In 1969 the global agreement on the Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce was proposed by WHO. The aim was to facilitate international trade in pharmaceuticals through mutual recognition of GMP inspection results. Today, almost 50 years later, up to one hundred countries conduct foreign inspections. As a result a manufacturing site well established, might be inspected many times in one year by local and different foreign authorities. This leads to duplication of work and waste of recourses both by regulators and industry.
Apart from political reasons several professional factors might explain this situation. The most obvious one is the sovereignty of countries and the lack of mutual confidence between national inspectorates. This may be related to regulatory and GMP differences, real or perceived, in expertise and/or resources. Also different legal approaches and local procedures in inspection practice may make results of foreign inspectorates less relevant in relation to the defined local requirements. Occasionally inadequate economic incentives for inspectorates may preclude work sharing.
Better use of recourses may be achieved through enhanced collaboration between regulators and reliance on inspection outcomes from trustworthy inspectorates. For this further convergence of similar national/regional GMP inspection practices and supporting legislation worldwide is needed. To this end a facts finding project on essential details of inspection process is suggested. It may be regarded as an extension of annual surveys conducted by EFPIA *.
* S. Rönninger, J. Berberich, V. Davoust, P. Kitz, A. Pfenninger, Landscape of GMP/GDP inspections in research-based pharmaceutical industry – Part I: Data, Pharm. Tech. Europe, 2017, in press; Part II: Opportunities, Pharm. Tech. Europe, 2017, in press.
Currently GMP expectations and related standards are largely similar and so far harmonized on a global level. EU or PIC/S guides, which are almost identical, are recognized by some 50 member inspectorates of one or both organizations. Some other countries, forming sub-regional economic cooperation initiatives, may be added to the list, e.g. Russia, Belarus, and Kazakhstan, ASEAN, Gulf Cooperation Council (GCC). The WHO GMP, not much different from the above mentioned guides, is used in one way or another by a number of countries outside the two groups. The “pharmerging” markets in IMS Health terms: China, India, Venezuela, Viet Nam, Indonesia, Egypt, Pakistan, with their growing pharmaceutical production and exportation potential, may be mentioned in this context. Additionally ICH guidelines, such as ICH Q7, ICH Q9 and ICH Q10 are instrumental in bridging the gap between different GMP norms (EU – PIC/S, WHO, US FDA, ASEAN, GCC) and thus assist mutual reliance or recognition. At the same time the relevant assessment instruments, which is GMP inspection practices are lagging behind in formal local procedures as far as their international harmonization is concerned.
Pharmaceutical inspection, that is official oversight of pharmacies, pharmaceutical laboratories, manufacturers and warehouses, existed in many parts of the world long before appearance of GMPs. Pharmaceutical inspection practices in the modern sense emerged in 1960-s in parallel with adoption of GMPs. Later the term was extended to cover also Good Distribution Practice (GDP) inspections also covering the importation of medicines. Originally national GMP inspection practices differed because of differences in traditions, legislation/regulations, resources available and institutional responsibility with health versus trade ministries.
Harmonization efforts in the area of GMP inspection practice were initiated in 1960-es at sub-regional (Nordic countries), regional/interregional (European Community, PIC) and global (WHO) levels. As a result in the following decades a certain consensus on common principles has been achieved. The role of pharmaceutical inspection in the overall sectoral regulatory process was first emphasized by WHO. In the document “Guiding principles for small drug regulatory authorities”  licensing of medicinal products was identified as a pivotal function for “any system of drug control”. It was explained, however, that without a pharmaceutical inspectorate (supported by a QC lab) “licensing provisions cannot be effectively enforced”*.
* It may be noted that the role of a pharmaceutical inspectorate often goes beyond assessment of GMP/GDP compliance. In some cases it were inspectors who drafted national GMP texts and took active part in training of industrial personnel in principles of GMP. Self-inspection teams at manufacturers, educators with academic training programmes, as well as commercial consultants draw heavily on the experience of official inspectors.
In the following years WHO issued “Provisional guidelines on the inspection of pharmaceutical manufacturers”  highlighting essential elements of the inspection procedure:
Additional guidance by WHO included recommendations on inspection of manufacture of investigational products, on pre-approval inspections , on quality systems for national inspectorates, on inspection report and GMP certificate [3-6].
