pharmaceutical process validation

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1.INTRODUCTION Validation begins with good process development. It requires that process developers understand the necessity to design a process that will be capable of ultimately meeting predetermined specifications without being subject to deviations within a defined range of preset operating parameters. The Common Technical Technology transfer from process development to pilot or manufacturing is a challenge. The frustration level is high when a manufacturing process change is made that invalidates previously validated studies. It is a two-way process, however. The process developers must understand manufacturing capabilities. Validation documentation is extensive and includes master validation plans, validation protocols, and validation reports. A master validation plan is a useful essential and is now specified in EU as a requirement. Validation protocols are also an essential basic. The protocol must state what will be done, how it will be done, and what the outcome must be for the validation to be a success. Validation cannot be just going back to a process step repeated three times and stating it is validated. Validation is an ongoing process. It is not a one-time effort that can then be ignored. Most validation is performed prospectively, i.e., prior to market approval. However, today there is more acceptance of also using concurrent validation for some aspects. Certainly, data collected at the manufacturing

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Page 1: Pharmaceutical Process Validation

1. INTRODUCTION

Validation begins with good process development. It requires that process developers understand

the necessity to design a process that will be capable of ultimately meeting predetermined

specifications without being subject to deviations within a defined range of preset operating

parameters. The Common Technical Technology transfer from process development to pilot or

manufacturing is a challenge. The frustration level is high when a manufacturing process change

is made that invalidates previously validated studies. It is a two-way process, however. The

process developers must understand manufacturing capabilities. Validation documentation is

extensive and includes master validation plans, validation protocols, and validation reports. A

master validation plan is a useful essential and is now specified in EU as a requirement.

Validation protocols are also an essential basic. The protocol must state what will be done, how

it will be done, and what the outcome must be for the validation to be a success. Validation

cannot be just going back to a process step repeated three times and stating it is validated.

Validation is an ongoing process. It is not a one-time effort that can then be ignored. Most

validation is performed prospectively, i.e., prior to market approval. However, today there is

more acceptance of also using concurrent validation for some aspects. Certainly, data collected at

the manufacturing scale can be more relevant provided that in-process analysis is sufficiently

sensitive.

The development of a drug product is a lengthy process involving drug discovery, laboratory

testing, animal studies, clinical trials and regulatory registration. To further enhance the

effectiveness and safety of the drug product after approval, many regulatory agencies such as the

United States Food and Drug Administration (FDA) also require that the drug product be tested

for its identity, strength, quality, purity and stability before it can be released for use. For this

reason, pharmaceutical validation is important in spite of the problems that may be encountered.

In general, an entire process is validated and a particular object within that process is verified.

The regulations also set out an expectation that the different parts of the production process are

well defined and controlled, such that the results of that production will not substantially change

over time.

Page 2: Pharmaceutical Process Validation

2. VALIDATION

Validation in the pharmaceutical industry is defined as the documented act of demonstrating that

a procedure, process, and activity will consistently lead to the expected results. Validation is an

essential procedure that demonstrates that a manufacturing process operating under defined

standard conditions is capable of consistently producing a product that meets the established

product specifications. It often includes the qualification of systems and equipment. It is a

requirement for Good Manufacturing Practices and other regulatory requirements. A wide

variety of procedures, processes, and activities need to be validated.

(http://en.wikipedia.org/wiki/Validation_(drug_manufacture))

Validation is an integral part of quality assurance, but the use of this term in connection with

manufacturing often gives rise to difficulties. As defined above, it involves the systematic study

of systems, facilities and processes aimed at determining whether they perform their intended

functions adequately and consistently as specified. A validated operation is one, which has been

demonstrated to provide a high degree of assurance that uniform batches will be produced that

meet the required specifications, and has there fore been formally approved.

Unlike many other requirements of GMP, validation in itself does not improve processes. It can

only confirm (or not, as the case may be) that the process has been properly developed and is

under control. Ideally, any development activity in the later stages should be finalized by a

validation phase. This includes, in particular, the manufacture of investigational products and the

scaling up of processes from pilot plant to production unit. In this event, GMP as manufacturing

practice may only be concerned with revalidation, e.g. when processes are transferred from

development to production, after modifications are introduced (in starting materials, equipment,

etc.) or when periodic revalidation are required at the pre registration stage (in the submission of,

or application for, marketing authorizations).

Good validation practice requires the close collaboration of departments such as those concerned

with development, production, engineering, quality assurance and control. This is most important

when processes go into routine full-scale production following pharmaceutical development and

pilot-plant operations.

(http://prismpharmatech.com/pdf/Validation.pdf)

Page 3: Pharmaceutical Process Validation

2.1 History of validation

The concept of validation was first proposed by two Food and Drug Administration (FDA)

officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the quality of

pharmaceuticals (Agalloco 1995). It was proposed in direct response to several problems in the

sterility of large volume parenteral market. The first validation activities were focused on the

processes involved in making these products, but quickly spread to associated processes

including environmental control, media fill, equipment sanitization and purified water

production. (http://en.wikipedia.org/wiki/Validation_(drug_manufacture))

2.2 Essentials of Pharmaceutical Validation

As validation is an integral part of quality assurance; it involves the systematic study of systems,

facilities and processes aimed at determining whether they perform their intended functions

adequately and consistently as specified. A validated process is one which has been

demonstrated to provide a high degree of assurance that uniform batches will be produced that

meet the required specifications and has therefore been formally approved. Validation in itself

does not improve processes but confirms that the processes have been properly developed and

are under control. Adequate validation is beneficial to the manufacturer in many ways:

1. It deepens the understanding of processes; decreases the risk of preventing problems and

thus assures the smooth running of the process.

