In the Bioprocess Zone

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Since the turn of the century, industry analysts have touted the “coming of age” of the biotech industry — and they’re inevitably talking about biopharmaceuticals. In fact, biotech has become the innovation engine for the pharmaceutical industry as a whole. Advances in genomics, proteomics, and other biotech research are bringing about not only new drug molecules, but also whole new therapeutic classes such as gene and cell therapies. Biotherapeutics represent the fastest-growing segment of the pharmaceutical industry, with more than 200 marketed products and hundreds more in development.

The maturation of this industry has created in its leaders an urgent desire to find solutions to manufacturing problems. Some perennially successful biotech companies such as Amgen and Genentech are joining the ranks of “Big Pharma” themselves, and “Little Biotech” isn’t so little anymore. And a grown-up industry has grown-up concerns. Any discussion these days of biomanufacturing systems inevitably falls under the growing regulatory emphasis on increasing sophistication of in-process controls and other tools for risk assessment and management.

Risk management is a term that’s finding its way into many conversations in the biopharmaceutical industry these days. Along with it, you’ll see operational excellence, lean manufacturing, and six sigma. These are all approaches to development and manufacturing operations intended to build quality and efficiency into bioprocesses rather than, as has often been the case in the past, merely testing products at the end of a poorly understood manufacturing process.

Bioprocesses were once considered too complex to optimize for cost and efficiency. But as scientific and technical understanding have grown, so has belief in the possibility of saving money while improving safety, efficacy, and quality of biotech products. New methods of product and process characterization have even brought about the emergence of a sort of “biogeneric” industry, with follow-on companies beginning to offer biosimilar products as early biotech blockbusters begin to lose their time-limited patent protection. We’re only beginning to see the first of this new segment of the industry, but if classical generic pharmaceuticals are any indication, it is poised for impressive growth.

Even as biotech companies grow and pharmaceutical giants such as GlaxoSmithKline, Eli Lilly, and Novartis have built powerful biotech groups of their own, academic research is still leading to numerous entrepreneurial entries into the biopharmaceutical arena. The roots of biotechnology are in academia, and long-term strategic collaborations between industry and universities remain a critical component of R&D today. Because regulatory oversight is less of a concern for them, government and academic institutions push the envelope ahead of the industry, so they are great sources of technologies for licensing.

In a recent interview with BPI’s associate editor, Leah Rosin, chemical engineering professor David Wood of Princeton University said, “What interests us most in academia are very new processes that depart from established ones… I think that in industry there’s a lot of attachment to the past because they know they have processes the FDA will approve, so it’s hard to embrace totally new technology.” Regulatory compliance has always been high on the list of priorities for biotechnology companies. It has to be. Without regulatory approval, their products can’t leave the factory, and no amount of great research will ever find its way to treating patients.

Single-Use Technology: Many new processes are including preassembled, plastic-based process components in various upstream and downstream processing steps. Presterilized, preassembled, disposable systems with flexible tubing, bioprocess containers, capsule filters, and connecting devices are best-sellers. The FDA is a major proponent of disposables technology. By eliminating cleaning requirements these can improve process security and flexibility, as well as process economics, but their use in regulated manufacturing leaves certain validation responsibilities up to their suppliers. Drug manufacturers and regulators are not used to putting such trust in vendor companies — and it should be done with caution. Every drug product’s sponsor company still is ultimately responsible for quality, safety, and efficacy.

Single-use options range from stand-alone components and devices to multicomponent systems designed for entire unit operations. These can improve process safety and quality by lowering the risks of cross contamination (especially valuable in multiuse/multiproduct facilities and for contract manufacturers) and human error by reducing cleaning requirements and the number of aseptic connections needed. Because they are less expensive than large, stainless steel processing equipment — and they eliminate the time and material costs of cleaning, sterilization, and associated validation — disposables use also reduces initial capital costs and can thus have a dramatic impact on facility-design decisions.

Single-use technology represents a fundamental change in bioprocessing approaches and facility design. When used in a closed-loop system, disposables prevent the need to disassemble, transport, clean, validate, and reassemble components in a classified cleanroom environment. In many cases, single-use products are supplied presterilized to eliminate the need for clean-or steam-in-place (CIP, SIP) procedures or autoclaving prior to use. The result is not only labor savings, but also a shift in facility design toward smaller cleanrooms and reduced environmental monitoring requirements.

