FDA Guidance for Industry

Guidance for Industry CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports

March 2014 CMC

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Changes to an Approved NDA or ANDA

2004

This guidance provides recommendations to holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) who intend to make postapproval changes in accordance with section 506A of the Federal Food, Drug, and Cosmetic Act (the Act) and § 314.70 (21 CFR 314.70).  The guidance covers recommended reporting categories for postapproval changes for drugs other than specified biotechnology and specified synthetic biological products.

It supersedes the guidance of the same title published November 1999.  

Recommendations are provided for postapproval changes in:

  • (1) components and composition
  • (2) manufacturing sites
  • (3) manufacturing process
  • (4) specifications
  • (5) container closure system
  • (6) labeling
  • (7) miscellaneous changes and
  • (8) multiple related changes

Recommendations on reporting categories for changes relating to specified biotechnology and  specified synthetic biological products regulated by CDER are found in the guidance for industry.

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Guidance for Industry Changes to an Approved NDA or ANDA Questions and Answers

January 2001 CMC

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Reporting Categories

Section 506A of the Act and § 314.70 provide for four reporting categories that are distinguished in the following paragraphs.

A major change is a change that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. A major change requires the submission of a supplement and approval by FDA prior to distribution of the drug product made using the change. This type of supplement is called, and should be clearly labeled, a Prior Approval Supplement (§ 314.70(b)). An applicant may ask FDA to expedite its review of a prior approval supplement for public health reasons (e.g., drug shortage) or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. This type of supplement is called, and should be clearly labeled, a Prior Approval Supplement – Expedited Review Requested (§ 314.70(b)(4)).5 FDA is most likely to grant requests for expedited review based on extraordinary hardship for manufacturing changes made necessary by catastrophic events (e.g., fire) or by events that could not be reasonably foreseen and for which the applicant could not plan.

A moderate change is a change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. There are two types of moderate change. One type of moderate change requires the submission of a supplement to FDA at least 30 days before the distribution of the drug product made using the change. This type of supplement is called, and should be clearly labeled, Supplement – Changes Being Effected in 30 Days (§ 314.70(c)(3)).

The drug product made using a moderate change cannot be distributed if FDA informs the applicant within 30 days of receipt of the supplement that a prior approval supplement is required (§ 314.70(c)(5)(i)). For each change, the supplement must contain information determined by FDA to be appropriate and must include the information developed by the applicant in assessing the effects of the change (§ 314.70(a)(2) and (c)(4)). If FDA informs the applicant within 30 days of receipt of the supplement that information is missing, distribution must be delayed until the supplement has been amended to provide the missing information (§ 314.70(c)(5)(ii)).

FDA may identify certain moderate changes for which distribution can occur when FDA receives the supplement (§ 314.70(c)(6)). This type of supplement is called, and should be clearly labeled, a Supplement – Changes Being Effected.

How to Submit Revised Labeling

All ANDA labeling changes needed because of approved changes to the labeling of the RLD may be submitted as a Special Supplement – Changes Being Effected. Such supplements should include:

  • 12 copies of final printed labeling
  • the date the revised labeling will be used (go into effect)
  • a side-by-side comparison of the ANDA labeling with the approved labeling of the RLD with all differences annotated and explained, as described in 21 CFR 314.94 (a)(8)(iv)

Sponsors should contact the OGD Labeling Review Branch if there are any questions about the information in this guidance.

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Guidance for Industry Labeling OTC Human Drug Products Updating Labeling in RLDs and ANDAs

2002

This guidance is intended to assist manufacturers, packers, and distributors of over-the-counter (OTC) drug products marketed under abbreviated new drug applications (ANDAs) and the manufacturers of corresponding reference listed drugs (RLDs) implement the Agency’s regulation on standardized content and format requirements for the labeling of OTC drug products. The guidance contains recommendations on how RLD and ANDA holders can update their labeling in a timely manner consistent with the regulation on OTC drug product labeling (21 CFR 201.66).

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Labeling for Human Prescription Drug and Biological Products – Implementing the PLR Content and Format Requirements

2013

This guidance is intended to assist applicants in complying with the content and format requirements of labeling for human prescription drug and biological products under 21 CFR 201.56(d) and 201.57.  FDA is issuing this guidance to provide recommendations for applicants developing labeling for new prescription drugs and revising labeling for already approved prescription drugs. This guidance also provides recommendations on developing Highlights of Prescribing Information (Highlights), formatting labeling, and procedural information.

Download “Labeling for Human Prescription Drug and Biological Products – Implementing the PLR Content and Format Requirements” ucm075082.pdf – Downloaded 323 times – 527 KB

Summary: Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products

The proposed rule would amend the current regulations on submission of changes being effected (CBE-0) supplements for safety-related labeling changes to permit abbreviated new drug application (ANDA) holders to distribute revised product labeling that differs from the labeling of its reference listed drug upon submission to FDA of a CBE-0 supplement.

The proposed rule would also allow changes to the Highlights of Prescribing Information (Highlights) of drug labeling in the “Physician Labeling Rule” (PLR) format through a CBE-0 supplement.  In addition, the proposed rule would establish a Web page where FDA would post information on pending CBE-0 supplements submitted for safety-related labeling changes.

  • Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products
    • http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/UCM375128.pdf
  • Federal Register: 78 FR 67985-67999, Nov. 13, 2013