

 

The purpose of this guide is to provide field investigators, who are familiar with the provisions of the Current Good Manufacturing Practice (CGMP) regulations for pharmaceuticals, with guidance on inspecting selected facets of topical drug product production. The subjects covered in the guide are generally applicable to all forms of topical drug products, including those that are intended to be sterile. However, this guide does not address every problem area that the investigator may encounter, nor every policy that pertains to topical drug products.

 

II. INTRODUCTION

 

This inspectional guide addresses several problem areas that may be encountered in the production of topical drug products potency, active ingredient uniformity, physical characteristics, microbial purity and chemical purity. The guide also addresses problems relating to the growing number of transdermal products. If a new drug pre-approval inspection is being conducted, then an examination of the filed manufacturing and control data, and correspondence should be accomplished early in the inspection. As with other pre-approval inspections, the manufacturing and controls information filed in the relevant application should be compared with the data used for clinical batches and for production (validation) batches. Filed production control data should be specific and complete.

 

III. POTENCY UNIFORMITY

 

Active ingredient solubility and particle size are generally important ingredient characteristics that need to be controlled to assure potency uniformity in many topical drug products such as emulsions, creams and ointments. Crystalline form is also important where the active ingredient is dispersed as a solid phase in either the oil or water phase of an emulsion, cream, or ointment.

 

It is important that active ingredient solubility in the carrier vehicle be known and quantified at the manufacturing step in which the ingredient is added to the liquid phase. The inspection should determine if the manufacturer has data on such solubility and how that data was considered by the firm in validating the process.

 

Substances which are very soluble, as is frequently the case with ointments, would be expected to present less of a problem than if the drug substance were to be suspended, as is the case with creams. If the drug substance is soluble, then potency uniformity

would be based largely upon adequate distribution of the component throughout the mix.

 

If the active ingredient is insoluble in the vehicle, then in addition to assuring uniformity of distribution in the mix, potency uniformity depends upon control of particle size, and use of a validated mixing process. Particle size can also affect the activity of the drug substance because the smaller the particle size the greater its surface area, which may influence its activity. Particle size also affects the degree to which the product may be physically irritating when applied; generally, smaller particles are less irritating.

 

Production controls should be implemented that account for the solubility characteristics of the drug substance; inadequate controls can adversely affect product potency, efficacy and safety. For example, in one instance, residual water remaining in the manufacturing vessel, used to produce an ophthalmic ointment, resulted in partial solubilization and subsequent recrystallization of the drug substance; the substance recrystallized in a larger particle size than expected and thereby raised questions about the product efficacy.

 

In addition to ingredient solubility/particle size, the inspection should include a review of other physical characteristics and specifications for both ingredients and finished products.

 

IV. EQUIPMENT AND PRODUCTION CONTROL

 

Mixers

 

There are many different kinds of mixers used in the manufacture of topical products. It is important that the design of a given mixer is appropriate for the type of topical product being mixed. One important aspect of mixer design is how well the internal walls of the mixer are scraped during the mixing process. This can present some problems with stainless steel mixers because scraper blades should be flexible enough to remove interior material, yet not rigid enough to damage the mixer itself. Generally, good design of a stainless steel mixer includes blades which are made of some hard plastic, such as teflon, which facilitates scrapping of the mixer walls without damaging the mixer.

 

If the internal walls of the mixer are not adequately scraped during mixing, and the residual material becomes part of the batch, the result may be non-uniformity. Such non-uniformity may occur, for example, if operators use hand held spatulas to scrape the walls of the mixer.

 

Another mixer design concern is the presence of "dead spots" where quantities of the formula are stationary and not subject to mixing. Where such "dead spots" exist, there should be adequate procedures for recirculation or non-use of the cream or ointment removed from the dead spots in the tank.

 

Ideally, during the inspection, mixers should be observed under operating conditions.

 

Filling and Packaging

 

Suspension products often require constant mixing of the bulk suspension during filling to maintain uniformity. When inspecting a suspension manufacturing process determine how the firm assures that the product remains homogeneous during the filling process and audit the data that supports the adequacy of the firm's process. When the batch size is large and the bulk suspension is in large tanks, determine how the firm deals with low levels of bulk suspension near the end of the filling process. Does the bulk suspension drop below a level where it can be adequately mixed? Is residual material transferred to a smaller tank? Does the firm rely upon hand mixing of the residual material? The firm should have demonstrated the adequacy of the process for dealing with residual material.

 

Process Temperature Control

 

Typically, heat is applied in the manufacture of topicals to facilitate mixing and/or filling operations. Heat may also be generated by the action of high energy mixers. It is important to control the temperature within specified parameters, not only to facilitate those operations, but also to assure that product stability is not adversely affected. Excessive temperatures may cause physical and/or chemical degradation of the drug product, vehicle, the active ingredient(s), and/or preservatives. Furthermore, excessive temperatures may cause insoluble ingredients to dissolve, reprecipitate, or change particle size or crystalline form.

 

Temperature control is also important where microbial quality of the product is a concern. The processing of topicals at higher temperatures can destroy some of the objectionable microorganisms that may be present. However, elevated temperatures may also promote incubation of microorganisms.

 

Temperature uniformity within a mixer should be controlled. In addressing temperature uniformity, firms should consider the complex interaction among vat size, mixer speed, blade design, viscosity of the contents and the rate of heat transfer. Where temperature control is critical, use of recording thermometers to continuously monitor/document temperature measurements is preferred to frequent manual checks. Where temperature control is not critical, it may be adequate to manually monitor/document temperatures periodically by use of hand held thermometers.

 

V. CLEANING VALIDATION

 

It is CGMP for a manufacturer to establish and follow written SOPs to clean production equipment in a manner that precludes contamination of current and future batches. This is especially critical where contamination may present direct safety concerns, as with a potent drug, such as a steroid (e.g., cortisone, and estrogen), antibiotic, or a sulfa drug where there are hypersensitivity concerns.

 

The insolubility of some excipients and active substances used in the manufacture of topicals makes some equipment, such as mixing vessels, pipes and plastic hoses, difficult to clean. Often, piping and transfer lines are inaccessible to direct physical cleaning. Some firms address this problem by dedicating lines and hoses to specific products or product classes.

 

It is therefore important that the following considerations be adequately addressed in a firm's cleaning validation protocol and in the procedures that are established for production batches.

 

Detailed Cleaning Procedures

 

Cleaning procedures should be detailed and provide specific understandable instructions. The procedure should identify equipment, cleaning method(s), solvents/detergents approved for use, inspection/release mechanisms, and

documentation. For some of the more complex systems, such as clean-in-place (CIP) systems, it is usually necessary to provide a level of detail that includes drawings, and provision to label valves. The time that may elapse from completion of a manufacturing operation to initiation of equipment cleaning should also be stated where excessive delay may affect the adequacy of the established cleaning procedure. For example, residual product may dry and become more difficult to clean.

 

Sampling Plan For Contaminants

 

As part of the validation of the cleaning method, the cleaned surface is sampled for the presence of residues. Sampling should be by an appropriate method, selected based on factors such as equipment and solubility of residues. For example, representative swabbing of surfaces is often used, especially in hard to clean areas and/or where the residue is relatively insoluble. Analysis of rinse solutions for residues has also been shown to be of value where the residue is soluble and/or difficult to access for direct swabbing. Both methods are useful when there is a direct measurement of the residual substance. However, it is unacceptable to test rinse solutions (such as purified water) for conformance to the purity specifications for those solutions, instead of testing directly for the presence of possible residues.

 

Equipment Residue Limits

 

Because of improved technology, analytical methods are becoming much more sensitive and capable of determining very low levels of residues. Thus, it is important that a firm establish appropriate limits on levels of post-equipment cleaning residues. Such limits must be safe, practical, achievable, verifiable and must ensure that residues remaining in the equipment will not cause the quality of subsequent batches to be altered beyond established product specifications. During inspections, the rationale for residue limits should be reviewed.

 

Because surface residues will not be uniform, it should be recognized that a detected residue level may not represent the maximum amount that may be present. This is particularly true when surface sampling by swabs is performed on equipment.

 

VI. MICROBIOLOGICAL

 

CONTROLS (NON-STERILE

 

TOPICALS)

 

The extent of microbiological controls needed for a given topical product will depend upon the nature of the product, the use of the product, and the potential hazard to users posed by microbial contamination. This concept is reflected in the Current Good Manufacturing (CGMP) regulations at 21 Code of Federal Regulations (CFR) 211.113(a) (Control of microbiological contamination), and in the U.S. Pharmacopeia (USP). It is therefore vital that manufacturers assess the health hazard of all organisms isolated from the product.

 

Deionized Water Systems For Purified Water

 

Inspectional coverage should extend to microbiological control of deionized water systems used to produce purified water. Deionizers are usually excellent breeding areas for microorganisms. The microbial population tends to increase as the length of time between deionizer service periods increases. Other factors which influence microbial growth include flow rates, temperature, surface area of resin beds and, of course, the microbial quality of the feed water. These factors should be considered in assessing the suitability of deionizing systems where microbial integrity of the product incorporating the purified water is significant. From this assessment, a firm should be able to design a suitable routine water monitoring program and a program of other controls as necessary.

 

It would be inappropriate for a firm to assess and monitor the suitability of a deionizer by relying solely upon representations of the deionizer manufacturer. Specifically, product quality could be compromised if a firm had a deionizer serviced at intervals based not on validation studies, but rather on the "recharge" indicator built into the unit. Unfortunately, such indicators are not triggered by microbial population, but rather they are typically triggered by measures of electrical conductivity or resistance. If a unit is infrequently used, sufficient time could elapse between recharging/sanitizing to allow the microbial population to increase significantly.

 

Pre-use validation of deionizing systems used to produce purified water should include consideration of such factors as microbial quality of feed water (and residual chlorine levels of feed water where applicable), surface area of ion-exchange resin beds, temperature range of water during processing, operational range of flow rates,

recirculation systems to minimize intermittent use and low flow, frequency of use, quality of regenerant chemicals, and frequency and method of sanitization.

 

A monitoring program used to control deionizing systems should include established water quality and conductivity monitoring intervals, measurement of conditions and quality at significant stages through the deionizer (influent, post cation, post anion, post mixed-bed, etc.), microbial conditions of the bed, and specific methods of microbial testing. Frequency of monitoring should be based upon the firm's experience with the systems.

 

Other methods of controlling deionizing systems include establishment of water quality specifications and corresponding action levels, remedial action when microbial levels are exceeded, documentation of regeneration and a description of sanitization/ sterilization procedures for piping, filters, etc..

 

Microbiological Specifications and Test Methods

 

During inspections it is important to audit the microbiological specifications and microbial test methods used for each topical product to assure that they are consistent with any described in the relevant application, or U.S.P.. It is often helpful for the inspection to include an FDA microbiologist.

 

Generally, product specifications should cover the total number of organisms permitted, as well as specific organisms that must not be present. These specifications must be based on use of specified sampling and analytical procedures. Where appropriate, the specifications should describe action levels where additional sampling and/or speciation of organisms is necessary.

 

Manufacturers must demonstrate that the test methods and specifications are appropriate for their intended purpose. Where possible, firms should utilize methods that isolate and identify organisms that may present a hazard to the user under the intended use. It should be noted that the USP does not state methods that are specific for water insoluble topical products.

 

One test deficiency to be aware of during inspections is inadequate dispersement of a cream or ointment on microbial test plates. Firms may claim to follow USP procedures,

yet in actual practice may not disperse product over the test plate, resulting in inhibited growth due to concentrated preservative in the non- dispersed inoculate. The spread technique is critical and the firm should have documentation that the personnel performing the technique have been adequately trained and are capable of performing the task. Validation of the spread plate technique is particularly important where the product has a potential antimicrobial affect.

 

In assessing the significance of microbial contamination of a topical product, both the identification of the isolated organisms and the number of organisms found are significant. For example, the presence of a high number of organisms may indicate that the manufacturing process, component quality, and/or container integrity may be deficient. Although high numbers of non-pathogenic organisms may not pose a health hazard, they may affect product efficacy and/or physical/chemical stability. Inconsistent batch to batch microbial levels may indicate some process or control failure in the batch. The batch release evaluation should extend to both organism identification and numbers and, if limits are exceeded, there should be an investigation into the cause.

 

Preservative Activity

 

Manufacturing controls necessary to maintain the anti- microbiological effectiveness of preservatives should be evaluated by the firm. For example, For those products that separate on standing, the firm should have data that show the continued effectiveness of the preservative throughout the product's shelf-life.

 

For preservative-containing products, finished product testing must ensure that the specified level of preservative is present prior to release. In addition, preservative effectiveness must be monitored as part of the final on-going stability program. This can be accomplished through analysis for the level of preservative previously shown to be effective and/or through appropriate microbiological challenge at testing intervals.

 

For concepts relating to sterility assurance and bioburden controls on the manufacture of sterile topicals see the Guideline On Sterile Drug Products Produced by Aseptic Processing.

 

VII. CHANGE CONTROL

 

As with other dosage forms, it is important for the firm to carefully control how changes are made in the production of topical products. Firms should be able to support changes which represent departures from approved and validated manufacturing processes.

 

Firms should have written change control procedures that have been reviewed and approved by the quality control unit. The procedures should provide for full description of the proposed change, the purpose of the change, and controls to assure that the change will not adversely alter product safety and efficacy. Factors to consider include potency and/or bioactivity, uniformity, particle size (if the active ingredient is suspended), viscosity, chemical and physical stability, and microbiological quality.

 

Of particular concern are the effects that formulation and process changes may have on the therapeutic activity and uniformity of the product. For example, changes in vehicle can affect absorption, and processing changes can alter the solubility and microbiological quality of the product.

 

VIII. TRANSDERMAL TOPICAL

 

PRODUCTS

 

Inspections of topical transdermal products (patches) have identified many problems in scale-up and validation. Problems analogous to production of topical creams or ointments include uniformity of the drug substance and particle size in the bulk gel or ointment. Uniformity and particle size are particularly significant where the drug substance is suspended or partially suspended in the vehicle. Viscosity also needs control because it can affect the absorption of the drug; the dissolution test is important in this regard.

 

Other areas that need special inspectional attention are assembly and packaging of the patch, including adhesion, package integrity (regarding pinholes) and controls to assure that a dose is present in each unit.

 

Because of the many quality parameters that must be considered in the manufacture and control of a transdermal dosage form, scale- up may be considerably more difficult than for many other dosage forms. Therefore, special attention should be given to evaluating the adequacy of the process validation efforts. As with other dosage forms, process

validation must be based on multiple lots, typically at least three consecutive successful batches. Inspection of summary data should be augmented by comparison to selected data contained in supporting batch records, particularly where the data appear unusually uniform or disparate. Given the complexities associated with this dosage form, you may encounter tolerances and/or variances broader than for other dosage forms. In addition, batches may not be entirely problem-free. Nevertheless, the firm should have adequate rationale for the tolerances and production experiences, based on appropriate developmental efforts and investigation of problems.

 

IX. OTHER REFERENCES

 

Other relevant inspection guides that should be used in conjunction with this guide include:

 

o Guide to Inspections of Validation of Cleaning Processes.

 

o Guide to Inspections of High Purity Water Systems

 Oral Solutions and Suspensions (8/94) 

GUIDE TO INSPECTIONS ORAL SOLUTIONS AND SUSPENSIONS

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).

 

I. INTRODUCTION

 

The manufacture and control of oral solutions and oral suspensions has presented some problems to the industry. While bioequivalency concerns are minimal (except for the antiseptic products such as phenytoin suspension), there are other issues which have led to recalls. These include microbiological, potency and stability problems. Additionally, because the population using these oral dosage forms includes newborns, pediatrics and geriatrics who may not be able to take oral solid dosage forms and may be compromised, defective dosage forms can pose a greater risk because of the population

being dosed. Thus, this guide will review some of the significant potential problem areas and provide direction to the investigator when giving inspectional coverage.

 

II. FACILITIES

 

The design of the facilities are largely dependent upon the type of products manufactured and the potential for cross-contamination and microbiological contamination. For example, the facilities used for the manufacture of OTC oral products might not require the isolation that a steroid or sulfa product would require.

 

Review the products manufactured and the procedures used by the firm for the isolation of processes to minimize contamination. Observe the addition of drug substance and powdered excipients to manufacturing vessels to determine if operations generate dust. Observe the systems and the efficiency of the dust removal system.

 

The firm's HVAC (Heating Ventilation and Air Conditioning) system may also warrant coverage particularly where potent or highly sensitizing drugs are processed. Some manufacturers recirculate air without adequate filtration. Where air is recirculated, review the firm's data which demonstrates the efficiency of air filtration such should include surface and/or air sampling.

 

III. EQUIPMENT

 

Equipment should be of sanitary design. This includes sanitary pumps, valves, flow meters and other equipment which can be easily sanitized. Ball valves, packing in pumps and pockets in flow meters have been identified as sources of contamination.

 

In order to facilitate cleaning and sanitization, manufacturing and filling lines should be identified and detailed in drawings and SOPs. In some cases, long delivery lines between manufacturing areas and filling areas have been a source of contamination. Also, SOPs, particularly with regard to time limitations between batches and for cleaning have been found deficient in many manufacturers. Review cleaning SOPs, including drawings and validation data with regard to cleaning and sanitization.

 

Equipment used for batching and mixing of oral solutions and suspensions is relatively basic. Generally, these products are formulated on a weight basis with the batching tank on load cells so that a final Q.S. can be made by weight. Volumetric means, such as using a dip stick or line on a tank, have been found to be inaccurate.

 

In most cases, manufacturers will assay samples of the bulk solution or suspension prior to filling. A much greater variability has been found with batches that have been manufactured volumetrically rather than by weight. For example, one manufacturer had to adjust approximately 8% of the batches manufactured after the final Q.S. because of failure to comply with potency specifications. Unfortunately, the manufacturer relied solely on the bulk assay. After readjustment of the potency based on the assay, batches occasionally were found out of specification because of analytical errors.

 

The design of the batching tank with regard to the location of the bottom discharge valve has also presented problems. Ideally, the bottom discharge valve is flush with the bottom of the tank. In some cases valves, including undesirable ball valves, have been found to be several inches to a foot below the bottom of the tank. In others, drug or preservative was not completely dissolved and was lying in the "dead leg" below the tank with initial samples being found to be subpotent. For the manufacture of suspensions, valves should be flush. Review and observe the batching equipment and transfer lines.