Some biotech start-ups can benefit from single-use technology to manufacture products in house without having to endure the high capital costs of building a traditional facility or even of outsourcing their work — especially at early clinical stages in which product failure is still a high risk. So new companies have potentially greater flexibility and control over their costs of development and production, which will make their “angel” and venture-capitalist investors happy. And Asian manufacturers of follow-on biologics are seeing this technology as a way into the lucrative biopharmaceutical market.


We asked representatives of companies exhibiting in the Product Focus Zones to talk with us about some of the issues facing modern bioprocessors, as described herein. Here are answers from three companies.

Integrated Project Services (Lafayette, PA)

IPS’s manager of process engineering (Saul A. Edenbaum) and director of biotechnology (Paul Muraglia) were kind enough to provi
de these answers. IPS is a full-service engineering design, construction, and validation firm specializing in the pharmaceutical and biotechnology industries. Its primary areas of expertise include cell culture, fermentation, protein purification, formulation and filling, oral solid dosage, APIs, pilot plants, laboratories, and physical containment.

What new technologies are most likely to drive innovation? From an engineering perspective, successful implementation of an in-line dilution system would obviate the need for large buffer-hold tanks currently required for large-scale production of monoclonal antibodies (MAbs). Some manufactures have embraced this technology and are just starting to use it on a commercial scale. Development of cost-effective disposable sensors would facilitate the greater use of single-use technology. It is also now possible to design a single-use technology facility for products derived from mammalian cell culture. Even though there are sizing limitations, many companies are adopting this technology as a lower-cost, faster means to market.

The downstream bottleneck: Where is it, and what have companies been doing to address it? Are these efforts adequate? How and how not? The downstream bottleneck is chromatography for processing systems and clean-in-place/water-for injection (CIP/WFI) capacity for utilities. Attention is usually focused on processing systems, and when a facility is in operation it is noticed there is inadequate or limited residual utility capacity. This serves to expand equipment cycle times and limit production. We have found that the use of more rigorous simulations can assure a greater use of equipment and detection of unanticipated bottlenecks.

One area of concern is CIP, a traditional bottleneck. This situation has become especially acute with the rapid advance of cell culture bioreactor productivity. Higher cell titers and product yields may require increased downstream purification capacities, either due to bioreactor yield improvements or in some cases new product introductions onto existing production lines.

Single-use technologies: How far will they take us? There is growing acceptance of single-use technology. Currently, buffer-mix systems, buffer and media hold, and smaller cell-culture systems are used in a commercial environment. There is interest in disposable equipment for downstream processes, such as membrane-based separations and chromatography. There is a size limitation to bags of around 1,000 L.

Some companies are reluctant to place final bulk product in bags, believing an unacceptable level of risk is associated with the potential for a breach in bag integrity. There is also concern about the handling of large bags. These concerns involve the proper bag unfolding during filling, proper suspension and support of large bags, temperature control, and the stresses that occur during these operations. And single-use technology would have limited application in processes requiring high levels of agitation, in very large systems (>5,000 L), and in chromatography systems involving reused resins.

Development of cost-effective and reliable disposable sensors (e.g., conductivity and pH) will serve to facilitate the successful implementation of these systems. Reduction in the cost of the bags themselves will also be required for greater acceptance.

What advantages can current advances in expression systems bring to large-scale protein production? IPS offers a unique perspective regarding the implications a new expression system may have on operation and cost of a new facility. It is assumed that a new expression system would involve secretion of product beyond 7–10 g/L in a shorter time that currently expected from typical mammalian systems. Perhaps the greatest advantage would be in reduction of buffer prep and hold capacity required for downstream processing. There would also be a corresponding decrease in the clean utilities to support such systems. Reduction in bioreactors and protein purification equipment necessary would be a secondary benefit.

Contact Edenbaum or Muraglia at Integrated Project Services, 2001 Joshua Road, Lafayette Hill, PA 19444; 1-610-828-4090 x217, fax 1-610.828.3656;

Laureate Pharma, Inc.

