Biotech was “born” in the 1970s. Since that time innovation by biotech pioneers has brought more than 200 medicines and vaccines to fruition for difficult-to-treat indications including oncology, HIV/AIDs, diabetes, and immune disorders. Another 400 biotech products targeting 200 diseases are currently in clinical trials, and 700 compounds are in preclinical development (
1
). Overall, the industry had a banner year in 2007, with an 8% increase in biotech revenues and a total of more than $29.9 billion (US) in investment capital raised in Europe and the Americas. Record levels of financing and deal making suggest strong confidence in this sector, with mergers, acquisitions, and alliances in the amounts of US$60 billion in the United States and $34 billion in Europe (
2
).
Biotech is poised to capitalize on the current challenges confronting Big Pharma: looming patent expirations on blockbuster medicines and a dearth of new compounds in the pipeline to replace them. Current pharmaceutical business models a...
+2Single-use (disposable) systems are being considered and introduced into many biopharmaceutical processes because manufacturers have identified significant benefits they offer over traditional reusable systems. These benefits are often more evident when a new process and product are being developed. Lower capital expenditures, shorter development times for new facilities, and reduced validation costs are some of the reasons single-use technology may be selected. Here, a contract manufacturer’s case study is described in which an existing stainless steel system was completely replaced with a ∼90% disposable manufacturing train. The specific benefits gained by this change were improved product quality, substantially reduced processing times, and lower operating costs.
Changing an existing reusable system to a disposable system may not always seem attractive. In a recent survey of manufacturers, 65% of respondents stated that investment in existing equipment restricted their implementation of disposables, as...
Pharmaceutical products are critical to the social, economic, and political stability of societies around the world. No other business sector is more dependent on consumer confidence. Like food products, drugs are highly vulnerable to deliberate and/or accidental disruption. A small tablet has almost no intrinsic value on its own; its value derives from the pedigree of its manufacturer and the belief that the pill will change someone’s life for the better. Manufacturers hold a sacred trust (given them by their customers) to provide safe and effective therapeutic products. Counterfeit drugs breach the promise that is carefully established by the legitimate healthcare industry.
Threats the pharmaceutical industry faces in our “post–9-11” era are categorically different from those of a decade ago — but they are quite similar to those of two decades ago. In 1982, seven innocent people died in Chicago as victims of a criminal (never identified) who replaced the Tylenol pain reliever in over-the-counter capsule...
Many biopharmaceutical companies are evaluating the option of working with contract manufacturing organizations (CMOs) in China. There are probably as many reasons for following that strategy as there are companies doing the evaluating. However, regardless of the strategic plan behind pursuit of a CMO in China, there are key issues each company must consider as part of its due diligence before selecting one.
Through a fast growing economy and government supported transition from low-margin to high-margin products, China is quickly expanding its pharmaceutical opportunities. There are 700 Chinese drug makers and 3,000 Chinese medical device companies registered with the FDA to market their products in the United State or sell them for further manufacturing. Drug imports from China to the United States have more than quadrupled in the past five years, and they exceeded $400 million in 2007 according to the International Trade Administration (part of the US Department of Commerce) (
1
).
Although most Chines...
The classic F-test for nonparallelism is widely used for bioassays with linear log dose-response lines to assess parallelism, or, more correctly, to examine the strength of evidence against a null hypothesis that the two lines are parallel. Alternative methods for assessing parallelism have been proposed, but their suitability for any particular case needs to be carefully considered. Here we examine some advantages and disadvantages of the different approaches.
PRODUCT FOCUS:
ALL BIOLOGICALS
PROCESS FOCUS:
QA/QC
WHO SHOULD READ:
QA/QC, ASSAY DEVELOPMENT, AND ANALYTICAL PERSONNEL
KEYWORDS:
PARALLELISM, BIOASSAYS, STATISTICAL ANALYSIS, PRODUCT TESTING
LEVEL:
INTERMEDIATE
Why Bioassays Are Necessary:
For most biological therapeutic products and vaccines, a bioassay for potency measurement is a required part of the specifications for batch release.
Potency
is defined in ICH Q6B as “the measure of the biological activity using a suitably quantitative biological assay (also called potency assay or bioas...
+1 Organizations outsource tasks to contract service providers for diverse reasons ranging from internal resource constraints (particularly in virtual or start-up companies) to overflow capacity, or to avoid or delay capital or resource investment. The scope of outsourced work varies from limited tasks such as an outsourced assay to complete process development and GMP manufacturing. In a highly competitive outsourcing market, customers expect successful and timely execution of the outsourced work, but they also seek “added value” to the overall program.
Added value
can be defined as elements in addition to a contracted service that enhance the economic, scientific, environmental impact, or regulatory status of a project.
