This document is meant to establish uniform considerations for evaluating the significance of changes involving the manufacture of bulk pharmaceutical excipients (BPEs). The purpose of the evaluation is to determine the need for informing the excipient user and regulatory authorities about the nature of the change.

The principles and information in this chapter can be applied to the manufacture of all bulk pharmaceutical excipients [referred to throughout this document as “excipient(s)”] intended for use in human drugs, veterinary drugs, and biologics. The principles set forth here must be applied once it has been determined that a chemical is intended for use as a component of a drug product. As the excipient manufacturing process progresses, the degree of assurance concerning the quality of the product should increase and should be controlled and documented. However, at some logical processing step, as determined by the manufacturer, the GMP as described in Good Manufacturing Practices for Bulk Pharmaceutical Excipients 1078 should be applied and maintained. Judgment, based on risk analysis and a thorough knowledge of the process, is required to determine from which processing step the GMPs should be implemented.

This chapter should be of international application, bearing in mind that pharmaceutical excipients are diverse and often have uses other than pharmaceutical applications. It provides minimum recommendations when considering the impact of a change on the excipient. As an international guidance document, it cannot specify all national legal requirements nor cover in detail the particular characteristics of every excipient.

When considering how to use this chapter, each manufacturer should consider how it may apply to that manufacturer's product and processes. The diversity of excipients means that some principles of the chapter may not be applicable to certain products and processes. The terminology “should” and “it is recommended” do not necessarily mean “must” as used in the application of this chapter.

Excipients may contain minor components that are known to be or might be necessary for the correct functioning of the excipient. The presence of these “essential concomitant components” in the excipient should not be construed as undesirable. These concomitant components are not considered part of the impurity profile, but should be considered separately. Water may be a concomitant component in some excipients, but may be included in the impurity profile for others. (See Impurity Profile in Appendix C for more information.)

This chapter is divided into several sections. The first section provides a background discussion necessary for evaluating a change and determining the necessity of informing the user and/or regulatory authorities. A second section provides criteria for determining the risk that a change will be significant, including guidance on development of an impurity profile. Also included are the following: The Glossary contains terms and definitions used in all sections of this document. Appendix A includes some examples of changes that would be classified into each of the three risk levels. Appendix B provides a decision tree useful in considering the potential impact of a change on excipient performance. Appendix C delineates the development of an impurity profile.

Evaluating the impact of a change in the manufacture of an excipient could be more difficult than that for an active pharmaceutical ingredient (API). Although the API is seldom used for more than a handful of therapeutic purposes, the BPE is often used with a broad range of active ingredients and in a diverse range of finished dosage forms. Whereas the API is typically of high purity and well characterized by the quality control and analytical laboratory, the BPE is often a natural substance, mixture, or polymer, the chemical and physical properties of which are more difficult to quantify. For a more thorough discussion of GMPs that apply to excipient manufacture, see the general information chapter Good Manufacturing Practices for Bulk Pharmaceutical Excipients 1078.

Any change by the manufacturer of an excipient that alters an excipient's physical or chemical property outside the established limits, or that is likely to alter the excipient performance in the dosage form, is considered significant. Such changes may necessitate notifying the local regulatory authority if required. Regardless of whether there is a regulatory requirement, the manufacturer has an obligation to notify its users of a significant change so that the user can evaluate the impact of the change on the user's products. It is suggested that unless there is clear indication from evaluation of the change that it is not significant as stipulated by this general chapter, the pharmaceutical user should be notified.

The types of change that are considered here are changes to the following: site, scale, equipment, process, packaging and labeling, and specification (including raw materials).

The requirement for evaluating the impact of change on the excipient begins, at a minimum, with the raw materials for the first processing step from where GMP compliance begins. GMP requirements increase as the manufacturing process progresses. Thus, at some logical processing step, usually well before the final finishing operation, appropriate GMPs should be imposed and maintained throughout the remainder of the process. Methods such as HACCP (Hazard Analysis and Critical Control Point), FEMA (Failure Effects Mode Analysis), or a detailed process flow diagram may be used to identify the unit operations, required equipment, stages at which various substances are added, key steps in the process, critical parameters (time, temperature, pressure, etc.), and necessary monitoring points. Judgment, based on risk analysis and a thorough knowledge of the process, is required to determine at which processing step the GMP should be implemented.1

It is important to give careful consideration to any processing changes that occur after the excipient has been synthesized or isolated but prior to packaging. However, it must be recognized that a change made earlier in the process can result in a change in the excipient functionality, and it is recommended that such changes also be considered.