(East Princeton, NJ) Booth #2331

Laureate’s senior marketing manager, Yamuna Dasarathy, provided these answers. Her company focuses on CGMP manufacturing of protein-based biologics (especially MAbs and recombinant proteins) for all phases of clinical trials and modest commercial scale. Laureate’s full-service offerings range from development through aseptic filling.

What new technologies are most likely to drive innovation? Very high-yield expression cell line platforms and disposable bioreactor technologies will streamline and economize the manufacturing process. More automation coupled with high-capacity ion-exchange and affinity membranes for downstream protein purification will accelerate production.

The downstream bottleneck…? Yes, a downstream bottleneck does exist in purification process development. It is less of a bottleneck for antibodies than for other proteins. Non–protein-A affinity-based purification processes can involve several unit operations, with packing of different columns, validation, and qualification slowing down the process. For small companies, equipment availability, turnaround time, and stability studies can add to the bottleneck. Simplified purification processes as well as very careful planning and coordination between upstream and downstream processing will minimize it somewhat.

Single-use technologies…? Single-use technologies greatly enhance productivity. Single-use, adjustable-volume bioreactors offer much-needed flexibility for a manufacturing facility. Disposables obviate the need for cleaning validation and conserve WFI, resulting in less downtime and reducing operating costs. Small-scale disposable columns (20-L) are on the market currently for antibody purification. However, for larger scales, the economics of nondisposable hardware must be considered. Unavailability of large-scale bioreactors and a lack of high-capacity charged membranes for downstream processing (e.g., capture steps) are some limitations that need to be overcome to make the whole manufacturing process a disposable one.

Contact Yamuna Dasarathy at Laureate Pharma, Inc., 201 College Road, East Princeton, NJ 08540; 1-609-919-3393, 1-609-651-5324;


(Allendale, NJ) Booth #2421

Assistant vice president of Lonza Innovation for Future Technology, Hans-Peter Meyer, provided the following answers for us. Her company is a leading supplier of products and services to the pharmaceutical, health-care, and life-science industries.

The downstream bottleneck…? Yes, it exists. We have dedicated teams exploring novel approaches and developing technologies in cooperation with external partners.

What do you see as the impact of operational excellence (and related initiatives such as lean manufacturing and six sigma) on day-to-day manufacturing practices? The goal of 6s is to improve quality, requiring disciplined training and commitment of practitioners, known as “black belts” and “green belts” to drive identified improvement projects. Our global lean 6s organization focuses on reducing every kind of waste, steadily optimizing how things are done and “getting it right the first time,” systematically nurturing a culture of continuous improvement, and supporting green-belt and process-excellence projects across all functions.

What advantages can current
advances in expression systems bring to large-scale protein production?
The strain is key to successful commercial production. Lonza develops proprietary expression systems for mammalian cell culture and microbial fermentation. In microbial fermentation, our effort for better expression stretches over various Gram-negative and Gram-positive bacteria as well as yeasts.

Contact Melanie Disa at Lonza America, Inc., 90 Boroline Road, Allendale, NJ 07401; 1-201-316-9413, fax 1-201-696-3533; ;

Expression and Production

In an interview with BPI associate editor Leah Rosin, Majid Mehtali (chief scientific officer and vice president of R&D for Vivalis SA in France) spoke about recombinant protein expression systems. “Systematic developmental work in particular on expression vectors, cell culture media, and production processes have led to major improvements in protein production over the past five years, with yields over a gram per liter and higher. And there is no slow-down in the work of cell culture engineers to speed up the generation and isolation of high-producer clones — and in particular to improve the quality of the produced proteins.”

“CHO cells are so well established and characterized in terms of technical handling, regulatory knowledge, and safety profile that any new system must provide clear advantages. A growing list of new protein expression systems is being developed by biotechnology or pharma companies to provide added biological value to their produced proteins. Some systems are in fact pure alternatives to CHO in cost and speed of production (e.g., transgenic systems).

“Transgenic systems have even recently had regulatory approval (Atryn made by transgenic goats at Genzyme Transgenics, approved in 2006 in Europe, is in phase 3 in the United States). Such systems are, however, still harmed by negative perceptions and difficult regulatory paths (transgenic animals) or less appropriate glycosylation (transgenic plants).

