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Highlights of IPEC Europe Forum 2017
Susanne Keitel, director of the European Directorate for the Quality of Medicines and Healthcare (EDQM), updated delegates on a diverse range of topics, including ongoing efforts to reform the Pharmacopoeial Discussion Group (PDG) procedure which despite improvements in recent years is still slow and not fully understood. Changes under consideration include a reduction in the number of steps within the PDG procedure, involving more experts, more often and considering bilateral rather than trilateral harmonisation efforts where there are ‘roadblocks’. Participation with interested parties could also be improved, for example by contributing methods, specifications and batch data earlier in the harmonisation process, taking part in collaborative studies and providing comments at the public enquiry stage. Tackling the evolving regulatory requirements for excipients in China, IPEC China chair and manager of Colorcon’s regulatory operations in China Colin Li, explained the changes introduced since the China Food and Drug Administration (CFDA) updated its excipients regulation in August 2016, and published detailed dossier requirements the following November. The new rules state that both domestic and imported excipients will be handled by the Centre of Drug Evaluation (CDE) under the same approval system, whereas previously they were reviewed separately. It is imperative that excipient considerations are included in the drug development process for new products to avoid any possible approval delays. He went on to say that guidance on change management for excipients has not yet been published. Possible upcoming developments to look out for include drug master files, the growing importance of the Chinese Pharmacopoeia (ChP) in the regulation of excipients and the possibility that imported drugs – currently exempted from these excipient registration rules – will in time fall under the same requirements as domestically-produced medicines. Excipients manufactured outside of China could be included in inspection programmes, based on risk.
Companies should carefully document the traceability process, identify products at each step using a unique batch number and material name, and carry out upstream and downstream testing in accordance with a risk analysis. The result is an ‘approximate’ traceability covering the whole manufacturing and supply chain, she said. Staying on the theme of continuous manufacturing, Chris Vervaet, head of the Laboratory of Pharmaceutical Technology in the Faculty of Pharmaceutical Sciences at Ghent University in Belgium, gave a presentation on the critical material attributes (CMA) for excipients deployed in continuous processing. Drawing from case studies involving microcrystalline cellulose (MCC) and hypromellose (HPMC), he presented studies exploring whether the impact of CMAs during continuous manufacturing is similar to batch processing, and whether specific CMAs are more critical during continuous manufacturing compared to batch processing. He concluded that CMAs not relevant during batch processing can be vital during continuous processing, while CMAs can have different impact during continuous manufacturing. Eckart Kraemer – who chairs IPEC Europe’s GDP committee – introduced delegates to the changes incorporated into the soon-to-be-published 2017 IPEC GDP guide for Pharmaceutical Excipients, which will replace the 2006 edition. The revised version offers practical guidance and examples, targeting excipients to complement the World Health Organization (WHO) Good Trade and Distribution practice (GTDP) guide for Starting Materials. Among the changes and additions in the GTDP guide that need to be taken into account were the incorporation of a risk-management approach to GDP, a greater emphasis on supplier management to ensure authenticity and traceability of the supply chain, and elements designed to ensure the independence of the quality unit. It also advises greater use of preventive actions, including verification of the effectiveness of the distribution system. Continuing in the same vein, Astrid Stockrahm-Uhling of DFE Pharma, who led the taskforce for the revision of IPEC’s Quality Agreement guide, gave a review of the new version which is currently at the final draft stage. The guide covers quality agreements between excipient suppliers, distributors and customers and includes a template with ‘how to’ notes, to help reduce the time needed to draw up such agreements.
