Stephan Rönninger

This paper presents the most recent results from the European Federation of Pharmaceutical Industries and Association’s (EFPIA’s) annual survey and their conclusions. The year 2020 demonstrated the ability of the pharmaceutical industry and regulators to be agile whilst maintaining the same high standards as previous years because of the COVID-19 pandemic.

Inspections of a firm’s manufacturing operation are essential to evaluate commercial manufacturing capability, adequacy of production and control procedures, suitability of equipment and facilities, and effectiveness of the quality management system in assuring the overall state of control (1). Notably, pre-approval inspection (PAI) includes the added evaluation of authenticity of submitted data and link to dossier (1).

Since 2003, EFPIA has conducted and reported an annual survey of good manufacturing practice (GMP) and good distribution practice (GDP) inspections and related International Organization for Standardization (ISO) audits to monitor inspection activity and trends in research-based industry (2–4). The annual survey is performed to shape the future based on data. Companies can compare the results with their own situation.

 A shortened version of this article was published in 

Based on the outcome of the survey results, the efficiency and reliance approaches can be demonstrated. The conclusion of the data assessment supports promoting alternative approaches to inspection with physical (on-site) presence.Harmonizing requirements and expectations will maximize effectiveness and reduce uncertainties for companies and inspectorates. Furthermore, the annual survey intends to demonstrate the benefits of Mutual Recognition Agreements (MRAs) and Pharmaceutical Inspection Co-operation Scheme (PIC/S) membership in optimizing use of inspection resources while maintaining patient safety (5).

As in previous years, the scope of the EFPIA regarding the 2020 regulatory GMP/GDP inspections and related ISO-certification audits included inspections by regulatory authorities and Notified Bodies at manufacturing sites and commercial affiliates for both manufacturing of investigational medicinal products (IMPs) and commercial products. The scope included inspections inside (i.e., domestic) and outside (i.e., foreign) the regulatory authority’s country or region.

EFPIA asked companies in the survey to specify all inspection tools (or a combination of them), including on-site, virtual (‘remote’), or paper-based, as well as reliance and recognition approaches used. The product type manufactured at the site and the duration and outcome of each inspection were reported. Companies also reported the type of inspection and whether inspections were scheduled or unannounced. EFPIA also asked a set of questions related to how inspections had been performed and about the impact of the restrictions during the pandemic.

The 2020 survey received responses from 25 global research-based pharmaceutical companies (EFPIA members) and eight local companies reported by National Trade Associations. Full results are available on the EFPIA website (4). As expected, there were significantly fewer inspections overall in 2020 (approximately –40%, 1106 inspections, compared with 1733 inspections in 2019 and 1748 inspections in 2018 [4]) while the number of manufacturing sites included in the survey was comparable with previous years (

Data from the 2020 survey compared with 2019 and 2018.

The total number of foreign inspections in 2020 was reduced by approximately 50%. However, the number of manufacturing sites without an inspection (domestic or foreign) was in the same range as in previous years (36% in 2020; 26% in 2019; 31% in 2018 [4]). Therefore, the regulatory oversight of manufacturing sites is consistent.

Domestic inspections are defined as inspections performed in the country/region of the inspectorate. In 2020:

There were 453 domestic inspections (including ISO-certification audits) at manufacturing sites, compared to 709 domestic inspections in 2019.

Inspectors spent 2321 days on-site in 2020 for domestic inspections, compared to 4316 days in 2019.

Domestic inspection with physical presence took an average of 3.1 days in 2020 (2.7 days in 2019) at the site, with an average of 6.7 inspector days in 2020 (6.3 in 2019)

The ratio of the inspection type performed was almost unchanged in 2020 compared to 2019; there was no increase in domestic for-cause inspections.

Few domestic inspections (0.3%) resulted in follow-up regulatory action leading to interruption of supply (versus 0% of foreign inspections) and 11% of domestic inspections resulted in follow-up regulatory action, which was not leading to an interruption of supply (versus 7% of foreign inspections).

Foreign inspections are defined as inspections performed in a third country/region to the inspectorate. In 2020:

Twenty-seven different inspectorates (where the European Union [EU] counts as one inspectorate) performed 264 foreign inspections, compared to 36 inspectorates performing 526 foreign inspections in 2019.

The maximum number of foreign inspections of one site was nine.

Foreign inspections with physical presence took an average of 4.3 days (3.6 in 2019), with an average of 9.5 inspector days (7.4 in 2019).

Foreign pre-approval inspections (PAIs) increased from 19% in 2019 to 32% in 2020; foreign surveillance inspections were reduced from 81% in 2019 to 68% in 2020.

All (100%) foreign inspections had a positive outcome (defined as no disruption to product supply or to approval of new product applications).

