Early on in the life of BPI we offered a few “closer” pages that we called “Defining Moments.” It was to be a forum for distinguishing between terms that are misused and for proposing new definitions for new approaches. In fact, because one particular topic came up again in a conference I attended this past January regarding the terms
analytical
and
bioanalytical
, we decided to revisit one of these entries from 2005 (with a few updates from the author) on our last page this month.
Agreement on terminology (which I’ve talked about before) is only part of a larger issue — not a new one, but one that is compounded by the prevalence of Internet publications and proliferating forms of social media. I do enjoy using some of these outlets, and they can be powerful publication and advertising tools. But anyone can so easily present him- or herself as an “expert,” and it is all too easy for a shady group to create a legitimate-looking Internet site and frame itself as a reputable source. I have several friends...
The history of the biopharmaceutical industry is one of continual invention and reinvention, of business models that have adapted to weather uncertain product futures and shifting economic fortunes. Some of us followed the up-and-down (and often financially painful) progress of monoclonal antibodies toward their eventual commercial success — a wealth of experience to draw from as other classes of products make their way from laboratories and onto the market.
The vast majority of regenerative medicines are still produced at laboratory scale, with suppliers targeting the current market: research hospitals and laboratories. These therapies could transform our approach to healthcare and have a profound effect on the biotechnology industry as a whole. They have the potential to reap tremendous commercial successes.
What has been lacking is a strategic bridge connecting current lab-scale cell therapies to commercialization. The core challenge faced by this market lies in securing funding — which in turn rests o...
Live cells are being incorporated as active agents and delivery vehicles for a broad range of emerging therapeutic strategies. Successful commercialization of a cell therapy requires more than proving its safety and efficacy to regulators. Ultimately a therapy must be commercially viable, allowing enough patients to be treated with an adequate financial margin to justify investment in it as a product. “Whether the cells used are universal (allogeneic) or patient-specific (autologous), it is unlikely to be wholly one or the other that will dominate” (
1
). Commercial viability of conventional therapeutic products rests on economies of scale. Investment in plants, facilities, and personnel can serve a significant patient population with a defined candidature profile for a given therapy. Factories used to produce high-volume products are based around established, scalable processes with batch-control and risk-management strategies that focus on monitoring product quality. “A drug manufacturer can change the ...
Nearly a year ago, the International Society for Cell Therapies (ISCT) decided to integrate industry into its organization to build a stronger platform for commercializing therapies. Robert Deans, vice president of regenerative medicine at Athersys, was invited to serve as a leader of ISCT’s Industry Task Force, which aimed to identify industry roles in its organization. Within two months, the task force invited industry members and chartered a white paper (
1
) that described how ISCT should go forward. As a result, its Commercialization committee was formed.
Deans currently serves as Commercialization committee chair, with co-chairs Richard Maziarz (Oregon Health and Science University) and Francesco Lanza (Hospital of Cremona, Italy). This committee aims to set specific benchmark objectives for the relationship among industry, academia, regulators, and ISCT members this year. Along with ISCT, it is also committed to forming an “Industry Community,” an advisory panel of industry representatives. These t...
C
apitol Hill fly-in days (see the last page of this issue) … A focus of Google Ventures (
www.google.com/ventures
)
… A favored new investment arena for GE’s CEO Jeffrey Immelt, the recently named head of President Obama’s economic recovery advisory panel, and Life Technologies’ Greg Lucier … Hardly a day skipped without a major news publication covering some exciting aspect of the science … The provocative cover of Wired magazine’s (
www.wired.com/magazine
) November 2010 issue …
It all sounds like the stuff of a major blockbuster industry, but that was regenerative medicine (RM) in 2010. Some people may see this as unfounded hype very divorced from commercial reality; others view it as warranted attention. The general consensus is that a large gap remains between the commercial promise and reality of the cell therapy sector of regenerative medicine. Given the paucity of revenue, rarity of profitability, relative scarcity of venture capitalists interested in early stage companies, and a general feeling...
A recent review of therapeutics in clinical development revealed 68 stem cell-based approaches (
1
). The majority of those leverage a patient’s own hematopoietic stem cells; others are exploring use of mesenchymal, neural, or embryonic stem cells. Here I highlight new therapeutic applications of stem cells and explore advances in the areas of induced pluripotent stem cells (iPS cells) and process-scale production of stem cells. Both should create new opportunities for stem cell-based therapies.
