Finalizing GMP requirements and quality standards for the development, manufacture, and clinical testing of ATMPs in the EU is proving to be a complex task.
By Sean Milmo
A consultation period on GMP guidelines (1) in the European Union, specifically for advanced therapy medicinal products (ATMPs), comprising gene- and cell-therapy products and tissue-engineered treatments, was due to be completed in November 2015. The guidelines, which will be drawn up by the European Commission, however, are taking a long time to complete. They are a requirement of an EU regulation on ATMPs (2) which was approved in 2007.
The objective behind the guidelines is to bring together in a single document GMP standards from a variety of sources, mainly other pieces of EU legislation. But even when the first dedicated GMP guidelines for ATMPs are finalized, probably in 2016, they are likely to have to be constantly revised.
Compliance with GMP standards has been a major challenge for ATMP developers in Europe. In fact, these difficulties could be a prime reason why, up until 2014, only four medicines under the ATMP regulation had been given marketing authorization in the EU’s centralized medicines licensing procedure. Just how GMP problems for advanced medicines are sorted out in Europe could be a key influence over the future of personalized medicines and other new pharmaceutical technologies in the region.
The current R&D structure
At the core of the difficulties with GMP is the R&D structure in the advanced medicines sector. Much of the development work on ATMPs is carried out by academic scientists and clinicians attached to hospitals of universities and other research institutes. They lack the regulatory expertise and resources to establish and operate GMP-compliant manufacturing processes. In particular, they often do not have adequate systems in place for evaluating the quality of starting and raw materials, which is a vital necessity in the production of advanced, usually biological, medicines.
Academics seeking to arrange preclinical and clinical trials for their innovations are so concerned about the complexities of compliance with GMP that they try to avoid having them classified as ATMPs by the regulatory authorities, according to AGORA, an EU-funded research project on solutions to GMP problems in the sector (3).
Lack of harmonization in applying GMP standards
The difficulties with GMP are aggravated by the lack of harmonization in the way GMP standards are applied by the EU’s member states. “Research [has] found substantial heterogeneity in the regulatory practice across member states, which is leading to confusion and uncertainty and is creating a severe barrier to the development and delivery of [ATMP] medicines,” said AGORA in a progress report to the European Commission on its project (3). “[This is] weakening the position of the EU academics and industry to collaborate and compete globally in this expanding field.”
Advanced medicines may need the adoption of a different strategy to manufacturing standards within the sector. The consultation document (1) itself does not call for any radical changes in GMP, but stakeholders in their comments on the document may take a different view.
Defining manufacturing quality
Senior members of the European Medicines Agency, which is responsible for the EU’s centralized approval procedure, have hinted that different concepts of manufacturing quality may need to be applied to advanced medicines. “ATMPs are complex pharmaceuticals, for which traditional approaches may not be possible,” Paula Salmikangas, chair of the EMA’s committee for advanced therapies (CAT), told an European Directorate for the Quality of Medicines & Healthcare (EDQM) workshop on Paving the Way for the Future—Biologicals at Strasbourg, France, in 2014 (4).
Because ATMPs are in the front line of scientific discovery, new standards become outdated. By the time the standards are implemented, the products for which they have been drawn up have been superceded by a new technology. “Manipulation of cells and use of recombinant nucleic acids may bear unknown risks, which may not be solvable through standardization or quality control,” Salmikangas added.
A major problem area with advanced medicines is the quality assessment of starting and raw materials, which often comprise high-risk raw materials. The availability of these in high-quality grades was limited because they were mainly sold “for research use only” and were accompanied by little product documentation from the suppliers, according to Salmikangas. Raw-material suppliers claim that their products are “GMP compliant,” but many ATMP developers are sceptical about the value of such claims.
Delegates at a symposium in April 2013 on gene and cell therapy raw materials at Strasbourg, France, jointly organized by EMA and EDQM, complained about the lack of a definition of GMP compliance. The meeting also acknowledged that the term “GMP grade” meant different things to different groups, according to an EDQM report on the conference (5).
Adapting GMP implementation based on risk
Some research organizations are calling for a relaxing of GMP rules at the early stages of ATMP development, for example, in first-in-man (FiM) studies. “The level of application [of GMP requirements] should be appropriate to the ultimate risk associated with their use (e.g., the number of patients in a Phase I/FiM study can vary and so does the risk),” says the cell therapy unit of the government-funded Catapult UK, which runs a network of late-stage R&D centres in the country, in comments (6) on a European Commission review last year of the ATMP regulation (7).
