significant change guide for bulk … [1195...usp 35 general information / 〈1195〉 significant...

USP 35 General Information / ⟨1195⟩ Significant Change Guide 843

cessive microbial contamination and growth. Instability may mediate need, maintain suitable repackaging records show-be indicated by cloudiness or precipitation in a solution, ing name of manufacturer, lot number, date, and designa-breaking of an emulsion, nonresuspendable caking of a sus- tion of persons responsible for repackaging and for checkingpension, or organoleptic changes. Microbial growth may be (see General Notices), (6) if safety closures are required, useaccompanied by discoloration, turbidity, or gas formation. container closure systems that ensure compliance with com-

pendial and regulatory standards for storage.SOLUTIONS, ELIXIRS, AND SYRUPS—Precipitation and evidenceof microbial or chemical gas formation are the two major Dilution or Mixing—If a product is diluted, or if two prod-signs of instability. ucts are mixed, the pharmacist should observe good profes-

sional and scientific procedures to guard against incompati-EMULSIONS—The breaking of an emulsion (i.e., separationbility and instability. For example, tinctures such as those ofof an oil phase that is not easily dispersed) is a characteristicbelladonna and digitalis contain high concentrations of alco-sign of instability; this is not to be confused with creaming,hol to dissolve the active ingredient(s), and they may de-an easily redispersible separation of the oil phase that is avelop a precipitate if they are diluted or mixed with aque-common occurrence with stable emulsions.ous systems. Pertinent technical literature and labelingSUSPENSIONS—A caked solid phase that cannot be resus- should be consulted routinely; it should be current litera-pended by a reasonable amount of shaking is a primary ture, because at times formulas are changed by the manu-indication of instability in a suspension. The presence of rel- facturer. If a particular combination is commonly used, con-atively large particles may mean that excessive crystal sultation with the manufacturer(s) is advisable. Since thegrowth has occurred. chemical stability of extemporaneously prepared mixtures is

TINCTURES AND FLUIDEXTRACTS—Tinctures, fluidextracts, and unknown, the use of such combinations should be discour-similar preparations usually are dark because they are con- aged; if such a mixture involves an incompatibility, thecentrated, and thus they should be scrutinized carefully for pharmacist might be responsible. Oral antibiotic prepara-evidence of precipitation. tions constituted from powder into liquid form should never

STERILE LIQUIDS—Maintenance of sterility is of course critical be mixed with other products.for sterile liquids. The presence of microbial contamination Combining parenteral products necessitates special care,in sterile liquids usually cannot be detected visually, but any particularly in the case of intravenous solutions, primarilyhaze, color change, cloudiness, surface film, particulate or because of the route of administration. This area of practiceflocculent matter, or gas formation is sufficient reason to demands the utmost in care, aseptic technique, judgment,suspect possible contamination. Clarity of sterile solutions in- and diligence. Because of potential unobservable problemstended for ophthalmic or parenteral use is of utmost impor- with respect to sterility and chemical stability, all extempo-tance. Evidence that the integrity of the seal has been vio- raneous parenteral preparations should be used within 24lated on such products should make them suspect. hours unless data are available to support longer storage.

Semisolids (Creams, Ointments, and Suppositories)—For Informing and Educating the Patient—As a final step increams, ointments, and suppositories, the primary indication meeting responsibility for the stability of drugs dispensed,of instability is often either discoloration or a noticeable the pharmacist is obligated to inform the patient about thechange in consistency or odor. proper storage conditions (for example, in a cool, dry

place—not in the bathroom) for both prescription and non-CREAMS—Unlike ointments, creams usually are emulsionsprescription products, and to suggest a reasonable estimatecontaining water and oil. Indications of instability in creamsof the time after which the medication should be discarded.are emulsion breakage, crystal growth, shrinking due toWhen beyond-use dates are applied, the pharmacist shouldevaporation of water, and gross microbial contamination.emphasize to the patient that the dates are applicable onlyOINTMENTS—Common signs of instability in ointments arewhen proper storage conditions are observed. Patientsa change in consistency and excessive “bleeding” (i.e., sepa-should be encouraged to clean out their drug storage cabi-ration of excessive amounts of liquid) and formation ofnets periodically.granules or grittiness.

SUPPOSITORIES—Excessive softening is the major indicationof instability in suppositories, although some suppositoriesmay dry out and harden or shrivel. Evidence of oil stains onpackaging material should warn the pharmacist to examineindividual suppositories more closely by removing any foilcovering. As a general rule (although there are exceptions), ⟨1195⟩ SIGNIFICANT CHANGEsuppositories should be stored in a refrigerator (see StorageTemperature in the General Notices). GUIDE FOR BULKProper Treatment of Products Subjected to AdditionalManipulations—In repackaging, diluting a product or mix- PHARMACEUTICAL EXCIPIENTSing it with another product, the pharmacist may becomeresponsible for its stability.

Repackaging—In general, repackaging is inadvisable.However, if repackaging is necessary, the manufacturershould be consulted concerning potential problems. In the BACKGROUNDfilling of prescriptions, it is essential that suitable containersbe used. Appropriate storage conditions and, when appro- This general information chapter was derived from an in-priate, an expiration date and beyond use date should be ternational guidance on the evaluation of the significance ofindicated on the label of the prescription container. Single- changes involving the manufacture of bulk pharmaceuticalunit packaging calls for care and judgment and for strict excipients. It is intended to assist excipient manufacturers inobservance of the following guidelines: (1) use appropriate determining the need for informing the excipient user andpackaging materials, (2) if stability data on the new package regulatory authorities about the nature of the change.are not available, repackage at any one time only sufficient The chapter provides minimum recommendations whenstock for a limited time, (3) include on the unit-dose label a considering the effect of a change in the manufacturinglot number and an appropriate beyond-use date, (4) if a process on the excipient. When deciding how to use thissterile product is repackaged from a multiple-dose vial into chapter, each manufacturer must consider how it may applyunit-dose (disposable) syringes, discard the latter if not used to that manufacturer’s product and processes. The diversitywithin 24 hours, unless data are available to support longer of excipients means that some principles of this chapter maystorage, (5) if quantities are repackaged in advance of im- not be applicable to certain products and processes.

