By William Whitford, Strategic Solutions Leader, BioProcess, GE Healthcare Life Sciences
The industry is abuzz with talk about continuous biomanufacturing (CB), and its virtues have been well described (1). Here we will look at some of the barriers or concerns perceived to limit its value to the industry. Justified or not, quite a few concerns have been expressed regarding the implementation of this new, rather disruptive technology.
1. Economic Justifications And Investment Risks
Everyone concedes continuous processing is the very best way to produce many products, from gasoline to shortbread. But, what specifically will it contribute to the bottom line in monoclonal antibodies (MAbs), enzymes, and vaccines (2)? What are the capital expenditure (CapEx) and operational expenditure (OpEx) parameters? How does the diminishing contribution of API costs to some total costs fit-in? And, beyond simply looking at the batch vs continuous equation, what about such other variables as single-use manufacturing or ballroom-based flexible facilities (3)? These good questions are now being addressed using multi-attribute, risk-based tools. Intermediate answers are now being provided by many of the best experts in the bioproduction world (4). Start-up and shut down material losses and costs: This question is easily calculated once a particular continuous operation is designed. There really should be no mysteries here.
2. Performance Reliability (Incidence Of Failure)
Batch production isn’t perfect, but just how often and from what will a continuous process fail? For novel designs in CB, this legitimate concern is being ameliorated by advances in bioprocess understanding through existing operational excellence initiatives, as well as developments in enterprise process control.
3. Implementation: Process Control And QS Procedures
We are on the cusp of many new and powerful in-line, at-line, and on-line near real-time monitoring capabilities, but which side of the cusp are we on? In batch, we have a good idea of simple, non-critical, and critical validation exceptions. What about in continuous processes? How will intra- or post-production tests or quarantine now performed on bulk WIP intermediates be made? How will CB processes influence CAPA, FEMA, and OSS procedures? What will vertically-integrated supervisory process control between previously individual unit operations look like? Do such systems now exist? New and more comprehensive adaptive/closed loop enterprise control systems must not only be instituted, but in many cases, developed. This is being actively addressed by not only advances in control algorithms but also by a number of hardware advances. For example, in SCADA-based higher-level distributed process control supported by fieldbus two-way network systems supporting integrated device-side control. For many new, and especially inter-operation, CB initiatives, many of these questions are really yet to be answered.
4. Regulatory Body Dispositions/Filing Concerns
Anything new carries the baggage of additional work, risk, and unexpected delays, but the FDA and EMA now actively promote continuous manufacturing initiatives and existing regulations and guidance are generally neutral on modes of manufacturing. It is of note that some code, such as 21 CFR 210.3, expressly acknowledges continuous processes in pharmaceutical manufacturing. All in all, it appears that any legitimate concern for hurdles in implementing CB might be properly designated as a lack of experience and filing precedent, as opposed to a true conflict in technology or regulation. CB certainly has nominal support at the highest levels of relevant agencies. However, from past experience, many are concerned about sticky validation and/or filing details as well as uninformed regulatory personnel at lower levels.
5. Equipment Fitness For Extended Usage
Single-use systems have become mainstream (5). Despite their recent appearance and diversity of styles, their function has been well-characterized as a robust solution for batch culture. But how will a bioreactor perform in its second (or third) month of continuous use? How will a plastic connector or probe operate at such usage durations? For classical steel, single use, or hybrid systems the issue of fouling of product contact surfaces, and especially ports and specialized constructions, is a very real concern. Most containers, transport systems, and special purpose equipment in the process flow have only been validated for use over a matter of weeks, not months. The solution lies in two steps: Consideration of the plausibility of such extended use for each component and actual real time equipment and process qualification/validation activities.
6. Platform Fitness For Extended Times
Sponsors have gone to great lengths to establish clones that won’t deteriorate through working stock generation, seed train progression, and fed batch production. What will adding months of high-density production (i.e., cell generation number) do? Can existing clones support this? How robust will they be out that far? For some platforms, the technical answers to these questions have already been discovered (for unrelated reasons). Should it be that sufficiently robust clones are generated, validation for CB applications is really a rather straightforward enterprise.
7. Operational Concerns
- Lot designations. For batch cultures, this is easy. Essentially (with exceptions), the batch is the lot, but concerns pop up regularly for CB lot or batch portion designations and such related activities as FMECA. In reality, many of these questions have been answered by those using continuous processes in other industries and even by those few who have already been operating in CB over the past 25 years. Basically, lots can be determined by mass, volume, throughput, or time-stamp. Preventative steps must, however, be taken, such as limiting the continual “topping-up” of raw material feed containers.