PIC-PIC/S and EU formulated a number of specific recommendations relevant for national inspection services [10-23]. The first version of the European guideline “Conduct of Inspections
of Pharmaceutical Manufacturers or Importers” was issued in 1996. The current version of this document is included in the European Commission/EMA “Compilation of Community Procedures on Inspections and Exchange of Information” .
By early 1990s the following common principles were agreed upon on the international level, largely as a result of combined efforts by WHO, PIC and EEC:
As for imported pharmaceutical products some countries e.g. USA, EU, Australia practiced direct inspection of foreign manufacturers. However, in view of resource intensive foreign inspections and not-infrequent technical complications bi-lateral and multi-lateral mutual recognition agreements (MRAs) were identified as the most promising approach to control of manufacturers in exporting countries. A very simple alternative exists: any state could issue a regulatory statute to accept inspections by specific countries (e.g. Columbia for US and many EU countries).
In 1970 ten some European countries signed the Convention for the Mutual Recognition of Inspections in Respect of the inspection of manufactures of pharmaceutical products (Pharmaceutical Inspection Convention (PIC)) . The Contracting States accepted and recognized inspections of pharmaceutical manufacturers carried out by the competent authorities of other Contracting States as equivalent to their own national inspections. In mid-1990s the same principle of mutual recognition of inspections of pharmaceutical manufacturers was adopted by the European Community (presently EU).
This Convention had a growing membership attaining an interregional dimension. As the EU was formed in 1995 in fact PIC was hibernated and an alternative agreement was signed involving more countries already b then: Pharmaceutical Inspections Cooperation Scheme (PIC/S). Under this mechanism the exchange of inspection reports and company responses does not automatically lead to reducing the number of inspections*. It is used as a preparation step for upcoming inspections. Currently over 50 states participate in the Scheme, including accession and pre-accession countries, which is one fourth of the UN list of Member States.
* Indirectly PIC/S membership assists in reducing inspections number by forming a basis for MRAs.
Already in 1969 the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce was recommended to importing and exporting Member States (World Health Assembly Resolution 22.50, 1969). The Scheme was developed with the
view to facilitate international trade in pharmaceutical products on a global level through mutual recognition of GMP inspection results. However, no measures were foreseen for independent outside assessment of regulatory capacities of participating authorities. For this reason the credibility of certificates issued under the Scheme is unfortunately not widely recognized by importers. Over 140 countries participate in the Scheme. This arrangement is used for information exchange on imported finished medicinal products and APIs. Here are opportunities.
Presently on the global level there is no international agreement regarding mutual recognition of GMP inspection results under the WHO umbrella. Recently EMA published an overview of international cooperation initiatives related to medicines regulation . According to this work at present no global cooperation programme has convergence of GMP inspection practice on its agenda.
Following appearance in 1987 of ISO International Standards on quality systems (ISO 9000 family standards) new approaches were adopted by GMP inspectorates. One should note in this context that certification under these standards, though aimed at the same goal as GMP inspection (assessment of the quality assurance potential of a manufacturer), differs from this activity in some important aspects. Since ISO 9000 certification is not a regulatory function, it has no mandatory character, is performed by private groups, at request of the applicant and at a time when the latter feels being prepared for the audit. The audit is focused on the final result: the certificate, not on the report describing the state of affairs. The certificate is not related to quality of any particular product; there is no link to product file (dossier). The sole beneficiary is the applicant; the certificate gives him (or her) market advantage. In practical terms certification is not aimed primarily at protection of public interests.
The most important element “borrowed” by GMP inspection services from ISO certification practice is the internal Quality System of an inspectorate. International guidance on this issue was provided by PIC/S (seminars of 1994 and 1998), WHO and EU (guidelines of 2002 and 2003 respectively). According to these documents a quality system of a GMP inspectorate is aimed at prevention and exclusion of conflict of interest of personnel. The system of obtaining fees should not improperly influence the inspection procedure and results. Independence and impartiality of inspectors should be assured by strict adherence to SOPs, procedures, rules and codes of conduct. According to WHO text, they should not be under control of pharmaceutical manufacturers, and must be assessed and licensed.
