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36 Pharmaceutical Technology ® Regulating Innovation, Quality, and Risk eBook January 2024 PharmTech.com Qualit y The importance of continual improvement to enable drug quality and availability In addition, an FDA paper (68) in 2012 noted that shortages of critical sterile medicines were often as- sociated with nearly obsolete, low capability equip- ment. The paper emphasizes that it was not unusual for the pharmaceutical industr y to use equipment that is circa 30–50 years old. The authors state that "A review of inspection reports for key facilities sug- gests that some facilities at the heart of current drug shortages have been in operation continually since the 1960s and that certain manufacturing lines have undergone only limited upgrades during that time." In a commentary in the PDA Journal (69) then Center for Drug Evaluation and Research (CDER) Center Direc- tor Janet Woodcock, MD, observed that "Clearly the re- sponsibility for maintaining quality rests squarely with the manufacturers themselves … the widespread and successful adoption of Six Sigma and related quality management techniques in other manufacturing sec- tors would imply that reliable, high-quality manufac- turing is also attainable in the pharmaceutical sector … We must ask ourselves, in an area where the stakes are so high, why is this not being achieved?" In 2020, an FDA Shortage Task Force reinforced this focus on manufacturing robustness (70). The report describes the finding that some companies "keep costs down by minimizing quality investments," and adds that a lack of investment in manufacturing quality "eventually leads to quality problems, trig- gering supply disruptions and shortages." Organizational willingness to modernize manufacturing facilities Most organizations understand the importance of con- tinual improvement but garnering sufficient support to achieve activation energy is often difficult. Silos, lack of sponsorship by leaders, overcoming a culture that is resistant to change, and other communication issues are typically cited as reasons for failed improvement proposals. While all organizations speak of the need to continually improve, not all do it. Clearly, there are both behavioral and economic factors at play when a firm makes the pivotal decision to improve an operation or to accept the current state. A core indicator of the strength of a quality culture is whether changes are made in a timely (71) fashion when deficient facilities, equipment, processes, or related sys- tems exist (72). A critical marker of an organization's ca- pacity to resolve complex problems is whether it makes ongoing improvements and implements major technol- ogy shifts, when needed. There is significant literature devoted to use of mod- ern technological innovations to resolve quality prob- lems that are rooted in low capability (73). One paper (74) notes that the organization that is most likely to succeed is one that "co-innovates" by developing an "innovation ecosystem" of internal and external partners. This net- work can create ideas, evaluate, and converge "through all useful sources such as internal R&D, collaboration, open sourcing, co-creation with customers and partner organizations" and other steps to develop plans that can be implemented (75). This affinity in the organizational quality culture to partnership and exploring contempo- rary manufacturing solutions is pivotal in determining whether a factory will ultimately move forward with its plans and successfully modernize its infrastructure. The consideration of modern technologies can also create some inertia. Early adopters frequently encoun- ter hurdles when considering new technologies (76). But some of these technologies have overcome the hurdles and rapidly propagated. An example includes the remarkable shift of the sterile drug sector of the industry to isolator and restricted access barrier tech- nologies. Only a handful of sites had built prototype isolators or Restricted Access Barrier Systems (RABS) at the start of the 21st Century. Yet, only 20 years later, ISPE (77) found that "virtually no systems would be delivered without a form of RABS or isolator, illustrat- ing that the industry is decidedly moving to the use of barrier systems. This is great news for patients and product safety." Notably, ISPE repeatedly presented de- tailed costs and benefit data that influenced their deci- sion to invest in these advanced barrier technology op- tions at annual conferences, leading the large part of the industry to see the clear cost benefits of converting from traditional cleanrooms to barrier technologies. Eary adopter companies collegially shared practical case studies at conferences, and the industry adapted their designs and procedures. Regulators also facili- tated the evolution by publishing technical guidance and encouraging the beneficial innovations (Figure 2). At the time of this publication, adoption of isolators has transformed sterile manufacturing reliability in a substantial proportion of the industry. Of course, a technological innovation must also be suitable for its intended use. A 2017 review article that was focused on how to expand use ("diffusion") of in- novations also included this warning: "The pro-inno- vation bias is the implication in diffusion research that an innovation should be diffused and adopted by all members of a social system, that it should be diffused more rapidly, and that the innovation should be neither re-invented nor rejected" (78). From a societal perspec- tive, this bias is very dangerous if the innovation is on balance not beneficial to the consumer (i.e., undesir- able tradeoffs). Many studies have indeed explored the accidents and detrimental effects of such innovations (79,80). It is clear that any technology, including one that is innovative, should be applied only for appropri- ate uses and adapted as needed to align with quality needs. ICH Q9(R1) addresses this issue, stating: