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Quality by Design – a paradigm change in bioprocess development

Bioprocess technology has undergone a fundamental change with regard to the criteria used for validating product quality: around ten years ago, the U.S. Food and Drug Administration (FDA) revised the 1987 process validation guidance and the subsequent establishment of the Process Analytical Technology (PAT) initiative heralded a paradigm change in bioprocess understanding and control. The FDA’s guidance underwent a paradigm shift from what was originally a static, end-product oriented claim to a dynamic object-oriented quality concept. In the following interview, Dr. Helmut Trautmann, CEO of abiotec AG, speaks about the impact of PAT on bioprocessing.

Dr. Helmut Trautmann, CEO of abiotec AG, has been focusing on bioprocess technologies for about two decades.

Dr. Trautmann, why did the FDA shift from an originally static, end-product oriented claim to a dynamic object-oriented quality concept?

Poor quality of drugs on the market, evidenced by recalls, compliants and other indicators, from supposedly validated processes pointed to a lack of process understanding and inadequate process control. This insight represented already about 10 years ago an impetus for the FDA to revise their 1987 guideline. In 2004, they launched their Process Analytical Technology (PAT) initiative entitled “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach”, which was then followed by the drafting of additional guidelines that took “Quality by Design” (QbD) issues into account. The radical change in the FDA’s paradigm from a static, end-product oriented claim towards an overall dynamic object-oriented and scientifically motivated quality concept was the beginning of a new era: PAT called for the design and development of bioprocesses through the application of the latest advances in science and technology that should consistently ensure a predefined product quality at the end of the manufacturing process. The goal finally aimed at is to ensure for the product a so-called ”quality by design”.

What kind of resistance has PAT encountered since its inception? How does PAT affect drug manufacturing companies?

The PAT concept leads to a considerable increase in the resources required by drug manufacturers: new PAT working groups need to be established in order to implement the new and partly complex concept; this can often involve time-consuming processes. The field of “process engineering” in particular requires more personnel and more resources to comply with the requirements. In addition, the implementation of the concept is associated with a lot red tape, as every step needs to be meticulously documented. It appears that at present, projects are promoted because of regulatory pressure rather than on the basis of economic drivers.

From an industry perspective, the expected advantage of a parametric release of the product is not really visible yet. In addition, the still unanswered questions relating to regulatory inspections represent further hurdles on the path to implementing QbD. A possible preliminary conclusion is that the PAT process is often hampered by industrial cost-benefit considerations.

However, it is worth noting that the opportunities offered by a process that conforms to PAT and QbD cannot be overlooked despite the higher expenditures that arise from the implementation of the PAT/QbD concept: the expensive production processes put in place by PAT and QbD are highly efficient and have a high degree of product safety, which is particularly important in the sensitive area of medical applications. The initial high costs associated with the implementation of PAT and QbD can be compensated by the aspired higher quality of the products and a major increase in productivity. However, pharmaceutical companies are well advised to create at an early stage an environment that allows them to launch economically motivated development projects. In order to do this, companies require methods and analytical equipment which are able to make the synergies of the QbD solutions available to other products, at different locations and in different phases of the drug discovery process, from process development to production.

“Multiple high-precision bioprocessing“ in research and development is the basis for the reliable and efficient acquisition of transferable process understanding. © DSM/ Novartis Pharma AG

What effect does the PAT initiative have on the communication between science and economy?

Academic science, with its current-interest research topics and results, has always provided impulses to industrially relevant process technology tasks. The PAT initiative has virtually turned this on its head: nowadays, the major impulses come from industry. The PAT concept has proved to be very complex and also very comprehensive, especially as far as biological systems are concerned, which by nature are rather complex; therefore, industry welcomes competent research and technology support. Prof. Dr. Herwig from the Department of Bioprocess Technology at the Vienna University of Technology, who has extensive long-term industry experience in this area as well as research and teaching success, is currently the major source of inspiration in this field. He believes that the PAT and QbD initiatives have shown that solely recombinant biotechnology does not lead to safe and economically viable products without scientifically founded knowledge of products and production processes. It can therefore be concluded that bioprocess technology must be seen on equal terms with recombinant technology, and even more importantly, the two technologies need to be combined.

