Issue link: http://www.e-digitaleditions.com/i/1222740
Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 27 procedure used to control impurities in a drug substance, a specified impurity may be identified by a relative retention time (RRT) in the chromatogram, based on standardization of the column and equipment used across the company. The use of RRT to identify the specified impurity becomes prob- lematic when the method is incorporated into the mono- graph, since equipment and column standardization are no longer guaranteed. Any analyst who has run a chromato- graphic procedure recognizes the differences that may be observed, for example, when using different C-18 columns, as allowed in monograph methods. To address this challenge in identifying a specified impurity, the pharmacopoeias often require that a reference standard be available that enables unequivocal confirmation that an ob- served peak corresponds to the specified impurity. In many instances, the company that developed the chromatographic procedure does not have a sample of the specified impurity to provide to the pharmacopoeia to establish the reference stan- dard. Also, the company may not have a "dirty batch" of the drug substance that would include the specified impurity and enable identification for the corresponding chromatographic peak. In this situation, taking into account the current pro- cess-capability and stability data, the pharmacopoeia may determine that the specified impurity must instead become an unspecified impurity, potentially resulting in a significant tightening of the limit compared to the approved registration. A related challenge that applies to the drug product is determining whether an impurity peak observed in the chromatogram for the product corresponds to a degradation product or is instead, a process impurity from the drug substance. This issue makes it difficult for the monograph to reflect the principle in ICH Q3B that only degradation products need to be controlled in the drug product, and not drug substance process impurities. Another significant difference and compliance challenge can result if the company has developed two different methods for assay and impurities in the drug product, or different methods for different product formulations or strengths, whereas the pharmacopoeia determines that a single method may be used for impurities and assay across the entire product line. Other differences may emerge in the monograph, which seem to be less impactful than that experienced with impu- rities. However, the steps necessary for a company to address these differences in their quality documents and regulatory filings can still pose significant challenges. An example is the addition of a new identity test in the monograph, such as infrared (IR), to complement a chromatographic identity test for the drug substance to ensure that all stakeholders who use the monograph can demonstrate unequivocal identification of the active ingredient. Another example is the widening of an assay limit for the drug substance to ref lect appropriate analytical variability. Other examples include modifications to the chromatographic procedure, perhaps adding an iso- cratic hold at the start of the run to address dwell volume, which will also impact peak retention times, or the addition of new requirements to ensure acceptable system suitability for the method, such as peak resolution. As will be shown later, these changes range from minor to major impact when exploring the options of how to resolve the differences and ensure compliance with the monograph and the registration. The differences will likely impact quality documents and test- ing performed in the laboratory, with duplicate testing of the same quality attribute as the worst-case outcome to comply with the registration and the monograph. Depending on the company's compliance strategy, the differences may also im- pact product registrations, requiring updates or variations in countries around the world. Some requirements in the monograph may be very difficult to meet (e.g., tighter impurity limits). If the monograph has already been published as official, another possible approach to resolve differences is communication with the pharmaco- poeia to request revision of the monograph to better align with the registration. However, the pharmacopoeia revision process can be slow and is not always successful in achieving the requested changes. The probability of successful revision is also reduced if the company did not provide comments and concerns to the pharmacopoeia when the monograph was first proposed. This points, once again, to the benefit of proactive surveillance of pharmacopoeia updates with an ap- propriate response at the proposal stage (9). Not only does this provide the company an opportunity to possibly influence the requirements before the monograph becomes official, but it also enables internal discussion to plan for implementation of the requirements in the new monograph, when it does be- come official. Aligning registrations and monographs This situation, emphasizing the challenge of resolving differ- ences between a new monograph in the pharmacopoeia for a drug substance or product and the information included in product registrations approved by regulatory agencies around the world can best be understood through an illustration that follows the product lifecycle. Figure 1 represents the situation • Before Monograph Elaboration • Quality Standard (QS) reflects global product registrations (methods, limits) • ≥ 150 country-specific registrations US EU (~30) Japan China MOW #10 MOW #1 MOW #150 Registrations / QS (Updates / Renewals / Change Control) Product Life-Cycle Figure 1. Aligning product registration requirements. MOW is most of the world. ALL FIGURES COURTESY OF THE AUTHOR.