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This guidance provides recommendations to you, the applicant, on preparing and using comparability protocols for changes in chemistry, manufacturing, and controls (CMC) of products2 in approved marketing applications. A comparability protocol is a comprehensive plan that describes the specific tests and validation studies and acceptable limits to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, or potency of the product, as they may relate to the safety or effectiveness of the product. FDA's review of the comparability protocol will include a determination of whether changes made in accordance with that protocol may be submitted under a reduced reporting category for the change because the use of the protocol reduces the potential risk of an adverse effect. This guidance applies to comparability protocols that you would submit in biologics license applications (BLA), or supplements to BLA applications, for therapeutic recombinant DNA derived protein products, naturally derived protein products, plasma derivatives, vaccines, allergenics and therapeutic DNA plasmids. This guidance also applies to new drug applications (NDAs), abbreviated new drug applications (ANDAs),3 new animal drug applications (NADAs), abbreviated new animal drug applications (ANADAs), or supplements to hese applications for protein drug products, and not sufficiently characterizable peptide products (e.g., complex mixture of small peptides).4 This guidance does not pertain to comparability protocols for human blood and blood components intended for transfusion and for further manufacture,5 somatic cell therapy, or gene therapy vectors (except therapeutic DNA plasmids). This guidance also does not pertain to vaccines for veterinary use, which are regulated by United States Department of Agriculture. FDA guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in agency guidances means that something is suggested or recommended, but not required.
You are responsible for assessing, prior to distribution of a product, the effect of any postapproval CMC changes on the identity, strength, quality, purity, and potency of the product as they may relate to the safety or efficacy of the product). Such an assessment often includes data that demonstrate that the pre- and post-change products (i.e., the products manufactured prior to and subsequent to a manufacturing change) are comparable. You must report postapproval CMC changes to FDA, us, in one of the reporting categories described by FDA (section 506A(b) of the Federal Food, Drug, and Cosmetic Act (the act) (21 USC 356a).6 (See II.E for references). As part of its review and approval of a comparability protocol to evaluate the effects of a change, if supported by the submission, FDA may determine that a CMC change made under the comparability protocol will fall into a less restrictive reporting category. In many cases, using a comparability protocol will facilitate the subsequent implementation and reporting of CMC changes, which could result in moving a product into distribution sooner than if a protocol were not submitted.
This guidance describes the general principles and procedures associated with developing and submitting a comparability protocol to us. This guidance also describes the basic elements of a comparability protocol and specific issues to consider when developing comparability protocols for changes in:
This guidance also discusses submitting comparability protocols in master files.
A comparability protocol is a well-defined, detailed, written plan for assessing the effect of specific CMC changes on the identity, strength, quality, purity, and potency of a specific drug product as they may relate to the safety and effectiveness of the product. A comparability protocol describes the changes that are covered under the protocol and specifies the tests and studies that will be performed, including the analytical procedures that will be used, and acceptance criteria that will be met to demonstrate that specified CMC changes do not adversely affect the product. The submission of a comparability protocol is not required to make a CMC change.
At the same time we approve a comparability protocol, we can designate,8 if appropriate, a reduced reporting category for future reporting of CMC changes covered by the approved comparability protocol (See section III.A). Furthermore, because a detailed plan will be provided in the comparability protocol, we are less likely to request additional information to support changes made under the protocol (See section IV.D for a potential exception). The use of a comparability protocol could allow an applicant to implement CMC changes and place a product in distribution sooner than without the use of a comparability protocol.
For many years, applicants have used protocols to implement certain types of CMC changes, such as to extend an expiration dating period or to demonstrate the interchangeability of certain plastic containers. More recently, there have been many improvements in the techniques for characterizing products, production processes, process controls, and release testing. Because of these improvements and because we are able to better assess the potential effect of CMC changes on a product, protocols are now being used with other types of CMC changes (e.g., manufacturing process, analytical procedure changes). This expanded use of comparability protocols has been recognized in FDA regulations,9 and we have received a number of requests for guidance from applicants interested in using comparability protocols for these other types of changes. The use of comparability protocols for expanded types of CMC changes has allowed some applicants to implement CMC changes sooner.
We have received a number of requests for guidance from applicants interested in using comparability protocols for CMC changes. Our experience in reviewing comparability protocols for a variety of CMC changes for biologics, including specified products and protein drug products, has been incorporated into this guidance.