2. It decreases the risk of defect costs.

3. It decreases the risk of regulatory non-compliance.

4. A fully validated process may require less in-process controls and end- product testing.

Validation should thus be considered in the following situations:

Totally new process;

New equipment;

Process and equipment which have been altered to suit changing priorities;

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Process where the end-product test is poor and an unreliable indicator of product quality.

When any new manufacturing formula or method of preparation is adopted, steps should be

taken to demonstrate its suitability for routine processing. The defined process should be shown

to yield a product consistent with the required quality. In this phase, the extent to which

deviations from chosen parameters can influence product quality should also be evaluated. When

certain processes or products have been validated during the development stage, it is not always

necessary to revalidate the whole process or product if similar equipment is used or similar

products have been produced, provided that the final product conforms to the in-process controls

and final product specification. There should be a clear distinction between in-process control

and validation. In production, tests are performed each time on a batch to batch basis using

specifications and methods devised during the development phase. The objective is to monitor

the process continuously. (http://www.tjpr.org/vol1%20no2/okhamafe12.pdf)

2.3 Validation Master Plan:

A validation master plan is a document that summaries the company’s overall philosophy,

intentions and approaches to be used for establishing performance adequacy. The Validation

Master Plan should be agreed upon by management.

Validation in general requires meticulous preparation and careful planning of the various steps in

the process. In addition, all work should be carried out in a structured way according to formally

authorized standard operating procedures. All observations must be documented and where

possible must be recorded as actual numerical results.

The validation master plan should provide an overview of the entire validation operation, its

organizational structure, its content and planning. The main elements of it being the

list/inventory of the items to be validated and the planning schedule. All validation activities

relating to critical technical operations, relevant to product and process controls within a firm

should be included in the validation master plan. It should comprise all prospective, concurrent

and retrospective validations as well as re validation.

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The Validation Master Plan should be a summary document and should therefore be brief,

concise and clear. It should not repeat information documented elsewhere but should refer to

existing documents such as policy documents, SOP’s and validation protocols and reports

The format and content should include:

• Introduction: validation policy, scope, location and schedule

• Organizational structure: personnel responsibilities

• Plant /process/product description: rational for inclusions or exclusions and extent of validation

• Specific process considerations that are critical and those requiring extra attention

• List of products/ processes/ systems to be validated, summarized in a matrix format, validation

approach

• Re-validation activities, actual status and future planning

• Key acceptance criteria

• Documentation format

• Reference to the required SOP’s

• Time plans of each validation project and sub-project.

(http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/compli-conform/gmp-bpf/validation/GUI-

0029-eng.pdf)

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3. PROCESS VALIDATION

Process validation is the means of ensuring and providing documentary evidence that processes

(within their specified design parameters) are capable of repeatedly and reliably producing a

finished product of the required quality. It would normally be expected that process validation be

completed prior to the release of the finished product for sale (prospective validation). Where

this is not possible, it may be necessary to validate processes during routine production

(concurrent validation). Processes, which have been in use for some time without any significant

changes, may also be validated according to an approved protocol (retrospective validation).

(http://www.tjpr.org/vol1%20no2/okhamafe12.pdf)

Process validation is defined by various organizations 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” -1987 FDA Guideline

“The action of proving, in accordance with the principles of GMP, that any procedure, process,

equipment, material, activity or system actually leads to the expected results”-(European Union

Drug Regulatory Authorities, 1998)

“The means of ensuring and providing documentary evidence that processes (within their

specified design parameters) are capable of consistently producing a finished product of the

required quality”-(European Medicines Agency, 2001)

(http://www.bioprocessconsultants.com/PDFs/Kanarek.ProcessValidation2009.pdf)

3.1 Pre-requisites for Process Validation

Before process validation can be started, manufacturing equipment and control instruments as

well as the formulation must be qualified. The information on a pharmaceutical product should

be studied in detail and qualified at the development stage, i.e., before an application for

marketing authorization is submitted. This involves studies on the compatibility of active

ingredients and recipients, and of final drug product and packaging materials, stability studies,

etc. Other aspects of manufacture must be validated including critical services (water, air,

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nitrogen, power supply, etc.) and supporting operations such as equipment cleaning and

sanitation of premises. Proper training and motivation of personnel are pre- requisites to

successful validation. (http://www.tjpr.org/vol1%20no2/okhamafe12.pdf).

3.2 Stages of Process Validation

The activities relating to validation studies may be classified into three stages:

Stage 1: Process Design

This is the step where building and capturing of the process knowledge and understanding took

place. Early design of processes and experiments should be performed during this stage. It covers

all activities relating to product research and development, formulation, pilot batch studies,

scale-up studies, transfer of technology to commercial scale batches, establishing stability

conditions, storage and handling of in-process and finished dosage forms, equipment

qualification, installation qualification, master production documents, operational qualification,

process capability. Also this is the stage in which the establishment of a strategy for process

control is taking place using accumulation knowledge and understanding of the process.

Stage 2: Process Qualification

This stage is confirmation that the process design is capable of reproducing the manufacturing

process. It confirms that all established limits of the Critical Process parameters are valid and

that satisfactory products can be produced even under “worst case” conditions. GMP compliant

procedures must be followed in this stage and successful completion of this stage is necessary

before commercial distribution of a product.

Stage 3: Continued Process Verification

The Validation Maintenance Stage requires frequent review of all process related documents,

including validation audit reports to assure that there have been no changes, deviations, failures,

modifications to the production process, and that all SOPs have been followed, including change

control procedures. Before any batch is distributed for marketing, the manufacturer must have

full assurance of its performance. A successful validation program depends on the knowledge

and understanding and the approach to control manufacturing processes. These include the

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source of variation, the limitation of the detection of the variation, and the attributes susceptible

of the variation.

