Regulations of health care products are in place to ensure they are safe to use and effective according to their intended purposes. Good manufacturing practice (GMP) or current good manufacturing practice (CGMP) guidelines are a set of regulations designed to ensure manufacturers of food, drugs, medical devices, and cosmetics consistently produce products within safe environments and in accordance with strict protocols, thereby reducing possible contamination and manufacturing errors.(1)
The CGMP regulations are set up and maintained by the U.S. Food and Drug Administration (FDA). The European Medicines Agency (EMA) oversees the European good manufacturing practices (GMPs). The quality processes for complying with the guidelines of each regulatory agency are relatively similar. However, one significant difference is that in the European Union (EU) the title of the person responsible for batch certification and the majority of the quality processes and tasks is the Qualified Person (QP).
If you are a U.S.-based company exporting drug products into the EU, either by yourself or through a partner, it is essential to understand the role of a QP. It’s also helpful to understand all other EU GMP requirements to be better prepared for inspections.
The European Directive 2001/83/EC defines the responsibilities of the QP. Article 51 of the Directive states that "… the QP is responsible for ensuring that each individual batch has been manufactured and checked in compliance with the laws in force in the member state where certification takes place, in accordance with the requirements of the marketing authorization (MA) with good manufacturing practice (GMP)."
Each batch of finished product must be certified by a QP within the EU before being released for sale or supply in the EU or for export. Certification can only be performed by a QP of the manufacturer and/or importer, which are described in the MA.
Annex 16 of the EU Guidelines for GMP details the routine duties of the QP. For example, some of the duties include ensuring:
The QP also needs to consider all other factors relevant to the quality of a batch. The QP can delegate the above tasks — including to a U.S.-based manufacturer and its quality control unit — except batch certification and release. Because QPs are responsible for ensuring all quality tasks are complete according to GMP regulations, they decide the extent to which certain tasks are delegated. The QP should have ongoing assurance with the completion and compliance of delegated tasks.
Various stages of product manufacturing are often completed by external companies. The following are some of the key guidelines for managing suppliers:
Provided that all suppliers comply with GMP guidelines, the QP certifying the finished product may rely on confirmation from the QPs of each organization. Manufacturers employ supplier quality management systems (QMS) to ensure they only receive materials that meet the required level quality.(2)
The QP Declaration should be provided by the Marketing Authorization Holder (MAH) in support of an application for a new marketing authorization, variation, or renewal of a medicinal product authorized in the Community, following EU or national registration procedures. With this QP declaration, it is confirmed that the active substance has been manufactured in accordance with GMP guidelines. Therefore, the QP needs to fully understand the active pharmaceutical ingredient (API) supply chain and demonstrate that each batch of APIs has been sourced via the approved supply chain. Applicants are encouraged to use authorized templates to more efficiently facilitate the validation of their regulatory submissions.(3)
A QP Declaration template published by the EMA provides a basis for demonstrating compliance with the active substance manufacture and supply chain with GMP requirements and that the manufacturer and QP has relevant knowledge and assurance of the supply chain.(4)
In 2013, the European Commission published the “New EU Template for QP Declaration IMPs.” This template concerns GMP compliance of investigational medicinal products (IMPs) manufactured in non-EU countries, which includes these guidelines:(5)
Prior to certifying a batch, the QP should ensure that it complies with the provisions of the marketing authorization. Is the QP empowered to decide on the release of a batch — even in cases where deviations occurred during its manufacture or testing? For these situations, the QP can also consult the EU Guidelines for GMP, Annex 16, which discusses how to deal with unexpected deviations.
A batch with an unexpected deviation concerning the manufacturing process may be certified if the result of a risk analysis shows that the “… potential impact of the deviation on quality, safety, or efficacy of the batch(es) is negligible.”(6) It’s important to note that in the case of a repetition of the event, this cannot be classified as unexpected anymore. Therefore, the batch either needs corrective action or an assessment on a decision to certify. In cases where a deviation concerns a specification defined in the marketing authorization as essential for the release (out of specification), the QP will have no scope left.
The EU consists of 27 member states with over 40 national competent (GMP) authorities. According to the Treaty on the Functioning of the European Union (formerly the Treaty of Rome), Article 288, "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."(7)
Essentially, this means that EU Directives are implemented into the national law of the member state with certain flexibilities around a company’s approach to compliance. Consequently, this leads to potential inconsistencies, different interpretations, and varying tolerances between authorities in Europe regarding the role of the QP. It's a given that all companies have a unique culture and that QPs have differing characteristics, industry knowledge, and skill levels. That said, every QP likely has a different interpretation of the role within the organization.
While the interpretation of a QP's position varies from company to company, a few things are consistent regardless of the organization. QPs must review batch-specific data before certifying the material, and a QP needs to have access to all information relevant to the batch. It’s also important for them to have a comprehensive knowledge about the company’s quality system and processes.
As a key person in the quality system of a European medical product manufacturer, the QP has a wide range of responsibilities and deals with numerous issues. For example, only a QP can certify a batch or its intermediates. The QP is expected to make sure the organization has an appropriate quality system in place in order to fulfill the regulatory requirements for batch certification and release.
Overall, the ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality, and efficacy, lies with the MAH. However, the QP is responsible for ensuring that each individual batch has been manufactured and checked in accordance with the MA and with the GMP. QPs continue to face ongoing changes to regulations and advancements in medical product innovation. That said, more companies in regulated environments are implementing a digital QMS to integrate and streamline all quality processes and ensure no aspect of quality management falls through the cracks.