Case Studies in the Applicability of Drug Substance Design Spaces Developed on the Laboratory Scale to Commercial Manufacturing

Abstract

A number of strategies have been employed within the pharmaceutical industry in order to mitigate the risk of applying design space boundaries developed on the laboratory scale to commercial drug substance manufacturing. The following communication presents a number of case histories from members of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), with the aim of exemplifying strategies used to confirm applicability of design spaces developed on the laboratory scale. The strategies presented have a common aim of ensuring that appropriate quality standards are developed, maintained, and enhanced during the product lifecycle whilst delivering rapid and costeffective mechanisms for drug substance commercialization.

Mutagenic Impurities: Precompetitive/Competitive Collaborative and Data Sharing Initiatives

“…independent research) and/or where the third party provides a 'consensus voice' on behalf of the industry collaborators, e.g. scalability of API design space from IQ consortium 3 . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 …”

“…Funding projects at external providers is where the contributing pharmaceutical companies provide monies/time/effort for mutually beneficial research via an independent third party, e.g., Product Quality Research Institute (PQRI), International Society for Pharmaceutical Engineering (ISPE), Innovation and Quality Consortium (IQ), etc. The objective here is to demonstrate that the activities/findings have not been overly influenced by the pharmaceutical collaborators (i.e., independent research) and/or where the third party provides a “consensus voice” on behalf of the industry collaborators, e.g., scalability of API design space from IQ consortium …”

“…The objective here is to demonstrate that the activities/findings have not been overly influenced by the pharmaceutical collaborators (i.e., independent research) and/or where the third party provides a "consensus voice" on behalf of the industry collaborators, e.g., scalability of API design space from IQ consortium. 3 Different Types of Precompetitive Collaborations. Honest Broker is where a formal entity is created on behalf of the collaboration consortium: for example, the Consortium for the Investigation of Genotoxicity of Aromatic Amines (CIGAA)), joint venture, or "not for profit" corporations, e.g., Lhasa Limited, etc.…”

A ligand-free, powerful, and practical method for methoxylation of unactivated aryl bromides by use of the CuCl/HCOOMe/MeONa/MeOH system

“…Treatment of the recovered pure MeOH with sodium metal could be used for direct production of methanolic MeONa in the plant to achieve economy of recycling. The reaction has no significant risk of scale sensitivity, and long-term process robustness was observed in large-scale production [47].…”

PAT-Facilitated Pharmaceutical Crystallization Development through Mechanistic Understanding

“…Current industry practice under the QbD paradigm usually starts with establishing a functional relationship between processes and product CQAs through quality risk management followed by crafting the control strategy . An expected output of the workflow is normally a selected and verified design space, in which the multivariate interaction of process parameters and their impact on quality is well-understood, as defined by ICH Q8 and Q11. , However, a clear-cut design space does not have to be the only product of the exercise, as ultimately it is the control strategy in the submission’s manufacturing process description (Module 3, Section S.2.2) that dictates the level of flexibility available to the manufacturer, if the scientific understanding can support wider or one-sided parameters .…”