Fraud and Major GMP Violations at API Manufacturers in India and China

Recommendation

22/23 February 2024
Munich, Germany

API Regulatory Starting Materials
Definition, Manufacture, Assessment and handling post-approval Changes

The Non-Compliance reports in the Eudra-GMDP database of the European Medicines Agency (EMA) are - to a certain extent - the European counterpart of FDA's Warning Letters. These reports are first drawn up then put in the database after a GMP inspection performed by a representative of the European national competent authorities at an API or medicinal product manufacturer showed serious GMP deficiencies. Similar to Warning Letters, the consequences of Non-Compliance reports are for the companies concerned critical, e.g. withdrawal of the GMP certificate or product recalls.

Two Non-Compliance reports issued at the end of last year concerned API production sites in China and India.

Regarding the Chinese manufacturer "Minsheng Group Shaoxing Pharmaceutical Co. Ltd", GMP inspectors from the French competent authority found 2 critical and 4 "major" deficiencies. Those deficiencies are summarised below:

• Falsification of source of starting materials: the starting materials supposed to have been manufactured in-house actually came from an external non GMP-compliant supplier and have been repackaged and relabelled accordingly (critical deficiency).
• The API manufactured according to the Chinese Pharmacopoeia was wrongly and intentionally released as USP quality; there was no traceability of the testing activities (critical deficiency).
• The cleaning and maintenance operations of the manufacturing line were insufficient (major).
• Deficient equipment design (pipelines); non-compliant transfer of the intermediate solution using nitrogen; non-compliant change management with regard to equipment (major).
• Hoses were lying on a dirty floor of an area not mentioned in the general layout of the site. Those hoses were unidentified and their cleaning status was unclear (major).
• Audit trail function in the chromatographic system was deactivated; there was no procedure in place for audit trail (major).

By the way, the inspection of the Chinese manufacturer performed by the French authority was part of the prequalification programme of the WHO which means that it had been initiated by the manufacturer himself within the framework of his application for the inclusion of his products in the list of prequalified pharmaceutical APIs of the WHO.

Secondly, the inspection of the Indian company "AstraZeneca Pharma India Ltd." was carried our by inspectors of the Swedish competent authority. The GMP deviations observed are summarised below:

• The manufacturing process of the API was not sufficiently validated (major).
• The documentation routine was not GMP-compliant (major).
• Data integrity wasn't assured (major).
• Design and maintenance of the equipment was insufficient (major).

The GMP deficiencies discovered in both production sites concern essential GMP requirements for the manufacture of APIs as laid down in the ICH Q7 Guideline and in the EG GMP Guide Part II since already 16 years. Unfortunately, GMP inspectors from European authorities, the EDQM and the FDA are - again and again - confronted to such GMP deficiencies, mainly in Indian and Chinese manufacturing sites.