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This guidance provides recommendations to applicants on preparing and using comparability protocols for postapproval changes in chemistry, manufacturing, and controls (CMC). The guidance applies to comparability protocols that would be submitted in new drug applications (NDAs), abbreviated new drug applications (ANDAs), new animal drug applications (NADAs), abbreviated new animal drug applications (ANADAs), or supplements to these applications, except for applications for protein products.2 Well-characterized synthetic peptides submitted in these applications are included within the scope of this guidance. This guidance also applies to comparability protocols submitted in drug master files (DMFs) and veterinary master files (VMFs) that are referenced in these applications.3 The FDA is providing this guidance in response to requests from those interested in using comparability protocols. 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.
As an applicant, 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 these factors relate to the safety or efficacy of the product (section 506A(b) of the Federal Food, Drug, and Cosmetic Act (the act)). Such an assessment often includes demonstration that the pre- and postchange products (i.e., products manufactured prior to and subsequent to a change) are equivalent. Postapproval CMC changes must be reported to FDA in one of four reporting categories (Section 506A of the Act):
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 used. This guidance describes the general principles and procedures associated with developing and submitting a comparability protocol to the FDA. The guidance also describes the basic elements of a comparability protocol and specific issues to consider when developing comparability protocols for changes in:
The 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 in the identity, strength, quality, purity, and potency of a specific drug product as these factors 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 achieved to demonstrate that specified CMC changes do not adversely affect the product. The submission of a comparability protocol is optional.
At the time the application containing the comparability protocol is approved, the FDA can designate5, where appropriate, a reduced reporting category for future reporting of CMC changes covered by the approved comparability protocol (see III.A). Furthermore, because a detailed plan will be provided in the comparability protocol, the FDA is less likely to request additional information to support changes made under the protocol (see 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 methods, 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). We have received a number of requests for guidance from applicants interested in using comparability protocols for these other types of changes.
This guidance, once finalized, is not intended to supersede other FDA guidance documents, rather it supplements them with information on using comparability protocols to implement postapproval CMC changes. We recommend that applicants consult all relevant guidances6 for information relating to postapproval changes. The following guidances provide especially relevant information on (1) demonstrating equivalence, (2) documentation to be provided to support postapproval changes, and (3) the recommended reporting categories.
A comparability protocol prospectively specifies the tests and studies that will be performed, analytical procedures that will be used, and acceptance criteria that will be achieved to assess the effect of CMC changes. A well-planned protocol provides sufficient information for FDA to determine whether the potential for an adverse effect on the product can be adequately evaluated. With a comparability protocol, the FDA can determine if a specified change can be reported in a category lower than the category for the same change, were the change to be 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, or 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. However, we recommend that each change be discrete and specific. A comparability protocol can be particularly useful for changes of a repetitive nature. We recommend that you have sufficient manufacturing information (e.g., developmental studies, manufacturing experience, demonstrated process capability, out-of-specification (OOS) investigations, stability data) with the particular product or process or similar products or processes so you can specify a priori the tests, studies, analytical procedures, and acceptance criteria appropriate for demonstrating that the CMC change or changes will not adversely affect the product. We recommend that comparability protocols be considered for CMC changes that applicants anticipate will be made. We recommend 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:
In general, we recommend that a comparability protocol be considered only if the product resulting from the changes is expected to meet the approved drug substance and/or drug product specifications and appropriate and sensitive analytical procedures have been established and validated or qualified (i.e., for nonroutine tests such as characterization studies) to detect the effect of the change on the approved product.
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 a priori. 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 some of these CMC changes, but FDA may be limited in its ability to designate a reporting category other than PAS for changes implemented under such a protocol. Specific examples of changes that may be difficult to justify under a comparability protocol can include10:
You can submit a comparability protocol in a prior approval supplement or as part of the original application. We recommend that you indicate clearly in the cover letter that you are submitting a comparability protocol. The submission can consist of the proposed comparability protocol in
In all cases, a comparability protocol would be reviewed and approved by FDA prior to an applicant implementing a change under the protocol. Furthermore, an applicant who is using an approved comparability protocol to implement postapproval CMC changes must assess the effect of the changes on the identity, strength, quality, purity, and potency of the product as these factors relate to the safety or efficacy of the product prior to distributing product made with the change. (Section 506A(b) of the act)).
After a protocol is approved, you should document and submit each implemented change within the scope of the protocol using the reporting category designated by FDA. The submission would include (1) the results of all tests and studies specified in your comparability protocol, (2) discussions of any deviations that occurred during the tests or studies, (3) a summary of any investigations performed, and (4) any other pertinent information. To ensure prompt and accurate review, we recommend that you indicate in the cover letter to 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 tests and 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, you should 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 these factors 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 you review the tests, studies, analytical procedures, and acceptance criteria in your approved comparability protocol to ensure they remain current and consistent with the approved application and current FDA policy. We recommend 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. If you find the comparability protocol is no longer correct or adequate, the current protocol should be modified or withdrawn. FDA can request additional information to support a change that is implemented using an obsolete protocol.
