QPs—Qualified Persons–serve as the eyes and ears of the UK Medicines and Healthcare product Regulatory Agency (MHRA). Their primary focus is to protect patients by ensuring that medicinal products have been manufactured and handled according to GMP and European Union regulations. By protecting the patient, QPs also serve to help and protect the manufacturer.
The QP’s task is just as complex as the therapy and its manufacturing process. Consider the difference between the chemotherapy drug paclitaxel (Taxol), which has a relatively high (for a small molecule drug) molecular weight of 854, while the monoclonal antibody Rituximab, used to treat certain lymphomas and other disorders, has a molecular weight of 145,000. As we all know, alterations in molecular structure can result in changes in biological activity, which can involve decreased therapeutic effect as well as risk of immune response following administration: this is a primary concern of the QP.
As the Responsible Person (RP) for Fisher BioServices UK, I oversee the QPs who certify batches of product entering the EU through our site. This eBook will tell you more about the role of the QP, and what is involved in meeting the requirements of the MHRA and the EU, to help ensure the commercial success of your biologic or cell therapeutic product in the European marketplace and beyond.
The Qualified Person's Responsibilities and Licensable Activities
A Qualified Person (QP) is an individual who is responsible for ensuring that drug products that are manufactured in or Imported into the European Union (EU) were manufactured and handled according to GMP and EU regulations. The concept of the Qualified Person was first established in 1975 and is a unique regulatory requirement that currently applies only within the European Union, but is being extended into other countries, such as Israel, in 2013.
Specifically, a QP must release, or certify that each batch of product, whether investigational medicinal product (IMP) or commercially approved drug for human use, was produced according to EU Directives. The critical Directives concerning QP release include 2003/94/EC, which specified that all medicinal products for human use that are manufactured or imported into the EU must be manufactured in accordance with cGMP; 2001/20/EC, which extended QP oversight to materials for use in clinical trials; and 2001/83/EC, which dealt with disparities between national provisions in the internal market of the European Union. Advanced Therapeutic Medicinal Products (ATMPS) are covered under EU Regulation 1394/2007 and Veterinary Medicinal Products are addressed in Directive 2001/82/EC. It should be noted that these Directives are expected to be updated shortly.
Companies importing IMP must be licensed by the country of import, and all companies holding a license to manufacture or import medicines in the EU must have a QP named on their license. The identified QP, although employed by (or contracted to) the company holding the license, in effect serves as the eyes and ears of the Regulatory Body. As a company that provides biorepository storage, labeling, secondary packaging, and distribution services for IMP and clinical agents, Fisher BioServices holds a license for the UK. I am the Responsible Person (RP) for the MHRA license at our Bishops’ Stortford site, allowing us to release ATMPs into Europe. All Fisher BioServices QPs report to the MHRA as well as to me.
A QP is typically a licensed pharmacist, biologist, chemist, or person with other appropriate academic qualifications who has several years of experience working in pharmaceutical manufacturing operations, and who has passed the required examinations.
The QP responsibilities are spelled out in the Rules and Guidance for Pharmaceutical Manufacturers and Distributors, published by the UK Medicines and Healthcare Products Regulatory Agency, also known as the “Orange Guide”. In addition, QP’s have a Code of Practice which was updated in February 2013. Companies planning to conduct clinical trials in the EU must have a QP Declaration stating that the QP is satisfied that the manufacturing and storing sites are compliant with GMP, from an EU perspective, as part of their Clinical Trial Application. The QP is on the front line, protecting the patient by ensuring that Medicinal Products are safe and fit for their intended use. The QP’s legal responsibility focuses primarily on the safety of a product, i.e., whether it was manufactured according to GMP and meets all applicable regulations. However, QPs also consider the larger picture of patient safety, including quality and efficacy issues, in fulfilling their obligations.
This is especially important where biopharmaceuticals and cell therapeutics are concerned, as biological manufacturing processes are far more complex compared to that of the small molecules (table 1).
Protein based biologics often involve multiple highly technical steps between cloning the target gene and the end product, and biological preparations can vary significantly; for instance, glycosylation, which significantly influences the isoform of manufactured erythropoietins, is highly sensitive to cell growth conditions. Even autologous therapies, where the batch size is minimal and immune response to foreign proteins is not a primary concern, require intensely controlled manufacturing and temperature conditions for therapeutic efficacy. You can read more about these challenges from my colleague Dan O’Donnell’s eBook “Commercially Successful Cell Therapies : Navigating the Ultra Cold Chain Minefield”.
What a QP Does
The QP must ensure that all documentation is correct and GMP compliant, that the product is manufactured according to the IMP Dossier, and is within product specifications. Manufacturers must provide all the documentation needed to allow the QP to make an informed decision (see the list on page 15). The QP will need access to all parts of the supply chain critical to the product, and may perform an audit of the sites of storage and manufacture. As the eyes and ears of the MHRA, the QP must ensure that each batch is manufactured in compliance with GMP and EU regulations, including verifying that all the principle manufacturing and testing processes were validated, verifying that the production and quality control documentation was completed and signed by authorised staff, and that the sites involved in manufacturing and storage are EU GMP compliant, which is typically done
through a QP audit.
In addition, the manufacturer must report to the QP all deviations and out-of-specification events in the manufacturing process and supply chain that can affect the batch. The QP will then verify that the necessary checks and tests were performed and the batch can be certified.
A number of factors may result in batch certification failure, particularly for ATMPs. Two main reasons are the sterility of the product at point of manufacture, and temperature excursions without suitable stability data. Without stability data, the QP cannot make a conclusive decision on the suitability of the product with regard to temperature variations. Temperature control is the primary issue with cell based therapies. Manufacturers must ensure that the product was maintained within correct temperature specifications throughout the manufacturing and distribution process, and this compliance must be verifiable by the QP.
What You Should Know About Working with a QP
1. QPs are eligible to certify only the materials for which they are qualified, which are divided into human medicine, veterinary medicine, and traditional herbal medicine products. According to the Code of Practice, QPs “have a professional duty to decline to act as Qualified Persons in the release of product types for which they do not possess the relevant experience and knowledge.”
Download the full version eBook to learn more about QP.