Official from May 1, 2012Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.

Accessed from 128.83.63.20 by nEwp0rt1 on Sat Dec 03 01:40:10 EST 2011

844 ⟨1195⟩ Significant Change Guide / General Information USP 35

This chapter is divided into several sections. The first sec- Layouttion provides the general guidance necessary for evaluatinga change and determining the necessity of informing the This chapter is divided into several sections. The first sec-user and/or regulatory authorities. One section provides cri- tion provides a background discussion necessary for evaluat-teria for determining whether a change will involve a signifi- ing a change and determining the necessity of informingcant risk. Also included is a decision tree that is useful in the user and/or regulatory authorities. A second section pro-considering the potential effect of a change on excipient vides criteria for determining the risk that a change will beperformance. significant, including guidance on development of an impu-

rity profile. Also included are the following: The Glossarycontains terms and definitions used in all sections of thisINTRODUCTION document. Appendix A includes some examples of changesthat would be classified into each of the three risk levels.Appendix B provides a decision tree useful in considering thepotential impact of a change on excipient performance. Ap-Purposependix C delineates the development of an impurity profile.

This document is meant to establish uniform considera-tions for evaluating the significance of changes involving the GENERAL GUIDANCEmanufacture of bulk pharmaceutical excipients (BPEs). Thepurpose of the evaluation is to determine the need for in-forming the excipient user and regulatory authorities aboutthe nature of the change. Differentiation of Excipient Manufacture

Evaluating the impact of a change in the manufacture ofScope an excipient could be more difficult than that for an activepharmaceutical ingredient (API). Although the API is seldomThe principles and information in this chapter can be ap- used for more than a handful of therapeutic purposes, theplied to the manufacture of all bulk pharmaceutical excipi- BPE is often used with a broad range of active ingredientsents intended for use in human drugs, veterinary drugs, and in a diverse range of finished dosage forms. Whereasand biologics. The principles set forth here must be applied the API is typically of high purity and well characterized byonce it has been determined that a chemical is intended for the quality control and analytical laboratory, the BPE is oftenuse as a component of a drug product. As the excipient a natural substance, mixture, or polymer, the chemical andmanufacturing process progresses, the degree of assurance physical properties of which are more difficult to quantify.concerning the quality of the product should increase and For a more thorough discussion of GMPs that apply to ex-should be controlled and documented. However, at some cipient manufacture, see the general information chapterlogical processing step, as determined by the manufacturer, Good Manufacturing Practices for Bulk Pharmaceutical Excipi-the GMP as described in Good Manufacturing Practices for ents ⟨1078⟩.Bulk Pharmaceutical Excipients ⟨1078⟩ should be applied and

maintained. Judgment, based on risk analysis and a thor-ough knowledge of the process, is required to determine Definition of Significant Changefrom which processing step the GMPs should beimplemented. Any change by the manufacturer of an excipient that al-

ters an excipient’s physical or chemical property outside theestablished limits, or that is likely to alter the excipient per-Principles Adopted formance in the dosage form, is considered significant. Suchchanges may necessitate notifying the local regulatory au-This chapter should be of international application, bear- thority if required. Regardless of whether there is a regula-ing in mind that pharmaceutical excipients are diverse and tory requirement, the manufacturer has an obligation to no-often have uses other than pharmaceutical applications. It tify its users of a significant change so that the user canprovides minimum recommendations when considering the evaluate the impact of the change on the user’s products. Itimpact of a change on the excipient. As an international is suggested that unless there is clear indication from evalu-guidance document, it cannot specify all national legal re- ation of the change that it is not significant as stipulated byquirements nor cover in detail the particular characteristics this general chapter, the pharmaceutical user should beof every excipient. notified.When considering how to use this chapter, each manufac- The types of change that are considered here are changesturer should consider how it may apply to that manufactur- to the following: site, scale, equipment, process, packaginger’s product and processes. The diversity of excipients and labeling, and specification (including raw materials).means that some principles of the chapter may not be ap- The requirement for evaluating the impact of change onplicable to certain products and processes. The terminology the excipient begins, at a minimum, with the raw materials“should” and “it is recommended” do not necessarily mean for the first processing step from where GMP compliance“must” as used in the application of this chapter. begins. GMP requirements increase as the manufacturingExcipients may contain minor components that are process progresses. Thus, at some logical processing step,known to be or might be necessary for the correct function- usually well before the final finishing operation, appropriateing of the excipient. The presence of these “essential con- GMPs should be imposed and maintained throughout thecomitant components” in the excipient should not be con- remainder of the process. Methods such as HACCP (Hazardstrued as undesirable. These concomitant components are Analysis and Critical Control Point), FEMA (Failure Effectsnot considered part of the impurity profile, but should be Mode Analysis), or a detailed process flow diagram may beconsidered separately. Water may be a concomitant compo- used to identify the unit operations, required equipment,nent in some excipients, but may be included in the impu- stages at which various substances are added, key steps inrity profile for others. (See Impurity Profile in Appendix C for the process, critical parameters (time, temperature, pressure,more information.) etc.), and necessary monitoring points. Judgment, based onrisk analysis and a thorough knowledge of the process, isrequired to determine at which processing step the GMPshould be implemented.1

1 See chapter ⟨1078⟩, GMPs For Excipients.




It is important to give careful consideration to any pro- • unidentified organic impurities at or above 0.10%,cessing changes that occur after the excipient has been syn- whether specified or not,2thesized or isolated but prior to packaging. However, it • residual solvents, andmust be recognized that a change made earlier in the pro- • inorganic impuritiescess can result in a change in the excipient functionality, The feasibility of developing an impurity profile variesand it is recommended that such changes also be with the composition and origin of the excipient. It is im-considered. portant to note that identifying and quantifying impurities

in some excipients are extremely difficult. Thus, an excipientmanufacturer may not have developed an impurity profile.

