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Sean Milmo is a freelance writer based in Essex, UK.
Delays in revisions to guidelines by the European Union are impeding the pharmaceutical industry.
The European Union has a lengthening queue of revisions and other changes to good manufacturing practice (GMP) guidelines, which is worrying industry because of the impact the delays are having on pharmaceutical businesses, particularly investment decisions. The guidelines comprise key sections of the EU’s GMP guide, which also includes good distribution practice (GDP).
Among the areas covered by the revised or new guidelines are sterile products, imported medicines, data integrity, drug device combinations (DDCs), investigational medicinal products, and streamlining of information on the GMP responsibilities of marketing authorization holders (MAHs). In a joint letter to the European Medicines Agency (EMA), sent in October 2018 on behalf of 13 trade associations and professional associations, Sini Eskola, regulatory, drug development, and manufacturing director at the European Federation of Pharmaceutical Industries and Associations (EFPIA), said the topics covered by the guidelines were ‘urgent’ (1).
The delays have been exacerbated by the disruption to the operations of the EMA’s expert committees, particularly the GMP/GDP inspectors working group (GMDP IWG) as a result of Brexit. The planned withdrawal of the United Kingdom from the EU has forced EMA to move its headquarters from London to Amsterdam to ensure it was based in an EU member state.
The IWG and other specialist committees have had to confine their work on revisions to four guidelines on the manufacture of sterile medicinal products, guidances for medicine importers, a reflection paper on GMP and MAHs, and on quality requirements for DDCs. Scheduled activities on other guidelines were temporarily suspended in October 2018, and are anticipated to last for at least a year according to EMA. Even with those guidelines on which revision work is continuing, activities have been slowed down without any new target dates for completion or meetings with industry representatives being announced.
“More transparency on the actual status of these few projects shortlisted (for continued work) would be more than welcome as currently industry has no idea when the IWG would communicate back or when it foresees further actions,” Koen Laenen told BioPharm International. Laenen is regulatory affairs and quality manager at Medicines for Europe, which represents generics and biosimilars producers and was one of the signatories of the joint letter to EMA. “For 2019, no stakeholder meetings with industry are foreseen by IWG,” he continued. “This is a long period for no official meetings with different stakeholders.”
Despite the hold-up in the IWG’s operations, the industry is pressing for a continued dialogue with the group, preferably through face-to-face meetings on some issues. The need for consultations with stakeholders, especially industry representatives, is a major reason for the length of time it can take to revise or draw up new versions of GMP guidelines. A consultation period after the publication of a draft, the processing of comments and then the finalization of the guideline, can extend to one-to-two years.
Once a guideline is completed, there can be further delays while the industry and EMA or the European Commission-the EU executive to which the agency is accountable-sort out how the new or modified guideline should be implemented.
This is what has happened on a new, lengthy guideline on the manufacture of sterile medicinal products, work on which started in 2014 with a draft being published late in 2017, and a consultation period being completed in March 2018. However, its finalization has been held up because of disagreement of how it should be implemented, which is unlikely to be resolved until the IWG is fully operational again.
The new guideline, which comprises Annex 1 of the EU GMP guide, has tripled in size from its 16-page original document, which was introduced in 1971, to a 50-page document. The enlargement contains the principles of quality risk management to “ensure that microbial, particulate, and pyrogen contamination associated with microbes is prevented in the final product” (2).
Other additions include details on the use of new technologies, also mainly to provide protection against particulates and microbes. Another expanded area is the training and skills required of personnel to ensure they have the appropriate engineering and microbiological knowledge.
The complexity and detail of the guideline is expected to lead to the closure of sterile capacity serving the European market in anticipation of its extra costs. “[On the basis of] the current draft, we expect that for several sterile manufacturing sites, the capacity for some products will be reduced by 50% during the [guideline’s] implementation phase,” Laenen explained. “This implementation phase could be lengthy, amounting to several years. Hence, reduced sterile production capacity could occur for products that are already on [the World Health Organization’s] WHO’s shortage list. It’s important also that once the new Annex 1 is adopted, inspectorates are treating and interpreting it in a uniform way to prevent differences in audit findings and outcomes.”
The additional work the industry is wanting EMA to perform on the guideline could postpone its full implementation even further. In their joint letter to the agency, the trade associations and professional organizations have asked for the opportunity to provide further feedback to the IWG before the document is finalized. This is because of the large number of comments submitted during the first consultation round.
