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20th APIC Conference in 2017

Quality Metrics, the FDA/MRA Mutual Recognition Agreement and more
Highlights of the 20th APIC Conference

Ever since its foundation 25 years ago, the APIC has been representing the interests of its member companies regarding quality and regulatory issues in the production of active pharmaceutical ingredients. This is achieved, for one, by publishing a variety of Best Practice Guides and position papers on recent developments in the areas of GMP and regulatory affairs; secondly, the annual APIC Conference is the main forum for representatives from the API industry and international regulatory agencies to discuss current issues. In the APIC anniversary year, the now 20th summit has lost none of its dynamic and topicality.

At the beginning of the conference, Betsy Fritschel (Johnson & Johnson, New Brunswick, USA) gave a talk about the Quality Metrics program the FDA developed as a planning tool for their risk-based inspections. Based upon three quality indicators (as described in the FDA draft guidance “Submission of Quality Metrics Data”) and further statistical calculations, the agency determines appropriate risk criteria from which results the risk classification of the company is derived. The FDA calls upon manufacturers of finished medicinal products and active pharmaceutical ingredients to submit these figures (Lot Acceptance Rate, Complaint Rate and Invalidated OOS Rate) from the beginning of 2018 onward. The notification is on a voluntary basis, however, since there is no legal obligation for it.

The cooperation of authorities on an international level is of great significance for the supervision of global API production sites and flows of goods. GMP/GDP inspections can be conducted much more efficiently on the basis of an agreement by which such inspections are mutually recognised. According to Anabela Marcal of the European Medicines Agency EMA in London, the Mutual Recognition Agreement between the EU und the FDA, which entered into force in November 2017, is in a transitional state right now. The assessment of the inspectorates of all EU member states is supposed to be completed by July 2019; currently, there are positive results for eight member states. The assessment of the FDA by the EU has already been concluded in July 2017. By July 2019, all veterinary products and by July 2022, all vaccines for human use and plasma derivatives are meant to be added to the scope of the MRA.

Where does GMP start in the production of APIs? The questions and insecurities regarding justification of the selection of a starting material in the approval dossier have increased greatly over recent years. François Vandeweyer (Janssen Pharmaceutica, Belgium) reported on the trend of determining the starting materials just a few synthesis steps away from the finished API product. This practice increases the risk of deficiencies in the quality of an API and delays application processing due to further inquiries from regulatory agencies. The APIC has provided practical assistance on the issue of selection, justification and auditing of starting materials in various documents, such as the How to do Guide for the ICH Q7 Q&A document or the position paper on API Starting Materials. A relevant guideline in this context is the Q&A document for ICH Q11, which will enter into force at the end of February, 2018. In a question and answer format, the ambiguities and inaccuracies regarding the interpretation of the requirements in ICH Q11 are considered and clarified. In view of this guideline, Keith McDonald outlined the issue from the viewpoint of the European regulatory agencies and elaborated on the challenges assessors have to meet when processing authorisation applications.

Another important APIC Guidance from the How to do Document series covers GDP for active substances. Jelle van Gauwbergen from Janssen Pharmaceutica, Belgium introduced the revision of “GDP for APIs: How to do Document” from 2014. This document, together with the “Statement on Good Distribution Practices” recently published on APIC’s official website, provides useful information on how traceability and transparency can be guaranteed for global supply chains. This is an important step in the battle against counterfeit drugs, which are still in increasing circulation in some parts of the world. Hugo Bonar of the HPRA in Ireland gave an overview of recent developments in the counterfeiting of medicines, the challenges regulatory agencies have to face and the various legislative initiatives to combat such counterfeits.

The commonly practiced production method for manufacturing active pharmaceutical ingredients is the batch method, in which the implementation of a control strategy is a basic GMP requirement. But how is an efficient control strategy to be implemented in a continuous production process? Raymond Boyse of Eli Lilly, Kinsale, Ireland, illustrated this with a case study about the production of “Prexasertib”, a medicinal product used in the treatment of lung cancer. Process, equipment and facilities are to be designed in a way that allows for process analytical methods to be implemented optimally into the whole process in order to enable a comprehensive surveillance of the continuous manufacturing process.

Changes in the production of APIs are common practice and usually driven by steps taken to increase efficiency and innovation. On the regulatory side, changes also come with efforts relating to the approval documentation. Changes must be categorised as specified in the EU variations regulation and notification deadlines must be determined. To make the procedure for post approval changes transparent and predictable in a way that benefits the industry as well as the regulatory agencies, the new guideline ICH Q12 “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management” was developed. This guideline has been available as a Step 2 document since November 2017. According to Jean-Louis Robert, co-opted CHMP member, the guideline is meant to facilitate the management of post approval changes over the complete product lifecycle, basing regulatory decisions on the growing understanding of the process and the product as well as risk-based assessments.

With the aid of practical case studies, Marieke van Dalen (Aspen Oss, The Netherlands) explained what challenges regulatory affairs departments have to meet when managing changes that are only to be reported in the three ICH regions EU, USA and Japan. The different change categories, deadlines and communication channels with the competent authorities of these three regions alone turn such changes into complex projects. Here, the provisions of ICH Q12 can make an important contribution towards more transparency and harmonisation. This applies in particular to changes in the supply chain, which are usually globally oriented and of a significant complexity.

Koen Nauwelaerts of “Medicines for Europe”, the industrial association for generics, pleads for a management of the approval documentation of an API that is independent from the product, based on the model of the CEP procedure. In such a scenario, a harmonised ASMF would be a central, independent document which would be examined, approved and individually numbered in the already existing work-sharing pilot project and therefore contribute considerably to an efficient processing of changes.

Since December 2017, risk assessments as per ICH Q3D are a requirement for already approved and marketed medicinal products, as well. Connected to this, there are particular expectations towards manufacturers and suppliers of active substances regarding the communication and cooperation with their customers. According to Mechthild Sander, Alfred E. Tiefenbacher, Hamburg, supplying a Risk Management Summary for the drug manufacturer is of great importance. Moreover, API manufacturers should keep close and transparent relations with the suppliers of their starting materials and intermediates as well as maintain continuous, prompt communication with their customers. The Risk Management Summary, while not mandatory, is a highly recommended document within the CEP procedure, as Hélène Bruguera from EDQM in Strasbourg elaborated. Besides content requirements, an EDQM policy from September 2016 also includes a Risk Management Summary template. According to the policy, this is to be included in the annex of a CEP application.

The risk assessment regarding elemental impurities is the key aspect of guideline ICH Q3D altogether. According to Sven-Erik Hillver, Senior Expert of the Medical Products Agency, Sweden and member of the ICH Expert Working Group Q3D, it depends on the risk assessment’s outcome whether or not a specification regarding these impurities is necessary. Previous experience showed that many companies still struggle with such a risk assessment; in some cases, it is too short or missing completely. Using various examples, he illustrated what distinguishes an ideal risk assessment, such as the summary of analytical values, magnitudes of purging, qualified worst case scenarios and their reference to corresponding PDE values.

As in previous years, the 20th APIC Conference was brought alive by the encounter between representatives of authorities and the industry. The great importance the information exchange holds for all participants showed in various lively discussions. These were not only held in the plenum and the parallel sessions, but also in many conversations during the breaks and the joint dinner of the first conference day. The event provided the perfect setting for this.

Note: the 21th APIC Conference will be held on 24 – 26 October, 2018 in Budapest. Leading representatives from international drug authorities and the industry will talk about current quality and regulatory related developments in active pharmaceutical ingredients in Europe and the world.