CMO PAT implementation: Time for strategic decisions

Process analytical technology (PAT) is a vital step towards a future where continuous manufacturing and real time product release can become real in the pharmaceutical sector. After a slow start, PAT is high on the agenda for Big Pharma. But it is not so common among contract manufacturers (CMOs). What is holding them back and what are the issues they need to consider? Rebecca Vangenechten argues that, while the pace of change will vary from company to company, all CMOs need to have a PAT strategy in place.

PAT offers immense potential for pharmaceutical manufacturing. With PAT, quality becomes something that is designed into the process rather than checked afterwards. Introducing PAT, thus, has a considerable positive impact on reducing production costs. PAT speeds decisions on the unit operation level and improves quality/efficiency of process steps. This leads to shorter batch runs, increased quality consistency and reduced waste.

However, investment in PAT comes at a price and CMOs have to balance that against a wide range of considerations. In other industries, such as food and beverages, PAT is commonplace and the stuff of competitive advantage. In pharmaceuticals, however, regulation has been framed around batch processes and it was not until 2004 that the FDA's 'critical path initiative' provided a starting point for the development of PAT. The 'critical path initiative' gave a very clear regulatory encouragement to PAT. Even so, it is encouragement rather than compulsion and only pockets of pharma manufacturing are becoming PAT-enabled.

In many respects, life would be simpler for CMOs if there was the same 'keep up or fall behind' compulsion to introducing PAT in contract manufacturing that is present in other industries and is beginning to be felt in Big Pharma. So how should CMOs judge whether to implement PAT or not in their manufacturing facilities? Five key questions need to be addressed:

• What do their clients need?
• What part of the CMO market is the CMO in?
• What stage of the product life cycle is the product in?
• What is the CMO's attitude towards and willingness to change?
• What is the overall cost benefit and return on investment picture?

A crucial consideration is what part of the pharma sector they are serving. A 'wait and see' approach, or even worse a 'wait and be pushed' approach, could be highly risky in a context where some of their Big Pharma clients are moving forward on PAT. For example, a major benefit of PAT in the new product market is to reduce development time by reducing the gap between R&D and manufacturing. Big Pharma companies who have deployed laboratory-scale PAT are unlikely to be impressed by CMOs who are not ready for a quick PAT-enabled transfer to full production. CMOs need to be ready and, in some contexts, working in partnership with their clients, dovetailing their respective PAT capabilities. Indeed, in some instances, there may be advantages to CMOs setting the pace and guiding their clients on the benefits of a PAT-enabled manufacturing solution.

Decisions on PAT will also be closely related to what services CMOs are offering to their clients. Is the focus on specific processes, such as filling, blending or drying, or is it full service covering the whole production process from raw material to packaging? PAT can deliver significant added value for each. CMOs covering the full production process are likely to find it easier to introduce for new product contracts because there is a chance to start with PAT built-in rather than having to retro-fit existing plant.

Nonetheless, there are also relatively easily obtainable gains to be derived from introducing PAT into existing specific processes. For example, the blending of active pharmaceutical ingredients (APIs) with various excipients is a common step in the pharmaceutical solid dosage form manufacturing process. The homogeneity of the blend is critical in defining the uniformity of dosage units within a batch of tablets. Near infrared (NIR) spectra can be used to show when the blended product has reached its blend endpoint.

A key consideration for CMOs considering PAT is what stage the client's product is in its life cycle. Is it a product that is about to go off-patent where the drive to bring costs down is crucial to counter competition from generics or is it a completely new product? As discussed earlier, the latter offers the chance to introduce PAT from the start. It also means that PAT can be implemented at a stage where formulation development is still ongoing when there is a lot to learn from process understanding. Such implementation also offers regulatory advantages. Unlike implementing PAT with products that are already being manufactured, where such a change requires revalidation, 'green field' PAT can be part of initial validation.

The CMO's attitude towards innovation, and indeed the attitude of their clients, is also very important in any consideration of PAT. CMOs need to consider how well their organisation will embrace and deliver change. How will its people react to and adapt to the more multi-disciplinary environment needed for PAT? Culture and people considerations are central to making the move to PAT effectively. The migration is much more than just a technological one. While innovation in technology lies at the heart of PAT, its successful application relies on full integration with a company's people, knowledge systems and risk management.

Finally, there is the company's calculation of the overall cost picture and return on investment (ROI). As we have seen, this will be influenced by the fact that there are a number of different levels of PAT implementation, from 'easy wins' such as end point detection in blending or drying to PAT on a number of unit operations or a whole production process. Timing and match with where the client is and the product life cycle stage will also be a key determinant on the ROI.

How can CMOs feel more confident and certain about their PAT journey? Siemens' involvement with the FDA PAT initiative, together with our cross-industry experience and know-how, has helped us to develop a PAT implementation methodology for pharmaceutical manufacturing. Pharmaceutical companies implementing PAT can make use of the steps outlined in the "Siemens PAT method implementation Roadmap". This follows eight steps, moving from off-line to on-line activity, which allows the user controlled quality growth of their PAT initiative to fit their market requirement.

Rebecca Vangenechten is a Life Sciences Industry Consultant with Siemens. She is responsible for business development life sciences US and focuses on innovative technologies, including Process Analytic Technology (PAT), out of the Siemens Headquarter Pharma, located in Antwerp (Belgium). She holds a Msc. in BioMedical Sciences from the Catholic University of Louvain and a Master in Global Management from the University Antwerp Management School. Working for one of the largest electro-technical companies as a scientist, Rebecca understands the importance for life sciences companies to build bridges between R&D and manufacturing.