Nitrosamine Impurities - A Global Challenge for API Manufacturers and Pharmaceutical Companies

Launch Conference Final version: ECA's Integrated Qualification and Validation Guide

Working with Suppliers towards modern Qualification and Validation

27/28 October 2020 in Berlin, Germany (on site) or broadcasted live to your desk!

Highlights of APIC's 22nd API Conference in Prague

APIC's annual Conference on Active Pharmaceutical Ingredients is the most important forum for manufacturers of active pharmaceutical ingredients and the pharmaceutical industry. Representatives from both sectors and from international authorities meet there to discuss current developments.

At the beginning of the conference, Andrei Spinei from the European Medicines Agency, EMA, gave a brief overview of the principles of quality risk management and identified the fundamental shortcomings in dealing with quality risks that GMP inspectors often encounter. The case of nitrosamine contamination in Sartan APIs, which first occurred in June 2018, served as an example, causing the authorities to conduct a comprehensive review and take extensive regulatory measures. Due to the mutagenic potential of nitrosamines, these measures were necessary and consequently also led to an expanded level of knowledge about the various causes for these contaminations. According to Andrei Spinei, GMP inspections often revealed an inadequate, non-scientific approach to root cause analysis and a lack of understanding of the process. He clarified that from the point of view of the authorities, the main principles that need to be met in order to adequately deal with quality deficiencies (including, in particular, the occurrence of nitrosamine impurities) are: the best possible understanding of products and processes together with a comprehensive risk assessment in the development phase, robust change control procedures, thorough investigation of deviations with the aim of truly understanding their cause, and proactive, timely and transparent communication with authorities, suppliers, customers and other parties that are directly or indirectly affected.

A close examination of the risks is also crucial in cases where nonsterile APIs are used for the manufacture of sterile finished medicinal products. In his presentation on this topic, Francois Vandeweyer, Belgium, first referred to the requirements for the design of buildings and production equipment as laid down in the ICH Q7 guideline. However, how can these requirements be practically implemented while ensuring that microbial contamination and crosscontamination are avoided? According to Francois Vandeweyer, an  important principle is to carry out the final manufacturing step of a chemically-synthetic API under environmental conditions that are at least equivalent to those of the first manufacturing step of the finished medicinal product. Risk assessments are absolutely necessary if a closed system is temporarily opened to the environment during the manufacturing process, e.g. during a visual inspection or when docking solvent tanks or a packaging system. Likewise, cleaning of production equipment or preparation of primary packaging materials in a controlled, non-classified environment should only be done on the basis of risk assessment.

Due to the increasing complexity of supply chains, GDP has become as relevant as GMP. According to the EU Commission's guideline valid since September 2015, pharmaceutical manufacturers may only process APIs that have been manufactured and transported according to GMP and GDP principles. According to Jelle van Gauwbergen, Janssen Pharmaceutica, Belgium, some questions remain unanswered regarding the practical implementation of GDP in a highly complex global distribution network for APIs despite this official document. The APIC has published a "How to do" document and a "Statement" on GDP to help clarify these issues. In her presentation, Jelle van Gauwbergen referred to these best practice documents and the possibilities for minimising risks in complex supply chains.

Despite stricter security standards, counterfeit medicines unfortunately are a growing focus for individuals with criminal energy. Bastiaan Venhuis from the National Institute for Public Health and Environment, Netherlands, used impressive examples to illustrate the characteristics of counterfeits and the security gaps in the supply chain that represent a high risk. Manufacturers of APIs and finished pharmaceuticals should have a thorough knowledge of their supply chains. Particular attention should be paid to expired preparations or packaging materials that can no longer be used; in any case, these must be withdrawn from the market or destroyed under controlled conditions.

Careful risk management is also essential for so-called "indirect" materials or services. These include processing aids such as filters, hoses, spatulas, gloves, etc. or cleaning, calibration or maintenance services. Georg Strasser, Janssen, Switzerland explained the importance of GMP in the procurement of such materials and services. Chapter 7 of the ICH Q7 guideline and the ICH Q7 Q&A document contain requirements regarding the qualification of suppliers. These requirements are mandatory in the EU. Further requirements for "Good Procurement Practice" can be found in the EU Medical Device Regulation and ISO 13485:2016.

Particles may occur as an undesirable impurity in the manufacture of solid, semi-solid or liquid dosage forms, but they are to some extent technically unavoidable. Dirk Overrödder, Janssen, Switzerland, used various examples to present the different causes for the occurrence of particles and how a pragmatic approach to this problem can be achieved. He presented the "Guidance on Handling of Insoluble Matter and Foreign Particles in APIs", which, in the absence of "official" guidelines, was prepared by the APIC and shows practical ways to minimize and control particles.

Brazil has made significant progress in simplifying regulatory processes. Gabriel Ramos Ferronatto, ANVISA, Brazil, presented a report on the processing of applications for API registration, which is now more efficient due to new legislation. This also applies to the processing of variation applications for a marketing authorisation. Other innovations relate to the adoption of ICH guidelines Q2 and Q3D and the requirement that temperature and humidity must be controlled and documented during storage and transport of APIs. For a new marketing authorisation, 12-month data can now be submitted at 30 degrees and 65% relative humidity and for variations 6-month data at 25 degrees and 60% relative humidity.

