The European Union (EU) and US GMPs are broadly aligned, with differences generally easily managed. One exception is the requirement for the Qualified Person (QP) when manufacturing within or importing into the EU. For many US companies, this concept is unfamiliar, however within the US a similar role is fulfilled by the Head of Quality, whereby they are legally responsible for all quality decisions, including batch certification, but there are differences and they apply to US companies.
If you are a US-based company manufacturing in the US 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 based on those EU requirements.
Duties and Responsibilities
One significant difference between the QP and the US Quality Manager is that the QP's role and their personal accountability are defined in legislation, Directive 2001/83/EC, Article 51 for Medicinal Products and Article 13 of Directive 2001/20/EC for Investigational Medicinal Products.
Directive 2001/83/EC 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" and that “in the case in the case of medicinal products coming from third countries, (countries outside of the E.U.) ……..each production batch has undergone in a Member State a full qualitative analysis, a quantitative analysis of at least all the active substances and all the other tests or checks necessary to ensure the quality of medicinal products in accordance with the requirements of the marketing authorisation.”
Directive 2001/20/EC states that “the qualified person……is responsible……for ensuring that each batch of medicinal products has been manufactured and checked in compliance with the requirements of …….. the principles and guidelines of good manufacturing practice for medicinal products for human use (and) the product specification file” and that “in the case of investigational medicinal products manufactured in a third country, that each production batch has been manufactured and checked in accordance with standards of good manufacturing practice at least equivalent to those laid down in Commission Directive 91/356/EEC (and) in accordance with the product specification file”.
In addition to the legal responsibilities, the professional responsibilities of the QP are defined in detail in Eudralex, Volume 4. Annex 16, Section 1.7. In summary, the QP has to ensure that:
- All activities associated with manufacture and testing of the medicinal product have been conducted in accordance with the principles and guidelines of EU GMP.
- The entire supply chain of the active substance and medicinal product up to the stage of certification is documented and available for the QP. This should include the manufacturing sites of the starting materials and packaging materials for the medicinal product and any other materials deemed critical through a risk assessment of the manufacturing process.
- All audits of sites involved in the manufacture and the testing of the medicinal products and in the manufacture of the active substance have been carried out and that the audit reports are available to the QP performing the certification.
- All sites of manufacture, analysis and certification are compliant with the terms of the MA/PSF for the intended territory.
- All manufacturing activities and testing activities are consistent with those described in the MA/PSF.
- The source and specifications of starting materials and packaging materials used in the batch are compliant with the MA/PSF. Supplier quality management systems are in place that ensure only materials of the required quality have been supplied.
- The active substances have been manufactured in accordance with GMP and, where required, distributed in accordance with Good Distribution Practice (GDP) for Active Substances.
- The excipients have been manufactured in accordance with the ascertained GMP.
- When relevant, the TSE (Transmissible Spongiform Encephalopathy) status of all materials used in batch manufacture is compliant.
- All records are complete and endorsed by appropriate personnel. All required in-process controls and checks have been made.
- All manufacturing and testing processes remain in the validated state. Personnel are trained and qualified as appropriate.
- Finished product quality control (QC) test data complies with the Finished Product Specification described in the MA, PSF, or where authorised, the Real Time Release Testing programme.
- Any regulatory post-marketing commitments relating to manufacture or testing of the product have been addressed. On-going stability data continues to support certification.
- The impact of any change to product manufacturing or testing has been evaluated and any additional checks and tests are complete.
- All investigations pertaining to the batch being certified (including out of specification and out of trend investigations) have been completed to a sufficient level to support certification.
- Any on-going complaints, investigations or recalls do not negate the conditions for certification of the batch in question.
- The required technical agreements are in place.
- The self-inspection programme is active and current.
- The appropriate arrangements for distribution and shipment are in place.
- Safety features have been affixed to the packaging where appropriate.