The industry wants workshops, seminars, and training sessions to be held to achieve a clearer understanding between the pharmaceutical sector and the inspectorate on the purpose, scope, and expectations of the guideline’s risk-based approaches. There is a need to understand more clearly how the risk control measures in the guideline help to enhance levels of sterility, according to the joint letter. To enable a “harmonized understanding and implementation” of the new guideline, industry suggests in the letter that training materials be developed for both pharmaceutical companies and regulators.
Finally, industry wants at least parts of the guideline to be implemented gradually over a period of up to five years because of risk assessment requirements and the complexity of the changes. One area likely to cause complications, for example, is the risks created by poor quality control of filters, which may necessitate pre-use, post-sterilization integrity testing.
A large proportion of guideline revisions have been triggered by the establishment of new technologies, which indicates that there will be an increasing number of new versions of guidelines over the next several years. Much of the impetus behind the drawing up of the new guideline on sterile manufacturing has come from the use of new technologies, particularly in dealing with microbial contamination.
EMA published in November 2018, with a consultation period due to end in May 2019, a draft guideline on the quality of water for pharmaceutical use because the two existing guidelines on the subject, issued in 2001 and 2002, were out of date (3). The existing guidelines allowed only distillation for purification of water for injection. The new guideline permits the use of new technologies such as reverse osmosis coupled with techniques like electrodeionization, ultrafiltration, and nanofiltration.
In a draft document on EMA Regulatory Science to 2025, published in December 2018, the agency outlines how it is aiming to keep pace with technological advances (4). “The pace of innovation has accelerated dramatically in recent years,” said Guido Rasi, EMA executive director, in the document. “Regulators need to be ready to support the development of increasingly complex medicines.”
Among the agency’s strategic goals will be the facilitation of the introduction of novel manufacturing technologies by taking a ‘flexible approach’ in the application of GMP. This policy has already run into difficulties with controls of advanced therapy medicinal products (ATMPs). Instead of issuing new up-to-date guidelines on the manufacture of active biological substances, the EC adopted, in November 2017, a standalone regulation of GMP for ATMPs (5).
This action raised accusations of a lowering of GMP standards. The Geneva-based Pharmaceutical Inspection Co-operation Scheme (PIC/S), which aims to develop common GMP standards among inspectorates worldwide, claimed that the EU guideline risked leading to divergencies in GMP internationally, particularly with ATMPs.
Participants in PIC/S include EMA, FDA, and WHO. EMA’s guideline on sterile manufacturing was, for example, drawn up in close collaboration with PIC/S and the WHO. PIC/S now comprises 52 authorities mainly in Europe and North America but also including Asia-Pacific, South America, and Africa so that it provides a global network of inspectorates.
The primary aim behind efforts to achieve harmonization of GMP standards is to make efficient use of inspection resources by avoiding the necessity for duplicate inspections of pharmaceutical plants across the world, especially those exporting their products into the global pharmaceuticals market. A joint report last year on an international inspection program of API plants in 2011–2016, involving EMA, FDA, WHO, and approximately 10 other authorities, mainly in Europe, concluded that more work was needed to be done to avoid duplication. National legislation requiring unnecessary inspections was, for example, still to be left unamended.
The dispute between the EU and PIC/S over the ATMP guidance underlines the challenges facing the EMA and other regulators in both keeping in step with new technologies while also ensuring that guideline revisions and changes remain consistent with international GMP standards.
1. EFPIA and other organizations, “Letter to Brendan Cuddy, EMA’s Head of Manufacturing and Quality Compliance, from Sini Eskola, EFPIA’s Director of Regulatory, Drug Development and Manufacturing” (Brussels, October 31, 2018).
2. European Commission, EU GMP Annex 1 Revision: Manufacture of Sterile Medicinal Products (Draft) (Brussels, December 20, 2017).
3. EMA, Guideline on the Quality of Water for Pharmaceutical Use EMA/CHMP/CVMP/QWP/4986873/2018 (London, November 13, 2018).
4. EMA, EMA Regulatory Science to 2025-Strategic Ref lection (Draft) EMA/872479/2018 (London, December 2018).
5. European Commission, Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (Brussels, November 22, 2017).
Volume 32, No. 5
When referring to this article, please cite it as S. Milmo, "Playing the Waiting Game with GMP Guideline Revisions,"BioPharm International 32 (5) 2019.