SIGNIFICANT CHANGE In that case, it is important for excipient manufacturers toeither document their efforts to identify and quantify theimpurities that may be present to justify their limited resultsor to justify other means by which changes may beEvaluation Criteria evaluated.

The significance of the change can be determined byThese criteria, in the form of questions, are presented for comparing the impurity profile of the pre-change materialconsideration when evaluating the impact of a change relat- with that of the post-change product. Therefore, once theing to excipient manufacture: profile has been developed, it should be reassessed follow-1. Has there been a change in the chemical properties ing changes to the process. An impurity should be moni-or composition of the excipient as a result of the tored as part of the profile if it is present at or greater thanchange? 0.10%, if it has an established physiological effect, or if it is2. Has there been a change in the physical properties of known to be unsafe at a lower level.the excipient as a result of the change? The content of the impurity profile varies with the nature3. Has there been a change in the “essential concomi- of the excipient, the raw materials used in its manufacture,tant components” profile for the excipient as a result and its chemical composition. Where possible, changes areof the change? considered significant whenever a new impurity is intro-4. Has there been a change in the functionality of the duced at the 0.10% concentration or higher, or when anexcipient as a result of the change? impurity previously present at or greater than 0.10% disap-5. Where applicable, has the moisture level changed? pears. Changes to the quantity of an existing impurity speci-6. Where applicable, has the bioburden changed? fied in a monograph and reported on the Certificate of7. Has there been a change in the origin of any raw Analysis (COA) should be treated as a chemical property formaterials or contact packaging? the purposes of this evaluation.An affirmative answer to any of these questions indicates Changes in the levels of residual solvents should be con-that the impact of the change on the excipient may lead to sidered when determining the significance of change. Seechanges in its performance in the dosage form. Residual Solvents ⟨467⟩ for details.It is important to provide objective criteria for evaluating Criterion 4: Objective criteria for evaluating changes towhen a change has occurred in an excipient property or excipient functionality are desirable. However, the nature ofcomposition, in the essential concomitant components pro- this type of study can vary broadly based upon the excipi-file, in biological origin, or in its functionality. This enables ent and its application in the dosage form. It must also bethe BPE manufacturer to evaluate the significance of the recognized that the excipient manufacturer does not alwayschange on the excipient for the purpose of notifying the know each use of the excipient. Therefore this chapter can-regulatory authorities and/or the user. not provide objective criteria for this study but stresses theimportance of such a consideration by the manufacturer. Ifthere is the potential that the functionality of the excipientDetermination of Significancemay be affected by the change, users should be notifiedand material provided upon request so that they can deter-Criterion 1: Evaluation of the chemical properties or com-mine the impact of the change in their finished pharmaceu-position of an excipient should include, at a minimum, alltical products.monograph and manufacturer specification parameters. A

Criterion 5: Often the excipient contains moisture, thecomparison of these test results for the excipient before andpresence of which can have an impact on excipient perfor-after a change should be done to determine if there is amance in the preparation of the pharmaceutical dosagestatistically significant difference.form. Therefore a change in the moisture level beyond theCriterion 2: Physical properties should be consideredrange typical of production, even though within the com-based upon the physical form of the excipient and its func-pendial or specification limit, can affect its stability and/ortionality as known or as used by the end users. A physicalend use.property that is part of a mutually agreed-upon specification

Criterion 6: Change in the processing steps, raw materi-between the manufacturer and end user should also beals, or equipment can adversely affect control of microor-evaluated. For example, a manufacturer of an excipientganisms in the excipient. Therefore the effect of the changepowder should consider measuring the impact of changeson the bioburden should be evaluated, particularly for ex-on such physical parameters as bulk density, surface area,cipients susceptible to microbial growth.particle shape, and particle size distribution. Liquid excipi-

Criterion 7: Change in the origin of a raw material orents might be evaluated for changes in their pH and viscos-contact packaging can result in a change to the other sixity. For all polymeric excipients, the effect of a change on achange criteria. Change in origin can involve the country ofphysical property, such as molecular weight distribution,origin, geological origin, or species of origin for the rawshould be considered.material.Criterion 3: Objective criteria are also necessary when

A change in the country of origin of a raw material orconsidering changes to the “essential concomitant compo-contact packaging material can affect the status of the ex-nents” profile for an excipient as a result of changes. Thecipient as it relates to the potential presence of bovine spon-profile, as noted in Appendix C, contains the following:giform encephalopathies (BSEs), transmissible spongiform• identified organic impurities,encephalopathy (TSE) material, or genetically modified or-2 It is recognized that while desirable, it may not be possible to achieve thisfor all excipients, particularly those of a more complex chemical nature, e.g.natural polymers, for which there may be no adequate means of determiningrelated substances. However, the impurity profile documentation shoulddemonstrate why this was not achievable.




ganisms (GMOs). The country of origin of animal raw mate- Protocol Designrial, or of components used in the manufacture of the rawmaterial, can result in noncompliance with relevant TSE reg- There should be a written protocol for the evaluation of aulations.3,4 Current information on BSE and related diseases change to determine whether it is significant. The protocolcan be accessed on the United States Department of Agri- should describe the nature of the change, the reason it mayculture (USDA) website (usda.gov). be significant, the testing to be performed to evaluate the

A change in the geological origin of a mineral-based ex- change, and the criteria for determining the significance. Ifcipient can alter the composition of the excipient. Geologi- the change is attributable to a new biological source for rawcal formations containing the same mineral can differ in materials used in the manufacture of the excipient, it is rec-their chemical composition, crystalline structure, density, ommended that the regulatory status of the raw materialetc. A change in geological origin of raw material can affect (i.e., BSE/TSE, GMO agents) be evaluated first. Then, wherethe excipient’s chemical or physical properties, the impurity possible, the results from the testing of a minimum of 10profile, or excipient functionality. pre- and 3 post-change batches of excipient should be com-