What has the paradigm change brought to the bioprocess technologies you are offering?

With my company abiotec – advanced bioprocess technologies – I offer services and turn-key solutions that ensure the quality and efficiency of bioprocessing in conformance with the PAT paradigm. My academic approaches related to the topic are based on the major research priorities of my animal cell culture research group at the ETH Zurich in the early 1990s: expanded strategies of optimised processing are derived from the finding that the modulation of the cellular micro-environment has a considerable influence on the metabolism and hence on the numerous biochemical pathways of cells. The identification and control of the concentration of media components required for cellular energy generation or as building blocks for the biosynthesis of proteins, etc., plays a major role. On a different note it seems that industry is still unsure of what must be done and how it should be done, even now, seven years after the launch of the PAT initiative. The high demands on QbD-related processing can only be fulfilled in practice through a series of small steps, which often are cost-intensive. The most important action that needs to be taken is identifying successful processing parameters from the plethora of scientifically founded options that are necessary to produce a high-quality product and then go on to translate them into technically manageable solutions that are suitable for everyday use. With the establishment of the “EASY-PAT” approach, I hope that I am able to alleviate people’s fear of the topic and enable them to make considerable progress at reasonable cost in what is a basically iterative process.

How important is the acquisition of biochemical and biological information in the process technology you are offering?

In principle, PAT is about the scientifically founded understanding of a production processes that leads to the consistent, pre-defined quality of a product. First, Critical Quality Attributes (CQAs), i.e. molecular characteristics found to be substantial for ensuring the safety and efficacy of the product, need to be determined. The next step involves the identification of those process parameters that affect the critical quality attributes of the product. These parameters are referred to as Critical Process Parameters (CPPs). The first essential step required to gain an in-depth understanding of the process involves the acquisition of biochemical and biological primary data. By applying suitable mathematical algorithms to these data, process information with regard to multiple aspects can be derived, which contributes to the aspired process understanding in its entirety. In order to gain high frequency online data and information on a 24/7 basis, new automated analysis systems have to be developed and applied. This task could otherwise only be done “off-line” by expert laboratory staff at unjustifiably high costs and with a significant time delay.

An integral approach leading to PAT-conform process understanding from raw data and information derived from these data is the basis for efficient process control. The concept of determining specific metabolic rates is expected to enable the scale-independent transfer of the results from development and scale-up to production. © H. Trautmann/ C. Herwig, TU Wien

What kind of products does your company develop and how can these products be positioned in the PAT paradigm change we’ve talked about before?

The first step in the workflow of PAT-compliant process understanding focuses on the generation of primary process data. In addition to invasive systems allowing the implementation of routine laboratory analytics by involving automated sterile sampling systems and subsequent sample processing units, we are currently involved in an interesting project related to the use of non-invasive techniques for the measurement of fluorescence using optical bioreactor probes: the optical properties of biogenic fluorophores and of fluorescent reporter proteins enable the efficient and rapid detection of relevant process states, including, for example, aspects of the cellular metabolism as well as productivity. In order to provide a small and robust online measurement system with the precision of a large top-quality benchtop device that is able to function as a direct “fluorescence eye” into the process, we are currently developing a modular system for made-to-measure applications that is based on the highly powerful fluorescence measurement technique offered by Stockach-based Qiagen Lake Constance GmbH. We hope that this development will bring us one step closer to reaching the ambitious goal of a PAT- and QbD-based process.

Additional Information:
abiotec AG
Dr. Helmut Trautmann, CEO
Buchenweg 21
CH–4310 Rheinfelden
Tel.: +41 (0) 56 633 11 77
E-Mail: info(at)abiotec.ch

 

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