Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Process validation of a medicinal product: Compilation of relevant legislative, guidelines and literature

Oliver Klaas (Abschlußjahr: 2008)

Summary
Language: English
This present thesis relates to current thinking about process validation of medicinal products in the pharmaceutical industry, in detail non - sterile, chemical medicinal products for human use. It comprises the legal framework, basic principles as well as new approaches considering EU, US and ICH region.
According to Annex 15 of the EU guide to GMP process validation is the documented evidence that a process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes. Process validation is a GMP requirement and a key element of quality assurance. In general only products from validated processes may be used for market. Marketing authorisations as regulatory basis ensures that all medicinal products are assessed by a competent authority to guarantee compliance with contemporary requirements of quality, safety and efficacy. To enforce these goals process validation data has to be provided in the section 3.2.P.3.5 of the CTD format referring to ICH M4, usually prior to granting MA.
In short, process validation proofs that it works and that it will always work. Process validation is an endpoint of development, so it shall document general process understanding, critical product properties and how they are influenced by critical process parameters. The choice of acceptance criteria including tolerance ranges, their correctness and finally the comprehensive control of the risk associated with the process is also demonstrated.
Each manufacturer himself is required to define, perform, evaluate and document his entire validation activities according to standard operating procedures and further documents, e.g. validation master plan, validation protocol, validation report.
Apart from this a systematic risk analysis is the key element of each process validation. By using different kind of methods (e.g. Ishikawa diagram, FMEA - failure mode effects analysis, FTA - fault tree analysis, HACCP - hazard analysis and critical control point) the whole process may be broken down into several individual steps. Following the subdivision of the production process the individual steps are evaluated on the basis of past experience and / or theoretical considerations (additional, general process knowledge) to determine whether they may have critical impact on the finished product`s quality and / or process reproducibility (e.g. process parameters like mixing time, inlet air temperature, specific equipment risks etc.).
The new GMP Annex 20, which corresponds to the ICH Q9 guideline, provides guidance on a systematic approach to quality risk management of medicinal products for human use leading to compliance with GMP and other quality requirements.
QRM is a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle. While the GMP guide is primarily addressed to manufacturers, the ICH Q9 guideline, has relevance for other quality guidelines and includes specific sections for regulatory agencies. Effective quality risk management will facilitate better, more informed decisions and shall provide greater assurance of a company`s ability to deal with the potential risks. In general QRM as well as process validation activities are carried out by multidisciplinary teams. The teams shall include experts from appropriate areas (e.g. engineering, research & development, production, quality control, quality assurance, regulatory affairs etc.). Most important is an adequate qualification combined with sufficient experience.
Generally process validation may be conducted prospective, concurrent or retrospective. Prospective validation is carried out prior first routine production batches. It is completed prior to distribution and sale of the medicinal product. Prospective validation is most common and whenever possible, this type is preferred. According to the "Note for Guidance on Process Validation" and Annex 15 of the EU guide to GMP generally three consecutive batches are considered acceptable to demonstrate validity. But usually compliance with the finished product specification alone is not sufficient due to variable factors as the nature of the medicinal product and the complexity of the process. Therefore in-depth testing has to be carried out.
Regarding the product portfolio and method of manufacture a compilation into product, equipment or manufacturing groups is possible. This approach is called bracketing and accepted by competent authorities. Because of certain reasons it may be possible that at the time of submission of the MAA necessary validation studies on production scale batches are not completed (e.g. high batch sizes which cannot be reduced due to equipment capacity, certain orphan drug products, products with a short shelf-life). Under these circumstances, if well justified the submission of the validation protocol and all available supportive data (e.g. pharmaceutical development: pilot scale, laboratory) is needed and accepted. Moreover the manufacturer shall provide for adequate and timely assessment of the validity of the process once all validation batches are manufactured. An appropriate programme for the monitoring of distributed batches (e.g. complaints, recalls, subsequent batch failures) is required, too.
Generally process validation can not be considered once-off exercises. An ongoing programme to collect and analyse product and process data relating to product quality shall be established (re-validation, product lifecycle). The lifecycle concept links product and process development, qualification of commercial manufacturing process, maintenance of the process in a state of control during routine commercial production. In this context significant changes to premises, facilities, equipment, systems and the processes which may effect the quality or reproducibility, directly or indirectly shall be validated. Modifications, changes in formulation and manufacturing process during development and lifecycle management shall not be avoided at all because this also gain additional knowledge and may lead to process optimisation and improvement. Therefore a suitable change control procedure and deviation management is unalterable.
Regarding their severity, deviations may result in corrective or preventive actions (CAPA) and changes may require regulatory action (e.g. notification, variation procedure). To reduce re-validation activities and avoid unnecessary personnel and documentation effort a simple and often used approach is linked to the product quality review (PQR). In addition to that some statistical tools (e.g. Six Sigma) are used to determine the process capability to trend analysis and IPC. Goals are the maintenance of the valid status of processes in routine production, the improvement of processes as well as cost reduction.
Besides the last few years advanced strategies are considered to support and improve process validation. For example the newly revised ICH Q8 guideline "Pharmaceutical Development" describes the Quality by design approach which shall provide that quality cannot be tested into products, but shall be built in by design. An appropriate tool is the design space which is a modern risk control strategy. It is a systematic approach to development, a multidimensional combination and interaction of input variables (e.g. materials) and process parameters that have been demonstrated to provide assurance of quality. It shall lead to a greater knowledge and understanding of the product and its manufacturing process. This may create a basis for flexible regulatory approaches, whereas the degree of the flexibility depends on the scientific knowledge provided. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process.
Among the design space and quality risk management the last few years the attention on "Process Analytical Technologies (PAT)" is increased. PAT is the idea of gaining more process understanding by on-line measurement, the concept of using on-line data to control the process and a concept of controlling critical process parameters hence to be validated. In principle PAT is comparable with an on-line, continuous validation.
Since November 2008 a draft version of the "Guidance for Industry - Process Validation: General Principles and Practices" of the FDA is available. In contrast to other comparable documents the alignment of process validation activities with the product lifecycle concept as well as with existing ICH guidelines Q8, Q9 and Q10 is focused and explained in detail. Regarding to this the use of technological advances in pharmaceutical manufacturing and implementation of modern quality risk management is strongly recommended. The continuous gain of greater process and product knowledge as well as understanding throughout the complete lifecycle concept is the basic goal of this approach.
The future goal of process validation will be a process yielding the quality by design and possibly a parametric release (real-time release) which may be supported by advanced strategies (e.g. Design space, PAT).
Pages: 44, Annexes: pages: 3