QUALITY AND SECURITY OF ACTIVE SUNSTANCES: HIGHLIGHTS OF THE 14th EUROPEAN APIC CONFERENCE
The amount of sub-standard or falsified active substances has increased substantially over the last few years. In the light of non-harmonised statutory bases in the European context, regulatory supervision measures are often ineffective and unable to prevent such potentially dangerous substances from entering the European Economic Area. But after incidents such as the Heparin scandal, the necessity for rapid action at an international level has been realised. Stephan Führing from the European Commission in Brussels sees the new 2011/62/EU Directive as an important step towards a statutory initiative for combating falsified active substances, harmonised within Europe. According to the new Article 46b (2), active substances can only be imported into the EU if accompanied by written confirmation from the competent authority of the exporting country that the following conditions are fulfilled:
- The standards of good manufacturing practice of the exporting country are at least equivalent to those laid down by the EU.
- The manufacturing company is subject to regular and strict controls. The inspections take place unannounced. Measures are taken in the case of non-compliance with GMP.
- The EU (i.e. the competent authorities of the Member States) is informed without delay of findings of noncompliance with GMP
It is only possible to waive this written confirmation if the exporting country is included in a list set up by the European Commission. This list includes countries whose level of compliance with GMP (see the requirements mentioned above) has been assessed positively by the European Commission. For this, an on-site assessment of the third country must be carried out by the Commission. This will only be done at the request of the third country.
Manufacturers of medicinal products (holders of the manufacturing authorisation) still are responsible for demonstrating that their supplier of active ingredients produces in compliance with GMP. The manufacturer must confirm this in the marketing authorisation documentation.
The deadlines for implementing these provisions are rather long. The European Parliament adopted the Falsified Medicines Directive on 8 June 2011. The time-frame for transposition of the Directive into national law by the relevant Member States is 18 months. Hence, the provisions of the Directive must be enshrined in national legislation as of 2 January 2013. This does not apply to the rules of importation of active substances which must be transposed as of 2 July 2013. In Germany, the transposition is planned to take place within the context of the 16th AMG (German Medicines Law) Amendment.
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The Medicrime convention is a broad international alliance for the fight against the counterfeiting of medicinal products. It was adopted by the Council of Europe in December 2010. The Council of Europe is an international organisation with 47 member states. Its headquarters are in Strasbourg. (Members of the Council of Europe are the member states of the European Union, as well as neighbouring states such as Albania, the Ukraine or Georgia). Hélène Bruguera from the European Directorate for the Quality of Medicines and Health Care (EDQM) in Strasbourg (the EDQM is affiliated directly with the Council of Europe) explained the focus of this regulatory framework which was opened for signature on 28 October 2011. (Then, signatory states must enshrine the Convention in their national law.) Purpose of the Medicrime Convention is criminalisation of counterfeiting of medicinal products. Elements of offence are defined as follows:
- manufacturing of counterfeit medicinal products
- supplying, offering to supply and trafficking in counterfeit medicinal products
- falsification of documents
- unauthorised manufacturing or supplying of medicinal products/placing on the market of medical devices which do not comply with conformity requirements
Hence, the scope of the Medicrime Conventions does not only comprise medicinal products including active substances and excipients but also medical devices as well as parts and materials to be used in the production of medical devices. It also includes the illegal internet sale of these products. So far the Medicrime Convention has been signed by 12 of the 47 member states of the Council of Europe.
Another important initiative in the fight against counterfeit medicinal products, entitled "eTACT", was devoloped by EDQM. The Falsified Medicinal Directive already requires forgery-proof safety features for medicinal products. Currently, only few member states of the European Union have already established serialisation systems. Unfortunately, matching of data is not possible due to different standards used in the member states. Therefore, the system's benefit for monitoring the flow of goods is very limited, particularly since internet sales of medicinal products are not covered. eTACT is expected to provide the decisive benefit by means of the following improvements:
- Assigning/marking each medicinal product with a forgery- proof safety feature ensuring uninterrupted traceability throughout the complete supply chain from the manufacturer to the patient ("end-to-end tracking)
- use of uniform, human and machine readable standards
- covering of internet sales
- centralised technical administration of the system by EDQM
- data responsibility (safety features) remains with the single stakeholders of the distribution chain (manufacturer, distributors, wholesalers, traders and pharmacies).
