Issue link: https://www.e-digitaleditions.com/i/1514991
PharmTech.com Regulating Innovation, Quality, and Risk eBook January 2024 Pharmaceutical Technology ® 35 Qualit y One such report was prepared by industry leaders of the International Leadership Forum, which stated that pharmaceutical manufacturing facilities were largely built "using technologies and processes from the 1950s and 1960s." The report, published by the International Society for Pharmaceutical Engineering (ISPE), added that the facilities were often inefficient and not always capable (55). ISPE noted that the industry should shift to modern facilities and technologies, and highlighted the use of closed systems, improved automation and process control, better analytics (e.g., smart factories), and a more highly skilled workforce. It also highlighted efficiencies from these infrastructure improvements, such as "staff cost savings" via adoption of automation. These observations were consistent with those from a PDA/FDA ICH Q10 Executive Management Work- shop (56). The workshop concluded that too often the cost of poor quality is either never measured or it is not well understood by leadership. Workshop attendees also noted that allocating resources only to "react" is not sufficient, and that leaders need to dedicate time for staff to focus on the "PA" in CAPA (Corrective Ac- tion and Preventive Action). It also emphasized that some companies have made major strides toward a quality-focused culture, including establishing de- partments dedicated to quality improvement using techniques such as Six Sigma or human error reduc- tion. At these companies, dedicated staff focus on the operational or systemic failure modes in the company that need improvements, and Subject Matter Experts (SME) are allotted time to help do the job right. These evolutions in quality system governance will be essen- tial in an overall industry shift toward more robust manufacturing performance. The Parenteral Drug Association (PDA) also con- vened a Task Force on Aging Facilities and published a survey in 2015 and an Aging Facilities Points to Con- sider (PTC) report in 2017 (57,58). The report discussed the problem of older facilities, associated mainte- nance challenges, unit operation breakdowns, sup- ply issues, low yields, and quality issues. Equipment age, extensive human interactions with machinery, outdated analytics, excessive process drift, and the scarcity of spare parts were among the many liabil- ities of these facilities. This report highlighted the importance of using risk management approaches to not only identify aging facility hazards, but also quantify and categorize them in an analytical man- ner that helps determine the best path forward. Using this approach, the threat to achieving company goals becomes real rather than hypothetical. The report indicates that product quality and sup- ply eventually suffer unless aging facilities are up- graded to contemporary technologies. The PTC report further emphasizes that demonstrating the ROI to be accrued from modernizing a factory is "critical." ISPE has also done extensive analyses on ensuring availability of good quality medicines and highlights the specific adverse inf luence of deficient equipment and facilities. Their published sur veys and expert analysis outlines in detail the manufacturing fac- tors that lead to excessive variability, adverse qual- ity impacts, supply shortfalls, and other substantial inefficiencies (59). A core reason for lower capability operations is that the industry too often relies on manually-intensive or semi-automated production processes (60). An industry partnership known as the BioPhorum Op- erations Group has researched how to improve op- erational performance, and noted the excessive reli- ance on manual steps during many manufacturing operations. BioPhorum (61,62) states a key driver for forming their industry organization was to improve pharmaceutical manufacturing, adding they "recog- nized our common 'human error problem' and began efforts to address this critical issue." Notably, while pricing differences between generic and innovator companies are not addressed in this paper, the efficiencies associated with replacing oper- ations prone to human error with highly automated op- erations should be attractive to both industry segments. Evolution of regulatory landscape Regulators have also noted concerns with antiquated technologies and systems. In 2002, FDA launched an initiative known as Pharmaceutical Quality for the 21st Century (63), to encourage improved manufac- turing and quality. This initiative was aided by the publication of international consensus standards, including but not limited to the ICH Q8, Q9, and Q10 guidelines, which establish a jointly agreed regulato- ry-industry implementation framework for better de- sign, quality risk management, and quality systems. Implementation of these and other modernizations has been gradual. While notable improvements have been made by some companies or for certain prod- ucts, the progress is uneven and major performance gaps and implementation heterogeneity remain. Harmonization of change management (64, 65) has been considered a challenge for some drug ap- plication sponsors in implementing major changes. To address this issue, an internationally harmonized guideline (ICH Q12) (66) was recently published that established a consensus standard endorsed by in- dustry and regulators. The guideline builds on the change management principles in the ICH Q10 guid- ance to define mechanisms for continual improve- ment, including harmonized approaches to report- ing changes and related submission standards. The prior SUPAC (Scale-up and Post-Approval Changes) guidance documents also created a clear framework to facilitate process changes (67).