It is the responsibility of the manufacturer to judge and provide evidence of a high degree of

assurance in its manufacturing processes. They are also responsible for maintaining the degree of

assurance accomplished, even if some minor changes occurred due to personnel, material and

process changes.

(http://www.sfda.gov.sa/NR/rdonlyres/E0A05984-1CCE-4168-87B9-28D3A8545404/0/

GuidelinesforProcessValidationofPharmaceuticalDosageForms_v21.pdf)

3.3 Relationships between Product Development, Manufacturing Processes,

Product Specifications and Process Validation

3.3.1 Relationship between development studies and process validation data

It is expected that during the development stage, the manufacturer of the product should gain

sufficient information about the behavior and the physical and chemical properties of the drug

substance, the composition of the product in terms of active ingredients and key excipients and

the manufacturing process to clearly define the critical steps in the manufacturing process.

Critical parameters of the product should be identified at an early stage; for example the

dissolution rate of an active substance and the effect of the presence, type and amount of

lubricant.

Information generated during the development stage should thus be used to identify and evaluate

the critical pharmaceutical process parameters which may need to be examined and possibly

controlled in order to ensure batch to batch reproducibility. In order to define these critical

parameters it may be necessary to challenge the process by making deliberate changes to

demonstrate the robustness of the process and define the limits of tolerance. Such parameters

will vary depending upon the nature of the product, the composition and the proposed method of

manufacture, as highlighted in the note for guidance “Development Pharmaceutics”. The choice

of the method of manufacture should be properly justified in the context of the development data

obtained

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3.3.2 Relationship between method of manufacturing and process validation data

Having defined and justified a particular method of manufacture based on a consideration of the

physical and chemical properties of the active ingredient, the key excipients, the choice of

formulation and the impact of processing on the product quality and stability, the applicant

should progress to fully describe the manufacturing process.

Such a description should address also the need and value of in-process controls and the

manufacturer’s approach to process optimization. The evaluation of the process should provide

adequate proof of the feasibility of the process at the production scale thereby ensuring the

consistent quality of the product in line with the approved specification.

3.3.3 Relationship between Process Validation and the Specification of the Finished

Product

Data generated through process evaluation or validation can be used to justify why certain test

need not be conducted routinely on the finished product at release.

(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/

WC500002913.pdf)

3.4 Process Validation and Quality Assurance

Process Validation and Quality Assurance (QA) have expanded to include not only technology

transfer but also some of the development activity; namely, Process Validation associated with

clinical supplies production. Another factor that has influenced the need to validate the

manufacturing process is the involvement of the contractor, whose site has become the primary

or alternate location for the sponsor to manufacture the clinical or commercial product. With this

expansion it was inevitable that organizations would formalize the master validation plan as a

building block of Total Quality Management. Furthermore, it is appropriate to include the

validation plan for each clinical production process in the master validation plan.

Quality Assurance is the activity of providing to all concerned the evidence needed to establish

confidence that the quality function is being performed adequately. The definition of process

validation is that it is the total activity, showing that the process will do what it is purported to

do. The relationship of Quality Assurance and Process Validation goes well beyond the

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responsibility of any quality assurance function; nevertheless, it is fair to say that process

validation is a quality assurance tool because it establishes a quality standard for a specific

process.

3.4.1 Pharmaceutical development

Process validation verifies that the process will consistently produce the desired product each

time it is run. It must be remembered that process validation for the development process may

not contain as much supporting data as is collected for the process when the product’s New Drug

Application (NDA) is being reviewed. The development group must still view the validation

effort in a way that adds value to its work, however. The steps are as follows:

1. Define the process and determine which process steps are the critical ones. If the technologist

has progressed adequately from the checklist stage to the stage at which the process is known

and understood, these steps should be readily identified.

When the development function looks at the Process validation activity as a quality assurance

tool, it must view each process step very closely. The development plan must ensure that the

ability and limitations of the process design are known. This can come about only if sound

planning occurs at the beginning, which should include dissection of the process into discrete

parts and the ability to evaluate them.

2. Define which process variable will be used as the monitoring device of each process step.

3. Generate the data. During the development effort, the data generated while the process is

being qualified will determine what the specification limits will be for each test.

4. Statistically evaluate the data from the validation effort. Compare the data with the

specification limits listed in the protocol. Conformance to these limits is essential, because this

effort must also include the determination of whether failure signifies a missing link in the

scientists understands of the process. This exercise is especially important when the size of the

validation batch is significantly larger than the largest development batch made to date.

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5. The validation function reviews the results of all the validation batches using the protocol as a

basis of comparison. In addition, the group will review the equipment qualification work and/or

its calibration program. This total effort will help to ensure the quality of the finished product.

3.4.2 Production

This department needs process validation for a number of reasons. First, the completed

validation program serves as the formal transfer of the process to the production function.

Through validation, it would be demonstrated that a controlled process was established. It

doesn’t guarantee that nothing will go wrong, but it will say what process was validated and it

will require that any change must be examined beforehand. In this way, it will require that the

organization formally evaluate whether or not a proposed change warrants a new development

and/or validation effort. This will also avoid the comment that the previous validated process is

no longer validated.

Process validation is also useful for the production function, because the data generated may be

used as a basis for SPC. Statistical process control is useful for collecting data, but there must be

useful limits to control the process variables by allowing standard equipment adjustments to

obtain quality product continuously. Validation data enable a company to develop a database to

do just that. Furthermore, when normal adjustments no longer control the process variables, the

validation data become the basis to judge whether there has been a statistical change in the

process. The rational process to such a finding would be a demonstrated need for process

improvement or a troubleshooting effort.