The Brexit now completed brings with it some uncertainties for many pharmaceutical and API companies regarding the import and export of APIs following the UK's transition to the third country status. Ulrich Kissel, Chairman of the European QP Association, described the uncertainties of a Qualified Person in the EU, after the Brexit, using the following example, among others: Under the current legal situation in the UK, an API manufacturing site there receives a GMP certificate after passing a GMP inspection by the MHRA; after entering the third country status, API exports from the UK to the EU will have also to be accompanied by a Written Confirmation. QPs must therefore ensure that these two documents are available. However, the GMP certificate issued by the MHRA prior to the Brexit must be still valid for the API export. If it has not yet been replaced by a certificate issued by the EU before it expires (3 years from the date of issue), the QP in the EU cannot, strictly speaking, release or certify the batch of the API concerned. According to Ulrich Kissel, there is currently no clarity about how to deal pragmatically with this and other situations.

A successful pre-approval inspection represents an important milestone for the placement of a medicinal product on the market. Careful preliminary preparation of such an inspection is therefore absolutely essential. Carlos Herrero Sanchez, Centrient Pharmaceuticals, The Netherlands, explained the most important points to be considered prior to an inspection and the specific differences between a pre-approval inspection by European GMP inspectors and FDA inspectors.

For companies submitting an application to the FDA for the approval of a generic drug, it is important to know the various processing deadlines and review cycles, e.g. for Drug Master Files. In her presentation, Ee-Sunn Chia, FDA, used a timeline to explain the different phases of the approval process and explained the options for communicating with the FDA review teams that are necessary at certain points in the process, for example, to clarify deficiencies in the submitted documents.

At the beginning of 2019, the revised EDQM guideline on the amendment or renewal of CEPs came into force. In her comments on the current changes in the CEP procedure, Hélène Bruguera of the EDQM highlighted the stricter regulations for the revision of a CEP. In most cases, a separate CEP is now required, which must be applied for using the "sister file procedure", for example if there is a change in the location of manufacture of the API and that API belongs to a different group of companies. In the long term, the EDQM is planning a comprehensive modernisation of the CEPs and will soon initiate a corresponding survey.

Shortly after the nitrosamine impurities in Valsartan and in other Sartan APIs were discovered, the EDQM started a comprehensive review of all CEP applications. Hélène Bruguera presented a report on the measures initiated for a total of 125 applications affected.

Analytical data and risk assessments were requested from the respective CEP holders, numerous samples were tested for nitrosamine contamination and, finally, 11 CEPs were withdrawn. The analytical review was carried out in close cooperation with the Official Medical Control Laboratories (OMCLs). A number of so-called joint inspections with inspectors from the EMA and the EDQM were another part of this package of measures. Besides, 5 Sartan monographs of the European Pharmacopoeia are being revised, which are expected to come into force in April 2021. As a consequence, some CEP applications will have to be updated again until then. In her presentation, Hélène Bruguera explained the procedure and the corresponding deadlines.

China is one of the fastest growing economies in the world, so it is important for European API manufacturers to understand the regulatory landscape in this country. Sabina Jurca, Lek Pharmaceuticals, Slovenia, and Chairperson of the Chinese Regulatory Affairs Subgroup of the APIC, reported on the latest reforms since 2015 and the resulting changes in the structure of the national health authority as well as the dialogue process of the APIC with the Chinese Chamber of Commerce for Import and Export of Pharmaceuticals and Medical Devices.

Japan is an equally important market for the European pharmaceutical and API industry; here, too, the legislation for pharmaceutical products has been revised. Using various examples, Katsuaki Ura, MHLW, Japan explained the special features of the review and approval procedure for medicinal products already approved in Japan or other countries, but for which a different mechanism of action is used therapeutically (SAKIGAKE designation). Further topics of this presentation included the procedure of the Japanese regulatory authority in case of changes for already existing marketing authorisations, the official GMP inspection practice as well as current information on the Mutual Recognition Agreement of the EU with Japan.

Pharmaceutical companies pursuing global approval strategies are repeatedly confronted with the challenge that neither the formal and content-related requirements for the information on APIs nor the change procedures are harmonized. According to Marieke van Dalen, Aspen Oss, The Netherlands, there are significant differences in the content of Drug Master Files worldwide, due to different processing procedures by the regulatory authorities. The same applies to the processing of variation applications. As a result, the corresponding documents are kept as minimalist as possible in order to minimise the workload for marketing authorisation holders in the event of changes.

Once again this year, the lively exchange between representatives of industry and authorities was the characteristic feature of this conference. The intensive discussions held in the plenary session and during the breaks were then continued in a relaxed atmosphere at the common dinner on the first conference day. This event once again offered the perfect setting for this.

Note: The 23rd European API Conference will take place from 28 - 30 October 2020 in Amsterdam. High-ranking representatives from international drug authorities and industry will report on current developments in the quality and approval of APIs in Europe and non-European countries.

Author:
Gerhard Becker
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in analytical and compliance topics.

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