These criteria, in the form of questions, are presented for consideration when evaluating the impact of a change relating to excipient manufacture:

An affirmative answer to any of these questions indicates that the impact of the change on the excipient may lead to changes in its performance in the dosage form.

It is important to provide objective criteria for evaluating when a change has occurred in an excipient property or composition, in the essential concomitant components profile, in biological origin, or in its functionality. This enables the BPE manufacturer to evaluate the significance of the change on the excipient for the purpose of notifying the regulatory authorities and/or the user.

Criterion 1: Evaluation of the chemical properties or composition of an excipient should include, at a minimum, all monograph and manufacturer specification parameters. A comparison of these test results for the excipient before and after a change should be done to determine if there is a statistically significant difference.

Criterion 2: Physical properties should be considered based upon the physical form of the excipient and its functionality as known or as used by the end users. A physical property that is part of a mutually agreed-upon specification between the manufacturer and end user should also be evaluated. For example, a manufacturer of an excipient powder should consider measuring the impact of changes on such physical parameters as bulk density, surface area, particle shape, and particle size distribution. Liquid excipients might be evaluated for changes in their pH and viscosity. For all polymeric excipients, the effect of a change on a physical property, such as molecular weight distribution, should be considered.

Criterion 3: Objective criteria are also necessary when considering changes to the “essential concomitant components” profile for an excipient as a result of changes. The profile, as noted in Appendix C, contains the following:

The feasibility of developing an impurity profile varies with the composition and origin of the excipient. It is important to note that identifying and quantifying impurities in some excipients are extremely difficult. Thus, an excipient manufacturer may not have developed an impurity profile. In that case, it is important for excipient manufacturers to either document their efforts to identify and quantify the impurities that may be present to justify their limited results or to justify other means by which changes may be evaluated.

The significance of the change can be determined by comparing the impurity profile of the pre-change material with that of the post-change product. Therefore, once the profile has been developed, it should be reassessed following changes to the process. An impurity should be monitored as part of the profile if it is present at or greater than 0.10%, if it has an established physiological effect, or if it is known to be unsafe at a lower level.

The content of the impurity profile varies with the nature of the excipient, the raw materials used in its manufacture, and its chemical composition. Where possible, changes are considered significant whenever a new impurity is introduced at the 0.10% concentration or higher, or when an impurity previously present at or greater than 0.10% disappears. Changes to the quantity of an existing impurity specified in a monograph and reported on the Certificate of Analysis (COA) should be treated as a chemical property for the purposes of this evaluation.

Changes in the levels of residual solvents should be considered when determining the significance of change. See Residual Solvents 467 for details.

Criterion 4: Objective criteria for evaluating changes to excipient functionality are desirable. However, the nature of this type of study can vary broadly based upon the excipient and its application in the dosage form. It must also be recognized that the excipient manufacturer does not always know each use of the excipient. Therefore this chapter cannot provide objective criteria for this study but stresses the importance of such a consideration by the manufacturer. If there is the potential that the functionality of the excipient may be affected by the change, users should be notified and material provided upon request so that they can determine the impact of the change in their finished pharmaceutical products.

Criterion 5: Often the excipient contains moisture, the presence of which can have an impact on excipient performance in the preparation of the pharmaceutical dosage form. Therefore a change in the moisture level beyond the range typical of production, even though within the compendial or specification limit, can affect its stability and/or end use.

Criterion 6: Change in the processing steps, raw materials, or equipment can adversely affect control of microorganisms in the excipient. Therefore the effect of the change on the bioburden should be evaluated, particularly for excipients susceptible to microbial growth.

Criterion 7: Change in the origin of a raw material or contact packaging can result in a change to the other six change criteria. Change in origin can involve the country of origin, geological origin, or species of origin for the raw material.

A change in the country of origin of a raw material or contact packaging material can affect the status of the excipient as it relates to the potential presence of bovine spongiform encephalopathies (BSEs), transmissible spongiform encephalopathy (TSE) material, or genetically modified organisms (GMOs). The country of origin of animal raw material, or of components used in the manufacture of the raw material, can result in noncompliance with relevant TSE regulations.3,4 Current information on BSE and related diseases can be accessed on the United States Department of Agriculture (USDA) website (usda.gov).

