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60 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2018 P h a r mTe c h . c o m Quality ing the product and establishes the set of criteria for demonstrating the product is acceptable for its intended use. It is one part of the overall product control strategy and forms the basis for the critical quality standards (CQAs) that will be approved by regulatory authorities. The product specification is established through evaluation of the process design, process capability determinations, and characteriza- tion of the product. Acceptance criteria are estab- lished based on data obtained from preclinical and clinical studies as well as from demonstration lots used to show manufacturing consistency and from stability studies. ICH Q8(R2) is an excellent source of information about linking material attributes and process parameters with drug product CQAs (10). It stands to reason, however, that at the time of regulatory approval not all sources of process or product variability may be fully understood. For example, the impact of raw material variability or commercial-scale processing conditions on qual- ity attributes may not have been fully determined. These factors are usually related to production scale and can only be fully elucidated once commercial scale has been achieved. In any event, the goal of de- velopment and scale-up studies should be to mini- mize any surprises later on. Problems result when technology transfer does not embrace quality and compliance issues from the beginning, tasks and requirements are not fully defined and understood, and project management is inadequate (20). Historically, acceptance criteria have been set based on process capability and stability informa- tion, but it important that clinically-relevant speci- fications (i.e., acceptance criteria) link the process with the product and the patient. To establish sci- entifically and clinically relevant specifications, a comprehensive understanding of the process is re- quired through clinical and commercial develop- ment. In terms of quality by design (QbD), specifi- cations account for only one element of the overall product control strategy, which should employ a science and risk-based approach to define quality attributes based on overall assessment of the process. ICH Q6B contains comprehensive guidance on set- ting specifications for biological products (8). The control strategy assessment requires evalua- tion of the criticality, probability, and detectability of an event or condition affecting the process, the product, and the patient. Criticality assessments in- clude efficacy, safety, and immunogenicity consider- ations, and these are used to define CQAs. Process capability is determined through univariate assess- ment, an understanding of design space, and pro- cess history. Testing strategies should be based on analytical method capability, stability, in-process control, and validation results. ICH Q9 provides a comprehensive discussion of quality risk manage- ment and risk management tools that apply to phar- maceutical and biopharmaceutical quality (11). Maintaining the validated state of control through the product lifecycle extends from product develop- ment, through process and analytical development, to process and analysis implementation and com- mercial manufacturing. The formalized control strategy is primarily employed during the imple- mentation and commercial manufacturing phases. During product development, the target product profile and CQAs are identified, assessed, and estab- lished. Process and analytical development includes validation master planning, process characteriza- tion, and process parameter criticality assessment and classification. During the implementation and commercial manufacturing phases, engineer- ing designs are finalized, equipment is qualified,