CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (PDF - 106KB)

Guidance for Industry CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) March 2014 CMC OMB Control Number 0910-0758 Expiration Date: 01/31/2017 (Expiration date will be updated periodically.) See additional PRA statement in section VI of this guidance. Guidance for Industry CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports Additional copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave. Silver Spring, MD 20993-0002 Phone: 301-796-3400; Fax: 301-847-8714 druginfo@fda.hhs.gov www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) March 2014 CMC Contains Nonbinding Recommendations TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND ............................................................................................................... 2 III. DISCUSSION .................................................................................................................... 2 IV. CONTENTS OF ANNUAL REPORT NOTIFICATION ............................................. 4 V. RESOURCES .................................................................................................................... 5 VI. PAPERWORK REDUCTION ACT OF 1995 ................................................................ 6 APPENDIX A: EXAMPLES OF CMC POSTAPROVAL MANUFACTURING CHANGES TO BE DOCUMENTED IN ANNUAL REPORTS IF THEY HAVE A MINIMAL POTENTIAL TO HAVE AN ADVERSE EFFECT ON PRODUCT QUALITY ............................................................................... 8 APPENDIX B: EXAMPLES OF CHANGES TO BE DOCUMENTED IN AN ANNUAL REPORT FROM FDA’S SUPAC-IR, SUPAC-MR, SUPAC-SS, AND CHANGES TO AN APPROVED NDA OR ANDA GUIDANCES ................ 12 Contains Nonbinding Recommendations 1 Guidance for Industry1 CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION This guidance provides recommendations to holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) regarding the types of changes to be documented in annual reports. Specifically, the guidance describes chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes that we have determined will likely have a minimal potential to have an adverse effect on product quality2 and, therefore, should be documented by applicants in an annual report.3,4 Appendix A lists examples of CMC postapproval manufacturing changes previously submitted under manufacturing supplements that we have determined generally to be of low risk to product quality. Appendix B provides examples of minor changes to be documented in an annual report that were previously published in FDA’s Scale-up and Postapproval Changes (SUPAC) guidances and other postapproval change CMC guidances (see Section V. Resources for a list of those guidances). FDA’s 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. 1 This guidance has been prepared by the Office of Pharmaceutical Science (OPS) in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. 2 In this guidance, the term “product quality” refers to drug product identity, strength, quality, purity, or potency, as these factors may relate to the safety or effectiveness of the drug product. 3 See 21 CFR 314.70(d). 4 This guidance excludes positron emission tomography (PET) drug products. See the guidance for industry, PET Drugs — Current Good Manufacturing Practice (CGMP), for information about PET drug products. CDER updates guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance web page at www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. benlelu Highlight benlelu Highlight benlelu Highlight Contains Nonbinding Recommendations 2 II. BACKGROUND An applicant must notify FDA of a change to an approved application in accordance with all statutory and regulatory requirements—including section 506A of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 356a) (FD&C Act), which was added by section 116 of the Food and Drug Administration Modernization Act,5 and 21 CFR 314.70. Section 506A of the FD&C Act provides requirements for making and reporting manufacturing changes to an approved application and for distributing a drug product made with such changes. Under 21 CFR 314.70, all postapproval CMC changes beyond the variations provided for in an approved NDA and ANDA are categorized into one of three reporting categories: major, moderate, or minor. If a change is considered to be major, an applicant must submit and receive FDA approval of a supplemental application to the NDA or ANDA before the product made with the manufacturing change is distributed (also known as a prior approval supplement (PAS)). If a change is considered to be moderate, an applicant must submit a supplement at least 30 days before the product is distributed (CBE-30 supplement) or, in some cases, submit a supplement at the time of distribution (CBE-0 supplement).6 If a change is considered to be minor, an applicant may proceed with the change, but must notify FDA of the change in an annual report. For any change, applicants must assess the effects of the change on product quality through appropriate studies. For additional background information regarding the reporting categories for NDAs and ANDAs, see FDA’s guidance for industry on Changes to an Approved NDA or ANDA (April 2004). In our September 2004 final report, Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century – A Risk-Based Approach (Pharmaceutical Product Quality Initiative), the Agency stated that to keep pace with the many advances in quality management practices in