Surveying BPI readers’ experiences SANJA GJENERO (WWW.SXC.HU)
Better, faster, safer: The current drug-development “paradigm” emerging from the FDA is pushing for innovations that reduce process inefficiency and cost. The plethora of new risk-based methodologies include tools being developed as process-analytical-technology (PAT) tools within the encircling parameters of a process design space. All this parallels (and drives) some predictions that the biotechnology industry has seen the last of its blockbuster models, as predictive genomic tools enable personalized approaches to therapeutic development.
Robert Goldberg wrote the following in the
DrugWonks
blog (
www.fiercepharma.com/forward/emailref/9481
):
The key to better drug development is not more bureaucrats or lawsuits, but a stronger scientific foundation for risk assessment, which is at the foundation of everything the FDA does. And genomics should play a central role in building that scientific platform…. How well will the future crop of drug ...
Process development for large-scale bioproduction is generally more labor-intensive, time-consuming, and expensive than for comparable nonbiological processes because of the large number of individual processes and potential variables involved. To ensure the future commercial viability of biological manufacturing processes and prevent bottlenecks, it is essential to accelerate development of both upstream and downstream processing, as well as to improve process analytics. This not only reduces time and cost factors involved in design of robust bioprocessing protocols, but also reduces the time to market for new products, offering better returns on research and development investments before patent expiry. The large number of variables and complex processing requirements of biological products are especially challenging for early phase process design, requiring a variety of strategies to achieve rapid bioprocess optimization.
Miniaturization of bioprocess unit operations to the microliter scale offers a co...
+2Typical serum-free culture media used in bioprocessing can have 60–90 components at differing concentrations to feed a single cell line. Media used to grow different cell lines for bioprocessing applications may each require unique optimal chemical formulations. Adding complexity, optimal process conditions such as pH and stirring rate may also differ from cell line to cell line depending on the unique characteristics of process performance.
To tackle all those variables, we at Invitrogen Corporation of Carlsbad, CA (
www.invitrogen.com/pddirect
) use design-of-experiments (DoE) statistical methods, which reveal the complicated array of multifactor interactions involved in bioprocess development. Some experiments conducted include the use of high-throughput tools such as a robotically controlled microbioreactor system capable of conducting hundreds of simultaneous bioreactor experiments (Figure 1.
Figure 1: ()
We know that a sound DoE strategy combined with the right tools can be used to identify truly op...
Streamlining process development has been the focus of the biotechnology industry over the past several years. To be financially viable in the current market, a company has to be competitive in all three of the following areas: quality, speed, and price (
1
). Attaining any two of the three attributes at a time is no longer sufficient. With new tools and technologies along with improved understanding of the cell-culture process, doing high-quality process development while reducing both cycle time and cost is becoming a reality.
Effective process development must include accurate scale-down model(s) of the large-scale manufacturing processes. For most downstream unit operations, the important scale-up and scale-down considerations are understood; normalization of flow rates and column geometries at different scales are straightforward concepts to implement for purification operations. For bioreactor process development, however, the important factors such as mass transfer and mixing are more difficult to ...
As an updated US FDA guidance document emphasizes, the life sciences industry needs to use data to better understand manufacturing processes and sources of variation to minimize product risk and achieve better process control in future batches (
1
). Lessons learned through such efforts also can be applied to future process design, extending the value of data analysis. Bioprocess manufacturers typically rely on lot traceability to determine the composition of their final manufactured products. Lot traceability is only one aspect of the required capability. It requires knowing all the upstream components that made up a final batch — and, therefore, which product lots need to be recalled when there is a defect in an upstream material or process condition. But lot traceability alone cannot meet all needs, especially when process streams undergo multiple splits and recombinations during the course of production.
A better solution is to use an appropriately designed enterprise manufacturing intelligence (EMI) ...
Most people in the industry are struggling with quality by design and how it relates to the acceleration of process development. Many are confused by the new FDA approach to bioprocess development, unsure of the specific implications of QbD on the CMC section of their marketing applications, and unclear how the risk-based approach applies to their particular operations. Some have trouble understanding the precise link between CQA and CPPs under a life-cycle approach and are stuck considering the exact definitions of such terms as
critical
and
variable.
But help is coming from many fronts. FDA reviewers are being specifically trained to expect and assist in the incorporation of QbD principles in regulatory filings. Results from the QbD pilot program are emerging as a valuable resource for guidance. Industry leaders are publishing and providing case studies about their experiences, as seen in this special issue.
Independent associations such as the ISPE, IEEE, and IFPAC are providing tools for comprehen...
The New World
In 2002, responding to public outrage over a series of corporate accounting scandals, the US Congress enacted a law now generally referred to as “Sarbanes–Oxley” or SOX (
2
). Under this law, the US Securities and Exchange Commission (SEC) issued regulations defining new requirements. Promulgated for misdeeds arising in the financial sector and driven by the SEC, most analysts now view this legislation as financially unifunctional. The growing complexity of business organizations, however, and the interdependency of their operating systems warrants a more expansive view than SOX offers. The integrity of financial statements — or more appropriately, the “quality” systems supporting financials — may be the real issue at hand.
Simply stated, SOX requires the chief executive (CEO) and chief financial (CFO) officers of a company to sign off on its quarterly financial statements. Executives who knowingly sign off on financials that contain any false statement(s) are subject to fines or imprisonmen...
It has been 50 years since the first Sephadex paper was published (
1
). Readers of
BioProcess International
work in a field that was fundamentally affected by what happened after that paper appeared in 1959. So this anniversary is certainly worthy of a party and a few speeches. But there are lessons to be learned, too. Here we take a look at threads connecting events before and after the discovery of gel filtration chromatography and introduction of the Sephadex product.
