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PharmTech.com Regulating Innovation, Quality, and Risk eBook January 2024 Pharmaceutical Technology ® 37 Qualit y "The application of digitalization and emerging technologies in the manufacture and control of drug (medicinal) products can lead to risk reduction, when such technologies are fit for their intended use. How- ever, they can also introduce other risks that may need to be controlled. The application of quality risk management to the design, validation and technol- ogy transfer of advanced production processes and analytical methods, advanced data analysis methods and computerized systems is important" (11). With that caveat, many modern technologies ap- pear ready for implementation. Yet, with the rare ex- ception of isolator/barrier technology, overall uptake of modernization in the pharmaceutical industry is slow. In other industries, once early adopters have successf u l ly deployed a tech nolog y a nd demon- strated its benefits, other companies will follow suit by adopting the better technology to keep up with current quality standards and remain competitive. While early adopters of a truly novel technology take on some additional risk, their efforts typically lead to major efficiency advantages and blaze the way forward for spurring wider industry adoption. This quick uptake is less characteristic of the pharmaceu- tical industry. The need for "accessible and published business cases" to promote uptake of continuous manufacturing (CM) is considered by the authors of a white paper in the Journal of Pharmaceutical Sciences to be essential in promoting more adoption of CM (81). Consequences of status quo We have noted in this paper (Table I) that inconsis- tent operations include surprises that disrupt pro- duction planning and supply availabilit y. Special workarounds are of ten created to overcome inher- ent design f laws, reprocessing or reworking might be performed, or extra examinations of finished units are conducted in an attempt to cull out detectable defects. Of course, inherent attributes of medicines such as dissolution, dose uniformit y, presence of contamination (e.g., non-sterility, chemical impuri- ties), and many other attributes are not readily de- tectable by customers. In addition, continuous up- stream monitoring of these attributes is rather rare or currently infeasible, which too often means that a company must rely on the statistical probability of catching such a defect before shipment by testing a small quality control sample. While the final batch quality control test is essential and has prevented dis- tribution of many hazardous batches, the final test on its own is far from exhaustive and is only the last in a series of required steps that ensure quality before product distribution. So, if a company has an unre- liable operation, drug defects may escape detection and can be shipped for consumer use. If a defective product is discovered in distribution, it can culmi- nate in costly recalls. In short, as with all industries, high manufactur- ing variation yields inconsistent products. Unreliable quality exposes consumers to increased potential for harm from unsafe, inefficacious, or unavailable drugs. As ICH Q9(R1) states: "Processes that exhibit excessive variability (e.g., process drif t, non-uniformity) have capability gaps that can result in unpredictable outputs (e.g., quality, timeliness, and yield)" (11). These critical consequences of substandard phar- maceutical quality are well understood. For example, in 2010, a Product Quality Research Institute (PQRI) workshop explored the impact of excessive manufac- turing variation and stated the patient and business impacts as follows: "Failure to adequately control pro- cesses and prevent defects can pose risk to patients/ consumers, affect product availability, and yield un- desirable regulatory and business outcomes" (82). In addition, the revised ICH Q9(R1) guideline includes a new section that describes with substantial detail the manufacturing and quality oversight lapses that lead to an undependable supply of needed medicine ("6.1. The Role of Quality Risk Management in Addressing Product Availabilit y Risks Arising f rom Qualit y/ Manufacturing Issues"). The ICHQ9(R1) Expert Working Group also worked in conjunction with PDA to develop a facility lifecycle case study that contrasted a company that consistently FIGURE 2. Installation of isolators, RABS, and traditional filling lines in 2020, based on ISPE survey data.