Good Manufacturing Practice Committee
News and Updates
GMP at the 2016 RQA Annual Conference, Brighton
Philip Butson, GMP Committee
Session 1: GMP Regulatory Update
The first GMP session at the conference, chaired by Rhona McAteer (TMQA/RQA GMP Committee), provided regulatory updates from Philip Butson (GSK/RQA GMP Committee) and Alan Moon (MHRA).
Recent changes have included updates to Chapters 3 (Premises and Equipment) and 5 (Production); Annexes 15 (Qualification and Validation) and 16 (QP Certification and batch release) together with new Part III guidance to help ensure that excipients are manufactured to appropriate GMP.
Chapters 3 and 5
Alan flagged the changes in these chapters, together with the associated Part III guidance, relating to the toxicological evaluation of compounds handled in shared facilities leading to the setting of appropriate cleaning limits.
Within Annex 15, Section 6 on verification of transportation was highlighted, as investigational medicinal products (IMPs) are specifically within scope and whilst it is possible to justify not doing so, the expectation is that there is continuous monitoring of critical environmental conditions, which for most IMPs means temperature. Philip urged caution regarding justifications for not monitoring, since products are outside your control whilst in transit and every shipment is unique. It cannot be assumed on the basis of climate/weather data that a product will not be subject to adverse conditions – he has seen data from shipments that have exceeded 65°C despite weather data showing a maximum temperature in the low 20°C. GSK have rejected 11 (eleven) shipments in the past three years due to adverse temperature excursions – rare in the context of over 100,000 shipments, but significant for the trial subjects who would otherwise have been dosed with the product in those shipments.
The principles of Annex 16 apply to IMPs. In practice, because the whole annex has been rewritten with a focus on principles rather than the specific supply chain scenarios of the previous version, the majority of the content is likely to be applicable and it was suggested that any differences in practice have a documented justification which can be used during regulatory inspections. A recent survey and benchmarking suggest that the most challenging area for implementation has probably been in relation to supply chain documentation (which the Annex suggests ‘should preferably be in the format of a comprehensive diagram’). Also challenging is proving the qualified person’s (QP’s) ‘detailed knowledge’ and ‘continuous training’ – whilst training/CPD records cover this to some extent, the ultimate test is likely to be whether they can satisfactorily answer an inspector’s questions. Alan particularly highlighted Section 3 on the handling of unexpected deviations – the term ‘unexpected’ implies that the deviation is not a repeat and it must be remembered that compliance with the specification is not negotiable. Alan also commented on the requirement for audit reports to be available to QPs – this does not mean that they have to have copies of them all, but they do need to be able to demonstrate confidence in the GMP compliance of the full supply chain and be able to access them if they wish, with clearly defined responsibilities of each QP in a supply chain captured in written agreements.
Although written with direct applicability to excipients used in the manufacture of authorised medicinal products (due to the legal basis being the Falsified Medicines Directive, 2011/62), this is seen as equally applicable to IMPs. The guideline sets out a very specific risk assessment process. Alternative approaches are accepted by MHRA, but the expectation is that it will be documented how these provide assurance at least equivalent to that of the guideline; it cannot simply be argued that a system was in place before the guideline came into effect.
Fragmentation of EU GMP
Before going on to discuss Clinical Trial Regulation (CTR)-related changes, Philip quickly used slides from last year’s conference (see Quasar 134) showing how the EU GMPs are being fragmented with new, separate, regulations for IMPs and authorised medicinal products together with standalone guidelines (not annexes to EudraLex volume 4) for IMPs and Advanced Therapy Medicinal Products (the latter covering both investigational and authorised products). These new regulations and guidelines are currently going through the process of being finalised at the European Commission and are expectations to be published in 2Q2017. Implementation of the IMP texts will be tied to the implementation of the CTR, as confirmed at the earlier plenary session by Anabela Marcal (EMA).
