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18th APIC Conference in 2015

Quality Metrics, Data Integrity, and Elemental Impurities –
Highlights of the 18th European Conference of active ingredient of APIC

Since the FDA launched its "Quality Metrics" program, there is an increased need for information for pharmaceutical companies and manufacturers of active pharmaceutical ingredients. The company specific data collected by the FDA are important information for establishing a risk profile for a corresponding production site. And, ultimately, it is a control instrument for the authority’s inspections planning. What quality data are now requested by the companies and what consequences arise from this for the authority’s monitoring practice as well as for the companies themselves? This was one of the subjects discussed at the 18th European APIC/CEFIC Conference. 

At the beginning of the conference Alex Viehmann from the US FDA provided an overview of the type of data collected by the authority and their statistical processing. One of the goals of the quality metrics program is the monitoring of the quality status of individual products and the early discovery of (critical) variations in the quality. On the basis of the risk profile derived from these data, the Agency then determines a reduced (or increased) inspection frequency for the site concerned. An important message for the companies is hence: the quality metrics program is seen only as a monitoring tool. Delivering the quality relevant data will not result in failure reports (483s) or other enforcement actions by the authority. 

The key document describing the specifics of the data collection was issued as a draft guidance for industry entitled "Request for Quality Metrics" in July 2015. Against the background of this guidance, Betsy Fritschel, Johnson & Johnson, explained which data the FDA specifically requires and in what form as well as in what time lines these data have to be submitted to the FDA. It is important that actual data are delivered and no "metrics", i.e. already calculated key figures. This right the authority explicitly reserves for itself.

The industry side also launched quality metrics initiatives. Betsy Fritschel reported from a pilot program of the International Society for Pharmaceutical Engineering (ISPE), in which 18 companies participated – including 44 sites with a total of 14 product-related measures throughout the entire supply chain. Ultimately, such data are also a solid foundation for a dialogue with the authorities and the further development and promotion of a quality culture in the companies. 

The evaluation of supply chains is of paramount importance for the prediction and the timely prevention of supply shortages. According to Anabela Marçal by the European Medicines Agency (EMA) in London, the prime objective of the authority is to ensure the supply of the population with high quality medicines. This can only be achieved if the highly complex supply chains have a certain degree of resistance - "Resilience" - and do not collapse when a link in this chain fails due to quality problems. Thus, to accomplish this, the industry can make a contribution in the form of a proactive and continuous risk management. The EMA has established an rapid alert system for potential bottlenecks and communicates in quarterly teleconferences with the FDA, Health Canada, and the Australian therapeutic goods administration TGA. 

Data integrity problems are frequently associated with companies in the Far East economic area - wrongly, as Ewan Norton, GMDP Inspector of the UK authority MHRA explained. The causes that lead to errors in the area of quality assurance of electronic data are not necessarily cultural. The GMP Inspector also encounters these causes at European companies. These causes can be summarised in a "fraud triangle" consisting of security gaps, rationalization/time pressure and psychological pressure under which the employees are. From the authorities’ perspective data integrity is an integral part of the quality assurance. It is therefore in the focus of almost every GMP inspection – as the FDA Warning Letters and some entries in the EudraGMDP database show. 

Since its publication in December 2014 the ICH Q3D "Guideline on Elemental Impurities" dominates the discussion between pharmaceutical companies, API manufacturers and the authorities. According to Janeen Skutnik Wilkinson from Biogen in the US, the requirements of ICH Q3D are frequently misinterpreted. This document is not a testing guideline, and the companies are not requested to prove the absence of elemental impurities. It is first and foremost to carry out risk assessments considering all potential sources of contamination. Depending on the outcome of this assessment a control strategy has to be established. A routine test on elemental impurities is not mandatory, unless this is a result of the risk assessment. Generally speaking, a profound understanding of the manufacturing process and the focus on the later critical process steps provide the best conditions for a realistic risk assessment.  