A change to the species of origin for raw materials of pared (see Supporting Data, below). If significant changeseither animal or vegetable origin can raise concern. Switch- are seen, then an assessment of the significance should being from one animal species to another can affect the status made.of the excipient as it relates to the presence of BSE or TSE The manufacturer should test the excipient made after thematerial in the excipient, as noted above. Switching from change for all specification properties and compare the re-animal-derived to plant-derived raw materials, although sults to the historical data. A standard statistical test, such aseliminating the issue of BSE or TSE material, raises the po- a t-test of the means, should be used to compare the newtential for the presence of plant-based allergenic material in data with the historical data. If when using an appropriatethe excipient. Switching from one plant species to another statistical analysis there is sufficient evidence that the popu-also can result in the possible presence of an allergen in the lations are different at the 95% confidence interval, theexcipient. In addition to this issue with allergens, use of change should be considered significant. As an additionalplant-derived raw materials can affect pharmaceutical manu- check on consistency, it is also recommended that the newfacturers who have a concern about the presence of GMOs batch specification properties be plotted on standard Statis-in the excipient. tical Quality Control (SQC) control charts, along with stan-

dard batch results.

Risk LevelsSupporting Data

In the evaluation of the effect of changes on the excipi-ent, it is recognized that even with objective criteria, some It is preferable to use data to measure the effect of ajudgment may be necessary. To facilitate the decision as to change on the excipient. The comparison should begin withthe significance of a change and the likely effect on the chemical and physical properties, followed, where appropri-dosage form, the types of changes are classified using three ate, by moisture, bioburden, impurity profile, and function-levels: ality. The manufacturer should use good judgment on sam-

• Level 1: Minor Change ple comparisons for the other evaluations.• Level 2: Might be Significant Chemical and physical properties lend themselves to• Level 3: Always Significant quantitative measurement. Often these properties are part

of the specification for the excipient. As such there shouldbe a large body of test data to use for the properties af-LEVEL 1: MINOR CHANGE fected for comparison to the corresponding data of the ex-cipient made after the change.These changes are considered unlikely to affect the excipi- Equivalence of impurity profiles is shown by comparingent’s chemical or physical properties, impurity profile, or the data for the pre-change and post-change batches. If thefunctionality. Such changes should be documented, but no- following conditions are met, there has been no significanttifications to the users and regulatory authorities are not change in the impurity profile. [NOTE—Residual Solventsnecessary. ⟨467⟩ notes that under certain circumstances an impurityconcentration below 0.10% may be of concern and the ex-cipient manufacturer should take this under consideration.]LEVEL 2: MIGHT BE SIGNIFICANT

1. No new impurity is present at or above 0.10%, norhas an impurity at this level disappeared that wasThe effect of the change should be evaluated against Cri-previously in the impurity profile.terion 1, Criterion 2, and Criterion 3 (chemical and physical

2. Residual solvent and impurities remain within theproperties and impurity profile) to determine its potential95% confidence interval of the mean of the batcheseffect on excipient functionality. A change in the biologicalproduced before the change.origin of a raw material should be considered with regard to

TSE or GMO regulations. A Level 2 change should always becommunicated to the users and regulatory authorities. TYPES OF CHANGES

LEVEL 3: ALWAYS SIGNIFICANTSite ChangeThis type of change should always be communicated to

the users and regulatory authorities. Shipment of the A change in site can involve either the production orchanged excipient to the user should not occur without packaging of the excipient or its quality control testing. Ifconsent from the user’s company. the proposed manufacturing site was never used to produce3 European Pharmacopoeia, General Text 5.2.8, Minimizing the Risk of Transmit- the excipient, then the change poses a greater risk of alter-ting Animal Spongiform Encephalopathy Agents Via Medicinal Products. ing the excipient’s performance and is considered a Level 34 U.S. Department of Agriculture, Animal and Plant Health Inspection Service change. If the proposed site was used for this purpose(APHIS), Federal Register: November 4, 2003, Volume 68, Number 213 (Pro-

within the past year and the process, equipment, utilities,posed Rules), 9 CFR Parts 93, 94, and 95, Bovine Spongiform Encephalopathy;Minimal Risk Regions and Importation of Commodities. and raw materials are all unchanged, the risk is considered

minor and thus a Level 1 change. However, if the excipientwas produced before at the proposed site with the same




process, equipment, utilities, and raw materials more than 1 components. Any change that is not a replacement in kindyear ago, the risk is moderate and thus Level 2. should be evaluated as a Level 3. Any change to labeling

If the change involves the quality control laboratory, then pertaining to the site of manufacture or testing, the biologi-the impact hinges on the test method. If the method re- cal origin, additives, or storage and handling conditionsmains the same, the change is a Level 1, provided a formal should be evaluated as a Level 3.method transfer or validation is conducted. If the new labuses a different analytical technique or analytical equipment,

Specificationsthen the change should be evaluated more carefully, as re-quired by a Level 2 change.

Differences in raw materials can be further defined by thesupplier used, their specifications, biological origin, country

Scale of origin for those derived from animals, or the addition toor removal of the raw material from the BPE process. If the

Manufacturers often find ways to increase the scale of new supplier provides its raw material against a specificationproduction. If the excipient is being scaled up from pilot to essentially the same as that of the former supplier and theproduction, the change is likely to be significant and thus a raw material method of manufacture is similar, the changeLevel 3. When the change in scale results from the use of is minor and treated as Level 1. However, if the specifica-new and larger, or smaller, production equipment using the tions, biological origin, or country of origin changes, or thesame operating principle, which is often the case in batch manufacturing process is different, then the change shouldprocessing, the change is a Level 2. If the existing equip- be evaluated as potentially significant (Level 2). Also, anyment is optimized to increase capacity without altering the change of source for an animal-origin material should beprocess, often found in continuous processing, the change treated as a Level 2 change, if the source is determined tois considered minor and treated as Level 1 provided that a be not from a risk country as codified in 9 CFR 94.18. Fi-comparison of pre- and post-change data shows no statisti- nally, if the change in raw material involves the addition orcally significant difference. However, careful consideration removal of an ingredient from the process to produce orshould be given to changes that are made that can clearly preserve the BPE or is otherwise used to produce the bulkaffect the properties of the excipient. excipient, the change is likely to be significant (Level 3).