More than half (51%) of foreign inspections were reported to be conducted by a PIC/S participating authority in a country where the inspectorate is also a PIC/S participating authority).

Locations of inspected manufacturing sites. 

Over 50% of all inspections reported were at sites in Europe, indicating that research-based manufacturers have a strong presence in this region. The locations of manufacturing sites for foreign inspections are shown in 

, along with a breakdown of EU member states (including the United Kingdom, for 2020).

Locations of manufacturing facilities hosting foreign inspections. 

[ALL FIGURES ARE COURTESY OF THE AUTHORS]

The pandemic restrictions drove the need for inspectorates to use alternative approaches to on-site inspections at manufacturing sites and affiliates after 1 March 2020.

Use of the virtual (‘remote’) tool, document reviews (paper-based inspections), and the hybrid approach (virtual and on-site) increased in domestic inspections; nevertheless, a large percentage of domestic inspections were still conducted on site after the outbreak.

Use of virtual (‘remote’) tools and document reviews (paper-based inspections) increased in foreign inspections and the proportion of inspection with physical presences was reduced.

The number of inspections decreased from >200/month before the outbreak to around 125/month after 1 March 2020.

Some data remained unchanged, for example:

The proportion of unannounced versus scheduled inspections has remained consistent since EFPIA started collecting these data in 2015, with scheduled domestic inspections around 60%, scheduled foreign inspections around 32%, unannounced domestic inspections around 7%, and unannounced foreign inspections around 1% of the total.

The outcome of unannounced inspections at manufacturing sites is comparable to those that are announced: there are around 87% of scheduled inspections and 95% of unannounced inspections having no follow-up actions to be provided by the company. These proportions are consistent since EFPIA started collecting this specific data in 2015.

Companies’ answers to survey questions revealed the following:

No change in the number and severity of observations was reported.

No significant differences in the outcome of GMP-, GDP-inspections, or ISO certification audits were reported.

Companies (>90%) reported no change was observed in the number or type of observations.

Individual companies reported shifts in observations towards quality system areas, risk-assessment thoroughness, documentation accuracy, documentation practices.

Companies reported no challenges regarding drug shortage prevention measures.

Trends in the number of reported foreign inspections are summarized in 

. While the member of foreign inspections performed by Russia and Japan are constant all other inspectorates reduce the number of foreign inspections in 2020.

Trends in the number of foreign inspections. PIC/S is Pharmaceutical Inspection Co-operation Scheme, EU is European Union. USA is United States of America, EAEU is Eurasian Economic Union.

Efficient application of inspection process and tools

In 2020, the pandemic revealed the range of tools available to inspectorates and the flexibility offered by the toolbox for conducting inspections using physical presence, document review, virtual presence, and experience, recognition, and trust. Implementation of these tools confirm compliance and capability implementing efficient risk-based approaches (

). Inspectorates used a variety of tools stand-alone and in combination (4). The tools are not equivalent for the knowledge gained and trust applied. Each approach has challenges and opportunities.

 Inspectorates used a variety of tools in 2020. GMP is good manufacturing practice, GDP is good distribution practice, PAI is pre-approval inspection.

The COVID-19 pandemic impacted the ability of inspectorates to be present on site to perform inspections.

More than 80% of domestic inspections had at least a partial on-site presence. In conclusion, most domestic inspections still occurred with an on-site facility review after the outbreak of COVID-19, which we dated to 1 March 2020 when restrictions started.

Less than 25% of foreign inspections were conducted with on-site presence (compared to >80% in previous years); inspectorates that did use on-site presence for foreign inspections included Belarus, EU, and United States.

The virtual (‘remote’) tool offered a logical alternative for inspectorates mostly adopted for performing foreign inspections in 2020 (6,7). Implementing this tool varied: it was used, for example, mainly by EU inspectorates (which employed virtual and on-site tools in 50:50 ratio), Republic of Korea, and Russia (

 Examples of inspectorates varying in their use of inspection tools.

 No agency was reported to use a hybrid approach (e.g., on-site and virtual) in foreign inspections. This hybrid approach was used mostly for domestic inspections, for example by European Union (EU) member states and Switzerland.

Some inspectorates used a hybrid approach, with a combination of on-site presence and the virtual tool. This combination was used mostly for domestic inspections (

). Use of the virtual tool alone was reported for domestic inspections by EU inspectorates (including Belgium, France, Germany, Ireland, Poland, and UK), the US, and Brazil.