 

With regard to transfer lines, they are generally hard piped and easily cleaned and sanitized. In some cases manufacturers have used flexible hoses to transfer product. It is not unusual to see flexible hoses lying on the floor, thus significantly increasing the potential for contamination. Such contamination can occur by operators picking up or handling hoses, and possibly even placing them in transfer or batching tanks after they had been lying on the floor. It is also a good practice to store hoses in a way that allows them to drain rather than be coiled which may allow moisture to collect and be a potential source of microbial contamination. Observe manufacturing areas and operator practices, particularly when flexible hose connection are employed.

 

Another common problem occurs when a manifold or common connections are used, especially in water supply, premix or raw material supply tanks. Such common connections have been shown to be a source of contamination.

 

IV. RAW MATERIALS

 

The physical characteristics, particularly the particle size of the drug substance, are very important for suspensions. As with topical products in which the drug is suspended, particles are usually very fine to micronized (less than 25 microns). For syrups, elixir or solution dosage forms in which there is nothing suspended, particle size and physical characteristics of raw materials are not that important. However, they can affect the rate of dissolution of such raw materials in the manufacturing process. Raw materials of a finer particle size may dissolve faster than those of a larger particle size when the product is compounded.

 

Examples of a few of the oral suspensions in which a specific and well defined particle size specification for the drug substance is important include phenytoin suspension, carbamazepine suspension, trimethoprim and sulfamethoxazole suspension, and hydrocortisone suspension. Review the physical specifications for any drug substance which is suspended in the dosage form.

 

V. COMPOUNDING

 

In addition to a determination of the final volume (Q.S.) as previously discussed, there are microbiological concerns. For oral suspensions, there is the additional concern with uniformity, particularly because of the potential for segregation during manufacture and storage of the bulk suspension, during transfer to the filling line and during filling. Review the firm's data that support storage times and transfer operations. There should be established procedures and time limits for such operations to address the potential for segregation or settling as well as other unexpected effects that may be caused by extended holding or stirring.

 

For oral solutions and suspensions, the amount and control of temperature is important from a microbiological as well as a potency aspect. For those products in which temperature is identified as a critical part of the operation, the firm's documentation of temperature, such as by control charts, should be reviewed.

 

There are some manufacturers that rely on heat during compounding to control the microbiological levels in product. For such products, the addition of purified water to final Q.S., the batch, and the temperatures during processing should be reviewed.

 

In addition to drug substances, some additives, such as the parabens are difficult to dissolve and require heat. The control and assurance of their dissolution during the compounding stage should be reviewed. From a potency aspect, the storage of product

at high temperatures may increase the level of degradants. Storage limitations (time and temperature) should be justified by the firm and evaluated during your inspection.

 

There are also some oral liquids which are sensitive to oxygen and have been known to undergo degradation. This is particularly true of the phenothiazine class of drugs, such as perphenazine and chlorpromazine. The manufacture of such products might require the removal of oxygen such as by nitrogen purging. Additionally, such products might also require storage in sealed tanks, rather than those with loose lids. Manufacturing directions for these products should be reviewed.

 

VI. MICROBIOLOGICAL

 

QUALITY

 

There are some oral liquids in which microbiological contamination can present significant health hazards. For example, some oral liquids, such as nystatin suspension are used in infants and immuno-compromised patients, and microbiological contamination with organisms, such as Gram-negative organisms, is objectionable. There are other oral liquid preparations such as antacids in which Pseudomonas sp. contamination is also objectionable. For other oral liquids such as cough preparations, the contamination with Pseudomonas sp. might not present the same health hazard. Obviously, the contamination of any preparation with Gram-negative organisms is not desirable.

 

In addition to the specific contaminant being objectionable, such contamination would be indicative of a deficient process as well as an inadequate preservative system. The presence of a specific Pseudomonas sp. may also indicate that other plant or raw material contaminants could survive the process. For example, the fact that a Pseudomonas putida contaminant is present could also indicate that Pseudomonas aeruginosa, a similar source organism, could also be present.

 

Both the topical and microbiological inspection guides discuss the methods and limitations of microbiological testing. Similar microbiological testing concepts discussed apply to the testing of oral liquids for microbiological contamination. Review the microbiological testing of raw materials, including purified water, as well as the microbiological testing of finished products. Since FDA laboratories typically utilize more sensitive test methods than industry, consider sampling any oral liquids in which

manufacturers have found microbiological counts, no matter how low. Submit samples for testing for objectionable microorganisms.

 

VII. ORAL SUSPENSIONS

 

UNIFORMITY

 

Those liquid products in which the drug is suspended (and not in solution) present manufacturer and control problems.

 

Those liquid products in which the drug is suspended (and not in solution) present manufacture and control problems. Depending upon the viscosity, many suspensions require continuous or periodic agitation during the filling process. If delivery lines are used between the bulk storage tank and the filling equipment, some segregation may occur, particularly if the product is not viscous. Review the firm's procedures for filling and diagrams for line set-up prior to the filling equipment.

 

Good manufacturing practice would warrant testing bottles from the beginning, middle and end to assure that segregation has not occurred. Such samples should not be composited.

 

In-process testing for suspensions might also include an assay of a sample from the bulk tank. More important, however, may be testing for viscosity.

 

VIII. PRODUCT

 

SPECIFICATIONS

 

Important specifications for the manufacture of all solutions include assay and microbial limits. Additional important specifications for suspensions include particle size of the suspended drug, viscosity, pH, and in some cases dissolution. Viscosity can be important from a processing aspect to minimize segregation. Additionally, viscosity has

also been shown to be associated with bioequivalency. pH may also have some meaning regarding effectiveness of preservative systems and may even have an effect on the amount of drug in solution. With regard to dissolution, there are at least three products which have dissolution specifications. These products include phenytoin suspension, carbamazepine suspension, and sulfamethoxazole and trimethoprim suspension. Particle size is also important and at this point it would seem that any suspension should have some type of particle size specification. As with other dosage forms, the underlying data to support specifications should be reviewed.

 

IX. PROCESS VALIDATION

 

As with other products, the amount of data needed to support the manufacturing process will vary from product to product. Development (data) should have identified critical phases of the operation, including the predetermined specifications, that should be monitored during process validation.

 

For example, for solutions the key aspects that should be addressed during validation include assurance that the drug substance and preservatives are dissolved. Parameters, such as heat and time should be measured. Also, in-process assay of the bulk solution during and/or after compounding according to predetermined limits are also an important aspects of process validation. For solutions that are sensitive to oxygen and/or light, dissolved oxygen levels would also be an important test. Again, the development data and the protocol should provide limits. Review firm's development data and/or documentation for their justification of the process.

 

As discussed, the manufacture of suspensions presents additional problems, particularly in the area of uniformity. Again, development data should have addressed the key compounding and filling steps that assure uniformity. The protocol should provide for the key in-process and finished product tests, along with their specifications. For oral solutions, bioequivalency studies may not always be needed. However, oral suspensions, with the possible exception of some of the antacids, OTC products, usually require a bioequivalency or clinical study to demonstrate effectiveness. As with oral solid dosage forms, comparison to the biobatch is an important part of validation of the process.

 

Review the firm's protocol and process validation report and, if appropriate, compare data for full scale batches to biobatch, data and manufacturing processes.

 

X. STABILITY

 

One area that has presented a number of problems includes the assurance of stability of oral liquid products throughout their expiry period. For example, there have been a number of recalls of the vitamins with fluoride oral liquid products because of vitamin degradation. Drugs in the phenothiazine class, such as perphenazine, chlorpromazine and promethazine have also shown evidence of instability. Good practice for this class of drug products would include quantitation of both the active and primary degradant. Dosage form manufacturers should know and have specifications for the primary degradant. Review the firm's data and validation data for methods used to quantitate both the active drug and degradant.

 

Because interactions of products with closure systems are possible, liquids and suspensions undergoing stability studies should be stored on their side or inverted in order to determine whether contact of the drug product with the closure system affects product integrity.

 

Moisture loss which can cause the remaining contents to become superpotent and microbiological contamination are other problems associated with inadequate closure systems.

 

XI. PACKAGING

 

Problems in the packaging of oral liquids have included potency (fill) of unit dose products, accurate calibration of measuring devices such as droppers that are often provided. The USP does not provide for dose uniformity testing for oral solutions. Thus, for unit dose solution products, they should deliver the label claim within the limits described in the USP. Review the firm's data to assure uniformity of fill and test procedures to assure that unit dose samples are being tested.

 

Another problem in the packaging of Oral Liquids is the lack of cleanliness of containers prior to filling. Fibers and even insects have been identified as debris in containers, and particularly plastic containers used for these products. Many manufacturers receive containers shrink-wrapped in plastic to minimize contamination from fiberboard cartons. Many manufacturers utilize compressed air to clean containers. Vapors, such as oil vapors, from the compressed air have occasionally been found to present problems. Review the firm's systems for the cleaning of containers.

Aseptic Processing and Packaging for the Food Industry 

Updated: 2005-07-14

 

GUIDE1 TO INSPECTIONSOF ASPECTIC PROCESSING AND

PACKAGING FOR THE FOOD INDUSTRY

 

1This document is reference materials for investigators and other FDA personnel. The document does not bind FDA, and does not confer any rights, privileges, benefits, or

immunities for or on any person(s).

 

This document is also available in PDF format (1,144KB)1

 

TABLE OF CONTENTS

 

INTRODUCTION

 

INSPECTION  

 

Process Flow Chart

 

Scheduled Process

 

PROCESSING  

 

Product Heating Systems

 

EQUIPMENT AND CONTROLS

 

Raw Material and Formulations

 

Timing or Metering Pump

 

Sterilizer

 

OPERATION

 

Start-up

 

Records

 

Process Deviations

 

Clean-up and Re-Sterilization After Process Deviation

 

Scheduled Process for Reprocessed Products

 

Package Sterilization Systems

 

CONTAINER STERILIZING, FILLING AND CLOSING OPERATIONS

 

METAL CONTAINERS AND CLOSURES

 

Equipment and Controls 

 

Operation 

 

Process Deviations 

 

PAPERBOARD OR PLASITC CONTAINERS 

 

Equipment and Controls 

 

Operation 

 

THERMOFORM-FILLED-SEAL CONATINERS-PRE-STERILIZED BY HEAT OR CO-EXTRUSION 

 

Equipment and Controls 

 

Processing 

 

Operation 

 

Process Deviations 

 

BAG IN BOX PACKAGE SYSTEMS 

 

Equipment and Controls 

 

RECORDS 

 

CONTAINER CLOSURE EVALUATION 

 

POST PROCESS HANDLING 

 

TRAINING 

 

MAINTENANCE 

 

SAMPLE COLLECTION 

 

TABLE 1: ADVANTAGES AND DISADVANTAGES OF HEATING SYSTEMS 

 

FIGURES 

 

Figure # 1: Steam Injection 

 

Figure # 2: Steam Infusion 

 

Figure # 3: Product-to-Product 

 

Figure # 4: Tubular Heat Exchanger 

 

Figure # 5: Scraped Surface Heat Exchanger 

 

Figure # 6: Superheated Steam Metal Container System 

 

Figure # 7: Webfed Paperboard System I 

 

Figure # 8: Webfed Paperboard System II 

 

Figure # 9: Preformed Cup System.........pg. # 20  

 

Figure #10: Thermoform-Fill-Seal System 

 

Figure #11: Aseptic System

 

 

 

INTRODUCTION

 

Inspections of aseptic processing and packaging systems for Low Acid Canned Food (LACF) are some of the most complex inspections of food manufacturing operations. The major difference between aseptic processing and the more "conventional" types of LACF processing is that a process authority(s) must establish a process that ensures commercial sterility not only of the product but also for:

 

1. the product sterilization system (hold tube) and all equipment downstream from the holding tube including the filler;

2. the packaging equipment; and

3. the packaging material.

 

Documentation of production operations must be maintained by the firm showing that commercially sterile conditions are achieved and maintained in all these areas. Any breach of a scheduled process for the processing or packaging system means that the affected product must be destroyed, reprocessed or segregated and held for further evaluation. In addition, the processing and packaging system must be cleaned and re-sterilized before processing and/or packaging operations can resume.

 

Aseptic processing equipment sterilization procedures often use steam or hot water under pressure. Packaging equipment and packaging materials are sterilized with various medium or combination of mediums (i.e., saturated steam, superheated steam, hydrogen peroxide and heat and other treatments). Sterilization procedures are often validated by placing resistant microbial spores on adhesive strips at strategic locations in equipment or on container materials. Results of microbial validation studies are filed with CFSAN in support of scheduled process filings.

 

In addition to instructions and information provided in the Guide To Inspections Of Low Acid Canned Food Manufacturers (Parts 1, 2 and 3, hereafter referred to as the LACF Inspection Guide), direct attention to the following points when inspecting firms using aseptic processing and packaging. Before conducting the inspection, review the file jacket for the firm for previous establishment inspection reports (EIR's) and other pertinent information. Previous EIR's may provide a history of the installation of new, or modifications to, equipment and instrumentation. Review prior documentation dealing with incidents such as recalls, container integrity problems (involving leakers, swollen containers and visual external defects).

 

INSPECTION

 

Process Flow Chart

 

It is important to become thoroughly familiar with each step in the process, before attempting to evaluate the system for compliance with 21 CFR 108 and 113. This includes those components that are responsible for controlling critical elements in the process.

 

At the beginning of the inspection, obtain a diagram or blueprint of the entire processing and packaging system and conduct a walk-through review of the system, noting the various components on the diagram. In some cases, the firm may have a diagram or blueprint only of the product sterilization portion of the line, i.e., that portion from the raw product tank to the filler. If the diagram is only for a portion of the line, supplement this with your own diagram(s).

 

If a diagram or blueprint is not available, prepare a process flow diagram - from incoming raw materials to finished product warehouse storage. The critical control points - those points where lack of control could cause, allow, or contribute to a microbiological hazard in the final product - should be identified on the process flow diagram.

 

The firm should have written instructions for the operation of the product and packaging system, including pre-sterilization procedures to bring the product sterilizer (hold tube) and equipment downstream to the filler and the packaging system to commercial sterility prior to onset of product sterilization and/or packaging. Obtain copies of these procedures and submit with the diagram, blue print or process flow diagram as an exhibit to the EIR.

 

If the firm employs more than one aseptic processing system i.e., one product sterilization unit combined with one type of packaging unit (e.g., Dole, Tetra-Pak or Conofast), choose the system which appears to offer the greatest potential for contamination if the critical control points are not controlled.

 

Focus the inspection on one complete aseptic process and packaging system. If, after making an evaluation of the system you have selected, it is deemed necessary or advantageous to cover another during the same inspection, do so; but only if you can devote sufficient time to thoroughly evaluate a second system.

 

Scheduled Processes

 

Scheduled processes must be filed with FDA listing the critical factors necessary to reach a condition of commercial sterility for:

 

1. the product,2. the "sterile zones" of the product sterilization system (hold tube and equipment

downstream from the hold tube),

3. the packaging system and,

4. the packaging material.

 

The firm is required to list such information on Form FDA-2541c and its attachments. Become familiar with this form and the "Aseptic Packaging System Supplement" to the instructions for establishment registration and process filing for acidified and low-acid canned foods. Copies of each should be available in your district or they may be obtained from the LACF Registration Coordinator at (202) 205-5282.

 

Review and compare copies of the firm's current scheduled processes with those filed with FDA. Filed processes may have been obtained during a previous inspection; or they may be obtained using procedures outlined in the LACF Inspection Guide - Part 1. Supplemental information on pre-sterilization and sterility maintenance of processing, packaging equipment and sterilization of packaging material can be obtained from the Center for Food Safety and Applied Nutrition (HFS-617 - Regulatory Food Processing and Technology Branch).

 

Review the scheduled processes used by the firm to assure they have been recommended by a process authority (letter, standard operating procedures manual, transmittal, bulletin, etc.). Do not routinely request actual process establishment information unless instructed to do so by your district and by HFS-617(See the LACF Inspection Guide - Part 1). Compare the critical factors in the filed scheduled process to make sure they correspond to those in the transmittal from the process authority. Compare the filed process with the written documentation from the process authority prior to the walk-through for a more efficient evaluation of the critical components in the line.

 

Review the section in the supplement entitled "Required Supplemental Information For Aseptic Packaging Systems", which details information concerning the procedures necessary for bringing the processing and the packaging unit to a condition of commercial sterility and maintaining commercial sterility throughout processing operations.

 

PROCESSING

 

Product Heating Systems

 

There are three basic types of product heating: direct, indirect and ohmic. Each type will be discussed separately. There are advantages and disadvantages to using each type of heating system, the advantages and disadvantages are listed in Table I on page 14.

 

Direct heating systems -involve having steam condense into the product. This can be done in two ways:

 

I. Steam injection (Figure 1): where steam is injected directly into product flowing through an injection chamber.

II. Steam infusion (Figure 2): where the product is sprayed into a large pressurized steam chamber and is sterilized when falling as film or droplets through the chamber. In most cases, a flash chamber is used after the hold tube to evaporate added water, which results in a rapid cooling of the commercially sterilized product.

 

Indirect Heating Systems –Involve the use of equipment to exchange heat between the surface that is heated, and the product. There are three major way the indirect heat is used in aseptic processing. They are:

 

I. Plate heat exchangers -(Figure 3), Where the plates in the system serve as a heat transfer surface and barrier with circulating hot water (for pre-heater) on one side and product on the other. This system is similar to those used in the pasteurized milk industry, are used most often for homogeneous liquids such as milk and other dairy products.

II. Tubular heat exchangers-(Figure 4), generally employ concentric tubes as the barrier/ heat exchange surface. Product flows through the inner tube of two-tube systems and the middle tube in three-tube systems, with the heating medium flowing in the opposite direction through the other tubes. With shell-in tube heat exchangers , as shown in figure 4, the tube may be coiled inside a large shell, with product also flowing through the tube in a direction opposite to the flow of heating medium. As with plate heat exchangers, generally homogeneous products such as milk are normally processed in these systems.

III. Scraped-surface heat exchangers -(Figure 5), consists of a mutator shaft with scraper blades, generally concentrically located within a jacketed, insulated heat exchanger tube. Product is pushed against the inner heat exchange/barrier wall by the force of a pump, which transports product through the heater. The blades, which have a slight degree of independent movement, then "scrape" product build-up off of the heat exchange surface. The heating medium is circulating water or steam which flows on the opposite side of the inner heat exchange/barrier wall.

These heat exchange systems are normally used for processing viscous products, such as puddings, or products containing particulates such as certain soups.

 

Ohmic heating - is a relatively new method of product heating where an electrical current is passed through a suitable conducting product causing product heating. The system operates under continuous flow conditions with the product passing over electrodes in one or more heating tubes, followed by product cooling in scraped surface, tube in shell or plate heat exchangers. The conductivity and electrical resistance of the product influences the heating rate. Because of this, product formulation becomes critical to the process. Food products, which are not good conductors of electrical current, are not good candidates for ohmic heating.

 

Equipment and Controls 

 

Raw Materials and Formulation 

 

Describe the firm's method for ensuring the microbiological quality of its raw materials.

Determine whether any formulation changes (e.g., changing starch types or amounts) might adversely affect the adequacy of the thermal process.

Determine how the firm controls the formulation and batching of product to insure that the product meets the desired characteristics.

 

If the product contains particulates in its formulation (tapioca pudding, certain sauces and soups, etc.), review the scheduled process transmittal from the processing authority in order to determine the critical factors associated with the particulates. Document that the firm's procedures are sufficient to meet the appropriate levels for these critical factors. For example, if particle size is a critical factor according to the processing authority, determine how the firm insures that the size of the particulates used is at or

below the size specified or if a rehydration period is required for dry particulates. Document the firm's procedures to meet the requirements specified by the processing authority.

 

Metering(Timing) Pump

 

Aseptic processes are based on a continuous flow of product through a holding tube. This continuous flow relies on pumps, and as such, these pumps are critical in the design of the system. 21CFR 113.40 (g)(i)(f) states "A metering pump shall be located upstream from the holding tube and shall be operated to maintain the required rate of product flow". A positive displacement pump is used as the metering (sometimes called the timing) pump because they are less sensitive to pressure drops and slippage than centrifugal pumps. The product characteristics may determine the type of positive displacement pump used. When the pressure drop in the system is low (less than 150 lbs.) and the product contains only small particles or is homogenous, a rotary positive displacement pump may be used. At higher-pressure drops and for large particulates, a reciprocating piston pump is normally the pump of choice.

 

Metering(Timing) pumps may be variable speed or fixed-rate. In the latter, the pumping rate cannot be changed without dismantling the pump. If the pump is a variable speed device (e.g., has a Reeves-type drive), a means of preventing unauthorized speed changes must be provided. This can be a lock on the device or a notice from management posted on or near it, giving suitable warning.

 

Flow Meters

Some newer systems may use a flow meter to control the flow of product through the system. The flow meter may be used in conjunction with a fixed rate pump and a flow control valve or with a variable speed pump controlled by the flow meter. When these flow control systems are used it is extremely important to determine how the flow control system operates, the procedures used to validate the flow rate, and how the system is maintained.

 

Product flow rate through the hold tube affects the residence time of the individual element in the hold tube. Each fluid element may receive a different degree of sterility, depending on the length of time that particular element spends in the hold tube (residence time). The design of the system, pumping rates and product characteristics can effect the flow rate through the heating and holding portions of the system. This is why product formulation is critical.

 

The residence time of the fastest moving element is determined and calculated by the processing authority for the product being heat processed. Then the processor documents that the flow rates and flow characteristics of the product are not different from those established by the process authority. The specified product flow rate should be monitored or verified by the processor as a routine part of the system operation. One method of doing this is by correlating the flow rate under no load conditions with the pump speed. By counting pump strokes per set time period, or by equipping the pump with a recording tachometer, an indirect record of product flow rate can be documented. The efficiency of some pumps may be affected by viscosity of the product and the absence of pressure or backpressure in the system. Thus pumping rates established with water may not reflect a true flow rate for the food product. Various types of flow measuring devices have been developed which indirectly provide an indication of product flow. The use of a flow meter to indicate product flow rate should be validated by the firm and documentation should be available which supports the use of the flow meter as an accurate indication of actual product flow. Physical measurement of product flow (e.g. 3 gal per minute, number of containers per set time interval) may be an acceptable method to determine product flow rates. Sampling sites and product temperature must be specified, as product temperature may have an effect on product volume. If product is going directly to a filling line, product fill rates can be determined over a set time period and correlated to product flow rates. Means do exist where chemical or radiological tracers are injected into the product stream to measure product flow. However these methods are normally not used on a routine daily basis to verify product flow rates.

 

Document the firm’s validation procedures for insuring that the pumping rate determined by the processing authority is met by the system.

 

Sterilizer (Hold Tube)

 

Temperature Indicating Device

Sterilizers or hold tubes must be equipped with at least one TID’s: During the inspection, check that the device complies with the specifications listed in 21 CFR 113.40(g)(l)(i)(a). which gives the parameters of the TID and how often it is checked for accuracy.

 

If the system is equipped with only one temperature indicating device, the probe for this device is normally located in the vicinity of the temperature recording device. Mercury-in-glass thermometers and other temperature indicating devices are the reference

instrument and, as the regulations state, “shall be tested for accuracy against a known standard upon installation and at least once a year thereafter.” The regulations do not require maintenance of calibration records, however, as the reference instrument for indicating the processing temperature it is important that the firm be able to document that required tests for accuracy were accomplished. If possible obtain copies of the records of testing for accuracy as well as copies of the method used, and the name of the firm or individuals performing the tests.

 

Temperature Recording Device

21 CFR 113.40(g)(l)(i)(b), states in part: “The temperature recording device shall be installed in the product flow at the holding-tube outlet between the holding tube and the inlet to the cooler.” It goes on to say: “The temperature chart shall be adjusted to agree as nearly as possible with, but to be in no event higher than, a known accurate mercury-in-glass thermometer. “

 

The firm must also have a means to prevent unauthorized changes in adjustment of the recording device.

 

Temperature Recorder-Controller 

21 CFR 113.40(g)(l)(i)(c). Describes where an accurate temperature recorder controller shall be located an the specifications of the recording chart.

 

Describe the operation of the recorder-controller and report the name of the manufacturer. It goes on to say that if it is air-actuated, the firm needs to assure a supply of clean dry air to the controller. Check to see if there is filter on the air line and if so, how often is it changed or monitored to assure the quality of air to the controller.

 

In some instances, a firm may have a recorder-controller with two or more pens, one marking the recorder-controller temperature at the exit end of the final heater; and one recording the temperature at the exit end of the holding tube. Describe how the firm adjusts the recorder controller, how often, and what reference instrument is used to adjust the recorder controller. The pens are adjusted by reading the indicating thermometer and using a thumb wheel on the pen on making adjustments inherent in the particular design.

 

Product to Product Regenerators

21 CFR part 113.40(g)(1)(i)(d), states: “When a product-to-product regenerator is used to heat the cold unsterilized product… it shall be designed, operated and controlled so that the pressure of the sterilized product in the regenerator is greater than the pressure of any unsterilized product in the regenerator to ensure that any leakage in the regenerator is from the sterilized product into the unsterilized product.”

 

Differential pressure recorder-controller

 21 CFR 113.40(g)(1)(i)(e). Is the means of controlling pressure in a product-to-product regenerator. The device must comply with the specification listed in the regulation and the nature of the control action taken by the device in the event of improper pressures. It is necessary for one pressure sensor to be located in the sterilized product regenerator outlet (point of lowest pressure) and one in the non-sterilized product regenerator inlet (point of highest pressure).

 

During the inspection, note were the sensors are located and document then on the process flow diagram. Also, the controller must “be tested for accuracy against a known accurate pressure indicator upon installation and at least every three months of operation thereafter, or more frequently, if necessary... “ This part of the regulation does not address a record-keeping requirement or recommendation relative to this testing schedule, however, it is important that the firm keep such records. Review copies of the records of testing as well as a copy of the methodology used and determine the name of the firm or individuals performing the tests. This information should be included in the EIR.

 

Product Holding Tube

21 CFR 113.40(g)(1)(i)(f). The regulation states that the product sterilizing holding tube must be designed to give continuos holding of every particle of food for at least the minimum holding time specified in the scheduled process.

 

To assure this, the tube must be sloped upward at least 0.25 inches per foot. Pitch of hold tube can be determine with a T square or by using a line level. Verify that the holding tube diameter and length conforms to that listed in the filed scheduled process and that the slope is adequate. If the holding tube is capable of being dismantled (for cleaning, repairs, etc.), record in the EIR how the firm assures that when reassembled, it conforms to the scheduled process parameters.

 

Also, the holding tube must be designed so that no portion of the tube between the product inlet and the product outlet can be heated. Hold tubes may be insulated to protect the hold tube from external extreme temperatures. This is acceptable as long as no external heat source is applied to the hold tube.

 

Flow diversion system-

21 CFR 113.40(g)(1)(i)(h). Describe in detail the firm's method for diverting non-sterile product flow away from the filler or aseptic surge tank, including any documentation from a processing authority that may list specific recommendations for the design and operation of the system. Some firms may elect to install a flow-diversion system. The regulation describes where the device should be located but does not require the placement of the device in the line. If it has an automatic flow diversion device or system, document the variables (e.g., loss of temperature, loss of pressure in a product-to-product regenerator, etc.) that will activate it to divert flow. Document what system is in place to notify the operator to divert manually operated systems. Record how diversion incidents are recorded, including corrective action and disposition of diverted product. Verify that the first divert drain is sterilized following each use and that a gravity-drain flow diversion device is not used.

 

Equipment downstream from the holding tube 

21 CFR 113.40(g)(1)(i)(i). Entry of microorganisms into the product can happen at product coolers, aseptic surge tanks, flow diversion valves, homogenizers, aseptic pumps or any other equipment that is downstream from the holding tube. Rotating or reciprocating shafts and valve stems should be equipped with steam seals or other effective barriers at the potential access points. The firm needs to monitor the performance of these seals or barriers for proper function during operations.

 

Aseptic Surge Tank - are sometimes employed by a firm as a means to temporarily store sterile product. This is done to provide a continuous supply of product to the filler or to divert sterile product in the event of a stoppage of the packaging machine. Surge tanks are sterilized before start-up of product flow with steam or water up to any air filter in the line or up to the filler valve. Generally, aseptic surge tanks must be vented, in a manner similar to still retorts, to ensure there are no remaining air pockets, which would prevent certain areas within the surge tank from reaching sterilization temperature.

 

Typically, a processing authority establishes this “venting” or air purge schedule, and the firm has documentation from this authority, specifying the sterilization procedure. During the inspection review the firm’s data to make sure the purge schedule is listed. Sterile air over-pressure must be maintained on aseptic surge tanks to ensure proper operation (i.e., product flow to the filler). Sterile air or gas is produced by incineration and/or filtration. Determine how the firm monitors sterile air or gas over-pressure and the method of achieving sterility. With incineration, a thermocouple monitoring system is probably the easiest means. If a sterile filter is used, determine the specifications of the filter, filter location and number of filters. Determine if the firm changes the filter at intervals recommended by the manufacturer or process authority for their method of use. Filter changes should be documented on the processing records. Determine whether the firm has taken into account any possible adverse effects that may affect the working life of the filter, such as, repeated contact with incinerated air.

 

If a filtration system is used and the downstream side is sterilized with steam during the vent or purge cycle, determine whether the process authority or the manufacturer took into account the effects of steam on the filter. The firm should have a procedure to determine the integrity of filters.

 

There are several commercial methods for testing filter integrity, but basically the firm should use the method recommended by the filter supplier or their process authority. Loss of filter integrity is a process deviation and places the commercial sterility of all product produced in question.

 

Gases, such as sterile nitrogen or carbon dioxide - either singly or in combination - may be used to provide overpressure and create a sterile barrier. Determine the firm's procedure for ensuring the sterility of these gases and any filters used to filter the sterile gases including lines/piping downstream to the point where the gases are delivered to the aseptic system.

 

Backpressure - Backpressure valves or orifices may be used in aseptic systems to assure that pressure in the system prevents flashing of the product in the hold tube. Flashing in the holding tube may cause an increase in velocity of the product, thereby reducing the residence time specified in the schedule process. Determine how the firm monitors the proper operation of the backpressure valve(s). For examples, in direct heating systems (e.g., steam injection or infusion), the added water from the condensed steam must be removed for standardized products such as milk. This is normally done in a sterile "flash" or expansion chamber. A firm must have a back pressure valve to separate the holding tube from the flash chamber in order to prevent "flashing" (i.e., water vapor expanding as steam) from taking place in the holding tube.

 

Control system- Product heating and sterilizing systems run the entire spectrum, from manually operated systems to computer-controlled highly automated systems. For the manually operated systems, review of the production logs and recording charts by management represent the principal method of verifying that the product received the scheduled process. For highly automated systems, there are controls that, if operating properly, will automatically preclude the packaging of non-sterile product into sterile containers. Consequently, routine challenge and calibration of the automatic controls represent an additional method of verifying that the product received the scheduled process. During the inspection, obtain from the firm a copy of the most recent challenge and calibration record for the automatic controls. Included should be the methodology employed, the frequency of testing, and the individuals who conducted the tests. Computerized control systems must be validated upon installation to insure that they will operate as designed.

 

OPERATION

 

Start-Up 

21 CFR 113.40 (g)(l)(i)(ii)(a): The firm must follow its filed scheduled process for bringing the equipment to a condition of commercial sterility (i.e., as listed in the "Required Supplemental Information for Aseptic Packaging Systems") prior to "switching-over" to product sterilization. Determine if the temperature sensor, which is monitoring the equipment sterilization temperature, is located at the defined coldest point in the line, downstream from the hold tube. This sensor is usually located at a point beyond the valve, which interfaces the hold tube with the filling equipment. If, for example, the firm is using the temperature indicating device (e.g., a mercury-in-glass thermometer) at the exit end of the holding tube to indicate equipment sterilization, document how the firm assures that the equipment downstream of the holding tube reaches the proper temperature.

 

And, determine how the firm assures a proper switchover from water to product without causing a process deviation to occur in either the equipment sterilization or product sterilization cycle. For example, the sterilization temperature for bringing the equipment to a condition of commercial sterility may be several degrees F more - or less - than that which is scheduled for the product.

 

Records

21 CFR 113.40 (g)(l)(i)(ii)(e). Monitoring records for aseptic processing should as appropriate include readings for the following

 

1. Temperature indicating device(s) at holding tube outlet.2. Temperature recorder at holding tube outlet.

3. Temperature recorder-controller at final heater outlet.

4. Differential pressure recorder-controller, if a product-to-product regenerator is used.

5. Product flow rate (in gallons per minute, cans per minute, etc.).

6. Aseptic surge tank sterile air overpressure or other protective means.

7. Proper performance of steam seals.

8. The sterilization of equipment or "pre-sterilization" cycle. The records should indicate when the equipment is in the pre-sterilization cycle, when flow diversion occurs and when product is flowing through the system.

Process Deviations

Following is a list of some possible process deviations:

 

1. Temperature drop in the holding tube.2. Loss of differential pressure in product-to-product regenerator.

3. Loss of sterile air or gas pressure or other protection level in the aseptic surge tank.

4. Loss of sterility of air or gas supplies to sterile zones.

5. Critical factors in the scheduled process outside specifications.

6. Increasing the speed of the variable speed-metering pump.

 

If a process deviation occurs and potentially non-sterile product is filled into a container, the firm must perform corrective action on the affected product. This could include reprocessing or destroying the product or having the process evaluated by a processing authority. During the inspection, review all process deviations and, if the firm chose to have a deviation evaluated by a process authority, collect those records and responses and submit them as an exhibit to the EIR.

 

Clean-Up and Re-sterilization After Process Deviations

The firm should have written procedures for ensuring effective clean up and re-sterilization of the sterile product portion of the line after a process deviation. Determine

the re-sterilization cycle for the equipment. If it is different, determine if a process authority recommended the re-sterilization cycle, and if the firm has a letter or other form of documentation establishing the parameters of the re-sterilization cycle.

 

When reviewing process deviation records, make sure they document:

 

1. Clean up of the system following a process deviation.2. Return of product sterilizer and all downstream equipment to a condition of

commercial sterility.

3. Disposition of any suspect product filled into containers.

 

If the firm does not keep the appropriate records, this should be an item for discussion on the FD483.

 

Scheduled Process for Reprocessed Products

If a firm decides to reprocess product that was involved in a deviation, several factors need to be taken into account, as not all products will flow the same. If the original product has turbulent flow characteristics, the product could exhibit laminar flow characteristics after the first process. This is especially true of products containing starch or other binders. Also, factors such as reprocessing the affected lots separately or together; or blended with new product can affect the process. During the inspection, determine if the firm has considered all factors that might affect reprocessing have been taken into account.

 

Package Sterilization Systems 

There are a variety of aseptic filling and packaging systems currently used in the United States for acid and low-acid foods. Generally, these may be described by inclusion in one of six categories:

 

1. Metal containers and closures: Figure 6 shows a system where containers are sterilized and filled using superheated steam as the sterilizing medium. (e.g., the superheated steam system).

2. Webfed paperboard: Figure 7 and 8 are sterilized using hydrogen peroxide and heat.

3. Preformed or partially formed paperboard is sterilized using hydrogen peroxide and heat.

4. Preformed plastic cups: Figure 9 are also sterilized using hydrogen peroxide and heat.

5. Thermoform-fill-seal: Figure 10 shows a system which uses hydrogen peroxide and heat or the heat of co-extrusion to sterilize.

6. Bag-in-Box system uses containers pre-sterilized by gamma irradiation.

 

The firm must file a scheduled process for its packaging system, including supplemental information regarding the critical factors involved in bringing the system to a condition of commercial sterility prior to start-up. This is done on Form FDA 2541c - "Food Canning Establishment Process Filing For Aseptic Packaging Systems." Also, the firm must have on file, a letter or other documentation from a process authority, which supports the filed scheduled process. Obtain a copy of the document, compare it to the filed scheduled process and become thoroughly familiar with the critical factors involved. A deviation from any of these specified critical factors constitutes a process deviation, which must be handled in accordance with 21 CFR 113.89.

 

CONTAINER STERILIZING, FILLING AND CLOSING OPERATIONS

 

Metal Containers and Closures

Equipment and controls

 

Recording devices- In order to demonstrate that the required sterilization is accomplished, firms use automatic recording devices. During the inspection it is important to document the number, location, and type of sensors used. In a steam sterilization system, such as the Dole unit, the basic components of the system are:

 

1. container sterilizing section,2. filling section,

3. cover or lid sterilizing unit, and

4. container closing section.

 

You should also know what critical factors are being monitored, e.g., temperature, sterilization media flow rate, etc...And determine if they are being recorded accurately. After identifying where the recording devices are, check to make sure equipment correspond in number and location to those on the filed scheduled process.

 

The firm also needs to assure that their recording devices are accurate.

 

If indicating-type thermometers are used, they must agree with the recording thermometers. For TID’s(Temperature Indicating Devices), determine if, how and when the firmscalibrate them and if calibration is accomplished at the scheduled process conditions.

 

Obtain a copy of the last calibration, the methodology used, and who conducted the test. It is important that monitoring equipment be calibrated in the range of operation (e.g., if the temperature is 200°C (400°F) for hot air used for container sterilization, then the monitoring equipment should be calibrated near that temperature).

