Issue link: https://www.e-digitaleditions.com/i/1171020
Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2019 41 cal reference standards to perform certain test procedures. Pharmacopoeias make these reference standards avail- able for purchase and call for their use in the testing for excipients, drug substances, and drug products, impacting makers and users of these materials. There are also refer- ence standards that may be required in compendial tests for specific impurities. The use of reference standards may be included in the tests for biological products, which raises potential issues due to the complex nature of these products. In all these cases, the appropriate use of com- pendial reference standards for pharmacopoeial testing represents another challenge to compliance throughout a product's lifecycle. Companies must decide whether refer- ence standards will be maintained by a central group or at many individual manufacturing and testing sites around the world. The material used by the pharmacopoeias to establish these compendial reference standards may have been provided by an innovator or generic-drug company, which may enter into compliance considerations. The USP, Ph. Eur., BP, JP, and other pharmacopoeias may each offer their own separate reference standard, with different assay or purity values 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 will manage the expectations around these compendial reference standards, including whether and how to qualify any "in-house" primary or secondary reference standards against the official compendial reference standards to en- sure compliance with the applicable testing procedures in the pharmacopoeias. The regulatory expectations regarding reference standard qualification was included in a presenta- tion in 2011 (4), which pointed to the Compliance Program Guidance Manual for US FDA Staff–Drug Manufacturing Inspections, 7356.002. The following is noted in this manual, Part III–Inspectional, Section C–System Inspection Cover- age, Laboratory Control System: "For each of the following, the firm should have written and approved procedures and documentation resulting therefrom … reference standards; source, purity and assay, and tests to establish equivalency to current official reference standards as appropriate" (5). The same 2011 presentation provided an example of the enforcement of this requirement, listing an FDA 483 ob- servation given to a firm because they did not compare or qualify their working standard against the official USP reference standard. Internal stakeholders. In addition to the challenges de- scribed previously, which are largely driven by external fac- tors, there are several internal challenges that make phar- macopoeia compliance difficult to establish and maintain. There may be a lack of understanding within a bio/phar- maceutical company regarding the need for, the complex- ity of, and the challenges to compendial compliance, which may result in insufficient focus and resources allocated to this critical work. Even if there is understanding, there is often insufficient value attached to the work needed to achieve compendial compliance, resulting in potential de- prioritization of compendial activities when challenged with competing priorities. The need for and value of effective compendial processes to ensure compliance should now be clear, as should be the need to have appropriate tools for tracking and communicating new and revised pharmaco- poeia requirements for impact assessment. Establishing collaborative partnerships with internal stakeholders, who are essential in the compendial review process can be difficult. Establishing collaborative partnerships with internal stakeholders, who are essential in the compendial review process can be difficult, especially in large companies with a multitude of functional areas and manufacturing sites that may be impacted by compendial revisions. Maintain- ing these partnerships is complicated by potential transi- tion and turnover of personnel involved in the work. There may be a lack of awareness of or disregard for the pharma- copoeia requirements and discrepancies may emerge from the absence of a C-LOS perspective during product and an- alytical development. There is often a lack of understanding by internal stakeholders as to their role in the assessment of compendial revisions, and many may have the perspective of "not my job" when asked to provide input to the impact of compendial changes. Taken together, compliance with the pharmacopoeias is usually not well understood in a company, so it can be difficult gaining buy in from SMEs and their managers to perform impact assessments. Deadlines for commenting on proposals and implementing changes that are becom- ing official are often not well understood. The requests for review, assessment, and implementation of compendial re- quirements may not receive the proper priority or urgency needed to ensure compliance. It is not uncommon to hear stakeholders remark: • "Why do we need to comply? We are the innovator company." • "Why do we need to comply? We have our approved registration." • "It's not my job. Check with another department to ensure we comply." • "Are you serious? This applies to stability testing also?" • "I am in R&D. Why is this applicable to me?" • "Is this really necessary?"