Feedback provided by companies on the use of the virtual tool varied. Some companies reported technological and privacy issues, and difficulties with time zone management. The point was made that certain inspectorates (e.g., Russia) did not make it clear that the inspection had finished (i.e., no additional discussions are needed to formulate the regulatory decision). Companies reported that a defined agenda would be useful. Other companies reported that a longer time was needed when preparing for a virtual inspection, with many more documents being requested in advance than with other tools. It seemed that both industry and regulators were on a learning curve with the application of the virtual tool. Nevertheless, inspections proceeded at a time when travel was severely restricted.

Note that there was uncertainty in the 2020 data evaluation about the number of inspector days used for virtual inspections. If a company named more than 10 days for a virtual inspection, we set the value to 10 days. Our reason for this value was because we assumed that not all days specified by the company were full days when the inspection was performed. Similarly, with paper-based inspections, some companies reported the start and end date of a paper-based inspection, even if the days in between were not used. Thus, the duration of paper-based inspections was not accounted for.

Documents to be submitted prior to an inspection continued to be used as a tool in 2020, when there were 139 paper-based inspections (compared to 62 paper-based inspections in 2019) reported, primarily involving inspectorates from Japan (40%), US (10%), Republic of Korea (7%), and Turkey (7%).

Although document reviews without virtual interaction or physical presence of the inspector can be less time-consuming for a company and inspectors, provision of documentation still uses resources, and the document request process is not currently harmonized. Companies can be asked to provide documentation in advance not just for paper-based or virtual inspections, but also for all inspections with physical presence. In addition, translations may be required with the risk of misinterpretation, even with the best translation service. This process can be time consuming. Data from a separate survey in 2020 revealed that up to 700 documents, of a broad variety, have been requested before an inspection with a physical presence (4).

In 2020, there were seven inspections (five foreign; four of them as of an MRA or Memorandum of Understanding [MoU], and two domestic) reported where it was indicated that licences had been renewed without performing an inspection (’waived’ inspections). EFPIA advocates the use of waivers and leveraging the benefits of fully implemented MRAs. An effective risk management process adopted by the inspectorate (8) allows for waivers. Waivers are increasingly granted for sites located in a country where a formal MoU is established or in a country where the inspectorate is a member of PIC/S, provided that all tools required (e.g., on-site, virtual, paper-based, reliance on prior knowledge) are available.

Inspections by the EU in the US have dropped by 80% since 2017 (

). The study revealed that there were 50% fewer foreign inspections by the US in the EU compared with 2019 (when the MRA between the two territories was fully implemented). It is expected that this trend will continue going forward, and the observed reduction of inspections is not just a reflection of pandemic restrictions or government shutdowns due to the budget situation in the US.

 Number of foreign inspections by United States in European Union and vice versa.

The COVID-19 pandemic caused a significant reduction in the number of inspections in 2020, but there was no discernible drop in oversight of manufacturing facilities ensuring that industry maintained high standards of quality, safety, and efficacy of medicines. The authors feel that lessons learned from this year’s survey could be permanently implemented, in compliance with existing legislation (9).

Risk-based approach for inspection planning. 

A risk-based approach to planning and conducting inspections was used more effectively in 2020, and the authors advocate that it will continue in future years, using the PIC/S guidance on risk-based inspection planning (8). This approach facilitates planning of inspections by regulators by providing risk ranking of sites, along with a suggestion for the number of inspectors and scope (including focus and depth) of the next surveillance inspection.

Best use of the different inspection tools. 

The pandemic drove companies and inspectorates to seek new, innovative tools to provide alternatives to inspection with physical presence. The virtual tool was used extensively; although companies reported certain difficulties. It was an enabler for an informed compliance decision by the inspector. Some companies found it difficult to interact virtually, especially if they experienced technological problems or if an interpreter needed to be used. In this case, the involvement of local affiliates in foreign virtual inspections may allow better communication. Hybrid approaches (i.e., a combination of virtual and physical presence) could be valuable in future years. Application of virtual tools can confirm compliance while replacing a physical presence or a document assessment by issuing a GMP-certificate to guarantee continuous patient access, for example. The authors acknowledge the variety of opinions on the interpretation of the legislation, if virtual assessments can be used as the basis for a legal decision to confirm GMP compliance and capability of a site to manufacture a product but understand that gaining knowledge using virtual tools is better that only do a document review. It is most important that in the end, patients continuously receive good quality medicines (9).

Inspectorates also made more use of existing tools, particularly paper-based inspections. Supporting document reviews as part of inspections, EFPIA recommends that a standard set of documents could be agreed upon the various harmonization initiatives to be available for each site to the inspector (5). The use of such a globally aligned and consistent list of required documents in English, as acceptable would enable advanced preparation and ensure consistent documentation reviews. This would simplify the process by eliminating variability in the requested documents. Such variability results in a time-consuming nonvalue added exercise for the collection of a very large number of documents (

: Proposed standard document package for consideration by Pharmaceutical Inspection Co-operation Scheme based on a separate survey of 270 data points (1 January 2019–31 June 2020) supported by 11 companies.

