With a growing proportion of APIs and finished medicines being manufactured outside Europe, tackling the problem of quality defects has become a major challenge to the region’s pharmaceuticals inspection systems. “The causes of this increase (in defects) are multifactorial,” says an official at the European Medicines Agency (EMA). “We are studying the root causes to draw general lessons from these incidents.” As a result, there has been a steady rise in the number of regulatory measures and initiatives aimed at curbing the increase in deficient products.
EMA shares the task of coordinating the monitoring and testing of the quality of APIs and finished medicines for centrally approved products with the European Directorate for the Quality of Medicines & Healthcare (EDQM), part of the Council of Europe, whose members comprise all European states including the 28 European Union countries. The 2014 Work Programme of EMA, which was agreed upon by the agency in December but only published in March, gives priority to raising the efficiency of inspections in relation to suspected defects, as well as GMP and good pharmacovigilance practice (GVP) (1).
One of EMA’s key objectives this year is improvements in dealing with the “causes and impact of shortages of human medicines caused by GMP non-compliance and quality defects,” according to the programme. The EDQM, which is responsible for the European Pharmacopoeia but also runs its own inspection operations, has been tightening and updating guidelines on the testing of products.
Because globalisation has been closely linked with the increase in product imperfections, greater international cooperation is regarded as being crucial to solving the problem. A key part of this international collaboration is the exchange and dissemination of information about inspections, which not only expand the knowledge of agencies about quality issues but also make more effective use of already stretched inspection resources.
“We actively participate in international regulatory collaboration programmes for API and finished product inspections (since) this enables the sharing of risk information and ensures the best use of inspectorate resources between trusted regulatory partners,” says a spokesperson for the UK Medicines and Healthcare Products Regulatory Agency (MHRA), London. “Continued international collaboration is a high priority for MHRA in achieving the required regulatory oversight of the global supply chain for medicines supplied to UK and EU patients.”
Statements of GMP non-compliance available to public
European agencies now follow a risk-based approach to their choice of sites and products to be inspected or tested. Manufacturers with a history of non-compliance are, therefore, most likely to be targeted. Experience has so far shown that the vast majority of manufacturers ensure their sites and products meet quality standards with only a small minority being offenders.
Now the pressure on these companies is being stepped up after EMA announced in December 2013 that it would be publishing details of breaches of GMP standards by publishing statements of GMP non-compliance. These documents are now available on the agency’s EudraGMDP database (2), which gives public access to information on GMP certification and manufacturing and import authorisations.
A list of eight non-compliance reports on the EudraGMDP website in late March lists plants in India, China, Czech Republic, Spain and France (2). The statement issued by the French Health Products Safety Agency of the non-compliance for an API site in Maharashtra, India, of Smruthi Organics, details 29 deficiencies of which two were critical and four were major (3). One of the critical defects referred to “manipulation and falsification of documents and data” in different departments of the plant.
Another non-compliance statement issued by the same agency for an API manufacturing site in Monaco, France listed 31 deficiencies, two of them critical and 12 major (4). One of the critical deficiencies covered the manufacturing and cleaning operations for 15 APIs, for which also records were missing.
Some of the latest listed non-compliance statements were for agency inspections that had followed separate inspections of the same sites by EDQM, which had subsequently withdrawn its Certification of Suitability to the Monographs of the European Pharmacopoeia (CEP) for products made at the plants. Certifications of Suitability are issued to show that the quality of individual API meets the European Pharmacopoeia standards.
Of the 32 on-site inspections subjected to EDQM inspections in 2012, 13 (41%) were found to be non-compliant with GMP standards (5). In line with its own risk-based policy for site selections, more than half of the inspections were re-inspections. Approximately 60% of companies being re-inspected were again found to be non-compliant. “This evidenced a lack of commitment to sustaining GMP by a number of companies,” says EDQM in its latest annual report (5).
In 2012, 53% of EDQM’s on-site inspections were of plants in India and 31% in China, with only 3% in Europe (5). In response to the trend towards information exchanges, another 25 sites were covered by the directorate by sharing information with inspectorates of member states and partners.
Sampling and testing
In collaboration with EMA, EDQM runs a sampling and testing programme covering medicines approved under the EU’s centralised licensing procedure. EMA’s scientific committees choose the sample of products, the testing of which is then co-ordinated by EDQM through the pan-European network of Official Medicines Control Laboratories (OMCL). National agencies also conduct their own sampling and testing on medicines authorised under the EU’s state-based decentralised system.
“Samples are selected on the basis of risk, such as the extent of use, number of different products, manufacturing process, chemical stability and information/intelligence from across MHRA divisions,” the agency’s spokesperson told Pharmaceutical Technology Europe.
The vast majority of human products tested under the centralised or decentralised scheme have been found to be within specifications. Nonetheless, 16 out of 33 human medicines tested by the EMA/EDQM programme in 2012 were found to have deficiencies, mainly relating to “technical, scientific, regulatory or editorial (relating to leaflets) nature,” according to an EMA report issued in December 2013 (6).
The results also seemed to confirm an underlying weakness in quality management among certain companies. Approximately half the total 45 samples were those that had already been tested in previous programmes, says the EDQM. The repeated inspections are consistent with a strategy of checking certain products several times during their lifecycle.
At the same time, possibly as a result of more rigorous testing, the number of defective products is likely to continue to rise. EMA has reported that in 2013, the number of reports of quality defects went up by 20% (1). In its Work Programme for 2014, the agency is expecting a smaller increase.
Implications of new pharmacovigilance regulations
The scope of inspections is also being expanded. There will be more coverage of human biological pharmaceuticals. Also, the amount of post-authorisation inspections will increase, particularly as a result of the implementation of new pharmacovigilance regulations. Evidence of a manufacturer being non-compliant with not just GMP but also other safety issues, such as poor quality management, can trigger inspections under the EU’s pharmacovigilance legislation. These inspections can either be ‘for-cause’ investigations to focus on particular aspects of production or other processes, or they can be ‘full-system’ inspections.
EDQM reckons that there are opportunities for more inspections by laboratories in the OMCL network doing more testing of products from outside their own countries. Currently within the decentralised system of sampling and testing of medicines, only 10% of products tested have originated from outside the country of the OMCL laboratory.
“Analysing a series of samples from other countries together with samples from one’s own national market is both cost effective and work-reducing for all the concerned OMCLs,” says the EDQM in a position paper published last year (7).
“This feature of the (decentralised) scheme has been underutilised to date.”
With the continued squeeze on public sector expenditure in Europe, it is unlikely that much more money will be allocated to inspection operations. Instead, better use will have to be made of existing resources.
1. EMA, Work Programme of the European Medicines Agency 2014, EMA/695772/2013 (London, Mar. 2014).
2. EUDRAGMDP database, GMP Compliance Menu, Non-compliance reports, accessed 9 Apr. 2014.
3. EUDRAGMDP database, Non-compliance reports—Report No. 13MPP057, accessed 9 Apr. 2014.
4. EUDRAGMDP database,Non-compliance reports—Report No.14MPP024, accessed 9 Apr. 2014.
5. EDQM,Annual Report 2012, accessed 9 Apr. 2014.
6. EMA, Results of the sampling and testing programme for the year 2012, EMA/INS/S&T/613387/2013 (London, Dec. 2013).
7. EDQM OMCL Network of the Council of Europe, General Document, History, results and benefits of testing MRP/DCP products, PA/PH/OMCL (12) 57 3R (France, July 2013).
About the Author
Sean Milmo is a freelance writer based in Essex, UK, [email protected]