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www.biopharminternational.com September 2019 BioPharm International eBook 31 Regulatory Sourcebook Pharmacopoeia Compliance Series Given this end-to-end perspec- tive, a company must ensure suf- ficient resources are available and organized within an appropriate functional area to enable and facil- itate the specific work that must be performed by the individuals assigned to carry out these tasks. Cross-f unctional and cross-divi- siona l pro cesses, pa r t ne r sh ips, tools, a nd t ra i n i ng a re needed to enable effective execution of the activities that ensure ongoing compendial compliance. CHALLENGES TO PHARMACOPOEIA COMPLIANCE The challenges that make phar- macopoeia compliance diff ic ult ( Table I) ca n b est b e e xa m i ned t hrough t he end-to - end f ra me- work detailed previously to help address the impact of the phar- macopoeias. The standards pub- lished by pharmacopoeias affect the entire lifecycle of a product, and compendial compliance must be addressed from early develop- ment to late-phase clinical trials, continuing to commercial launch and beyond. There are differing regulatory expectations and pro- cesses around the world, which contr ibute to the challenges of pharmacopoeia compliance. Once a drug product is licensed, a man- ufacturer must comply with their approved reg ist rat ion and w it h applicable monographs and asso- c iate d ge ne ra l c hapte r s, a long with other applicable content in the pharmacopoeias. Compliance can be difficult if there are differ- ences between the country-specific registrations 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. Additionally, as stated i n t he pha r macopoe - i a s , c omp e nd i a l r e qu i r e me nt s apply t hroughout shelf life for drug products and their ingredi- ents, and these requirements must be incorporated in the company's stabilit y prog ram. 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 production to expira- tion." The BP General Notices, Part II state (3): "A formulated prepa- ration must comply throughout its assigned shelf-life (period of validity). The subject of any other monograph must comply through- out its period of use." Bio/phar- maceut ica l d r ug ma nu fac t u rers and distributors, including innova- tor, 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. Another challenge is the significant volume of new and revised compendial requirements that are published by pharmacopoeias around the world. Pharmacopoeias and harmonization One significant factor that makes compl ia nce c ha l le ng i ng is t he multiple pharmacopoeias around the world and the lack of broad ha r mon i z at ion of t he re qu i re - ments and standards they each contain. There has been consider- able effort by the Pharmacopoeial Discussion Group (PDG)—which includes representation from the USP–NF, Ph. Eur., and the Japanese Pharmacopoeia ( JP) —and f urther suppor ted by t he Inter nat iona l Council for Harmonization (ICH) Q4B process to harmonize com- pendial requirements across these pharmacopoeias. This effort has y ie ld e d s e ve r a l ge ne r a l c h ap - ters a nd exc ipient monog raphs that contain essentially the same requirements. However, this out- put represents only a small frac- tion of the entire pharmacopoeia content and the harmonized stan- dards have not been incorporated broad ly ac ross t he ma ny ot her pha r macop o e ia s i n t he world . A lso, t h is ha r mon i zat ion work does not include monographs for d r ug subst a nces a nd produc t s, which are out of scope of both the PDG and ICH Q4B processes, so the pharmacopoeia requirements for the same mater ial can var y greatly. There have been success- ful efforts to develop prospectively harmonized monographs for drug substances and products 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, sev- eral important national pharma- copoeias were not included in the harmonization processes, which has created differences in the offi- cial general chapters and mono- graph requirements for excipients, drug substances, and drug prod- ucts in the respective pharmaco- poeial publications. This situation potentially hinders future harmo- nization efforts for these materials,