Similar consideration should be given for any change in ori-gin of raw materials that results in a potential that the raw

Equipment material might contain risk materials (i.e., BSE, TSE, aller-gens, or GMOs).

The evaluation of equipment change concerns the issue of Changes are sometimes made to the excipient specifica-whether it is equivalent to the equipment it replaces. Gener- tion or the quality control test method. When changes areally, equipment that is a replacement in kind is considered a not the result of a monograph change, their significanceminor Level 1 change. If the new equipment is not a re- should be evaluated. Such test or specification changes mayplacement in kind but is included in the process validation, be made to the excipient product or to the intermediatethen the change is still a Level 1. Otherwise the change is component. [NOTE—In some circumstances, relaxing theconsidered Level 3. specification may lower the quality if the specification is for

a significant property; therefore any change needs to beevaluated and its significance needs to be documented.]Manufacturing Process Changes to an excipient specification or test method areLevel 3 changes. For example, adding a new specificationA change in process often involves changes to the pro- parameter for the purpose of improving the quality of thecessing instructions, such as target levels for such parame- excipient through lot selection is potentially a very signifi-ters as temperature, pressure, and flow rate; the raw materi- cant Level 3 change. If the specification change relaxes aals to be used; the sequence of operating steps; and the specification parameter, the effect on excipient qualityoperation to be performed, including reprocessing. As illus- should be evaluated as a Level 2 change. An example of atrated in the decision tree in Appendix B, each type of pro- minor change is the additional testing of the excipient initi-cess change can be further detailed. ated with the sole purpose of further characterizing the ma-If there is a change in a process parameter that is within terial without altering its quality, and is a Level 1 risk; how-the process validation, such as operating at a new target ever, notification is supported.within the qualified range, then the change is a Level 1. If a specification for a raw material from the same suppli-However, if the process parameter is outside of the valida- er(s) is made more stringent, then the change is unlikely totion, then the change should be evaluated as a Level 2. be significant (Level 1), whereas if the specification becomesIf minor changes are made to the processing steps, such less stringent, then the change should be evaluated carefullyas a small change outside of the validated range in the rate (Level 2).of addition of an ingredient, then the change is a Level 2. A When a change is made that either increases or maintainsmajor change, such as changing the point at which an in- the level of process control in the manufacturing process, itgredient is added to earlier or later in the process, is poten- should be treated as a Level 1. If the change in processtially significant and thus a Level 3. control relaxes the control, then the effect should be care-Reprocessing of an excipient followed by a purification fully evaluated as Level 2. An illustrative example is pH con-step, when not typical of the process, should be evaluated trol. If a new pH meter allows for more precise measure-as a Level 2 change. However, if no further purification of ment, the process control is improved and the change fallsthe bulk excipient occurs, this type of change is considered under Level 1. However, if the pH control is relaxed by usinga Level 3. a less precise measuring device, the change is treated asLevel 2.

Packaging and LabelingMultiple ChangesThese changes involve the package components meant

for protection and distribution of the excipient. Any change Multiple changes involve more than one change occur-in the package or packaging components such as the drum, ring simultaneously. The risk level for consideration of thebox, liner, or tamper-evident seal that is a replacement in impact of the changes should be the highest level for anykind is a minor change (Level 1). Replacement in kind ap- single change. However, the effect of the totality of changesplies to containers constructed of the same materials andsealed in a similar manner, and liners made of the same




should also be assessed, because this may suggest that the tion mean, is expected to lie, with a given level ofoverall risk is higher. confidence.

CONTINUOUS PROCESS: A manufacturing process that contin-ually produces the excipient from a continuous supply of

REPORTING REQUIREMENTS raw material.DECISION TREE: A visual presentation of the sequence of

events that can occur, including decision points.DRUG SUBSTANCE: See Active Pharmaceutical Ingredient.Documentation EQUIPMENT: The implements used in the manufacture of an

excipient.It is recommended that the evaluation of changes to the EXCIPIENT: Any substance, other than the drug substance,excipient be documented, regardless of the level of change. in a drug product that has been appropriately evaluated forThe report should indicate the basis for evaluating the effect safety and is included in a drug delivery system to either aidof the change on the excipient, the significance of the data the processing of the drug product during its manufacture;used in reaching the conclusion, and the actions taken. protect, support or enhance stability, bioavailability, or pa-Where appropriate, the process validation should be up- tient acceptability; assist in product identification; or en-dated to reflect the changed process. This is clearly indi- hance any other attribute of the overall safety and effective-cated where the evaluation has led to the conclusion that ness of the drug product during storage or use.the change should be considered significant. FOREIGN SUBSTANCE: A component that is present in the BPEbut that is not introduced into the excipient as a conse-quence of its synthesis or purification and is not necessaryNotificationto achieve the required functionality (formerly referred to asa contaminant).The user should be given as much advance notification of

FUNCTIONALITY: The set of performance criteria that the ex-impending change as possible. For Level 3 changes in partic-cipient is intended to meet when used in a formulation.ular, the user may require time to complete the evaluation

GENETICALLY MODIFIED ORGANISM (GMO): Living organisms suchof the impact of the change on their formulations. Duringas animals, plants, or microbes with an altered geneticthis period the user may request inventory of the excipientmakeup produced using a special set of technologies.produced before the change was made. The manufacturer

IMPURITY: A component of an excipient that is not the in-should plan for the change with this eventuality in mind.tended chemical entity or a concomitant component but isRegardless of the apparent level of the change, changespresent as a consequence of either the raw materials usedthat are found to meet the definition of significant changeor the manufacturing process and is not a foreignresulting from the evaluation require user notification.substance.Regulatory authorities often require notification of signifi-

IMPURITY PROFILE: A description of the impurities present incant changes involving the manufacture of excipients. Suchthe excipient.notification should be done as required by the applicable

MASS BALANCE: The sum of the quantifiable material presentauthority.in the excipient.

