A growing trend in US Food and Drug Administration (FDA) warning letters has been citations for “no justified rationale.” Since 2004, warning letters taking companies to task for poorly documented decision-making and risk-assessment practices has more than doubled — from two in 2004 to four in 2008 and five in 2009. These citations are always in relationship to risk-based decisions: sampling (what, how often, and how much), nonconformances and corrective/preventative actions (when is “root cause” actual root cause, when and why should an open nonconformance investigation be closed out), and clinical data decisions (what data to include or exclude, what patients to include or exclude).
As the FDA continues to cajole companies to adopt risk-based quality systems, such citations are becoming more common. One area increasingly coming under fire for poor decision-making is supplier oversight. Of the eleven warning letters noted above, 30% are directly related to supplier selection, qualification, and control. ...
Single-use technologies are coming of age and joining other driving forces to reshape the landscape of biopharmaceutical industry. This innovation has created new platforms for bioprocessing, offering competitive advantages and tremendous opportunities to current biomanufacturers. Moreover, the increasing acceptance of disposable systems with proven success will help enable niche products and bring emergent players to the market.
The Age of Stainless Steel
The discovery of DNA structure in the middle of the 20th century led to numerous breakthroughs in biological science and inspired a generation of entrepreneurs. The 1980s and 1990s saw a booming biotech industry with all eyes on bringing biologic products to market. As with small-molecule drugs, biologic development faces challenges in long development cycles, low success rates, and high costs. According to Tufts, it was estimated to take about $1.2 billion to commercialize a single biologic drug in 2008 (
1
).
Several additional barriers of entry are u...
Effective terminology management is an essential risk-management strategy for biopharmaceutical organizations. With a terminology management strategy in place, organizations of all sizes can use the same terms consistently within and across the various documents and labeling that accompany a product or service. Because such documents are typically created in a collaborative environment, terminology management is the most efficient solution for ensuring that the organization as a whole uses the same terms to describe the same features and functions.
With comprehensive, project-specific “termbases” available at the beginning of a project, team members are free from the tedious task of researching terms on their own. The availability of a project termbase also reduces the risk of multiple coworkers inadvertently coining multiple terms for the same feature, which, if undetected, can confuse users or cause unnecessary expense and delays for terminology harmonization later on.
More Efficient External Communicat...
With strong growth in biologics, large molecules, and biopharmaceutical therapeutics in recent years, the pharmaceutical and biotech industries are increasingly turning toward peptides and proteins in their search for drug discovery targets. While both offer significant therapeutic potential, there are fundamental differences between the two types of molecule.
Definitions:
Peptides are short polymers formed from the linking of (usually ≤100) amino acids. They comprise some of the most basic components of human biological processes, including enzymes and hormones. The link between one amino acid residue and the next is known as a peptide bond or an amide bond — formed when a carboxyl group reacts with an amine group of an adjacent residue — giving this class of chemicals its name.
Proteins, by contrast, are longer chains of (>100) amino acids similarly linked by peptide bonds. They play a critical role in biochemical reactions within cells. Proteins are ubiquitous in cellular chemistry and structure and a...
Albumin is the most abundant serum protein. It serves several functions in vivo: e.g., binding and transport of fatty acids, hormones, and metal ions; maintenance of osmotic pressure and pH; and binding of exogenous toxins and products of lipid oxidation (
1
). Over time, development of large–scale purification methods have translated those functions into diagnostic, cell culture, and microbiological applications. It is important to note, however, that purification procedures can promote molecular changes and thereby add to the already complex nature of albumin. That increase in heterogeneity can cause unpredictable performance in vitro. Consequently, it is important for suppliers to understand how the process modifies the end product — and for buyers to consider the potential effects that process-induced modifications can have on the performance of their process. Relying strictly on published product specifications is often insufficient when making a decision to purchase.
PRODUCT FOCUS: ALL BIOLOGICS
PRO...
Maintaining the supply chain of single-source raw materials is of utmost importance for a biopharmaceutical company’s manufacturing operations. As often happens, a supplier will notify its customer of process changes that might affect the quality or properties of supplied materials. Occasionally, a supplier might notify the customer of substitutions in its own supply chain or other changes in the source of its own raw materials. Customers must conduct appropriate testing using the “new” raw material(s) to ensure acceptable comparability, even if the change is only in sourcing and not the process itself.
Here we illustrate one such example in which a supply chain notification (SCN) described a source change in one of our supplier’s cellulose-based ion-exchange chromatography media raw materials (cotton linter). Upon receipt of the SCN, chromatography tests were executed in the laboratory using a representative small-scale model of the affected manufacturing process using new and prechange media to test the...
