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www.biopharminternational.com September 2019 BioPharm International eBook 11 Regulatory Sourcebook Good Manufacturing Practices FDA's Center for Drug Evaluation and Research (CDER). Unlike vol- untary guidances and best prac- tices, cGMPs are the law and must be followed by drug manufactur- ers. Recently, FDA has extended cGMPs into dietary supplements and compounding. UPDATES VIA GUIDANCE FDA last formally revised phar- maceutical cGMPs in 1977; since that time, the agency has pub- lished new guidance documents meant to improve manufacturers' approaches to risk assessment and process understanding and control, with the 21st Century cGMPs (5) and process analytical technolo- gies (6) guidances in 2004, and the revised process validation guidance (7) in 2011. T he i ndust r y has u ndergone radical changes, however, since 1977. I n s te a d of fo c u s i n g on large-volume "blockbuster" drug markets, pharmaceutical manufac- turers now juggle larger product portfolios with smaller, globally diverse markets. In addition, they source most APIs from India and China, and outsource more strate- gic operations to contract research organizations (CROs) and contract development and manufacturing organizations (CDMOs). At the same time, the indus- try has become far more complex with the growth of biopharma- ceuticals, the shift from branded to generic pharmaceuticals, and t h e m ov e t o b io s i m i l a r s a n d persona li zed med ic ine. "W hen cGMP came into effect, pharma companies were vertically inte- grated," says Hedley Rees, man- aging consultant of PharmaFlow L t d . , b a s e d i n t h e U n i t e d Kingdom. "Quality systems were under the ownership of the com- pa n ie s de ve lopi ng a nd m a nu - fac t u r ing t he produc ts, w it h a shared set of standard operating procedures and business objec- tives. The people working in the pharma companies all had skin in the game; they shared the pain and the rewards in the journey to regulatory approval," he adds. The past four decades have seen supply chain complexity increase by an order of magnitude, Rees says. KEEPING UP WITH CHANGE Should cGMPs be rev isited and updated, given the fundamental cha nges t hat have ta ken place w ithin the industr y since they were published? Opinion on the subject is divided. At this point, FDA has no plans for any major r e v i s io n s o f U S c G M P s . " We intend to continue modernizing or clarif y ing the reg ulations as needed to harmonize them with other FDA regulations and inter- nat iona l c GM P sta nda rds, a nd to use guidance for industry as a primary way of developing and explaining our recommendations for comply ing w ith the stat ute and regulations," says FDA's OPQ Director Kopcha. H o w e v e r, s o m e w it h i n t h e industry believe that cGMPs need an overhaul. "The current CGMP reg ulations clearly need updat- ing to reflect the current state of complex it y in pha r maceut ica ls materials, processes, products, and supply chain," says Ajaz Hussain, consultant, head of the National I n s t i t u t e o f P h a r m a c e u t i c a l Te c h n o l o g y a n d E d u c a t i o n ( N IP T E), a nd for merly head of FDA's Off ice of Phar maceutical Sciences at CDER. "FDA's periodic updates have been a bit like patches on software or add-ons to an existing building. It may take years, but cGMPs need to be modernized," says consultant Emil Ciurczak, an early adopter of process analytical technology (PAT) and president of DoraMax Consultants. The task would be herculean, notes Hussain. "We have done all that we can to avoid having to do the update, with guidelines and guidances. That has been the entire basis of the 21st century ini- tiative," he says. O ne c ha l lenge is t hat F DA's guidance documents, whether on PAT or process validation, only present suggestions and compa- nies can—and often do —bypass them, as long as they meet legal pro duc t qu a l it y re qu i re me nt s. Some observers ask whether some suggested practices might need to become required ones if the indus- try is to develop a more scientific approach to manufacturing and quality control. Industry observers pinpoint the need for more cGMP clarity in: • T r a i n i n g a n d e m p l o y e e ' s personal development • Statistics and sampling • Process validation. ORGANIZATION AND PERSONNEL Hussain believes that US 21 CFR 211 Part 11 Subpart B, which cov- ers requirements for organization and personnel, should be a high priority target for cGMP clarifi- cation and updates. He points to recent FDA warning letters that refer to CFR 211, specifying defi- c ie nc ie s i n pro duc t ion re cord review, batch record and mainte- nance data practices, training, and investigation of batch failures or other discrepancies. Even though regulators may not explicitly refer to Subpart B in their citations, Hussain suggests, com- panies' failure to follow its require- ments is often the root cause of