When production develops an operation plan, it will include quality standards that complement

the validation effort. These are as follows:

1. Equipment calibration. This quality functions for production consists of a viable

calibration program for equipment that provides in-process test data or a measurable indication

of the controlled process used. This activity is needed so that the manufacturing unit will know

whether the equipment is operating consistently during the time period covered by the calibration

activity.

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2. In-process testing and monitoring. Quality assurance of the production effort also

occurs within its inspection plan, which it carries out through in-process testing. The generated

data are often collected through the SPC system, but other activities come from in-process

testing. The purpose of testing is to provide assurance that the ongoing process is yielding a

uniform product and a consistently reproducible process.

3. Training of personnel. This quality function enables management to determine the

real productivity level of its personnel, because productivity is no longer just measured in terms

of units made; rather, it concentrates on the number of units made correctly. Training has been

viewed as an element of Process validation, but the activity probably is more correctly

interpreted as being a measure of the validation of an organization’s personnel.

4. Development of standard operating procedures (SOPs). Training is achieved

through the use of SOPs or operating manuals. The SOP is mainly written to provide a “how-to”

approach for the activity it covers and to document that approach so that the audit activity will

have a basis. Standard operating procedures complement the Process Validation effort by

ensuring that personnel will perform their work in a manner consistent with the objectives of the

validation.

5. Development of a logbook system. Logbooks are another quality assurance vehicle

that complements the Process Validation effort. They are used to document any activity that

involves the equipment they cover (e.g., cleaning or maintenance).

6. Use of clear, precise operating instructions, including the documentation of

process performance and verification. A company’s system includes the issuance of a master

production and control record and the batch production and control record (for each batch).

These records document the fact that the company continues to manufacture each batch of

product with the validated process of record.

3.4.3 Quality Assurance

Quality assurance functions primarily to monitor the fact that the quality function is being

performed. Its role in Process Validation is readily associated with its main functions. For

example, it performs the tests that demonstrate the product’s content uniformity. It may also

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perform the statistical evaluation of the test results to show that the process is reproducible.

Quality assurance initiates the action to dispose of nonconforming product. It implements the

inspection criteria and sets the specifications for product approval or rejection. It analyzes the

product complaints to learn how effective its test program has been in preventing rejectable

product from reaching the market place.

Quality assurance carries out the ongoing stability programs for each product at least once a year.

It performs the physical and chemical tests that are used as the basis for approval or rejection of

individual batches. In conjunction with setting specification limits as a basis for releasing or

rejecting product, it will carry out programs to determine whether or not the new information

indicates that a change in product or process has occurred. Finally, it performs the analytical tests

that are used to generate the validation data required by the protocol.

3.5 Validation Protocol

A written plan stating how validation will be conducted, including test parameters, product

characteristics, production and packaging equipment, and decision points on what constitutes

acceptable test results. This document should give details of critical steps of the manufacturing

process that should be measured, the allowable range of variability and the manner in which the

system will be tested.

The validation protocol provides a synopsis of what is hoped to be accomplished. The protocol

should list the selected process and control parameters, state the number of batches to be

included in the study, and specify how the data, once assembled, will be treated for relevance.

The date of approval by the validation team should also be noted.

In the case where a protocol is altered or modified after its approval, appropriate reasoning for

such a change must be documented.

The validation protocol should be numbered, signed and dated, and should contain as a minimum

the following information:

Objectives, scope of coverage of the validation study.

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Validation team membership, their qualifications and responsibilities.

Type of validation: prospective, concurrent, retrospective, re-validation.

Number and selection of batches to be on the validation study.

A list of all equipment to be used; their normal and worst case operating parameters.

Outcome of IQ, OQ for critical equipment.

Requirements for calibration of all measuring devices.

Critical process parameters and their respective tolerances.

Description of the processing steps: copy of the master documents for the product

.Sampling points, stages of sampling, methods of sampling, sampling plans.

Statistical tools to be used in the analysis of data.

Training requirements for the processing operators.

Validated test methods to be used in in-process testing and for the finished product.

Specifications for raw and packaging materials and test methods.

Forms and charts to be used for documenting results.

Format for presentation of results, documenting conclusions and for approval of study

results.

(http://www.sfda.gov.sa/NR/rdonlyres/E0A05984-1CCE-4168-87B9-28D3A8545404/0/

GuidelinesforProcessValidationofPharmaceuticalDosageForms_v21.pdf)

3.6Different Types of Process Validation

1. Analytical procedure validation

2. Prospective process validation

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3. Concurrent process validation

4. Retrospective process validation

5. Revalidation

6. Cleaning process validation

3.6.1 Analytical Procedure Validation

Analytical procedure validation is defined as the process of demonstrating that the analytical

procedure is suitable for its intended purpose, for example, identification, determination of

impurities, assay of active or other ingredients.( http://www.tga.gov.au/cm/startval.pdf)

The validation of an analytical procedure is the process of confirming that the analytical

procedure employed for a test of pharmaceutics is suitable for its intended use. In other word, the

validation of an analytical procedure requires us to demonstrate scientifically that risks in

decision by testing caused by errors from analytical steps are acceptably small. The performance

of an analytical procedure is established by various kinds of validation characteristics. The

validity of a proposed analytical procedure can be shown by demonstrating experimentally that

the validation characteristics of the analytical procedure satisfy the standards set up according to

the acceptable limits of testing.

