By William Whitford, Thermo Fisher Scientific
It’s been years since the FDA articulated, in its PAT (process analytical technology) guidance, the goal of “facilitating continuous processing to improve efficiency.” Since that time, many have invested in establishing continuous processing (CP). Janet Woodcock, of the Center for Drug Evaluation and Research (CDER), recently commented “continuous manufacturing is going to become a reality.” However, despite some early successes in particular unit operations, we have seen little application in biopharm manufacturing. But this is changing, and from seed stock expansion to fill and finish, we now see the development of a number of CP operations for biopharm.
The power of continuous processing (or production) has been recognized since its application to chemical manufacturing in the late 19th century. Its popularity stems from advantages in efficiency, economy, and product quality. Beyond its practicality, CP is consistent with the goals of QbD (Quality by Design) and is supported by results from PAT. In continuous processing, materials constantly flow from operation to operation, in and out of specialized equipment. While batch processing is a current standard in bioproduction, the significant limitations of such a discrete and discontinuous format have been well catalogued — and range from scale-factor issues in development to the consequences of interruptions and delays in production.
In CP, materials and intermediates experience a more consistent condition in a steady state. Reactions are not “warmed-up,” materials are not exhausted in gradients over time, and a bolus reaction (or culture) is not run to the point of inefficiency. CP’s heightened processing parameter consistency provides improved product uniformity and quality. Quality also can be improved by CP’s simplified control strategy and its close control of operating parameters around one (optimized) point. It’s simplified and shortened process stream, lower reactor residency times, and more concentrated intermediate product also contribute to improved quality. CP can reduce both the amount of, and operator intervention in, process intermediates. Not only can process capability be heightened, but chemistries and procedures unavailable in batch can be presented. CP provides advantages in facility design and construction through reduced footprint and increased facility utilization. Its equipment is inherently easy to clean, provides a shortened production train, and an easy product changeover. A number of sustainability methods are supported as CP’s methods provide reduced service and energy consumption. The online monitoring and real-time quality assurance supported makes it amenable to such goals as continuous quality verification as well as parametric and real-time release (see the EMA [European Medicines Agency] new bioprocessing-relevant guideline). Process development and technology transfer is eased, both because development can be accomplished at the final scale of manufacturing, and because CP approaches support numerous “hybrid” technologies (e.g. between classical and single-use systems).
Surprisingly, relevant regulations and guidance are silent on designating the manufacturing mode to be used, yet some considerations for CP approaches are presented. The ICH (International Conference on Harmonization) notes in its Q7 guidance, “In the case of continuous production, a batch may correspond to a defined fraction of the production,” and the IPEC (International Pharmaceutical Excipients Council) states “For continuous processes the batch and its records should be defined.” It is also noteworthy that drug product manufactured by continuous process is specifically defined in 21 CFR 210.3(b)(10).
Quality and safety are reasons for the designation of manufacturing lots, as it has implications on such activities as material rework, process deviations, recalls, and pharmacovigilance. Lot definitions in batch processing are rather clear and intuitive, but in CP significant issues arise in their designation. A CP lot may be delineated by such means as time-stamp, volume, or mass-determined portions of the entire batch.
Pharma CP Concerns
There are a few financial, engineering, and regulatory concerns slowing the uptake of CP in pharma. Some still have concerns regarding the FDA’s reception in general, or just how CP-specific approaches will look in a design space concept or failure analysis methods. CP does require some new in-process testing and release approaches, as well as new, more robust adaptive and closed-loop control systems. Some new strategies will be needed as well in such areas as regulatory applications and knowledge management. While some unit operations can be very readily converted to CP right now, for others the means of monitoring some required parameters are not yet adequate. Often both the definition and frequency of measurement of CPPs (critical process parameters) are yet to be determined. This is notable because a clear definition of both critical product quality attributes and process parameters is required for transition from an existing batch to a knowledge-based CP approach. Well-founded or not, process-related concerns include start-up and shut-down material losses, achieving the robust throughput balancing required and fears regarding equipment cleaning — as well as the fact that when any unit op in CP is down for any reason, the whole process is down. Finally, because of existing batch process capacity, others see potential business case issues.
CP In Biotechnology
While not common, successful examples of continuous procedures in biopharmaceutical production do exist and such unit operations can be thought of as “building blocks” toward a fully continuous manufacturing line. Modern enablers to this approach are the gains afforded by the PAT and QbD initiatives, as well as the rapid uptake of single-use technologies (SUT). The modularity and flexibility of SUT can aid in reducing process steps and facilitate adaptability in a CP flow and layout. Single-use technologies support hybrid reconfigurations where required, and easily accommodate novelty in process design. Beyond the general concerns noted above, there are a few bioprocess-specific concerns in CP for such major production applications as recombinant protein secretion or viral vaccine production.
CP In Upstream Bioproduction
Methods supporting continuous or semi-continuous manufacturing include distinct implementations of intermittent harvest, repeated-batch, and perfusion culture. In perfusion, cells are separated or retained (by one of many distinct means) while the culture medium is continuously exchanged. Perfusion culture applications in bioproduction were established, with limited adoption, decades ago —but have lately been growing in popularity. Centocor (now Janssen Biotech) has long been employing perfusion culture in the production of approved product. Genzyme manufactures such products as Lumizyme in CHO-based perfusion culture, and its continued commitment to perfusion is demonstrated by a recent expansion of such capacity at its Geel, Belgium plant. At this spring’s ACS meeting in San Diego, Bayer HealthCare presented on methods for operation of steady state perfusion bioreactors during production in mammalian cells. Practical implementation of the perfusion mode has been facilitated by increased process understanding, innovation in real-time measurement and improved control technologies. Maybe a dozen distinct perfusion-like approaches for both research and production scale culture have been commercialized in recent years, including alternating tangential flow, and number of packed-bed and hollow fiber bioreactors.
CP In Downstream Bioproduction
Bulk harvest from large-scale production traditionally undergoes processing operations in employing stainless steel tanks for process fluid and product storage. We’ve recently heard much regarding downstream bottlenecks, and CP is actually one way of addressing them. Use of such adsorption media as Protein A resins are easily envisioned in a batch mode, however they can be implemented in more continuous processes. Examples of this range from simulated moving bed to countercurrent tangential flow chromatography appearing in entirely disposable flow paths. Because of the higher volumetric product titers and reduced contaminates of serum-free culture, a number of novel chemistries and “flow-through mode” chromatographys supporting CP are now appearing. Surprisingly, the “topping-up” of large-scale containers with a newly prepared buffer providing a virtually unlimited supply has been validated for cGMP manufacturing. Continuous buffer preparation using in-line dilution of concentrated stock solutions has been attempted for years. Lately, this is being realized by advancements in dilution instrumentation, monitoring technologies, and feedback control methods based upon such criteria as component concentration, pH, conductivity, or mass balance.
Equipment and systems supporting continuous processing in operations from seed-stock expansion to fill and finish are appearing. As contiguously combined with such other enabling technologies as single-use mixers and storage systems, the design of flexible, disposable, and continuous biomanufacturing systems is finally being realized.
About The Author
William Whitford is senior manager for the bioprocessing market in Thermo Scientific Cell Culture and BioProcessing at Thermo Fisher Scientific.