Potential differences in terminology could be harmonized, for example by PIC/S, that local regulators could use to develop a specific glossary linking local terminology with these harmonized terms. This standardized package would allow streamlining of efforts so that companies and inspectors could be more focussed and effective.

Although the number of inspections overall was reduced significantly, the proportion of sites undergoing an inspection remained comparable with previous years. This suggests that there has been duplication of inspections in previous years, a situation that we are seeking to improve.

Despite the reduced number of inspections, industry continued to deliver safe and effective medicines of an appropriate quality, although companies noted delayed approvals because of postponing scheduled pre-approval inspections. Whether there will now be a surge in PAIs remains to be seen. The authors suggest that the duration of a PAI could be reduced at least, for example, to one day focussing on the clarification of the content of the dossier by referencing the results from surveillance GMP inspections (e.g., by a PIC/S member inspectorate or under existing MRAs, such as the EU-US MRA, which is an agreement for recognition of inspections, including PAIs). We encourage continuing the discussions of the scope of that and other MRAs to improve efficiency in planning and performing of all types of inspections.

The robust domestic inspection system that was evident in 2020 (10) can be leveraged going forward to allow reduction in redundant on-site foreign inspections. EFPIA supports the global implementation of the harmonized PIC/S (11) and WHO reliance guideline (12) to perform remote assessment of GMP facilities based on reliance. The guideline describes how “

informed decisions on the GMP compliance of a manufacturing facility can be made, in certain circumstances, based on the outcome of work by another regulatory authority or authorities

” (11). It allows for reliance outside of existing MRAs and recommends confirming GMP compliance based on available data, where appropriate, to reduce regulatory burden and allow a more efficient deployment of global resources to bring products to patients much faster.

Lessons learned from GMP/GDP inspections during the pandemic. 

The COVID-19 pandemic showcased opportunities for future adoption in the GMP/GDP inspection practices.

Increased reliance on decisions by recognized inspectorates (e.g., PIC/S participating authorities)

Further development and implementation of MRAs

Inspection waivers granted automatically if an inspection report by a recognised inspectorate is available (‘unilateral waivers’).

We believe that the legal requirements for GMP/GDP inspections can be fulfilled with increasing application of reliance approaches based on the positive experience gained during the pandemic, because there was no negative impact observed on the oversight of compliance of manufacturing facilities (13).

The following opportunities to optimize the inspection process based on the EFPIA 2020 survey outcome could be considered:

reliance on available information about inspections at a manufacturing site

standardization of the package of documents to streamline efforts for all inspection types

focus on domestic inspections and on sites never inspected before.

Agencies’ risk-based inspection planning approaches could recognize all available inspection tools (i.e., physical or virtual presence), review of and reliance on documents, or considering combinations of those tools. Furthermore, EFPIA suggests leveraging existing MRAs such as those between EU–Japan, EU–US and accepted comparable standards like inspections conducted by an inspector from a PIC/S participating authority as an opportunity to simplify the inspection process (4,11).The results from the survey on the 2020 data reveal that inspectors ask for many documents, especially since the pandemic, to be submitted prior to the inspection, which is very time- and resource-consuming for industry (4). Inspections with virtual presence increases knowledge. This can provide better bases for decision-making, rather than just requesting and reviewing paper documentation. Finally, a regulatory decision on GMP compliance and capability of the manufacturing site will support a smoother regulatory approval process leading to earlier and continuous access of medicines to patients (14).

The authors thank the other EFPIA inspection topic team members for the discussion: Janeen Skutnik Wilkinson, Biogen; Julien Parain, Sanofi; Sinéad Redmond, BMS; Ute Lichtenberg, Bayer; Véronique Davoust, Pfizer and Michele Hunter for support as well as Nidia Acevedo, Dinesh Khokal and Mark Schweitzer at Amgen.

1. ICH Quality Implementation Working Group, 

Implementation of ICH Q8, Q9, Q10: Inspection,

 Training Programme (November 2010).
2. S. Rönninger, et al., 

, 29 (1) 6–10 (2017).
3. S. Rönninger, et al., 

Annual Regulatory GMP/GDP Inspection Survey 2020 Data

, Summary Document, 17 May 2021. Further information is provided, taken from the raw data (summaries from previous year as also published).
5. EFPIA, 

Enhanced Good Manufacturing and Good Distribution Practices (GMP/GDP) Inspection Efficiency

