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

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).

Facts on inspections

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 Table I. 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 Figure 1. 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

• Establishing GDP and oversight

• 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.

Mutual recognition and mutual reliance

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.

Increase inspection efficacy

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.

Interaction with and within industry 

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.

Paper-based 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 with and within regulators

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 Figure 2, 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.

Conclusion

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.

Acknowledgements

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.

References

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.

Article Details

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

Citation

When referring to this article, please cite it as S. Rönninger et al., "The GMP/GDP Inspections Landscape-Part II: Considerations and Opportunities," Pharmaceutical Technology Europe 29 (2) 2017.