+2The materials used to fabricate single-use processing equipment for biopharmaceutical manufacturing are usually polymers, such as plastic or elastomers (rubber), rather than the traditional metal or glass. Polymers offer more versatility because they are light-weight, flexible, and much more durable than their traditional counterparts. Plastic and rubber are also disposable, so issues associated with cleaning and its validation can be avoided. Additives can also be incorporated into polymers to give them clarity rivaling that of glass or to add color that can be used to label or code various types of processing components.
Given all the positive attributes that polymers possess, there are also some negatives to consider when working with them in pharmaceutical applications. In the presence of heat, light, oxygen, and various external influences (such as sterilization), polymers can degrade over time if not properly stabilized. Degradation can manifest itself as cracking, discoloration, or surface blooming...
A common objective in pharmaceutical processing is the removal of solids from fluid suspensions through filtration. The usual purpose is the removal of the solid particles to a specified extent, within a given time interval, at the largest possible throughput. Attainment of those goals is managed by proper selection of filtration conditions: principally an adequate effective filtration area (EFA) as defined by filter porosity and a proper rate of flow as regulated by applied differential pressure (Δ
P
) over the period of filtration. Were the fluid “clean,” by definition free of particles whether of microbial or of other origin, the task would be amenable to mathematical analysis. Flow rate would be directly related to Δ
P
over time and also to the EFA’s porosity in terms of pore numbers, dimensions, and so on. Time required could be calculated from the batch size processed over the duration.
PRODUCT FOCUS: BIOLOGICS
PROCESS FOCUS: DOWNSTREAM PROCESSING
WHO SHOULD READ: MANUFACTURING, ANALYTICAL, AND PRO...
+1 Recent technological advances in cell line and bioprocess development have driven significant improvements in product titers and enabled scientists to accelerate product development timelines (
1
). Despite those successes, many limitations in developing cell lines for biotherapeutics remain. One example in fed-batch cultures is an apparent paradox: when cell growth is inhibited by high osmolarity after multiple additions of concentrated nutrients intended to enhance cell growth and protein production. Generation of novel host cells to overcome specific bottlenecks found in bioprocessing is highly desirable.
Imposing hyperosmotic stress conditions on commercially popular production lines such as Chinese hamster ovary (CHO) and NS0 has previously been shown to improve specific productivity (
2
,
3
). That appears to correlate with cellular changes in transcription, translation, protein secretion, and metabolism (
4
,
5
). Shen and Sharfstein analyzed transcriptional response to osmotic shock using DNA micr...
+6 Small-Scale Fluid Control
Product:
Flipper 6650 solenoid valve
Applications:
Analytical fluid dosing
Features:
With a pitch of only 4.5 mm, the Flipper 6650 solenoid valve comes in 2/2- and 3/2-way versions that offer performance comparable to 10-mm and 16-mm valves. The media-separated valve is compact and fast-switching, optimized especially for reproducible and precise dosing of aggressive fluids. Because of its compact size, the valve requires smaller internal volume in the connecting plates, thus increasing efficiency of media use, which can significantly reduce costs.
Contact Bürkert Fluid Control Systems
www.burkert.com
Single-Use Tubing
Literature:
One-Touch Fluid Path Assemblies brochure
Features:
One-Touch single-use fluid path assemblies are highlighted in detail in a brochure from Meissner. It illustrates common process configurations that use the company’s library of prequalified components. Additionally, fluid path assemblies are shown with attached capsule filters for filtration of vol...
I BC’s sixth annual Cell Line Development and Engineering conference will deliver 37 presentations in a three-day, single-track format for the most valuable and intensive learning experience you can attend. This program has earned its reputation by attracting thought leaders in industry and academia to collectively examine and provide solutions to the industry’s most daunting challenges. For 2010, we developed an agenda that will help you achieve your ultimate goal of improving quality and understanding of your cell lines while reducing time and cost of development.
By joining us, you will hear exclusive case studies and data-driven presentations from Abbott, Amgen, Bayer, Biogen Idec, Centocor, Genzyme, Genentech, GSK, Lonza, MedImmune, Millennium, Pfizer, Regeneron, and more to help your company do the following:
New this Year
IBC’s sixth annual Cell Line Development and Engineering event will focus on the next steps that await upstream scientists, engineers, and technical specialists. Several presenter...
The nonprofit Center of Research Technology and Entrepreneurial Exchange (CORTEX) was formed to facilitate development of two redevelopment areas in St. Louis, MO. Last month, I explained their vision and introduced the participants, along with highlighting an example development on the campus of St. Louis University. This month, I conclude with several more examples.
Center For Emerging Technologies
The Center for Emerging Technologies in St. Louis is ranked a top-10 business incubation facilities in the United States. In under nine years, CET companies have obtained >$800 million in funding from investors, grants, and revenues. The center is a national leader in initiatives to promote best practices for funding translational R&D, technology transfer, biomedical incubators, and research collaborations among industry and academia.
Two renovated buildings form its core center, and CET is now planning its first new building, which will provide 60,000 ft
2
of primarily wet lab space for lease in a facility ...