Clinical Trial Regulation-related changes
A number of up-coming changes driven by the CTR were covered with the focus being on the new guidance on auxiliary medicinal products since this has been drafted since the last conference. Industry feedback has highlighted the fact that the draft guidance leaves gaps, since some products used in trials may not be classified as either IMPs or auxiliary medicinal products. There is also a lack of clarity regarding the justification of deviations from ‘full GMP’, which the feedback proposes can be dealt with in the local quality system. A brief update was provided on the progress with advocacy to change Annex VI of the CTR on labelling to retain the current flexibility within Annex 13. Alan reminded everyone that those who are IMP Qualified Persons via the transitional arrangements implementing the Clinical Trials Directive in 2004 will need to go through a reassessment process – details were released by MHRA in April 2016 and those affected are encouraged to send their forms in soon. Alan also informed that some of the text from the current Annex 13 which is at the GMP/GCP interface, such as the two-step process to release of IMPs for shipment, will not be in the new IMP GMP guideline, but is expected to be retained in a new guidance document in EudraLex Volume 10.
Other changes to watch for
Other changes in the pipeline are revisions to GMP Annexes 1 (Sterile Products) and 17 (currently ‘Parametric Release’; to be ‘Real Time Release’) together with a new Annex 21 on Importation and the new standalone GMP guideline for Advanced Therapy Medicinal Products (ATMP). In addition, the introduction of ‘safety features’ to the packs of authorised products will have implications for IMP supply chains; more details are likely to emerge during 2017 as the verification organisations and systems are put in place.
Regarding Annex 1, Alan explained how, although there have been various revisions, this is the first review of the full text since its original publication. The revision is being led by MHRA’s Andrew Hopkins and involves not only representatives from other EU regulatory agencies but also from The Pharmaceutical Inspection Co-operation Scheme (PIC/S). It will have an improved structure, will incorporate quality risk management principles and include coverage of new and emerging technologies as well as reinforcing current expectations. A couple of specific changes highlighted were the ability to create water for injection by reverse osmosis, subject to appropriate assurance of control of biofilms (a topic on which EMA produced a draft Q&A document earlier this year) and the removal of ‘average values’ in relation to environmental monitoring.
As was well covered through many of the conference sessions, data integrity is currently the hottest of hot topics with global regulators. A number of companies have received significant regulatory sanctions and MHRA, EMA, PIC/S, US FDA and WHO have all issued guidance documents. It was stressed that the expectations are not new and apply to the control of all data, whether electronic or paper. Regulators have no issue with mistakes being made and corrected provided this correction is done appropriately.
Brexit was also touched on by both speakers. Philip reminded everyone that the UK is still part of the EU and is likely to be so for at least another 2 years. Consequently, from an operational perspective, nothing has changed yet. However, some impacts are already starting to be felt and there are a number of specific IMP-related concerns. In particular, he highlighted the potentially significant impact on supply chains if it is not possible to retain free movement of IMPs to clinical sites in Europe following UK QP certification. The attractiveness of the UK as a location for conducting clinical trials is likely to be negatively impacted if an additional UK regulatory submission is required in addition to the single submission for the EEA introduced by the CTR. Alan assured the audience that MHRA continues to play a full and active role in EU regulatory matters and also advised that a team has been set up to identify the implications of different scenarios and to provide data and advice to the government during the negotiations.
Session 2: Porter’s Value Chain and Good Distribution Practice
The second GMP session, chaired by Sue Mann (Sue Mann Consultancy/RQA GMP Committee), saw a presentation by Louise Handy (Handy Consulting). In her presentation, Louise introduced Porter’s Value Chain and went on to show how an analysis of distribution activities using this tool provides a good correlation with the requirements of the EU Good Distribution Practice (GDP) guideline.
Porter was an engineer/economist and his Value Chain tool is perhaps better known in strategic management circles than in quality areas. Although the tool dates from the 1980s it has stood the test of time well.
Value Chain can be defined in various ways, but it is fundamentally about looking at the process activities that create and build value – the total value delivered by the company is the sum total of the value built up all throughout the company and this includes activities such as marketing and after-sales services as well as more obvious activities such as production. Whilst we may prefer not to consider it in this way, all companies need to make money, so there needs to be a profit margin, which Porter defines as the value created and captured less the cost of creating that value.
Porter’s tool is made up of five primary activities (inbound logistics; operations; outbound logistics; marketing/sales; services) and four support activities (procurement; human resources management; technological development; infrastructure). Louise gave examples of activities falling within each category and summarised the model with the diagram in figure 1.
