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34 BioPharm International eBook March 2020 www.biopharminternational.com Regulatory Sourcebook Pharmacopoeia Compliance Series This created a compliance issue in the interim, with the adoption of the monograph approved in some impacted countries, but not yet in others. How can a company com- ply with both the monograph and existing registrations during this transitional period? One option is to perform testing using both meth- ods until all approvals are received, with obvious impact on the labora- tory. Another option is to continue to use the currently approved meth- ods until a fixed implementation date or until approvals are received in key markets, then switching over to the monograph methods, while still waiting for approval in the remaining markets. This approach carries some risk in ensuring com- pliance with both methods, but relieves the laboratory from having to perform duplicate testing in the interim. The compliance risk can be mitigated by the documented equiv- alency between the two methods, mentioned earlier. Another compli- ance risk can emerge if the regulators in one country reject the updated registration, forcing the company to continue duplicate testing to ensure global compliance and release of the product to all countries. Given the range and nuance of compliance challenges associated with the "replace" option, it is clearly important that all impacted stakeholders across the company, i nc lud i n g a n a ly t ic a l, qu a l it y, and regulatory, work together to develop and align on the strategy and then execute the implementa- tion plan for adopting the mono- graph, while ensuring compliance w it h produc t reg ist rat ions. A s noted previously, despite the chal- lenges, one benefit of the "replace" option is that the company can remove many of the details of the analytical methods from the reg- istration to refer instead to com- pliance with the monograph. This simplifies the information detailed in the registration and enables the company to more easily imple- ment subsequent revisions to the monograph, which ensures ongo- i ng compl ia nce w it h "c u r re nt pharmacopoeia requirements", as expected by regulatory agencies around the world (3). Keep The other option, with a signifi- cantly different method in the monog r aph c omp a r e d to t he approved registration, is to "keep" the currently approved method instead of switching to the mono- graph method. There may be a strong preference for a company to continue using an analytical pro- cedure that has been used for many years to ensure the quality and stability of the drug substance and product. Again, the equiva- lency of the approved method and the monograph method must be demonstrated. The General Notices in most pharmacopoeias allow the use of alternative methods that are equivalent or better than those in the monograph. Because of this, for most countries, there would be no need to update the product registra- tion if the decision has been made to keep using the currently approved method instead of the monograph method. The demonstration of equivalency would be shown upon facility inspection, if requested, as evidence of compliance with the monograph requirements. However, if the new or signifi- cantly different method is listed specif ically in a monog raph of the Ph. Eur., then submission of a variation is required in European cou nt r ies t hat a re member s of the EMA or signatories to the Ph. Eur. Convention. The reason for this is the specific lang uage in the Ph. Eur. General Notices (11) that states an alternative method may be used instead of one in the Ph. Eur., provided the alter- native method ensures compli- a nce w it h t he monog raph a nd the use of the alternative method has gained the "agreement of the competent authorit y," meaning approval by the European regu- lator y agencies. In the authors' experience, no other pharmaco- poeia or regulatory agencies man- date t h is pr ior-approva l before t he a lter nat ive met hod ca n be used to replace a method in the pha r macopoeia. I n t he case of the publication of a new Ph. Eur. monograph, where a monograph did not previously exist, this reg- ulatory approval for a company to continue using the previously a p p r o v e d m e t h o d i n E u r o p e rather than a method in the new Ph. Eur. monograph is necessary, even t hough t he compa ny had There are compliance challenges that are internally-based, resulting from decisions made by one functional area in the company without consideration of the broader impact to other functional areas throughout the organization. The authors present one such example with raw materials and excipients, where a consistent, cross-functional approach is needed to ensure the appropriate selection, sourcing, testing, and filing of the materials used to manufacture bio/pharmaceutical products in a global environment, ensuring compliance with applicable compendial and regulatory requirements. This case study is based on the experience of one of the authors but is applicable to all companies across the broader industry, illustrating the potentially surprising point that some compliance difficulties may be of the company's own making. Read the full case study at BioPharmInternational.com A Case Study in Pharmacopoeia Compliance: Excipients and Raw Materials