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50 Pharmaceutical Technology Regulatory Sourcebook October 2020 P h a r mTe c h . c o m Regulatory Guidance Council for Harmonization's (ICH's) Q9 (7), PDA Technical Report 54 (8), and practices such as fishbone diagram analysis, says Dana. Smalley agrees. "Regulators advanced the concept of risk assessment almost 20 years ago and it has taken a long time for companies to embrace it, but some great pharma training is now centered around risk. Genentech and Amgen are leaders in quality risk management, and use of the methods behind this concept is growing in the more traditional pharma companies," he says, suggesting that compounders should also adopt these practices. Better root-cause analysis needed Dana also sees a need for compounders (along with their counterparts in drug manufacturing) to im- prove root-cause investigations into quality-related problems and to the implementation of corrective action and preventive action (CAPA) programs. A good approach would require a cross-functional team staffed by representatives from operations, quality, engineering, and the regulatory side, each of whom could bring to bear his or her individual skills and expertise to understand what happened. Companies often focus with laser-like accuracy on specific events when they occur yet miss looking at the big picture, he says, thus, they "correct a problem, only to find the same problem crop up with a differ- ent operation or piece of equipment because the root cause was never identified the first time." One of the simplest and most effective root-cause analysis tools is the "five whys" approach. "Just keep asking questions until there are no more whys," Dana says, noting that compounders also need to take a closer look at batch failures to learn how to prevent them in the future. Internal audits and mock inspections should also be routine, he says. Another potential issue is analytical testing. Cur- rently, at large compounders, only finished product testing is mandated, not raw material and intermedi- ates testing, says Smalley. Beyond PowerPoints: training in CGMPS needed In the end, training promises to be the key to improving pharmaceutical compounding, but change is needed, Dana and Smalley note. Phar- macists are legally required to take continuing education courses in order to maintain their li- censes, but many of the courses that they tend to choose focus on the R&D pipeline, side effects, or business and legal issues and updates, rather than compounding and the manufacturing and quality challenges that it entails. Dana's course for PDA was developed to help address this need. As he explains, compounded products have not been subject to review and approval by the FDA, and the pharmacists mak- ing them may or may not be familiar with all the appropriate FDA requirements to ensure the products are safe and effective, and why these requirements exist. "Gaining an understanding of FDA operations … will help ensure a better understanding of the regulations (i.e., what they require and why, and how to conduct compound- ing operations in a way to ensure compliance with those regulations). This is not only important to the industry, but to the patients who take com- pounded drugs," he says. In the end, training promises to be the key to improving pharmaceutical compounding, but change is needed.