 

Sterile Water- In aseptic systems using metal containers and closures, if cold sterile water is directed against the bottom of the containers after filling (or on the lids prior to closing), determine the firm's controls for ensuring the sterility of the water on a continual basis. If non-sterile water entered the filling area, this would constitute a process deviation.

 

Timing Method- Describe the firm's controls for ensuring the proper residence time of the containers and lids in the sterilizing medium. Check the container/closure flow rate with a calibrated stopwatch. If the firm uses an automatic device to monitor container/closure flow rates, determine how does the firm assure these devices are accurate. Describe the method for preventing unauthorized speed changes.

 

For the Dole can sterilizer, it is crucial that the sterilizer be at full speed at all times since any gaps in container flow through the sterilizer can result in some cans being retained for less than the scheduled time. This is because the conveyor or chain through the sterilizer may attempt to "catch-up" the trailing cans to the leading cans where a gap in containers occur.

 

Operation

 

Start-Up- The firm must follow their filed scheduled process for bringing the equipment to a condition of commercial sterility. A lack of proper time/temperature sterilization of the equipment is a process deviation and must be handled in accordance with 21 CFR 113.89. The thermocouple indicating sterilization temperature for the equipment will probably be the same one used to indicate the temperature during operations, and should be located in the most-difficult-to-sterilize area.

 

Suitability of containers and closures for sterilization-Determine how the firm assures that containers and covers are clean and dry prior to entering the steam chambers. Wet containers or covers cause a condensation of steam at the surface of the container. As sterilization takes place under atmospheric conditions, this means that the temperature of the can bodies and/or covers would rise no higher than 100°C (212°F), whereas the temperatures employed in the superheated steam unit are designed to give can temperatures of approximately 215.6-218.3°C (420-425°F) and cover temperatures of approximately 210-212.8°C (410-415°F).

 

Process deviations

 

Loss of temperature- During start-up, failure to achieve the time-temperature listed in the scheduled process for containers, closures and equipment is a process deviation and must be handled in accordance with 21 CFR 113.89.

 

In the event there is a loss of temperature during filling, determine what corrective action the firm takes. The corrective action should include things such as, automatically or manually stopping the line, diverting the product, and fixing the problem. If product was filled into containers, part of the corrective action would be to make sure that affected product is segregated.

 

Decreased residence time- If there is a decrease in residence time, determine if there is an alarm system or automatic stop of the line. If not, determine if the product is diverted or if filled containers are properly segregated. The firm also has to assure that the unit is properly re-sterilized after the deviation.

 

Loss of sterility in cooling water- Determine what the possibility is that there would be a loss of sterility in the cooling water and what the firm’s procedures are for recognizing the deviation and what corrective action would be taken.

 

Clearing container jams -If an operator has to enter the sterile zone (e.g., the seamer) with tools to clear can jams; determine the firm’s procedures to re-sterilize the zone.

 

PAPERBOARD OR PLASTIC CONTAINERS

 

(Webfed, Pre-formed or Thermoformed are filled/sealed using Hydrogen Peroxide as a Sterilizing Medium)

 

Equipment and Controls- Describe in detail, the firm's procedure for monitoring the following (if they are filed as critical factors for the scheduled process):

 

1. Peroxide consumption rate2. Peroxide concentration

3. Peroxide level (if immersion method used) or deposition (if roller applicator or fogger is used)

4. Temperature of warming air used to transport chemical sterilants

5. Air or heating element temperature (for removal of H2O2 and completion of sterilization)Note: Heat is generally applied by one of four primary methods:

a. A tube heater, located in the center of webfed paperboard as it is being formed into a tube.

b. A horizontally placed heating element located above containers into which H2O2 has been sprayed.

c. Air knives that blow hot sterile air against webfed paperboard or plastic after emergence from an H2O2 immersion tank and prior to forming.

d. Water-heated stainless steel drum.

6. Sterile air temperature (for incinerated air, subsequently cooled and used to provide over-pressure in a sterile zone)

7. Sterile air filters

8. Sterile air over-pressure

9. Gas flush - nitrogen or other sterile gases used to flush equipment or container headspace must be sterilized and maintained in a sterile condition. Determine how the

firm assures that the sterility of the gas is not compromised. Determine the maintenance schedule for filters used for sterile gases.

 

Determine if the sensors for monitoring the above factors are located to provide assurance that the factor is being monitored at its coldest or weakest point. Also, find out if the firm maintains nozzles that are used to spray chemical sterilants, or if pumps such as peristaltic pumps, are used to control sterilant spray volumes.

 

Operations

 

Start-Up- The firm must follow their filed scheduled process with respect to bringing the equipment to a condition of commercial sterility prior to filling. Firms will generally use a combination of steam or hot water (for the filling apparatus) and H2O2 mist or spray for the sterile forming (if necessary), filling and closing or sealing areas, collectively referred to often as the "sterile tunnel" or "sterile zone". Warming air to transport fog sterilants and drying air temperatures are often critical factors because they contribute to sterilization.

 

Packaging Materials, Handling Procedures-Determine the firm’s procedures for assuring high microbiological quality of packaging material received and used.

 

Process Deviations- Many of these packaging systems or units are equipped with controls which, if functioning properly, will automatically stop the machine and preclude the packaging of sterile product into insufficiently sterilized containers. Of critical importance is a determination that these controls or "guards" will operate as designed (i.e., in the event of a failure to meet a factor specified as critical to the scheduled process, the machine will, in fact, shut down automatically). Determine:

 

1. Who calibrates or checks the automatic controls or guards for proper operation, and the frequency of these checks and obtain a copy of the last calibration methodology and results.

2. How the firm challenges the control system and if possible, obtain a copy of the procedure as well as a copy of the most recent results.

Although these systems usually are operated in an automatic mode, most, if not all, appear to be equipped with a capability for a manual override of the automatic controls. Determine under what circumstances the machine would be operated in a manual mode, if product would be packed in this mode, and who has the authority to order such

operation. Also determine if inadvertent manual operation be detected during a routine review of processing records.

 

With respect to any controls or guards which are not automatically controlled, and which are critical to the scheduled process, determine how a process deviation would be detected and how would such a situation be handled by the firm?

 

H2O2 residual testing

 

Describe the firm's procedure for testing for H2O2 residual on the packaging material. Is the residual level in compliance with 21 CFR Part 178.1005(d)?

 

THERMOFORM-FILLED-SEAL CONTAINERS-PRE-STERILIZED BY HEAT OR CO-EXTRUSION

 

Equipment and Controls- Describe the firm's procedure for monitoring the following (if specified as critical to the scheduled process):

 

1. Pre-Sterilization (bringing equipment to condition of commercial sterility prior to thermoforming and filling)

2. Surface temperatures in various components of the sterile zone.

3. Hold time after temperatures have reached that specified in the scheduled process.

4. Overriding air pressure in the sterile zone.

 

Processing -

 

1. Filters for sterile air providing overriding air pressure during processing operations must be changed after a specified number of uses because they are in contact with incinerated air during the pre-sterilization cycle. Determine how often filters are changed to comply with that specified in the scheduled process and how the firm documents this.

 

Describe measures the firm employs to ensure protection of the sterile inner layer of the cup and lid material as it is received and used. Describe procedures for splice sterilization of cup and lidstock material rolls.

 

Operation - Determine the firm's procedure for ensuring that equipment is brought to a condition of commercial sterility, and that exposure of the sterile inner layer to the sterile zone at the beginning of the pre-sterilization cycle is performed in such a manner as to maintain the sterility of both the packaging material and the sterile form-fill-seal area (sterile tunnel).

 

Process deviations - Obtain the same type of information as previously discussed under process deviations involving systems using chemical sterilizers (e.g., H2O2).

 

BAG IN BOX PACKAGE SYSTEMS

 

Several manufacturing firms offer large bulk bags capable of holding several hundred gallons of product for aseptic filling. These bags are normally pre-sterilized with radiation. The bags are stabilized by an outer carton during filling and shipping. The outer carton may be reused several times, however, the bags and filler valves are used only once. Each bag is equipped with a fitment or valve which, when matched with the correct filler will allow for aseptic filling and emptying of the bag. Depending upon the system the filler nozzle may be sterilized by using chemicals (i.e., hydrogen peroxide) or steam.

 

Equipment and Controls - Describe in detail the procedures for monitoring the following:

 

1. Operation of the fitment.2. If steam is used to sterilize the fitment, how the sterilization process is monitored.

3. If chemicals are used to sterilize the fitment, how the chemical concentration is monitored.

4. What procedures the firm has in place to assure that sterile packaging materials are received and maintained sterile.

 

Note: Procedures used to sterilize the fitment are specified by a process authority.

 

RECORDS

 

Observations and measurements of operating conditions or factors critical to the scheduled process must be made and recorded at intervals of sufficient frequency to ensure the product is being maintained in a condition of commercial sterility. These measurements should be made at intervals not to exceed one hour. Describe the firm's record-keeping procedures for monitoring critical control points on the packaging systems or units. On initial inspections collect blank copies of record forms used and describe the type of information recorded.

 

CONTAINER CLOSURE EVALUATION

 

Describe in detail the firm's container closure evaluation system. For metal containers and closures, check for compliance with 21 CFR 113.60(a) & (a)(1). Determine the source and obtain copies of any container closure guidelines.

 

POST-PROCESS HANDLING

 

Describe the firm's post-process handling procedures. Check for compliance with specifications established by the container manufacturer. Describe in detail any deviations from container supplier recommendations for post-process handling.

 

TRAINING

 

Describe the firm's training program for operators of the product and package sterilization systems or units. The firm should maintain a documented training program for operators of sterilization and packaging systems. Determine if the equipment manufacturers offer additional technical support.

 

MAINTENANCE

 

Evaluate the firm's maintenance procedures packaging systems. Pay particular attention to that portion of the product sterilization system downstream of the holding tube. For example, plate-to-plate heat exchangers are susceptible to pin holing, flex cracks and gasket leaks. This would be a critical maintenance area for such a heat exchanger (such as a product-to-product regenerator or product cooler) located downstream of the holding tube. Proper maintenance of in-line static seals or gaskets in system piping downstream of the holding tube, particularly from the exit end of the final cooler to the filler is also critical. The firm should maintain a documented maintenance program for all equipment. Maintenance should be performed on at least the minimum schedule recommended by the equipment manufacturer.

 

SAMPLE COLLECTION

 

See IOM Sample Schedule Chart 2 for guidance.

 

Incubation Tests. Incubation is not a mandatory requirement of the regulations. When performed by a firm determine:

 

1. if containers are statistically sampled.2. how many containers are incubated.

3. time and temperature of incubation.

4. firm specifications for acceptability of lot.

5. if spoilage is detected by firms, do they perform spoilage diagnosis to determine cause. Specify method and describe lot disposition procedures.

 

Procedures for the evaluation of various containers used for packing aseptic LACF are contained in the LACF Inspection Guide Part 3.

 

TABLE I: ADVANTAGES AND DISTADVANTAGES :

 

DIRECT HEATING

 

The advantages are:

 

1. Rapid heating and cooling times resulting in less organoleptic damage to the product during heating.

2. Less fouling or "burn-on" of product in the heater.

 

The disadvantages are:

 

 

1. Because of the large volumes of steam that must be condensed, direct heating systems may be more difficult to control.

2. The addition of water (from the condensation of the steam) increases the product volume by approximately 1% per 10°F temperature increase above initial product temperature as it enters the product sterilizer. This increase in product volume must be compensated for by the process authority establishing the thermal processes if flow rate is controlled prior to direct heating. If such, initial temperature must be controlled and recorded (volume increases with temperature). For these systems flow rate would not need compensation for volume increase.

3. Steam used in direct heating of the product must be of culinary quality (appropriate for food contact). Culinary steam should be produced under conditions that meet safe boiler water requirements. Verify that the boiler water treatment compounds labeling meet the requirements of 21 CFR 173.310 by checking labeling of inventory or by examining letters of guarantee.

 

INDIRECT HEATING

 

The advantages are:

 

1. You can control temperatures of the food to be heated.2. You can process viscous products (i.e., purees, puddings and shake bases) without

burning the food.

3. Energy conservation (e.g., using sterilized product to heat unsterilized product and thereby cooling the sterilized product).

 

The disadvantages are:

 

1. Particle shear can occur.

 

OHMIC HEATING

 

The advantages are:

 

1. Rapid heating2. Can process foods with discrete particles.

 

The disadvantages are:

 

1. Requires extensive process validation testing.2. Complex control system.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Computerized Systems in the Food Processing Industry 

GUIDE TO INSPECTIONS OF

COMPUTERIZED SYSTEMS IN THE

FOOD PROCESSING INDUSTRY

 

 

TABLE OF CONTENTS

 

INTRODUCTION....Pg 1

 

CHAPTER 1 REGULATION OF COMPUTERIZED SYSTEMS . . Pg 1

 

Food Drug and Cosmetic Act

 

Good Manufacturing Practic Regulations

 

Inspection Concepts for Computerized Systems

 

 

 

CHAPTER 2 COMPUTER SYSTEM TECHNOLOGY . . Pg 6

 

Technology Overview

 

Computerized System Hardware

 

Environmental/EMI Hazards

 

Maintenance/Calibration

 

Computerized System Software

 

Personnel Qualifications

 

Process Documentation

 

CHAPTER 3 COMPUTERIZED SYSTEM VALIDATION . . Pg 12

 

CHAPTER 4 MONITORING OF COMPUTERIZED SYSTEM OPERATIONS. . .Pg 14

 

Input/Output Device Operation

 

Alarms

 

Manual Back-up Systems

 

Shutdown Recovery

 

REFERENCES . . Pg 17

 

APPENDIX 1 QUICK GUIDE TO COMPUTER SYSTEM EVALUATION. . .Pg 18

 

APPENDIX 2 DIAGRAM OF LOGIC CIRCUIT . . Pg 20

 

APPENDIX 3 DIAGRAM OF ALGORITHM . . Pg 21

 

 

 

INTRODUCTION

 

The use of computerized systems within the food processing industry regulated by the Food and Drug Administration (FDA) continues to increase. The use of computerized system technology is expected to continue to grow in the food industry as the cost of components decrease, as components are continually improved to withstand the rigors of the food processing environment, and as food companies continue to update production facilities, equipment and manufacturing processes in an attempt to produce high quality, high value products. New process design will strive to achieve safe quality products, while at the same time reducing production time and cost. The use of computerized control systems in the production of food products lends itself to fulfilling those goals.

 

As computer systems become instrumental in providing for the safety of FDA regulated food products, the FDA must verify that proper controls were employed to assure that accurate, consistent and reliable results are obtained from computer control and data storage systems.

 

This document is intended to serve as a resource for FDA investigators who conduct inspections of regulated food firms that use computers and computer software to control operations and record data that may affect the safety of the finished food product. The Guide was written by the Office of Regulatory Affairs (ORA), Division of Emergency and Investigational Operations (DEIO) and the Center for Food Safety and Applied Nutrition (CFSAN). If you discover errors in printing or have suggestions for changes which you feel will contribute to the goal of increasing inspectional quality and uniformity, please communicate your written comments or suggestions to DEIO, HFC-130 or send via e-mail (internal Banyan address) to: DEIOFOODS@LISTS.LOCAL@FDAORAHQ.

 

CHAPTER 1: REGULATION OF COMPUTERIZED SYSTEMS

 

A. FOOD, DRUG AND COSMETIC ACT

 

FDA's authority to regulate the use of computers in food plants is derived from the Food Drug and Cosmetic (FD&C) Act Section 402 (a) (3) "A food shall be deemed to be adulterated if it consists in whole or in part of any filthy, putrid, or decomposed substance, or if it is otherwise unfit for food,"Section 402 (a) (4)"A food shall be deemed to be adulterated if it has been prepared, packed or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health," Section 412, Requirements for Infant Formula, and the Emergency Permit Control section 404 for thermally processed low-acid canned and acidified low-acid foods.

 

Documents governing the use of computerized systems under the PMO (Pasteurized Milk Ordinance) Cooperative Program contain additional requirements and/or guidelines.

 

B. GOOD MANUFACTURING PRACTICE REGULATIONS (CFR TITLE 21)

 

The following information provides a guide to those areas of specific 21 CFR regulations that have been or may be used to regulate the use of computerized systems in food manufacturing plants. This guide may not include all CFR references under which computerized systems can be regulated.

 

PART 11 ELECTRONIC RECORDS AND SIGNATURES

 

This regulation allows regulated industry to electronically maintain those records required to be kept by the current regulations. Records which are electronically maintained following the provisions of 21 CFR Part 11 will be recognized as equivalent to traditional records. In addition electronic signatures used as per the provisions of this regulation will be equivalent to full handwritten signatures and initials, unless specifically exempted by regulations issuing after the effective date of the regulations. In order to do so a firm must certify to the agency that validated controls are in place.

 

PART 106 INFANT FORMULA QUALITY CONTROL PROCEDURES

 

On July 9, 1996 the FDA published in the Federal Register proposed amendments to CFR Title 21 parts 106 and 107 titled Current Good Manufacturing Practice, Quality Control Procedures, Quality Factors, Notification Requirements, and Records and Reports, for the Production of Infant Formula which add specific requirements for the use of computerized equipment in the manufacturing of infant formula. The proposed requirements include:

 

1. Definitions of hardware, software, system, and validation.2. Requirements that systems be designed, installed, tested and maintained in a

manner that will insure that they are capable of performing their intended functions.

3. Requirements for system validation and calibration.

4. Requirements for verification of input/output data to insure its accuracy.

5. Requirements for revalidation when system changes are made.

6. Requirements for making and retaining records concerning electronic systems.

(Note the proposed regulations have been published but are not yet final)

 

 

 

PART 110 CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PACKING

 

AND HOLDING HUMAN FOOD.

 

FDA regulations 21 CFR Part 110, promulgated under the authority of the FD&C Act, do not specifically address the use of computerized systems. However, there are many inferences to the agency's authority over such systems.

 

1.) Subpart C Equipment, 110.40 (a) requires That "The design, construction, and use of equipment and utensils shall preclude the adulteration of food with lubricants, fuel, metal fragments, contaminated water, or any other contaminants."

 

2.) Subpart C Equipment, 110.40 (f) requires that "Instruments and controls used for measuring, regulating, or recording temperatures, pH, acidity, water activity, or other conditions that control or prevent the growth of undesirable microorganisms in food shall be accurate and adequately maintained."

 

3.) Subpart E, Production and Process Controls, 110.80 states that "all reasonable precautions shall be taken to ensure that production procedures do not contribute contamination from any source." It continues in 110.80 (b) (2) that "all food manufacturing . . . shall be conducted under such conditions and controls as are necessary to minimize the potential for growth of microorganisms, or for the contamination of food."