This guidance is not intended to supersede other FDA guidance documents, but rather to supplement them with information on using comparability protocols to implement postapproval CMC changes. We recommend that you consult all relevant guidances10 for information relating to postapproval changes. The following guidances provide relevant information on: (1) assessing the effect of CMC changes on product attributes, (2) providing documentation to support postapproval change, and (3) the recommended reporting categories.
A comparability protocol prospectively specifies the planned CMC change, the tests and studies that will be performed, analytical procedures that will be used, and acceptance criteria that will be met to assess the effect of CMC changes. A well-planned protocol provides sufficient information for us to determine whether the potential for an adverse effect on the product can be adequately evaluated. When we review a comparability protocol, we will determine if a specified change can be reported in a reporting category lower than the category for the same change implemented without an approved comparability protocol. Typically, categories designated for reporting changes under an approved comparability protocol are one category lower than normally would be the case (e.g., from PAS to CBE-30, CBE to AR). In some cases, a reduction of more than one reporting category may be possible (e.g., PAS to AR).
A comparability protocol could be useful for a variety of CMC changes, but there are some exceptions (See Section III.C). In addition, a comparability protocol can describe a single CMC change or multiple related changes, and can be particularly useful for changes of a repetitive nature. Because biologics and protein drug products are complex and heterogeneous, knowledge of how product attributes affect the safety and efficacy of the product is crucial in designing most comparability protocols. It is also important that you have sufficient manufacturing and analytical experience to specify in advance the tests, studies, analytical procedures, and acceptance criteria appropriate to assess the impact of the change on the product. We recommend that you include information from developmental and investigational studies, manufacturing experience, demonstrated process capability, out-of-specification (OOS) investigations, and stability data with the particular product and process, and in some cases manufacturing information with similar products or processes (e.g., for some monoclonal antibody products). However, we also recognize that some CMC changes (e.g., some packaging changes) would require less supportive information because they are less dependent on manufacturing experience. We recommend that you submit comparability protocols only for CMC changes that you intend to implement. We recommend that you consider product-specific and process-specific attributes when determining whether to develop a comparability protocol. Attributes can include, but are not limited to, the following:
We recommend that you consider a comparability protocol only if you expect: (a) the product resulting from the changes to meet the approved drug substance and/or drug product specifications and predetermined acceptance criteria for non-routine characterization studies; (b) appropriate and sensitive analytical procedures have been established and validated or qualified (i.e., for non-routine tests such as characterization studies) to assess the effect of the change on the approved product; and (c) the approved manufacturing process and equipment has been fully qualified and validated, when appropriate. Some specific examples submitted to us of changes to the manufacturing process where a comparability protocol has been used include, but are not limited to, the following:
A comparability protocol would be inappropriate for some CMC changes. In some cases, it may be impossible for the changes and/or plan for evaluating the effect of the CMC changes on the product to be fully described in advance. For example, a change may also be too complex to evaluate its effect on the product without efficacy, safety (clinical or nonclinical), or pharmacodynamic or pharmacokinetic (PK/PD) information. In general, we do not recommend comparability protocols for:
It may be possible to design a comparability protocol for certain CMC changes, but we may be limited in our ability to designate a reporting category other than PAS for changes implemented under such a protocol. Moreover, in some situations, these changes could require the submission of an IND, INAD, or new application. Examples of such changes can include:
You can submit a comparability protocol in a prior approval supplement or as part of the original application. However, we recommend that you evaluate the appropriateness of including the comparability protocol in the original application when your experience manufacturing the product is limited and it may be difficult to identify the elements of an appropriate comparability protocol (see considerations in Section III.B.). We recommend that you indicate that you are submitting a comparability protocol. You may submit the proposed comparability protocol in:
In all cases, the comparability protocol must be approved prior to distributing the product made using the CMC changes specified in the protocol. As specified in your protocol, you must also complete the studies that assess the effect of the changes on the identity, strength, quality, purity, and potency of the product and report the results to us in accordance with the reporting category we designated as part of our approval of the protocol, prior to distributing the product made with the change (Section 506A(b) of the act, and 21 CFR 601.12).
