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30 BioPharm International eBook March 2020 www.biopharminternational.com graph becomes official, but it also enables internal discussion to plan for implementation of the require- ments in t he new monog raph, when it does become official. ALIGNING REGISTRATIONS AND MONOGRAPHS This situation, emphasizing the c h a l le nge of r e s olv i ng d i f fe r- e nc e s b e t w e e n a ne w mo no - graph in the pharmacopoeia for a drug substance or product and the information included in prod- uc t r eg i st r at ion s approve d by reg ulator y agencies around the world ca n b est b e u nder stood through an illustration that fol- lows the product lifecycle. Figure 1 represents the situation for an in novator compa ny before t he m o n o g r a p h e l a b o r a t i o n p r o - c e s s h a s b e e n i n it i at e d . T h e smaller arrows represent regula- tory approvals received in vari- ou s c ou nt r ie s . C u r r e nt ly, t he r e g u l a t o r y s u b m i s s i o n a n d approval often occurs first in the United States and Europe (cover- ing 30 countr ies, when follow- ing the "centralized procedure" of assessment by the European Medicines Agency [EMA]). At this point in the product lifecycle, the approved registrations in the US and Europe are generally aligned, a lt hough t here may b e d i f fer- ences based on decisions by the regulators for one of the applica- tions, such as revising an impu- rit y limit from "not more than 0.1%" to "not more than 0.10%", which tightens the limit based on ge ne r a l ly ac c e pte d rou nd - ing rules for scientific data. The next submission might go to the Japanese health authorit y, with approval granted with some addi- tional changes. The additional dif- ferences may be minor, such as the requirement to use six injec- tions rather than five to estab - lish the percent relative standard deviation (%RSD) for a chromato- g raph ic pro ce du re. T he a r row for Japan in Figure 1 is intended to show that some divergence is starting to emerge in the approved registrations. The next approval might come in China, again with the possibility of some differences compared to the approvals in the US and Europe. The drug appli- cations continue, going next to a count r y desig nated as "Most of World #1" ("MOW #1") a nd continuing to "MOW #10" and "MOW #150". The arrows for these countries are intended to convey that the approved registrations in 150 or more countries are gener- ally aligned, despite some differ- ences. This is represented overall by the larger arrow, indicating at this point that the methods and limits in the quality standard (QS) may be used by the company to test the product and ensure com- pliance w ith the product regis- trations approved in 150 or more countries. Also at this point, the registrations and QS follow the t y pical process for updates and renewals to reflect subsequent reg- ulatory requirements and manu- facturing or analytical changes for the material. The large aqua arrow in Figure 2 summarizes the situation for the US, Europe, and MOW #150 countries, with the fundamental direction emphasizing the global alignment and necessary compli- ance with approved product reg- istrations. This figure, however, extends the product lifecycle to include the point of monograph elaboration. In the prospective harmonization pilot project ref- erenced in a previous article (1), t he United States Phar macopeia (USP) and European Pharmacopoeia (Ph. Eur.) monographs were devel- oped at the same time, and a har- monized outcome was achieved through the collaborative process. Many of the requirements in the ha r mon i zed monog raphs were aligned with the product registra- tions. However, the monographs also contained some differences from the registrations that were sig- Regulatory Sourcebook Pharmacopoeia Compliance Series ! B#0"%&$'$(%)*+,-.)/$%)01$',C,D##191). ! E+).."'("F,,G":$.H",61##"%"'9":,/"0I""', ;$'$(%)*+,)'6,=,>?@,(.$/).,%"(1:0%)01$': ! =,J@,:*"91#19,*+)%;)9$*$"1): !" #!$%&'() 123$456( !"$%!"7) #!$%7/8$#9:8) 123$%!"7) 123$%7/8$#9:8) *+,+-$%*7) ./0-+$%./7) !"#$%&'(&$)*% !"#$%&'()*+,-./&0, /)012$(*3"+451"3&(&$)*% !"#$%&'(&$)*% !"#$%&'(&$)*%+!"#6)*)#'(17% /)012$(*3"+451"3&(&$)*% !"#$%&'(&$)*% !"#$%&'(&$)*%+!"#6)*)#'(17% 6)*)#'(17% Figure 2. Trying to align product registrations and monograph requirements.