Figure 1: Diagrammatic summary of Porter’s Value Chain
The first step is to map the business processes and to allocate each of the different activities to one of Porter’s activity categories. Louise gave examples of activities that would fall into the different primary activity categories for a pharmaceutical distribution process – receipt of goods; storage; distribution; sales; complaint management.
Having identified the different business activities that fall into each of the primary activity categories, the next step is to dig down and identify the direct, indirect and quality assurance activities for each primary activity. Direct activities create value in themselves; indirect activities enable direct activities to run smoothly; quality assurance activities ensure that both direct and indirect activities meet the necessary standards. The same approach is applied to each support activity. Again, Louise provided examples for a pharmaceutical distribution process.
The third step is to make linkages between the different value activities and the fourth step is to use these to identify opportunities to increase value. The linkages are where things are most likely to go wrong, but, positively, they are also where there is the greatest opportunity to increase competitive advantage. So, for example, if there are issues with the processing of orders there will be an increase in calls from frustrated customers waiting for their deliveries. Improving the processing of orders will increase on-time delivery leading to fewer complaints. On-time delivery will be valued by the customer, making repeat orders more likely, and there will be reduced costs associated with the handling of complaints, both of which will add value to the company.
Louise cautioned that, whilst the concept was simple, it takes considerable time to apply it properly. She advised a focus on the highest value activities and, whilst the improvement opportunities come from the linkages, it is best to focus on one item at a time. You need to keep in mind what ‘value’ means to your organisation and also to be clear on your primary objective is when undertaking the exercise (e.g., setting yourself apart from your competitors or reducing your cost base). In discussing this, Louise reminded us that no business has ‘Compliance’ as its primary objective; compliance is part of being successful in the activities that are delivering the true objective of the business.
Session 3: GMP/GDP interfaces with GCP
The third GMP session was again chaired by Rhona McAteer (TMQA/RQA GMP Committee) with Sue Mann (Sue Mann Consultancy/RQA GMP Committee) and Kate Krachai (Quality Context/RQA GMP Committee) as speakers. This session focused on interfaces with GCP and we were very pleased to have a number of GCP colleagues with us to promote discussion since both Sue and Kate emphasised the importance of working cross-functionally.
GMP/GDP/GCP Boundary Issues
Sue Mann spoke first and whilst stressing the importance of avoiding silo working, suggested that a simple way to compartmentalise these three GxPs is to see GMP as being about the product that is supplied, both before and during the trial; GCP about how it is used and GDP about how it gets there.
Sue looked at a number of potential interface issues, some of which are specifically dealt with in the EU guidelines.
Reconstitution vs Manufacturing
The first example Sue looked at was reconstitution and how this differs from manufacturing. The guidance from EU GMP Annex 13 was presented followed by a couple of examples to challenge the audience and to bring out some of the nuances in the guidance. E.g., the preparation of a vial containing a sterile powder IMP for administration by adding water for injection is reconstitution, but if a hospital was to prepare multiple vials for use over a period of a week then this would become a manufacturing activity because the activity is not then being carried out as close to the time of administration as possible and further labelling will be required giving an expiry date of the reconstituted vial.
Where there are reconstitution activities as part of a trial, GMP and GCP colleagues should work closely together. GMP should ensure that it is clearly defined exactly what the site needs to do, but GCP trial monitors are likely to be best placed to oversee activities and ensure these happen as specified. Sue advised consideration of specific monitoring visits at the start of trials involving reconstitution and that if particular materials are required then these should be provided by the trial sponsor rather than leaving this to the clinical site and risk inappropriate sourcing.
Study design, Randomisation and Blinding
GMP and GCP working together early in the design of trials can help ensure practical solutions for the benefit of both patients (convenience) and the sponsor (cost and compliance). Sue gave a number of examples of how working together had prevented issues arising.
Distribution and Storage
Historically part of GMP, Good Distribution Practice (GDP) is now being more widely recognised in its own right with the 2011 Falsified Medicines Directive leading to new GDP guidelines and other measures to assure supply chains result in the right product arriving at the right site in the right condition.
Sue urged that the GMDP Quality involvement should not end at the point of product certification but that processes should also be in place to ensure receipt of the product at the site in good condition. Further, whilst it falls to GCP to ensure that product is correctly stored at sites, if there are temperature excursions, then there should be GMP engagement to ensure assessment of stability data.
