Date: Mar 12, 2001
Current good manufacturing practice (CGMP)requirements, while challenging in any pharmaceutical environment, present uniqueconcerns in a specialty chemical facility. In regulating manufacturers of activepharmaceutical ingredients (APIs), intermediates, and excipients, the Food and DrugAdministration (FDA) has recognized that "one size" does not fit all. The challenge is determining -- and consistentlyimplementing -- those steps that are necessary to ensure the quality and purity of aparticular chemical product that is intended for use in pharmaceutical applications.
The first step of any corporate compliance program is to identifythe applicable legal and regulatory requirements. Below is a list of laws, regulations,guidance documents, and other resources that API, intermediate, and excipient suppliersshould consider in developing a CGMP compliance program. These resources fall into sixprimary categories:
The Federal Food, Drug, and Cosmetic Act
FDA's CGMP Regulations for Finished Pharmaceuticals
FDA Guidance Documents for Industry
FDA Guidance Documents for Agency Staff Responsible for CGMP Enforcement
FDA Warning Letters
Organizations that Provide CGMP Guidance
THE FEDERAL FOOD, DRUG, AND COSMETIC ACT: THE STATUTORY BASIS FOR CGMP REQUIREMENTS
The Federal Food, Drug, and Cosmetic Act (FDC Act) provides the legal basis for CGMPrequirements. Under section 501(a)(2)(B) of the FDC Act, a "drug" is deemed tobe "adulterated" if --
The methods used in, or the facilities or controls used for, its manufacture,processing, packing, or holding do not conform or are not operated or administered inaccordance with current good manufacturing practice to assure that such drug meets therequirements of this Act as to safety and has the identity and strength, and meets thequality and purity characteristics, which it purports or is represented to possess . . .
FDC Act § 501(a)(2)(B) ("Adulterated drugs and devices").
The term drug is defined to include both finished drug products and components ofdrugs. Specifically, the term "drug" means --
(A) articles recognized in the official United States Pharmacopeia, officialHomeopathic Pharmacopeia of the United States, or official National Formulary,or any supplement to any of them; and
(B) articles intended for use in the diagnosis, cure, mitigation, treatment, or preventionof disease in man or other animals; and
(C) articles (other than food) intended to affect the structure or any function of thebody of man or other animals; and
(D) articles intended for use as a component of any articles specified in clause (A), (B),or (C).
FDC Act § 201(g).
This definition makes the statutory CGMP obligation applicable to API, intermediate,and excipient manufacturers as well as to manufacturers of finished drug products. Asnoted above, however, FDA does not have the same level of CGMP expectations for allsegments of the pharmaceutical industry. For drug component manufacturers, the practicalmeaning of the statutory term "current good manufacturing practice" must beinterpreted in the context of each product. The following documents and resources shouldprove helpful in this regard.
FDA CGMP REGULATIONS
FDA's CGMP regulations are applicable, and therefore legally binding, to finisheddrug products only. FDA has encouraged API and excipient manufacturers, however, to usethe regulations as "guidance."
21 C.F.R. 11
21 C.F.R. Parts 210 and 211
FDA proposed amendments that would address, among other things, process validation and out of specification findings on May 3, 1996(61 Fed. Reg. 20103).
FDA GUIDANCE AND DRAFT GUIDANCE FOR INDUSTRY
(This is a select list of guidance documents; a full list is available on FDA'sweb site.)
General API CGMP Guidance
Part 11, Electronic Records; Electronic Signatures - Scope and Application (August 2003
Providing Regulatory Submissions in Electronic Format - General Considerations (October 2003 Draft)
Questions and Answers on Current Good Manufacturing Practices (cGMP) for Drugs (August 4, 2004)
PAT - A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance (Aug. 2003 Draft)
Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP (draft guidance) (August 2003 Draft)
FDA Issues Final Guidance on Good Manufacturing Practice forActive Pharmaceutical Ingredients
ICH Q7A Good Manufacturing PracticeGuide for Active Pharmaceutical Ingredients (2001)
Manufacturing, Processing or Holding ActivePharmaceutical Ingredients (1998 Draft)
Compliance Policy Guides Manual, Chapter 4, 490.100 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval (revised 03/12/2004)
Other Guidance Documents of Interest
Botanical Drug Products (June 2004)
Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (January 2003)
Q1E Evaluation of Stability Data (June 2004)
Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV, revision 1 (June 2004)
Q3B(R) Impurities in New Drug Products (November 2003)
Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process (November 2004)
FDA Export Certificates (July 2004)
Drug Substance: Chemistry, Manufacturing, and Controls Information (January 2004 Draft)
FDA'S INTERNAL CGMP DOCUMENTS
FDA Issues Guidance on Drug Manufacturing Inspections, Announces Workshops
FDA Compliance Program Guidance Manual, Chapter7356.002-F, Active Pharmaceutical Ingredients (May 20, 1998)
FDA Inspection Guides
Those of Particular Interest Include--
Bulk Pharmaceutical Chemicals (1991)
High Purity Water Systems (1993)
Validation of Cleaning Processes (1993)
Human Drug CGMP Notes
FDA WARNING LETTERS
Warning Letters Available on FDA's Web Page
EU CGMP REGULATIONS
Directive 2001/83/EC of 6 November 2001 on the Community code relating to medicinal products for human use
Draft Directive 2001/0253 (COD) amending Directive 2001/83/EC on the Community code relating to medicinal products for human use
ORGANIZATIONS THAT PROVIDE CGMP GUIDANCE
International Pharmaceutical Excipients Council (IPEC)
International Society of Pharmaceutical Engineers (ISPE)
United States Pharmacopeia (USP)