After a protocol is approved, we recommend that you document and submit each implemented change within the scope of the protocol using the reporting category that we designated. Include (1) the results of all tests and studies specified in your comparability protocol; (2) discussions of significant deviations that occurred during the tests or studies and that may have affected the tests or studies; (3) a summary of investigations performed, with analysis of the circumstances, product impact, corrective actions, and conclusions reached; and (4) any other pertinent information. We recommend that you indicate in the submission that it includes data from a change covered under a comparability protocol and provide a reference to the submission in which the comparability protocol was approved.
In certain instances, the changes, the tests, and/or the studies specified in an approved comparability protocol can lead to an unpredicted or unwanted outcome (e.g., test results do not meet predefined acceptance criteria). If this occurs, you can elect not to implement the change. If you decide to pursue the change, we recommend that you submit a prior approval supplement that provides the supporting data to justify why the change will not adversely affect the identity, strength, quality, purity, and potency of the specific drug product as they may relate to the safety and effectiveness of the product.
New regulatory requirements, identification of a safety issue (e.g., screening for new infectious agents in materials from a biological source), identification of a new scientific issue, or technological advancement after the comparability protocol has been approved can render a protocol obsolete. We recommend that you review the tests, studies, analytical procedures, and acceptance criteria in your approved comparability protocol to ensure that they remain current and consistent with the approved application and current regulatory and scientific standards. We recommend that you determine whether the tests, studies, analytical procedures, and acceptance criteria described in your comparability protocol are still appropriate prior to implementing and submitting a change under the protocol. We may determine that a reporting category made in the approval of a comparability protocol that becomes obsolete is no longer applicable. We may also request additional information to support a change that is evaluated using an obsolete protocol. If you find the comparability protocol is no longer correct or adequate, you should modify or withdraw the current protocol.
You can submit a revised protocol at any time. Like an original protocol, you can submit a revised protocol as a PAS to your application following the recommended submission procedures summarized in Section IV.A. We recommend that you indicate in the submission that it includes a revision to an approved comparability protocol and identify all modifications. A comparability protocol should also be modified to reflect relevant changes in the application. For example, you may ask FDA to approve a change in an analytical procedure that is used for release testing. The new analytical procedure should also be incorporated into approved comparability protocols, if appropriate. As part of the request to make the change in release testing, we recommend that you clearly indicate in your submission all comparability protocols that will also be affected. The specified comparability protocols would be updated as part of the submission for the change in release testing, using the reporting category appropriate for that change. There would be no need to make a separate submission requesting a modification of each comparability protocol. However, you should wait to implement the modified comparability protocol until you are authorized to implement the change in release testing.
We recommend that that you develop and use a comparability protocol within the context of existing change control procedures. Such procedures ensure that specified changes do not adversely affect the identity, strength, quality, purity, or potency of the product. In the comparability protocol, you can describe a single CMC change or multiple changes. We recommend that you specify each change and define the acceptance criteria for evaluating the effect of the changes. If multiple changes are included in a protocol, we recommend that the multiple changes be interrelated (i.e., one change cannot be made without the others; changes focus on a common goal such as production optimization). For example, a change in a fermentation medium component used to produce a protein results in more rapid cell growth that in turn, causes a higher production rate of the protein. Changes related to this change in culture medium could include modification in the length of cell fermentation, increase in harvesting time, and/or changes to purification columns. We recommend that you submit separate comparability protocols for unrelated changes.
In addition to the general considerations provided in Section V.A, we recommend that you consider the following issues related to changes in the manufacturing process, where applicable:
A comparability protocol for changing an analytical procedure should provide the plan for validation of the changed analytical procedure and indicate whether the protocol will be used to modify the existing analytical procedure (i.e. retaining the same principle), or to change from one analytical procedure to another. We recommend that you design the comparability protocol to demonstrate that the proposed changes in the analytical procedures improve or do not significantly change analytical procedure characteristics that are relevant to the type of analytical procedure, its validation, and intended use (e.g., accuracy, precision, specificity, detection limit, quantitation limit, linearity, range).17 Methods validation includes an assessment of the suitability of the analytical procedure. You should have in your validation plan prespecified acceptance criteria for relevant validation parameters such as precision, range, accuracy, specificity, detection limit, and quantitation limit. The proposed acceptance criteria for these parameters should ensure that the analytical procedure is appropriate for its intended use. In the validation plan you would assess whether a revised procedure is more susceptible than the original procedure to matrix effects by process buffers/media, product-related contaminants, or other components present in the dosage form. You should identify in the plan any statistical analyses that you will perform and whether you intend to perform product testing to compare the two procedures. The need and plan for providing product testing to compare the two procedures could vary depending on the extent of the proposed change, type of product, and type of test (e.g., chemical, biological). When you use the new revised analytical procedure for release or process control, you should not delete a test or relax acceptance criteria that we approved in your application, unless and until FDA informs you that the approved acceptance criteria are no longer required.
