Introductory Principles of the Pharmaceutical Quality System
Primary Guidance
This article primarily relates to legislation and approaches that are EU centric. However there are a range of quality system standards (EU, FDA, ICH etc) and the level of detail worldwide devoted to the definition of an appropriate Pharmaceutical Quality System is vast. This is a summary of the EU guidance and some sections are direct copies.
The primary EU Guidance on the handling of unexpected deviations, pertaining specifically to the Qualified Person and the ability of the QP to release a batch is outlined in Part 1 (Basic Requirements for Medicinal Products), Chapter 1 – Pharmaceutical Quality System of EudraLex Volume 4 (Volume 4 of "The rules governing medicinal products in the European Union")
There is a link to the full text of this Annex here. (EudraLex 4 – Part 1, Chapter 1). It came into operation on the 31st January 2013.
ICH Q10 is viewed as a supplement to the primary EU guidance chapter. It can be found here but will be covered in a separate notes page.
Why have a Pharmaceutical Quality System?
The holder of a Manufacturing Authorisation must manufacture medicinal products so as to ensure that:
They are fit for their intended use
Comply with the requirements of the Marketing Authorisation (or Clinical Trial Authorisation)
Do not place patients at risk due to inadequate safety, quality or efficacy.
This is particularly relevant to pharmaceuticals given their risk to the patient and the potentially large impact of quality defects.
As a result, Quality Management is a wide-ranging concept and any Pharmaceutical Quality System needs to encompass all matters, which individually or collectively influence the quality of a product.
The guidance is fundamentally rooted in the understanding that correct product realisation is achieved by the structured undertaking and continuously improvement of a system that enables the consistent delivery of products with appropriate and clearly defined quality attributes.
The founding principles of a PQS
1) Management responsibility but supply chain wide participation. All stages are relevant
While this is the responsibility of senior management it requires the participation (and compliance) of all staff (regardless of level) in all relevant departments. This participation is also required from suppliers (upstream) and distributors (downstream).
Leadership by senior management (including QPs) and active participation and contribution to the Pharmaceutical Quality System is essential. Leadership should ensure the support and commitment of all staff at all sites. This point is repeated multiple times in the guidance, highlighting it’s significance.
2) The system must incorporate GMP and Quality Risk Management.
GMP, QC and QRM are all components of a wider PQS. The basic concepts of Quality Management, Good Manufacturing Practice and Quality Risk Management are heavily inter-related. They have a fundamental importance to the production and control of medicinal products. Product and process knowledge is managed throughout all lifecycle stages before GMP, during GMP and after GMP relevant activities.
3) The system should be traceable and in control.
The system should be fully documented with its effectiveness subject to routine monitoring. A Quality Manual (company specific or suite specific) or equivalent documentation should be established and should contain a description of the quality management system including management responsibilities. While some aspects of the system can be company-wide and others site-specific, the effectiveness of the system is normally demonstrated/audited/reviewed at the site level.
There must be periodic management review of the Pharmaceutical Quality System to identify opportunities for continual improvement of products, processes and the PQS itself. Any system can be measured and improved.
There must be a process for self-inspection and/or quality self-audit, which regularly appraises the effectiveness and suitability of the Pharmaceutical Quality System.
4) The system should be adequately resourced.
Personnel should be competent with adequate training. There should be suitable and sufficient premises, equipment and facilities. The size and complexity of the company’s activities should be taken into consideration when developing a new Pharmaceutical Quality System or modifying an existing one.
Summary of Additional PQS Expectations.
In addition to the foundational principles articulated above there are a set of more specific exceptions outline in the guidance. These are summarised below. Most are duplicative of language used in GMP specific guidance. Not all have been reproduced here as I have incorporated them into the section above.
Medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice (GMP ready, GMP “Built in”)
Production and control operations are clearly specified (Documentation)
Arrangements are made for the manufacture, supply and use of the correct starting and packaging materials, the selection and monitoring of suppliers and for verifying that each delivery is from the approved supply chain; (Supplier audits, material traceability and control)
Processes are in place to assure the management of outsourced activities. (Audits, oversight, integration with own PQS)
A state of control is established and maintained by developing and using effective monitoring and control systems for process performance and product quality. (“Traditional” Process control approaches, QbD)
The results of product and processes monitoring are taken into account in batch release, in the investigation of deviations, and, with a view to taking preventive action to avoid potential deviations occurring in the future. (Trending, Proactive CAPAs)
All necessary controls on intermediate products, and any other in-process controls and validations are carried out; (Calibration, validation, process monitoring)
Continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge. (You cannot stand still)
Arrangements are in place for the prospective evaluation of planned changes and their approval prior to implementation taking into account regulatory notification and approval where required (Change control)
After implementation of any change, an evaluation is undertaken to confirm the quality objectives were achieved and that there was no unintended deleterious impact on product quality (Effectiveness checks, Periodic reviews, Product quality reviews)
Satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life (Temperature monitoring, stability programs)
Primary Role of a QP w.r.t the PQS?
In addition to supporting or carrying out the responsibilities expected of management the QP has a specific role within the PQS.
Medicinal products should not be sold or supplied before a Qualified Person has certified that each production batch has been produced and controlled in accordance with the requirements of the Marketing Authorisation and any other regulations relevant to the production, control and release of medicinal products (generally summarised as GMP).
The complexity in modern manufacturing and packaging, means that a QP cannot be expected to have overseen everything first hand - the PQS exists as their primary tool for ensuring all the relevant requirements are in place and the entire system that makes the product is in control.
Therefore the QP is like a farmer for the PQS, they need to monitor and tend to it, but hey also reap the benefits it brings.
Disclaimer
This document is not a legal document not should it be interpreted in any fashion as a guide. This is a set of notes compiled as part of a personal training program. Copying or reproduction of this document is permitted under creative commons.