- Establishing the means of achieving the required robust process throughput balancing. This is a legitimate concern, and establishing enterprise control, flow bypass, and intermediate containment for biological production is an ongoing initiative. Related to the above, it is envisioned that as more integrated unit operations appear, the manufacturing organization as a whole will have to respond with increased unity.
- Fears that equipment cleaning may be more difficult or complicated than in batch. In general, this is an unjustified concern, and the rapid establishment of single-use equipment in CB makes it a moot point.
- The fact that when any unit-op in CB is down for any reason, the whole process can be down. Another legitimate concern. However, most common-cause variability here can be anticipated and efficiently handled with proper process engineering and control.
- Supply-chain concerns. It is true that additional rigor must be applied to insuring a sufficient consistency of qualified raw materials appear throughout a campaign. This also is not a paradigm-shift, but a matter easily handled by adequate process planning and scheduling.
8. How Robust/Flexible the Process Is For New Platforms
Most existing systems and trials now use classical production cell lines and purification matrices. How will next-generation, highly engineered lines perform in perfusion bioreactors? How will newer resins and membranes perform in continuous purification apparatus? While we can’t really know until they are tried, there is no reason to suspect that a multiply recombinant avian line will fail in a perfusion process envisioned for CHO. Or, that a new high dynamic binding capacity resin developed for extended residence times can’t be optimized employed an optimized simulated moving bed process.
9. How Robust/Flexible The Process Is In Accommodating New Entity Types
The old days of blockbuster MAbs and enzymes may be over. How will CB support the manufacturing of synthetic light chain and Fc fusion antibodies and bioconjugates? New next-generation fragments, DARPins, adnectins, and other alternate scaffolds? Dual-ligand peptides and the various rVaccines and conjugates? Well, obviously these must ultimately be addressed individually, but in fact, the platform employed in the manufacturing of each is more significant here than the exotic structure or activity of the entities themselves.
10. How Robust/Flexible The Process Is In Accommodating New Business Models
This is a very good question and specific topics include new final product and material supply chain initiatives:
- New platform manufacturing requirements, like supporting multiple products per site
- Economic demands driving variable costs and flexibility requirements
- Increased competition from globalization and biosimilars
- Recent dedicated national (local) supply initiatives
Especially through the use of single-use systems, sponsors are now used to quite a high degree of flexibility in:
- An open architecture of subcomponents:
- Process flow and configuration latitude
- System and unit operation modularity
- Capacity expansion through “numbering-up” of production lines
- Physical and/or geographical relocation ease
- Campaign scheduling and product change-over ease.
How will the implementation of CB affect these (6)? In general, the latest single-use supported CB designs are anticipated to provide a highly transportable, economic, robust, and flexible approach to bioproduction (7).
- Whitford, W.G. (2012) Continued Progress in Continuous Processing for Bioproduction, Life Science Leader, P. 62-64, vol__ June. http://lifescienceleadermag.epubxp.com/i/67895/63
- Schaber, S.D., Gerogiorgis D.I., Ramachandran R., Evans J.M., Barton P.I., Trout B.L. (2011) Economic analysis of integrated continuous and batch pharmaceutical manufacturing: a case study. J. Ind. Engin. Chem. 50 (17), 10083–10092.
- Galliher, P and Pralong, A. (2013) When the Process Becomes the Product: Single-Use Technology and the Next Biomanufacturing Paradigm BioPharm International Supplements, Volume 26, Issue 4, pp. s27-s30.
- Biopharm Services BioSolve Process model. http://biopharmservices.com/services/biosolve-configuration/
- Whitford, W.G. (2013) Supporting continuous processing with advanced single-use technologies. BioProcess Intl. 11(4) (Suppl.) 46–52.
- Levine, H.L., Lilja, J.E., Stock, R., Hummel, H., Jones, S.D. (2012) Efficient, flexible facilities for the 21st century BioProcess Int. 10 (S11) 20–30.
- Warikoo, V., Godawat, R., Brower, K., et al. (2012) Integrated continuous production of recombinant therapeutic proteins. Biotechnol. Bioeng. 109(12), 3018–3029.
About The Author
Bill Whitford is Sr. Manager, HyClone Cell Culture, GE Healthcare in Logan, UT with over 20 years experience in biotechnology product and process development. He joined the company nine years ago as a team leader in R&D developing products supporting biomass expansion, protein expression, and virus secretion in mammalian and invertebrate cell lines. Products he has commercialized include defined and animal product-free hybridoma media, fed-batch supplements, and aqueous lipid dispersions. An invited lecturer at international conferences, Bill has published over 250 articles, book chapters and patents in a number of fields in the bioproduction arena. He now enjoys such industry activities as serving on the editorial advisory board for BioProcess International.
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