Issue link: https://www.e-digitaleditions.com/i/1171020
Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 39 the pharmacopoeias. The standards published by pharma- copoeias affect the entire lifecycle of a product, and com- pendial compliance must be addressed from early develop- ment to late-phase clinical trials, continuing to commercial launch and beyond. There are differing regulatory expecta- tions and processes around the world, which contribute to the challenges of pharmacopoeia compliance. Once a drug product is licensed, a manufacturer must comply with their approved registration and with applicable monographs and associated general chapters, along with other applicable con- tent in the pharmacopoeias. Compliance can be difficult if there are differences between the country-specific registra- tions and the applicable pharmacopoeias, in terms of the acceptance criteria or analytical approaches used to evaluate the material or product. Typically, a company must comply with the tightest limits, whether listed in the pharmacopoeia or included in the product registration, to ensure compliance globally. Typically, a company must comply with the tightest limits, whether listed in the pharmacopoeia or included in the prod- uct registration, to ensure compliance globally. Additionally, as stated in the pharmacopoeias, compendial requirements apply throughout shelf life for drug products and their in- gredients, and these requirements must be incorporated in the company's stability program. For example, the USP General Notices, Section 3.10 states (2): "The standards in the relevant monograph, general chapter(s), and General Notices apply at all times in the life of the article from pro- duction to expiration." The BP General Notices, Part II state (3): "A formulated preparation must comply throughout its assigned shelf-life (period of validity). The subject of any other monograph must comply throughout its period of use." Bio/pharmaceutical drug manufacturers and distributors, including innovator, generic, virtual, contract, and start-up companies need a strategy and a process to determine and document how they will ensure compliance with regulatory and pharmacopoeia requirements. Pharmacopoeias and harmonization. One significant factor that makes compliance challenging is the multiple pharmacopoe- ias around the world and the lack of broad harmonization of the requirements and standards they each contain. There has been considerable effort by the Pharmacopoeial Discus- sion Group (PDG)—which includes representation from the USP–NF, Ph. Eur., and the Japanese Pharmacopoeia (JP)—and further supported by the International Council for Harmoni- zation (ICH) Q4B process to harmonize compendial require- ments across these pharmacopoeias. This effort has yielded several general chapters and excipient monographs that con- tain essentially the same requirements. However, this output represents only a small fraction of the entire pharmacopoeia content and the harmonized standards have not been incor- porated broadly across the many other pharmacopoeias in the world. Also, this harmonization work does not include monographs for drug substances and products, which are out of scope of both the PDG and ICH Q4B processes, so the pharmacopoeia requirements for the same material can vary greatly. There have been successful efforts to develop prospec- tively harmonized monographs for drug substances and prod- ucts between the pharmacopoeias (e.g., USP, Ph. Eur., and BP), but results of this interaction are limited, and the true impact and value remain to be fully realized. Additionally, several important national pharmacopoeias were not included in the harmonization processes, which has created differences in the official general chapters and monograph requirements for excipients, drug substances, and drug products in the re- spective pharmacopoeial publications. This situation poten- tially hinders future harmonization efforts for these materials, because it is difficult to change existing standards, making a manufacturer's compliance to all pharmacopoeias a truly daunting task. It is hoped that the pharmacopoeias around the world, with the support of the industry, continue their harmonization efforts to reduce or eliminate differences be- tween their published standards, to the benefit of the global patient population. Updated and new requirements. Another challenge is the significant volume of new and revised compendial require- ments, including both proposed and official changes, that are published by pharmacopoeias around the world. Indeed, the number of individual compendial changes to monographs and general chapters can be staggering. In 2016, there were more than 3000 new or revised monographs and general chapters published in USP–NF, Ph. Eur., and BP alone, requir- ing review by bio/pharmaceutical manufacturers for potential impact. The following year saw a 20% increase in the num- ber of individual compendial changes that were published by the pharmacopoeias. These individual changes needed to be filtered so a company could further evaluate only those that were pertinent to them. Experience has shown that it is typical to identify as many as 500 new and revised items per year that require further assessment by internal subject matter experts (SMEs) to determine whether the specific compendial update requires action by the company, including change control to quality documents and procedures, as well as potential up- dates to product registrations. Some companies have indi- cated the number of changes with potential impact to them is even higher, and the necessary change control and regulatory updates are both costly and time-consuming. Physical reference standards. The monographs and gen- eral chapters published as documentary standards in the pharmacopoeias often include requirements to use physi-