Andy Martin, Pharmaceutical Training Centre Manager with RSSL, looks at how recent legislative changes are impacting on the roles of quality personnel
Since 1975, it has not been permissible to place medicinal products on the market in Europe, without the sanction of a Qualified Person (QP). The European Directive 75/319/EEC established the QP's personal responsibility to certify in a register that these products had been manufactured in accordance with relevant authorisations. Later, via amending directives, the QP was required to certify that the product had been made to the principles and guidelines of good manufacturing practice (GMP).
The first directive also described the basic requirements for a person to be eligible to act as a QP and many of the UK's first QPs became eligible as a result of work experience, rather than by formal assessment. This is because when the original directive came into force in 1975, anyone working as a QP was allowed to keep their status. Similarly, anyone who was engaged in activities such as production supervision and/or analysis of active ingredients and finished product between 1975 and 1985, was eligible to act as a QP. Neither case required further assessment, and both were referred to as transitional QPs. It was only in 1985 that a formal assessment was introduced.
Now, that the generation of work-experience QPs is steadily being lost from the industry as people reach retirement, there is a greater need in the industry for the next generation to be trained.
The QP has specific routine duties to perform by law, but the role is affected by such a diversity of issues that training in the legal obligations is only part of the story. Indeed, the routine duties of the QP, as described in the Royal Society of Chemistry, Institute Of Biology and the Royal Pharmaceutical Society of Great Britain joint code of practice include, but are not limited, to the following:
- Ensuring that all the main manufacturing processes and testing processes have been adequately validated.
- Ensuring that the Quality department has performed all the prescribed tests and checks (including the in-process tests and checks).
- Ensuring that the suitability of the production conditions has been evaluated.
- Ensuring that manufacturing records and any other necessary production and quality records have been completed and approved by authorised personnel.
- Ensuring that where it has been necessary to introduce a change to the manufacturing process or to the quality control testing, the change has been introduced through an effective change control system before the release of any product.
- Ensuring that where necessary, the changes indicated have been notified to the competent authority and approval obtained before the release of the product.
- Where it has been necessary to perform additional sampling, inspection, testing and checks in respect of the above changes the QP should ensure that these have been completed before the release of the product.
- Ensuring that there should be a system in operation, which provides for sufficient and appropriate self-inspection spot checks to be carried out on those activities that can affect the quality of the product.
- Ensuring that any relevant yet non-batch specific information has been taken account of such as those that might be necessary with continuous production runs. For example, while the QP would need to be certain that an operative had been trained to weigh out ingredients to make a particular product (batch specific information) they would also need to be satisfied that the same operative had received general GMP and refresher training (not batch specific). Equipment might also have validation and calibration criteria that are both batch-specific and non-batch specific. The QP must be satisfied that both are adhered to.
Despite the ideals of a single European market, it must be said that the levels of training and assessment for QPs vary widely across Europe. Indeed, training can differ widely within the UK, with a variety of approaches taken by different organisations. That is not to say that all differences are bad, at least in terms of the style of training on offer. Some trainees are able to spend many days away from their workplace in order to attend extensive classroom sessions. Others require more concentrated learning time with a minimum of disruption to the time they spend at work. Some courses are more practical, others rely heavily on theory, and the choice of which course to attend may largely be a question of the time and budget available.
In the UK, the joint professional bodies identified above have the responsibility of managing the training and assessment of QPs. To standardise the requirements they published a "Study guide" the most recent edition of which came out in May 2006. This is intended to provide guidance on the disciplines in which the delegate is expected to be competent and is divided into foundation modules and additional knowledge modules. The foundation modules are intended for the QP trainee to apply to all dosage forms while the additional knowledge modules are only intended to be applied to the trainee's specified dosage form.
The topics in which delegates are expected to demonstrate some understanding are extremely varied. As noted above, the QP Study Guide sets out three foundation knowledge elements, being pharmaceutical law and administration, the role and professional duties of a Qualified Person, and Quality Management Systems. Then there are a further eight modules described as additional knowledge requirements, covering disciplines such as mathematics and statistics, medicinal chemistry and therapeutics, and pharmaceutical packaging (see box 1).