Types of Stem Cells
Hematopoietic stem cell
transplants are routinely given to patients with cancers and other disorders of the blood and immune systems. Autologous transplantation can successfully reconstitute a patient’s own bone marrow and immune system after high-dose chemotherapy (as described in the “50 Years” box). Allogeneic transplantation is used to replace a patient’s defective marrow or immune system.
Current trials are further exploring uses of hematopoetic stem cells for immune modulation, tissue re...
The words of George Santayana — “Those who do not remember the past are condemned to repeat it” — ring especially true for companies regulated under good manufacturing practices (GMPs). Learning from and reacting to lessons from past inspections (both your own and those of other companies) is one of the best ways to prepare for future inspections. Regular review and close study of 483 notices issued during inspections can be an efficient and accessible means of identifying and absorbing those lessons.
483 “101”: An IntroductIon
A 483 is officially an
FDA Notice of Deficiency
. It is written by a member of an inspection team when he or she observes a situation, practice, or activity that in his or her opinion does not comply with current good manufacturing practice (CGMP) or other regulations in Title 21 of the
US Code of Federal Regulations
. The nickname “483” derives from the US government form (Form FDA 483) on which investigators or their team members record such observations. Numerically, For...
On the brink of bringing exciting new therapies to commercialization, cell therapy developers are taking notice of how other companies are addressing processing and technical challenges. Here, leaders from Dendreon, Advanced BioHealing, and Pluristem describe their current cell therapy programs. And two organizations —the Alliance for Regenerative Medicine (ARM) and McLaughlin–Rotman Center for Global Health —provide details on the promises of regenerative medicine.
Cellular Immunotherapy
Dendreon’s Provenge (sipuleucel-T) cell therapy induces an immune response to aid in treating existing prostate cancers. The US Food and Drug Administration (FDA) classifies it as an autologous cellular immunotherapy, although the company also uses the term
active immunotherapy
to distinguish it from a preventative immunotherapy such as a vaccine
.
Dave Urdal, chief scientific officer at Dendreon (
www.Dendreon.com
), explains its processing.
BPI:
How does time to manufacture become a critical factor?
DU:
Key raw m...
Global competition fueled by the power of information technology has forced the pharmaceutical and biotechnology industries to seek new ways to compete. The US Food and Drug Administration (FDA) has promoted quality by design (QbD) as an effective approach to speed up product and process development and create manufacturing processes that produce high-quality products that are safe and effective (
1
,
2
,
3
). Statistical design of experiments (DoE) is a tool that is central to QbD and the development of product and process “design space” (a combination of raw material and process variables that provide assurance that a quality product will be produced) (
4
). Much has been written about using DoE to create process design spaces. Here, I address factors that make it successful.
Experimentation Strategy
The first step in selecting a statistical design is creating a strategy for using DoE. You need a strategy based on a theory about experimentation. Experience over many decades in many different subje...
The past 15 years have seen approval and commercialization of the first cell-based therapeutics, including cartilage repair products; tissue-engineered skin; and the first personalized, cellular immunotherapy for cancer. Those successes are outnumbered, however, by all too common product failures. Notable failures can be attributed to commercial concerns such as high cost of goods (CoGs) and technical hurdles such as inadequate characterization, high process variability, and loss of product efficacy when manufacturing is scaled up (
1
).
Arguably, the root cause of those commercial and clinical failures is a lack of sophistication in developing living cell-based “drugs” with all the verifiable consistency of any other drug class. Many early cell therapy companies lacked drug development expertise and pursued products that were not feasible commercialization candidates. Some companies, unable to continue with iterative development and further characterization, instead relied on insufficient understanding o...
+4Evaluating a virus filter should, in theory, be a straightforward exercise. Membrane-based filtration is a robust virus reduction technology that plays an important role in virus safety for most drug production processes. An appropriate virus filter for a given process is generally selected through preliminary testing with relevant drug feed material. Data acquired during such tests are used to determine hydraulic performance targets such as expected flow rates and total throughputs. A virus clearance evaluation study is then performed in which virus is added (“spiked”) into process fluid. Scaled-down studies sometimes referred to as
virus validation
measure the capability of miniature filtration devices to remove spiked virus.