Key Concepts
Two key concepts in outsourcing biopharmaceutical development and manufacturing projects are project lifecycle and product lifecycle support. The former describes the evolution of a manufacturing process to deliver material for intended preclinical or clinical studies; the la...
Take six people and sample the microbial ecosystem on their forearms, and you will find more than 240 distinct microbes (
1
,
2
). So it becomes readily apparent why keeping a cleanroom “clean” is a difficult task. One problem is that we humans are limited in our visual capacities and can see objects down to only 50 µm (
3
). If we could see contaminating particles, we would likely be very quick to clean them away. In fact, cleaning and cleaning validation are such big issues that they have been cited as the number-one cause of FDA 483s in 2005 (
4
,
5
). But in talking to experts in this area, I found that the key to keeping an environment clean is not in diligent cleaning; rather, it is reducing the sources of contamination.
“One of the biggest problems you have in cleanrooms is people who use gels or facial makeup; women are often the hardest to ‘police’ as they often object to giving up their makeup,” explained Steve Silverman, president of Bartlett Bay Consulting. He clarified that this was not mea...
Deciding to outsource biopharmaceutical manufacturing is a strategic decision with long-term consequences. Most companies deliberate carefully as they select a contract manufacturing organization (CMO). Because the factors involved in such deliberations vary widely among organizations — and they shift over time — my company has included an analysis of critical outsourcing issues as part of its fifth annual report and survey of biopharmaceutical manufacturing capacity and production (
1
). In this year’s study of 434 global biomanufacturing facilities, we found the most important issue (as indicated by 43.6% of respondents) to be control of capacity, offering a secure supply of products (Figure 1). Following that were establishing a good working relationship and demonstrating a track record with similar products, as indicated by 41.4%, for each.
Figure 1:
Offering a Secure Supply
Clearly, control of capacity is an important issue, and it has continued to grow over the past three years from 32% to 44%. The ...
Almost every pharmaceutical and biopharmaceutical company in the world depends on the use of recombinant stable cell lines to enable drug discovery, development, and often manufacturing of biologics. It normally falls on multidisciplinary upstream development teams to attain this goal, requiring a wide variety of technologies and skill sets such as laboratory robotics, optical analyzers, molecular biology, and data processing. The large capital investment required to procure the equipment and expertise necessary to develop biologics can be cost prohibitive, which has spurred growth of a service sector to provide timely, cost-effective protein expression solutions. The outsourcing industry has grown consistently, paralleling the development of therapeutic biologics and leading to a wide array of protein expression technologies.
The impact protein expression level has on production costs cannot be overemphasized. High expression levels translate directly to lower cost of goods because of lowered capitalizat...
+1 Preformulation research, a critical component in the development of biotherapeutics, explores the effects of variables such as pH, ionic strength, and excipients on the solution behavior of a protein. This activity can greatly assist in guiding downstream formulation development, and it provides valuable information concerning protein stability, solubility, and structure. Successful preformulation research leads to identification of potential protein degradation pathways and development of robust formulations with acceptable product shelf-lives.
PRODUCT FOCUS:
PROTEINS
PROCESS FOCUS:
DOWNSTREAM PROCESSING, FORMULATION
WHO SHOULD READ:
FORMULATIONS, MANUFACTURING, PROCESS ENGINEERING, AND ANALYTICAL PERSONNEL
KEYWORDS:
AGGREGATION, PROTEIN UNFOLDING, DATA ANALYSIS, STABILITY
LEVEL:
INTERMEDIATE
The potential impact of preformulation research is not limited to merely guiding formulation development. By identifying conditions that best preserve the integrity of the molecule, a working knowledge of the p...
+3 The basic concepts and reasons for quality assurance (QA) in biotechnology are, of course, the same as for the manufacture of any other medicinal product or device: to assure the safety of the patient. So, what’s different about biotechnology?
The variety of products is vast — from well characterized proteins in production for the past couple of decades, to cell based products, genetically modified oncolytic viruses, viral gene vectors — and many more, with new innovations almost daily. Although their variety is vast, all are incredibly complex, potentially difficult to define by analysis alone (with the exception of certain well characterized proteins), and highly potent. Additionally, “things” potentially can grow in the process stream releasing unknown metabolites, or on the product itself causing molecular abnormalities that you didn’t even know were possible, let alone how to test for.
Furthermore, most of these products cannot be terminally sterilized, some cannot be filter sterilized without dramat...