Clearly, even the most experienced employee will not be an expert in all of these areas so training is needed to fill in the gaps. While it may seem a daunting prospect to take on all this extra information, many delegates find that QP training both enhances the skills needed for their main job, but also helps to put their work into the wider context of the whole business. It improves their understanding and appreciation of what it takes to produce a marketable medicine, and adds to their job satisfaction. It also gives the QP the chance and the authority to make a real difference to the processes and systems applied at work.
It is important that the QP remains aware of changes in legislation and guidance that affect the production of pharmaceuticals. Some recent changes apply directly to the product that the QP will ultimately have to sign off. For example, Statutory Instrument (2005:2789) published by the Stationery Office was introduced into the UK in October 2005.1 This repeals a number of Statutory Instruments like the original 1971:972 for product and manufacturing licences, and enforces the requirement for active ingredients to be obtained solely from GMP compliant suppliers. This requirement had been introduced via an amendment to the codified directive for medicines (2001/83/EC).2 The amending directive, 2004/27/EC also introduced the requirement that pharmaceutical products intended to be self-administered should be labelled in Braille with respect to the product name (and strength, where more than one is available).3
Other legislation relates to activity taking place much earlier in the life of a medicinal product. For example, in 2003 the new GMP directive 2003/94/EC replaced the GMP directive 91/356 for human medicinal products.4 The main driver for this change was the publication of the clinical trial directive 2001/20/EC, which called for clinical trials materials to be manufactured according to the rules and guidelines of GMP, and thus required a QP to release the clinical trials materials. However, at the time the unique features of clinical trial materials meant that the existing directive could not be adequately applied. The directive 2003/94 made a number of amendments to the majority of the articles in the original directive in order to resolve this difficulty.
Despite the focus on clinical trials a number of other more subtle changes were made. Potentially of major significance was the introduction of the need to assess the practical effectiveness of training. Similar statements had been incorporated into Chapter 2 (Personnel) of the guide to GMP for many years but until now there has been no legal basis for requiring that the effectiveness of training be assessed.5 Of course, one way to assess training is to sit an examination, as indeed happens with the QP case. But in other areas of pharmaceutical training, it is interesting to question how the effectiveness might be measured if no examination is taken.
Other changes to GMP have had an impact on the duties and responsibilities of a QP. For example, for many years the FDA has required the manufacturers of medicinal products to carry out an annual product review. Essentially this is a review of all batch related data, for every product manufactured, for the purpose of assessing trends and their potential impact on product quality. It is a process that enables weaknesses to be spotted, which should lead to product/process improvement. In October 2005, a similar requirement was written into the European GMPs. Chapter 1 of the European Guide to GMP now contains the requirements for an annual quality review to be undertaken for every marketed product.
Finally, for many years, stability testing has been viewed as a development test. To increase its profile as a GMP requirement and to ensure that the product remains of the intended quality for the duration of its shelf life, stability testing has been included in a revision to chapter 6 (Quality Control) of the European guide to GMP.
The role of the QP requires a significant amount of knowledge and experience, and with the ever-changing legal framework in which the QP is expected to work, it can be quite demanding. An appropriate level of training is clearly vital in helping the QP to exercise their statutory duties properly. However, there is a bigger picture to consider. When the QP is encouraged to adopt best practice, then they have the ability to improve many aspects of the production process and quality system. With this bigger role in mind, the experienced and well-trained QP is a valuable asset to any pharmaceutical manufacturer, and is someone with the skills and qualifications that will always serve them well in the jobs market.
Box 1. Taken from QP Study Guide May 2006
The three foundation knowledge elements:
Pharmaceutical law and administration
The role and professional duties of a Qualified Person
Quality management systems
Additional knowledge requirements for the Qualified Person:
Mathematics and statistics
Medicinal chemistry and therapeutics
Pharmaceutical formulation and processing
Pharmaceutical microbiology
Analysis and testing
Pharmaceutical packaging
Active pharmaceutical ingredients
Investigational medicinal products