PRODUCT FOCUS: PROTEINS, ANTIBODIES, PARENTERAL PRODUCTS
PROCESS FOCUS: DOWNSTREAM PROCESSING
WHO SHOULD READ: PROCESS DEVELOPMENT AND MANUFACTURING
KEYWORDS: FILTRATION, CONTAMINATION CONTROL, VIRAL CLEARANCE, VIRUS SPIKING
LEVEL: INTERMEDIATE
Ideally, during a scaled-d...
+6 Personalized medicine is a promising new approach to disease treatment. The ultimate in personalized medicine is a cellular therapy manufactured specifically for an individual patient using his or her own cells. But this autologous approach to generating immunotherapies has unique manufacturing challenges. Each patient receives an individual product batch, which needs to be manufactured, tested, and released. So thousands to tens of thousands of batches could be made for each indication every year. Given the personalized nature of these therapies, the production scale remains the same for each batch. Thus, scale-up is not required; scale-
out
is key for meeting the demands of autologous cell-therapy manufacturing.
Manufacturing Methods
Generating autologous cellular therapies can take several approaches. In general, all involve obtaining autologous cells from a patient by procedures performed at a hospital or blood center. Depending on the therapy, those cells are either transferred to a local laborator...
After production and purification of biopharmaceuticals generated by cell culture expression systems, endogenous cell line proteins — commonly referred to as host-cell proteins (HCPs) — sometimes contaminate finished products. HCPs can elicit an immune response following administration of those drugs to patients (
1
), and cause potentially deleterious side effects. It is therefore imperative to minimize HCP contamination in finished biologics. Regulatory health authorities require monitoring of HCP contamination. They expect validation of each purification process to demonstrate its capability to consistently remove HCPs to an acceptable level from batch to batch, according to the 47th report of the World Health Organization’s Expert Committee on Biological Standardization (
2
).
PRODUCT FOCUS: PROTEIN BIOLOGICS
PROCESS FOCUS: MANUFACTURING
WHO SHOULD READ: PRODUCT AND PROCESS DEVELOPMENT, ANALYTICAL, FORMULATIONS, AND QA/QC PERSONNEL
KEYWORDS: HOST-CELL PROTEIN, Sp 2/0 CELLS, IMMUNOASSAYS, DATA ANALYSIS...
+5 With one eye on commercialization and the other on monitoring every-day challenges, cell therapy manufacturers are asking critical questions about process efficiency, ensuring quality, and satisfying regulatory demands. In this “virtual” roundtable discussion (participants were asked questions separately), cell therapy industry representatives answer key questions in hopes of broadening understanding about this new class of biopharmaceuticals. Participants in this roundtable are Timothy Fong, PhD (director cell therapy, Becton Dickinson Biosciences), Annemarie Moseley, PhD, MD (CEO, Repair Technologies), Firman Ghouze (director of cell therapy, GE Healthcare), Aby Mathew, PhD (senior vice president and chief technology officer, BioLife Solutions), and Robert Deans (vice president of regenerative medicine at Athersys and ISCT committee chairman).
Processing
BPI:
How does the processing of therapeutic cells differ from that for traditional biologics?
Fong:
Cells are rather fragile, so techniques used for...
Concerns for safety in administration of injectable drug products have escalated in recent years. As a result, scrutiny of administration practices has increased. Pharmaceutical manufacturers are placing greater emphasis on providing the best patient and caregiver experience as well as improving the convenience of drug administration. In fact, many drugs that are regularly administered for chronic conditions are now being offered for at-home preparation and administration. These trends highlight the importance of providing therapies that are not only effective, but also easy and convenient to use. Regardless of treatment location, maintaining a consistent drug dosage to patients is a critical aspect of safety and therapeutic efficacy. To ensure that sufficient drug product is available to administer a full dose, many manufacturers include an certain volume of overfill in each vial. This practice can translate into significant additional expense and greater potential for dosing errors. Inadequate overfill ...