WHO further recommends that each inspection report be reviewed in accordance with the quality system of the inspectorate. This allows reports prepared by an individual inspector or by a small team of inspectors to be assessed by management, possibly assisted by the most experienced colleagues. In this process the head of the inspectorate verifies that the inspection has been carried out in accordance with procedures, that recommendations are firmly based on observations and neither of them is biased. As a result the quality of reports is improved, conclusions are more objective and better grounded, and regulatory actions recommended are carefully thought through.
With time certain other approaches of the ISO 9000 certification practice were taken aboard by regulators in the pharmaceutical sector. Examples are: audits as a service at the requests of manufacturers, collection of user fees, emphasis on GMP certificates with little (if any) attention to inspection reports and CAPA. International organizations followed suite. The WHO Prequalification Programme (presently Prequalification Team), the Ph. Eur. Suitability Certificates, the practice of issuing GMP certificates to APIs’ manufacturers by EU regulatory agencies may be quoted in this context.
As a result the development of GMP inspection practices took an unusual pathway: from initial national differences to acceptance of common principles and then in the opposite direction: to alternative approaches, essentially non-harmonized. Presently GMP inspection practice is only partly converged between countries and regions. National procedures differ in many important aspects. Some examples are listed below:
Practice of GMP inspections as a service (at the request of manufacturers) and related financing of this function by user fees merits additional comments. The obvious advantage of this approach is independence of the inspection service from the state budget. It should be noted however that the cost of inspection under this arrangement, though formally met by industry, in fact is transferred to the market price of medicines and thus to the consumer/patient. Also, in certain national settings the credibility of inspection function might be compromised if pharmaceutical sector professionals and general public regard issuance of GMP certificate as a commercial activity. In this context a reference to the scandal with ISO 9000 certificates of 2001* might be made
* On 30 November 2001 Lawrence D. Eicher, ISO Secretary-General has declared “We regularly receive complaints about certificates being awarded undeservedly to companies who have not been properly audited…” (ISO Press releases Ref.: 805).
Another point which usually goes unnoticed is that this approach tends to discourage international collaboration. When inspection function is financed through user fees only, information sharing and work sharing go against economic interests of inspectors. Most probably it is for this reason there is no cooperation in the area of ISO 9000 certification.
The present state of harmonization of inspection practice and resulted mutual trust between inspectorates allows for functioning of certain international agreements and or regulatory flexibility provided by local legislation. The outcome of inspections performed by an EU competent authority is accepted by all other EU authorities. Additionally the European Union
has operational MRAs which include GMP with Australia, Canada, Israel, Japan, New Zealand and Switzerland. Australia has bilateral mutual recognition agreements with Canada, Japan and Singapore. It was expected that the Eurasian Economic Union (Russia, Belarus, Kazakhstan, Kyrgyzstan, and Armenia) would be using the same approach in one way or another. . At present, however, the principle of mutual recognition of inspections is not being implemented within the Union.
Nonetheless advantages of wider mutual reliance and recognition of GMP certificates are not used to their full potential. One of the reasons for this is lack of confidence between national inspectorates which may be related to differences in regulatory capacities and/or proceedings and/or regulations/laws.
15 years ago FIP Industrial Pharmacy Section (IPS) compared the stringency of GMP inspectorates of certain countries. Results shown below support the premise of nonequivalence.
GMP Inspection Thoroughness (in descending order)
by Michael H. Anisfeld, Globpharm Consulting (US based) Presently President, FIP IPS Executive Committee.
However the past five years have seen major changes essentially harmonizing the equivalence of many inspection agencies. The main stumbling block to total GMP equivalence is the different capabilities, and GMP emphasis by different national authorities.
In recent years important developments in GMP inspection are seen in Asia. Apart from Japan mentioned above, countries such as Republic of Korea (South Korea) and Republic of China (Taiwan) are active in overseas GMP inspections of adequate level with considerable attention to detail. Also the People’s Republic of China (Mainland China) conducts such inspections. The latter, however, so far are less demanding due to limited capacity and experience.