 

Implied and explicit references for the need to have computerized controls be accurate and reliable may be found in other locations of the GMPs Part 110 depending upon the function of the computerized system in the food process.

 

PART 113/114 THERMALLY PROCESSED AND ACIDIFIED LOW-ACID CANNED FOODS.

 

FDA's Center for Food Safety and Applied Nutrition (CFSAN) has determined that the use of computerized systems to record LACF processing information and/or to perform real-time process deviation corrections as required under 21 CFR Part 113, Thermally Processed Low Acid Canned Foods in Hermetically Sealed Containers, is acceptable. CFSAN reviews these systems to determine the computerized system performs the function in a manner that is equivalent to the intent of the regulations.

 

Computer equipment vendors who wish to market their computer systems for LACF record keeping functions and/or to perform real time process deviation corrections, have been advised they may submit their computer systems to FDA's CFSAN for a review which may consist of:

 

1. a visit to FDA by the system vendor or user to explain the operation of the computer system;

2. a visit by FDA to the vendor to examine the hardware and software development, validation and documentation procedures; and,

3. a visit by FDA to a production site to evaluate the computerized record keeping/control system under commercial conditions.

In the past, vendors who submitted their computerized systems to this type of review and were found to be satisfactory, received a letter stating that FDA found the computerized system, as evaluated, to meet the intent of the regulations. Use of this voluntary submission of computerized systems to FDA for evaluation subjected the vendor to requirements to update FDA when substantial changes are made in the computerized system, a requirement that FDA investigators would be provided on-site access to the vendor's computer equipment/software operating instructions, and a requirement that the vendor instruct the customer in procedures for using, maintaining and updating the computer software and equipment.

 

Field Investigators should be aware that LACF computer controlled recording and real time process deviation correction systems do exist that have been evaluated by FDA. If the firm claims that the computerized system and/or software has been evaluated by FDA the firm should have on hand a copy of the FDA letter to the vendor stating that the computerized system or software has been evaluated and found to meet the intent of the regulations for record keeping. If there are questions or concerns, CFSAN (Chief Regulatory Food Processing and Technology Branch, HFS-617, Tel: 202-205-4842) should be contacted to verify that the vendor has been issued a letter or handled otherwise.

 

There is no requirement that computerized systems used to control or record LACF functions be evaluated by FDA prior to use. When computerized control/record keeping systems are encountered that have not received prior review by CFSAN, the Field Investigator must make a complete evaluation of the computerized system (See Inspection Concepts for Computerized Systems). A copy of the report should be submitted to HFS-617 for evaluation.

 

Computerized systems are used not only for the generation of LACF processing records, but for control functions such as: formulation control, process deviation calculations, process temperature, process pressure, process timing and container closure examination. The control of functions that may be critical to ensuring a safe food product, must also be reviewed by the investigator to determine that they meet the intent of the LACF regulations.

 

PART 123 FISH AND FISHERY PRODUCTS.

 

FDA's HACCP regulations Title 21 CFR Part 123-Fish and Fishery Products does not specifically state requirements for the use of computers and computer software except for section 123.9 (f) which requires that appropriate controls are implemented to ensure the integrity of electronic data and signatures. It is implied elsewhere in the regulations that systems used to control the production of Fish and Fishery Products shall not cause the products to be adulterated. Computerized systems controlling critical control points should be evaluated using HACCP techniques by the manufacturing firm during development of the firm's HACCP Plan.

 

 

PART 129 BOTTLED DRINKING WATER.

 

Title 21 CFR Part 129- Processing and Bottling of Bottled Drinking Water, Sub-part C-Equipment section 129.40 requires that all equipment used in the bottling operation be suitable for use. Section 129.80 of Sub-part E production and Process Controls requires that the treatment of product water shall be performed by equipment which does not adulterate the finished product.

 

C. INSPECTION CONCEPTS FOR COMPUTERIZED SYSTEMS

 

The investigator must keep in mind the limitations of specific regulations regarding the use of computers in food processing plants, other than infant formula manufacturers, and FDA's lack of specific authority to examine computer software and computer hardware documentation in those plants. However; as long as the computerized system controls or records part of or the entirety of a manufacturing process, the manufacturer is responsible for establishing that the computerized system functions as it was intended to function. During the inspection of a food manufacturer where a computerized system is in use, the investigator is entitled to be provided with the assurance that the process functions controlled by the computer operate as designed. It is important to remember that computer control and/or record keeping systems must provide for accurate, reliable and consistent results.

 

The investigator should evaluate the operations of computerized systems during the inspection to determine if the use of the computer and/or software may lead to adulteration of the finished food product. Many computers used in the food industry may be used for quality purposes only and will not affect the safety of the food product. For example, if the computer is controlling an oil fryer temperature in a potato chip factory, the criticality of the temperature control function may be a matter of resulting in a batch of darker tinted chips. On the other hand, if the computer system controls the

sterilization temperature of an LACF process, it is critical that the computerized function provide consistent and reliable performance. HACCP (Hazard Analysis Critical Control Point) inspection concepts can be used to identify those critical food processing and documentation steps controlled by a computerized system.

 

When a computerized system is encountered in a food establishment, it may be useful for inspection purposes to begin with a broad overview of the system(s). Determine exactly which functions are under computer control, monitoring or documentation and which are not. For each function of a food process under computer control determine the general system loop (sensors, central processor, activators). For example, the general system loop for a steam retort under computer control could consist of temperature/pressure sensors connected to a microprocessor that transmits commands to steam/pressure control valves. The overview should enable the investigator to identify those computer controlled functions that are critical to food product safety. These are the functions of the computerized systems that merit closer inspection.

 

Often food manufacturing firms may not have on hand detailed information covering the development and validation of the software and microprocessors used in their processing systems. Many firms buy the microprocessors as off the shelf technology from the equipment vendor. The investigator should then determine the functions of the control system in as much detail as possible. If the firm has a schematic drawing of the computerized system this may be obtained or the

 

investigator may prepare a simplified schematic drawing, which will be helpful in explaining the computerized systems operations and configuration. The drawing should include major input devices, output devices, signal converters, central processing unit(s), distribution systems, and how they are linked. During the inspection identify the manufacturers and suppliers of important computer hardware, including the make and model designations where possible. Hardware to identify this way includes CPUs, disk/ tape devices, CRTs, printers, input sensors, output activators and signal converters. Proper identification of hardware will enable further follow-up should that be needed. If the firm does not have detailed information on the computerized control system, the investigator should obtain any limited information that is available.

 

During the inspection identify key computer software used by the firm. Of particular importance are those software routines that control and document critical production steps and laboratory testing to support critical functions (such as the addition of nutrients to infant formulas). A schematic of the major software routines and how they interact should be obtained from the firm or prepared by the investigator based on observation or other documentation. Directories or list of software routines and subroutines can sometimes be displayed on the CRT display or printed out. For some

application software a list of routines can only be provided by the software vendor and may not be available at the manufacturing firm.

 

Determine how software is set up to handle input data. For example, determine what equations are used as the basis for calculations in a routine. When a food manufacturing process is under computer control describe, in simplified form such as a flow chart, how input is handled to accomplish the various steps in the process. This does not mean that a copy of the computer software source code itself needs to be reviewed. However, before applying computerized control and record keeping to a food process there usually needs to be some document, written in English, setting forth in logical steps what needs to be done; it would be useful to review such a document in evaluating the adequacy of conversion from manual to computerized processing.

 

Observation of the system as it operates can be used to determine if critical factors such as revolutions per minute (rpm), vent times, temperatures, pressures, thermal process times, and documentation are being controlled by the computerized system. Operation of the system should be observed through several process cycles. However, end product testing (observation) of the computer system should not in itself be relied upon to provide assurance that the system is operating as designed. End product observation will not test all of the different possibilities that a computer system will respond to during a process. Importantly it will not reveal the systems behavior at the permissible limit of functionality and performance. The only way to develop confidence that the computer system is going to function correctly is to have a validation program as part of the design, coding, testing, and implementation steps (See Section on Computerized System Validation).

 

The investigator should determine who is responsible for programming the system, how the system is programmed, the name and number of programmable functions, if the programming functions are password or otherwise protected, and who is responsible for record review (including system and process documentation records) and computerized system verification.

 

It is also important to find out if the operator or management can override any of the computer control functions. If operator/management override of computer functions are possible details on how this is done, what overrides are possible, and how overrides appear in the processing record should be determined.

 

The investigator should find out how the system handles deviations from set or expected results during processing. If the computer system can adjust critical manufacturing parameters, calculate new manufacturing parameters or choose alternate

preprogrammed procedures the investigator must determine the parameters for computing or selecting the alternate procedures.

 

During inspections of food firms using computerized systems to control and/or record critical functions (e.g., retort sterilization temperature, smoked fish internal temperatures) or to control other factors critical to the food manufacturing process (e.g., viscosity of a thermally processed LACF, water activity of a dehydrated food) the minimum information to obtain would include:

 

a. The equipment specifications for software and hardware.b. The critical factors controlled by the system.

c. How the critical factors are controlled?

d. How does the firm ensure that the microprocessor or computer is indicating the correct information (validation)?

e. How and how often is the equipment calibrated and/or checked for accuracy?

Documentation showing that a computerized operation may contribute or contributes to the adulteration of a food product will take an extended effort by the investigator. Development of evidence of food adulteration caused by the operations of a computerized system should be discussed with CFSAN/OFP/Division of Enforcement (HFS-605).

 

During the inspection of food processing facilities the responsibility of the food manufacturing firm regarding their use of computerized systems to control or record the critical safety aspects of food manufacturing should be discussed with the facilities management. The FDA investigator should make the firm's management aware that a computerized system includes the hardware, software, personnel, and operating procedures required to operate the system. Management at the firm should be made aware that the computerized system should be validated in place under actual operating conditions by the firm (See Section on Computerized System Validation).

 

 

 

The applicable sections of the listed references should be used, in addition to this guide when inspecting firms using complex computerized systems.

 

CHAPTER 2 COMPUTER SYSTEM TECHNOLOGY

 

A. TECHNOLOGY OVERVIEW

 

In recent years digital electronic controllers have replaced the relays and sensing switches of mechanical/analog-electrical control systems used in food processing. Digital control systems may range from the single-loop controller to complex high-end computer systems.

 

If the function to be controlled consists of numerous sequential (logical) steps, the controlling device can be a first-level computer device called a logic controller. The logic controller may be set up as a single loop controller.

 

A single loop controller would be responsible for controlling one function, such as temperature in a steam kettle. The controller loop would be programmed to control the kettle temperature within set temperature parameters. The loop would consist of the microprocessor controller, a temperature sensor, an actuator for the steam valve and a digital/analog signal converter.

 

Simple single loop controllers contain Read Only Memory (ROM) which is manufactured into the controller or programmed into the controller by using Programmable Read Only Memory (PROM), Erasable Programmable Read Only Memory (EPROM) or Electronically Erasable Programmable Read Only Memory (EEPROM).

 

PROM is field programmable by the manufacturer or customer once only by burning out fuses in the PROM microprocessor chips. EPROM is electronically programmed by the manufacturer or user. EPROM microprocessor chips are reprogrammed by exposing the chip to an ultraviolet light source that resets the original chip configuration. EEPROM microprocessor chips can be reprogrammed by electronically erasing the memory on the chip. ROM is normally used to control functions where the options of the customer or operator do not need to be changed. Random Access Memory (RAM) using battery backed volatile memory components is another type of memory component. This memory requires a power supply but lends itself to modification and

 

reprogramming. Advanced microprocessor or computer systems would normally use a combination of ROM and RAM to program control of processing functions.

 

A more advanced system would use a programmable logic controller (PLC) which would allow the operator or firm to alter the control limits of the controller (See Appendix 2). This type of controller would use algorithms (a programmed procedure for solving a problem) to control the loop. Algorithms are written to provide the microprocessor with a logical sequence of events for solving a problem (See Appendix 3).

 

Control of multiple parameters such as temperature, pressure, pumping rate, rotation, etc. may be performed by installation of several loop controllers controlled by one PLC, microprocessor or computer.

 

Computers are different from hardwired controls in three major categories. To provide for adequate control of critical control points in food processing and/or documentation, the design of the computerized controls must address these three major areas:

 

1. First, unlike conventional hardwired systems, which provide for full-time monitoring of critical functions, the computer performs its task sequentially, and the computer may be in real time contact with the sensor for only one millisecond. During the next 100 milliseconds (or however long it takes the computer to cycle one time through its task), the critical sensor is not monitored. Normally this is not a problem, because most computers can cycle through their program steps many times during one second. The problem occurs when the processing computer is directed away from its task by another computer, or the computer software program is changed, or a seldom used JUMP, BRANCH or GO TO Instruction diverts the processing control computer away from its control or monitoring function.

2. In a computerized system the control logic may be easily changed if the computer software can be easily changed. Some security measures are needed to ensure that the computer has the correct software in place.

3. Some computer experts have stated categorically that no computer software can be written error-free. While this may be true for very large software routines with thousands of lines of code, most of the software routines used for control and documentation of critical functions in food processing are relatively brief. Software that controls functions critical to food safety can and should be made error-free.

 

B. COMPUTERIZED SYSTEM HARDWARE

 

Input Devices: Equipment that translates external information into electrical pulses that the computer can understand. Examples are thermocouples, RTDs (Resistance Temperature Devices) flow meters, load cells, Ph meters, pressure gauges, control panels, modems, cathode ray tubes (CRT), data entry touch screens and operator keyboards.

 

Examples of functions are:

 

a. Thermocouple/RTD provides temperature input for operation of a retort.b. Flow meter provides volume of liquid component going into a mixing tank.

c. Operator keyboard used to enter weights, batch, menu number and other processing information.

 

Output Devices: Equipment that receives electrical pulses from the computer and either causes an action to occur, generally in controlling the manufacturing process functions, or passively records data. Examples are valves, switches, motors, solenoids, cathode ray tubes (CRTs), printers, and alarms. Examples of functions are:

 

a. Solenoid activates the impeller of a mixer.b. Valve controls the amount of steam delivered to a thermal process.

c. Printer records significant events during a sterilization process.

d. Alarm (buzzer, bell, light, etc.) sounds when temperature in a holding tank drops below the desired temperature.

 

Most output devices will be in proximity to the food processing equipment under control, but not necessarily close to the CPU. Some output devices such as printers may be located away from the immediate processing area.

 

Signal Converters: Many input and output devices operate by issuing/receiving electrical signals that are in analog form. These analog signals must be converted to digital signals for use by the computer; conversely, digital signals from the computer

must be converted into analog signals for use by analog devices. To accomplish this, signal converter devices are used.

 

Most signals are analog until they reach the computer. Transducers are often used to send the analog signals to the computer or PLC. For example a temperature measuring device will be attached to a transducer within a very short distance from the device itself. The transducer will have a defined span (0-150 C) to send its 4-20 milliamp signal to the computer, where it is then converted into a digital value. Digital transducers are available, but their expense has resulted in limited use. Many PLC systems will have only 8 bit A/D converters, which means that the span on the 4-20 milliamp transducer is now critical to the resolution of the signal as seen by the computer and thus, its ability to control the function. Another problem with transducers is that some new ones are "auto-calibrating." What this means is that when the system is powered up the base line and span of the transducer is recalibrated or adjusted, and this results in an adjustment in the signal sent to the computer that may be different from the device's original calibration. For example, temperature values may change as much as 0.5 C from day-to-day because of this. A properly validated system will have taken this into account, which means that maintenance of the system and the proper replacement of sensors and transducers is critical to the systems ability to control the food manufacturing process functions as originally designed. Design specifications should be reviewed to determine the type and model number of all the sensors and transducers to insure that as maintenance was performed on the system the correct electrical components were used.

 

Normally the only part of a control system that Communicates using a digital signal is the computer process control network. Most all A/D signal conversion occurs immediately at the PLC or computer and all PLC-PLC, PLC-computer and computer-computer interaction is digital.

 

Proper input/output signal conversion is important if the computer system is to function accurately. Poor signal conversion can cause interface problems. For example, an input sensor may be feeding an accurate reading to a signal converter, but a faulty signal converter may be sending the CPU an inappropriate signal. In some cases faulty signal converters may be recognized by observing the difference between what is indicated on a separate readout or by a separate instrument and the reading presented by the computerized system. For example if an RTD readout indicated a temperature of 80 C in a steam jacketed kettle and

 

the computerized system CRT reads 100 C you might suspect a faulty signal converter. One way to make sure that proper signal conversion is going on is to make sure that the original specifications for the system agree with the maintenance records for the system. If the maintenance records are not available the original specifications of the system

should be checked against the equipment on the system. Proper signal conversion is best addressed by performing input/output checks. The food manufacturer needs to have in place a procedure by which all input/output signals are checked for accuracy. (See Monitoring of Computerized Operations, Input/ Output Checks)

 

Central Processing Unit (CPU) This is the controller containing the logic circuitry of a computer system that conducts electronic switching. The size of the computer needed for control depends upon the number of loops to be controlled and whether the system is set up as an independent, centralized, or a distributed system. Logic circuits consist of three basic sections - memory, arithmetic, and control. The CPU receives electrical pulses from input devices and can send electrical pulses to output devices. It operates from input or memory instructions. Examples and functions are:

 

a. Programmable controllers used for relays, timers and counters.b. Microprocessors used for controlling a steam valve, maintaining pH, etc. They

consist of a single integrated circuit on a chip. This is the logic circuit of a microcomputer and microprocessors are often the same as a microcomputer.

c. Microcomputers and minicomputers used to control a sterilization cycle, keep records, run test programs, perform lab data analysis, etc.

d. Mainframe computers are generally used to coordinate an entire plant, such as environment, production, records, and inventory.

 

Distribution System: The method used for interconnection of two or more computers.

 

In the independent system, each manufacturing operation is controlled by its own PLC or microprocessor. If a control system fails, the remainder of the systems would continue to operate.

 

In a centralized system, all data would be collected and analyzed by a central computer. This provides for quick capture of all processing information and for control from a central location. Failure of this control system would mean that all processing systems would be down.

 

In the distributed system, a PLC or microprocessor can be used for independent control of each production system. The process microprocessor is then used to supply information to a separate host computer that captures all processing control data for

storage and printing. The host computer in turn stores process software and is used to program the logic controls of the microprocessor(s).

 

In distributed systems it is important to know how errors and command overrides at the computer are related to operations at another computer in the system. For example, if each of three interconnected microcomputers runs one of three retorts, can a command entered at one unit inadvertently alter the sterilization cycle of a retort under the control of a different microcomputer on the line? Can output data from one be incorrectly processed by another unit? The limits on information and command flow within a distributed system should be clearly established by the firm.

