The cell therapy industry continues to make progress, as measured by increasing numbers of clinical trials and patients treated (
1
). Although discussions of the differences between “off-the-shelf” (allogeneic) and “patient-specific” (autologous and matched allogeneic) therapies continue, we are confident that both will find success.
The best way to approach development for a cell therapy product is to consider these three fundamental drivers that guide development:
The clinical trial process is intended to provide a means by which candidate therapies can be proven to be safe and efficacious. Once a technology (e.g., chimeric antigen receptor-transduction, CAR-T) or cell type (e.g., mesenchymal stem cells, MSCs) has been targeted for development, a company wants to generate data as quickly as possible to support its safety and efficacy profiles. Figure 1 illustrates a typical development and commercialization pathway for a product candidate.
For cell therapies, product attributes heavily rely on manufact...
According to the late Norman Cousins, “Wisdom consists of the anticipation of consequences.” When it comes to regulatory inspections, those consequences can be severe. However, the consequences of a problem anticipated can be prevented — given effective action to remediate the issue. In two previous articles (
1
,
2
), I discussed the whys and hows of using the US Food and Drug Administration's (FDA's) notices of deficiency, FDA warning letters, and other information about inspection results to create an effective system to spot and rectify your own compliance issues before they become adverse inspectional outcomes. Here, I provide an analysis of more than 40 FDA warning letters to identify inspectional trends for cellular and tissue-based products.
The FDA's attempt to regulate human cells, tissues, and cellular and tissue-based products (HCT/Ps) emerged from its historic fragmentation in 1997 with the proposal of a new approach and an accompanying public meeting, first announced in the
Federal Registe...
Calorimetry (from the Latin
calor
for heat and the Greek
metry
for measuring) measures thermodynamics in chemistry. If energy enters or leaves a system, its temperature changes, and most chemical reactions involve changes in energy. Exothermic processes generate heat; endothermic processes consume it. So calorimeters measure the heat of chemical reactions or physical changes to a system.
Since calorimetry's advent in the late 18th century, a number of different techniques have been developed. Early techniques were based on simple measurement of temperature. Later advances in electronics and control enabled analysts to collect data and maintain samples under controlled conditions that were previously not possible. Primarily, the applicable uses of this laboratory technique to the biopharmaceutical industry include early product development, quality control, and metabolic analysis in bioproduction systems (
1
). An emerging calorimetry application involves self-organization and interactions of lipids wi...
Antibody-purity analysis is critical to successful development of monoclonal antibody (MAb) biopharmaceuticals. Their manufacture involves processes of protein purification, formulation, and stability evaluation. All those processes need highly accurate and reproducible analytical results to support decisions made by product developers and manufacturers.
A common technology for antibody-purity analysis is sodium-dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). In this technique, a polypeptide chain binds SDS proportionally to its relative molecular mass. The detergent nature of SDS denatures proteins by disrupting their noncovalent bonds, thereby simplifying the molecular structure. Negatively charged SDS also acts to coat proteins consistently, allowing for electrically driven separation toward an anode (a positively charged electrode). With an SDS–protein constant-weight binding ratio of 1:1.4, intrinsic polypeptide charge becomes negligible. So the final separation of such proteins depend...
Purification process development of monoclonal antibodies (MAbs) has traditionally relied on a strategic trial-and-error approach using small-scale preparative chromatography for determining the operational parameters that would be optimal for clinical manufacturing. Doing so is demanding of both time and resources, and it thus restricts the number of early phase therapeutic drug molecules that can be evaluated in a company's development pipeline toward clinical trials. With high-throughput (HT) technologies incorporated at key points in development and laboratory operations, an operating space for in-process conditions can be quickly defined and allow for significant improvement in product and process knowledge before scaled-up experiments. HT work allows for rapid process development of a therapeutic MAb while minimizing material requirements for early stage development and thus overall costs. As these technologies continue to emerge, the HT approach will become increasingly powerful and be applied to d...
+7The only method of stable and long-term — practically infinite — preservation and storage of perishable biological materials (
biostabilization
) is to keep them in a glassy (vitreous) state. This was understood by Father Luyet when he titled his pioneering works in the 1930s, “The Vitrification of Organic Colloids and of Protoplasm” and “Revival of Frog's Spermatozoa Vitrified in Liquid Air” (
1
,
2
). He and other pioneers of the cryobiological frontiers clearly understood that only a glassy state would ensure stable and nonlethal preservation of cells.
Over time, a number of biopreservation methods were developed (
3
). Slow freezing (SF), for one, is a way of achieving a glassy state inside and within close vicinity of cells. (Cells cannot live in ice without a glassy border between them and the ice, nor can they live with ice inside them.) Another method is equilibrium vitrification (E-VF) with large amounts of exogenous thickeners (vitrification agents or VFAs).
PRODUCT FOCUS:
CELL THERAPIES, BIOLO...
At the core of every drug development program is the challenge to successfully express active and high-quality proteins. Drug developers often are faced with protein-expression issues, struggling to express a specific protein for months (and sometimes years) with varying degrees of success. Low or no expression, insoluble expression, and proteolytic clipping of an expressed protein or a combination thereof are examples of the hurdles encountered in product development efforts.
With protein expression being vital to the success of every stage of biopharmaceutical development, there is an inherent need to screen as many variables as rapidly as feasible to find optimal production strain and fermentation conditions. Focused on the rapid development of biologics, Pfenex Inc. has spent years specializing in high-throughput and parallel screening for strain engineering and process development. Using
Pf
ēnex expression technology, a
Pseudomonas fluorescens
– based platform, Pfenex can rapidly screen thousands o...
The biopharmaceutical industry is experiencing a surge of collaborations among large and small companies seeking to develop new drug candidates. Often, such efforts have been a result of a merger or acquisition. But other factors also are pushing the rise in collaborations, including dwindling drug pipelines, increasing generics and biosimilars, rising costs of drug development, and changing regulations that are already complex.
High costs of drug development in particular have created greater risks. That is especially true for small biotechnology companies that have limited budgets to bring new drugs through to completion. Such companies need to focus on core competencies. Conversely, large pharmaceutical companies that depend on promising drug candidates might have resources but lack worthy drug candidates. So they are looking for new ways to replenish their portfolios. Most often, such “replenishing” translates into searching for promising opportunities among small biotechnology candidates.
Small facil...
