The interface between Good Clinical Practice and Good Manufacturing Practice

1 The interface between Good Clinical Practice and Good Manufacturing Practice your partner in compliance

1 The interface between GCP and GMP Generally, studies are designed and planned by physicians who have a good understanding of both the potential beneficial and adverse effects of medicinal products. However, the same physicians tend to have a relatively poor understanding of what is required of the actual Investigational Medicinal Product (IMP) being studied in the clinical trial. A key part of planning for a clinical trial is ensuring that the IMP is of sufficient quality and quantity for the full duration of the study. It is not unusual for a study to be substantially delayed because sufficient IMP is not available. A more problematic scenario is an IMP that is not fit for purpose being used in a study, thus potentially invalidating the study results and, more importantly, placing study subjects at risk. This article explores some of the challenges associated with preparation of an IMP for a clinical trial. Technical aspects A comprehensive technical section called the Investigational Medicinal Product Dossier (IMPD), must be submitted as part of the Clinical Trial Application (CTA) 1. This must cover the specification of both the active ingredient and the finished product. be presented to reassure the Competent Authority and / or ethics committee that the formulation is fit for purpose 2. It is important that no matter how early the stage of development, the ability to manufacture the product commercially must be considered and the commercial manufacturing process must be technically feasible. Therefore, the final specification of the IMP must anticipate both scale-up and stability requirements in order to be commercially viable. There are also special requirements for bioequivalence studies 3. Manufacturing site IMP must be manufactured at a site which has a specific EU IMP Manufacturing Licence. It is not sufficient to manufacture IMP at a site approved for manufacture of marketed product. Where the IMP is manufactured outside the EU, the appropriate licence must be in place for the site of manufacture and the IMP must be 'imported' under a licence permitting the holder to do so. A written order will stipulate the exact amount of IMP to be manufactured and must refer to the approved version of the Product Specification File (PSF) and the relevant clinical trial protocol. Batch records must be retained as they are required for the Qualified Person (QP), who will be responsible for batch certification. Information on the manufacturing process and controls, testing and stability data must

2 It is often not appreciated that experimental batches manufactured for validation or stability purposes, and where their data is submitted in the CTA, must also be manufactured at approved sites; otherwise, data from these studies used as part of the IMPD to support a CTA may be invalid. Where a comparator is used, any modifications or re-labelling must also be detailed in the PSF and carried out under GMP conditions at a licensed site. The quality of the comparator must be known and a level of analytical testing may be required to confirm this. Both reference and retention samples must be stored under GMP conditions for as long as is necessary. Stability studies It is common for study start to be delayed due to a lack of adequate stability data to justify a retest date that will cover the IMP for the duration of the trial. Stability data can be invalidated either by a substantial change in the specifications of the finished product after stability studies have been completed or because either the manufacture of the IMP or stability studies were not carried out under sufficient control at a site licensed to manufacture IMP. the study because availability of the IMP must be maintained throughout. The IMP must be available beyond any expiry date by either extending the date (justified by suitable stability data presented to the Competent Authority / ethics committee in advance) or where the batch expires, by manufacturing a new batch. Packaging and labelling All packaging and labelling must be carried out at a licensed manufacturing site. Where blinding is carried out, the licence must state this specifically. Blinding is not permitted at the study site because it is not possible for the site to conduct any quality control checks for correct randomisation at a later date. A mix-up at this late stage is impossible to detect later. Arrangements must be made for treatment allocation as study subjects are enrolled and for decoding when required. Depending on the trial, a hospital pharmacy may need to compound the IMP (e.g. dilutions). The labelling of the product may be a dispensing label that needs to comply with prescription legislation. Trial sponsors / manufacturers rarely consider labelling requirements in these scenarios. Advance liaison with the pharmacy is; therefore, strongly recommended. Over-optimistic recruitment expectations and un-anticipated problems with enrolment (e.g. over-restrictive exclusion criteria), commonly delay the clinical part of When the expiry date of an IMP is being extended, the physical labelling of IMP to amend the expiry date on the existing

3 labelling also needs to be carried out at an appropriately authorised manufacturing site. However, when justified, it may be performed at the investigation site by / or under the supervision of the clinical trial site pharmacist or other health care professional in accordance with national regulations. Where this is not possible, it may be performed by the clinical trial monitor(s) who should be appropriately trained. Batch release A two-stage release procedure applies and is defined under Annex 13 of the EU GMP Guide. The QP at the manufacturing site releases the IMP to the study sponsor who is responsible for the release of the IMP to the trial. Depending on the business relationship between the parties, they need to agree who will confirm compliance with the CTA and other trial specific requirements (e.g. where the QP is at a contract manufacturing site and has the Interactive Voice Response Systems (IVRS) and Interactive Web Response systems (IWRS) have been developed to optimise overall drug management in relevant information relating to approval of the trial). In this scenario, the roles & responsibilities must be defined under a quality agreement between the parties. clinical trials. This technology has expanded to assist with expiry date updates and may be used to justify the removal of expiry dates from IMP labels 4. Annex 13 allows for omission of some information when the absence can be justified (e.g. use of IVRS / IWRS). A White Paper by the ISPE / PDA Expiry Date Task Force produced in 2009, also supports the use of IVRS / IWRS technology to manage IMP retest dates in lieu of placing retest dates on IMP labels 5. In order to batch release both test and comparator IMPs, the QP must be confident that every aspect of the IMPs has been evaluated. This includes the active ingredient, manufacture and testing of the finished product, review of the certificate of analysis and compliance of the IMP with the IMPD section of the CTA. Also, Competent Authority approval for the clinical trial must be in place. Study batches are not released until written approvals are in place for both the GMP aspects and the Careful management of IMP stock is also required in the event that stock needs to be moved between clinical sites to respond to study recruitment patterns. IVRS and IWBS have been developed to help optimise drug availability at clinical trial sites. clinical trial aspects (two stage release referred to earlier). Storage and shipment Arrangements for shipping must be considered carefully, especially for IMPs that require controlled storage. Storage