“Most expression systems that aim to provide added value are at an early stage. Engineered cell lines are being developed to improved the glycosylation profile and hence the biological activity of target proteins. Less-advanced but highly exciting is the possibility to combine the advantages of microorganisms (cost-effective culture and production) and of eukaryotic cells (producing complex proteins) by engineering yeast — humanized yeast cells. This is in particular what companies such as Glycofi (a subsidiary of Merck) are attempting, with promising data already published confirming the engineering of one yeast strain (Pichia pastoris) to produce proteins such as epoeitin with complex sugars, displaying terminally sialylated glycans.

“Most of these systems are proprietary, and companies obviously want to protect their investment and eventual technological lead. I do not believe this is an obstacle; actually, it promotes faster development and evaluation of such new technologies. Companies with proprietary technologies invest more to develop them according to the needs of the market with regulatory guidelines and expectations in mind. If a technology is promising, it allows for licensing deals with larger companies, which provide more means and lead to more players developing the technology. Eventually, companies with break-through technologies are acquired by larger pharmaceutical companies. This is illustrated by deals involving Glycofi and Merck; Glycart and Roche; Biowa, Medimmune, and Lonza; Vivalis and Sanofi-Aventis. Lonza’s GS system is already well established in the industry.”

Dennis M. Kraichely is a principal research scientist in pharmaceutical development at Centocor R&D, Inc. Recently he described the state of the production art to us this way: “Over the past decade, our industry has seen a dramatic improvement in productivity” (1). Titers of >3–5 g/L in fed-batch and >0.5 g/L in continuous perfusion have become the benchmark, with some exceptional reports of nearly 10 g/L (fed-batch) and 1 g/L (perfusion). “Most biopharmaceutical companies have adopted platform strategies to build further efficiencies.… Over the past few years, there has been increased interest and incorporation of disposable bioreactors” (1).

Nicole Borth of the Institute of Applied Microbiology in Vienna, Austria, recently told associate editor Leah Rosin that “the general trend is to have protein-free and defined media, which of course helps in downstream processing. Serum-containing media are sort of openly banned at the moment — and protein-free media are cheaper. The general trend that I see is that people would like to have more predictability in their processes — by which I mean that you would like to have a reliable process running repeatedly, all parameters the same every time you run the process. And you would like to have a defined output that will make it easier for the downstream people. You have more reliability with a defined medium.”

Separation and Purification

All companies are concerned about cost, especially new and/or small organizations with limited cash flows. But more expensive chromatography resins can offer better vendor reliability, improved resin packing permeabilities, or lower nonspecific binding than cheaper alternatives. So saving on some things can sometimes lead to less efficient processes. For example, expensive protein A affinity chromatography is a common choice because of its familiarity among regulatory agencies.

The ABCs of Downstream Processing: BPI associate editor Leah Rosin recently discussed the downstream bottleneck and “ABC” (“anything but chromatography”) with two biotechnology experts, one from industry and the other from academia. David W. Wood is a chemical engineering professor at Princeton University, and Joe Zhou is scientific director of process development at Amgen, Inc. Here’s part of their conversation, in which they discussed several proposed alternatives to chromatographic separations including self-cleaving fusion tags, membrane chromatography, and protein crystallization.

Zhou: “Currently we are looking for membrane chromatography and disposable systems for downstream processes and unit operations.”

Wood: “For me, highly scalable nonchromatographic separations are more interesting — or potentially chromatographic separations that have somehow managed to radically advance in capacity. The rules have all changed in the past two or three years, when the titers went through the roof for monoclonal antibodies. And now that the rules have changed, the technology needs to change as well.”

BPI: “From your perspective, what new technologies hold promise?”

Wood: “I think nonchromatographic separations are probably going to become more a part of it. The first capture steps are going to make the biggest impact because they have the potential to maybe replace protein A, which is very, very expensive and hard to scale up. If you could replace that and then go with ion exchange or HIC to polish, then you could theoretically scale up pretty quickly. You could make some pretty big changes. But I wonder if Joe sees protein A as the main bottleneck — or something downstream from that?”

