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28 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 P h a r mTe c h . c o m for an innovator company before the monograph elabora- tion process has been initiated. The smaller arrows represent regulatory approvals received in various countries. Cur- rently, the regulatory submission and approval often occurs first in the United States and Europe (covering 30 countries, when following 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, although there may be differences based on decisions by the regulators for one of the applications, such as revising an impurity limit from "not more than 0.1%" to "not more than 0.10%", which tight- ens the limit based on generally accepted rounding rules for scientific data. The next submission might go to the Japanese health authority, with approval granted with some additional changes. The additional differences may be minor, such as the requirement to use six injections rather than five to es- tablish the percent relative standard deviation (%RSD) for a chromatographic procedure. The arrow 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 com- pared to the approvals in the US and Europe. The drug appli- cations continue, going next to a country designated as "Most of World #1" ("MOW #1") and continuing to "MOW #10" and "MOW #150". The arrows for these countries are intended to convey that the approved registrations in 150 or more coun- tries are generally aligned, despite some differences. 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 compliance with the product registrations approved in 150 or more countries. Also at this point, the registrations and QS follow the typical process for updates and renewals to reflect subsequent regulatory requirements and manufacturing 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 fundamen- tal direction emphasizing the global alignment and necessary compliance with approved product registrations. This figure, however, extends the product lifecycle to include the point of monograph elaboration. In the prospective harmonization pilot project referenced in a previous article (1), the United States Pharmacopeia (USP) and European Pharmacopoeia (Ph. Eur.) monographs were developed at the same time, and a harmo- nized outcome was achieved through the collaborative process. Many of the requirements in the harmonized monographs were aligned with the product registrations. However, the mono- graphs also contained some differences from the registrations that were significant enough to make compliance with the new requirements difficult. This is indicated by the small red and blue arrows in Figure 2, which are pointing in a slightly different direction than the aqua registration arrow. Among the differ- ences were significant changes to the chromatographic proce- dure used for assay and impurities, as well as tightening of im- purity controls, changing a previously specified impurity to an unspecified impurity with a new limit of 0.10%, because there was no practical way to identify that impurity peak in the chro- matogram. The impact of these changes goes well beyond the US and Europe, because regulators in many countries around the world look at the USP and Ph. Eur. monographs as quality standards that must be met for medicines in these countries. The monograph situation in the figure becomes more compli- cated as other pharmacopoeias, such as those in Japan (Japanese Pharmacopoeia [JP]) and China (Chinese Pharmacopoeia [ChP]), subsequently develop their own requirements, which may differ from the USP and Ph. Eur. monograph, if not harmonized. Ul- timately, there may be as many as 40 different pharmacopoeias that contain monographs applicable to the drug substance or product (10). The overall picture for pharmacopoeias is repre- sented by the large purple arrow, which is not fully aligned with the large aqua arrow for product registrations. At the point when the pharmacopoeia monograph has been published as official, companies must comply with the new re- quirements contained therein, in addition to complying with their approved registrations. The question is how a company can resolve differences and ensure alignment with both the monograph requirements and the registrations. The answer is that this is done through modifications to testing procedures and limits in the quality standard and/or updates to the product registrations. It must be recognized that implementing these changes can have significant impact on available resources, ei- ther performing additional testing or submitting updates to 150 or more registrations around the world. It is incorrect for a company to assume they do not need to comply with the monograph just because they have a sepa- rate regulatory approval (4). Regulatory agencies around the world expect compliance with the requirements in the phar- macopoeia, including new monographs, that are applicable in their country. This is well understood, for example, in Eu- rope and in Japan where it is known that compliance with the 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. USP is United States Pharmacopeia. Ph. Eur. is European Pharmacopoeia. MOW is Most of the World.