On the Shelf Life of Pharmaceutical Products
- 1.4k Downloads
This article proposes new terminology that distinguishes between different concepts involved in the discussion of the shelf life of pharmaceutical products. Such comprehensive and common language is currently lacking from various guidelines, which confuses implementation and impedes comparisons of different methodologies. The five new terms that are necessary for a coherent discussion of shelf life are: true shelf life, estimated shelf life, supported shelf life, maximum shelf life, and labeled shelf life. These concepts are already in use, but not named as such. The article discusses various levels of “product” on which different stakeholders tend to focus (e.g., a single-dosage unit, a batch, a production process, etc.). The article also highlights a key missing element in the discussion of shelf life—a Quality Statement, which defines the quality standard for all key stakeholders. Arguments are presented that for regulatory and statistical reasons the true product shelf life should be defined in terms of a suitably small quantile (e.g., fifth) of the distribution of batch shelf lives. The choice of quantile translates to an upper bound on the probability that a randomly selected batch will be nonconforming when tested at the storage time defined by the labeled shelf life. For this strategy, a random-batch model is required. This approach, unlike a fixed-batch model, allows estimation of both within- and between-batch variability, and allows inferences to be made about the entire production process. This work was conducted by the Stability Shelf Life Working Group of the Product Quality Research Institute.
KEY WORDSICH method quantile for distribution of batch shelf lives random-batch model shelf life terminology stability
The Working Group is grateful to PQRI for supporting this project, to Suntara Cahya and Paula Hudson (Eli Lilly), and David Thomas (Johnson & Johnson) who participated in the early stages of this work and to Abhay Gupta (FDA) for his contributions to the manuscript development and discussions as an active PQRI Stability Shelf Life Working Group member.
- 1.International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Q1A(R2): Stability testing of new drug substances and products; 2003.Google Scholar
- 2.PQRI Stability Shelf Life Working Group. http://www.pqri.org/commworking/minutes/pdfs/dptc/sslwg/Addl/2007_MBSW.pdf. Additional presentations from SSL WG are available at http://www.pqri.org/structure/wg.asp#sslwg, 2007; Accessed 27 March 2012.
- 3.International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Q6A: specifications: test procedures and acceptance criteria for new drug substances and new drug products: Chemical Substances; 1999.Google Scholar
- 4.International Organization for Standardization. ISO 2859. Sampling procedures for inspection by attributes, parts 0–4. ISO 2859-0:1995; ISO 2859-1:1999; ISO 2859-2:1985; ISO 2859-3:1991; ISO 2859-4:2002. http://www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_detail.htm?csnumber=7865. Accessed 18 June 2012.
- 5.International Organization for Standardization. ISO 3951:1989. Sampling procedures and charts for inspection by variables for percent nonconforming. http://www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_detail.htm?csnumber=9602. Accessed 18 June 2012.
- 6.US Department of Defense. MIL-STD-690D Failure rate sampling plans and procedures. http://www.variation.com/anonftp/pub/MIL-STD-690D%20(10%20June%202005).pdf. Accessed 15 June 2011; 2005.
- 7.American National Standards Institute. ANSI/ASQC Z1.4-2008 Sampling procedures and tables for inspection by attributes; 2008. http://webstore.ansi.org/RecordDetail.aspx?sku=ANSI%2FASQ+Z1.4-2008. Accessed 18 June 2012.
- 8.Larner G, Cooper A, Lyapustina S, Leiner S, Christopher D, Strickland H, et al. Challenges and opportunities in implementing the FDA default parametric tolerance interval two one-sided test for delivered dose uniformity of orally inhaled products. AAPS PharmSciTech. 2011;12(4):1144–56.PubMedCrossRefGoogle Scholar
- 9.International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Q1E evaluation of stability data; 2004.Google Scholar
- 10.Quinlan M, Stroup W, Christopher D, Schwenke J. On the distribution of batch shelf lives. (Accepted for publication in J Biopharm Stat. 2011).Google Scholar
- 11.Quinlan M, Stroup W, Schwenke J, Christopher D. Evaluating the performance of the ICH guidelines for shelf life estimation. (Accepted for publication in J Biopharm Stat. 2011).Google Scholar
- 12.Stroup W, Quinlan, M. Alternative shelf life estimation methodologies. In JSM Proceedings, Biopharmaceutical Section. Alexandria, VA: American Statistical Association. 2010;2056–x2066.Google Scholar