Testing of Active Pharmaceutical Ingredients (APIs)
Testing of active pharmaceutical ingredients (APIs) is a routine activity in many Official Medicines Control Laboratories (OMCLs) of the General European OMCL Network (GEON). API testing increases the scope of control, as one source of API can be used in several batches of drug products. In addition, the sensitivity of the method and the ability to determine characteristic impurities at a lower level increase. The sensitivity of the method can be significantly decreased when the method is transferred from API to drug products due to matrix effects.
OMCLs also make important contributions to the development and improvement of European Pharmacopoeia (Ph. Eur.) monographs through their active participation in different Ph. Eur. working groups at the EDQM.
EU legislation in the field of medicines and, in particular, different provisions of the Falsified Medicines Directive (FMD) 2011/62/EC, which came into force as of 2013, highlight the need for better surveillance of APIs originating from unauthorised sources and, consequently, the necessity to establish appropriate measures to counteract them is also acknowledged and considered in the Strategy Paper (2015) of the Heads of Medicines Agencies (HMA), as well as the Council of Europe's Convention on the Counterfeiting of Medical Products and similar Crimes involving Threats to Public Health (referred to as the MEDICRIME Convention).
API Working Group
In order to respond to these developments in the most efficient way, an OMCL Working Group has been testing APIs since 2011. The task of the API Working Group is to develop strategies and programmes for the OMCL Network that contribute to the efforts of the European Health Authorities to ensure the high quality and safety of APIs on the European market in the future.
Achievements of the API Working Group to date
One major outcome of the work of this group has been to issue a GEON Position Paper that outlines the general risks with APIs and the possible contributions of the OMCL Network in the co-ordinated surveillance of APIs. The paper, which has been adopted by the OMCL Network and has undergone revision in 2019, also includes strategies for the future surveillance of APIs.
In February 2013, a new database on API testing was launched. This new computer application, which is only accessible to members of the OMCL Network and national competent authorities, allows the sharing of information with respect to the testing of substances for pharmaceutical use (including excipients and herbals) in the OMCL Network, with a focus on APIs. This database should promote API testing in the OMCL Network and collaboration in this field.
API Fingerprint Programme
After a number of incidents concerning falsified APIs (the heparin case in 2008 being one of the most well-known) and contamination of APIs (e.g. the sartan case in 2018), the OMCL Network decided to pursue the programme on surveillance of APIs based on fingerprint determination, which was initiated in 2009.
An API fingerprint is a specific analytical profile that includes information on the physico-chemical properties of a substance. Fingerprint determination can make it possible to distinguish samples based on their origin (manufacturer or site) and be used to verify the authenticity of suspect samples and detect falsified medicines.
Some pattern recognition techniques have also been used to successfully detect inter- and intra-batch composition variability of APIs.
To date, five API fingerprint studies on a variety of APIs have been conducted:
- statins & macrolide antibiotics
Based on the lessons learned from the first three studies, it was recommended to:
- perform the lab analysis under constant testing conditions (same laboratory, equipment, method, etc.);
- include a large number of samples per manufacturer, whenever possible;
- run the pre-study phase in order to identify methods that reveal the fingerprint features to be integrated into the test protocol;
- analyse more samples with all techniques;
- gather in advance as much information as possible about the manufacturing process and any links between manufacturers, including the exact location of the manufacturing site for each sample supplied;
- contact manufacturers and/or inspectors directly, if any atypical results are found.
These recommendations were taken into account for the next two studies. The fifth API fingerprint study, on tadalafil, was launched in June 2021 and finalised in October 2022. In this study, six OMCLs shared the testing, applying the following techniques to guarantee a robust data pool:
- Related substances by HPLC-DAD
- Impurities A, B and C by HPLC
- Residual solvents by GC-MS
- Polymorphism by X-ray diffraction
The results of the omeprazole, sildenafil and tadalafil studies were published in the following journals, respectively:
- "European fingerprint study on omeprazole drug substances using a multi analytical approach and chemometrics as a tool for the discrimination of manufacturing sources”; Journal of Pharmaceutical and Biomedical Analysis, Vol. 208 (2022) (10.1016/j.jpba.2021.114444)
- "GEONs API fingerprint project: Selection of analytical techniques for clustering of sildenafil citrate API samples"; Talanta, Vol. 239 (2022) (10.1016/j.talanta.2021.123123)
- "Clustering of Tadalafil API Samples According to their Manufacturer in the Context of API Falsification Detection"; Journal of Pharmaceutical Sciences, Vol. 112 (2023) (10.1016/j.xphs.2023.05.015)
Benefits of chemometrics for OMCLs
In view of the common interest of the Network in the possibilities offered by chemometrics, and on the basis of positive experience with the API fingerprint studies conducted by the API Working Group, it was decided to draft a chemometrics guide for beginners in the field to help them make the best use of their analytical data.
In addition to an introduction to the topic for interested parties, the document provides more advanced information for individuals looking to build on their knowledge of chemometrics.
Please note that the names of the software mentioned in the document are given as examples only.
Position paper – Benefits of Chemometrics for OMCLs
Work plan of the API Working Group
Topics in the work plan of the API Working Group include the following.
- Improved information-sharing with respect to API testing in the OMCL Network; development of appropriate measures for the maintenance of an API testing information IT platform with controlled access and the routine reporting of API testing in the Annual Reports of the GEON members.
- Support of the development and maintenance of a general risk assessment tool for the planning of national and common market surveillance programmes, with a focus on critical APIs.
- Improvements in sample planning and randomised sampling of APIs through collaboration with other stakeholders (in particular national GMP inspectors and customs officers).
- Scientific discussion to foster Market Surveillance Studies (MSS) on APIs for the determination of the quality, but also the authenticity and sources, of tested materials by different measures, such as the application of fingerprint techniques and chemometric analyses.
- Development of training programmes to support these tasks.
- Falsified Medicines Directive (FMD), 2011/62/EC
- Strategy Paper (2015) of the Heads of Medicines Agency (HMA)
- Convention on the counterfeiting of medical products and similar crimes involving threats to public health
- The MEDICRIME Convention