21st APIC Conference in 2018

GMP Inspections at API Manufacturers in the EU and Asia
– Highlights of APIC’s 21st European API Conference in Budapest –

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, Maria Filancia from the Manufacturing Quality and Supply Chain Integrity Committees and Inspections Department of the EMA explained some important aspects of international cooperation in GMP inspections of API and pharmaceutical companies. She also gave an overview of the status of the Mutual Recognition Agreement between the EU and the USA.

The EMA is an authority with mainly coordinative-administrative tasks, which are performed by experts with scientific-technical expertise in the fields of marketing authorisation, scientific advice and GMP inspections.

According to Maria Filancia, the first important steps in international cooperation with other monitoring authorities are to build mutual trust and harmonise inspection practices. Organisations such as PIC/S play an important role in this.

The next important milestone in the implementation process of the MRA between the EU and the USA will be reached on 15 July 2019. As of this date, the Qualified Person will no longer have to perform a new inspection for batches manufactured in the USA and exported to the EU with a relevant certificate. At this stage, a decision will also be made on how to proceed with veterinary products. Three years later, a decision will be made on human vaccines and blood plasma products.

During GMP inspections in the Far East but also in countries within the EU, GMP inspectors of the regulatory authorities regularly find violations of elementary GMP regulations. Rainer Gnibl, GMP inspector at the Regierungspräsidium Oberbayern, explained the most frequent deficiencies of the category "serious" and "critical", which he discovers at the different sites.

At the Asian production sites, there are also cultural characteristics that a GMP inspector must take into account to ensure that an inspection is as efficient as possible.

Emergency measures taken by the authority after one critical or 5 serious deficiencies have been identified - include a partial or total withdrawal of the GMP certificate, the import licence or the CEP (by the EDQM), the ordering of batch recalls or the refusal of an authorisation. In the worst case - a pharmaceutical company has only indicated one API supplier in the marketing authorisation application - a poor inspection result at this supplier can result in the loss of the respective marketing authorisation.

The forthcoming Brexit brings with it many uncertainties for pharmaceutical and API companies in Europe and the United Kingdom. Basically, the pharmaceutical world is preparing for a "hard Brexit", a situation in which there is no free movement of goods between the EU and the UK (which is then a "third country"). Arjen te Nijenhuis from Janssen Research & Development, UK, illustrated various scenarios relating to the manufacture and import/export of APIs, clinical trial products and finished products within the EU and the UK and the complications occurring in the supply chains.

In anticipation of the 'no deal' situation, the UK Government has already published a number of 'Technical Notes', with the intention of cushioning the impact of 'hard Brexit' on the pharmaceutical industry. Among other things, batch testing and certification carried out within the EU by a QP is to be recognised without restriction in the UK.

The same applies to the regulations for medical devices and the CE marking. Ultimately, the vision is to establish a parallel market for pharmaceutical products in the EU and the UK, similar to the European Economic Area (EEA), where the EU Member States and EFTA countries form a deepened free trade area.

Canada is an important market for many API manufacturers in the EU. Since 2007, the Canadian regulatory authority has accepted CEPs issued by the EDQM, but only for synthetic and semi-synthetic APIs. Amirthini Rajkumar of Health Canada reported on current developments with regard to facilitating the submission of marketing applications.

Since August 2017, CEPs can now be submitted directly and instead of an ASMF. Besides, CEPs have recently been accepted for sterile and fermentatively manufactured APIs. However, Health Canada still requires confirmation on eight points regarding compliance with the current EDQM regulations on the CEP procedure.

Up to now, data integrity hasn't suffer any loss of topicality. Danny de Scheemaecker from Janssen Pharmaceutica, Belgium, showed with examples from production and laboratory how a risk analysis of the respective data processing systems and their subsystems largely ensures the integrity of data and controls possible risks. A helpful first step in creating an overview of all GxP-critical activities is to follow FDA's six-system inspection approach.

Supply shortages have become common in the globally networked pharmaceutical world and can have different causes. The authorities of the EU Member States play a key role here. David Cockburn, former Head of Manufacturing and Quality Compliance at EMA, gave some examples to answer the question of how the authorities can influence supply shortages.

Such a measure consists, for example, in increased "regulatory flexibility" with regard to the processing of changes in the marketing authorisation dossier or the strengthening of "supply chain resilience" through a regular assessment of the supply chains by the pharmaceutical manufacturer. In addition, a proposal for the modification of the Site Master File Format was developed; such an extended Site Master File contains an overview of measures to maintain supply chain resilience.

The authorisation and registration procedures on the Russian market differ significantly from those within the EU. Oksana Golycheva, Associate Director Global CMC Regulatory Affairs of Johnson & Johnson, USA, explained the various requirements related to the registration process for APIs in Russia and the member states of the Eurasian Economic Union (EAEU), Belarus, Kazakhstan, Kyrgyzstan, Armenia and the Russian Federation.