The number of submitted change notifications has increased significantly in the last 5 years. According to Koen Nauwelaerts from the European Generic and Biosimilar Medicines Association (ECA), this number is currently on average 2.9 variations per marketing authorisation per year. For a contract manufactured API the number of involved parties in the supply chain can certainly rise to 12 additional. And, according to the strict interpretation of the variations regulation, these parties have to be included in the dossier. As a result, the number of change notifications and thus the workload in the regulatory area (regulatory burden) continues to increase. The EGA hence recommends to limit the API-specific information in the registration dossier to the manufacturers of the "final API" and the "final intermediate". 

The simplification of regulatory processes for changes with regard to already approved products (post approval changes) is supposed to be covered in the new Guideline ICH Q12. For this Guideline only a concept paper entitled "Technical and Regulatory Considerations for Pharmaceutical product lifecycle management" exists. Luisa Paulo from Hovione, Portugal, reported about the deliberations of the ICH expert working group to shape its content. Ultimately, this document will allow a "do and tell" procedure in many cases. This will promote the further development of manufacturing processes, and it will also provide a relieve of regulatory burden for both companies and regulatory authorities. The step 1 "Technical Document" of ICH Q12 is expected to be finalised in June 2016. 

The manufacture of highly sensitizing drug substances under GMP conditions is associated with special requirements on equipment and premises. How does an authority handle this? According to Mieke van der Meulen of the Dutch Healthcare Inspectorate, dedicated equipment is essential to minimize the risk of cross contamination. However, different buildings are not mandatory. What applies here also: the basis for a GMP compliant production of such substances is a comprehensive analysis of the contamination risk and a careful validation of the cleaning processes - both are requirements from chapters 4, 5 and 12 of the GMP Guide part II. 

The guidelines on good distribution practice of active ingredients have been effective since March 2015. How these principles can be implemented in practice explained Uwe Fischbeck from Merck in Darmstadt, Germany. A risk assessment of the storage and transport conditions for the different active ingredients is also the basis for the implementation of GDP according to the guidelines. In the end the initial efforts for this purpose are costly and tie up additional resources; ultimately, though, it is for the active ingredient manufacturer’s benefit as his experience with products and the quality of the ingredients and their derived products increases. 

Harmonization of standards and regulatory convergence - this is vision and program of the EDQM in Strasbourg. Hélène Bruguera, Manager of the EDQM’s Certification Division, reported about her authority’s various initiatives to accomplish this goal. They include, for example, the implementation of the ICH Q3D Guideline on "Elemental Impurities" in the European Pharmacopoeia or the further development of the now widely recognized procedure for the issuing of a certificate of suitability. Further examples on the way to the regulatory convergence concern, amongst others, the Joint Inspection Programs, the ASMF Worksharing Program, the International Generics Drug Regulators Programs and a number of further initiatives to strengthen the communication with authorities outside the EU Member States. 

What new developments will active ingredient manufacturers and pharmaceutical companies be facing in the near future? At the end of the conference the Chairman of the EMA’s Quality Working Party, Jean-Louis Robert, presented a list of documents that are currently in progress. In addition to others, some new guidelines are related to the sterilization of active ingredients and excipients, the manufacture of finished products, the quality and bioequivalence of topical products, and the meanwhile published reflection paper on the "New Active Substance" status of chemical substances. The guideline on the pharmaceutical quality documentation of investigational medicinal products (IMPs) will be revised. 

The 18th APIC Conference in Amsterdam showed once more, how important a fruitful exchange of views between representatives of the authorities and industry is. Both sides can take valuable impulses for their daily work, to face the growing challenges of an increasingly complex regulatory environment. Personal contacts and the also continued communication beyond the conference days further facilitate this. For this the event once again offered the perfect Setting. 

Note: The 19th European APIC/CEFIC Conference will take place in Barcelona from 23-25 November 2016. There, senior officials from international drug regulatory agencies and the industry will report about the current topics and developments in the monitoring, manufacture and distribution of active pharmaceutical ingredients in Europe and non-European countries.