In response to these evolving concepts of quality management, other approaches and tools to establish specifications have
been proposed and currently are under consideration. Some of these concepts such as periodic or skip-lot testing, parametric
release (i.e., real-time release), and the use of interim specifications to address inherent problems in deriving specifications from limited
data sets have been acknowledged in principle in the ICH Q6A and Q6B guidance on setting specifications. On the basis of the
results of the AAP Workshop on the Justification of Specifications, there is great interest and support for these initiatives
on the part of industry. Other initiatives, including sunset testing, also were strongly supported, particularly for products
in which a significant body of data from postmarketing experience indicated that the tests were no longer value-added controls
or were adequately controlled by another test (i.e., either a finished product or in-process control test). Finally, the use of appropriate statistical approaches to determining
acceptance criteria to set robust specifications deserves further emphasis. Such approaches must balance the evaluation of
process capability, shelf-life considerations, and the ultimate safety and efficacy requirements in the face of limited-size
datasets.
Further dialog between industry and regulatory agencies regarding these and other initiatives is needed and will lead to new
approaches to establishing performance-based specifications and controls that hopefully will shorten development time to market
for new products and ultimately reduce the overall cost of development and manufacturing.
Paul Kurtulik, PhD, is executive director, analytical R&D and quality operations, at Celgene Corporation. Terry Tougas works at Boehringer Ingelheim Pharma's CMC development office. Paul K.S. Tsang, PhD, is director and quality site head at Amgen. Edward Warner is director of global quality statistical services, Schering Plough Corporation. Jean M. Wyvratt, PhD,* is vice-president, analytical science and quality testing, global pharmaceutical commercialization at Merck & Co., tel. 732.594.7174,
jean_wyvratt@merck.com
*To whom all correspondence should be addressed.
Submitted: Oct. 18, 2006. Accepted: Dec. 8, 2006.Keywords: analysis, compliance, guidance, PhRMA, specifications.
References
1. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use,
ICH Harmonized Tripartite Guideline Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New
Drug Products: Chemical Substances Q6A (ICH, Geneva, Switzerland), Oct. 1999.
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Products Q6B, Mar. 1999.
3. G.C. Davis et al., "Rational Approaches to Specification Setting: An Opportunity for Harmonization," Pharm. Technol .
15 (9) (1991).
4. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use,
ICH Harmonized Tripartite Guideline: Impurities in New Drug Substances Q3A(R) (ICH, Geneva, Switzerland), Feb. 2003.
5. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use,
ICH Harmonized Tripartite Guideline Impurities in New Drug Products Q3B(R) (ICH, Geneva, Switzerland), Nov. 2003.
6. EMEA Committee for Proprietary Medicinal Products, "Note for Guidance on Parametric Release," CPMP/QWP/ 3015/99, Mar.
2004.
7. FDA, Guidance for Industry: Powder Blending and Finished Dosage units - Stratified In-Process Dosage Unit Sampling and Assessment,
Draft Guidance Oct. 2003.
8. FDA, Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance, Draft Guidance, p. 17 (Aug. 2003).
9. PQRI/FDA Report, presented at "A Drug Quality System for the 21st Century," Apr. 22–24, 2003, Washington DC (report prepared
on June 16, 2003).
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