SAFETY ISSUES: THE MANUFCATURE OF APIs IN THE FAR EAST AND ITS SURVEILLANCE
Nowadays, APIs for the European medicinal products market are predominantly produced in non-European countries, mainly in India and China. Although Article 46(f) of Directive 2001/83/EC renders it mandatory to use only APIs produced in compliance with GMP, it happens again and again that APIs of inferior quality still find their way into medicinal products. One recent spectacular case involved contaminated heparin which led to several deaths in the USA. Obviously there are safety issues concerning the surveillance of the production and the transport chain of imported APIs.
At the 4th EFCG Pharma Business Conference entitled "Strategies for Compliant Pharma Sourcing" which took place in Brussels last May, Guy Villax, CEO of Hovione in Portugal presented his analysis of the situation in Europe as regards APIs using four categories: statutory regulations, registration of API manufacturers, inspection by the authorities and deterrence via sanction. He claims that in many member states national laws reveal deficits since the principles of ICH Q7 are not statutory.
General registration of API manufacturers is not necessary. Inspection of the manufacturing locations by the relevant authorities either does not take place at all, is inadequate or to a great extent not risk-oriented. Efficient co-ordination of the inspecting activities of the single states' inspection authorities extending beyond European borders is even further away. The measures for an effective deterrence leave a lot to be desired. There is no black list of firms or persons who have already been convicted of fraud. Furthermore, the European customs authorities let APIs pass although they know that they are not compliant to GMP.
In connection with the topic inspection of GMP/GDP compliance, the planned amendments to Directive 2001/83/ EC need to be considered. They are part of a European-wide strategy to combat counterfeit medicinal products. This strategy comprises three pillars, i.e. provisions concerning product characteristics and GMP, actors in the supply chain and Good Distribution Practices (GDP) and APIs. These amendments affect many articles of the Directive, including Article 46(f) which in future will make audits of API manufacturers mandatory. The manufacturer of medicinal products will either have to perform these audits himself or commission an accredited third party to conduct them. Implementing the amendment of the Directive will take a few months longer due to the European Parliament elections which have taken place in the meantime.
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The European Directorate for the Quality of Medicines and HealthCare (EDQM) is one of the European authorities that has been conducting inspections of non-European API manufacturers for the past 10 years - with increasing frequency. According to data from last year, 46% of inspections took place in China, 32% in India and 11% in other Asian countries. EDQM conducts inspections either before or following the issuance of a Certificate of Suitability (CEP). However, by far not all CEP owners are inspected. The CEP confirms compliance with the relevant monograph of the European Pharmacopoeia. But in the CEP procedure, the manufacturer is obliged to declare his willingness to be inspected and agrees to a GMP-compliant API production. If this declaration does not correspond to the reality found during the inspection, the CEP will be suspended. In 2008, six CEPs were suspended because of serious GMP deficiencies. Further cases of suspension of CEPs occurred in the first six months of this year. They were mostly related to API manufacturers in China and India.
What is the general situation concerning APIs compliant with GMP in Asian third countries? Dr Philippe André from Tianjin University explained the characteristics of the API manufacturing industry in China as seen by an insider. Usually little effort is made in the areas of pharmaceutical development, process validation, specifications of starting materials, investigation of critical variations and OOS results in quality control laboratories. The control for impurities usually is restricted to pharmacopoeia methods without first testing the applicability of the method. The prevailing paradigm is that quality can be "tested into" the product. From the safety perspective of medicinal products the following facts are extremely alarming:
- There are two unofficial API qualities: "chemical-grade" and "pharmaceutical-grade". The SFDA (Chinese State Food and Drug Administration) only controls the manufacturers of pharmaceutical-grade APIs. But many European manufacturers of medicinal products buy "chemical-grade" APIs (because they are cheaper).
- Frequently, manufacturers of medicinal products do not admit auditors to certain production areas, or they deny an audit at all.
- Firms still advertise on the Internet with a CEP that has already been suspended by EDQM.