 

Networks are generally extensions of distributed processing. They may consist of connections between complete computer systems that are geographically distant or they may consist of computer systems on a local area network (LAN) in the same facility.

 

If the firm is on a computer network it is important to know:

 

a. What output, such as batch production records, is sent to other parts of the network;

b. what kinds of input (instructions, software programs) are received;

c. the identity and location of establishments that interact with the firm;

d. the extent and nature of monitoring and controlling activities exercised by remote on-net establishments; and,

e. what security measures are used to prevent unauthorized entry into the network and possible unwarranted food process alteration, or obliteration of food process controls and records.

 

Peripheral Devices: All computer associated devices external to the CPU can be considered peripheral devices. This includes the previously discussed input and output devices. Many peripheral devices can be both input and output, they are commonly known as I/O devices. These include CRTs, printers, keyboards, disk, modems and tape drives.

 

 

C. ENVIRONMENTAL/EMI HAZARDS

 

Location: Potential problems have been identified with location of CPUs signal transmission lines and peripheral devices. These Include:

 

Hostile Environments: Environmental extremes of temperature, humidity, static, dust, power feed line voltage fluctuations, and electromagnetic interference should be avoided. Such conditions may be common in certain operations and the investigator should be alert to locating sensitive hardware in such areas. Environmental safeguards may be necessary to ensure proper operation.

 

Electromagnetic Interference (EMI): Low voltage electrical lines from input devices to the CPU are vulnerable to electromagnetic interference. EMI may result in inaccurate or distorted input data to the computer. Therefore, peripheral devices should be made immune to electromagnetic interference (EMI) such as electrical power lines, motors, portable telephones, walkie-talkies, radio/TV broadcasts, and fluorescent lighting fixtures. Peripheral devices and signal transmission lines should be located as far as possible from sources of electromagnetic interference. Shielding of signal transmission lines, grounding, filters, circuit design and proper design of the device's cabinet or housing are acceptable methods to prevent EMI.

 

Distance Between CPU and Peripheral Devices: Device proximity to the PLC/computer may be important concerning loss of signal due to electrical resistance of the signal transmission lines. To correct this problem the device may be located near the PLC/computer or signal transmission lines having less electrical resistance (i.e. 2 wire vs. 4 wire RTD) may be used.

 

Proximity of Input Devices to Food Processing.

 

Input devices such as employee interfaces should be located as close as possible to the operation being controlled.

 

D. MAINTENANCE/CALIBRATION

 

Computer systems normally require a minimum of complex maintenance. Electronic circuit boards, for example, are usually easily replaced and cleaning may be limited to

dust removal. Diagnostic software is usually available from the vendor to check computer performance and isolate defective integrated circuits. Maintenance procedures should be included in the firm's standard operating procedures. The availability of spare parts and access to qualified service personnel are important to the operation of the maintenance program.

 

The firm should use replacement parts which meet the specifications of the original computer system design or the system should be revalidated to document that the replacement parts perform as per the original specifications of the computer system.

 

Sensors used as part of the computerized system, monitoring or controlling process functions, should be checked for accuracy in the set operating range of the function being controlled or monitored during production. For example if an RTD is used to sense the temperature of a retort system operating at 250 F, the RTD should be accurate at 250 F and not just at some lower temperature, such as at 212 F.

 

Computerized systems used to control, monitor or record functions that may be critical to the safety of a food product should be checked for accuracy at intervals of sufficient frequency to provide assurance that the system is under control. If part of a computerized system that controls a function critical to the safety of the food product is found not to be accurate, then the safety of the food product back to the last known date that the equipment was accurate must be determined. (e.g., an RTD is providing a signal which indicates that a thermal process is operating at 95øC, when is fact the process is operating at 90øC. If 90øC is below the firms established critical limit for food safety, the safety of the food may be in question. If this was noted on March 23 and the RTD was last checked for accuracy on January 1, the food processed from January 1 to March 23 should be evaluated for safety).

 

The manufacturers/vendors of computerized system components normally recommend minimum maintenance schedules including accuracy checks of their components.

 

E. COMPUTERIZED SYSTEM SOFTWARE

 

Software is the term used to describe the total set of programs, procedures, rules, and any associated documentation pertaining to the operation of a computerized system and includes: application, operating system, and utility software used by the computerized system (see Glossary of Computerized System and Software Development Terminology, August 1995).

 

Name: Software routines are usually named with some relationship to what they do, i.e., Production Initiation, Batch Production or Alarm. The name of the software may be followed by a version number (i.e., DOS 6.0) that indicates where that particular software version falls in the release history of the software (i.e., between DOS 5.2 and DOS 6.2)

 

Function: Software routines should have a defined function or purpose, i.e., start production, record and print alarms, or calculate Fo.

 

Input: Inputs, such as thermocouple signals, timer, or analytical test results should be identified.

 

Output: Output signals generated by the software may result in a form of mechanical action (valve actuation) or recorded data (generation of records). Outputs should be identified.

 

Fixed Set point: This is the desired value of a software function variable that cannot be changed by the operator during execution. Determine major fixed set-points, such as desired time/temperature curve, desired pH, etc. Time may also be used as a set point to stop the computer controlled process to allow the operator to interact with the system.

 

Variable Set point: This is the desired value of a software function variable that may change from run to run and must usually be entered by the operator. For example, entering the initial temperature of a LACF thermal process for each retort load.

 

Fuzzy Logic: Computerized systems utilizing fuzzy logic are increasingly being developed and used in food processing. Fuzzy logic differs from conventional logic in that the information used to control the system is neither definitely true nor false. Fuzzy logic control is carried out by implementing linguistic decision rules that come from the experience of operators or the knowledge of industry experts. Input from several sources may be used by the fuzzy logic controller to form the output decision of the computer system. A complete discussion of fuzzy logic control systems is beyond the scope of this document, the investigator should however be aware that this type of logic controller may be found in food manufacturing. Examples of everyday equipment using fuzzy logic would be: Television sets with automatic color control, hand held camcorders that compensate for operator movement and anti-lock braking systems used

on automobiles. Potential problems with these type of control systems is that they can be programmed where there is no fixed set point by which the software function is controlled. When fuzzy logic controllers are used to control factors critical to the safety of a food manufacturing process a more detailed review of the control system is warranted. Determine if a record is made of control of the critical factor by the computerized system. A permanent record or an alarm function may be used to verify that a fuzzy logic controller controls each critical factor at or beyond its critical limit.

 

Edits: Software may be written to reject or alter certain input or output information that does not conform to some predetermined criterion or otherwise fall within certain pre-established limits. This is an edit and it can be a useful way of reducing errors; for example, if a certain piece of input data must consist of a four-character number, software edits can be used to reject erroneous entry of a five-character number or four characters comprised of both numbers and letters. On the other hand, edits can also be used to falsify information and give the erroneous impression that a function is under control. For example, a software output edit may add a spurious "correction" factor to temperature values that fall outside the Pre-established limits, thus turning an unacceptable value into an "acceptable" value. It is, therefore, important to attempt to identify significant software edits during the inspection, whenever possible. Sometimes such edits can manifest themselves in unusually consistent input/output information.

 

Software Over-rides: Software may be designed so that the sequence of programmed events or edits can be overridden by the operator. For example, a function controlling routine may cause an ingredient auger motor to stop when the weigh scale contents reach a predetermined weight. The software may prevent the auger motor from resuming activity until the weight has dropped back to the established set point. However, the same software may allow an operator to override the stop and reactivate the auger motor even at a weight that exceeds the set point limit. It is therefore important to know what overrides are allowed, if they conflict with the firm's operating instructions and how the system documents the override event(s).

 

Software Development: During the inspection determine if the computer software used by the firm has been purchased as "off the shelf" from outside vendors, developed within the firm, prepared on a customized basis by a software producer, developed by a third party vendor or some combination of these sources. Some software is highly specialized and may be licensed to food establishments. If the software used by the firm is purchased or developed by outside vendors, determine which firms prepared the software.

 

Sometimes "off the shelf" or customized software may contain segments (such as complex algorithms) which are proprietary to their authors and which cannot normally be readily retrieved in program code without executing complex code breaking

schemes. In these cases the buyer should obtain validation documentation from the supplier to ensure that the software will perform as designed. If the food manufacturer is using such software to control or monitor a critical control point in the food process, determine what steps the firm has taken to verify that the software is performing as it was designed. Where food firms develop their own application software, review the firm's documentation of the approval process. This approval process should be addressed in the firm's written development instructions. It may be useful to review the firm's development (English) documents that formed the basis of the computer software (See Software Development Activities, July 1987, U.S. Department of Health and Human Services, Food and Drug Administration).

 

Software Security: Determine how the firm prevents unauthorized software changes and how data is secure from alteration, inadvertent erasures, or loss. Determine whom in the firm has the ability and/or is authorized to write, alter or have access to software. The firm's security procedures should be in writing. Security should also extend to devices used to store software, such as tapes and disks. Determine if accountability is maintained for these devices and if access to them is limited.

 

An important part of software security is change control. The firm should have in place a written procedure by which changes are made to software. This will include identification of a software error, how it was corrected, who performed the correction, did the changes influence any other portions of the software program, were the changes validated specifically and then as they related to other portions of the software program, and how the changes were documented. Software has a circular life-cycle that requires a defined maintenance procedure be followed (See Computerized System Validation ).

 

F. PERSONNEL QUALIFICATIONS

 

Personnel operating, maintaining and programming computerized control systems should have adequate training and experience for performance of their assigned duties. Determine the extent of operator, system managers, and computer system technical personnel training in the functions, requirements and operation of the computerized system. Training should include not only system operation but cover the significance of system faults (bugs), regulatory requirements, system changes, security procedures, manual operation of the system, and documentation of system errors. Training of computerized system personnel should be documented by the manufacturing firm.

 

The investigator should determine the key computerized system personnel during the inspection. This may include not only the firm's own employees but outside vendors or consultants. For each of the key employees, determine to the extent possible, that

employee's responsibility for the computerized system. It is important that technical personnel are available or can be reached during computerized system failures.

 

G. PROCESS DOCUMENTATION

 

Most computerized systems are capable of generating accurate and detailed documentation of the food process under computer control. What is important is that the computer generated records contain all of the information required by the CGMPS. For example, if production records are generated by computer, determine if they contain all of the information required to be in each record(s).

 

The firm should have security measures in place to insure that data captured by the computerized system cannot be altered. If provisions are made to allow correction of data entries, the entry should identify the person making the changes and the reason for the change should be identified. For example an operator misreads a temperature indicator and enters the information into the system. The computer system then alarms the operator that the entry is out of the correct range. The operator then enters the correct temperature which is accepted by the system. All of the above should be captured on the firms records. For those firms storing records electronically, provisions should be made to store the records in a format which cannot be easily altered.

 

Computerized systems generating critical control monitoring records must be capable of recording the lowest and/or highest value (depending upon the critical control limits) measured between two recording points. (for example, the sensor sends a vessel pressure to a computer continuously, even though the signal is recognized by the computer every few milliseconds, it is only printed out once every 2 minutes, it may be critical to know the lowest vessel pressure during that 2 minute period).

 

Electronic records must be maintained in a format that can be presented to the investigator in a readable form. This could be in the form of electronic data that can easily be accessed and read by common computer software or in the form of accurate hard copy documents produced from electronic records maintained by the firm.

 

Electronic Signatures if used should be controlled by the firm under written operating procedures, which insure that the electronic signature is a valid representation of the individual making the entry. Operator entry codes should be protected so that they can be used only by the person assigned that code. Electronic signatures should meet all of the requirements of FDA's final rule, 21 CFR Part 11, regarding electronic signatures.

 

CHAPTER 3 COMPUTERIZED SYSTEM VALIDATION

 

A computerized system includes: the computer hardware, computer software, peripheral devices, personnel, and computer system documentation (including computer hardware and software manuals, specifications for peripheral devices and standard operating procedures).

 

The computerized system used to control critical functions in food processing should be validated in its entirety.

 

The suitability of a computerized system for the tasks assigned to food production should be shown through appropriate tests and challenges. The depth and scope of computerized system validation will depend upon the complexity of the system and its potential effect on food safety. The validation program need not be elaborate but should be sufficient to support a high degree of confidence that the computerized system (software, hardware, personnel and operating procedures) will consistently perform as it is supposed to (See System Testing Reference "Software Development Activities Report). Although various components of the computerized system may be tested separately (qualification), the total computerized system should be validated. Validation requires the system, as it will be configured and used in production to be shown to behave as expected (defined or specified) not only for normal conditions and inputs, but importantly that it continues to provide control and useful, meaningful outputs when unusual, or unexpected conditions and events occur and when inputs occur at the specified ranges or boundaries. That is, worst case conditions must be identified and tested. It is vital that a firm have assurance that software routines, especially those that control critical manufacturing functions, consistently perform as they are supposed to within pre-established operational limits. Determine who conducted the computerized system validation and how key computerized system routines were tested.

 

In considering computerized system validation, the following points should be addressed:

 

1. Does the capacity of the hardware match its assigned function? For example, in a system using an RTD for temperature control, is the RTD capable of sensing temperatures through out the processing control range, has the RTD been checked for accuracy in the operating temperature range(s), does the computer receive an accurate signal from the RTD, and does the computer react to the RTD signals as designed?

2. Have operational limits been identified and considered in establishing production procedures? For example, a PLC may be able to only receive input from two thermocouples at one time. This would limit the number of locations at which temperatures could be obtained in this manufacturing process.

3. Does the software match the assigned operational function? For example, if software is assigned to generate complete thermal processing records for a LACF process, then it should account for all of the information required to be recorded for that retort system as required by the GMPs Part 113.

4. Have test conditions simulated "worst case" production conditions? A computerized system may function well under minimal production stress (as in a vendor's controlled environment) but falter under high stresses of equipment speed, data input overload or frequent or continuous multi-shift use, unexpected sequences or order of events and a harsh environment. Therefore, it is insufficient to test the computerized system for proper operation during a short interval, when the system will be called upon in worst case conditions to run continuously for days at a time. Some firms may test the circuits of a computer by "feeding" it electrical signals from a signal simulator. The simulator sends out voltages designed to correspond to voltages normally transmitted by input devices. When simulators are connected to the computer, the software program should be executed as if the emulated input devices were actually connected. These signal simulators can be useful tools for equipment qualification; however, they may not pose worse case conditions and their accuracy in mimicking input device performance should be established. In addition, validation runs should be accomplished on line using actual input devices.

5. Have computerized system tests been repeated enough times to assure a reasonable measure of consistent reproducible results? In general, at least three consecutive, successful test runs should be made to cover different operating conditions. If test results are widely divergent they may indicate a software bug or an out of control state.

6. Has the validation program been thoroughly documented? Documentation should include a validation protocol and test results that are specific and meaningful in relation to the attribute being tested. For example, if a temperature sensor's reliability is being tested, it would be insufficient to express the results merely as "acceptable," without other qualifying data such as temperatures observed, duration of the test, and the temperature range tested. The individual(s) responsible for conducting, reviewing and approval of the system validation should be identified in the documentation.

7. Are documented systems in place to initiate revalidation when significant changes are made to the computerized system or when computer system errors are noted? Documentation should include the reason for the system change, the date of the system change, the changes made to the computerized system, and identification of who made the changes. Revalidation is indicated, for example, when a major piece of equipment such as a circuit board or an entire CPU is replaced and when software changes such as time, temperature, sequence of routine events, data edits or data handling are made. Sometimes identical hardware replacements may adequately be tested by using diagnostic programs available from the vendor. In other cases, such as when different models of

hardware are introduced, more extensive testing under worst case production conditions, is indicated.

 

Computerized system vendors routinely perform an installation qualification to ascertain that the equipment is functioning within the hardware manufacturers specifications after being installed. However, hardware qualification is only part of the verification process and the complete computerized system should be validated.

 

The ultimate responsibility for suitability of the computerized system used in food processing rests with the food manufacturer. Computerized system validation data and protocols should be kept at the food manufacturer's facility. When validation information is produced by an outside firm, such as the computer vendor or software developer, the records maintained by the food establishment need not be all inclusive of voluminous test data; however, such records should be reasonably complete (including system specifications, protocols and general results) to allow the food manufacturer to assess the adequacy of the system validation. A mere certification of suitability from the vendor, for example, may be inadequate.

 

CHAPTER 4 MONITORING OF COMPUTERIZED SYSTEM OPERATIONS

 

A. INPUT/OUTPUT DEVICE OPERATION.

 

The accuracy and performance of these devices are vital to the proper operation of the computer system. Improper inputs from thermocouples, RTDs, pressure gauges, etc., can compromise the most sophisticated microprocessor controlled system. These sensors should be systematically calibrated and checked for accurate signal outputs.

 

Input to and output from the computer system should be checked by the processing firm for accuracy. While this does not mean that every bit of input and output needs to be checked, it does mean that checking must be sufficient to provide a high degree of assurance that input and output is accurate. In this regard there needs to be some reasonable judgment as to the extent and frequency of checking based upon a variety of factors such as the complexity of the computer systems. The right kinds of input edits, for example, could mitigate the need for extensive checks.

 

During the inspection determine the degree and nature of input/output checks and the use of edits and other built-in audits.

 

Input/output error handling has been a problem in computerized systems. Determine the firm's error handling procedures including documentation, error verification, correction verification, and allowed error overrides.

 

An illustration of inadequate input/output checks and error handling would be where a firm used a computer to sense and record retort temperatures during the thermal processing of an LACF. Failure of the firm to verify that the computer is providing an accurate reading of the correct temperature by independent observations of the Mercury-in-Glass thermometer during the thermal process would be a lack of adequate input checks. Failure of the firm to respond in some way to differences between the recorded (computer sensed temperature) and the observed temperature would indicate inadequate error handling. Determine the degree to which the firm's personnel monitor computerized operations. Is such monitoring continuous or periodic, what functions are monitored? For example, a firm's computer system may be used to maintain the pH in a mixing kettle, but if the firm does not sufficiently monitor the system they may fail to detect a hardware problem that allows the pH to go out of tolerance. During the inspection, where possible, spot-check computer operations such as:

 

1. Calculations; compare manual calculations of input data with the automated calculations or ask the firm to enter a given set of input values and compare automated results against known results.

2. Input recording; compare sensor indications with what the computer indicates, for example. As mentioned previously, some signals may be incorrectly converted and built-in software programming edits may alter input data. For example, a thermocouple indicating 80 C may read out on a view screen as 100 C or any other temperature if the signal converter is malfunctioning.