A change in the geological origin of a mineral-based excipient can alter the composition of the excipient. Geological formations containing the same mineral can differ in their chemical composition, crystalline structure, density, etc. A change in geological origin of raw material can affect the excipient's chemical or physical properties, the impurity profile, or excipient functionality.

A change to the species of origin for raw materials of either animal or vegetable origin can raise concern. Switching from one animal species to another can affect the status of the excipient as it relates to the presence of BSE or TSE material in the excipient, as noted above. Switching from animal-derived to plant-derived raw materials, although eliminating the issue of BSE or TSE material, raises the potential for the presence of plant-based allergenic material in the excipient. Switching from one plant species to another also can result in the possible presence of an allergen in the excipient. In addition to this issue with allergens, use of plant-derived raw materials can affect pharmaceutical manufacturers who have a concern about the presence of GMOs in the excipient.

In the evaluation of the effect of changes on the excipient, it is recognized that even with objective criteria, some judgment may be necessary. To facilitate the decision as to the significance of a change and the likely effect on the dosage form, the types of changes are classified using three levels:

There should be a written protocol for the evaluation of a change to determine whether it is significant. The protocol should describe the nature of the change, the reason it may be significant, the testing to be performed to evaluate the change, and the criteria for determining the significance. If the change is attributable to a new biological source for raw materials used in the manufacture of the excipient, it is recommended that the regulatory status of the raw material (i.e., BSE/TSE, GMO agents) be evaluated first. Then, where possible, the results from the testing of a minimum of 10 pre- and 3 post-change batches of excipient should be compared (see Supporting Data, below). If significant changes are seen, then an assessment of the significance should be made.

The manufacturer should test the excipient made after the change for all specification properties and compare the results to the historical data. A standard statistical test, such as a t-test of the means, should be used to compare the new data with the historical data. If when using an appropriate statistical analysis there is sufficient evidence that the populations are different at the 95% confidence interval, the change should be considered significant. As an additional check on consistency, it is also recommended that the new batch specification properties be plotted on standard Statistical Quality Control (SQC) control charts, along with standard batch results.

It is preferable to use data to measure the effect of a change on the excipient. The comparison should begin with chemical and physical properties, followed, where appropriate, by moisture, bioburden, impurity profile, and functionality. The manufacturer should use good judgment on sample comparisons for the other evaluations.

Chemical and physical properties lend themselves to quantitative measurement. Often these properties are part of the specification for the excipient. As such there should be a large body of test data to use for the properties affected for comparison to the corresponding data of the excipient made after the change.

Equivalence of impurity profiles is shown by comparing the data for the pre-change and post-change batches. If the following conditions are met, there has been no significant change in the impurity profile. [Note—Residual Solvents 467 notes that under certain circumstances an impurity concentration below 0.10% may be of concern and the excipient manufacturer should take this under consideration. ]

A change in site can involve either the production or packaging of the excipient or its quality control testing. If the proposed manufacturing site was never used to produce the excipient, then the change poses a greater risk of altering the excipient's performance and is considered a Level 3 change. If the proposed site was used for this purpose within the past year and the process, equipment, utilities, and raw materials are all unchanged, the risk is considered minor and thus a Level 1 change. However, if the excipient was produced before at the proposed site with the same process, equipment, utilities, and raw materials more than 1 year ago, the risk is moderate and thus Level 2.

If the change involves the quality control laboratory, then the impact hinges on the test method. If the method remains the same, the change is a Level 1, provided a formal method transfer or validation is conducted. If the new lab uses a different analytical technique or analytical equipment, then the change should be evaluated more carefully, as required by a Level 2 change.

Manufacturers often find ways to increase the scale of production. If the excipient is being scaled up from pilot to production, the change is likely to be significant and thus a Level 3. When the change in scale results from the use of new and larger, or smaller, production equipment using the same operating principle, which is often the case in batch processing, the change is a Level 2. If the existing equipment is optimized to increase capacity without altering the process, often found in continuous processing, the change is considered minor and treated as Level 1 provided that a comparison of pre- and post-change data shows no statistically significant difference. However, careful consideration should be given to changes that are made that can clearly affect the properties of the excipient.

The evaluation of equipment change concerns the issue of whether it is equivalent to the equipment it replaces. Generally, equipment that is a replacement in kind is considered a minor Level 1 change. If the new equipment is not a replacement in kind but is included in the process validation, then the change is still a Level 1. Otherwise the change is considered Level 3.

