Conclusion
Organizations involved in manufacture of Phase 1 and 2a clinical supplies should recognize that process understanding is very
limited in early development. Quality systems must be robust enough to ensure patient safety, but should also be flexible
enough to accommodate accelerated timelines and process changes in real time. The special needs of small scale GMP manufacturing
should also be considered when designing facilities, purchasing equipment, and selecting the type of dosage forms to use in
early clinical studies. Companies are encouraged to apply quality risk management principles to support these risk-based decisions.
The authors also believe that underutilized approaches exist (e.g., on-site preparation of more complex dosage forms) for
quickly and efficiently answering formulation related questions about bioavailability, pharmacokinetics, and target release
rates for controlled-release formulations. The potential benefits and risks of these approaches warrant further discussion.
Finally, documentation of manufacturing operations should be risk-based. Manufacturing instructions in early development should
not be overly prescriptive as to restrict process changes or discourage sampling for further process understanding. Changes
should be expected, and able to be quickly reviewed and approved by the Quality department, or a qualified delegate.
To further stimulate discussions on these approaches within the industry and with worldwide health authorities, the IQ Consortium's
GMPs in Early Development Working Group is planning on conducting a workshop in the near future to promote robust debate and
discussion on these recommended approaches to GMPs in early development. The group strongly believes that such dialogue will
improve alignment between development, quality assurance, and chemistry/manufacturing/controls (CMC) regulatory groups within
the pharmaceutical industry. In addition, agreement between the industry and drug regulatory authorities regarding acceptable
approaches to applying GMPs in early phases of drug development would allow for a more nimble and flexible approach in early
development, while still providing appropriate controls to ensure patient safety.
Richard Creekmore is in pharmaceutical development at AstraZeneca (Wilmington, DE); Eleni Dokou is in pharmaceutical development at Vertex Pharmaceuticals (Cambridge, MA); Amnon Eylath is in quality at ARIAD Pharmaceuticals (Cambridge, MA); Dennis Joiner is in pharmaceutical sciences and clinical supply at Merck (Summit, NJ); Michael Lovdahl is in pharmaceutical sciences at Pfizer (Groton, CT); Jackson Pellett is in small molecule pharmaceutical sciences at Genentech (South San Francisco, CA); and Eric Schmitt and John W. Skoug* are in drug product development at Abbott Laboratories (Abbott Park, IL).
*To whom all correspondence should be addressed.
REFERENCES
1. A. Eylath et al., Pharm. Technol.
36 (6) 54–58 (2012).
2. FDA, Guidance for Industry: CGMP for Phase 1 Investigational Drugs (Rockville, MD, July 2008).
3. FDA, "Current Good Manufacturing Practice and Investigational New Drugs Intended for Use in Clinical Trials," Fed. Reg.
73 (136), 40453–63 (2008).
4. EU, Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use, Annex 13: Investigational Medicinal Products (Feb. 2010).
5. D. Chambers, Pharm. Technol.
36 (7) 76–84 (2012).
6. D.A. LeBlanc, in "Validated Cleaning Technologies for Pharmaceutical Manufacturing," (Interpharm/CRC, Washington, DC, 2000).
7. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC).
8. Personal communication with Mike Kress, Leader, IQ Consortium Drug Product Working Group on Extemporaneous Formulations
(May 2012).
9. USP 35–NF 30 General Chapter <795> Pharmaceutical Compounding—Nonsterile Preparation, 344–350.
10. USP 35–NF 30 General Chapter <797> Pharmaceutical Compounding—Sterile Preparations, 350–387.
11. L.V. Allen, The Art, Science and Technology of Pharmaceutical Compounding (American Pharmacists Association, 2008).
12. See, for example: the USP Excipient Supplier Qualification Program, Section 10 (V. 1.1, Sept. 2008), and references therein,
for specific guidance.
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