, Position Paper, Final v8a, 19 May 2014.
6. EMA, 

Guidance Related to GMP/GDP and PMF Distant Assessments

, Guidance Document, 15 Oct. 2020.
7. FDA,

Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency

Guidance for Industry (April 2021).
8. PIC/S, 

A Recommended Model for Risk-Based Inspection Planning in the GMP Environment

, Recommendation, 1 Jan. 2012.
9. EFPIA, 

Alternative GMP/GDP Inspection Practices in a Pandemic Situation (COVID-19) and Beyond

, Reflection Paper, Final v3, 28 May 2020.
10. PIC/S, 

COVID-19 Risk Assessment for National Routine On-Site Inspections

, Assessment Form, 15 July 2021.
11. PIC/S, 

, Guidance Document, 1 June 2018.
12. WHO, 

Annex 10: Good Reliance Practices in the Regulation of Medical Products: High Level Principles and Considerations

Opportunities for Optimising the GMP Inspection Process Post Pandemic

IFPMA Position on Convergence of Good Manufacturing Practice (GMP) Standards and Related Inspections

 sroennin@amgen.com, director, Quality External Affairs, Amgen (Europe) GmbH (corresponding author); 

, vice director, External Collaboration Europe, F. Hoffmann-La Roche Ltd.; and 

, quality assurance head, Almirall.
*To whom all correspondence should be sent.


Vol. 33, No. 11
November 2021
Pages: 36–39

When referring to this article, please cite it as S. Rönninger, A. Kurz, and F. Raya, “GMP/GDP Inspections: Challenges and Opportunities from COVID-19,” 

Articles

An annual survey on inspections and audits has revealed opportunities to use more flexible approaches to optimize processes.

GMP/GDP Inspections: Challenges and Opportunities Revealed by the COVID-19 Pandemic

	The European Federation of Pharmaceutical Industries and Associations (EFPIA) conducts an annual survey of inspections among its member companies, which are research-based pharmaceutical firms. The data (1) generated demonstrated the workload, the use of resources, and the outcome of inspection practices for the oversight of good manufacturing practice (GMP) and good distribution practice (GDP) by domestic and foreign regulatory authorities. Member companies are confronted with more inspections of their manufacturing sites by authorities from other countries (i.e., foreign inspections). Part II of the article describes additional challenges and opportunities to improve inspection efficiency, based on data from the survey (1).

	Industry and regulators have made the point that inspections are resource-consuming. Here are some calculations based on the data (1).

	Estimated resources involved in inspections

	Based on data from the EFPIA survey, an estimation of resources per foreign on-site inspection is given in 

. For on-site inspections, many companies were asked to submit documents prior to inspections. The data showed that the submitted documents helped to focus and reduce the inspection time on-site. The preparation effort might additionally be driven by specific requirements from individual inspectorates. Compared to the regulators, the inspected companies needed 10 times more resources for preparation, conduct, and follow-up of inspections.

	Resources calculated as the duration of inspections

	The average duration of foreign inspections by country, where more than four inspections were performed (not including paper-based inspections), is shown in 

. Based on the 2015 data of inspections at manufacturing sites, the following can be calculated:

		On average, two inspectors come for each inspection

		Foreign inspections last, on average, 4.1 days at the site, requiring 8.6 inspector days

		Domestic inspections use, on average, 3.1 days per site, requiring 6.4 inspector days

		The industry requires approximately 160 person days for preparation, conduct, and follow-up of inspections

		An average inspection fee is assumed to be €30,000.

	For inspectorates, it is assumed 20 person days per inspection (including pre- and post-inspection and travel for experts and participants from corporate departments). For the 486 inspections in 2015, the sum is estimated to be up to 9720 person days.

	The 2015 survey (1) asked seven questions on specific and general issues related to inspection practice. These questions covered, for example, noticeable change regarding how inspections have been conducted; unique question content in the scope of inspection that had not been expected; topics raised in inspections that are beyond the announced scope of the inspection; the approach taken by inspectorates to identify data-integrity topics; and if the national agency implemented a risk-based approach for scheduling/conducting inspections.

	A summary of the received responses on all the specific questions conclude the following priorities of inspection practices:

		Data integrity with focus on quality control laboratories, pharmacovigilance data, and the manufacturing environment, including the corporate environment

		Sterile manufacturing processes and operations

		Approaches for application of new and revised or not yet implemented guidelines. Some answers reflected this area to be an “unusual inspection practice” that might represent an opportunity for inspectorates for training of new staff or to challenge regulations in practice.

	Considerations to optimize inspection practice

	After 12 years of data collection, EFPIA recognizes that there are significant opportunities for better use of resources and suggests the following points for consideration to optimize inspection practice:

		Inspections should be scheduled and conducted using a risk-based methodology. The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) model for risk-based inspection planning in the GMP environment could be used as a basis for inspection planning (2).

