FDA Warning Letters and EU Non-Compliance Reports after Inspections of API Plants - a Comparison

Recommendation

23-25 April 2024
Barcelona, Spain

Global Registration and Life Cycle Management for APIs

On the legal basis of the "Freedom of Information Act", the FDA publishes Warning Letters on their website, where they are accessible free of charge and without further constraints like a login procedure. Inspection reviews by European authorities - the "Statements of Non-Compliance with GMP" - have been publicly available in the EudraGMP database since the beginning of 2011 (EMEA Database on GMP Inspections now publicly available (EudraGMP)). It's thus possible to identify production sites which received a Warning Letter as well as a non-compliance report (NCR).

In the period between October 1st, 2015 and June 30th, 2017, three API manufacturers (two in China and one in India) received an FDA Warning Letter as well as a NCR issued by the authority of an EU member state. The following comparison of the documents reveals interesting details.

1. Dongying Tiandong Pharmaceutical Co., Ltd., Dongying City, China

• Inspection by GMP inspectors of the EU on December 9th, 2015, Publication of the NCR on February 25th, 2016; issuing authority: French National Agency for Medicines and Health products Safety
• Inspection by FDA inspectors on October 12th-16th, 2015; Date of the WL: November 10th, 2016

Results of the EU inspection

• 10 deviations, amongst which 3 are rated "critical" and 2 are rated "major".
  - critical: PCR analyses of the crude heparin provided by an approved supplier confirmed the presence of foreign DNA (DNA of ruminants). The analysis results had been manipulated.
  The crude heparin's journey from its supplier to the site of its processing cannot be reproduced. Relevant documents do not exist; the quality assurance shows considerable gaps.
  - major: Non-GMP-compliant handling of deviations and OOS results; inappropriate qualification of new suppliers of crude heparin; insufficient assessment of NMR spektra (identity verification), an additional peak which points to a contamination is ignored.
  
  Official measures/recommendations:
  - Withdrawal of the GMP certificate
  - Suggested removal of the manufacturer from the dossier of medicinal products approved in the EU (variation process)
  - Recommended product recall, in consideration of the national supply situation
  - Withdrawal of the CEP for enoxaparin sodium

Results of the FDA inspection

• Non-GMP-compliant handling of OOS results (PCR) in the analysis of crude heparin; no CAPA; PCR analysis in regards to foreign DNA (ruminants) not validated; insufficient evaluation/qualification of suppliers of crude heparin.
  
  Official measures/recommendations:
  - Approval for marketing authorisation applications listing the manufacturer as a supplier will be withheld until the GMP deficiencies are corrected.

The FDA inspectors encountered the same GMP deficiencies as the EU GMP inspectors did 2 months ago. During that time, the Chinese manufacturer apparently did nothing to correct those deficiencies.

2. Polydrug Laboratories PVT. Ltd., Ambernath (East), India

• Inspection by GMP inspectors of the EU on February 24th, 2016, Publication of the NCR on November 11th, 2016; issuing authority: Agency for Medicinal Products and Medical Devices of Croatia
• Inspection by FDA inspectors on March 16th-23rd, 2015; Date of the WL: April 14th, 2016

Result of the EU inspection

• 22 deviations, amongst which 4 are rated "major".
  - major: deficiencies in quality management relating to the repacking of batches and their storage; inadequate validation of computerized systems; CAPA to remedy deficiencies found in earlier inspections had not been applied.
  - other: reduced testing is not GMP compliant; manual integration of HPLC analyses; insufficient cleaning validation.
  
  Official measures/recommendations:
  - Suggested removal of the manufacturer from the dossier of medicinal products approved in the EU (variation process)
  - Stop deliveries of API batches by the manufacturer
  - Withdrawal of the CEP for 5 APIs

Results from the FDA inspection

• Non-GMP-compliant handling of customer complaints relating to product quality; no reviews for deviations and no investigations; no access control to raw data; no adequate quality control procedures.
  
  Official measures/recommendations:
  - Approval for marketing authorisation applications listing the manufacturer as a supplier will be withheld until the GMP deficiencies are corrected.
  - Import alert

The EU GMP inspection was conducted almost a year after the inspection by the FDA. During that time, either some of the GMP deficiencies had been corrected or the focus of the EU inspectors had been on different areas. At the time of the EU inspection, the FDA Warning Letter hadn't been published yet, at least.

3. Jinan Jinda Pharmaceutical Chemistry Co., Ltd., Zhangqiu City, China

• Inspection by GMP inspectors of the EU on June 1st, 2016, Publication of the NCR on July 29th, 2016; issuing authority: Spanish Agency of Medicines and Medical Devices
• Joint EDQM / US FDA inspection on May 30th- June 1st, 2016; Date of the WL: February 24th, 2017

Results of the EU inspection

• 30 deviations, amongst which 2 are rated "critical" and 8 are rated "major".
  - critical: GMP violations in the area monitoring of raw data and the review/handling of OOS results
  - major: GMP violations in the areas training, change control, quality assessment, process validation, cleaning validation.
  
  Official measures/recommendations:
  - Delivery stop
  - Withdrawal of one CEP

Results of the FDA inspection

• Non-GMP-compliant handling of OOS results, no investigation, no access control to raw data.
  
  Official measures/recommendations:
  - Approval for marketing authorisation applications listing the manufacturer as a supplier will be withheld until the GMP deficiencies are corrected.
  - Import alert

This inspection was conducted together by the two agencies at the same time as an EDQM / US FDA joint inspection.

A comparison of the inspection reviews shows that the inspected sites share the same GMP deficiencies in some instances. Sadly, a more thorough comparison with the elaborate Warning Letters is hardly possible because of the brief descriptions - often made in keywords - in the non-compliance reports.