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Siegfried Schmitt, principal consultant, PAREXEL, discusses how the regulatory requirements for CGMPs is the different phases of drug development and manufacture.
Q: Our company covers the entire lifecycle for our drugs, from R&D through clinical trials to commercial product. The quality management system covers good clinical practice (GCP) and current good manufacturing practice (cGMP). In a recent client audit, we received an observation: “You do not apply the same level of cGMP to clinical-trial material manufacture as you apply to commercial product.” Is this a new regulatory expectation?
A: It is not a regulatory expectation to apply the same level of cGMP to investigational new drug (IND) and marketed products. Although it is correct that you need to apply cGMP to all your clinical-trial supplies (referred to as investigational medicinal products [IMP] in the European Union [EU] and IND in the United States) and to commercial operations, the level of CGMP differs. The reasons for this are practical constraints as well as regulatory requirements. Under FDA regulations, the manufacture of most INDs used in Phase I clinical trials is exempt from cGMPs (1) (i.e., 21 Code of Federal Regulations Part 211 is not applicable). For INDs for clinical Phases II and III and for commercial product, cGMP applies (2, 3).
In the EU, the relevant regulations are in EudraLex Vol. 4, Part I (drug product) and Part II (drug substance/API), and IMPs are covered specifically in Annex 13 “Manufacture of Investigational Medicinal Products,” which was last updated in 2010 (4). EudraLex, and any laws and regulations laid down by EU member states, are based on Commission Directive 2003/94/EC, which applies to both IMP and marketed products (5).
Paragraph 17 in Annex 13 summarizes the differences in cGMP for IMP and marketed product: “Production processes for investigational medicinal products are not expected to be validated to the extent necessary for routine production but premises and equipment are expected to be qualified. For sterile products, the validation of sterilizing processes should be of the same standard as for products authorized for marketing.”
Though these guidances are useful, they will not necessarily answer all questions. The common adage supported by the majority of regulatory agencies is to apply a scientifically sound risk-based approach to compliance. More information can be found in several publications, including a widely publicized technical report by the Parenteral Drug Association (6).
The regulators do understand that product and process knowledge will continue to grow during the lifecycle from clinical Phase I to launch and beyond. With increased understanding, companies can and need to apply more controls and move towards a fully validated process. You may wish to discuss the observation with the auditor in light of the regulations and guidance documents mentioned above.
1. FDA, Guidance for Industry: cGMP for Phase 1 Investigational Drugs (Rockville, MD, July 2008).
2. FDA, Draft Guidance for Industry: INDs for Phase 2 and 3 Studies of Drugs, Including Specified and Therapeutic Biotechnology Derived Products (Rockville, MD, February 1999).
3. 21 CFR Parts 210 and 211.
4. European Commission, EudraLex-Volume 4 Good Manufacturing Practice (GMP) Guidelines,
5. Commission Directive 2003/94/EC on the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use.
6. PDA Technical Report 56 Application of Phase-Appropriate Quality System and CGMP to the Development of Therapeutic Protein Drug Substance (PDA, 2012).
Article DetailsPharmaceutical Technology
Volume 40, Number 3
When referring to this article, please cite as S. Schmitt, "Phase-Appropriate GMP," Pharmaceutical Technology 40 (3) 2016.