		Regulatory authorities should give first priority to ensuring that manufacturers and affiliates in their own territory are compliant through adequate local oversight. To this end, information in the EudraGMDP database should be kept up-to-date.

		Foreign inspections should be conducted only if deemed necessary. First of all, such inspections can be facilitated through application of the principle of mutual reliance. Where possible, regulatory authorities should aim to rely on the partner authority’s supervisory oversight, based on risk and best use of resources.

	Currently, the exchange of inspection reports and company responses does not seem to reduce the number of inspections; instead, this information is used often as a preparation step for upcoming inspections. Resources could be better leveraged by mutual recognition or reliance on inspection outcomes from trusted inspectorates, for example, from PIC/S member inspectorates. In 2013, EFPIA proposed in a position paper that PIC/S member inspectorates should agree on equivalence of the domestic GMP requirement (3). This approach could lead to opportunities to reduce the number of redundant inspections by relying on inspections previously conducted by other members who maintain harmonized standards.

	Statutory agreements, in the form of mutual recognition agreements (MRAs) or memoranda of understanding (MoU), also offer an opportunity to reduce the number of inspections. For example, the United States is committed to bilateral and multilateral dialogue with other countries (e.g., in form of a MRA with the European Union independent of the Transatlantic Trade and Investment Partnership [TTIP]).

	In the longer term, inspection reports along with the inspected company’s responses could be shared in an international inspection database, provided confidentiality issues are addressed and respected.

	The EFPIA position paper of 2014 (4) proposes effective and balanced risk-based regulatory oversight to improve the use of resources. Inspection efficiency can be improved by harmonization of standards and regulatory processes including:

		Certification process for regulatory inspectorates

		Risk-based approach to inspection planning and scheduling

		Standard data packs for on-site and paper-based inspections for faster provision of information as well as better facilitation and use of resources

		Standard terminology for categorization and ranking of observations, and standard reporting template

		Globally accepted GMP/GDP certificate format to document compliance of an inspected siteGlobal database for sites approved by certified inspectorates. The EudraGMDP database is a source of compliance information of sites inspected globally. EFPIA encourages regulatory agencies from outside the European Economic Community (EEC) and MRA countries to use this platform. EFPIA further suggests global product numbers (International Organization for Standaradization [ISO] Identification of Medicinal Products [IDMP]) could be incorporated into this database.

	It is proposed that shared inspection outcomes may avoid duplication of effort and help facilitate early access to markets. The reasons for performing unannounced inspections are well understood; however, comparison of the outcomes from the EFPIA survey shows no difference, either for domestic or foreign inspections. The only difference is that unannounced inspections need longer to gain access to experts than announced inspections.

	EFPIA has proposed the development of a standardized preparation documentation package to enable faster provision of information and better facilitation and use of resources (4). This package could include:

		Site-related information: site master file (PIC/S SMF)

		Product related information: annual product/annual quality reviews

		Quality system-related information: quality manual (reflecting quality management system)

		Additional compliance information: GMP/GDP certificates for the site, list of inspections, list of internal audits and number of customer/contractor audits, major changes, rejected batches, out of specifications, and others.

	Interaction between regulatory authorities might facilitate waivers for inspections. Time to market could be improved if inspectorates exchanged data on inspection activities, including pre-approval inspections. The industry would benefit from a harmonized guidance for inspectorates defining documents to send for a paper-based inspection prior to an on-site inspection.

	Interaction with and within inspectorates. EFPIA encourages PIC/S member inspectorates to rely on conclusions from domestic inspections by PIC/S members. The industry understands that PIC/S does not have a legal obligation to share information, but PIC/S membership does have the opportunity to increase mutual reliance. The data show the potential to take advantage of resources that could be redirected to domestic oversight or higher risk sites. As shown in 

, 46% of foreign inspections were conducted by PIC/S member inspectorates; these inspections resources could be saved by relying on the results of inspections already conducted, such as the GMP certificate of an inspectorate that is a member of PIC/S. To create greater efficiencies, while maintaining an effective programme, the authors believe it is worth encouraging PIC/S member inspectorates to rely on conclusions from domestic inspections by PIC/S member inspectorates.

	Furthermore, the existing EU/EMA joint inspections process can be extended to include the local regulatory authority in foreign countries to provide greater efficiency with the same inspection. The continued use and success of risk-based approaches as applied by long-time PIC/S members can be a role model for new PIC/S member inspectorates to continue building confidence in other PIC/S member inspectorates.

	PIC/S member inspectorates could reference PIC/S-GMP requirements in their inspection report or in a comparison table with the local requirements. In addition, another aspect that the authors believe to be worth considering, is to extend the sharing of inspection reports among PIC/S member inspectorates at a harmonized platform (e.g., EudraGMDP). Continuous education is encouraged, and useful sources include PIC/S trainings/seminars and the PIC/S Inspectors Academy, which can help to build trust among inspectorates. Finally, PIC/S could facilitate mutual reliance on inspections by adopting local statutes.