A MRA between the European Union and the United States has been signed in 1999 with a chapter 6 on “Pharmaceutical Good Manufacturing Practices (GMPs)”. After performing several observed inspections, the FDA made proposal to have the MRA limited to only some Member States. As the set of observed inspection is finally about to be completed with all EU member states in 2017 and the MRA text was updated it might became effective soon. There is the political agenda to do this independent from the Transatlantic Trade and Investment Partnership (TTIP) as the MRA covers a public health and not a trade subject
Some countries with emerging regulatory capacities tend to copy and translate in non-systematic ways arrangements of stringent regulatory authorities or of neighboring states. Some other countries, e.g. among New Independent States adopt unorthodox approaches, such as creating different structures for domestic and foreign inspections. It may be noted in this context, that WHO discourages copying national regulatory decisions without consideration of wider experience and global/regional trends.
Lack of confidence in GMP inspectorates of other countries leads to repeated inspections of manufacturers (up to 9 inspections per site in a single year) resulting in duplication of efforts and additional expenses both for regulators and for industry. As stated above additional resources are needed and respective costs are finally somehow transferred to patients. Multiple GMP inspections also delay access of the needed medicines to patients as GMP certificates are often mandatory to submit with regulatory filings.
The international harmonization efforts in this area continue. The format of the inspection report e.g. recommended by WHO was recently revised . All in all the package of WHO guidelines on the pharmaceutical inspection is impressive (see selected references). It is, however, fragmented and not complete. Specific documents were published in between 1990 and 2016 and some are due for revision. In view of global trends and recent developments additional efforts seem to be recommended. Possibly there is a case for WHO to revisit its recommendations in the area of updating and combining separate documents into one guide.
The global atmosphere for such a move seems to be favorable. At the recent WHO sponsored 17th International Conference of Drug Regulatory Authorities (ICDRA), Cape Town, S. Africa, 27 November-2 December 2016, opportunities of closer cooperation between international harmonization initiatives on a global level were discussed. The revised MoU between WHO and PIC/S entered into force in February 2016. PIC/S strengthens its collaborative activities with EU (EMA, heads of Medicines Agencies), ICH, and International Coalition of Medicines Regulatory Authorities (ICMRA). Proposal is discussed to allow inspection units of partner organizations to join the Scheme as participating authorities.
The European Federation of Pharmaceutical Industry and Associations (EFPIA) representing research-based companies in EU conducts since 2003 annual surveys on inspections among its member companies. According to data collected from some 660 manufacturing sites worldwide over the past 12 years 64 countries all in all performed foreign inspections. Here and below EU is counted as one country. It means that the real number of countries involved is approaching one hundred.
Over the last few years (2011-2015) the largest number of foreign inspections was performed by countries with stringent regulatory systems: US (90) and EU (some 65). Countries with emerging regulatory capacity, such as S. Korea, Brazil, Turkey, Kenya and Japan, conducted between 20 and 60 overseas inspections each. The third group, consisting of countries with inspection services having limited experience (except for Australia and WHO Prequalification Team), is lagging behind with one to 20 foreign inspections.
Interestingly, while countries of the first two groups in recent years reduced the number of inspections, those in the third group intensified their foreign inspection programmes. One example is China with 5 foreign inspections in 2011 against 16 in 2015. In the same years Belarus quadrupled its results from 3 to 12 foreign inspections.
In 2015 640 manufacturing sites covered by the EFPIA survey received 1495 domestic and foreign inspections. Overseas inspectors came from 34 countries. Most active were inspectors from US, EU, S. Korea, Brazil, Turkey, Kenya and Japan. Almost one half (46%) of inspections were performed by inspectorates that are members of PIC/S, in a country where the inspectorate is also a PIC/S member. Countries with limited capacities, such as Ivory Coast, Colombia, Kenya, Libya, Nigeria, Sudan and Uganda were also active in inspecting manufacturers in many countries worldwide. Out of 1495 inspections 167 (11%) were PAI. Of these 71 were domestic and 96 foreign. Among countries performing PAI those with different categories of inspectorates are found: PIC/S members (Canada, Japan, EU, US, S. Korea), PIC/S accession and pre-accession countries (Belarus, Brazil, Kazakhstan, Mexico), and others (China, Kenya). Five of 640 sites received 15 inspections each in 2015. Fifty two sites were inspected more than four times. 570 sites reported receiving between one and four inspections and 118 were not inspected in the course of that year.