manufacturing and to enable the Agency to more effectively allocate our limited regulatory resources, we would implement a cooperative, risk-based approach for regulating pharmaceutical manufacturing. As part of this approach, the Agency determined that to provide the most effective public health protection, our CMC regulatory review should be based on an understanding of product risk and how best to manage this risk. In addition to the requirements in section 506A of the FD&C Act and 21 CFR 314.70, applicants are required to comply with other applicable laws and regulations, including the Current Good Manufacturing Practice for Finished Pharmaceuticals (CGMP) regulations in 21 CFR Parts 210 and 211. III. DISCUSSION The number of CMC manufacturing supplements for NDAs and ANDAs has continued to increase over the last several years. In connection with FDA’s Pharmaceutical Product Quality Initiative and our risk-based approach to CMC review, we have evaluated the types of changes that have been submitted in CMC postapproval manufacturing supplements and determined 5 Public Law 105-115. 6 CBE is changes being effected. benlelu Highlight benlelu Highlight benlelu Highlight benlelu Highlight benlelu Highlight benlelu Highlight benlelu Highlight benlelu Highlight Contains Nonbinding Recommendations 3 that many of the changes being reported present low risk to the quality of the product and do not need to be submitted in supplements. Based on our risk-based evaluation, we developed a list (see Appendix A) to provide additional current recommendations to companies regarding some postapproval manufacturing changes for NDAs and ANDAs that may be considered to have a minimal potential to have an adverse effect on product quality, and, therefore, may be classified as a change to be documented in the next annual report (i.e., notification of a change after implementation) rather than in a supplement. The changes listed in Appendix A are categorized according to the type of manufacturing change. These changes are either additions or revisions to the CMC changes recommended for documentation in an annual report that were previously published in the guidance for industry on Changes to an Approved NDA or ANDA, the SUPAC guidances, and other related guidances (see Section V. Resources). Thus, before you submit a supplement based on recommendations provided in these previously published guidances, you also should refer to the list of risk-based recommendations that are provided in Appendix A of this guidance. These recommendations clarify whether submission of a supplement or documentation of the change in an annual report may be appropriate. We expect NDA and ANDA holders to evaluate the specific change that they are planning to make in the context of their particular circumstances to determine whether the proposed change would present a minimal potential to have an adverse effect on product quality. When a risk- based evaluation shows that the proposed change would have a minimal potential to have an adverse effect on product quality, the change can be documented in the next annual report. An NDA or ANDA holder may, based on their specific circumstances, decide that a change described in Appendices A and B would more appropriately be submitted as a supplement rather than in an annual report. In such cases, changes should be reported to the Agency according to the results of the risk-based evaluation and 21 CFR 314.70. Accordingly, we consider this guidance to provide recommendations for changes that are appropriately documented in an annual report rather than to establish a requirement to document these changes in annual reports pursuant to 21 CFR 314.70(a)(3).7 To the extent that a recommendation in this guidance to document a single change in an annual report is found to be inconsistent with previously published FDA guidances, the reporting category recommended in this guidance would apply, assuming that the applicant’s proposed change would present a minimal potential to have an adverse effect on product quality. For changes not addressed in this guidance, or for multiple related changes implemented simultaneously, applicants should refer to other CDER guidances (see Section V. Resources), as well as Appendix B, to determine the appropriate reporting categories (i.e., PAS, CBE-30, CBE-0, or annual report) for notifying the Agency of the changes. 7 Under 21 CFR 314.70(a)(3), an applicant is required to make a change in accordance with a regulation or guidance that provides for a less burdensome notification of the change. In this guidance, we are asking applicants to use scientific data from appropriate studies and risk analysis to determine whether changes should be submitted in a PAS, CBE-30, CBE-0, or annual report. benlelu Highlight benlelu Highlight benlelu Highlight benlelu Highlight benlelu Highlight benlelu Highlight benlelu Highlight Contains Nonbinding Recommendations 4 Applicants should note FDA’s recommendations for active pharmaceutical ingredient manufacturing that are provided in the guidance for industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (August 2001). CGMP regulations for finished pharmaceuticals contain specific requirements relevant to the types of changes addressed in this guidance, and compliance with the CGMP regulations is required regardless of how the change is reported to the Agency. CGMP requirements include establishing and following appropriate written procedures reviewed and approved by the quality unit, qualifying equipment as suitable for its intended use, using validated test methods, scientifically establishing the commercial manufacturing process, and ensuring the manufacturing process’s ongoing state of control (which may include additional process validation and stability studies depending on the nature of the change).8 If you have specific questions associated with whether or not the change should be submitted to the Agency in a supplement or documented in an annual report, we recommend that you contact the appropriate CDER review division in the Office of New Drug Quality Assessment, the Office of Generic Drugs, or OPS’s New Drug Microbiology Staff. IV. CONTENTS OF ANNUAL REPORT NOTIFICATION To document changes in an annual report in accordance with 21 CFR 314.81(b)(2)(iv)(b) and 314.70(d)(3), the applicant must include a full description of the CMC changes that were made that the applicant believes did not require a supplemental application under sections 314.70(b) and (c). This description should include: • A list of each change and the date each change was implemented; and • Relevant summary of data from studies and tests performed to assess the effects of each change on product quality, including (where applicable) a list of cross-references to change control and change validation protocols and standard operating procedures (SOPs) that were used to assess or demonstrate the effect of the change. The description also should include: • The name(s) of one or more drug products affected or involved in the change (e.g., different label strengths/product presentations); or • Reference to any previously approved grouped supplements if the change affected multiple products. Executed batch records, SOPs, and data from studies and tests performed to assess the effects of each change should be kept on file and made available to the Agency on request (e.g., during an inspection). The applicant should describe each change in an annual report in enough detail to allow the Agency to efficiently determine whether the appropriate reporting category has 8 See 21 CFR 210 and 211. Contains Nonbinding Recommendations 5 been used. If the submitted change is inappropriate for documentation in an annual report, the applicant will be notified of the correct category and additional information may be requested. V. RESOURCES Provided below are other FDA guidances that discuss reporting of CMC postapproval changes. They should be referred to in addition to this guidance. • FDA guidances applicable to the CMC section of a drug application: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm 064979.htm In prior CMC postapproval changes guidance documents, recommendations are provided for changes in components and composition, manufacturing sites, manufacturing process, specifications, container/closure system, labeling, miscellaneous changes, and multiple related changes. • PAC-ATLS: Postapproval Changes – Analytical Testing Laboratory Sites, dated April 28, 1998, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui dances/UCM070582.pdf. • SUPAC-IR: Immediate Release Solid Oral Dosage Forms: Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation, dated November 1995, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui dances/UCM070636.pdf. • SUPAC-IR Questions and Answers about SUPAC-IR Guidance, dated February 18, 1997, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm 124826.htm. • SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms Manufacturing Equipment Addendum, dated January 1999, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui dances/UCM070637.pdf. • SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation, dated September 1997, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui dances/UCM070640.pdf. Contains Nonbinding Recommendations 6 • SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation, dated May 1997, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui dances/UCM070930.pdf. • SUPAC-SS: Nonsterile Semisolid Dosage Forms Manufacturing Equipment Addendum, dated December 1998, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui dances/UCM070928.pdf. • Changes to an Approved NDA or ANDA: Questions and Answers, dated January 2001, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui dances/UCM122871.pdf. • Changes to an Approved NDA or ANDA, Revision 1, dated April 2004, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui dances/UCM077097.pdf. • Changes to an Approved NDA or ANDA; Specifications – Use of Enforcement Discretion for Compendial Changes, dated November 2004, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui dances/UCM070544.pdf. VI. PAPERWORK REDUCTION ACT OF 1995 This guidance contains information collection provisions that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The expiration of the OMB control number will be updated periodically. The total number of supplements submitted per year is estimated to reduce based on the recommendations in the guidance because certain changes submitted as supplements would now be documented in annual reports. Therefore, for such changes, the information collection with respect to the submission of supplements will be reduced. Because the number of supplements per year is estimated to reduce, the total number of hours for preparing supplements would correspondingly reduce. Send comments regarding this burden estimate or suggestions for reducing this burden to: The Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 4178, Silver Spring, MD 20993-0002. This guidance also refer