	The pharmaceutical industry has become increasingly global, and new risks have emerged, such as falsification of medicines. Although increased cooperation between regulatory agencies has been noted, there is still significant duplication of inspection oversight at manufacturing sites. Avoidance of inspection duplication would allow resources to be directed towards higher risk areas of the supply chain.

	Although the number of foreign inspections has not increased, it has levelled at a high number (1). In the 2015 survey, 640 sites from innovative medicine manufacturers received foreign inspections, costing more than 75,000 regulator hours and €80,000,000 spent by EFPIA member companies.

	Globally accepted certification systems have proven to be efficient and effective in other industries, such as aviation, nuclear energy, and food. EFPIA advocates the use of a globally accepted GMP/GDP certificate format to demonstrate compliance of an inspected site. Such certificates should be available on a public database. EFPIA suggests that harmonization of inspections of pharmaceutical products is possible, in which the right quality in the lifecycle of inspections is balanced through making best use of resources.

	Data were evaluated by the following members of the EFPIA GMP network reporting to the Technical Development Expert Group (TDEG): Stephan Rönninger, Amgen (Moderator); Johanna Berberich, Bayer; Véronique Davoust, Pfizer; Peter Kitz, Bristol-Myers Squibb; and Andreas Pfenninger, Interpharma. Support was provided by Gerd Fischer, Boehringer Ingelheim. The authors thank Michele Hunter for technical writing.

	In addition, that authors thank the companies that provided input to the survey in 2015 and before: AbbVie, Almirall, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Biogen, Bristol-Myers Squibb, Eli Lilly and Company, Grünenthal GmbH, GlaxoSmithKline, Johnson & Johnson, Merck (MSD), Merck Serono, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Servier, Takeda, and UCB.

	1. S. Rönninger et al., “The GMP/GDP Inspections Landscape--Part I: Data,” Pharm. Tech. Europe 29 (1) (January 2017).
	2. PIC/S, A Recommended Model for Risk-Based Inspection Planning in the GMP Environment, PI037-1 (January 2012).
	3. EFPIA, A Concept for Harmonized Reporting of Inspections, position paper (May 2015).
	4. EFPIA, 

Enhanced Good Manufacturing and Good Distribution Practices (GMP/GDP) Inspection 5

. Efficiency (May 2014), accessed July 2016.

	Pharmaceutical Technology Europe
	Vol. 29 No. 2
	Pages: 5-9

	When referring to this article, please cite it as S. Rönninger et al., "The GMP/GDP Inspections Landscape-Part II: Considerations and Opportunities," 

The authors look at challenges and considerations to continuously improve inspection efficiency.

The GMP/GDP Inspections Landscape—Part II: Considerations and Opportunities

	Good manufacturing practice (GMP) inspections are fundamental for ensuring that medicinal products are produced to the high standards required for patient safety. The European Federation of Pharmaceutical Industries and Associations (EFPIA) represents research-based pharmaceutical companies in Europe. For reasons of transparency, EFPIA conducts an annual survey of inspections among its member companies. The data generated demonstrate the workload, use of resources, and the outcome of inspection practices for oversight of GMP and good distribution practice (GDP) by domestic and foreign regulatory authorities.

	Member companies are confronted with more inspections of their manufacturing sites by authorities from other countries (i.e., foreign inspections). The purpose of this data collection is to create awareness and develop potential opportunities to redirect resources toward better site coverage and, therefore, protection of the patients. Part I of this article reports, for the first time, the results of the annual inspections survey. Part II will look at additional challenges and opportunities for improving inspection efficiency (1).

	According to the International Council for Harmonization of Technical Requirements for Human Use (ICH), inspections of a firm’s manufacturing operation are essential to evaluate commercial manufacturing capability, adequacy of production and control procedures, suitability of equipment and facilities, and effectiveness of the quality management system in assuring the overall state of control. Notably, pre-approval inspections include the added evaluation of authenticity of submitted data and link to dossier (2). Inspections of a firm’s manufacturing operations assess GMP and GDP compliance and are legally required for drug (medicinal) products in most countries worldwide. In some regions, inspections of API manufacturers are also mandatory. Furthermore, relevant regulations for quality systems (3) require companies to have an independent auditing scheme of their sites, contractors, and suppliers. Recent emerging regulations require regulatory authorities to inspect manufacturers in the countries where the medicines and APIs are produced.

