The Friday workshop of the 2011 BPI Conference in November may have been titled “Industrialization of Single-Use Manufacturing Technologies,” but in the discussion afterward, the mainly end-user audience zeroed in on an on-going debate in single-use implementation: standardization. Comments and questions echoed the current opinions, most of which were well known to the all-supplier panel and others present. To follow up on this discussion, I spoke with members of that panel because — as one expert put it —“there is a huge need to compare apples and oranges to see where everyone is. Everyone is asking for this, primarily end users, but there is a fair amount of equipment companies as well.” That’s from James Vogel, founder of the BioProcess Institute and member of BPSA, ISPE, and ASME BPE, and although not on the workshop panel came highly recommended for inclusion here.
The Stance on Standardization
The standardization debate has gone on for some time with issues familiar to all industry stakeholders. “Th...
Cellular therapy continues to expand and gain momentum, as evidenced by the growing number of companies and clinical trials in the field each year. Early potential therapies were developed solely by investigators without communication or input from manufacturing experts. That communication gap led to numerous setbacks as potential products were developed without roadmaps for feasible manufacturing scale-up (or scale-out). Contributions from members of the cell therapy community over the past few years have significantly improved the situation in the form of peer-reviewed articles and organized meetings (
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,
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,
3
). Now, early stage development teams and clinical investigators are much more aware of impending manufacturing scaling challenges as future products move through clinical stages. Their cross-functional collaboration will undoubtedly lead to higher chances for product success.
Cell therapy can be considered a hybrid of disciplines and processes. Although its origin can be traced to blood transfu...
Clarifying cell culture broth is the first downstream unit operation in an elaborate sequence of steps required to purify a biological therapeutic. A combination of centrifugation, depth filtration, or tangential-flow filtration (TFF) is used for that operation. The availability of largescale, single-use, depth filtration technology in the recent years, however, has given process developers the capability to improve and simplify downstream processes.
Clarification of Cell Culture Streams
The main purpose of clarification is to efficiently separate cells, cell debris, and other colloidal matter and deliver a particle-free feed to downstream processes such as protein A capture chromatography. Various commercial technologies are available for this purpose. Figure 1 presents schematics of centrifugation, flocculation, TFF, and depth filtration combinations that are used in bioprocessing.
Figure 1: ()
When
only depth filtration
(also referred to as
depth microfiltration
or
prefiltration
) is used at this ...
+3Vaccines are among biotechnological products characterized by continuous growth over the past decade. According to a 2011 report, the global vaccine market is expected to reach US$34 billion in sales by 2013 (
1
). Much development can be ascribed to vaccine treatments for cancer, autoimmune, and infectious diseases (which have risen significantly) as well as the growing worldwide population and emergence of new pandemics. Although to date the main health impact of vaccines is still in disease prevention, the first generation of therapeutic vaccines have been FDA-approved (e.g., such as Provenge cell therapy from Dendreon), and further candidates are under development (
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).
Classical vaccine production using embryonated chicken eggs requires very long production times, up to 22 months. Consequently, many vaccine manufacturers (e.g., GlaxoSmithKline, Sanofi Pasteur, Merck, Novartis, and Chiron) have established other options: either virus production with mammalian cells or expression of single virus prote...
+4 Biotechnology companies have invested billions of US dollars in new manufacturing infrastructure, expanding the industry’s total mammalian cell culture production capacity from 670,000 L in 2002 to 2,550,000 L in 2010 (Figure 1) (
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). This capacity expansion is estimated to have cost the industry about $20 billion (Figure 2) (
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).
Figure 1:
Macroporous structure of Natrix chromatography media (see ()
Figure 1: ()
Figure 2: ()
That production capacity (and the investment it represents) is severely underutilized. Current estimates are that some 75% is controlled by just 10 large companies (
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). Plants at the five largest product companies are estimated to be running at ∼45% of their capacity, with the rest of the industry using just 38% of installed and available capacity (
2
). In other words, roughly 60% of available capacity is currently dormant.