This view is consistent with a growing support in the R&D sector in Europe for a phased approach to the application of GMP standards, as detailed by the Parenteral Drug Association (PDA) in a 2012 technical report (8). This proposed that standards should become more stringent as new drugs move from the discovery stage through to Phase III clinical trials and market launch. It is also in line with the emphasis placed by the European Commission’s consultative document on the need for a risk-based approach with the application of GMP for ATMPs.
The document (1) is mainly focused on conditions of GMP compliance that would be applied in the marketing authorization of advanced medicines, as well as those required in the manufacture of ATMPs for clinical trials. It, however, acknowledges that with investigational or experimental ATMPs, which are often developed in an academic or hospital setting operating under different quality systems to those for conventional drugs, “additional flexibility is warranted, in particular for early phases of clinical trials” (1). The document also says that under a risk-based approach, the ATMP manufacturer has a responsibility “to put in place additional measures—beyond those suggested in the [EU’s] GMP guidelines—if that is necessary to address the specific risk of the product” (1).
The AGORA project
The two-year AGORA project has been testing schemes for giving personnel in academic R&D facilities more expertise in basic GMP standards. “[Our own data] has consistently shown that GMP manufacturing knowledge remains a barrier for academic triallists aiming to perform the full cycle from preclinical investigations to early and subsequent late-stage clinical trials,” it says (3). As a result, it has been designing training course packages aimed at specific target groups, such as cell biology scientists who know about ATMPs but need to learn GMP skills.
The project, whose participants are mainly academics from the United Kingdom, German, and Dutch universities, has attempted to extend the scope of its exploratory training courses by working together with other researchers in biologicals and with industrial partners with GMP experience. It has had a close co-operation with Pharmacell BV, Maastricht, Netherland, a contract manufacturer of cell therapy and regenerative medicine products, which has two GMP plants, one of which was first certified in 2006.
The AGORA team has spoken out against proposals to reduce the product quality requirements for ATMPs in academic development on the grounds this would lead to the “creation of a two-tier ATMP development process, which would substantially undermine the delivery of safe and effective ATMPs across the EU.” A major issue to be sorted out in the discussions following the issuing of the consultative document is how the flexibility proposed by the document in the application of GMP standards in ATMP manufacturing can be made consistent with the maintenance of existing GMP rules.
National regulatory agencies, which are responsible for the enforcement of GMP standards in clinical trials of ATMPs, tend to apply them in ways they think fit for individual medicines. “Concerns about GMP [with ATMPs] are handled on a case-by-case basis,” says a spokesperson for the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK, which is a leading European country in advanced medicines development. In the many years in which the agency had been in discussions with ATMP developers, its message had been that GMP is about applying “an appropriate quality standard” for consistent manufacture in the “wide range of situations under which ATMPs are developed,” the spokesman told Pharmaceutical Technology Europe.
Clearly, a great deal of adaptability is required with GMP in the early-stage development of ATMPs. Just how this can be balanced against the need for greater consistency in the implementation of GMP with advanced medicines in the later clinical trial phases and the post-marketing period could be a matter of debate for some time.
1. European Commission, Consultative Document: Good Manufacturing Practice for Advanced Therapy Products (Brussels, July 2015).
2. European Union, Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products (Brussels, November 2007).
3. AGORA, Progress Report: Advanced Therapy Medicinal Product Good Manufacturing Practice, Open Access Research Alliance (London, 2015).
4. P. Salmikangas, “Advanced Therapies and the RCG Working Party—Preliminary Aspects,” presentation at workshop on 50 Years of EDQM Leadership in the Quality of Medicines (Strasbourg, October 2014).
5. EDQM, Symposium Report: Raw Materials for the Production of Cell-based and Gene Therapy Products (Strasbourg, 2013).
6. Cell Therapy Catapult UK, EC Review of the ATMP Regulation—Cell Therapy Catapult Responses (London, 2014).
7. European Commission, Report to European Parliament and the Council: Regulation (EC) No. 1394/2007 on Advanced Therapy Medicinal Products, COM 2014/188 (Brussels, March 2014).
8. Parenteral Drug Association (PDA), Technical Report No. 56: Application of Phase-Appropriate Quality Systems and CGMP for the Development of Therapeutic Protein Drug Substance (Bethesda, US, 2012).
About the author:
Sean Milmo is a freelance writer based in Essex, UK, [email protected]