The early ISCT organization provided a powerful forum for sharing solutions, developing standards, and moving the emerging concepts in cell therapy forward as the field grew up and out of academia. Currently, the ISCT organization is uniquely positioned to facilitate sharing of best practices, standards, and strategies across the for- profit cell therapy industry through its Commercialization committee. The Business Models, Reimbursement and CoGS (cost of goods sold) subcommittee of the ISCT Commercialization committee was formed to address several key business topics with direct impact on the industry’s ability to develop, register, and ultimately market cell therapies successfully. The subcommittee aims to define the issues as well as examine successful approaches and solutions companies have used, with a goal of sharing best practices and strategies. Activities in the United States, the European Union, Japan, and China will be evaluated, as well as in other Asia-Pacific countries such as Singapore and ...
Process modeling is a core technology in biopharmaceutical production that ensures faster, safer processing and process development. Developing a model involves quite some work, so it is important to use the model efficiently. We describe an industry example of how a mechanistic model is best used under process development and how it increases process understanding and performance.
Present State of Process Development
Biopharmaceutical process development relies heavily on experimentation and previous experience expressed as “rules of thumb” and empirical correlations. This is a limitation when it comes to getting the most out of a process: Insufficient process knowledge makes a process run suboptimally. Problems that should be handled at-line are not, and batches are lost. Both industry and regulating agencies are working toward changing this state of affairs: The Food and Drug Administration’s (FDA’s) quality by design (QbD) initiative (
1
,
2
) and the International Conference on Harmonization’s (ICH’s...
+3 Within the International Society for Cellular Therapy’s (ISCT’s) Industry Commercialization committee, Tracey Lodie, director of immunology and stem cell biology at Genzyme, chairs the Industry Education subcommittee, which was established in May 2010. In an interview with BPI, she described the subcommittee’s objectives and how they tie into the manufacturing, testing, and commercialization challenges for cellular therapies.
Reducing the Risk
“ISCT is working toward becoming an informational hub, acting as a resource to de-risk cell therapy and get products to market. We work together in four subgroups: process/product development, clinical development/new product introduction, business models/reimbursement/COG, and industry education. We seek to aid in developing business models from early discovery to pre-clinical research through to clinical development. The goal of the education committee is to evaluate how the industry is addressing these needs, discovering where we find overlap with other societies...
New treatment modalities — as transformative as they may be of our approaches to human healthcare — still need to be profitable for their developers, provide the sorts of returns desired by investors, and be accessible to patients financially. As many industry experts have told us, the venture capital climate these days is much different from that of the early, giddier days of monoclonal antibodies. And with criteria still-emerging around the world for how regenerative medicines are and will be assessed for reimbursement, the message is clear: The extent to which cell-therapy developers can integrate pricing, reimbursement, and marketing strategies early in development will determine much of their success.
A number of contributors to this month’s supplement spoke with us about these topics as we put it together (see box, right). Additionally, speakers at the recent Cell and Gene-Therapy Forum, organized by Phacilitate Ltd. (24–26 January 2011, in Washington DC;
www.phacilitate.co.uk
) presented detailed ...
Most individuals who choose to pursue a career in healthcare would say they do so because they are driven by a fundamental desire to help people. If you ask people why they decided to work in the field of regenerative medicine, many will tell you it’s because they believe it is the most exciting area of medical research and that it holds the greatest potential to transform medicine as we know it. The transformational potential of stem cells and regenerative medicine is intuitively obvious to most people whether or not they have a scientific or technical background. If we can effectively harness the power and potential of regenerative medicine technology, we can truly transform the way medicine is practiced in many areas.
Conventional medical approaches are highly successful in many areas, but unfortunately they cannot effectively address problems and challenges that many patients face when dealing with the consequences of a stroke, heart disease, progressive medical conditions, autoimmune disease, or trau...
Analytical methods used for characterization, release, and stability testing of biotechnological/biological products are often automatically referred to as “bioanalytical” methods by some in the field. Many times the term is used to distinguish between test methods applied to small-molecule chemical products and those for macromolecular, biologically based products. It seems sensible enough: We use analytical methods to test chemical pharmaceutical products, so aren’t test methods used for
bio
pharmaceutical products therefore
bio
analytical methods?
Any way, who cares whether the term is misapplied in this manner? What difference does it make so long as we understand what we mean? But that’s precisely the problem: Does everyone really understand what is meant by the term
bioanalytical methods?
Apparently not, based on its (mis)use in publications and presentations in our field over the past decade. Although ramifications can be minor, for some people (including me) this mistake is akin to people pron...