Directive 2001/83/EC Article 56 lays down the requirement for a professional code of conduct, which in the UK is published by the UK Joint Professional Bodies (Royal Pharmaceutical Society, Royal Society of Biology and Royal Society of Chemistry). “The aims and objectives of the Code of Practice are to provide operational guidelines for carrying out the functions of the Qualified Person” and “is in the interests of Qualified Persons, their employers, patients and the Competent Authorities of the Member States.” Section 7 lays out the Routine Duties of a Qualified Person, broadly in line with the professional duties stated above.
The combined legal and routine duties require the QP to build strong and effective working relationships with operations, manufacturing and quality teams; have access to production facilities, key personnel and key documentation (i.e. batch records, analytical data, deviations, change controls etc.); and have knowledge and experience of the dosage form, the medicinal product, the manufacturing processes and the Quality Management System.
The QP has key obligations to be discharged, summarised as Ethical, Professional and Legal. Acknowledging the breadth of duties, with batch certification being the exception, 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. Some of these tasks could delegated to a manufacturer and its quality control unit in the US
Quality & Technical Agreements (QTA)
As specified in Eudralex Vol. 4, Chapter 7; “Any activity covered by the GMP guide that is outsourced should be appropriately defined, agreed and controlled……..There must be a written Contract……which clearly establishes duties of each party”
If various stages of manufacture will be completed by different companies a contract (Quality & Technical Agreement) is required to describe the arrangements. Eudralex Vol. 4, Annex 16 states “There may be several sites involved in the various stages of manufacture, importation, testing and storage of a batch before it undergoes certification. Regardless of how many sites are involved, the QP performing certification of the finished product must ensure that all necessary steps have been completed under accepted pharmaceutical quality systems to assure compliance of the batch with GMP, the MA and any other legal obligations in the Member State where certification is taking place.”
Templates and Declarations
The QP will be required to fill out declarations. The EMA Guidance states “Marketing authorisations require a QP declaration to confirm that the active substance has been manufactured in accordance with Good Manufacturing Practice (GMP)” and that “the QP declaration should be based upon an audit of the active substance manufacturers”. 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.
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.
When it comes to clinical trial supplies (Investigational Medicinal Products - IMPs), additional templates will be required.
The European Commission has published a 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.
Additional new requirements for the importation of an API into the EU, for use in medicinal products, were laid out in the ‘Falsified Medicines Directive’ which requires a formal declaration from ‘third countries’ competent authorities to be provided prior to importation.
Handling Unexpected Deviations
As covered previously, prior to certifying a batch, the QP must ensure that it complies with the provisions of the marketing authorisation. So, how does the QP perform this certification where deviations occurred during a batch manufacture or testing? For these cases, an update to Eudralex Vol. 4, Annex 16 has been implemented, which discusses how to deal with unexpected deviations from details described in the Marketing Authorisation. With this new guidance, certain flexibility is given to the QP with regard to unexpected deviations in the manufacturing process and/or analytical control methods. A batch can only be certified if the deviation has been assessed in accordance with a quality risk management process and the batch has been assessed to have a negligible 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.
One challenge in the EU is that the Union consists of 28 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 translated 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. US-based companies are not in isolation when struggling with these circumstances!
But why should US companies know all about this?
If you are a US-based company manufacturing in the US 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 have access to 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.
The role of the QP is an integral part of the pharmaceutical quality system of a company with EU-based facilities and the manufacturing/importation activities cannot be operated legally in the absence of a QP. The QP has obligations from an ethical, professional, and legal aspect to discharge and has broad personal responsibility. The QP must have knowledge and experience of products and processes and confidence in the Pharmaceutical Quality System for which they are responsible for.
The Qualified Person is expected not only to fulfil the basic principles of batch certification, but will also ensure and guarantee that an appropriate Quality System is in place for both the medicinal product/investigational medicinal product and the active substance. The process of certification of a batch can only be delegated to another QP named on the manufacturing and importation authorisation.
So in a globalising world, the EU Qualified Person has to be involved in most aspects of the drug product supply chain, with patient safety and product quality being their personal responsibility. However, there is also a significant amount of commercial awareness and business management required of the modern day QP and the role of the QP has evolved to that of a ‘business partner’.