Interdisciplinary Research
When someone with expertise in one field joins a team from another field, great leaps of mind can occur, and sometimes longstanding problems are suddenly solved with ease. Science has seen numerous examples of this phenomenon, particularly the field of bioseparations.
One such example involves Theodor Svedberg, a physical chemist, who helped define what we today call
biochemistry.
In 1908, as a young and gifted student of physical chemistry, Svedberg was studying metal colloids at Uppsala University in Swed...
Production of biologics is an expensive process, and to optimize capacity use, bulk protein solution is often produced in manufacturing campaigns. It is converted into drug product based on market demand and therefore may have to be stored for relatively long periods. To decouple the bulk solution production from that of the final drug product, bulk is often stored frozen.
Transport of frozen bulk product between sites offers several practical advantages over its transport in the liquid state (2–8 °C). Maintaining 2–8 °C requires accurate control systems to ensure that a product does not get too cold and (partially) freeze. A liquid shipment also subjects protein to greater degrees of agitation stress at air–liquid interfaces. So a successful bulk storage program will enhance bioprocess capacity use and reduce overall cost of production. However, success requires careful consideration of biophysical and engineering principles in development of a frozen-storage operation and its impact on the product to be...
+2 Depth filtration is widely used in the biopharmaceutical industry to purify target proteins by removing whole cells, cellular debris, fines, aggregates, and colloidal particles from the fermentation broth (
1
,
2
). At large scale (>2,000 L), culture harvest from a bioreactor is typically processed with a disc-stack centrifuge to remove cells and cell debris. Although centrifugation is very effective for removing whole cells and larger debris, it cannot remove small-size particles, which remain suspended in the centrate. Depth filters are commonly used after centrifuges to remove smaller impurities before further processing downstream.
Accurate scale-up of bioseparation unit operations adds value by expediting a development process and allowing for the use of lower safety margins in sizing filtration area, which improves process economics.
PRODUCT FOCUS:
BIOLOGICS
PROCESS FOCUS:
Recovery and separations (downstream processing)
WHO SHOULD READ:
MANUFACTURING AND PROCESS ENGINEERS
KEYWORDS:
HARVESTING, ...
+4 People who regularly culture animal cells become so comfortable with standard techniques that novel approaches can seem contrived or even unnatural. However, the typical cycle of seeding cells at very low density in an excess of medium and harvesting (often quite aggressively) just before the point of medium exhaustion is quite an unphysiologic process. Popular culture systems often take cells that originally grew attached to a porous matrix at high densities, with little variability in nutrient and oxygen supply, and adapt them to low-density, styrene-bound or amorphous suspension cultures. Although these methods are well understood and convenient, classical batch-style two-dimensional culture in T-flasks or three-dimensional suspension culture in shake-flasks and bioreactors really aren’t physiologically relevant models.
A remarkable number of alternative culture approaches operating with such unusual mechanisms as rocking bags and depth filters have been introduced over recent years. These are often ca...
Given the prevalence of lyophilization and the growing pipeline of sensitive biological drugs requiring stabilization, pharmaceutical development and manufacturing personnel need complete, reproducible control over the operation, scale-up, and transfer of their lyophilization processes. To address the nucleation problem, Praxair has developed a step-change technology that adds consistent control to the freezing step of lyophilization. This low-capital, plug-and-play option can be readily implemented on most existing freeze-dryers with minor equipment additions and controls integration. Adoption of the technology requires no changes to existing drug formulations and has minimal impact on established lyophilization protocols. This truly enables the broad application of quality by design (QbD) to lyophilization and provides pharmaceutical manufacturers with a novel means of addressing capacity, yield, and quality issues for this critical fill-and-finish operation.
Figure 1:
PRODUCT FOCUS:
ALL FREEZE-DRIED P...
+1 Contamination Control
Product:
Endosafe-PTS glucan assay
Applications:
Biopharmaceutical process validation
Features:
The Endosafe-PTS glucan assay is a rapid test designed to help companies validate that products are free of (1,3)-β-D glucans. Glucans contaminate cell culture fluids, yeast protein production, air quality samples, and cellulose filter preparations. Glucans can cause false positive results in LAL assays. The Endosafe-PTS glucan cartridges have a sensitivity range of 10–1,000 pg/mL, yield results in <30 minutes. They can be run on the same Charles River PTS reader used for endotoxin detection and Gram identification.
Contact
Charles River
www.criver.com
Single-Use Bioreactor
Product:
CelliGen BLU bench-top bioreactor
Application:
Mammalian/animal cell culture, research through production
Features:
New Brunswick Scientific’s CelliGen BLU benchtop bioreactor combines all the advantages of single-use technology with the trusted performance, advanced process management, and true scala...
The Biopharmaceutical Emerging Best Practices Association (BEBPA) hit the scene in September 2008 with its inaugural Bioassay Conference in Berlin, Germany. A not-for-profit association, BEBPA (
www.bebpa.org
) is managed by the biopharmaceutical scientific community for the benefit of the biopharmaceutical scientific community: companies, regulators, and clinicians. BEBPA provides an open international forum for the presentation and discussion of scientific issues and problems encountered in the biopharmaceutical community. The purpose of this open discussion is to promote development of innovative approaches and solutions, thus facilitating safer and faster biopharmaceutical product development. In support of this mission, BEBPA is committed to
FINDING A FORUM
BEBPA was created after a number of scientists from various companies, institutes, and regulatory agencies realized that, despite the various existing venues for meetings and publications, there was no forum for new approaches and ideas about comm...
