Missing glycerin test for diethylene glycol leads to FDA warning letter

Recommendation

22/23 February 2024
Munich, Germany

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

One of the most severe incidents involving contaminated drugs occurred 1995 in Haiti, where 88 children died of diethylene glycol poisoning. They had taken a cough syrup which instead of the excipient glycerin contained DEG, which is usually used as an antifreeze agent. Despite the extensive media coverage of the scandal, drug products containing DEG kept turning up during the following years (in Argentina, Bangladesh, India, Nigeria) - another tragic case took place in Panama, where over 100 people lost their lives. In almost all cases, this could be traced back to a failure in the quality assurance/quality control of the companies that processed the excipient in their preparations:

• Glycerin had not been tested for DEG contamination. Certificates of Analysis by the supplier had been adopted unvalidated.
• The supply chain was intransparent and the original manufacturer of the glycerin unknown.

In order to get a grip on this threatening situation and reduce the potential threat for consumers (in the USA), the FDA published their Guidance for Industry "Testing of Glycerin for Diethylene Glycol" in May 2007. This guideline contains recommendations on how to test the excipient glycerin for DEG contamination before its further processing in the manufacturing process of the medicinal product.

This guideline and the basic expectations of the FDA on the topic of glycerin do not appear to be familiar to the Irish company Europharma Concepts Limited. Half a year after the FDA inspectors visit, general management received an FDA warning letter, in which the critical finding regarding the poor quality control for glycerin as well as other failures concerning the control of incoming starting materials and the validation of manufacturing processes are described in detail. Here is a short summary:

• Glycerin has not been tested for contamination with DEG and EG (ethylene glycol) before its release for further processing (or after).
• Other components of the medicinal product, e.g. the active ingredient, had not been tested for conformity with the specifications, either.
• There was no validation or validation program for the manufacturing process.

The FDA does not issue a warning letter solely based on the deficiencies the inspectors discover at the site of a company; the company's response is decisive. Europharma's response was deemed inadequate by the FDA for the following reasons:

• The ultimate responsibility for testing all incoming drug components lies with the drug product manufacturer. An evaluation of the supplier's testing methods, as Europharma initiated after the FDA inspection, is no substitute for this.
• The response contained no information on interim measures to ensure that all currently used components are tested for compliance with the specifications before further processing.

This resulted in the following additional demands, for which Europharma was given 15 working days:

• Written procedures for supplier qualification.
• A statement on how incoming components will be tested in the future: complete quality control of each individual batch or acceptance of the supplier's certificate of analysis. The latter requires a description on how the analyses values in the certificate are going to be verified.
• A detailed risk assessment of all preparations that contain glycerin and are currently in the US market; testing of all retain samples and a notification and recall procedure in case of OOS results.
• A comprehensive assessment of all procedures and analytical methods in the QC laboratory, including information on the competence of lab personnel and an appropriate CAPA plan.

Europharma has been placed on Import Alert by the FDA.