PAT Paves the Way for Continuous Manufacturing

The pharmaceutical and biotechnological industries face unprecedented challenges as a consequence of increased competition and difficulty in bringing innovative products to market. Therefore, significant efforts are being made to improve product quality and productivity through technological innovation and cross-industry best practices.

In 2004, the US FDA published its process analytical technology (PAT) guideline, which promotes the adoption of innovative technologies to perform timely measurements on critical quality attributes of raw and in-process materials, allowing better process understanding and control (1). The PAT concept is embraced in the quality-by-design (QbD) framework, which endorses a control strategy that considers not only risk assessment, prior knowledge, and enhanced process understanding, but also how unit operations affect the quality and stability of the product (2, 3).

QbD/PAT-based strategies provide the cornerstone to move toward continuous manufacturing in pharmaceutical and biopharmaceutical production. There is a global interest in adopting cleaner, safer, shorter, and more flexible and efficient manufacturing processes through science and data-driven approaches. Continuous processing, however, requires a different mindset and implementation strategy from development up to commercial manufacturing, aligned with regulatory expectations. Today, health authorities have a clear view on the definition of batch/production lot (4, 5), and no other requirements are imposed. In that sense, the regulatory standpoint should not be a reason to avoid continuous manufacture. Yet, to foster continuous processing adoption, regulatory agencies, industry, and academia must collaborate to develop approaches and a roadmap for implementation.

Using PAT to set control strategies
To implement a control strategy in a continuous process, it is crucial to understand and minimize incoming material variation, perform timely in-process measurements, define representative sampling (depending on the dynamics of the system), set appropriate acceptance criteria, and characterize the propagation of changes and disturbances through the system (4). In contrast to batch processing, in which local control of each piece of equipment is in many occasions considered sufficient, in continuous manufacturing not only is local control mandatory, but also the entire process flow must be coordinated and equipped with second-level control systems that supervise and align the work of individual unit operations (6).

The selection of appropriate PAT tools is a crucial step toward setting efficient control strategies in continuous processes. Spectroscopic technologies have been widely applied in process analysis and increasingly for on-line process monitoring in both pharma and biopharma. Features such as easy-to-use instrumentation, high measuring frequencies, and the ability to monitor multiple process parameters in whole samples that more faithfully capture the real process state, allow PAT tools to surpass the limitations of traditional chromatographic techniques not suited to cope with high process dynamics (7, 8).

As reported in industrial case studies, various PAT tools have been used for reaction monitoring purposes, such as simultaneous use of mid-infrared and Raman probes to monitor early API synthesis, the combination of on-line analytics with Raman process analyzers for real-time detection of steady state in continuous flow reactors, and the employment of in-line, near-infrared monitoring tools to control the synthesis of API intermediates (8–11).

In an industrial scenario, the implementation of a successful end-to-end control strategy in continuous processing requires setting up a multidisciplinary team, thus integrating different types of knowledge (e.g., reaction chemistry, kinetic models, engineering principles) to establish performance requirements for the commercial process. The workflow from the implementation stage until validation of the control strategy is the limiting step, as it is technically demanding and the object of regulatory oversight. The use of a standard platform for continuous manufacturing (i.e., with equivalency of scale and equipment for pilot, clinical, and commercial production) can, however, minimize the challenges of scale-up and tech-transfer activities, facilitate training and validation procedures, and enhance collection of substantial amounts of data to enhance process understanding.

Continuous biopharmaceutical manufacturing
Even though continuous manufacturing is better established for bulk chemicals, there is growing interest as well as investment in realizing the benefits of continuous manufacturing for biopharmaceuticals. Moreover, the biopharmaceutical industry is particularly dominated by stringent regulatory and quality requirements, and the increasing pressure to reduce costs and growing competition from biosimilar products impacts development time. Thus, the benefits of continuous bioprocessing include steady-state operation, reduction of facility and equipment footprint (e.g., small bioreactors, single-use equipment), high-volumetric productivity, a streamlined process flow (e.g., elimination of hold tanks and non-value unit operations), low cycle times, a high degree of automation (minimizing manual operations and subjective decision making), the opportunity to implement standardized procedures, and more flexibility not only in terms of rapid capacity adjustments, but also to modulate the process duration based on product demand.