(http://lib.njutcm.edu.cn/yaodian/jp/14data/Validation_of_Analytical_Pr.pdf)

3.6.1.1 Types of Analytical Procedures to be validated

The discussion of the validation of analytical procedures is directed to the four most common

types of analytical procedures:

Identification tests;

Quantitative tests for impurities' content;

Limit tests for the control of impurities;

Quantitative tests of the active moiety in samples of drug substance or drug product or

other selected component(s) in the drug product.

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(http://www.bioforum.org.il/Uploads/Editor/karen/q2_r1_step4.pdf)

A brief description of the types of tests considered in this document is provided below-

- Identification tests are intended to ensure the identity of an analyte in a sample. This is

normally achieved by comparison of a property of the sample (e.g., spectrum, chromatographic

behavior, chemical reactivity, etc) to that of a reference standard;

- Testing for impurities can be either a quantitative test or a limit test for the impurity in a

sample. Either test is intended to accurately reflect the purity characteristics of the sample.

Different validation characteristics are required for a quantitative test than for a limit test;

- Assay procedures are intended to measure the analyte present in a given sample. In the context

of this document, the assay represents a quantitative measurement of the major component(s) in

the drug substance. For the drug product, similar validation characteristics also apply when

assaying for the active or other selected component(s). The same validation characteristics may

also apply to assays associated with other analytical procedures (e.g., dissolution).

(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/

ucm073381.pdf)

3.6.1.2 Characteristics Analytical Procedures Validation

Accuracy

The accuracy of an analytical procedure expresses the closeness of agreement between the value

which is accepted either as a conventional true value or an accepted reference value and the

value found. (http://www.bioforum.org.il/Uploads/Editor/karen/q2_r1_step4.pdf)

Precision

The precision of an analytical procedure is the closeness of agreement (degree of scatter)

between a series of measurements obtained from multiple sampling of the same homogeneous

sample under the prescribed conditions.

Precision may be considered at three levels:

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- Repeatability

- Intermediate precision and

- Reproducibility.

Repeatability expresses the precision under the same operating conditions over a short interval

of time. Repeatability is also termed intra-assay precision.

Intermediate precision expresses variations within laboratories, such as different days, different

analysts, different equipment, and so forth.

Reproducibility expresses the precision between laboratories (collaborative studies usually

applied to standardization of methodology).

(http://www.chem.agilent.com/Library/primers/Public/5990-5140EN.pdf)

Specificity

Specificity is the ability to assess unequivocally the analyte in the presence of components which

may be expected to be present. Typically these might include impurities, degradants, matrix, etc.

(http://www.bioforum.org.il/Uploads/Editor/karen/q2_r1_step4.pdf)

Detection limit

The detection limit of an individual analytical procedure is the lowest amount of analyte in a

sample which can be detected but not necessarily quantitated as an exact value.

Quantitation limit

The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a

sample which can be quantitatively determined with suitable precision and accuracy. The

quantitation limit is a parameter of quantitative assays for low levels of compounds in sample

matrices, and is used particularly for the determination of impurities and/or degradation products.

Linearity

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The linearity of an analytical procedure is its ability (within a given range) to obtain test results

which are directly proportional to the concentration (amount) of analyte in the sample.

Range

The range of an analytical procedure is the interval between the upper and lower concentration

(amounts) of analyte in the sample (including these concentrations) for which it has been

demonstrated that the analytical procedure has a suitable level of precision, accuracy and

linearity.

Robustness

The robustness of an analytical procedure is a measure of its capacity to remain unaffected by

small, but deliberate variations in method parameters and provides an indication of its reliability

during normal usage. (http://www.bioforum.org.il/Uploads/Editor/karen/q2_r1_step4.pdf)

3.6.2 Prospective process validation

Prospective Validation is conducted prior to the distribution of either a new product or a product

made under a modified production process, where the modifications are significant and may

affect the product’s characteristics. It is a pre-planned scientific approach and includes the initial

stages of formulation development, process development, setting of process specifications,

developing in-process tests, sampling plans, designing of batch records, defining raw material

specifications, completion of pilot runs, transfer of technology from scale-up batches to

commercial size batches, listing major process equipment and environmental controls.

(http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/compli-conform/gmp-bpf/validation/GUI-

0029-eng.pdf)

3.6.2.1 Organization

Prospective validation requires a planned program and organization to carry it to successful

completion. The organization must have clearly defined areas of responsibility and authority for

each of the groups involved in the program so that the objective of validating the process can be

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met. The important point is that a defined structure exists, is accepted, and is in operation. An

effective project management structure will have to be established in order to plan, execute, and

control the program.

3.6.2.2 Master Documentation

An effective prospective validation program must be supported by documentation extending

from product initiation to full-scale production. The complete documentation package can be

referred to as the master documentation file. It will accumulate as a product concept progresses

to the point of being placed in full-scale production, providing as complete a product history as

possible. The final package will be the work of many individual groups within the organization.

It will consist of reports, procedures, protocols, specifications, analytical methods, and any other

critical documents pertaining to the formulation, process, and analytical method development.

The ideal documentation package will contain a complete history of the final product that is

being manufactured.

3.6.2.3 Product Development

Product development usually begins when an active chemical entity has been shown to possess

the necessary attributes for a commercial product. The product development activities for the

active chemical entity, formulation, and process form the foundation upon which the subsequent

validation data are built. Generally, product development activities can be subdivided into

formulation and process development, along with scale-up development.

A. Formulation Development

Formulation development provides the basic information on the active chemical, the formula,

and the impact of raw materials or excipients on the product. Typical supportive data generated

during these activities may include the following:

1. Preformulation profile or characterization of the components of the formula, which

includes all the basic physical or chemical information about the active pharmaceutical

ingredients (API, or the chemical entity) and excipients.

