17th APIC Conference in 2014


“A sufficient supply of drugs of unchanging best quality, produced for the population by pharmaceutical manufacturers according to high quality standards and without needing extensive regulatory oversight” – this is FDA’s vision for 21st century pharmaceutical manufacturing in short. To turn this vision into reality, the authority has initiated a programme with quality metrics. This programme aims at creating a basis as objective as possible, for the risk oriented assessment of pharmaceutical manufacturers subject to GMP in the area supervised by the FDA. 

Russel Wesdyk, FDA, explained the main features of this initiative at the beginning of last year’s APIC/CEFIC Conference taking place in Vienna in November. The core element of the quality metrics are key indicators which the FDA collects for each manufacturer. Examples for these key indicators are the “lot acceptance rate” (1 minus the number of lots rejected divided by the number of lots produced) or the OOS rate (the number of OOS test results divided by the total number of analytical tests performed). The FDA expects that a number of such rates together with performance questions to be answered by the senior QA manager who has signed the annual product review will result in a largely objective picture of the production site’s respective quality standards and of its quality culture. 

The long-term objective is to commit the manufacturers to the quality metrics in such a way that the manufacturers receiving the best marks won’t require a very high supervising effort any longer. Legal basis for the collection of quality metrics-related data is the Food and Drug Administration Safety and Innovation Act (sections 705 and 706). This Act has been in force since 9 July 2012 and regulates for example the fees charged by the FDA for its activities (PDUFA, GDUFA etc.). Currently, the FDA is developing a draft guidance with the title “Quality Metrics and Risk- Based Inspections” that will be published for comments in the first half of 2015. 

At which step of the routes of synthesis that finally lead to an active pharmaceutical ingredient do the GMP rules apply? Or formulated in another way: Which one of the different intermediates of the route of synthesis is the starting material (subject to GMP)? This question has been pondered by the active ingredient industry and also by the regulatory authorities for several years already. And the conference participants took the chance to dispute both points of view and to take part in lively discussions on this subject. 

According to Robert Bream, European Medicines Agency (EMA) in London, assessors are often confronted with the following situation when processing the documents for marketing authorizations: The applicant justifies his selection of starting materials as follows: It constitutes a significant structural fragment, has a defined chemical structure, and is commercially available – as required by Guideline ICH Q11. But at the same time there is neither sufficient information on the chemical synthetic process nor a description and critical assessment of the substance’s impurity profile making it nearly impossible for the assessor to judge whether an adequate control strategy is established or not. This leads to questions and delays in the process for marketing authorization. As Robert Bream explains, it is absolutely necessary for the assessment of the dossier to describe clearly and completely which structures are built in the single steps of synthesis so that the occurrence and the depletion of quality related impurities can be understood. In single cases this may mean that a route of synthesis should comprise more than only one or two steps. In these cases it is not unusual that the starting material must be re-defined. Robert Bream expressly referred to EMAs Reflection Paper, published in September 2014 that provides important guidance on the selection and the justification of starting materials. 

The re-definition of a starting material is a central problem during the marketing authorization process that always leads to controversial discussions between industry and authority and to delays with additional costs. According to Marieke van Dalen, Aspen Oss, Netherlands, most of the manufacturers strive for specifying the shortest possible route of synthesis with starting materials “near the final product”. The reason is much less “to avoid as much GMP as possible” than rather to reduce the complexity of the change control procedures – as the effort the manufacturer has to undertake for an adequate change control increases significantly with each further synthesis step. Furthermore – and this is another huge problem for the applicant – the assessment of the dossiers is not harmonized at all by the different European regulatory authorities, and this applies a fortiori also to the authorities in other countries (USA, Japan, Latin America etc.). This leads to a significant effort if changes have to be applied for. This effort even increases disproportionately if longer routes of synthesis have to be described in the Drug Master Files. According to Marieke van Dalen EMA’s Reflection Paper gives assistance at least at European level. But it provides no information on how to deal with “older” drug master files (ASMFs) when referenced by a “new” marketing authorization application. 

Foreign particles that enter the product in the production of the active ingredient are generally undesirable, but not in any case inevitable. They can become a serious quality problem, if they do not originate from the process equipment or if they exceed the limits laid down in the specification. The APIC has established a project team within their Quality Working Group which has developed a guidance for dealing with foreign particles (“best practices”). According to Dirk Overrödder from Cilag and member of the project team, it is crucial to have the inevitable particles under control through clear specifications and tests. In any other case it is necessary to conduct thorough research of the cause and to take consistent CAPA measures. 

Good distribution practices for active pharmaceutical ingredients (“GDP for APIs”) is an issue that is getting increasingly in the focus of the authorities. As Karl Hensen from Merck explained, according to the now published GDP guidelines the term “Distribution” includes the areas export, import, procurement, supply and storage. The core idea of good distribution practice is characterized by a comprehensive risk assessment of all steps in these areas to identify deficiencies, to improve processes and thus to reduce the risk. This will be one of the most important tasks for all companies taking over responsibility within complex distribution channels for APIs. The process when submitting documents for marketing authorization or for registration in Europe and in the USA is uniform and transparent to a large extent, at least as concerns the forms to be used (CTD) and the communication ways. But the registration of active ingredients in emerging countries is a great challenge for the manufacturers concerned because processes and rules are completely inconsistent. For this reason an APIC “Interest Group Emerging Countries” was formed. This group aims at providing a common basis in the form of best practices for industry and authorities for the registration of active pharmaceutical ingredients. It also wants to develop measures for the cooperation with and the proactive intervention at the regulatory authorities of these countries. As Jan Smeets, DSM Sinochem, Netherlands stated, only few emerging countries fully accept a Certificate of Suitability (CEP) issued by the EDQM, for example. The regulatory authorities of most emerging countries accept a CEP only partly and require further documentation. In almost all cases a local caretaker or agent is mandatory for the registration process. This local caretaker maintains close contacts with the assessors of the authorities and can speed up the review process by short-term measures such as  arranging translations in the local language. There can be large differences in the requirements in the single countries and sometimes this causes a significant effort. Brazil, for example, is now enforcing stability data for climatic zone IVb and the confirmation of the shelf live based on these data. In Belarus the local drug product manufacturer himself must apply for the marketing authorization and he must hand in the same application for each new customer of the same API. China, India, Russia, Brazil and South Korea require compliance with the local pharmacopoeia. But the biggest problem for the manufacturers is the insecurity as concerns the disclosure of confidential information. Generally, there are many countries where the protection of confidential data is not guaranteed. 

As in previous years the 17th APIC conference in Vienna showed again clearly the importance of exchanging views and information between authority and industry. At a time with rapidly changing legal requirements and with the regulatory requirements always getting more complicated such conferences are increasingly important, especially if they provide the opportunity for personal contacts and direct communication. In the end this stimulates a stronger cooperation among the different interest groups and a bit of “harmonization” – not only at the regulatory Level.