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Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 39 It remains to be seen how AQbD will be integrated into the pharmacopoeia. Certainly, general chapters will be adapted to provide guidelines on how to properly implement AQbD for a method. Relevant chapters have been updated in the USP and Ph. Eur., in which f lexibility is allowed for an an- alytical method to be changed without the need for reval- idation if an AQbD approach has been implemented. The BP Commission is exploring an approach to allow AQbD, following their evaluation of how this could be done for a small-molecule drug product (30). The f lexibility provided by the AQbD approach can be used in drug substance and drug product monographs. A key question is whether mono- graphs will continue to contain a single method with specific operating parameters and system suitability requirements as they are today, or if they will evolve to present an ATP/ MODR that can be applicable to a particular method for the material. This will certainly be an area for bio/pharmaceu- tical companies to follow and provide comments as needed. Continuous manufacturing. Many small-molecule bio/phar- maceutical companies are moving toward a continuous man- ufacturing (CM) platform for production of drug substances and solid oral drug products. The CM platform moves the in- dustry away from the traditional batch or lot manufacturing and takes advantage of the QbD principles for manufacturing. The CM approach necessitates the use of constant monitoring of the materials as they move through the manufacturing process. As a result, "typical" release specifications are not applied in the same way as with batch testing. This change in manufacturing approach is gaining acceptance by global regulators for more products, and the impact to the pharma- copoeia may still be a few years away. The pharmacopoeias will have to evolve to understand how monographs will dif- ferentiate between release and shelf-life criteria in a quality standard that is applicable to all manufacturers using differ- ent manufacturing approaches. Currently, monographs only list one set of acceptance criteria that apply to both release and shelf-life. Although it is possible to differentiate specifi- cations in a regulatory filing, it will be a future challenge to the pharmacopoeias to accomplish this task. Pharmacopoe- ias may perhaps use the AQbD approach with an ATP for a given method or some other approach. Certainly, this will be important for all companies interested in CM to follow as the situation unfolds. It is interesting to note that USP has developed a week- long interactive training course for technical personnel in industry to gain direct insight and in-depth understanding of CM (31). As the use of CM evolves in the bio/pharma- ceutical industry, general chapters related to the CM topic, including process analytical technologies (PAT) and statis- tical design controls, will be impacted. Still, regulators and pharmacopoeias are not yet in the same place on CM topics, including requirements when changes occur to an approved CM process. This represents another area where collabora- tion between regulators, pharmacopoeia, and industry could help deliver harmonized standards. It would provide great benefit to the industry to have harmonized general chapters in the pharmacopoeias for CM, because CM helps to lower the cost of manufacturing and ultimately benefits patients. Multivariate statistical process controls. As the concepts of QbD, PAT, and real-time release testing (RTRT) were being introduced in the pharmaceutical industry, concerns were raised whether the pharmacopoeias were trying to develop standards too quickly that would impair rather than enable progress in this area. This largely did not happen. Instead, both the Ph. Eur. and USP today contain language making it clear that PAT and RTRT are acceptable as alternatives to ensure compliance with compendial requirements. The lan- guage of these chapters was crafted by the pharmacopoeias in partnership with industry and other stakeholders. The Ph. Eur. published a draft informational chapter, 5.28 Multivariate Statistical Process Controls (MSPC), to provide guidance on good practices and requirements (32). Ph. Eur. is the first pharmacopoeia to publish a general chapter on this topic, which will provide information complementing existing general chapters on chemometrics. The new Ph. Eur. chapter provides guidance on the use of MSPC being applied to CM, PAT, and RTRT (33,34). Concerns with impurities N-Nitrosamine contamination. Prompted by the discovery of two probable human carcinogens (N-nitrosamines) in drug products made by different manufacturers, EMA has man- dated that companies manufacturing sartan blood pressure medicines review their manufacturing processes to ensure N-nitrosamine impurities are not produced (17). There have been limits imposed on the maximum amount allowed for these products. Many governments have required that all drug substances be evaluated for the possible formation of nitrosamines, with screening required if they can be present in the mate- rial. Although needed to ensure patient safety, the impact to the industry is significant and could grow with additional controls being implemented by the pharmacopoeias. EDQM has begun revising Ph. Eur. monographs for the identified drug substances to add controls for N-nitrosamines and published a draft revision to the general monograph 2034 Substances for Pharmaceutical Use (35). The draft revision Many governments have required that all drug substances be evaluated for the possible formation of nitrosamines, with screening required if they can be present in the material.