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2. Formulation profile, which consists of physical and chemical characteristics required for

the products, drug-excipient compatibility studies, and the effect of formulation on in

vitro dissolution.

3. Effect of formulation variables on the bioavailability of the product

4. Specific test methods

5. Key product attributes and/or specifications

6. Optimum formulation

7. Development of cleaning procedures and test methods

Formulation development should not be considered complete until all those factors that could

significantly alter the formulation have been studied. Subsequent minor changes to the

formulation, however, may be acceptable, provided they are thoroughly tested and are shown to

have no adverse effect on product.

B. Process Development

The process development activities typically begin after the formulation has been developed,

they may also occur simultaneously. The majority of the process development activities occur

either in the pilot plant or in the proposed manufacturing plant. The process development

program should meet the following objectives:

1. Develop a suitable process to produce a product that meets all:

a. Product specifications

b. Economic constraints

c. Current good manufacturing practices (CGMPs)

2. Identify the key process parameters that affect the product attributes

3. Identify in-process specifications and test methods

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4. Identify generic and/or specific equipment that may be required

Stages of Process development

1. Design

2. Challenging of critical process parameters

3. Verification of the developed process

Typical activities in these areas are illustrated in Figure1.

Development of Manufacturing Capability

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There must be a suitable production facility for every manufacturing process that is developed.

This facility includes buildings, equipment, staff, and supporting functions.

As development activities progress and the process become more clearly defined, there must be a

parallel assessment of the capability to manufacture the product. The scope and timing of the

development of manufacturing capability will be dependent on the process and the need to utilize

or modify existing facilities or establish new ones.

Full-Scale Process Development

The development of the final full-scale production process proceeds through the following steps:

1. Process scale-up studies

2. Qualification trials

3. Process validation runs

Process Scale-up Studies

The transition from a successful pilot-scale process or research scale to a full scale process

requires careful planning and implementation. Although a large amount of information has been

gathered during the development of the process (i.e., process characterization and process

verification studies), it does not necessarily follow that the full-scale process can be completely

predicted. Many scale-up parameters are nonlinear. In fact, scale-up factors can be quite complex

and difficult to predict, based only on experience with smaller-scale equipment. For some

processes, the transition from pilot scale or research scale to full scale is relatively easy and

orderly. For others the transition is less predictable.

Qualification trials

Once the scale-up studies have been completed, it may be necessary to manufacture one or more

batches at full scale to confirm that the entire manufacturing process, comprising several

different unit operations, can be carried out smoothly. This may occur prior to or after the

regulatory submission, depending on the strategy used in filing.

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Process validation runs

After the qualification trials have been completed, the protocol for the full-scale process

validation runs can be written. Current industry standard for the validation batches is to attempt

to manufacture them at target values for both process parameters and specifications. The

validation protocol is usually the joint effort of the following groups:

Research and development

Pharmaceutical technology or technical services

Quality control (quality assurance)

Manufacturing

Engineering

3.6.3 Concurrent process validation

A process where current production batches are used to monitor processing parameters. It gives

assurance of the present batch being studied, and offers limited assurance regarding consistency

of quality from batch to batch.

Concurrent validation is carried out during normal production. This method is effective only if

the development stage has resulted in a proper understanding of the fundamentals of the process.

The first three production-scale batches must be monitored as comprehensively as possible. (This

careful monitoring of the first three production batches is sometimes regarded as prospective

validation.) The nature and specifications of subsequent in-process and final tests are based on

the evaluation of the results of such monitoring. Concurrent validation together with a trend

analysis including stability should be carried out to an appropriate extent throughout the life of

the product. (http://prismpharmatech.com/pdf/Validation.pdf)

Concurrent validation may be the practical approach under certain circumstances.

Examples of these may be when:

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A previously validated process is being transferred to a third party contract manufacturer

or to another manufacturing site

The product is a different strength of a previously validated product with the same ratio

of active/inactive ingredients

The number of lots evaluated under the Retrospective Validation were not sufficient to

obtain a high degree of assurance demonstrating that the process is fully under control

The number of batches produced is limited (e.g. orphan drugs).

Process with low production volume per batch ( e.g. radiopharmaceuticals, anti-cancer)

Process of manufacturing urgently needed drugs due to shortage (or absence) of supply.

It is important in these cases however, that the systems and equipment to be used have been fully

validated previously. The justification for conducting concurrent validation must be documented

and the protocol must be approved by the Validation Team. A report should be prepared and

approved prior to the sale of each batch and a final report should be prepared and approved after

the completion of all concurrent batches. It is generally considered acceptable that a minimum of

three consecutive batches within the finally agreed parameters, giving the product the desired

quality would constitute a proper validation of the process.

(http://www.sfda.gov.sa/NR/rdonlyres/E0A05984-1CCE-4168-87B9-28D3A8545404/0/

GuidelinesforProcessValidationofPharmaceuticalDosageForms_v21.pdf)

3.6.4 Retrospective process validation

It is validation of a process for a product already in distribution based upon accumulated

production, testing and control data.

Retrospective validation is used when historical data is available for existing manufacturing

processes. Types of useful data include design drawings and specifications, operating procedures

and work instructions, manufacturing instructions, inspection reports, production logs,

production test data, material review reports, service records, customer complaints, and audit

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reports. Retrospective validation may not be feasible if accumulated data is incomplete or

inadequate.

(http://www.clinivation.com/docs/procedures/mfgeng/ProcessValidation.doc?

