Building Quality into the Process and its Development
In September 2004, the American FDA issued the final version of the PAT Guidance document (references 1 and 5), a framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance. The guidance document will have a major impact on both the manufacturing and the development of biopharmaceutical products in the future.
FDA, in particular CDER, started as mentioned on the home page with the modification of the 30 year old GMP laws and the issue of five supporting guidance documents (
see reference 5). The PAT guidance document is the most innovative one in this series. ‘Building Quality into the Process and its Development’ is the starting point of the guidance document for PAT. In other words, as formulated by FDA, ‘quality cannot be tested into the products, it should be built in or be by design and not by inspection’. The guidance document represents this new view.
PAT summarized;
real time product release and no quality control at the end of the process, but instead quality is integrated in all steps of the process chain. The PAT approach starts with a careful study of side effects and the efficacy of the product in the target group. In the next step, these issues are translated into the typical chemical characteristics of the product and its consequences for the production process, resulting in the product with the desired characteristics. The consequence of this approach results in the definition of the critical unit operations and the critical parameters of these operations.
PAT offers the conditions for an innovative control of processes and the quality assurances linked to such a control. These conditions result in a complete control of the production processes and a real time release of their products and intermediates. The advantages after implementation of PAT are great. The reprocessing and quarantine of products waiting for release belongs in the past! PAT is synonym for consistent processes and the consistent quality of the products.
From the PAT guidance document, the clear conclusion can be drawn that the PAT approach is relevant for all stages of the development and manufacture of new and existing biopharmaceutical products. Incorporation of PAT in process development will reduce the risk of failure of the development of new biopharmaceuticals! The PAT approach is represented in the figure composed of five arrows representing the five stages. This approach has different characteristics depending on the stage the product finds itself in.
The FDA
requires a number of conditions in the application of PAT for real time product release. These conditions are: a complete understanding of the production process, maximum control of risks during the execution of the processes, the use of new sensors such as n-IR and the application of tools such as ‘multivariate process data analysis’ during manufacture.
Tools such as ‘design of experiments’ for the definition of the limits of the critical parameters are quite common during the developmental stage of the processes.
Recently, Douglas Mc McCormick, Editor in Chief of Pharmaceutical Technology, reported about the progress of the implementation of PAT in American pharmaceutical companies (
reference 2). About 50% of the people who were interviewed were not familiar with the Guidance Document but 26% of the Companies interviewed had a PAT team. It is expected that the percentage will increase in the coming years. In The Netherlands some companies have more than one PAT team. This was the conclusion of a recent meeting organized by the Dutch Division of ISPE. Recently, two PAT-applications used for the manufacture of pharmaceutical products have been approved by FDA (see the other part of the website of CDER mentioned on this page).
FDA inspections in the future will also be directed to the critical units operations in the manufacture of the products. Recently the FDA have issued a white paper entitled ‘Risk-Based Method for Prioritizing CGMP Inspections of Pharmaceutical Manufacturing Sites -a Pilot Risk Ranking Model’ on their approach to inspections.
The FDA is not alone in its clear view of the future of biopharmaceutical companies. A comparable innovative view is also presented by IBM Business Consulting Services as part of their Pharma 2010 document series (
reference 6). This series of 16 documents can be downloaded from the site mentioned on this page. Additional practical information about PAT can be obtained from the site of Pharmamanufacturing (
reference 7).
Unfortunately none of the documents dealing with the innovation of the biotechnology in The Netherlands issued by the Ministry of Economic Affairs (
EZ; reference 8) refer to these important changes which take place to the approach and culture of the companies active in this field. In issue 38 of Conceptuur, which appeared in 2004, a paper by Sam was published (
reference3) dealing with the major changes of quality systems in the future.
PAT Consultancy
is coordinating a project, subsidized by Senter (a subsidiary of EZ) , dealing with quality assurance of hard- and software to be used for the manufacture of biopharmaceutical products (
reference 4) and resulting, of course, in real time product release of the products. In the project two companies, an Institute and a University Group, are participating in implementing the PAT Guidance Document for the most critical unit operation -the upstream part- in the manufacture of a biopharmaceutical product. The choice has not been made for a secreting system, but for a system which aims to realize a well-defined bacterial suspension.