There are different process configurations in continuous biomanufacturing: hybrid systems with continuous upstream and batch mode downstream (or the opposite), and fully integrated continuous unit operations for the entire process train. Continuous upstream (i.e., perfusion cell culture) with batch downstream is widely used for commercial manufacturing of complex and labile proteins, providing short residence times and enabling the production of unstable proteins with minimal degradation. On the other hand, batch upstream with continuous downstream has been explored at development and pilot scales with economic benefits, because smaller chromatography columns result in significant cost savings. A fully integrated continuous bioprocess reduces equipment size, costs, and residence and cycle times. Even so, not all the necessary unit operations are commercially available, and additional efforts are required to develop interfaces between unit operations, which opens an opportunity to employ single-use technology. Continuous operations also have the potential to positively influence the supply chain, because shorter cycle times, reduced inventory, and the fact that scaling is defined by time extension offers greater flexibility in meeting variable market demands.

Selecting the appropriate process configuration requires reflecting on the different technological requirements when considering continuous upstream and/or downstream processing. Although continuous perfusion bioreactors have been broadly applied for commercial manufacturing of biopharmaceuticals, there are many necessary improvements, such as the development of robust and stable cell lines able to maintain high productivity, the design of media formulation to support high cell density, and the optimization of bioreactor conditions (e.g., cell-density control, efficient oxygenation and ventilation, and foam control, among others).

Experience with continuous operations in downstream processing is limited, and until recently, equipment for continuous protein purification was not available. An important design requirement for continuous downstream processing is the ability to intertwine several purification steps to operate over prolonged periods and under strict bioburden control conditions. Ultimately, significant experience needs to be accumulated in process scale-up, and the adoption of such tools for routine use will take some time to be evaluated, validated, and implemented.

Even though regulatory agencies are increasingly supportive of this new manufacturing paradigm, a partial or complete integration between upstream and downstream has not yet been commercially demonstrated. To motivate companies to adopt these approaches, regulatory authorities are currently promoting the benefits of continuous processing, and agency experts are available to discuss approaches and the operationalization roadmap. However, low tolerance of risk, management concerns about implementing new technologies, and overinvestment are some of the reasons that hold back the penetration of new processing methodologies.

Conclusion
The business strategy of both pharmaceutical and biopharmaceutical companies can benefit from the implementation of continuous manufacturing, because it enables more responsive and efficient supply-chain management. Lower production costs motivate smaller companies to start manufacturing earlier in their lifecycle, thus reducing their dependency on CMOs. Additionally, smaller plants permit establishing multipurpose facilities, and a standard production platform enables producing different products in the same unit, increasing operational flexibility, and allowing a better control of costs (6).

The coming years will certainly be exciting in the pharmaceutical industry, especially for those involved in manufacturing sciences and technologies, as the transformation from batch to continuous manufacturing takes root and allows faster and safer supply of new and more affordable drug products to patients.

References
1. FDA, Guidance for Industry: PAT-a Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Rockville, MD, Sept. 2004).
2. C. Schaefer et al., J. Pharm. Biomed. Anal. 83, 194-201 (2013).
3. S. Kozlowski et al., "The CMC Strategy Forums, Celebrating a Decade of Collaborative Technical and Regulatory Interaction, Part 1: QbD and Risk Management," BioProcess International Special Report (2015).
4. FDA, "FDA Perspective on Continuous Manufacturing," www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM341197.pdf, accessed 21 July, 2015.
5. EMA, Guideline on Process Validation for Finished Products-Information and Data to Be Provided in Regulatory Submissions (London, Feb. 2014).
6. K.B. Konstantinov and C.L. Cooney, J. Pharm. Sci. online, DOI:10.1002/jps.24268, 21 Nov. 2014.
7. Z. Chen, D. Lovett, and J. Morris, J. Process Control 21 (10) 1467-1482 (2011).
8. R. Chen et al., Pharma. Outsourcing 12 (4) 1-7 (2011).
9. M. Roberto et al., Processes 2 (1) 24-33 (2013).
10. Pedersen et al., Org. Process Res. Dev. 17 (9) 1142-1148 (2013).
11. A.E. Cervera-Padrell et al., Org. Process Res. Dev. 16 (5) 901-914 (2012).

About the Authors
Sofia T. Santos, Francisca F. Gouveia, and José C. Menezes ar with 4Tune Engineering, Av. António Augusto Aguiar 108, 4, 1050-019 Lisbon Portugal. 

Article DetailsPharmaceutical Technology 
APIs, Excipients, and Manufacturing Supplement 2015
Pages: 33–34, 39

Citation:
When referring to this article, please cite it as S. Santos, F. Gouveia, and J. Menezes, "PAT Paves the Way for Continuous Manufacturing," Supplement to Pharmaceutical Technology 39, s33-34, 39 (2015).