A change in process often involves changes to the processing instructions, such as target levels for such parameters as temperature, pressure, and flow rate; the raw materials to be used; the sequence of operating steps; and the operation to be performed, including reprocessing. As illustrated in the decision tree in Appendix B, each type of process change can be further detailed.

If there is a change in a process parameter that is within the process validation, such as operating at a new target within the qualified range, then the change is a Level 1. However, if the process parameter is outside of the validation, then the change should be evaluated as a Level 2.

If minor changes are made to the processing steps, such as a small change outside of the validated range in the rate of addition of an ingredient, then the change is a Level 2. A major change, such as changing the point at which an ingredient is added to earlier or later in the process, is potentially significant and thus a Level 3.

Reprocessing of an excipient followed by a purification step, when not typical of the process, should be evaluated as a Level 2 change. However, if no further purification of the bulk excipient occurs, this type of change is considered a Level 3.

These changes involve the package components meant for protection and distribution of the excipient. Any change in the package or packaging components such as the drum, box, liner, or tamper-evident seal that is a replacement in kind is a minor change (Level 1). Replacement in kind applies to containers constructed of the same materials and sealed in a similar manner, and liners made of the same components. Any change that is not a replacement in kind should be evaluated as a Level 3. Any change to labeling pertaining to the site of manufacture or testing, the biological origin, additives, or storage and handling conditions should be evaluated as a Level 3.

Differences in raw materials can be further defined by the supplier used, their specifications, biological origin, country of origin for those derived from animals, or the addition to or removal of the raw material from the BPE process. If the new supplier provides its raw material against a specification essentially the same as that of the former supplier and the raw material method of manufacture is similar, the change is minor and treated as Level 1. However, if the specifications, biological origin, or country of origin changes, or the manufacturing process is different, then the change should be evaluated as potentially significant (Level 2). Also, any change of source for an animal-origin material should be treated as a Level 2 change, if the source is determined to be not from a risk country as codified in 9 CFR 94.18. Finally, if the change in raw material involves the addition or removal of an ingredient from the process to produce or preserve the BPE or is otherwise used to produce the bulk excipient, the change is likely to be significant (Level 3). Similar consideration should be given for any change in origin of raw materials that results in a potential that the raw material might contain risk materials (i.e., BSE, TSE, allergens, or GMOs).

Changes are sometimes made to the excipient specification or the quality control test method. When changes are not the result of a monograph change, their significance should be evaluated. Such test or specification changes may be made to the excipient product or to the intermediate component. [Note—In some circumstances, relaxing the specification may lower the quality if the specification is for a significant property; therefore any change needs to be evaluated and its significance needs to be documented. ]

Changes to an excipient specification or test method are Level 3 changes. For example, adding a new specification parameter for the purpose of improving the quality of the excipient through lot selection is potentially a very significant Level 3 change. If the specification change relaxes a specification parameter, the effect on excipient quality should be evaluated as a Level 2 change. An example of a minor change is the additional testing of the excipient initiated with the sole purpose of further characterizing the material without altering its quality, and is a Level 1 risk; however, notification is supported.

If a specification for a raw material from the same supplier(s) is made more stringent, then the change is unlikely to be significant (Level 1), whereas if the specification becomes less stringent, then the change should be evaluated carefully (Level 2).

When a change is made that either increases or maintains the level of process control in the manufacturing process, it should be treated as a Level 1. If the change in process control relaxes the control, then the effect should be carefully evaluated as Level 2. An illustrative example is pH control. If a new pH meter allows for more precise measurement, the process control is improved and the change falls under Level 1. However, if the pH control is relaxed by using a less precise measuring device, the change is treated as Level 2.

Multiple changes involve more than one change occurring simultaneously. The risk level for consideration of the impact of the changes should be the highest level for any single change. However, the effect of the totality of changes should also be assessed, because this may suggest that the overall risk is higher.

It is recommended that the evaluation of changes to the excipient be documented, regardless of the level of change. The report should indicate the basis for evaluating the effect of the change on the excipient, the significance of the data used in reaching the conclusion, and the actions taken.

Where appropriate, the process validation should be updated to reflect the changed process. This is clearly indicated where the evaluation has led to the conclusion that the change should be considered significant.

The user should be given as much advance notification of impending change as possible. For Level 3 changes in particular, the user may require time to complete the evaluation of the impact of the change on their formulations. During this period the user may request inventory of the excipient produced before the change was made. The manufacturer should plan for the change with this eventuality in mind.