Since May 2017, the EAEU countries have been subject to a common regulatory framework that includes mutual recognition and decentralised authorisation procedures (there is no centralised authorisation procedure like the one in the EU). An EAEU pharmacopoeia is in preparation. Marketing authorisation holders in the EAEU states should note that there will be no delays, e.g. due to supply shortages. Indeed, when a product is not available on the market for more than 3 years, it is deleted from the state register, i.e. the marketing authorisation expires.

Brazil, another key country in the global movement of APIs, has been an ICH member since November 2016 and has adopted the ICH guidelines Q3A, Q3C, Q3D (for APIs), Q6A, Q11 and M7. Gabriel Ramos Ferronatto, ANVISA, presented the timeline for regulatory adjustments, according to which Brazil will implement further guidelines such as those for clinical safety (E2A, E2B, E2D) by November 2021.

Brazil has recently introduced new deadlines for processing new applications (120 days for priority applications and 356 days for standard applications) and changes (60 days for priority applications and 180 days for standard applications).

Following the COIFA initiative, there are now direct lines of communication between the Brazilian authority ANVISA and the European-based API manufacturers to accelerate the overall marketing authorisation process.

As part of a CEP procedure, the Risk Management Summary (RMS) is not a binding but a highly recommended document with regard to elemental impurities. The guideline "Implementation of ICH Q3D in the Certification Procedure", which has been in force since September 2016 and specifies which information on elemental impurities is to be provided in a CEP application with and without RMS, was revised last year. It has been in force since September 2018.

Hélène Bruguera of the EDQM explained what CEP applicants have to take into account in the application procedure due to this guideline and other recently updated "Public Documents" of the EDQM..

For example, the EDQM Guideline for the revision or renewal of a CEP contains further restrictions, i.e. additional scenarios are described in which a separate new CEP application is required instead of a CEP revision/renewal.

Hélène Bruguera gave a detailed presentation on the Valsartan case.

Shortly after the nitrosamine contamination in Valsartan and other Sartan preparations became public, the EDQM started a package of measures in two "waves" consisting of a comprehensive review of affected CEP dossiers and a call for CEP holders of Sartan-APIs containing a tetrazole ring to address all types of nitrosamines that might be present.

Since January 2017, the work-sharing procedure of the EU member states' authorities regarding the evaluation of Active Substance Master Files (ASMFs) has been established. According to Martijn Klop, Synthon, Netherlands, this means a considerable simplification and acceleration of authorisation procedures. If 10 authorities in the EU receive 10 ASMFs, theoretically each authority would have to evaluate all ASMFs, resulting in 100 assessment reports.

The work-sharing procedure allows a report created by one authority to be adopted by the other authorities. This procedure is advantageous for scenarios in which manufacturers supply several customers in different countries with APIs of different specifications. Another advantage is the creation and sending of an ASMF in eCTD format.

The provisions of ICH Guideline Q12 are also intended to simplify the regulatory burden that applies to changes to products that have already been approved (post approval changes).

According to Markus Goese, Hoffmann-La Roche, Switzerland, the risk-based categorization of post-approval changes and the use of the Product Lifecycle Management document in a change notification contributes to the harmonization of such change procedures.

The requirements of this guideline, which has been available as a Step 2 document (Draft Consensus Guideline) since November 2017, should enable the pharmaceutical industry to handle most of the post-approval CMC changes efficiently and with less regulatory control.

The regulations for the registration of APIs and for medicinal product authorisations in China have been subject to a change process for 6 years.

David Zhou of the China Chamber of Commerce for Import and Export of Medicines and Health Products explained the current status of the regulatory framework.

Basically, the review and authorisation process for a medicinal product should take place in combination with the API, excipients and packaging materials and no longer according to the usual practice of separate, uncorrelated procedures for the individual components of the medicinal product. The new regulation imposes an obligation for API manufacturers and pharmaceutical manufacturers to cooperate.

In the event of quality defects in the medicinal product which can be attributed to defects in the active substance, both the manufacturer of the active substance and the pharmaceutical company are held responsible by the Chinese supervisory authority CFDA.

Is the global harmonisation of authorisation procedures a utopian vision? According to Marieke van Dalen, Aspen Oss, Netherlands, such a final goal, the "ladder to heaven" to globally uniform procedures and standards, is quite realistic, provided that all stakeholders work together and find acceptable compromises.

A number of organisations and associations have already done pioneering work here, such as the APIC or the IPRP (International Pharmaceutical Regulators Programme). The MRAs EU-Japan and EU-USA also belong to this.

The 21st APIC Conference was again characterized by an extraordinarily lively exchange between representatives of industry and authorities, as the numerous dedicated discussions in the plenum and in the parallel sessions showed.

These were then continued in a relaxed atmosphere during dinner together on the first day of the Conference. Once again, this event provided the perfect environment.

Note: The 22nd European Conference on APIs will be held in Prague from 23 to 25 October 2019. High-ranking representatives from international medicinal product authorities and the industry will report on the current quality and marketing authorisation relevant developments of APIs in Europe and non-European countries.