Protein and peptide therapeutics may undergo numerous physical and chemical changes during manufacturing, shipping, storage, and administration that can adversely alter drug potency and safety. Earlier concerns focused upon denaturation (unfolding), oxidation, and deamidation of certain key aminoacyl residues. Recently, aggregation has emerged as a key issue underlying multiple deleterious effects for peptide- or protein-based therapeutics, including loss of efficacy, altered pharmacokinetics, reduced stability and product shelf life, and induction of unwanted immunogenicity. As a result, the US FDA and the EMEA have increased their scrutiny of peptide aggregation — and in response, biopharmaceutical companies have increased their efforts to understand and control this phenomenon. A number of excipients have been used to reduce aggregation with limited practical success. Recently, a group of them developed initially to increase transmucosal absorption of peptide and protein drugs (ProTek alkylsaccharide e...
One evening, during dinner with several colleagues, the topic of company collaborations and contract organizations came up. I related my own experiences as party to a failed effort and the lessons I’d learned. As our conversation continued, our late night conclusions were simple: Effective partnerships are the means by which we achieve market success, but building such partnerships is complicated. One mistake after another can quickly cascade into a company’s collapse.
Here I review six ways to ruin your company with outsourced providers — whether with a development partner, contract manufacturer, or clinical research organization — drawing on my own personal experiences with a biotechnology and medical device company. That company, after making all of these mistakes, one after the other, no longer exists today. As the case study unfolds, astute readers may wonder how the company managed to exist as long as it did despite compounding poor decisions with more poor decisions. So often, our decisions do not ...
In a typical monoclonal antibody (MAb) purification process, immediately after cell culture and supernatant clarification (its objective being to remove whole cells, cell debris, and particulates), the protein product is typically bound to an affinity chromatography resin and then recovered by elution using a buffer solution. Once recovered, the resulting protein solution is further purified through additional chromatography and virus clearance steps before being concentrated until a final solution is ready for filling and finishing operations.
PRODUCT FOCUS:
MONOCLONAL ANTIBODIES
PROCESS FOCUS:
DOWNSTREAM PROCESSING
WHO SHOULD READ:
PROCESS ENGINEERS, PRODUCT DEVELOPERS, FORMULATORS
KEYWORDS:
TFF, UF/DF, BUFFER EXCHANGE, CONCENTRATION
LEVEL:
INTERMEDIATE
Membrane-based tangential-flow filtration (TFF) unit operations are used for clarifying, concentrating, and purifying proteins. In TFF, a solution is pumped tangentially along the surface of a membrane filter. Applied pressure forces a portion of th...
Stainless Steel Sanitary Fittings
Product:
Swagelok Sanitary Fittings
Features:
Offered in up to 12-in. diameters in a variety of configurations, Swagelok sanitary fittings are available to meet ASME-BPE and 3-A standards, as well as ISO 2852 requirements. They feature polished and unpolished inside- and outside-diameter surface finishes. Swagelok sanitary fittings are typically used in biopharmaceutical and food, beverage, and dairy process systems, such as water and fermentation. The vacuum annealed, cold form tubular fittings minimize the likelihood of stress corrosion cracking. Tolerances, angularity, squareness, ovality and polish finishes are monitored by statistical quality control. The fittings are offered with Kwik-Clamp, tube butt weld, acme threaded and plain bevel set, and specialty end connections, and available in 304 and 316L stainless steel construction. Many machined sanitary fittings can be provided in alloy C-276, titanium, and alloy 6-moly on special order.
Contact Swagelok
www.swa...
The future legal and regulatory pathway for follow-on biologic (FOB) products will be as complex as are protein products themselves. Questions range from how to be certain of the similarity, safety, and efficacy of follow-on products to what will be the key drivers for success in the future marketplace for follow-on biologics — and many more. As approval from the US legislature becomes a reality, innovator and FOB companies will prepare for the future by taking a proactive, not reactive, approach to ensure success. This is the event to attend to find out what you need to know to position your company for success in a postapproval FOB world.
IBC’s sixth annual “Global Follow-On Biologics” conference will assess the science and safety of FOBs through an in-depth analysis of the questions posed above. Learn about likely challenges and strategies to help guarantee that your organization is poised for success and ready to maximize forthcoming opportunities. You will hear from scientific, legal, and financial e...
Our vision is to be the preferred partner for industry and academia for biotech training, research, and development in the American hemisphere by 2012.” That’s the vision statement of the Bioprocess Development and Training Complex (BDTC) in Mayaguez, Puerto Rico, which opened 11 September 2008. The BDTC is the latest in a series of developments designed to make Puerto Rico “Bio Island,” the goal of Governor Anibal Acevedo-Vila. As he described in a conversation with BPI at the 2008 BIO International Convention, unlike most biotech hubs that began with small start-up companies focused on R&D that evolved into drug development companies, Puerto Rico started with manufacturing capabilities that attracted some of the world’s biggest pharmaceutical companies. Now it hopes to become an innovation center too.
The island is home to an educated bilingual workforce and 40 years’ pharmaceutical manufacturing experience. Recent biotech investments include $800 million by Amgen, $450 million by Eli Lilly, and $350 mi...
