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www.biopharminternational.com October 2020 BioPharm International eBook 33 T he def i n it ion of t he Q T PP s h o u l d b e a c c o m p a n i e d b y t he def init ion of t he CQA s of t he d r u g p r o d u c t . Ac c o r d i n g t o I nt e r n at io n a l C o u nc i l fo r Harmonization (ICH) Q8 (2), a CQA "is a physical, chemical, bio- logical, or microbiological prop- erty or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality." CQAs are generally associated with the API, excipients, intermediates, and drug product. Therefore, what can be referred to as a CQA for an API or an excipient (e.g., particle size, solid state, purity, etc.) can become a critical material attribute (CMA) for a unit operation delivering an intermediate or a drug product. PROCESS DESIGN Process design is the first stage of the FDA guidance for industry on process validation (3). The commer- cial manufacturing process should be defined in this stage based on knowledge gained through develop- ment and scale-up activities. Comprehensive process design is vital to understand sources of variabilit y and achieve product and process understanding. In the context of the new paradigm of the 2011 FDA guidance on process validation, an additional quality level is incorporated into the con- cept of product quality. Not only must a ll d r ug produc t batches manufactured for clinical studies and subsequently for the market comply with established specifi- cations, but the process must also be in a permanent state of control and product performance must be consistent from batch-to-batch and unit-to-unit. Prior k nowledge with similar processes and risk management can be used as the first step to identify a list of potential CQAs. Prior knowledge can also be use- f ul to identif y a list of process parameters and material attributes potentially impacting the CQAs. Using risk management (4), the risk of these parameters and mate- rials impacting the CQAs can be ranked. Based on these evalua- tions, experimental activities are prioritized, ultimately leading to a list of CMAs and critical process parameters (CPPs). Another goal is the identification of the most appropriate immediate packaging to ensure the consistency of the identified CQAs. The stage 1 output is as follows: • QT PP (at t he beg inning of stage 1) • CQAs • Product and process design • CMAs and CPPs and their limits • K nowledge of process var i- ables, enabling the establish- ment of control strategy (raw materials, in-process controls, finished product) • Design space (if applicable) • Process design report. The iterative approach leading to the above-mentioned outputs is illustrated schematically in Figure 1. Regulatory Sourcebook Process Development Figure 1. Scheme for pharmaceutical development and risk management to construct design space and control strategy. MAs are material attributes, PPs are process parameters, and CQAs are critical quality attributes. Target product profile and quality target product profile API characteristics (from preformulation and prior knowledge) Proposed formulation and manufacturing process Determine the functional relationships that link MAs and PPs to product CQAs Risk evaluation Parameters to investigate (risk reduction) Product and process design Control strategy Product and process understanding (re-evaluation and understanding) Monitoring and continuous improvement Figures and Tables are courtesy of the authors.