17 April, 2012 Wolfgang Schmitt, Director Operations, CONCEPT HEIDELBERG GmbH
Note: The views expressed in this article are those of the author and do not necessarily represent those of the employer, GxP Lifeline, its editor or MasterControl Inc.
Differences between the European Union (EU) and U.S. GMPs are generally small and easily manageable.There is one significant exception: the Qualified Person (QP). In many U.S. companies, this concept is unfamiliar. In the U.S., a similar role is fulfilled by the Head of Quality. He or she is legally responsible for all quality decisions, including batch release, but there are differences.
If you are a U.S.- based company manufacturing in the U.S. and you export your drug products in the EU, either by yourself or through a partner, you need to know EU requirements and you will face inspections.
One difference is that the QP's personal role and its personal accountability are defined in the legislation. Directive 2001/ 83 - Article 51 (1) (a) states that "The qualified person...is responsible...for securing that...each batch of medicinal products...has been manufactured and checked in compliance with the laws in force in that Member State and in accordance with the requirements of the marketing authorisation." That does mean that the QP needs to know the batch documentation. In many cases, an additional review is performed by the QP or other staff members. The routine duties of the QP are defined in more detail in Annex 16 of the EU-Guide to GMP. In summary, the QP has to ensure that:
- Manufacture has been carried out in accordance with GMP
- The QP might need to check additional documents and might take part in Quality Reviews
- Manufacturing and testing processes have been validated
- The QP at least needs to have access to the documentation or needs to be confident with the system
- Any deviations or changes in production or quality control have been authorised by the persons responsible
- Access to deviations, investigations, change control and CAPA documents should be possible. The QP must know if and how deviations are closed before certifying a batch and if changes requiring variation to the marketing manufacturing authorisation have been notified to and authorised by the relevant authority. At least the QP needs to be very confident with the system.
- All necessary production and quality control documentation has been completed and authorised and all necessary checks and tests have been performed;
- Mostly done by batch documentation review by a quality function.
- All audist have been carried out as required.
- An audit might also be conducted by a third party or by another QP employed by the importer.
The QP should consider any other factors which are relevant to the quality of the batch. Except for batch certification and release, the execution of the duties mentioned above can be delegated. However the overall responsibility stays with the QP. The QP decides the extent to which certain tasks are delegated. These tasks could also be performed by a manufacturer and its quality control unit in the U.S.
If various stages of manufacture will be completed by different companies, a contract will be needed to describe arrangements for each company's QP certification. Than the QP may rely on confirmation by one or more QPs concerning compliance with the relevant requirements at the intermediate stages of the supply chain.
In the future, the QP will be required to fill out pre-defined declarations. The "QP Declaration Template" (EMA/CHMP/CVMP/QWP/696270/2010) is currently available as a draft and should provide "a basis for demonstrating compliance of the active substance manufacture with the GMP requirements and that the manufacturer has relevant knowledge of the supply chain."
This QP declaration should be provided in support of an application for a new marketing authorisation, variation or renewal of a medicinal product(s) authorised in the EU. This requirement shows increasing regulatory interest in the supply chain, leading to further obligations for the QP. This means that the QP needs to fully understand the active pharmaceutical ingredient (API) supply chain and demonstrate that each batch of API has been sourced via the 'approved' supply chain.
When it comes to clinical trial supplies (Investigational Medicinal Products - IMPs), additional templates will be required. In the EMA Reflection paper published in 2011 on interactive voice recognition and interactive web recognition (IVR/IWR) systems, a QP Declaration is introduced for managing expiry dates. Overall the "Reflection paper on the use of interactive response technologies (interactive voice/web response systems) in clinical trials" seeks to provide guidance on IVR/IWR systems and in particular on their use in expiry updating. If such a system is used to control expiry dates, a declaration by the Qualified Person (QP) is needed.
Just recently, the European Commission has published a draft template for the Qualified Person's (QP) declaration concerning GMP compliance of IMPs manufactured in non-EU countries. This template would be part of the dossier submitted with a request for authorisation of a clinical trial (IMPD).
In this template, the QP should confirm that the IMP manufactured in a third country meets EU GMP standards for IMPs. This could be proved by either a personal on-site audit or an audit conducted by a third party. If no audit has been performed, a brief justification and explanation should be provided, describing how the QP knows that standards at least equivalent to EU GMP are being followed at the site.