Comparability protocols may be useful if applicants plan to use different equipment or plan equipment changes that would effectively result in different equipment. These changes are often made in conjunction with changes to the manufacturing process. Different equipment can include new models, changes in capacity, construction materials (e.g., glass-lined tanks to stainless steel), equipment design, and/or equipment operating principles. Comparability protocols may also be useful when additional duplicative process trains (such as fermentation trains) or equipment will be added to an approved manufacturing facility. We recommend that you evaluate these types of change with respect to its effect on the production process prior to deciding whether a comparability protocol would be appropriate. We encourage you to initiate early dialogue with us to facilitate the change, as needed.
The utility of a comparability protocol is often limited due to the scope of the change and the need, in some cases, for an inspection. For example, a move to a new facility can involve many changes (e.g., new equipment, modified manufacturing process) that are difficult to prospectively identify as part of a comparability protocol because the new facility is unknown or not constructed at the time the comparability protocol is being considered. We recommend that you consider carefully the appropriateness of a comparability protocol for a facility change, especially one that involves many other changes. For biologics, which also have application requirements described in an Establishment Description section, there may be additional situations when a comparability protocol can be useful. We encourage early dialogue with us. There are CMC changes where a preapproval inspection may be conducted prior to distribution of product made with the change to confirm an acceptable cGMP compliance status.18 You may consult the guidance documents listed in section II.E, or consult FDA, to determine whether FDA would require such a prepproval inspection. If a preapproval inspection would be needed, your comparability protocol would identify the preapproval inspection requirement and acknowledge that product made at a different drug substance or different drug product manufacturing site will not be distributed until FDA has verified the satisfactory cGMP compliance status for the type of operation at the new site. Furthermore, in the case of aseptically processed product, your protocol would also provide that a product manufactured in a different facility or area (e.g., room or building on a campus) will be distributed only when that specific facility or area has a satisfactory cGMP compliance status. For a move to another type of site (e.g., drug substance intermediate manufacturing site, packaging, testing laboratory), the protocol would provide that a product manufactured at the site would not be distributed if there were an unsatisfactory cGMP compliance status for the site. For BLAs, some major changes at an existing facility (i.e., those that have a substantial potential to adversely affect the product) may require, under 21 CFR 601.2(d), a satisfactory cGMP compliance status prior to distribution of the product made with the change. For these major changes the comparability protocol would provide that the product would not be distributed if an unsatisfactory cGMP compliance status exists. A comparability protocol has been beneficial when introducing additional products into an approved dedicated area in a facility for biologics and protein drug products. In addition, for products with facility/establishment information provided in a BLA or postapproval supplement to a BLA, (i.e., Establishment Description section), FDA may be limited in its ability to designate a reduced reporting category for changes that include:
Yes. In the past, applicants have used protocols for container closure system changes, and they can continue to use them. A comparability protocol can be particularly useful for repetitive container closure system changes.
We anticipate that implementation of, or changes in, PAT could be addressed in a comparability protocol. We encourage early dialogue with us. We intend to publish a PAT guidance in the future.
You can cross-reference a master file in a comparability protocol that provides for CMC changes (e.g., container resin). We recommend that you include, in the protocol, a commitment to provide a letter authorizing us to review the master file when a postapproval CMC change implemented using the approved comparability protocol is reported to us. We recommend that you indicate in the comparability protocol the type of information (e.g., manufacturing and formulation information for a plastic resin) that will be referenced in the master file and the information that you will provide such as the studies you will perform to demonstrate the suitability of the new material (e.g., conformance to approved specification, compatibility studies, stability studies).