3. Time keeping; where computers are reporting events and controlling a function in real time, spot-check the time accuracy against a separate time piece; accurate time keeping is especially important where time is a determinative or limiting factor in a food manufacturing process such as during pasteurization or sterilization. It should be noted that some computer systems run on a 12-hour clock whereas others run on a 24-hour clock. When a host computer system is used, determine if the host or the process computer controls the time during process function control, record printing etc. Time keeping conflicts can arise when more than one of the computers is responsible for keeping or indicating time.

The firm should have a requirement for the computer clock to be reset at predetermined intervals to insure that the system is using the correct time of day.

This may be important in continuously operating systems and in those systems documenting the production time of day.

 

4. Automated cleaning in place (CIP); determine the procedure used, how the firm assures adequacy of cleaning, and residue elimination.

 

B. ALARMS:

 

A typical computer system will have several built-in alarms to alert personnel to some out-of-limits situations or malfunctions. Determine what functions are linked to alarms. For example, alarms may be linked to power supply devices, feedback signals to confirm execution of commands, and food process conditions such as empty or overflowing tanks. Determine the alarm thresholds for control of critical functions and whether or not such thresholds can be changed by the operator. For example, if the temperature of water in a pasteurization tank is linked to an alarm which sounds when the temperature drops below 95øC, can the operator change the threshold to 93øC?

 

Determine how the firm responds when an alarm is activated. This should be covered in the firm's written operating procedures. Determine the types of alarms (lights, buzzers, whistles, etc.) and how the firm assures their proper performance. Are they tested periodically and equipped with in-line monitoring lights to show they are ready? Because an activated alarm may signal a significant out of control situation it is important that such alarm activations are documented. Determine how alarms are documented in production records, in separate logs or automatic electronic recording, for instance. Can all alarm conditions be displayed simultaneously or must they be displayed and responded to consecutively? If an employee is monitoring a CRT display covering one phase of the operation, will that display alert the employee to an alarm condition at a different phase? If so, how? The operation of the computerized systems alarms should be validated as part of the complete computerized system under actual operating conditions.

 

C. MANUAL BACK-UP SYSTEMS:

 

Functions controlled by computerized systems may sometimes also be controlled by parallel manual backup systems. During the inspection find out what functions can be manually controlled and identify manual backup devices. Critical process controls are particularly important. Determine the interaction of manual and computerized controls and the degree to which manual intervention can override or defeat the computerized

function. The firm's operating instructions should describe what manual overrides are allowed, who may execute them, how and under what circumstances.

 

Determine if and how manual interventions are documented; a separate log may be kept of such interventions. The computerized system may be such that it detects, reacts to and automatically records manual interventions and this should be addressed during the inspection. It is important that system operators are trained in manual backup systems. Determine the extent of the operator training and if the firm has any procedures for testing the manual backup system on a routine basis (e.g., computer controlled systems would be manually operated for several hours once every month).

 

D. SHUTDOWN RECOVERY:

 

How a computer controlled function is handled in the event of computer shutdown (e.g., power failure) is significant and can pose a problem. Shutdown recovery procedures are not uniform in the industry. Some systems, for example, must be restarted from the initial step in the software routine sequence and memory of what has occurred is lost. Other systems have safeguards whereby memory is retained and the control function is resumed at the point where it was halted. Newer systems may have limited battery back-up which will allow the firm to complete the control and/or documentation function or to step the manufacturing process through a safe shutdown procedure. Determine the disposition of the computer's memory content (program and data) upon computer shutdown.

 

Determine the firm's shutdown recovery procedure and if, in the event of computer failure, the food manufacturing process or control function is brought into a "safe" condition to protect the product. Determine such safeguards and how they are implemented. Where is the point of restart in the cycle - at the initial step, a random step or the point of shutdown? Look for the inappropriate duplication of steps in the resumption of the process. The time it takes to resume a computerized process or switch to manual processing can be critical, especially where failure to maintain process conditions for a set time (e.g. temperature control during the thermal processing of LACF ) compromises product integrity. Therefore, note recovery time for delay-sensitive functions and investigate instances where excessive delays compromise product safety or where established time limits are exceeded. Many systems have the ability to be run manually in the event of computer shutdown. It is important that such backup manual systems provide adequate function control and documentation. Determine if backup manual controls (valves, gates, etc.) are sufficient to control the food manufacturing process and if employees are familiar with their operation. Records of manual operations may be less detailed, incomplete, and prone to error, compared to computerized documentation, especially when they are seldom exercised. Therefore,

determine how manual operations are documented and if the information recorded manually conforms with CGMP requirements.

 

The computerized systems shutdown and recovery process should be validated as part of the validation of the computerized system under actual operating conditions.

 

REFERENCES:

 

Software Development Activities Report, Feb. 1987, U.S. Food and Drug Administration, Office of Regulatory Affairs.

 

Guide to Inspection of Computerized Systems in Drug Processing, Feb. 1983, U.S. Food and Drug Administration, Office of Regulatory Affairs.

 

Guideline on General Principles of Process Validation, May 1987, U.S. Food and Drug Administration, Office of Regulatory Affairs.

 

Glossary of Computerized System and Software Development Terminology, August 1995, U.S. Food and Drug Administration, Office of Regulatory Affairs.

 

Guide to Inspection of LACF Manufacturers - Part 1 - Administrative Procedures/Scheduled Processes, November 1996; Part 2 - Processes/Procedures, April 1997; and Part 3 - (currently in draft, not yet released), U.S. Food and Drug Administration, Office of Regulatory Affairs.

 

Guide to Inspections of Dairy Product Manufacturers, April 1995, U.S. Food and Drug Administration, Office of Regulatory Affairs.

 

Guide to Inspections of Miscellaneous Food Products - Volume 1, May 1995, U.S. Food and Drug Administration, Office of Regulatory Affairs.

 

Guide to Inspections of Miscellaneous Food Products - Volume 2, October 1996, U.S. Food and Drug Administration, Office of Regulatory Affairs.

 

Guide to Inspections of Interstate Carriers and Support Facilities, April 1995, U.S. Food and Drug Administration, Office of Regulatory Affairs.

 

Inspectional Methods (Interim Guidance), October 1996, U.S. Food and Drug Administration, Office of Regulatory Affairs.

 

FDA Final Rule on Electronic Signatures, 21 CFR Part 11, published March 20, 1997.

 

Current Good Manufacturing Practice, Quality Control Procedures, Quality Factors, Notification Requirements, and Records and Reports, for the Production of Infant Formula; Proposed Rule, Federal Register July 09, 1996.

 

APPENDIX 1 - QUICK GUIDE TO EVALUATION OF COMPUTERIZED SYSTEMS USED IN FOOD PROCESSING

 

 

 

This appendix is provided as a quick reference guide for use by FDA investigators conducting inspections of food manufacturing plants using computer control/documentation systems. The guide should not be used without a through understanding of the information provided in the main text of the Guide To Inspection of Computerized Systems in the Food Processing Industry.

 

1.) Determine the critical control points in the food process using HACCP concepts. Examples would be:

 

Pasteurization

 

Sterilization

 

pH control

 

Nutrient control/weighing

 

Nutrient analysis

 

Record keeping

 

Control of microbiological growth

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2.) For those critical control points controlled by computerized systems determine if failure of the computerized system may cause food adulteration. Is the critical control point covered by GMP's or the FD&C Act?

 

 

 

 

 

3.) Identify computerized system components including:

 

 

 

Hardware:

 

Input devices

 

Output devices

 

Signal converters

 

Central Processing Unit

 

Distribution system

 

Peripheral devices

 

Alarms:

 

Types (visual, audible etc)

 

Functions

 

Records

 

Software:

 

Documentation:

 

Manuals

 

Operating procedures

 

Personnel:

 

Type

 

Training

 

 

 

4.) For computer hardware determine the manufacturer, make and model number.

 

 

 

5.) Obtain or make a simplified drawing of the computerized system control loop including:

 

Sensors

 

CPU

 

Signal converters

 

Actuators

 

Peripheral devices

 

 

 

6.) Software:

 

a. For all critical software determine:

 

Name

 

Function

 

Inputs

 

Outputs

 

Set-points

 

Edits

 

Input Manipulation of Data

 

Program Over-rides

 

b. Who developed software.

 

c. Software security to prevent unauthorized changes.

 

d. Firms checks on computerized systems inputs/outputs.

 

 

 

7.) Observe the system as it operates to determine if:

 

Critical processing limits are met

 

Records are accurate

 

Sensor input is accurate

 

Time keeping is accurate

 

Personnel are trained in systems operations and functions

 

 

 

8.) Determine if the operator or management can override computer

 

functions. Explain.

 

 

 

9.) Explain how the system handles deviations from set or expected

 

results.

 

 

 

 

10.) Determine the validation steps used to insure that the

computerized system is functioning as designed.

 

a. Was the computerized system validated upon installation?

 

Under worst case conditions?

 

Minimum of 3 test runs?

 

b. Are there procedures for routine maintenance and revalidation?

 

Does the equipment in-place meet the original specifications?

 

c. Is validation of the computerized system documented?

 

d. How often is system:

 

maintenance performed

 

revalidated

 

calibrated

 

 

11.) Are system components located in a hostile environment which may effect their operation?

 

 

 

 

12.) Determine if the computerized system can be operated manually. Explain.

 

 

13.) Automated CIP (cleaning in place).

 

How does firm ensure that cleaning is adequate.

 

Documentation of CIP steps.

 

 

 

14.) Shutdown Procedures

 

Does firm use battery backup system?

 

Is computer program retained in control system?

 

What is firms procedure in event power is lost to computer control system?

 

 

 

15.) Does the firm have a documented system for making changes to the computerized system which explains:

 

The reason for the change

 

The date of the change

 

The changes made to the system

 

Who made the changes

 

 

 

16.) Document computer functions which are causing or may cause food products to be adulterated or misbranded.

 

 

 

APPENDIX 2 DIAGRAM OF LOGIC CIRCUIT1

 

APPENDIX 3 DIAGRAM OF ALGORITHM2

 

REPRESENTATIVE DIAGRAM OF A PORTION OF AN ALGORITHM FOR A WATER IMMERSION RETORT WHICH CONTROLS THE PROCESS TIME AND TEMPERATURE

Water for Pharmacuetical Use[Previous Chapter1] [Table of Contents2] [Next Chapter3]

DEPT. OF HEALTH, EDUCATION, AND WELFARE PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION *ORA/ORO/DEIO/IB*

Date: 12/31/86 Number: 46 Related Program Areas:Drugs, Biologics, Medical Devices

_______________________________________________________________

 

ITG SUBJECT: WATER FOR PHARMACEUTICAL USE

 

PURPOSE

 

This ITG will cover the different types of water used in the manufacture of drug products.

 

THE 8 TYPES OF WATER ARE:

 

1. Non-potable

 

2. Potable (drinkable) water

 

3. USP purified water

 

4. USP water for injection (WFI)

 

5. USP sterile water for injection

 

6. USP sterile water for inhalation

 

7. USP bacteriostatic water for injection

 

8. USP sterile water for irrigation

 

The USP designation means that the water is the subject of an official monograph in the current US PHARMACOPEIA with various specifications for each type. The latter 4 waters are "finished" products that are packaged and labeled as such and need not be of concern during an inspection outside of plants which actually produce these products.

 

The USP purified water and the USP WFI on the other hand are components or "ingredient materials" as they are termed by the USP, intended to be used in the production of drug products.

 

But what about potable water as a component? Is it required to undergo routine sampling and testing before use in production? According to the preamble to the Current Good Manufacturing Practice regulations (CGMPs), no acceptance testing is required for potable water unless it is obtained from sources that do not control water quality to Environmental Protection Agency (EPA) standards. It is important to know that potable water may not be used to prepare USP dosage form drug products or for laboratory reagents to test solutions. However, potable water may be used to manufacture drug substances (also known as bulk drugs or bulk pharmaceutical chemicals).

 

During your inspection, determine the source of the water used for wet granulations or for any aqueous liquid preparations as well as for the laboratory. It should be of USP purified water quality both chemically and microbiologically.

 

Is non-potable water a concern during drug inspections? It may be present in a plant in the boiler feed water, cooling water for the air conditioning or the fire-sprinkler systems. Look carefully for any cross-connections to the potable water supply. Non-potable water supply lines should be clearly marked as such, especially when adjacent to potable water supply connections.

 

WATER PRODUCTION SOURCES

 

The USP defines acceptable means of producing the various types of component waters. USP WFI may be made only by distillation or reverse osmosis.

 

Potable water is obtained primarily from municipal water systems but may also be drawn from wells, rivers, or ponds.

 

SOURCES OF WATER CONTAMINATION

 

Piping system defects may cause contamination of clean incoming water. Because of this possibility, point-of-use sampling is indicated, that is, drawing the water sample after it has passed through the piping system.

 

Microbial contamination of oral liquid and topical drug products continues to be a significant problem, and is usually rooted in the use of contaminated water. Because of the potential health risks involved with the use of contaminated water, particular attention should be paid to deionized (DI) water systems, especially at small, less sophisticated manufacturers.

 

To minimize this contamination, the USP notes that water systems for pharmaceutical manufacturing should have "corrective facilities." By this they mean access to the system for sanitization or introduction of steam, chlorinators, storage at elevated temperatures, filtration, etc. Inquire about these during your inspection.

 

Seasonal variations in temperature and growth of flora may also cause fluctuations in microbial content of source water. Monitoring should be frequent enough to cover these variations.

 

IN-PLANT WATER TREATMENT SYSTEMS

 

Sand bed filters with or without chlorination equipment are common in larger plants. However, these may be centrally located and the water piped to the pharmaceutical manufacturing site. The operations of these systems should be validated along with any subsequent treatment.

 

If storage tanks are used, determine the capacity, the rate of use, the frequency of flushing and sanitizing the internal surfaces.

 

While depth or membrane type filters are often used in water systems, final filtration as the sole treatment for water purification is generally not acceptable. However, filtration could be acceptable, for example, when used for reducing microbial/particulate loads in potable water used as an ingredient in chemical manufacturing where water need not be sterile.

 

Chlorination of potable water is an effective treatment if minimum levels of 0.2mg/liter of free chlorine are attained. Be aware however, that any carbon or charcoal filters in the system will remove this protective chlorine and thus eliminate any inhibitory effect on microbial growth after this point.

 

USP WFI is usually produced in a continuously circulating system maintained at an elevated temperature. The high temperature, maintained uniformly throughout the system by constant circulation, prevents significant microbial growth. A temperature of 80^oC is commonly used and is acceptable. Somewhat lower temperatures may also be acceptable, provided the firm has adequate data to demonstrate that a lower temperature works as intended. If WFI is held at ambient temperature rather than recirculation at elevated temperature, it must be dumped or diverted to non-WFI use 24 hours after being produced.

 

GENERAL COMMENT

 

Although there are no absolute microbial standards for water (other than water intended to be sterile), the CGMP regulations require that appropriate specifications be

established and monitored. The specification must take into account the intended use of the water; i.e., water used to formulate a product should contain no organisms capable of growing in the product. Action or alert limits must be based upon validation data and must be set low enough to signal significant changes from normal operating conditions.

 

REFERENCES

 

FDA Current Good Manufacturing Practice regulations, Federal Register, Vol.43, No. 190 - Sept. 29, 1978, I. General Comments and Subpart C, para. 211.48.

 

Water Programs, Environmental Protection Agency, National Interim Primary Drinking Water Regulations, Dec. 16, 1985, 40 Code of Federal Regulations, Part 141, para. 141.14 and 141.21.

 

United States Pharmacopeia XXI, Water for Pharmaceutical Purposes, section 1231 and Official Monographs-various types of water, 1985.

 

FDA LETTER TO THE PHARMACEUTICAL INDUSTRY Re: Validation and Control of Deionized Water Systems, - Daniel L. Michels, Bureau of Drugs, Aug. 1981.

 

FDA Inspection Technical Guide, Number 36, Reverse Osmosis, Oct. 1980.

 

FDA Inspection Technical Guide, Number 40, Bacterial Endotoxins/Pyrogens, March 1985.

 

Protection of Water Treatment Systems series, PMA Deionized Water Committee, PHARMACEUTICAL TECHNOLOGY - May, Sept. and Oct., 1983; Sept. 1984, and Nov. 1985.

 

Parenteral Drug Association, Design Concepts for the Validation of a Water for Injection System, Technical Report No. 4, 1983.

 

Monitoring and Validation of High Purity Water Systems with the LAL test for pyrogens, T.J. Novistsky, Pharmaceutical Engineering, March-April, 1984.

GUIDELINE ON GENERAL PRINCIPLES OF PROCESS VALIDATION 

MAY, 1987

Prepared by: Center for Drug Evaluation and Research,Center for Biologics Evaluation and Research, andCenter for Devices and Radiological HealthFood and Drug Administration

Maintained by: Division of Manufacturing and Product Quality (HFD-320)Office of ComplianceCenter for Drug Evaluation and ResearchFood and Drug Administration5600 Fishers LaneRockville, Maryland 20857

Reprinted February, 1993

by

The Division of Field InvestigationsOffice of Regional OperationsOffice of Regulatory AffairsU.S.Food and Drug Administration

 

TABLE OF CONTENTS

I. PURPOSE II. SCOPE

III. INTRODUCTION

IV. GENERAL CONCEPTS

V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS

VI. GMP REGULATION FOR MEDICAL DEVICES

VII. PRELIMINARY CONSIDERATIONS

VIII. ELEMENTS OF PROCESS VALIDATION

A. Prospective Validation

1. Equipment and Process

a. Equipment : Installation Qualification

b. Process: Performance Qualification

c. Product: Performance Qualification

2. System to Assure Timely Revalidation

3. Documentation

B. Retrospective Process Validation

IX. ACCEPTABILITY OF PRODUCT TESTING

Guideline on General Principles of Process Validation

 I. PURPOSE

This guideline outlines general principles that FDA considers to be acceptable elements of process validation for the preparation of human and animal drug products and medical devices.

 II. SCOPE

This guideline is issued under Section 10.90 (21 CFR 10.90) and is applicable to the manufacture of pharmaceuticals and medical devices. It states principles and practices of general applicability that are not legal requirements but are acceptable to the FDA. A person may rely upon this guideline with the assurance of its acceptability to FDA, or may follow different procedures. When different procedures are used, a person may, but is not required to, discuss the matter in advance with FDA to prevent the expenditure of money and effort on activities that may later be determined to be unacceptable. In short, this guideline lists principles and practices which are acceptable to the FDA for the process validation of drug products and medical devices; it does not list the principles and practices that must, in all instances, be used to comply with law.

