SWITZERLAND — The World Health Organization (WHO) has emphasized the need to revise its original guideline on excipient Good Manufacturing Practices (GMP) following reports of contaminated cough syrups linked to child fatalities.

The WHO’s latest excipient Good Manufacturing Practices (GMP) guidance is an update to the previous version, which was issued in WHO’s Technical Report 51 Series No 885 in 1999.

The aim is to provide a comprehensive framework that can help prevent future contamination incidents. Unfortunately, such incidents have already occurred in several countries, including Gambia, Indonesia, and Uzbekistan.

In January of this year, WHO issued a health alert, highlighting that contaminated cough syrups containing DEG and EG were linked to 300 deaths across three countries in the previous year.

Tragically, most of the fatalities were children. WHO’s alert warned that “these contaminants are toxic chemicals used as industrial solvents and antifreeze agents that can be fatal even taken in small amounts, and should never be found in medicines.”

In Gambia, 70 children died from acute kidney failure, while over 200 people died in Indonesia and 19 in Uzbekistan.

All of these incidents involved confirmed or suspected contamination with high levels of diethylene glycol (DEG) and ethylene glycol (EG) – industrial solvents and antifreeze agents that are toxic and fatal even in small quantities and should never be found in medicines.

The issue of glycol contamination in cough syrups is more widespread and affects several manufacturers, but the root cause is still unclear.

Maiden Pharmaceuticals Limited, a company based in Haryana, India, has been identified as the manufacturer of several products, including Promethazine Oral Solution, Kofexmalin Baby Cough Syrup, Makoff Baby Cough Syrup, and Magrip N Cold Syrup.

WHO has received reports from at least seven countries since September 2022, with most of the fatalities occurring in children under five years old.

Apart from cough syrup contamination incidents, the U.S. has also experienced contamination problems with eye drops.

Drug-resistant bacteria were found in contaminated eye drops, leading to serious eye infections in 55 people and one reported death.

In WHO’s view, these incidents have further highlighted the need for a revised guideline that incorporates a life cycle approach, better quality management systems, risk management, and management review.

Additionally, the guideline should include good storage, good trade, and good distribution practices to ensure the reliability of excipients throughout the supply chain.

According to WHO, it is the responsibility of finished product manufacturers and applicants to ensure that the finished product is manufactured using excipients of a suitable grade that conform to their intended use.

To that end, multiple systems are necessary for a manufacturer to assess the quality of excipients.

These include a quality management system and quality risk management system, management review, reviewing complaints and recalls, handling returns, conducting quality audits and supplier audits, and requirements governing personnel, sanitation, and hygiene.

Regarding quality management, WHO recommends that manufacturers involved in the production, control, storage, and distribution of excipients for pharmaceutical use should establish, document, implement, and maintain a comprehensive and clearly defined quality management system.

Senior management should assume responsibility for the quality management system and the quality of excipients for pharmaceutical use manufactured, controlled, released, stored, and distributed.

A quality risk management (QRM) system is also essential to ensure that risks are eliminated or mitigated, ultimately protecting patients from receiving a pharmaceutical product containing the wrong, contaminated, or unsuitable excipients for pharmaceutical use.

Additionally, the guideline recommends the establishment of a review system to ensure that the quality management system achieves its intended objectives.

This can be achieved by measuring performance using self-inspections, quality audits, and supplier audits, reviewing complaints, returns, and recalls, reviewing changes and deviations, and reviewing rejected batches.

The guideline further notes that manufacturers should have written procedures governing complaint investigations.

Complaint records should include the date of receiving the complaint, the name and address of the complainant, details of the complaint, including the name of the excipient and batch number, and details of the investigation and action taken.

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