You can submit a revised protocol at anytime. Like an original protocol, a revised protocol should be submitted as a PAS to your application following the recommended submission procedures summarized in section IV.A. To ensure prompt and accurate review, we recommend that you indicate in the cover letter to the submission that it includes a revision to an approved comparability protocol and identify all modifications. A comparability protocol would be modified to reflect relevant changes in the application. For example, an applicant could request a change in an analytical procedure that is used for release testing but is also cited in an approved comparability protocol. As part of the request to make such a change, FDA recommends that the applicant indicate up front all comparability protocols that will be affected. The specified comparability protocols can be updated as part of this submission using the appropriate reporting category for the change, rather than submitting a separate submission requesting a modification of the comparability protocol. Revisions to a protocol should be approved prior to distributing the product made using the CMC change specified in the protocol. Editorial changes can also be made. Notification of editorial changes to a comparability protocol can be provided in the AR.
We recommend that a comparability protocol be developed and used 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. The comparability protocol can describe a single CMC change or multiple changes. Each change should be specified and the acceptance criteria for evaluating the effect of the changes should be well defined. If multiple changes are included in a protocol, we recommend that the multiple changes be interrelated (i.e., one change cannot be made with out the others). For example, a change in a fermentation medium component used to produce an antibiotic can result in more rapid cell growth, which, in turn, causes a higher production rate of antibiotic. 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 for changes in the manufacturing process, where applicable:
A comparability protocol for changing an analytical procedure would 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 (e.g., normal to reverse phase HPLC). The comparability protocol would be designed to demonstrate that the proposed changes in the analytical procedures improve or do not significantly change characteristics used in methods validation that are relevant to the type of analytical procedure (e.g., accuracy, precision, specificity, detection limit, quantitation limit, linearity, range).14 Methods validation includes an assessment of the suitability of the analytical procedure. A validation plan would have 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 would ensure that the analytical procedure is appropriate for its intended use. The validation plan 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. A plan would identify any statistical analyses that will be performed and whether product testing to compare the two procedures is intended. 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 used for release or process control, use of the new revised analytical procedure should not result in deletion of a test or relaxation of acceptance criteria that are described in the approved application.
Comparability protocols may be most useful if applicants are planning to change to equipment with a different operating principal. Equipment changes are often made in conjunction with changes to the manufacturing process. We recommend that you evaluate this type of change with respect to its effect on the production process prior to deciding whether or not a comparability protocol would be appropriate.
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 you consider carefully the appropriateness of a comparability protocol for a facility change that involves many other changes. We recommend a statement be included in the comparability protocol for changing manufacturing facilities saying that a move to a different drug substance or drug product manufacturing site will be implemented only when the site has a satisfactory CGMP inspection for the type of operation. Furthermore, in the case of aseptically processed product, the statement would also indicate that a move to a different facility or area (e.g., room or building on a campus) will be made only when the specific facility or area has a satisfactory CGMP inspection (irrespective of the overall CGMP status for the campus). For a move to another type of site (e.g., drug substance intermediate manufacturing site, testing laboratory), a statement would be included that the move to this site would not be implemented if there were an unsatisfactory CGMP inspection for the site.15
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.
FDA anticipates that implementation of or changes in PAT could be addressed in a comparability protocol. Early dialogue with FDA is encouraged. The FDA intends to publish a guidance on PAT in the future.
A master file can be cross-referenced in a comparability protocol that provides for CMC changes (e.g., new manufacturer of drug substance, container resin). The protocol would include a commitment to provide a letter authorizing the FDA to review the master file when a postapproval CMC change implemented using the approved comparability protocol is reported to FDA. The comparability protocol would also indicate 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. An applicant's submission must include a letter authorizing the FDA to review the master file (e.g., 21 CFR 314.420(b)). Comparability protocols are product specific. Therefore, the applicant's submission would provide a comparability protocol that augments the information provided in the master file by specifying, for example, any additional studies that will be performed to demonstrate suitability of the postchange material (e.g., conformance to approved specification, compatibility studies, stability studies). The FDA ordinarily neither independently reviews master files nor approves or disapproves submissions to a master file.
1 This guidance has been prepared by the Comparability Protocol Working Group, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Veterinary Medicine (CVM) at the FDA. 2 The general term product as used in this guidance means drug substance, drug product, intermediate, or in-process material, as appropriate. 3 A separate guidance will address comparability protocols for proteins as well as for peptide products outside the scope of this guidance that are submitted in these applications. This separate guidance will also address comparability protocols for products submitted in biologics license applications (BLAs). 4 The term analytical procedure, as used in this guidance, includes chemical, physical, microbiological, and biological test procedures. 5 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 V.A.6. 6 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 7 This draft guidance is listed for completeness but is not intended for implementation until it has been finalized. 8 SUPAC (Scale-up and Post-Approval Changes) 9 INDs may be warranted in certain circumstances, such as for a change from a nontransgenic source to a transgenic plant or animal, a change from one plant or animal transgenic source material to another, or a change in the species of a microorganism or cell line used as source. 10 In some situations, these changes could warrant the submission of an IND, INAD, or new application. 11 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 (e.g., quantitative changes in an excipient beyond the ranges specified in the SUPAC guidances). 12 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 application. 13 For example, the recommended reporting categories for specification changes found in the guidance on Changes to an Approved NDA or ANDA. 14 Guidance on validation of 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. 15 A satisfactory CGMP inspection is 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)).
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