This guideline may be amended from time to time. Interested persons are invited to submit comments on this document and any subsequent revisions. Written comments should be submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration, Room 4-62, 5600 Fishers Lane, Rockville, Maryland 20857. Received

comments may be seen in that office between 9 a.m. and 4 p.m., Monday through Friday.

 III. INTRODUCTION

Process validation is a requirement of the Current Good Manufacturing Practices Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211, and of the Good Manufacturing Practice Regulations for Medical Devices, 21 CFR Part 820, and therefore, is applicable to the manufacture of pharmaceuticals and medical devices. Several firms have asked FDA for specific guidance on what FDA expects firms to do to assure compliance with the requirements for process validation. This guideline discusses process validation elements and concepts that are considered by FDA as acceptable parts of a validation program.The constituents of validation

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presented in this document are not intended to be all-inclusive. FDA recognizes that, because of the great variety of medical products (drug products and medical devices), processes and manufacturing facilities, it is not possible to state in one document all of the specific validation elements that are applicable. Several broad concepts, however, have general applicability which manufacturers can use successfully as a guide in validating a manufacturing process. Although the particular requirements of process validation will vary according to such factors as the nature of the medical product (e.g., sterile vs non-sterile) and the complexity of the process, the broad concepts stated in this document have general applicability and provide an acceptable framework for building a comprehensive approach to process validation.

Definitions

Installation qualification - Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.

Process performance qualification - Establishing confidence that the process is effective and reproducible.

Product performance qualification - Establishing confidence through appropriate testing that the finished product produced by a specified process meets all release requirements for functionality and safety.

Prospective validation - Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product's characteristics.

Retrospective validation - Validation of a process for a product already in distribution based upon accumulated production, testing and control data.

Validation - Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.

Validation protocol - A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results.

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Worst case - A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.

 IV. GENERAL CONCEPTS

Assurance of product quality is derived from careful attention to a number of factors including selection of quality parts and materials, adequate product and process design, control of the process, and in-process and end-product testing. Due to the complexity of today's medical products, routine end-product testing alone often is not sufficient to assure product quality for several reasons. Some end-product tests have limited sensitivity.(1) In some cases, destructive testing would be required to show that the manufacturing process was adequate, and in other situations end-product testing does not reveal all variations that may occur in the product that may impact on safety and effectiveness.(2)

The basic principles of quality assurance have as their goal the production of articles that are fit for their intended use. These principles may be stated as follows:

(1) quality, safety, and effectiveness must be designed and built into the product;

(2) quality cannot be inspected or tested into the finished product; and

(3) each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications.

Process validation is a key element in assuring that these quality assurance goals are met

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It is through careful design and validation of both the process and process controls that a manufacturer can establish a high degree of confidence that all manufactured units from successive lots will be acceptable. Successfully validating a process may reduce the dependence upon intensive in-process and finished product testing. It should be noted that in most all cases, end-product testing plays a major role in assuring that quality assurance goals are met; i.e., validation and end-product testing are not mutually exclusive.

The FDA defines process validation as follows:

Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics.

It is important that the manufacturer prepare a written validation protocol which specifies the procedures (and tests) to be conducted and the data to be collected. The purpose for which data are collected must be clear, the data must reflect facts and be collected carefully and accurately. The protocol should specify a sufficient number of replicate process runs to demonstrate reproducibility and provide an accurate measure of variability among successive runs. The test conditions for these runs should encompass upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure compared to ideal conditions; such conditions have become widely known as "worst case" conditions. (They are sometimes called "most appropriate challenge" conditions.) Validation documentation should include evidence of the suitability of materials and the performance and reliability of equipment and systems.

Key process variables should be monitored and documented. Analysis of the data collected from monitoring will establish the variability of process parameters for individual runs and will establish whether or not the equipment and process controls are adequate to assure that product specifications are met.

Finished product and in-process test data can be of value in process validation, particularly in those situations where quality attributes and variabilities can be readily measured. Where finished (or in-process) testing cannot adequately measure certain attributes, process validation should be derived primarily from qualification of each system used in production and from consideration of the interaction of the various systems.

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 V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS

Process validation is required, in both general and specific terms, by the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211. Examples of such requirements are listed below for informational purposes, and are not all-inclusive.

A requirement for process validation is set forth in general terms in Section 211.100 -- Written procedures; deviations -- which states, in part:

"There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess."

Several sections of the CGMP regulations state validation requirements in more specific terms. Excerpts from some of these sections are:

Section 211.110, Sampling and testing of in-process materials and drug products.

(a) "....control procedures shall be established to monitor the output and VALIDATE the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product." (emphasis added)

Section 211.113, Control of Microbiological Contamination.

(b) "Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include VALIDATION of any sterilization process." (emphasis added)

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 VI. GMP REGULATION FOR MEDICAL DEVICES

Process validation is required by the medical device GMP Regulations, 21 CFR Part 820. Section 820.5 requires every finished device manufacturer to:

"...prepare and implement a quality assurance program that is appropriate to the specific device manufactured..."

Section 820.3(n) defines quality assurance as:

"...all activities necessary to verify confidence in the quality of the process used to manufacture a finished device."

When applicable to a specific process, process validation is an essential element in establishing confidence that a process will consistently produce a product meeting the designed quality characteristics.

A generally stated requirement for process validation is contained in section 820.100:

"Written manufacturing specifications and processing procedures shall be established, implemented, and controlled to assure that the device conforms to its original design or any approved changes in that design."

Validation is an essential element in the establishment and implementation of a process procedure, as well as in determining what process controls are required in order to assure conformance to specifications.

Section 820.100(a) (1) states:

"...control measures shall be established to assure that the design basis for the device, components and packaging is correctly translated into approved specifications."

Validation is an essential control for assuring that the specifications for the device and manufacturing process are adequate to produce a device that will conform to the approved design characteristics

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 VII. PRELIMINARY CONSIDERATIONS

A manufacturer should evaluate all factors that affect product quality when designing and undertaking a process validation study. These factors may vary considerably among different products and manufacturing technologies and could include, for example, component specifications, air and water handling systems, environmental controls, equipment functions, and process control operations. No single approach to process validation will be appropriate and complete in all cases; however, the following quality activities should be undertaken in most situations.

During the research and development (R& D) phase, the desired product should be carefully defined in terms of its characteristics, such as physical, chemical, electrical and performance characteristics.(3) It is important to translate the product characteristics into specifications as a basis for description and control of the product.

Documentation of changes made during development provide traceability which can later be used to pinpoint solutions to future problems.

The product's end use should be a determining factor in the development of product (and component) characteristics and specifications. All pertinent aspects of the product which impact on safety and effectiveness should be considered. These aspects include performance, reliability and stability. Acceptable ranges or limits should be established for each characteristic to set up allowable variations.(4) These ranges should be expressed in readily measurable terms.

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The validity of acceptance specifications should be verified through testing and challenge of the product on a sound scientific basis during the initial development and production phase.

Once a specification is demonstrated as acceptable it is important that any changes to the specification be made in accordance with documented change control procedures.

 VIII. ELEMENTS OF PROCESS VALIDATION A. Prospective Validation

Prospective validation includes those considerations that should be made before an entirely new product is introduced by a firm or when there is a change in the manufacturing process which may affect the product's characteristics, such as uniformity and identity. The following are considered as key elements of prospective validation.

1. Equipment and Process

The equipment and process(es) should be designed and/or selected so that product specifications are consistently achieved. This should be done with the participation of all appropriate groups that are concerned with assuring a quality product, e.g., engineering design, production operations, and quality assurance personnel.

a. Equipment : Installation Qualification

Installation qualification studies establish confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. After process equipment is designed or selected, it should be evaluated and tested to verify that it is capable of operating satisfactorily within the operating limits required by the process.(5) This phase of validation includes examination of equipment design; determination of calibration, maintenance, and

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adjustment requirements; and identifying critical equipment features that could affect the process and product. Information obtained from these studies should be used to establish written procedures covering equipment calibration, maintenance, monitoring, and control.

In assessing the suitability of a given piece of equipment, it is usually insufficient to rely solely upon the representations of the equipment supplier, or upon experience in producing some other product.(6) Sound theoretical and practical engineering principles and considerations are a first step in the assessment.

It is important that equipment qualification simulate actual production conditions, including those which are "worst case" situations.

Tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results. All acceptance criteria must be met during the test or challenge. If any test or challenge shows that the equipment does not perform within its specifications, an evaluation should be performed to identify the cause of the failure. Corrections should be made and additional test runs performed, as needed, to verify that the equipment performs within specifications. The observed variability of the equipment between and within runs can be used as a basis for determining the total number of trials selected for the subsequent performance qualification studies of the process.(7)

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Once the equipment configuration and performance characteristics are established and qualified, they should be documented. The installation qualification should include a review of pertinent maintenance procedures, repair parts lists, and calibration methods for each piece of equipment. The objective is to assure that all repairs can be performed in such a way that will not affect the characteristics of material processed after the repair. In addition, special post-repair cleaning and calibration requirements should be developed to prevent inadvertent manufacture a of non-conforming product. Planning during the qualification phase can prevent confusion during emergency repairs which could lead to use of the wrong replacement part.

b. Process: Performance Qualification

The purpose of performance qualification is to provide rigorous testing to demonstrate the effectiveness and reproducibility of the process. In entering the performance qualification phase of validation, it is understood that the process specifications have

been established and essentially proven acceptable through laboratory or other trial methods and that the equipment has been judged acceptable on the basis of suitable installation studies.

Each process should be defined and described with sufficient specificity so that employees understand what is required. Parts of the process which may vary so as to affect important product quality should be challenged.(8) In challenging a process to assess its adequacy, it is important that challenge conditions simulate those that will be encountered during actual production, including "worst case" conditions. The challenges should be repeated enough times to assure that the results are meaningful and consistent.

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Each specific manufacturing process should be appropriately qualified and validated. There is an inherent danger in relying on what are perceived to be similarities between products, processes, and equipment without appropriate challenge.(9)

c. Product: Performance Qualification

For purposes of this guideline, product performance qualification activities apply only to medical devices. These steps should be viewed as pre-production quality assurance activities.

Before reaching the conclusion that a process has been successfully validated, it is necessary to demonstrate that the specified process has not adversely affected the finished product. Where possible, product performance qualification testing should include performance testing under conditions that simulate actual use. Product performance qualification testing should be conducted using product manufactured from the same type of production equipment, methods and procedures that will be used for routine production. Otherwise, the qualified product may not be representative of production units and cannot be used as evidence that the manufacturing process will produce a product that meets the pre-determined specifications and quality attributes.(10)

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After actual production units have successfully passed product performance qualification, a formal technical review should be conducted and should include:

Comparison of the approved product specifications and the actual qualified product. Determination of the validity of test methods used to determine compliance with the

approved specifications.

Determination of the adequacy of the specification change control program.

2. System to Assure Timely Revalidation

There should be a quality assurance system in place which requires revalidation whenever there are changes in packaging, formulation, equipment, or processes which

could impact on product effectiveness or product characteristics, and whenever there are changes in product characteristics. Furthermore, when a change is made in raw material supplier, the manufacturer should consider subtle, potentially adverse differences in the raw material characteristics. A determination of adverse differences in raw material indicates a need to revalidate the process.

One way of detecting the kind of changes that should initiate revalidation is the use of tests and methods of analysis which are capable of measuring characteristics which may vary. Such tests and methods usually yield specific results which go beyond the mere pass/fail basis, thereby detecting variations within product and process specifications and allowing determination of whether a process is slipping out of control.

The quality assurance procedures should establish the circumstances under which revalidation is required. These may be based upon equipment, process, and product performance observed during the initial validation challenge studies. It is desirable to designate individuals who have the responsibility to review product, process, equipment and personnel changes to determine if and when evalidation is warranted.

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The extent of revalidation will depend upon the nature of the changes and how they impact upon different aspects of production that had previously been validated. It may not be necessary to revalidate a process from scratch merely because a given circumstance has changed. However, it is important to carefully assess the nature of the change to determine potential ripple effects and what needs to be considered as part of revalidation.

3. Documentation

It is essential that the validation program is documented and that the documentation is properly maintained. Approval and release of the process for use in routine manufacturing should be based upon a review of all the validation documentation, including data from the equipment qualification, process performance qualification, and product/package testing to ensure compatibility with the process.

For routine production, it is important to adequately record process details (e.g., time, temperature, equipment used) and to record any changes which have occurred. A maintenance log can be useful in performing failure investigations concerning a specific manufacturing lot. Validation data (along with specific test data) may also determine expected variance in product or equipment characteristics.

B. Retrospective Process Validation

In some cases a product may have been on the market without sufficient premarket process validation. In these cases, it may be possible to validate, in some measure, the adequacy of the process by examination of accumulated test data on the product and records of the manufacturing procedures used.

Retrospective validation can also be useful to augment initial premarket prospective validation for new products or changed processes. In such cases, preliminary

prospective validation should have been sufficient to warrant product marketing. As additional data is gathered on production lots, such data can be used to build confidence in the adequacy of the process. Conversely, such data may indicate a declining confidence in the process and a commensurate need for corrective changes.

Test data may be useful only if the methods and results are adequately specific. As with prospective validation, it may be insufficient to assess the process solely on the basis of lot by lot conformance to specifications if test results are merely expressed in terms of pass/fail. Specific results, on the other hand, can be statistically analyzed and a determination can be made of what variance in data can be expected. It is important to maintain records which describe the operating characteristics of the process, e.g., time, temperature, humidity, and equipment settings.(11) Whenever test data are used to demonstrate conformance to specifications, it is important that the test methodology be qualified to assure that test results are objective and accurate.

 IX. ACCEPTABILITY OF PRODUCT TESTING

In some cases, a drug product or medical device may be manufactured individually or on a one-time basis. The concept of prospective or retrospective validation as it relates to those situations may have limited applicability, and data obtained during the manufacturing and assembly process may be used in conjunction with product testing to demonstrate that the instant run yielded a finished product meeting all of its specifications and quality characteristics. Such evaluation of data and product testing would be expected to be much more extensive than the usual situation where more reliance would be placed on prospective validation.

(1) For example, USP XXI states: "No sampling plan for applying sterility tests to a specified proportion of discrete units selected from a sterilization load is capable of demonstrating with complete assurance that all of the untested units are in fact sterile."

(2) As an example, in one instance a visual inspection failed to detect a defective structural weld which resulted in the failure of an infant warmer. The defect could only have been detected by using destructive testing or expensive test equipment.

(3) For example, in the case of a compressed tablet, physical characteristics would include size, weight, hardness, and freedom from defects, such as capping and splitting. Chemical characteristics would include quantitative formulation/potency; performance characteristics may include bioavailability (reflected by disintegration and dissolution). In the case of blood tubing, physical attributes would include internal and external diameters, length and color. Chemical characteristics would include raw material formulation. Mechanical properties would include hardness and tensile strength; performance characteristics would include biocompatibility and durability.

(4) For example, in order to assure that an oral, ophthalmic, or parenteral solution has an acceptable pH, a specification may be established by which a lot is released only if it has been shown to have a pH within a narrow established range. For a device, a specification for the electrical resistance of a pacemaker lead would be established so that the lead would be acceptable only if the resistance was within a specified range.

(5) Examples of equipment performance characteristics which may be measured include temperature and pressure of injection molding machines, uniformity of speed for mixers, temperature, speed and pressure for packaging machines, and temperature and pressure of sterilization chambers.

(6) The importance of assessing equipment suitability based upon how it will be used to attain desired product attributes is illustrated in the case of deionizers used to produce Purified Water, USP. In one case, a firm used such water to make a topical drug product solution which, in view of its intended use, should have been free from objectionable microorganisms. However, the product was found to be contaminated with a pathogenic microorganism. The apparent cause of the problem was failure to assess the performance of the deionizer from a microbiological standpoint. It is fairly well recognized that the deionizers are prone to build-up of microorganisms -- especially if the flow rates are low and the deionizers are not recharged and sanitized at suitable intervals. Therefore, these factors should have been considered. In this case, however, the firm relied upon the representations of the equipment itself, namely the "recharge" (i.e., conductivity) indicator, to signal the time for regeneration and cleaning. Considering the desired product characteristics, the firm should have determined the need for such procedures based upon pre-use testing, taking into account such factors as the length of time the equipment could produce deionized water of acceptable quality, flow rate, temperature, raw water quality, frequency of use, and surface area of deionizing resins.

(7) For example, the AAMI Guideline for Industrial Ethylene Oxide Sterilization of Medical Devices approved 2 December 1981, states: "The performance qualification should include a minimum of 3 successful, planned qualification runs, in which all of the acceptance criteria are met.....(5.3.1.2.)

(8) For example, in electroplating the metal case of an implantable pacemaker, the significant process steps to define, describe, and challenge include establishment and control of current density and temperature values for assuring adequate composition of electrolyte and for assuring cleanliness of the metal to be plated. In the production of parenteral solutions by aseptic filling, the significant aseptic filling process steps to define and challenge should include the sterilization and depyrogenation of containers/closures, sterilization of solutions, filling equipment and product contact surfaces, and the filling and closing of containers.

(9) For example, in the production of a compressed tablet, a firm may switch from one type of granulation blender to another with the erroneous assumption that both types have similar performance characteristics, and, therefore, granulation mixing times and procedures need not be altered. However, if the blenders are substantially different, use of the new blender with procedures used for the previous blender may result in a granulation with poor content uniformity. This, in turn, may lead to tablets having significantly differing potencies. This situation may be averted if the quality assurance system detects the equipment change' in the first place, challenges the blender performance, precipitates a revalidation of the process, and initiates appropriate changes. In this example, revalidation comprises installation qualification of the new equipment and performance qualification of the process intended for use in the new blender.

(10) For example, a manufacturer of heart valves received complaints that the valve-support structure was fracturing under use. Investigation by the manufacturer revealed that all material and dimensional specifications had been met but the production machining process created microscopic scratches on the valve supporting wireform. These scratches caused metal fatigue and subsequent fracture. Comprehensive fatigue testing of production units under simulated use conditions could have detected the process deficiency.

In another example, a manufacturer recalled insulin syringes because of complaints that the needles were clogged. Investigation revealed that the needles were clogged by silicone oil which was employed as a lubricant during manufacturing. Investigation further revealed that the method used to extract the silicone oil was only partially effective. Although visual inspection of the syringes seemed to support that the cleaning method was effective, actual use proved otherwise.

(11) For example, sterilizer time and temperature data collected on recording equipment found to be accurate and precise could establish that process parameters had been reliably delivered to previously processed loads. A retrospective qualification of the equipment could be performed to demonstrate that the recorded data represented conditions that were uniform throughout the chamber and that product load configurations, personnel practices, initial temperature, and other variables had been adequately controlled during the earlier runs.