PHPSESSID=575b6d4bdc5d472e955015b5e577e62b)

Retrospective validation involves the examination of past experience of production on the

assumption that composition, procedures, and equipment remain unchanged; such experience

and the results of in-process and final control tests are then evaluated. Recorded difficulties and

failure in production are analysed to determine the limits of process parameters. A trend analysis

may be conducted to determine the extent to which process parameters are within the permissible

range.

Retrospective validation is obviously not a quality assurance measure in itself, and should never

be applied to new processes or products. It may be considered in special circumstances only, e.g.

when validation requirements are first introduced in a company. Retrospective validation may

then be useful in establishing the priorities for the validation program. If the results of a

retrospective validation are positive, this indicates that the process is not in need of immediate

attention and may be individual accordance with the normal schedule. For tablets, which have

been compressed under individual pressure sensitive cells, and with qualified equipment,

retrospective validation is the most comprehensive test of the overall manufacturing process of

this dosage form. On the other hand, it should not be applied in the manufacture of sterile

products. (http://prismpharmatech.com/pdf/Validation.pdf)

For the purpose of retrospective validation studies, it is considered acceptable that data from a

minimum of ten consecutive batches produced be utilized. When less than ten batches are

available, it is considered that the data are not sufficient to demonstrate retrospectively that the

process is fully under control. In such cases the study should be supplemented with data

generated with concurrent or prospective validation.

Some of the essential elements for Retrospective Validation are:

Batches manufactured for a defined period (minimum of 10 last consecutive batches).

Number of lots released per year.

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Batch size/strength/manufacturer/year/period.

Master manufacturing/packaging documents.

Current specifications for active materials/finished products.

List of process deviations, corrective actions and changes to manufacturing documents.

Data for stability testing for several batches.

Trend analyses including those for quality related complaints.

(http://www.sfda.gov.sa/NR/rdonlyres/E0A05984-1CCE-4168-87B9-28D3A8545404/0/

GuidelinesforProcessValidationofPharmaceuticalDosageForms_v21.pdf)

3.6.5 Revalidation

Revalidation is needed to ensure that changes in the process and/or in the process environment,

whether intentional or unintentional, do not adversely affect process characteristics and product

quality.

Revalidation may be divided into two broad categories:

Revalidation after any change having a bearing on product quality.

Periodic revalidation carried out at scheduled intervals.

3.6.5.1 Revalidation after changes. Revalidation must be performed on introduction of any

changes affecting a manufacturing and/or standard procedure having a bearing on the established

product performance characteristics. Such changes may include those in starting material,

packaging material, manufacturing processes, equipment, in-process controls, manufacturing

areas, or support systems (water, steam, etc.). Every such change requested should be reviewed

by a qualified validation group, which will decide whether it is significant enough to justify

revalidation and, if so, its extent.

Revalidation after changes may be based on the performance of the same tests and activities as

those used during the original validation, including tests on sub processes and on the equipment

concerned. Some typical changes which require revalidation include the following:

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Changes in the starting material(s). Changes in the physical properties, such as density,

viscosity, particle size distribution, and crystal type and modification, of the active

ingredients or excipients may affect the mechanical properties of the material; as a

consequence, they may adversely affect the process or the product.

Changes in the packaging material, e.g. replacing plastics by glass, may require changes

in the packaging procedure and therefore affect product stability.

Changes in the process, e.g. changes in mixing time, drying temperature and cooling

regime, may affect subsequent process steps and product quality.

Changes in equipment, including measuring instruments, may affect both the process and

the product; repair and maintenance work, such as the replacement of major equipment

components, may affect the process.

Changes in the production area and support system, e.g. the rearrangement of

manufacturing areas and/or support systems, may result in changes in the process. The

repair and maintenance of support systems, such as ventilation, may change the

environmental conditions and, as a consequence, revalidation/requalification may be

necessary, mainly in the manufacture of sterile products.

Unexpected changes and deviations may be observed during self-inspection or audit, or

during the continuous trend analysis of process data.

3.6.5.2 Periodic revalidation. It is well known that process changes may occur gradually even if

experienced operators work correctly according to established methods. Similarly, equipment

wear may also cause gradual changes. Consequently, revalidation at scheduled times is advisable

even if no changes have been deliberately made.

The decision to introduce periodic revalidation should be based essentially on a review of

historical data, i.e. data generated during in-process and finished product testing after the latest

validation, aimed at verifying that the process is under control. During the review of such

historical data, any trend in the data collected should be evaluated.

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In some processes, such as sterilization, additional process testing is required to complement the

historical data. The degree of testing required will be apparent from the original validation.

Additionally, the following points should be checked at the time of a scheduled revalidation:

Have any changes in master formula and methods, batch size, etc., occurred? If so, has

their impact on the product been assessed?

Have calibrations been made in accordance with the established program and time

schedule?

Has preventive maintenance been performed in accordance with the program and time

schedule?

Have the standard operating procedures (SOPs) been properly updated?

Have the SOPs been implemented?

Have the cleaning and hygiene programs been carried out?

Have any changes been made in the analytical control methods?

(http://pharmaceuticalvalidation.blogspot.com/2008/01/types-of-process-validation.html)

3.6.6 Cleaning Validation

Cleaning Validation is the documented act of demonstrating that cleaning procedures for the

equipment used in fabricating/packaging will reduce to an acceptable level all residues

(products/cleaning agents) and to demonstrate that routine cleaning and storage of equipment

does not allow microbial proliferation.

(http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/compli-conform/gmp-bpf/validation/GUI-

0029-eng.pdf)

Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by

other pharmaceutical products or APIs, by cleaning agents, by micro-organisms or by other

material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries). In

many cases, the same equipment may be used for processing different products. To avoid

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contamination of the following pharmaceutical product, adequate cleaning procedures are

essential.