PACKAGING: The container and its components that holdthe excipient for transport to the user.GLOSSARY

PHYSICAL PROPERTY: A quality parameter that can be meas-ured solely by physical means.ACTIVE PHARMACEUTICAL INGREDIENT (API): Any substance or

PHYSIOLOGICAL EFFECT: Any effect on the normal health ofmixture of substances that is intended to be used in thethe human body.manufacture of a drug (medicinal) product and that, when

PROCESS: The set of operating instructions describing howused in the production of a drug, becomes an active ingre-the excipient is to be synthesized, isolated, purified, pack-dient of the drug product. Such substances are intended toaged, etc.furnish pharmacological activity or other direct effect in the

PROCESS PARAMETER: A measurable operating condition.diagnosis, cure, mitigation, treatment, or prevention of dis-PROCESS STEP: An instruction to the BPE manufacturing per-ease, or to affect the structure or any function of the body

sonnel directing that an operation be done.of humans or animals.PROCESS VALIDATION: A documented program that providesBATCH PROCESS: A manufacturing process that produces the

a high degree of assurance that a specific process will con-excipient from a discrete supply of the raw materials thatsistently produce a result that will meet predetermined ac-are present before the completion of the reaction.ceptance criteria.BIOBURDEN: The nature and quantity of microorganisms

RAW MATERIAL: Any substance used in the production of anpresent in the excipient.excipient, excluding packaging materials.BIOLOGICAL ORIGIN: Defined as either animal origin or

REPLACEMENT IN KIND: Manufacturing equipment that usesnonanimal origin, based on the source of the raw materialthe same operating principles and is of similar constructionused in the manufacture of the excipient, and also includesor packaging components made with the same materials ofmaterials that potentially come into contact with equipmentconstruction and sealed in a similar manner.used in the manufacture of other materials with animal-de-

REPROCESSING: Introduction of previously processed materialrived or GMO-derived components.that did not conform to standards or specifications backBOVINE SPONGIFORM ENCEPHALOPATHY (BSE): A pathologicalinto the process and with repetition of one or more neces-brain deterioration condition of cattle believed to be causedsary steps that are part of the normal manufacturingby a prion that can be transmitted to cause variantprocess.Creutzfeldt-Jakob disease (vCJD) in humans.

RESIDUAL SOLVENT: An organic volatile chemical that is usedBULK PHARMACEUTICAL EXCIPIENT (BPE): See Excipient.or produced in the manufacture of excipients. The residualCHEMICAL PROPERTY: A quality parameter that is measured bysolvent is not completely removed by practical manufactur-chemical or physicochemical test methods.ing techniques.CONCOMITANT COMPONENT: A substance found in an excipi-

SCALE: An increase or decrease in the batch size in batchent that is not the intended chemical entity, but may beprocessing or the throughput capability for continuous pro-necessary for ensuring the proper performance of the excipi-cessing, whether or not different equipment is used.ent in its intended use, and is not an impurity or a foreign

SIGNIFICANT CHANGE: A change that alters an excipient’ssubstance (formerly referred to as a minor component).physical or chemical property from the norm or that is likelyCONFIDENCE INTERVAL: A range, calculated from sample data,to alter the excipient’s performance in the dosage form.within which a population parameter, such as the popula-




SITE: A defined location of the equipment in which the 2. Manufacture at a new site never used for thisexcipient is manufactured. It may be within a larger facility. purpose.A change in site may be to a different part of the existing 3. Revision to a sales specification made for the purposefacility but in a different operational area or may be to a of improving the quality of the excipient eitherremote facility, including a contract manufacturer. through improved process control or lot selection.

SOLVENT: A vehicle, other than water, used in the synthesis 4. Use of a new package, such as a drum of a differentof the product that remains chemically unchanged. construction (i.e., plastic versus steel).

SPECIFICATION: The quality parameters to which the excipi- 5. Revision of the product label.ent, component, or intermediate must conform and that 6. Revision of the tamper-evident seal.serve as a basis for quality evaluation. 7. A change to the stated shelf life or retest interval.

STATISTICAL QUALITY CONTROL (SQC): The plotting of sequentialtest results to show their variation relative to the specifica-

APPENDIX B: DECISION TREEtion range and their normal variation.TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY (TSE): Any agent

A decision tree has been developed to aid in classifyingthat causes a symptomatic illness in animals or humans akinthe change into levels. The diagram begins with the pro-to BSE and variant Creutzfeldt-Jakob disease (vCJD), e.g.,posed change and guides the BPE maker to an indication ofscrapie in sheep.the likelihood that the change will affect the excipient user.The decision tree classifies the types of change that occur in

APPENDIX A: CHANGE LEVELS excipient manufacture as involving the site of manufacture,the processing steps, packaging, and testing and quality

For guidance, examples of changes that typically would control.be classified into the three change levels are provided.