Zhou: “We think protein A will be around for at least another five years because capacity so far is very good. From 20 to 40 g/L, scalability is not an issue, and there is minimal risk. So highly selective protein A will be still the way to go. I’m not saying that ABC is not an option. ABC strategy could be the option in the future. We also discuss another ABC meaning anything but centrifugation.

“There are a few tradeoffs between safe, inexpensive d
rug production actions with very cheap but high risk. We have to balance out cost. Protein A resins might be used for 200–300 cycles, and that whittles the cost down to one dollar per liter or equivalent. But if titers go up to 7–10 g/L with a strong market demand, people start to worry about the cost of protein A columns to handle that scale — and then new technologies have to be implemented for the future.

“Another thing we talk about is a two-column operation. This will actually do much better than traditional ABC because it can better handle the issues of viral clearance, host-cell protein removal, and reagent clearance.”

BPI: “Do you agree with David that industrial operators in downstream processing aren’t as willing to look at cheaper ”ABC“ options because of the regulatory requirements for viral clearance and validation? Do you think companies are risk averse in that way and would rather stick to what they know?”

Zhou: “At this moment, we need to evaluate more data. We identified that the Q membrane is a good unit operation because of its high product throughput. Many companies are using Q membranes for polishing in flow-though mode because they can efficiently remove different viruses and other impurities in a short time. But for ABC, to me, still there are many questions. Viral and reagent clearance are important. Companies can take a risk to a certain degree. But drug developers have to guarantee the safety of their products.”

Analytical Science and Engineering

The FDA’s process analytical technology initiative describes a system for designing, analyzing, and controlling manufacturing through timely measurement of critical quality and performance attributes for raw and in-process materials and processes toward the goal of ensuring final product quality. Incorporating PATs as tools predictive of a product’s success at early stages of development is intended to lessen biotech companies’ financial risk should their products fail in clinical trials, to perhaps speed successful products to market by reducing the need for lot-release testing, and to prevent the occurrence of adverse events and (therefore) product recalls. Together with a quality systems approach to inspections and an increasing focus on risk analysis and management, PAT presents what some are calling a new paradigm in regulatory oversight of biotechnology products and processes.


Look for the following breakout sessions at the 2008 BIO International Convention in San Diego to learn more about the topics addressed in this chapter. Find more information online at

A New Improved Directive 2001/20/EC Boosting Clinical Research in Europe?

Aiming for the Bull’s-Eye: The Pursuit of Personalized, Targeted Therapeutics

Beyond the Bench: Protein Production Systems at an Industrial Scale

Biologic Product Development and Regulatory Science: FDA’s Critical Path

Chemical Modifications of Biologics to Improve Performance

Combination Therapies: Best of Both Worlds

Drug Safety: How the Public and Private Sectors Collaborate to Drive Change

In-sourcing Innovative Products from Asia and South America

International Networking of R&D for Neglected Diseases

Is Biomanufacturing the Next Product-Enabling Technology?

Large Scale Genotyping Projects in Developing Countries: Future Opportunities

Moore’s Law for Biomanufacturing: Innovation in a Maturing Biologicals Industry

Needle in a Haystack: Picking Winners in the Discovery Stage of Drug Development

New Biotech-Pharma Partnership Models That Retain Greater Value

Not Lost in Translation: Forging Japanese Pharma and Western Biotech Collaborations

Outsourcing Biologics Manufacturing: The CMO Advantage in Asia

Risk-Reduced Models for the Biotech Industry

The Aftermath of PDUFA IV for Industry and Investors

The Future of Indian Biotechnology Industry

The New Kids on the Block: Alternatives to MAbs

Toward Global Pricing for Pharmaceuticals

Vaccines: Breakthrough Technologies, Burgeoning Business

In discussion over the advent of “generic” biotherapeutics, some people argue that quality control specifications are not enough to ensure full safety and therapeutic response. “The process is still the product,” they say, and process control data alone cannot steer even a well-characterized biologic to success as a product. But PATs are challenging that traditional viewpoint — continuing what the advent of well-characterized biologics began a few years ago. Disposable sensors and information technology will play a major role in confirming that bioprocesses could be interchangeable and potentially “generic.” If abbreviated new drug applications come about for biologics, in fact, these are likely to be a critical aspect of them.

