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A Science and Risk Based Proposal for Understanding Scale and Equipment Dependencies of Small Molecule Drug Substance Manufacturing Processes

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Abstract

ICH Q8(R2) established general guidelines around the Relationship of a Design Space to Scale and Equipment (Section 2.4.4); however, the guideline is not intended to provide guidance on scientific strategy for the application and implementation. It is widely recognized that drug product processes are typically scale and equipment sensitive; however, the same expectation should not be applied broadly to drug substance processes due to fundamental difference between the disciplines. This paper proposes a scientific perspective and strategy of how to develop design spaces that include scale and equipment knowledge for drug substance processes, and how to use that knowledge to mitigate the risk when changing from laboratory thorough commercial facilities.

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Notes

  1. (a) http://www.ich.org/cache/compo/276-254-1.html. (b) Continuum of Criticality is a concept introduced by ISPE’s criticality team (to be published). Presented by Tim Watson and Roger Nosal at Pharmaceutical Technology, CBI Research Inc Conference, Philadelphia PA USA, August 11, 2009.

  2. http://www.ich.org/cache/html/3557-272-1.html.

  3. Supply chain flexibility is especially vital in the early years of commercialization since market projections are not particularly predictive of future API demand. Thus, in order to sustain the supply chain, particularly for products that exceed prediction, this requires the ability to change batch sizes, equipment trains, and sometimes sizes very rapidly.

  4. Currently, implementing low-risk as well as high-risk scale and equipment changes requires regulatory submissions in the approved markets. These post-approval submissions have agency-specific requirements, different review period, and application costs. The longest review period for a major change is 18 months to 2 years, and the global filing expenses can approach one million dollars.

  5. Steady state is when the processing conditions (i.e., material flow rates, temperature, and/or pressure) are within normal processing variations, and the processing conditions do not significantly change with time. Steady state may also be when the process controls are at the pre-determined, desired set points (for example, a reactor temperature set point) and there are only normal process variations.

  6. This paper, along with case studies, is scheduled for presentation at the AIChE annual meeting in Nashville TN, USA in November of 2009 by Tim Watson.

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Authors and Affiliations

  1. Pfizer Global Research and Development, Eastern Point Road, MS8118N-202, Groton, CT, 06340-8013, USA

    David J. am Ende, Christine B. Seymour & Timothy J. N. Watson

Authors
  1. David J. am Ende
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  2. Christine B. Seymour
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  3. Timothy J. N. Watson
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Correspondence to Timothy J. N. Watson.

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am Ende, D.J., Seymour, C.B. & Watson, T.J.N. A Science and Risk Based Proposal for Understanding Scale and Equipment Dependencies of Small Molecule Drug Substance Manufacturing Processes. J Pharm Innov 5, 72–78 (2010). https://doi.org/10.1007/s12247-010-9083-1

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  • DOI: https://doi.org/10.1007/s12247-010-9083-1

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