Actually, eTACT is in the second phase of its development. EDQM has a testing system, carries out live demos and collects feedback from interested parties and participants in the project, in order to further develop the system.
The American authorisation and surveillance authority FDA has also realised the necessity for international cooperation with the competent authorities outside the USA. Recently, some initiatives were developed. A new project started in January 2012 is carried out conjointly by FDA and EMA. Thanks to this initiative, the American authority and the authorities of the European Economic Area can rely on the results of inspections carried out in the partner area. This should make it possible to postpone or completely cancel some inspections (possibly carried out twice).
Christine Moore, FDA, spoke about other important initiatives in the area of the authorisation of medicinal products. One important project for the optimisation of human resources is the FDA-EMA pilot programme for a joint review of QbD components during new marketing authorisations of medicinal products. This "FDA-EMA Parallel Assessment Pilot" was started in March 2011 and supports joint pre-approval inspections by FDA and EMA, joint training programmes and knowledge and experience sharing among the authorities.
FDA started a further pioneering initiative when announcing the ratification of a draft law entitled the "Generic Drug User Fee Act" (GDUFA) in September 2011. Guy Villax, Hovione, Portugal explained that the central part of this regulatory framework comprises fees to be paid by the manufacturers of active substances and drugs when submitting an application for marketing authorisation of a generic drug (ANDA), an application for a change or a Drug Master File. Inspection of companies producing generic drugs will also be subject to a fee. These fees are estimated to yield a sum of 229 million US dollars in the fiscal year 2013. This money will be used to recruit at least 150 additional reviewers and as many additional investigators in order to reduce the huge number of ANDAS and pending inspections waiting to be carried out. The advantage for applicants who have paid the fee is an accelerated processing of their applications. Furthermore, the relevant Drug Master File will be listed as "available for reference". If the fee is not paid, FDA refuses to further process the application. The relevant company will be identified publicly as a "defaulter" with the result that it will no longer be able to sell its products in the USA.
Companies with several sites will be obliged to pay the GDUFA fees more than once. Accordingly, this Act is criticised as causing a competitive disadvantage for those companies. In any case, this Fee Act will result in a certain market adjustment and - as anticipated by FDA - accelerate the reduction of applications to be processed, reduce the period for market introduction of lower-cost and higherquality drugs while increasing the number of GMP inspections carried out by FDA.
This last point somehow contradicts the above-mentioned current initiative for co-ordination between FDA and EMA concerning GMP inspections to avoid unnecessary double inspections. FDA still rejects co-ordination in terms of mutual recognition of inspections in Europe. As Guy Villaxreported the EFCG (European Fine Chemicals Group) has tried to convince FDA to avert the impending fee burden by keeping the inspection level of companies manufacturing generic drugs in Europe low using a mechanism of mutual recognition - unfortunately, without success (FDA's answer: "Maybe in GDUFA 2…"). Therefore, it remains to be seen which benefit the initiative from January 2012 will bring.
Another important aspect of this Act is that after its introduction, FDA will accept applications for marketing authorisation and for a change in electronic form only. For the companies concerned, this might necessitate capital expenditure for the corresponding IT equipment. GDUFA shall come into force on 1 October 2012.
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Once again, the 14th APIC Conference showed that the initiatives and projects targeting the assurance of quality and safety of pharmaceutical active substances are a necessary response to an increasing threat for the safety of patients by sub-standard or falsified products. But it also indicated the need for urgency. At a time when it is more profitable to place falsified active substances and medicinal products on the market than to deal with narcotics and when producing without GMP compliance might represent a competitive advantage, it is high time for effective counter measures to be taken by authorities and associations. Events such as this annual APIC Conference represent a suitable platform for the necessary exchange of information between industry and the authorities. Ultimately, they make an important contribution to bundling their activities.
Author:
Dr Gerhard Becker
CONCEPT HEIDELBERG
