Following the Rules
The differing requirements of the underly the GMP guidelines may also lead to real noncompliance. This for instance is the case, if topics defined within the ICH Q7 are not (or are only superficially) covered in national GMP guidelines.
Eg, topic 1.3 of the ICH Q7 (and topic 1.2 of the EU-GMP guideline, part II and topic 1.2 of the PIC/S GMP Guide for Medicinal Products part II) suggests the stage (starting point) within the manufacturing process where GMP requirements need to be fulfilled for different kinds of API starting materials.
During the auditing of the process validation and manufacturing flow according to ICH standards, an auditor will emphasize on the adherence of the early stages of the manufacturing process to essential GMP requirements. With subsequent process steps up to the point of the purified, finished API, the auditor expects increasing GMP compliance.
The SFDA GMP rules on the other hand, are primarily focused on the final manufacturing steps. For the API manufacturing process, batch records are (only) required starting from the “refinement from crude” step (appendix 4, topic 10 of SFDA-GMP). Since regulations for the early manufacturing steps are not contained within the guideline, Chinese companies may be non-compliant according to ICH criteria – depending on their selection of the API starting material. The subject of “change control” is covered in chapter 13 of the ICH Q7. Every change that is related to the production process that “may affect the production and control of the intermediate or API” has to be identified, documented, assessed and approved. This means that the API purchaser has to be informed about changes in the production process based on the ICH Q7 requirements.
However, local GMP regulations may not require API manufacturers to inform their purchasers about such changes. The Chinese SFDA GMP guideline does not explicitly dictate change control procedures. The Indian schedule M covers the changes in the manufacturing process in chapter 26.5. However, these changes are only regarded as a task for validation: “Significant changes to the manufacturing process, including any changes in equipment or materials that may affect product quality and/or the reproducibility of the process, shall be validated.”
Changes in the manufacturing process may potentially lead to extremely altered properties of APIs, eg, the bioavailability and the resulting efficacy – the API exhibits identical chemistry properties with different eventual polymorphic forms. Therefore, unqualified and undocumented changes in the production process can result in serious consequences for the marketing authorization holder to the point of a termination of the manufacturing authorization.
Manufacturers from Asia should therefore align their quality management systems and manufacturing processes not only to their respective national standards but also to the requirements of ICH Q7. Otherwise, European and American companies cannot accept the APIs. In most cases, the adaption of the quality systems is feasible. The topics are covered in the respective guidelines, but with different levels of complexity in the rules. The guidelines can be combined by implementing requirements from ICH as an extension to the national legislations.