Analytical science is forever improving to offer new solutions to scientists working in the biotechnology field. Production process development incorporates a large amount of analytical laboratory work, from cell line engineering and characterization to the formulation of culture media. Typical downstream process characterization and/or validation studies might measure membrane and resin lifetimes; in-process hold times, buffer hold times; protein load limits for columns; pH and conductivity specifications for buffers; extractables and leachables from product-contact surfaces; virus removal/inactivation; impurity removal; and small-molecule clearance.

Product Design: In a recent supplement to BioProcess International, two authors described a major paradigm change in the bioprocess industry (2).

“Currently the biopharmaceutical industry is transitioning to a new business model of production efficiency through implementing operational excellence (Op Ex). Borrowing from such principles as ‘lean manufacturing’ and ‘Six Sigma” (6 < QC > ), and incorporating quality by design (QbD), Op Ex is being applied through the implementation of such advanced enabling concepts and technologies as quality risk management (QRM), PAT, and systems biology (SB).

“Some people see a conflict here: This paradigm shift is occurring amid ever-increasing product development costs, looming biogenerics and biosimiliars, and shortened product life-cycles. On the contrary, however, those very burdens contribute to the industry’s increasing need for innovation and efficiency, whether that be in product and process development (including control strategies), manufacturing, or quality assurance. And that is precisely what the FDA intended to address with its guidances on PAT and the quality systems approach to pharmaceutical CGMP regulations.

“Anticipated difficulties in applying QbD and PAT principles in biopharmaceutical production may have been overstated. Despite the inherent complexity of therapeutic proteins, manufacturers historically placed significant emphasis on product and process characterization, which has led them to better understand their manufacturing processes and the inherent sources and levels of variability therein.


