The World Health Organisation (WHO) recently proposed updated guidance to assist pharmaceutical manufacturers in assessing the quality of excipients after child deaths were reported in several countries linked to contaminated cough syrups containing unacceptable levels of diethylene glycol (DEG) and ethylene glycol (EG) in their formulations.
According to WHO’s health alert issued in January, reports of contaminated cough syrups containing DEG and EG were linked to 300 deaths in three countries last year, with most of the fatalities occurring in children. WHO’s alert said “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.” The international agency’s excipient GMP guide was last updated in 1999 in WHO’s Technical Report 51 Series No 885.
In Gambia, 70 children died from acute kidney injury potentially linked to cough syrups manufactured in India.
These reports “have further highlighted the need for a revision of the original guideline,” said WHO.
“Furthermore, the concept of ongoing improvement, life cycle approach, better quality management systems, risk management and management review should be described in such a guideline, alongside the necessary good storage, good trade and good distribution practices to ensure their reliability throughout the supply chain.”
“It is the responsibility of the finished product manufacturer and of the applicant to ensure that the finished product is manufactured using excipients of a suitable grade conforming to its intended use,” said WHO.
WHO said multiple systems that are necessary for a manufacturer to assess the quality of excipients; including a quality management system and quality risk managements system; management review; reviewing complaints and recalls; handling returns; conducting quality audits and supplier audits; and requirements governing personnel, sanitation and hygiene.
With respect to quality management, WHO stated that “manufacturers involved in the production, control, storage and distribution of excipients for pharmaceutical use should establish, document, implement and maintain a comprehensively designed and clearly defined quality management system. Senior management should assume responsibility for the quality management system, as well as the quality of the excipients for pharmaceutical use manufactured, controlled, released, stored and distributed.”
A quality risk management (QRM) system should also be in place to “ensure that risks are eliminated or mitigated, and ultimately protect the patient from receiving a pharmaceutical product containing the wrong, contaminated, or unsuitable excipients for pharmaceutical use.”
There should also be a review system in place to ensure that the quality management system achieves its intended objectives by measuring performance using such benchmarks as 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 in place governing complaint investigations. Complaint records should include the date of receiving the complaint; name and address of complainant; details of the complaint including name of the excipient and batch number; and details of the investigation and action taken.