A comparability protocol can be included in a master file. The protocol can be cross-referenced for CMC changes. In your PAS submission for your product, you must include a letter authorizing us to review the master file (21 CFR 314.420(b)). Comparability protocols are product specific. Therefore, in your PAS submission we recommend that you provide a comparability protocol that augments the information provided in the master file by specifying, for example, any additional studies that you will perform to demonstrate the suitability of the postchange material (e.g., conformance to approved specification, compatibility studies, stability studies). Ordinarily, we neither independently review master files nor approve nor disapprove submissions to a master file.
1 This guidance has been prepared by the Comparability Protocol Working Group, Center for Biologics Evaluation and Research (CBER), Center for Drug Evaluation and Research (CDER), and Center for Veterinary Medicine (CVM) at FDA. 2 The general term product as used in this guidance means drug substance, drug product, and intermediate, or in-process material, as appropriate. 3 Section 505 of the Federal Food, Drug, and Cosmetic Act describes three types of new drug applications: (1) an application that contains full reports of investigations of safety and effectiveness (section 505(b)(1)); (2) an application that contains full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference (section 505(b)(2)); and (3) an application that contains information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics, and intended use, among other things, to a previously approved product (section 505(j)). 4 When finalized, guidance on comparability protocols that can be submitted in NDAs, ANDAs, NADA, and ANADAs for many products outside the scope of this guidance will be provided in "Guidance For Industry: Comparability Protocols-Chemistry, Manufacturing, and Controls Documentation." FDA published a draft version of this guidance on February 25, 2003 (68 FR 8772). 5 Guidance on comparability protocols for human blood and blood products can be found in "Guidance For Industry: Changes to an Approved Application: Biologics Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture, July 2001." 6 See also 21 CFR 601.12. 7 The term analytical procedure, as used in this guidance, includes, biochemical, chemical, physicochemical, immunochemical, microbiological, and biological test procedures. 8 The term designate, in this context, refers to the reporting category agreed to by the applicant and FDA during the review of the submission containing the comparability protocol. See Section V.A.6. 9 See, for example, 21 CFR 601.12(e). These regulations provided for the use of a pre-specified protocol, or a comparability protocol, that describes how to assess the effects of specific manufacturing changes. 10 Relevant guidance documents can be found on the internet at http://www.fda.gov/cder/guidance/index.htm, http://www.fda.gov/cber/guidelines.htm, or http://www.fda.gov/cvm/guidance/published.htm 11 Guidance for naturally derived protein drug products 12 This draft guidance is listed for completeness but is not intended for implementation until it has been finalized. 13 INDs may be warranted in certain circumstances, such as for a change from plant, animal, or multicellular (e.g., algae, macroscopic fungi) source material to a different one (e.g., different plant species, different tissue and/or plant part, plant to animal), a change in the species of a microorganism or cell line used as source, a change in the microorganism or cell line used as source from non-recombinant to recombinant-DNA-modified, a change from a non-transgenic source to a transgenic plant or animal, or a change from one plant or animal transgenic source material to another. 14 A comparability protocol might be useful in certain cases for quantitative changes in excipients, and FDA might designate a reduced reporting category for certain types of products and changes if you have sufficient information to assess the potential effect of the change. 15 For brevity, the text focuses on comparability protocols submitted in postapproval supplements, although the option is available to include a comparability protocol in an original submission. 16 The recommended reporting categories for specification changes may be found in the guidance on Changes to an Approved Application For Specified Biotechnology and Specified Synthetic Products and Changes To An Approved Application For Biologics. 17 Guidance on validation of some analytical procedures can be found in the ICH guidances on Q2A Text on Validation of Analytical Procedures and Q2B Validation of Analytical Procedures: Methodology or VICH guidances on GL1 Validation of Analytical Procedures: Definition and Terminology and GL2 Validation of Analytical Procedures: Methodology. 18 A satisfactory cGMP compliance status includes a satisfactory cGMP inspection - an FDA inspection during which (1) no objectionable conditions or practices were found (No Action Indicated (NAI)) or (2) objectionable conditions were found, but, corrective action is left to the firm to take voluntarily and the objectionable conditions will not be the subject of further administrative or regulatory actions (Voluntary Action Indicated (VAI), and satisfactory disposition of other relevant actions (e.g., investigations, warning letter, product recalls).
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