As said before, prior to certifying a batch, the QP should ensure that it complies with the provisions of the marketing authorisation. But is the QP empowered to decide upon the release of a batch, even in cases where deviations occurred during its manufacture or testing? For these cases, an EMA reflection paper is available. It discusses how to deal with minor deviations from details described in the Marketing Authorisation. With that paper, certain flexibility is given to the QP with regard to one-off type, unplanned deviations in the manufacturing process and/or analytical control methods. A batch can only be certified if the deviation is classified as minor and has no effect on product safety and efficacy or the overall product quality. In case a deviation affects the safety or efficacy of a batch, the batch must not be released. Trends, recurrences, and other deviations are not in scope and considered problems that require resolution with the competent authorities.
One challenge in the EU is that the Union consists of 27 Member States with over 40 national competent (GMP) authorities. According the Treaty of Rome, Article 249, "a directive shall be binding, as to the result to be achieved, upon each Member State to which it is addressed, but shall leave to the national authorities the choice of form and methods." This means that EU Directives are implemented into the national law of Member State with certain flexibility, leading to some inconsistencies, different interpretations and tolerances between authorities in Europe. This fact, combined with the different company cultures and diverse characters of QPs, means significant variations are possible in the QP's interpretation of its own role and different interpretations of the position of the QP in an organisation's structure. U.S.- based companies are not the only ones struggling with these circumstances.
But why should U.S. companies know all about this?
If you are a U.S.- based company manufacturing in the U.S. and you export your drug products in the EU, either by yourself or through a partner, you need to know EU requirements and you will face inspections. You must also have a QP based within the EU to provide the final batch certification for release into the EU market. This can be done by a QP of a legal entity of your company in the EU or through a QP in a company importing your product.
The interpretation of a QP's position might vary from company to company. What is important to know is they must review batch-specific data before certifying the material. A QP needs to have access to all information relevant to the batch release and the quality system of the manufacturer, including information relevant to products in the EU market, such as complaints and deviations.
As a key person in the quality system of a European company, the QP has to consider many issues and has a broad personal responsibility. In addition, it is expected that the Qualified Person will not only have to fulfil the basic principles of batch release and certification, but will also ensure and guarantee that an appropriate Quality System is in place. The process of certification and release of a batch or its intermediates can only be delegated to another QP. Some companies may use external QPs who provide an independent service.
So in a globalising world, the EU Qualified Person has to be involved in many quality- related processes in the supply chain. Some do more than others and some do more than expected. Product quality is their personal decision and responsibility.
The role of the QP will be discussed in detail at the upcoming conference "The Bridge to European GMPs and the Role of the Qualified Person (QP)", from June 19-20 2013 in San Francisco, California. For further details please see the program (http://www.gmp-compliance.org/eca_seminar_7866.html).
- Directive 2001/83/EC
- Annex 16 to the EU Guide to Good Manufacturing Practice: Certification by a Qualified Person and Batch Release
- ECA Good Practice Guide No. 2 "Duties and Responsibilities for Qualified Persons in the EU" - Version 1.1
- Template for the Qualified Person's declaration concerning GMP compliance of the active substance used as starting material and verification of its supply chain "The QP declaration template" (EMA/CHMP/CVMP/QWP/696270/2010)
- EMA Reflection paper on the use of interactive response technologies (interactive voice/web response systems) in clinical trials (EMA/INS/GCP/600788/2011)
- Commission draft template for the Qualified Person's (QP) declaration concerning GMP compliance of investigational medicinal products (IMPs) manufactured in non-EU countries (Ref. Ares(2013)148089 - 05/02/2013)
- Reflection paper on a proposed solution for dealing with minor deviations from the detail described in the Marketing Authorisation for human and veterinary Medicinal Products (Doc. Ref. EMEA/INS/GMP/227075/2008)
Before Wolfgang Schmitt started working for the European QP Association, he worked for Abbott (the former Knoll AG, Germany). He was Head of Quality Management at SOLIQS (Abbott's global Drug Delivery Business Unit) and later an Associate Director and Qualified Person at Abbott's Global Pharmaceutical Research and Development QA. Wolfgang is also a Director of Operations at Concept Heidelberg, Europe's leading training and information services provider in the area of pharmaceutical quality assurance and drug safety.
Wolfgang Schmitt may be contacted at:Wolfgang SchmittEuropean QP Association, an Interest Group of the ECA FoundationP.O. Box 10 21 68 69011 Heidelberg Germanywww.qp-association.eu