The average duration of foreign inspections is slightly over four days, and one day shorter for the domestic inspections. On the average two inspectors are involved in one visit. Resources needed for one inspection in terms of inspectors/days vary from country to country. For some countries these may be roughly estimated as follows. Equal or over 10 inspectors/days for Taiwan, Mexico, China, US, Canada, Colombia, Saudi Arabia; between 5 and 10 inspectors/days for Canada, Turkey, Brazil, Belarus, S. Korea, EU, Japan and Kazakhstan, and less than 5 inspectors/days for Nigeria, Uganda, Australia, Russia and Kenya.
Data available suggest that inspected companies spend 10 times more resources for the preparation, conduct, and follow-up than regulators. In many cases companies are asked to submit documents prior to visits of inspectors. Involvement of industry’s personnel in the course and post-inspection is estimated on the average as 70 person/days. Average inspection fee is approximately €30,000. For the 2015 oversight of EFPIA member companies costed over 75,000 person/days to regulators and some €80,000,000 to industry.
The following conclusions and recommendations formulated by EFPIA on the basis of the survey merit consideration.
The pharmaceutical industry has become increasingly global. Numerous manufacturing sites (from 6 to 30) located in multiple countries might be involved in the manufacture of one medicinal product. More than one site might need to be registered e.g. to mitigate risk of drug shortages. One site may have several manufacturing licenses which may call for several inspections. As a result not one regulatory agency can inspect all manufacturing sites in the supply chain. It follows that authorities should be aiming to rely on each other’s regulatory oversight where possible based on risk assessment and best use of own resources.
In recent years the number of foreign inspections has stabilized at a high rate. Although cooperation between national/regional regulatory authorities has been noted, there is still significant duplication of regulatory oversight at manufacturing sites. In view of the industry multiple inspections are not always risk driven.
Inspections are resource intensive both for regulators and industry. In some cases the inspection fee is hard to justify. The added value of inspection activity in general is not high. The results of the survey suggest that regulatory resources could be better balanced.
The data available suggest that globally accepted GMP certification system would be beneficial. It may lead to reduced duplication of inspection efforts and would allow resources to be redirected towards higher risk segments of the medicines supply chain. To facilitate mutual recognition of inspections results and to reduce repeated audits GMP inspection procedures, operational principles of responsible authorities in different economies ought to be further converged.
The slide (see figure) presented by Professor Rönninger, Amgen, Switzerland, at the 17th International Conference of Drug Regulatory Authorities (ICDRA), illustrates an important point: reliance on data received from other inspectorates may allow better use of resources with increased number of sites on which information is available.
Courtesy S. Rönninger, Amgen for EFPIA presented at WHO pre-ICDRA, December 2016
The results of the EFPIA review data go a long way in exploring the global landscape regarding GMP inspection practices from the companies’ point of view. These data, however, being focused essentially on statistics of inspections and resources incurred, do not cover all aspects of practical interest. It is suggested that some form of a structured benchmarking with focus on the country point of view under the stewardship of a competent global programmer, such as WHO Essential Medicines and Health Products (EMP). PIC/S obviously is a competent organization in this context. In view of its current membership, very impressive and growing, the support of the Scheme regarding advice on strengthening inspection systems might be of great value.
As a first step in this direction a Survey on national GMP inspection practices is suggested. It may be regarded as a contribution to the global harmonization efforts in the area of regulation of Pharmaceutical industry. Such a facts-finding exercise, if successful, may provide background material for a publication or an information paper. Eventually the outcome of the project may be used in the preparation of a WHO working document to update the regulatory practices.
The proposed project would be complementary to the annual EFPIA surveys. It is seen as a one-time activity aimed at information at the country level and as of this automatically would include the requirements for generic manufacturers. Therefore the questions focus on topics not covered by the EFPIA survey and data assessment. The questionnaire is addressed not to companies but to natural persons. These may have experience of working with industry, regulators, academia, or private consultancies.
Russian pharmaceutical company NovaMedica, a portfolio company of RUSNANO, announces the start of construction of a plant for the production of sterile injectable drugs as part of its long-term strategy to localize innovative medicines and technologies of their development and production in Russia. The plant will be built in the industrial park “Vorsino” in the Kaluga region.
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