Rounding off the trio of new guide presentations, Kevin McGlue of Colorcon gave an update on behalf of the GMP guide revision taskforce, which has been working on an update to the 2006 IPEC-Pharmaceutical Quality Group GMP guide edition since mid-2015. The revised version has so far been aligned to the EXCiPACT certification standard and brings in newer concepts such as risk assessment and, having been approved by the IPEC Federation, will soon be published as an IPEC Federation-PQG document. The work will not stop there, however, as the plan is to further revise it to fully align with ISO 9001:2015 and expand it to include more ‘how to’ guidance on GMP implementation. The guide sits alongside EXCiPACT and the NSF/IPEC/ANSI 363-2014 and is designed to help producers who are just starting with GMP or as an alternative to certification. Kicking off the afternoon session, Åsa Pettersson – process engineer expert at AstraZeneca (AZ) – tackled the topic of excipient qualification, giving the pharmaceutical manufacturer’s viewpoint when it comes to evaluating new excipients as well as handling changes to the supply of or problems surfacing with established materials. Pettersson described how AZ handles the excipient life cycle from the screening, pre-project and project stages through to ‘business as usual’ supply. Once again risk management is the watchword, she noted, along with reliable two-way communication. Uniform excipient quality is critical to the manufacturability and quality of the finished product, and physical characteristics must be taken into account, not only the specification. Peter Brun of HWI Development took on the topic of modern methods for excipient characterisation/distribution in solid dosage forms, discussing how new technologies such as X-ray micro tomography (XMT), scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM-EDX) and Raman spectroscopy can be valuable tools to understand product properties and tackle quality issues. Such methods provide “nearly forensic precision” and can provide full understanding of internal structures and defects in most drug dosage forms. It is also possible to fulfil Quality-by-Design (QbD) requirements using these techniques in combination with drug development, variation and optimization programmes. Data integrity panel The afternoon rounded off with a panel discussion on the hot topic of data integrity, which is already a major compliance issue for active pharmaceutical ingredients (APIs) and is increasingly in scope for excipients even if the regulatory landscape does not specifically apply to them. Setting the scene, Tracy Moore, senior GMDP inspector at the UK Medicines and Healthcare products Regulatory Agency (MHRA), told delegates that data integrity is defined as the extent to which all data are complete, consistent and accurate throughout the data lifecycle. Regulators have has been paying more attention to this since 2013 and it is anticipated that changes will come in the inspection approach taken by authorities. “International inspection findings have identified data integrity as a priority area of focus,” she said, pointing to cases in which certificates of analysis (CoA) and GMP certificates have been wilfully falsified, along with other examples of ‘tidying’ of data by materials suppliers. Companies should design systems and a culture that reduce the chances of any data integrity failures, particularly as there is a migration from paper to electronic records, while regulators and industry must “remain vigilant”. Anne-Catherine Bildstein of Novartis picked up the baton to provide the perspective of the excipient user, acknowledging that it can be difficult for companies to get data integrity right because of performance and business pressure, lack of awareness or capability and inadequate processes and technology. Data integrity is still not fully integrated into the pharma industry culture, she said, but this can be remedied by raising awareness with communication, training and sharing of information, and making sure technical aspects such as user logins and audit trails are enabled and monitored. Iain Moore of Croda delivered the point-of-view of the excipient supplier, noting that there should be no fundamental gaps in data integrity principles if producers are following the IPEC-PQG GMP guide. The question is whether this has been applied to data, beyond electronic and paper records, and it will be good practice to do a check on the activities listed in regulatory guidance documents that have been published by the FDA, MHRA and EMA. A gap analysis could be conducted with questions such as: are records reviewed for completeness; are forms reconciled; and are audit record retention practices audited?, he suggested. It may be an opportunity to check fundamental IT security measures, for example whether logins and passwords are shared, whether records can be edited or deleted, and if leaving workers are systematically removed from the system. More details of a survey which was conducted to provide some perspectives on data integrity in the excipient community are included in this edition of Excipients Insights. Please contact the IPEC Europe Secretariat for any questions related to the IPEC Europe Forum 2017.
Link: Excipients Inside January / February 2017 |
Continuous manufacturing of pharmaceuticals has received a lot of attention in recent years. One of the challenges often cited in switching from batch production is traceability, which can be used to find the root cause of quality issues and facilitate the withdrawal or recall of products. Katia Jambart, head of global quality management system at Roquette, described a method for handling traceability and batch records in continuous processing, noting that it relies on three pillars – documentation, identification and testing.
New topics added to the 2017 templates cover tamper-evidence features, reworking and reprocessing, and returned excipients, and there are new sections for the customer on ensuring the excipient is appropriate for its intended use and quality control testing of incoming materials. Where an intermediate party may be involved in excipient supply, the use of a Manufacturer’s Quality Statement’ is proposed as an alternative to three-way agreements.