4 facilities at the clinical site must be adequate to ensure the IMP cannot be tampered with and IMP quality will be maintained throughout the duration of the study. For example, it is not acceptable to store medicines requiring refrigeration at 2 to 8 C in a domestic refrigerator, nor can a domestic refrigerator be used as a back-up should the pharmacy refrigerator fail. The continued suitability of IMP stock to be moved between trial sites requires formal evaluation, taking into consideration the storage requirements of the product in question and the handling of it during the trial to date. For example, could the quality of the product be compromised due to inappropriate storage at a trial site rendering it unsuitable to be shipped and used at another site? Study end At the end of the study, it is necessary to conduct a thorough reconciliation of the IMP usage. Electronic systems (commonly using IVRs and IWRS technology) for drug accountability enables tracking of the IMP from distribution of the medication to the study site, through the dispensing process, to returns and destruction. Such systems are being increasingly used to enable sponsors to produce a fully integrated accountability report and allow early remote review of the available data and immediate identification of any issues. Arrangements must be in place to return any unused or surplus IMP to a suitable site that can store it for as long as is necessary and, ultimately, dispose of it safely and legally in a way that is not harmful to the environment. On-going product quality monitoring at the study site The investigator and sponsor will need to be confident that study site staff are familiar with the IMP and that any special handling or storage conditions or any reconstitution procedures are clear and understood. The investigator and sponsor will also need to have arrangements in place to deal competently and promptly with any quality complaints, quality defects and batch recalls. The QP and Competent Authority / ethics committee must also be notified in the event of a quality defect. Recommendations Trial sponsors and manufacturers are moving towards a model whereby a clinical trial pharmacist provides co-ordination of all aspects of a trial to ensure that the integrity of the trial will not be compromised due to problems relating to the IMP. Technology is also advancing to support remote traceability of trial IMPs, as well as electronic control of expiry dating. This has the potential to overcome the challenging requirements for re-labelling all stocks of an IMP when an expiry date is subsequently extended. These and other developments offer enhanced methods for

5 industry management of clinical trials and IMPs. A core requirement is that the manufacturer s pharmaceutical quality system is appropriately structured and managed to ensure regulatory compliance. The pharmaceutical quality system must be evaluated under its self-inspection program and the principles of continuous improvement must be applied to IMP GMP operations as much as they are applied to commercial manufacture GMP operations. McGee Pharma International McGee Pharma International provides expert EU and US GxP quality and compliance consultancy to Irish and international pharmaceutical, biopharmaceutical, medical device and healthcare organisations. We deliver a unique compliance service that extends across the entire product life cycle, from development to post-market compliance and pharmacovigilance. Our clients range from small and medium sized organisations to the global top ten. Our team of over 30 consultants and technical specialists, including a number of former EU regulatory inspectors, provides practical compliance and business solutions, ensuring the effective and efficient delivery of our services against a backdrop of regulatory compliance. References 1. European Medicines Agency, (2006), Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning Investigational Medicinal Products in clinical trials, Official Journal of the European Communities, London 2. European Commission, (2010), The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines to Good Manufacturing Practice; Medicinal Products for Human and Veterinary Use, Annex 13, Investigational Medicinal Products, EudraLex, Brussels. 3. EMA Guideline on the Investigation of Bioequivalence; January 2010. 4. Investigational Medicinal Products Reflection paper on the Use of Interactive Response Technologies (Interactive Voice/Web Response Systems) in Clinical Trials (Draft; 05 Aug 2011) 5. White Paper by the ISPE/PDA Expiry Date Task Force 2009

6 McGee Pharma International McGee Pharma International (MPI) provides the pharmaceutical, biopharmaceutical, medical device and healthcare sectors with expert EU Regulatory Affairs, Quality and Compliance advice, across all stages of the product lifecycle. Our team of over 30 consultants and technical specialists, with extensive expertise across all GxPs, includes a number of former EU Regulatory Inspectors. This ensures that the service we provide our clients is in line with current international regulatory requirements. Services McGee Pharma International s Quality, Compliance, Regulatory Affairs and Technical services include: Quality Management System (QMS) Design Process Mapping System Development SOP writing Inspection readiness / mock regulatory audits and remediation support Quality Risk Management, in compliance with ICH Q9 Marketing Authorisation support MAH compliance, ensuring all activities are conducted in accordance with the holder s obligations Pharmacovigilance services including EU QPPV Virtual Quality Assurance (VQA), including developments and updates of Technical / Quality agreements Qualified Person (QP) services Responsible Person (RP) services Technical support services Tailored training your partner in compliance e p w info@mcgeepharma.com +353 (0)1 846 4742 www.mcgeepharma.com