ACR Image Metrix ( Booth #2302

Advanced Analytical Technologies, Inc. (< /a>) Booth #5342

AMETEK Process Instruments ( Booth #5544

AMRI ( Booth #5251

Angel Biotechnology plc ( Booth #2301

Aptuit ( Booth #2537

Aragen Bioscience ( Booth #2321

ARVYS Proteins, Inc. ( Booth #5345

Asahi Glass ( Booth #5246

Asahi Kasei Medical ( Booth #2310

Aseptic Technologies ( Booth #2414

Avecia Biologics, Ltd. ( Booth #2215

Azopharma ( Booth #2422

Bachem ( Booth #2306

Bioprocessing, Inc. ( Booth #2418

BioProcess International (

BioUETIKON Limited ( Booth #5244

Cinvention AG ( Booth #2409

CMC ICOS Biologics, Inc. ( Booth #2333

Commissioning Agents, Inc. ( Booth #2506

Contract Pharma ( Booth #2406

Cook Pharmica LLC ( Booth #2223

Cytovance Biologics ( Booth #2323

Do-Coop Technologies ( Booth #2401

Enzon Pharmaceuticals, Inc. ( Booth #2300

ERA Biotech ( Booth #2317

Formatech, Inc. ( Booth #2436

Goodwin Biotechnology, Inc. ( Booth #2432

Hospira, Inc. ( Booth #2515

IIT Research Institute ( Booth #2304

InVitria ( Booth #2434

IPS ( Booth #2320

KBI Biopharma, Inc. ( Booth #2408

Laureate Pharma ( Booth #2331

Lonza Custom Manufacturing ( Booth #2421

Meissner Filtration Products, Inc. ( Booth #5143

NanoBioNexus Inc. ( Booth #2412


National Institute for Biological Standards and Control ( Booth #2207

NCSRT ( Booth #2519

NYSA Membrane Technologies ( Booth #2324

Pall Life Sciences ( Booth #2307

Parenteral Drug Association ( Booth #2614

PendoTECH ( Booth #2420

PharmaZell ( Booth #2205

PII ( Booth #2335

Plastilite Corp. ( Booth #5145

QSV Biologics ( Booth #2415

Rao Design Engineering ( Booth #2221

Regis Technologies ( Booth #2517

Reliance Life Sciences US ( Booth #2201

Siemens ( Booth #2514

SPEX SamplePrep LLC ( Booth #5427

Stanbio Life Sciences ( Booth #5147

Sterigenics ( Booth #2319

Symphogen ( Booth #2341

Taconic ( Booth #2337

TechniKrom, Inc. ( Booth #2211

The Automation Partnership ( Booth #2311

The Integra Group ( Booth #5343

Toxikon Corporation ( Booth #2407

Vacuum Barrier Corporation ( Booth #2209

WuXi AppTech ( Booth #2530

“Op Ex, QRM, PAT-enabled QbD, and SB can appear a priori as respectively representing disparate business, regulatory, or scientific drivers. But upon closer evaluation, their biopharmaceu
tical applications in fact not only share common objectives, but also promise quite a number of similar gains (Table 1). Implementation of the PAT guidance and the QbD and QRM guidelines may be voluntary, but the adoption of new quality concepts in process development, enhanced process control strategies, or risk management approaches may not be. Therefore, perceived value propositions and actual implementations may differ significantly between individual manufacturers. However, these transitional concepts, especially when combined, promise substantial gains that would behoove manufacturers to set out on their respective journey to capture them.”

Historically, product characterization wasn’t much of an option with biologics. Classical pharmaceuticals are much smaller, simpler molecules and thus easier to describe in terms of their structure and chemical properties. But for biotherapeutics, like traditional vaccines and other biologicals before them, until quite recently “the product is the process” meant that companies documented their processes better than the products they made. Essentially, the only way to ensure the same results from a biomanufacturing process every time was to follow exactly the same procedures with exactly the same ingredients.

Around the turn of this century, regulators began to acknowledge the enormous progress in protein chemistry and analysis that had happened over the years and defined the concept of well-characterized or specified biologics to reflect the specificities that progress had led to in certain products of biotechnology. Biochemists use techniques such as amino-acid analysis, analytical chromatography, electrophoresis, immunoassays, mass spectrometry, microcalorimetry, peptide mapping, spectroscopy, total organic carbon analysis, and ultracentrifugation to describe recombinant proteins in great detail. This allows companies to make changes in their manufacturing processes and then prove that product safety, quality, and efficacy are unaffected.

In addition to optimizing product titers and purification step yields, a good process development program addresses economics, operability, scalability, robustness, comparability, and regulatory risk — as well as, of course, product quality, safety, and efficacy. The objective is to establish a robust cell culture process; an effective, reproducible purification method; and reliable analytical tests for manufacturing controlled lots to be used in clinical trials and ultimately offered for sale. Good process development can shorten time to market, but mistakes made can doom a product or even a company. Problems are best identified early on and solved in a laboratory setting before moving on to more expensive pilot-and commercial-scale operations.

The End of the Line

Early product characterization provides a scientific sketch of a drug in development, and later work fills in the details. As part of that, product formulation should be an issue from the beginning of development. Just as the physicochemical properties of a given molecule make all the difference in how it is purified, they also determine what type of formulation will suit it best.

It all ends with fill and finish: the actual process of dividing a bulk formulation into dosage forms for sale or clinical study use. Containers are filled, sealed, and labeled — and just as with every other aspect of biologics manufacturing, the paths different products take here will vary. Some are frozen in batches at various points along the way to make for more efficient large-scale processing later on; others may be frozen or lyophilized (freeze-dried) in their final containers once formulated. The fill-and-finish step is often at least partly automated, with aseptic conditions being the priority. Even more often, this work will be outsourced.

Outsourcing of many operations is increasing in importance. Industry insiders know that it’s no longer a question of whether to outsource, but what to outsource, when, and where. Regulators expect a sponsor company to understand everything about its process, however, not just toss a drug “over the wall” and expect a contract manufacturer to take care of things. Pressures from biosimilar competition are making Asian CMOs an attractive business solution, but whoever does the work must be able to do it to good manufacturing practice (GMP) standards.


1.) Kraichely, D. 2007. Increased Productivity Through a Combination of Cell Line Development and Bioreactor Process Optimization. BioProcess Int. 5:S30.

2.) Julien, C., B. Whitford. 2007: supplement. Process Design: Harmonizing the Concepts of QbD, PAT, and Systems Biology. BioProcess Int. 6.

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