Regardless of the apparent level of the change, changes that are found to meet the definition of significant change resulting from the evaluation require user notification.

Regulatory authorities often require notification of significant changes involving the manufacture of excipients. Such notification should be done as required by the applicable authority.

The impurity profile of an excipient may be defined as a description of the impurities present in a typical lot of excipient produced by a given manufacturing process. The impurity profile includes the identity of each major impurity or an appropriate qualitative description, such as peak retention time (if unidentified), the quantity of impurity observed expressed as a range, and the classification, as discussed below, of each identified impurity. Excipients frequently function because they are not “pure”. That is to say that often there are concomitant components that are necessary for the correct functioning of the excipient. These essential concomitant components should not be considered as part of the impurity profile but should be evaluated separately, if possible.

The composition of the impurity profile is dependent upon such variables as the raw materials, solvents, reagents, catalysts, and manufacturing process used in the excipient's manufacture. Foreign substances, such as manufacturing aids that can be present in the excipient, should be controlled to a level that is unobjectionable.5

It is recognized that the presence of essential concomitant components is important to the performance of the excipient in the drug product. Therefore, the presence of these essential concomitant components in the excipient should neither be construed as being undesirable nor be confused with the presence of foreign substances or impurities.

It should be noted that in some excipients, water may be an essential concomitant component, necessary to achieve the desired functionality. For other excipients, water may be included in the impurity profile, if appropriate, and should be classified as an inorganic impurity in such circumstances.

The impurity profile, as used in this chapter, is meant to help determine the significance of a change. Impurities should be profiled by the excipient manufacturer if possible. This may be accomplished through knowledge of the starting materials and manufacturing process and subsequent application of validated analytical testing to provide a qualitative and/or quantitative result of the impurity profile.

Because of the diverse nature of substances that may be incorporated as pharmaceutical excipients, including highly complex mixtures from animal, botanical, mineral, and/or synthetic sources, differing approaches to characterizing their properties may be required. It is recognized that the development of an impurity profile may not be technically feasible for certain excipients. In such cases, the manufacturer should document what method is being used to monitor the excipient for the effect of changes as noted in this chapter in Evaluation Criteria and Determination of Significance in Significant Change.

Excipient impurities are classified as follows.

The characterization of the impurity profile of an excipient should be attempted by the manufacturer, where possible, by taking into account the manufacturing process and potential impurities anticipated as a consequence. A sensible approach includes control of all impurities that have known toxicological characteristics. The limits of these impurities may be based upon the usage of the drug product when so informed by the user and should comply with the requirements of ICH Q3B(R) Impurities in Drug Products and of Residual Solvents 467.

For the purpose of developing an impurity profile, excipients may be classified as those where purity can be directly measured and those where purity cannot be directly measured. Examples of the former are excipients whose monograph or specification includes a requirement for purity. Polymers or derivatives of naturally occurring products are often examples of excipients where purity cannot be directly measured.

The material to be used for the development of the impurity profile should be sampled using the same sampling technique and sampling point in the manufacturing process as the sample taken for use in the quality control release of the lot.

A mass balance is desirable, but it is recognized that a mass balance of 100% cannot generally be achieved because of the inherent limitation in accuracy and precision of the available tests, as well as the possible lack of suitable tests for some components. Mass balance of the excipient composition should be computed through the addition of the organic impurities, inorganic impurities, residual solvents, and excipient. If there are measurable essential concomitant components, they should be included with the excipient for purposes of this calculation. The purpose of calculating the mass balance is to estimate the amount of material not measured in the impurity profile. The excipient manufacturer should include in the report of the development of the impurity profile the mass balance achieved and what are thought to be the components not fully quantified.

Although a mass balance of the excipient composition of 100% is desirable, it is recognized that this goal is often technically difficult, if not impossible, to achieve. Therefore, manufacturers should include reports of the development of the impurity profile, the mass balance achieved, and what are thought to be the components not otherwise quantified.

For excipients produced by continuous chemical processing, it may not be possible to calculate a chemical mass balance, only an overall process balance.

Where direct measurement of the excipient purity is not feasible, techniques should be used to provide an estimate of excipient purity. This information is then applied in the equations listed above under Excipients for Which Purity Can Be Measured.

The excipient supplier should develop documentation to support the development of an impurity profile. This documentation can be compiled in various ways by the supplier so that it can be retrieved to support the impurity profile. Documentation of an excipient impurity profile should include the following information: