ABSTRACT
I. Introduction................................................................................... 16 A. Globalization Requires Regulatory Affairs Integration
in the Change Control System ............................................... 16 B. Other Considerations .............................................................. 20 C. Relief in the Form of Harmonization .................................... 21
II. Risks of Noncompliance: Auditing and Documentation ........... 22 III. Current Regulations and Guidance for Evaluating and
Reporting Manufacturing Changes to the FDA ......................... 22 A. History and Revisions to Change Reporting Statutes
and Regulations....................................................................... 23 B. SUPAC: CDER Guidance Documents for Specific Drug
Product Dosage Forms............................................................ 23 1. SUPAC-IR: Immediate Release Dosage Forms................. 24 2. SUPAC-MR: Modified Release Dosage Forms ................. 25 3. SUPAC-SS: Nonsterile Semisolid Dosage Forms ............. 26
C. BACPAC: Bulk Active Chemical (Pharmaceutical Ingredient) Postapproval Changes......................................... 27
D. PAC-ATLS: Postapproval Changes — Analytical Testing Laboratory Sites....................................................................... 29
E. FDAMA and Manufacturing Changes ................................... 29 F. Expedited Review of Manufacturing Changes ..................... 31 G. Manufacturing Changes for Biologics ................................... 31
IV. Moving Forward in Managing Change....................................... 33 References ............................................................................................... 34
This chapter has been revised extensively due to numerous changes in regulations and approaches to change control implemented by the U.S. Food and Drug Administration (FDA) in recent years. Over the past decade, the U.S. has enacted legislation aimed at reforming the way the FDA reviews and approves products with an eye toward streamlining the approval process. The “GMP Initiative” announced by the FDA in 2002 will undoubtedly continue that evolution. The FDA has engaged in revising change reporting regulations and guidelines primarily to avoid discouraging innovation by manufacturers who, for example, may desire to improve processes, but decline to do so because of onerous change reporting requirements. With reference to postapproval change reporting, Section 116 of the 1997 Food and Drug Modernization Act (FDAMA),
the Code of Federal Regulations (CFR), and a variety of guidance documents (all detailed later in this chapter) provide requirements and guidance for making and reporting manufacturing changes to an approved application and for distributing the products made with these changes. Despite the volume of information supplied and examples enumerated in these documents, the specific situations manufacturers encounter often fail to neatly classify into the change levels (e.g., minor, major) and reporting mechanisms (e.g., prior approval, CBE-30, annual report) outlined in them. Typically, an organization’s regulatory personnel will be asked to interpret the regulations and guidance and, if appropriate, contact the agency to ultimately determine the most appropriate reporting mechanism for a given manufacturing change, or set of changes.