Dr André estimates that about 20-30% of the APIs in generic drugs on the European market contain either APIs that are not compliant with GMP or are counterfeited.
In the past, serious incidents with medicinal products were not only caused by substandard APIs, in many cases, tainted or fraudulently exchanged excipients also played a role (such as cough syrup containing diethylene glycol). However, whereas the principles of GMP are mandatory for the production of active ingredients and finished medicinal products and their observance is controlled by the authorities, there are no statutory rules governing the production and distribution of excipients in conformity with GMP. According to Article 46f of the Directive 2001/83/ EC pharmaceutical manufacturers must only use APIs and starting material produced in compliance with GMP. This requirement also includes some excipients which are listed in a separate Directive according to Article 46f.
A draft for a Directive entitled "Specific Conditions on the Application of Principles and Guidelines of GMP for Certain Excipients" was already published in December 2006. It lists some categories of excipients as well as the two individual excipients propylene glycol and glycerol. To identify the advantage of a legal regulation of GMP for certain excipients, the European Commission had given instructions to carry out a consultation of manufacturers of excipients and their users (pharmaceutical producers). The answers of 132 manufacturers of excipients and 153 users was comprised in an "Impact Assessment Report". This report was introduced at the 1st IPEC conference on "Good Manufacturing Practices on Pharmaceutical Excipients" in Munich, Germany, end of 2008.
According to this report, a regulation for certain excipients as intended in Article 46f would result in costs considerably exceeding the advantages. In the meantime, the European Commission reacted to the assessment report by publishing a declaration in early June 2009 that this draft for a Directive would no longer be pursued. But since Article 46 f still requires this Directive, it should be changed immediately. Hence there will be no direct statutory anchoring of GMP for certain pharmaceutical excipients for the time being.
This means that it will still be the duty of the manufacturers of medicinal products or of their Qualified Persons to ensure the harmlessness of all ingredients and excipients.
Excipients used in medicinal products are of quite a different nature (such as sodium chloride, corn starch, complex colouring agents and aromatic substances). Therefore it does not make sense to define a GMP standard analogical to the APIs. Dr Frithjof Holtz at Merck in Darmstadt, Germany, presented a classification scheme for excipients that has been developed by the International Pharmaceutical Excipients Council (IPEC). The aim of this scheme is to enable manufacturers of excipients to choose an appropriate level of GMP that corresponds to the intended use. For this classification, the final dosage form containing the API, the function of the API, the manufacturing process and the doses administered daily have to be considered. Then the risk is assessed on the basis of this data. Such a classification process generally takes place in three phases: in phases 1 and 2, the excipient manufacturer and the excipient user perform the relevant risk analyses independently. In the course of a business relationship, these two risk analyses are put together, resulting in a common risk assessment with the ensuing classification of the excipient ("foundation level", "intermediate level", "high level") (phase 3).
Since a mandatory GMP standard for excipients is not in place, the IPEC has published two documents, defining the minimum requirements for excipients manufacturers concerning GMP and GDP: the "Joint IPEC - PQG Good Manufacturing Practices Guide" (2006), whose main features also reflect the content of ISO 9001:2008, and the "IPEC Good Distribution Practices Guide" (2006). These guides contain auditable standards and form the basis for the European excipient certification project that was also initiated by IPEC.
Dr Iain Moore of Croda and Chairman of the GMP Committee of IPEC Europe explained the content of the documents and provided an account on the state of this ambitious project in which other associations such as IPEC Americas, FECC (European Association of Chemical Distributors) and PQG (Pharmaceutical Quality Group) also participate. The IPEC intends to conclude agreements with 3rd party audit organisations acknowledged by official certification institutes in the following months. These organisations will then carry out audits pursuant to the IPEC guides and issue certificates. According to Dr Moore, the project is at an advanced phase and will be concluded next year.
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Author:
Dr Gerhard Becker
CONCEPT HEIDELBERG