APPENDIX C: IMPURITY PROFILELevel 1

1. A processing parameter changed to a new set pointDefinition of Impurity Profilethat is within the process validation.

2. Use of alternate equipment that is listed as an alter-The impurity profile of an excipient may be defined as anate in a regulatory document (i.e., Drug Master

description of the impurities present in a typical lot of excip-File).ient produced by a given manufacturing process. The impu-3. Use of equipment that is a replacement in kind. Thisrity profile includes the identity of each major impurity oris typically new equipment that uses the same operat-an appropriate qualitative description, such as peak reten-ing principles as the equipment replaced.tion time (if unidentified), the quantity of impurity observed4. Revision to a specification for one of the excipient’sexpressed as a range, and the classification, as discussed be-raw materials that involves more stringent quality orlow, of each identified impurity. Excipients frequently func-conformance to additional pharmacopeias.tion because they are not “pure”. That is to say that often5. Addition of a test parameter or tightening of an ex-there are concomitant components that are necessary foristing parameter to an excipient specification that isthe correct functioning of the excipient. These essential con-used for informational purposes only. This is not usedcomitant components should not be considered as part offor quality improvement or control purposes.the impurity profile but should be evaluated separately, if6. Improved environmental control to prevent cross-con-possible.tamination of the excipient. An example of this is an

The composition of the impurity profile is dependentimproved packaging room or additional segregationupon such variables as the raw materials, solvents, reagents,of manufacturing equipment.catalysts, and manufacturing process used in the excipient’smanufacture. Foreign substances, such as manufacturing

Level 2 aids that can be present in the excipient, should be con-trolled to a level that is unobjectionable.5

1. A processing parameter changed to a new set point It is recognized that the presence of essential concomitantthat is outside of the process validation. components is important to the performance of the excipi-

2. A site change returning the manufacture of an excipient in the drug product. Therefore, the presence of theseent to a site previously used for this purpose more essential concomitant components in the excipient shouldthan 1 year ago. neither be construed as being undesirable nor be confused

3. Process control that is outside the normal limits of with the presence of foreign substances or impurities.variability. An example of this is new process control It should be noted that in some excipients, water may beequipment for control of excipient properties not pre- an essential concomitant component, necessary to achieveviously controlled that create process adjustments. the desired functionality. For other excipients, water may be

4. A change in the handling, storage, or delivery of the included in the impurity profile, if appropriate, and shouldexcipient. An example of a handling change is the be classified as an inorganic impurity in such circumstances.movement of a powder with new powder-conveyingequipment. The storage of the excipient in bulk ver-

Use of the Impurity Profilesus the shipping container is illustrative of a changein storage. The delivery of the excipient in tempera-

The impurity profile, as used in this chapter, is meant toture-controlled trucks versus uncontrolled trucks ex-help determine the significance of a change. Impuritiesemplifies a change in delivery but not vice versa.should be profiled by the excipient manufacturer if possible.5. A change in container size or shape.This may be accomplished through knowledge of the start-ing materials and manufacturing process and subsequent

Level 3 application of validated analytical testing to provide a quali-tative and/or quantitative result of the impurity profile.

1. Addition or removal of a chemical entity from the 5 Current USP General Notices.manufacturing process. An example would be the ad-dition or removal of a preservative agent, bufferingagent, stabilizer, or catalyst.




the source. See Residual Solvents ⟨467⟩ for details. Note thatProcedure for Development of an Impuritythe limits specified apply to the drug product as consideredProfile in Option 2 and to the excipient as in Option 1. It should benoted that a residual solvent can also be classified as a con-Because of the diverse nature of substances that may be comitant component but still must be considered.incorporated as pharmaceutical excipients, including highly

complex mixtures from animal, botanical, mineral, and/orsynthetic sources, differing approaches to characterizing Impurity Profiletheir properties may be required. It is recognized that thedevelopment of an impurity profile may not be technically The characterization of the impurity profile of an excipientfeasible for certain excipients. In such cases, the manufac- should be attempted by the manufacturer, where possible,turer should document what method is being used to moni- by taking into account the manufacturing process and po-tor the excipient for the effect of changes as noted in this tential impurities anticipated as a consequence. A sensiblechapter in Evaluation Criteria and Determination of Signifi- approach includes control of all impurities that have knowncance in Significant Change. toxicological characteristics. The limits of these impurities

may be based upon the usage of the drug product when soinformed by the user and should comply with the require-Classification of Impurities ments of ICH Q3B(R) Impurities in Drug Products and of Re-sidual Solvents ⟨467⟩.Excipient impurities are classified as follows. For the purpose of developing an impurity profile, excipi-

Organic Impurities: Any organic material that arises dur- ents may be classified as those where purity can be directlying the manufacturing process that is not listed as the in- measured and those where purity cannot be directly meas-tended excipient in the monograph or specification and is ured. Examples of the former are excipients whose mono-not a concomitant component or foreign substance. This graph or specification includes a requirement for purity.may include starting materials, byproducts, intermediates, Polymers or derivatives of naturally occurring products arereagents, ligands, and catalysts. often examples of excipients where purity cannot be directly

Inorganic Impurities: Any inorganic material that arises measured.during the manufacturing process that is not listed as the The material to be used for the development of the impu-intended excipient in the monograph or specification and is rity profile should be sampled using the same samplingnot a concomitant component or foreign substance. This technique and sampling point in the manufacturing processmay include starting materials, byproducts, intermediates, as the sample taken for use in the quality control release ofreagents, ligands, and catalysts. the lot.

Residual Solvents: Solvents resulting from the incom-plete removal of organic or inorganic liquids, regardless of




rect measurement of inorganic impurities is not possible, to-Excipients for Which Purity Can Be Measuredtal Inorganic Impurities may be estimated as:

A mass balance is desirable, but it is recognized that a100 − (Organic Impurities + Residual Solvents + Excipient)mass balance of 100% cannot generally be achieved be-

cause of the inherent limitation in accuracy and precision ofResidual Solvents: Report the solvents present by classifi-the available tests, as well as the possible lack of suitable

cation (see Residual Solvents ⟨467⟩) and level.tests for some components. Mass balance of the excipientcomposition should be computed through the addition ofthe organic impurities, inorganic impurities, residual sol- Excipients for Which Purity Cannot Bevents, and excipient. If there are measurable essential con-

Measuredcomitant components, they should be included with the ex-cipient for purposes of this calculation. The purpose of

Although a mass balance of the excipient composition ofcalculating the mass balance is to estimate the amount of100% is desirable, it is recognized that this goal is oftenmaterial not measured in the impurity profile. The excipienttechnically difficult, if not impossible, to achieve. Therefore,manufacturer should include in the report of the develop-manufacturers should include reports of the development ofment of the impurity profile the mass balance achieved andthe impurity profile, the mass balance achieved, and whatwhat are thought to be the components not fullyare thought to be the components not otherwise quantified.quantified.

