Registered Starting Materials (RSM) of API manufacturing are chemical entities that are registered in the Drug Master File (DMF) as the starting point for the GMP compliant part of the process. The DMF is registered in the EDQM (in case of CEP application) or in the Marketing Authorization application to Health Authorities of the drug product where the API is formulated. This is the reason for calling them “registered” starting materials.
The synthesis steps prior to the RSM need not be GMP compliant; however, it is necessary to guarantee that the RSM will not be a source of uncontrolled impurities that could dramatically affect the safety of the API to be used in a drug product.
The following scheme shows the model of synthesis where Steps 1–4 involve the formation of covalent bonds. The regulatory steps are disclosed in the Marketing Authorization Application and require regulatory approval for changes. Materials in the blue boxes have the greatest regulatory significance and they are usually given a comprehensive and robust specification. On the other hand, materials in the brown boxes are synthetic intermediates, which can be isolated or remain in situ but are controlled using a more limited specification.
Audits to RSM manufacturers are performed to assess risks of having some unexpected contamination that could affect the subsequent chemical processes or the finished API’s quality. The risk based approach should be focused on the following:
• Risks of cross contamination in the final stages of RSM manufacturing. This potential chemical contamination could introduce unexpected substances in the subsequent reaction steps and, as a consequence, unexpected impurities would be undetectable by routine QC procedures.
• Risk of contamination with forbidden solvents (Class 1).
• Risk of having an unstable impurity profile across different batches, which could compromise the consistency of the API manufacturing process and its validation.
Microbiology is generally not a concern, since the RSM is further processed under heavy chemical conditions.
The aforementioned considerations have led to the approach AFA is following for conducting audits to RSM suppliers, since 2014. The former considerations yield audit agendas with the following areas to cover:
• Basic quality system. This means controlled documentation management, especially for the documents related to the manufacturing and control protocols and records.
• Batch records and control records of the specific processes to prove that the manufacturing process is well established, consistent and reproducible.
• Cleaning practices of the last stages, especially in the case of multiproduct facilities (much less critical in dedicated ones).
• Materials management in a controlled manner (to eliminate the possibility of mix ups).
• Reasonable change control (not as strict as in GMP environments but sufficient to trace and assess the most significant changes).
• Deviation management system.
• Complaints management.
The Active Pharmaceutical Ingredients Committee (APIC) published the Guide For Auditing Registered Starting Material Manufacturers in February 2018, which matches the criteria detailed above.
Audits to Registered Starting Materials are necessary to ensure that the custom synthesis processes previous to the GMP controlled steps will not introduce unacceptable risks for the use of drug substance. It is important to remark that it is possible that the potential contaminants from the custom synthesis will not be detected neither in the reception control of RSM nor in the final control of the drug substance as the analytical methods are just designed to control the expected components.
High chemical expertise is required to conduct risk based approach audits to RSM manufacturers.