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32 BioPharm International eBook September 2019 www.biopharminternational.com Regulatory Sourcebook Pharmacopoeia Compliance Series because it is difficult to change e x i s t i n g s t a nd a r d s , m a k i n g a manufacturer's compliance to all pharmacopoeias a truly daunting task. It is hoped that the pharma- copoeias around the world, with the support of the industry, con- tinue their harmonization efforts to reduce or eliminate differences b et we e n t he i r publ ishe d st a n- dards, to the benefit of the global patient population. Updated and new requirements Another challenge is the signifi- cant volume of new and revised compendial requirements, includ- i n g b o t h p r o p o s e d a n d o f f i - cial changes, that are published by pha r macopoeias a round t he world . I nde e d, t he nu mb e r of indiv idual compendial changes to monographs and general chap- ters can be staggering. In 2016, there were more than 3000 new or revised monographs and gen- eral chapters published in USP– N F, P h . E u r. , a n d B P a l o n e , requiring review by bio/pharma- ceutical manufacturers for poten- tial impact. T he follow ing year saw a 20% increase in the num- b e r of i nd iv idu a l c omp e nd i a l changes that were published by the pharmacopoeias. These indi- vidual changes needed to be fil- tered so a company could further evaluate only those that were per- tinent to them. E xper ience has shown that it is typical to identify as many as 500 new and revised items per year that require f ur- ther assessment by internal sub- je c t m at te r e x p e r t s (S M E s) to deter mine whether the specif ic c o m p e n d i a l u p d a t e r e q u i r e s action by the company, includ- ing change control to quality doc- uments and procedures, as well a s p ote nt i a l up d ate s to pr o d - uc t reg ist rat ions. Some compa- nies have indicated the number of changes with potential impact to them is even higher, and the necessary change control and reg- ulator y updates are both costly and time-consuming. Physical reference standards T he mono g r aph s a nd ge ne r a l chapters published as documen- tary standards in the pharmaco- poeias often include requirements to use physica l reference sta n- dards to perform certain test pro- cedu res. Pha r macopoeias ma ke these reference standards avail- able for pu rc ha se a nd ca l l for their use in the testing for excipi- ents, drug substances, and drug products, impacting makers and users of t hese mater ia ls. T here are also reference standards that may be required in compendial tests for specific impurities. The use of reference standards may be included in the tests for biologi- cal products, which raises poten- t ia l issues due to t he comple x nature of these products. In all these cases, the appropriate use of compendial reference standards for pharmacopoeial testing repre- sents another challenge to com- pliance throughout a produc t 's lifecycle. Companies must decide whether reference standards will be maintained by a central group or at many individual manufac- t uring and testing sites around the world. The material used by the pharmacopoeias to establish these compendial reference stan- dards may have been provided by an innovator or generic-drug com- pany, which may enter into com- pliance considerations. The USP, Ph. Eur., BP, JP, and other phar- macopoeias may each offer their own separate reference standard, with different assay or purity val- ues assigned, which are to be used for testing according to their own monographs and general chapters, further increasing the complexity of compliance with the multiple pharmacopoeias. Consideration must be given by a company as to how they w ill manage the expectations around these compendial reference stan- dards, including whether and how to qualify any "in-house" primary or secondary reference standards against the off icial compendial r e fe r e nc e st a nd a rd s to e n s u r e compliance w ith the applicable testing procedures in the pharma- copoeias. The regulatory expecta- tions regarding reference standard qualif ication was included in a presentation in 2011 (4), which pointed to the Compliance Program Guidance Manual for US FDA Staff– Dr ug Manufact ur ing Inspect ions, 7356.002. Consideration must be given by a company as to how they will manage the expectations around these compendial reference standards. The following is noted in this ma nu a l, Pa r t I I I – I n sp e c t iona l, S e c t i o n C – S y s t e m I n s p e c t i o n C ove r age, L a b or ator y C ont r ol System: "For each of the follow- ing, the firm should have w rit- ten and approved procedures and doc umentation resulting there- f r o m … r e f e r e n c e s t a n d a r d s ; s ou rc e, p u r it y a nd a s s ay, a nd tests to establish equivalency to c u r rent of f ic ia l reference sta n- d a rd s a s appropr iate" (5). T he same 2011 presentation provided an example of the enforcement