In some industries, capacity underutilization is primarily a result of too much infrastructure chasing too little volume. But this is not the case in biotec...
Bioprocessing companies are hoping for a brighter future in biologics manufacturing that will include ever-higher titers of vaccines and therapeutic proteins grown in cell culture. It would also facilitate bioprocess operations without the recurring challenges that stem from process scale-up and human error. Moreover, that future would also comply with increasingly stringent regulatory and current good manufacturing practice (CGMP) requirements while providing better cost controls than we see today. How far away is this future? Perhaps not too far.
Traditional Design No Longer Ideal
For decades, stainless steel, impeller-driven bioreactor systems were the traditional choice for manufacturing biologics. This has been an adequate bioreactor design for delivering acceptable biological performance and meeting regulatory guidance that governs safe and effective use, especially for biologics manufacturing using robust cell lines.
However, manufacture of new biotherapeutics and vaccines exposed a number of signi...
+1 Cell-based products are becoming increasingly important as potential biotherapies. Cell therapy is predicted to have a huge impact on the healthcare sector over the coming decades. Stem cells, in particular, are investigated as potential treatments for a diverse range of applications (such as heart disease and metabolic and inflammatory disorders) in which they might be used to restore lost biological functions.
The cell therapy industry is starting to mature. Several emerging companies are now supporting late-stage clinical trials, and stem cell-based products should soon appear on the market. However, potential commercial success for such products is linked to the ability of sponsor organizations to industrialize manufacturing processes for ensuring cell supply and managing costs. Successful transition from laboratory scale, which is suitable for producing just a few batches per year, to an efficient and robust good manufacturing practice (GMP) process will be essential. If the economic model is to be v...
Committed to sustainability, EMD Millipore is working to provide solutions for the life sciences industry. This commitment is driven by four global issues: climate protection, global health, clean water, and resource efficiency. The company is designing product and process improvements to address these challenges and meet customer expectations.
Figure 1: ()
Life-cycle assessment
(LCA) is one of the most rigorous tools we use to help us understand and quantify our products’ environmental impacts (Figure 1). This holistic, science-based evaluation informs our company’s design, supply chain management, and product stewardship decisions. LCA allows us to identify improvement opportunities and provide environmental impact information to customers who seek such data to help them understand their own environmental footprints. EMD Millipore has performed LCAs on several representative products from key product lines, and it continues to build on that knowledge base with new LCA studies. The benefits of these ana...
“Learn from yesterday, live for today, hope for tomorrow. The important thing is not to stop questioning.”
—Albert Einstein
Single-use systems (SUSs) have been treated as novel technologies for some time. I have spent much of the past 10 years introducing clients to SUSs and integrating them into conventional processes. They are part of the biopharmaceutical development and production landscape and a mature, integrated option for bioprocessing.
The value of SUS integration is soundly substantiated: reduced cross-contamination risk in a multiproduct facility, reduced bioburden risk, overall cost effectiveness due to lower capital and cleaning labor, reduced cleaning, and timely integration. Effective integration into process and business systems is the difference between a successful application of a SUS and one that is not. Most of the industry’s focus has been on physical connections such as tubing, connectors, and other components. Very little focus has been on the business integration of such systems.
Follow-on biologics (FOBs, or biosimilars) differ from generic small-molecule compounds and pioneer biopharmaceuticals in several ways. Those differences affect aspects of their regulatory approval pathway, analytics, and marketing (
1
). Many biological active pharmaceutical ingredients (APIs) are actually incompletely characterized dynamic mixtures of macromolecules with slightly different primary compositions or higher-order structure (microheterogeneity). Those properties of macromolecules (unlike small molecules) are greatly influenced by their individual manufacturing process.
Emerging regulatory guidelines for follow-on biologics are clarifying aspects of their development (
2
). Nevertheless, product sponsors continue to see challenges in such areas as
Despite significant progress, satisfactory product– and market-segment–specific understanding of these issues remain to be achieved (
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,
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). Market dynamics and regulatory uncertainties contribute some unique issues that require consideration in ...