Cleaning procedures must strictly follow carefully established and validated methods of

execution. This applies equally to the manufacture of pharmaceutical products and active

pharmaceutical ingredients (APIs). In any case, manufacturing processes have to be designed and

carried out in a way that contamination is reduced to an acceptable level.

Objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that

the analytical monitoring may be omitted or reduced to a minimum in the routine phase.

(http://www.cptu.com.cn/bbs/attachment.aspx?attachmentid=2540)

3.6.6.1 Sampling

In developing the sampling plan for a validation study, it makes scientific sense to incorporate an

understanding of the acceptance criteria and the limitations of the sampling method relative to

the surface to be sampled.

The two methods of sampling generally employed are-

Swab method

Rinse method

Swab:

Swab sampling does not cover the entire equipment surface area therefore sites must be

chosen with care. It is important that, as a minimum, the swab sites represents worst case

locations on the equipment and that the result is then extrapolated to account for the total

product contact surface area. This calculation makes it possible to make a worst case

determination of potential carryover into subsequent product.

Due to the nature of this method which employs physical forces as well as chemical

forces it may be necessary to perform sampling technique evaluation.

Swabbing efficiency (% recovery) for the swabbing method must be determined.

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It is necessary to ensure that extractable of the swab do not interfere with the sampling

method.

Using this technique it is possible to sample insoluble residues due to the physical action

associated it.

Rinse:

The solvent rinse occurs after cleaning has been completed

This method is not as direct as swabbing but will cover the entire surface area (and parts

inaccessible to swabs)

It is important to ensure chosen solvent has appropriate recovery for residues being

quantified

This method allows much greater ease of sampling than swabbing

A reduced no of samples are required to generate a carryover figure.

(http://apic.cefic.org/pub/4CleaningVal9909.pdf)

3.6.6.2 Cleaning Validation Protocol

A Cleaning Validation Protocol is required laying down the procedure on how the cleaning

process will be validated. It should include the following:

The objective of the validation process,

Responsibilities for performing and approving the validation study,

Description of the equipment to be used,

The interval between the end of production and the beginning of the cleaning procedures,

Cleaning procedures to be used for each product, each manufacturing system or each

piece of equipment,

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The number of cleaning cycles to be performed consecutively,

Any routine monitoring requirement,

Sampling procedures, including the rationale for why a certain sampling method is used,

Clearly defined sampling locations,

Data on recovery studies where appropriate,

Analytical methods including the limit of detection and the limit of quantitation of those

methods,

The acceptance criteria, including the rationale for setting the specific limits,

Other products, processes, and equipment for which the planned validation is valid

according to a “bracketing” concept,

When Re-validation will be required.

The Cleaning Validation Protocol should be formally approved by the Plant Management, to

ensure that aspects relating to the work defined in the protocol, for example personnel resources,

are known and accepted by the management. Quality Assurance should be involved in the

approval of protocols and reports.

(http://www.cptu.com.cn/bbs/attachment.aspx?attachmentid=2540)

3.7 Change Control:

Clearly defined procedure is required in order to control any changes in the production

processes. These procedures should control all the planned changes and ensure the presence of

sufficient supporting data that show that modified process will result in a product of the desired

quality. Significant changes to process (e.g. mixing time, drying temperature, etc.), using new

equipments with different operating parameters.

Page 32: Pharmaceutical Process Validation

(http://www.sfda.gov.sa/NR/rdonlyres/E0A05984-1CCE-4168-87B9-28D3A8545404/0/

GuidelinesforProcessValidationofPharmaceuticalDosageForms_v21.pdf)

Written procedures should be in place to describe the actions to be taken if a change is proposed

to a product component, process equipment, process environment, processing site, method of

production or testing or any other change that may affect product quality or support system

operations.

All changes must be formally requested, documented and accepted by the Validation Team. The

likely impact/risk of the change on the product must be assessed and the need for the extent of

re-validation should be determined.

Commitment of the company to control all changes to premises, supporting utilities, systems,

materials, equipment and processes used in the fabrication/packaging of pharmaceutical dosage

forms is essential to ensure a continued validation status of the systems concerned.

The change control system should ensure that all notified or requested changes are satisfactorily

investigated, documented and authorized. Products made by processes subjected to changes

should not be released for sale without full awareness and consideration of the change by the

Validation Team. The Team should decide if a re-validation must be conducted prior to

implementing the proposed change.

(http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/compli-conform/gmp-bpf/validation/GUI-

0029-eng.pdf)

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4. CONCLUSION

It is necessary, before approval of a new drug, that an accurate and reliable assessment for its

effectiveness and safety for the intended indication and target patient population is demonstrated.

Pharmaceutical validation which includes assay validation, cleaning validation, equipment

validation as well as the overall process validation is crucial in stability analysis, animal studies

and early phases of clinical development such as bioavailability/bioequivalence studies. After the

drug is approved, pharmaceutical validation and process control are necessary to ensure that the

drug product will meet/set pharmaceutical standards for identity, strength, quality, purity,

stability, evaluation safety and efficacy.

In general, pharmaceutical validation and process control provide a certain assurance of batch

uniformity and integrity of the product manufactured. Process validation is a major requirement

of cGMP regulation for finished pharmaceutical products. It is a key element in assuring that the

quality goals are met. Successfully validating a process may reduce the dependence upon

intensive in process and finished product testing.

Finally, it can be concluded that Process validation is a key element in the quality assurance of

pharmaceutical product as the end product testing is not sufficient to assure quality of finished

product.