For excipients produced by continuous chemical process-Organic Impurities: Identify each impurity at or greatering, it may not be possible to calculate a chemical massthan 0.10% using appropriate analytical techniques. If or-balance, only an overall process balance.ganic impurities cannot be identified, a qualitative descrip-

Where direct measurement of the excipient purity is nottion, such as chromatographic retention time, should be as-feasible, techniques should be used to provide an estimatesigned for all impurities at or greater than 0.10%. If directof excipient purity. This information is then applied in themeasurement of organic impurities is not possible, total Or-equations listed above under Excipients for Which Purity Canganic Impurities can be reported as:Be Measured.

100 − (Inorganic Impurities + Residual Solvents + Excipient)

DocumentationInorganic Impurities: Identify each impurity at or

above 0.10% using appropriate analytical techniques. If di- The excipient supplier should develop documentation tosupport the development of an impurity profile. This docu-mentation can be compiled in various ways by the supplierso that it can be retrieved to support the impurity profile.




Documentation of an excipient impurity profile should in- Definition of Harmonizationclude the following information:

1. Sampling plan The PDG has defined harmonization of a pharmacopeial2. Analytical test methods monograph or general chapter as follows:3. Identity and quantity of each component of the ex- “A pharmacopeial general chapter or other pharmacopeial

cipient, including both the excipient components and document is harmonized when a pharmaceutical substanceidentified impurities or product tested by the document’s harmonized procedure

4. Discussion of the uncertainty in the measurement of yields the same results and the same accept/reject decisioneach component of the excipient and impurity is reached.”

5. Discussion of the mass balance When using a fully harmonized pharmacopeial mono-graph or general chapter, an analyst will perform the sameprocedures and reach the same accept/reject decisions irre-spective of which PDG pharmacopeia is referenced. This ap-proach is called interchangeability, and each pharmacopeiawill identify, in an appropriate manner, such a monographor general chapter.

When full harmonization of a pharmacopeial monograph⟨1196⟩ PHARMACOPEIALor general chapter is not possible, the PDG works to harmo-nize it using an approach termed harmonization by attri-HARMONIZATIONbute. In this approach, some elements of a monograph orgeneral chapter may be harmonized, but others may not.When a monograph is harmonized by attribute, a combina-This general information chapter provides information tion of approaches is needed. For nonharmonized elements,about the concept of harmonization by the Pharmacopeial reliance on the individual PDG pharmacopeia is necessary.Discussion Group (PDG). The chapter provides: (1) the PDG

Policy Statement; (2) the PDG Working Procedures; (3) a dis-cussion; (4) a status report; and (5) a glossary. Process

Harmonization of pharmacopeial documents in the PDG isHARMONIZATION POLICY based upon decisions of the expert bodies of each pharma-copeia. The PDG works transparently in many ways, princi-The following policy statement was approved by the PDG pally through the public notice and comment procedures ofat its September 2002 meeting. each pharmacopeia. The details are described below underPDG Working Procedures.

General InformationImplementationIn 1989, the PDG was formed with representatives from

the European Directorate for the Quality of Medicines in the The implementation of a harmonized document varies inCouncil of Europe, the United States Pharmacopeial Conven- the three PDG regions, depending upon their legal require-tion, Inc., and the Japanese Pharmacopoeia in the Ministry ments, need for translation, and publication schedules. Eachof Health and Welfare—now the Ministry of Health, Labor, pharmacopeia generally allows some period of time afterand Welfare (MHLW). Since that time, the PDG generally publication to implement official harmonized texts to allowmeets twice a year to work on pharmacopeial harmoniza- manufacturers and other users to achieve conformity. Har-tion topics. In May 2001, the PDG welcomed the World monization is not achieved until the text becomes official inHealth Organization as an observer. While not part of the all three pharmacopeias.International Conference on Harmonization of Technical Re-quirements for Registration of Pharmaceuticals for HumanUse (ICH), the PDG usually meets in conjunction with the Revision of Harmonized MonographsICH and provides the ICH Steering Committee with reportsof its progress. To facilitate harmonization of some ICH The pharmacopeias participating in the PDG have agreedQuality guidelines and the Quality section of the Common not to revise unilaterally any harmonized document afterTechnical Document, the PDG representatives sometimes at- publication. Should revisions be necessary for any appropri-tend ICH expert working group discussions as observers. ate reasons, the initiating pharmacopeia notifies the PDG,

and revision proceeds according to the PDG WorkingProcedures.Purpose

A pharmacopeial monograph for an active ingredient or PDG WORKING PROCEDURESexcipient, preparation, or other substance used in the man-ufacture or compounding of a medicinal product generally Working Procedures of the PDG were updated at the Oc-provides a name, definition, description, and sometimes tober 2006 PDG meeting.packaging, labeling, and storage statements. Thereafter, themonograph provides tests, procedures, and acceptance cri-teria that constitute the specification. For frequently cited Generalprocedures, a monograph may refer to a general chapter foreditorial convenience. The PDG works to harmonize excipi- Harmonization may be carried out retrospectively for ex-ent monographs and general chapters. This will reduce isting monographs or chapters or prospectively for newmanufacturers’ burden of performing analytical procedures monographs or chapters.in different ways, using different acceptance criteria. At all The three pharmacopeias have a commitment to respecttimes, the PDG works to maintain an optimal level of sci- the agreed working procedures and the associated timeence consistent with protection of the public health. deadlines as an essential part of the harmonization

procedure.Harmonization of pharmacopeial documents in the PDG is

performed on the basis of decisions of the expert bodies ofeach pharmacopeia. The PDG works transparently in many



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