In response to a question at the end of the presentation it was also stressed that responsibilities need to be very clear when depots are used. It is all too easy for delivery to the depot to be controlled but the ‘final miles’ from the depot to the clinic to be overlooked.
A scenario expected to be ‘exceptional’ but specifically covered by Annex 13 and requiring close collaboration across GMP, GCP and GDP is inter-site transfers. Potential implications for labelling and stability need to be covered. Clear instructions need to be provided and appropriate records made. Consideration should also be given to review of the transfer process and release for use at the new site after it has been assured that all requirements have been met.
Shelf life extensions
Shelf life extensions are often to be expected with stability data on products being generated in parallel with trial conduct. EU GMP Annex 13 has specific requirements for labelling activities associated with shelf life extensions. Collaboration is needed to agree where such extension labelling will take place, how it is to be controlled and where the records will be retained. Sue flagged that further risks will be associated with shelf life extensions under the current wording of Annex VI of the Clinical Trial Regulation because the expiry date will be required on all primary packs. Monitors and staff at clinical sites need to have a thorough understanding of the extension labelling requirements.
End of study activities
Further collaboration is required at the end of studies with the reconciliation and destruction of residual product. If product is returned to the manufacturing or distribution site for destruction, it needs to be very clear as to what level of reconciliation is expected both at the clinical site before it is sent and at the receiving site. It was suggested that the reconciliation required for GCP is performed at the clinical site and that the site managing destruction only needs to reconcile the boxes returned not account for every unit within them. It also needs to be clear who is responsible for authorising the destruction.
In summary, Sue urged us to think about the overall supply chain of the IMP to the trial subjects, to ensure clarity and alignment of responsibilities and, above all, to focus on the patient/subject needs.
PSF meet TMF
Last, but by no means least, Kate Krachai looked at the Product Specification File (PSF) and the Trial Master File (TMF) and what documentation is required for each.
Several sponsors have expressed frustration that certain documents they consider to be GMP documents, e.g., stability data, are increasingly being expected to reside in the TMF and are being subject to detailed inspection by GCP inspectors.
Timely retrieval of data is a common regulatory inspection issue for both PSF and TMF. Why is this? In addition to a lack of understanding of requirements, this can be caused by a lack of communication or lack of clarity of different individuals/functions for different data elements; without these, documents can ‘fall between cracks in the road’. Kate’s message was to avoid cross-functional battles by ensuring clear responsibilities and good communication.
Looking first at the PSF, Kate likened this to the ‘This is Your Life’ Red Book giving the life story for the product. It is a requirement of GMP Annex 13, forms the basis for GMP activities and needs to be accessible to the QP. Different companies meet the PSF requirements in many different ways. It does not have to be a single physical file, but the required documents should be readily accessible with complete histories/version controls in a form that is inspectable. It is a working document and should be continually updated with appropriate change control. Where activities take place across different sites, each site must have access to the documents relevant to its activities; this may be achieved through different files at each site. Where activities are outsourced, the PSF needs to be addressed in the Technical/Quality Agreement and it must be assured that the contracted site has access to all the information it needs in order to fulfil its obligations.
Moving on to the TMF, Kate first of all showed the similarities to the PSFwith a legal basis, various required documents and the importance of it being up-to-date and accessible to clinical personnel. Both files may also form the basis of an inspection. The purpose of the TMF is defined as allowing the conduct, data integrity and compliance of the trial to be evaluated. The TMF too is a working document and is expected to be added to throughout the duration of the trial leading to secure archive accessible for a defined period of time following trial completion. Echoing comments made at an earlier plenary session, Kate commented that there is no need to keep absolutely every email sent between trial personnel but a risk-based approach should be taken to ensure critical documents were filed. It should be possible to reconstruct the trial and key decisions made during its conduct through the TMF contents. Certain GMP documents are required as part of the TMF and Kate listed these. Where documents are required in both GMP files and TMF, it will be important to define who keeps the original and how it is ensured that copies are provided. Therefore, as Sue had already stressed, close working across GxP functions is necessary to achieve success. Whilst certain documents might need to be kept separately to avoid inadvertent unblinding, there could be benefits in extending this collaboration to the point of PSF and TMF being in a common document management system.