	Objective, scope, and definition of the EFPIA survey

The objective of the annual survey is to provide awareness of global health authority inspection activity, focusing on duplicate inspections as a means of determining the value to the patient while controlling risk. Through the annual survey, EFPIA aims to encourage regulatory authorities to focus their resources on activities that pose higher risks to patient safety and to drive a collaborative approach among health authorities in inspection practice and sharing of inspection outcomes. EFPIA recognizes that convergence in activities between regulators is essential to effectively evaluate commercial manufacturing capabilities.

	The EFPIA member companies reported inspections at companies of research-based manufacturers. The numbers should be seen as a snapshot. Aspects of the survey are as follows:

		Regulatory GMP/GDP inspections conducted at manufacturing sites and affiliates, inside and outside the regulatory authority’s own borders, including related International Organization of Standardization (ISO) certifications (e.g., for combination products/medical devices) are included in the data.

		Only companies that own facilities are reported, as inspections of contract manufacturers might be counted twice.

		Sites that manufacture both human and veterinary products are included in the scope of this survey. Other inspection types (e.g., on pharmacovigilance aspects [GPvP], inspection on narcotics, and environmental safety) had been reported in some cases, but not assessed.

		Sites manufacturing exclusively veterinary products are not reported.

	In addition to the data collection, there are specific questions concerning inspection activities that are adapted each year to reflect areas of particular interest to EFPIA. The definitions used in the survey are available online (listed online in 

	Over the span of the survey so far (2003 to 2015), data have been collected from approximately 660 manufacturing sites annually. Conducting and receiving inspections involve considerable regulator and industry resources. There were 486 foreign inspections and 693 domestic inspections, which required 3951 foreign inspector days and 4456 domestic inspector days. It should be noted that these days were spent by regulators only; industry resources are not included in the figures. Also, these days do not include resources used for paper-based inspections or inspections where no inspector days had been reported. Less than 10% of the inspections were reported as unannounced. Whether announced or unannounced, there was a high level of compliance (more than 95% of the inspections had positive outcomes, with no regulatory action required).

	Inspectorates performing foreign inspections

	Over the past 12 years, 64 countries have performed foreign inspections. In 2015, 34 countries performed foreign inspections, compared with 40 in 2014 and 31 in 2013. The survey results showed the number of foreign inspections per country in 2015 (see 

). Group 1 is formed by countries performing more than 60 foreign inspections; Group 2 is for countries performing more than 20 and less than 60 foreign inspections. In addition to those shown in Figure 1, there were also seven countries where one foreign inspection was made.

	The data show that countries in Group 1--the United States and the European Union (where all EU countries are counted as one inspectorate)--perform approximately twice the number of foreign inspections compared with countries in Group 2. A trend analysis of survey data from 2011 to 2015 revealed:

		A downward trend in the number of foreign inspections being performed annually by Group 1 and Group 2 countries from 2011 to 2015 with some exceptions.

		An upward trend in the number of foreign inspections being performed annually by other countries (e.g., China performed five foreign inspections in 2011 compared with 16 in 2015; Belarus performed three foreign inspections in 2011 compared with 12 in 2015).

		Analysis of foreign inspection activity between the ICH founding members of the US, EU, and Japan in 2015 revealed the following:

		The US performed 62 foreign inspections in the EU, compared with 104 inspections in the previous year. It performed no inspections in Japan in 2015, compared with one inspection in 2014.

		The EU performed 35 foreign inspections in the US, compared with 36 in 2014; it conducted no inspections in Japan, compared with one inspection in 2014.

		Japan conducted 12 inspections in Europe in 2015, compared with 23 in 2014; it performed 10 inspections in the US in 2015, versus 19 inspections in 2014.

	There were significantly fewer inspections from the US in Europe (approximately 40%) and from Japan in the EU (approximately 48%). Similar reductions had been reported in the 2014 data.

	The maximum number of inspections at a single site within one year has been reported to be 15, including seven foreign inspections. The same workload for foreign inspections had been reported by five sites. Overall, 52 sites received more than four inspections in 2015, 570 sites report having between one to four inspections in 2015, and 118 did not receive any inspections in 2015. Although the number of sites with no inspection is decreasing, indicating better overall coverage, there are still sites that are not inspected. This observation might suggest that resources could be better balanced.

	The survey asked for specific data from sites receiving multiple inspections, with the aim of addressing the question: “Are multiple inspections driven by risks?” It was noted that one manufacturing site can have several manufacturing licenses, thus there can be a need for several inspections at the same geographical location. However, there was no clear indication that these multiple inspections were always driven by risk. The data also confirmed that there is always intensive domestic oversight.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has conducted an annual survey of GMP/GDP inspections at sites and affiliates among its member companies from 2003 until the present time. This article describes findings of the EFPIA annual survey of site inspections among its member companies.