May 2009

Six years after the US FDA applied a narrower scope to its interpretation of 21 CFR Part 11 on electronic records and signatures ( 1 ), the agency is ready to release the revised Part 11. The 2008 release of a draft revision of Annex 11 — Europe’s version of Part 11 ( 2 ) — put pressure on the FDA to complete its long-overdue Part 11 revision. As I made clear to members of my SmarterCompliance executive advisory group in May of last year, the agency’s focus has shifted away from computer validation to electronic record integrity, including long-term information integrity and data quality. Last autumn, I was talking with FDA officials in preparation for my seminar on the specific revisions to Part 11 and Annex 11 ( 3 ), and it became clear that the revision group’s work was complete. As of this writing, the revised regulation only awaits final center approval before being published. Given the recent changes in the US presidential administration, Congress, and FDA leadership, I anticipate the revised Part 1...

In early April, I chatted with the chair of ESACT, Florian Wurm, a professor of biotechnology in the faculty of life sciences of école Polytechnique Fédérale de Lausanne in Switzerland. As chairman of ESACT, what are your duties? How is the chairperson selected, and how long does he or she serve? How long have you been chair? The ESACT chair is elected from among the members of the executive committee, which are elected by the membership. The executive committee organizes board meetings twice a year. A good deal of our time goes into making plans for the next ESACT meeting, in collaboration with the planning committee made up of volunteers from among the members. ESACT meetings are held every other year and are the highlights of our organizational activities. ESACT membership is relatively small, but our conferences are large; we have between 800 and 900 people in attendance at a typical meeting. It is a huge task for volunteers to put together such a meeting as this. Ours is really the only meeting of i...

Protein A affinity chromatography is traditionally used as the capture step for monoclonal antibodies (MAbs) ( 1 , 2 , 3 ). It yields high purity because only the fragment-crystallizable (Fc) region of an antibody (IgG 1 or IgG 2 ) or Fc-containing fusion protein can bind to the protein A ligand. The resulting specificity provides substantial reduction in impurities such as host cell proteins (HCPs) and DNA ( 4 , 5 , 6 , 7 , 8 ). The dynamic binding capacity of protein A chromatography resins is generally ≤40 g/L and depends highly on residence time because of the diffusional nature of the binding process. Most commercially available protein A resins can not withstand cleaning at high concentrations of sodium hydroxide except for MAbSelect SuRe brand from GE Healthcare ( www.gehealthcare.com ), which is chemically modified to tolerate extreme pH conditions ( 9 , 10 ). PRODUCT FOCUS : ANTIBODIES PROCESS FOCUS : DOWNSTREAM PROCESSING WHO SHOULD READ : PROCESS DEVELOPMENT PERSONNEL KEYWORDS : BINDING CAPA#C...

Stem cells are probably the most-discussed — and least understood — potential therapeutics biotechnology offers. Headlines in mainstream media tout their potential benefits and decry their ethical complications. Time magazine featured stem cells on its cover one week in February ( 1 ), and an ABC network drama depicted criminals selling stolen cord blood stem cells to the rich and vain as a high-end cosmetic treatment ( 2 ). It’s a safe bet that most nonscientists don’t know the difference between embryonic stem cells, so-called adult stem cells, induced pluripotent stem cells, and so forth. It’s another safe bet that most of those same people have an opinion anyway, pro or con, about the use of stem cells in research. Thus, the politics of stem cells, particularly in the United States, have had more of an effect on their use than the related science or technology. President Obama’s recent reversal of the Bush-era ban on new embryonic stem cell lines caused simultaneous celebration and backlash as some ...

Live whole-cell bacterial products have been used as vaccines for many years, and there are currently three such products licensed on the market. Over recent years, however, interest has renewed in this type of product as a delivery system for novel recombinant therapies and vaccines. A number of different organisms have been proposed, such as Escherichia coli and Salmonella species, which might have applicability for such applications. Vaccine applications tend to relate to the potential for low-cost orally delivered products against a range of infectious diseases. Injectible products are more focused on delivery of specific therapies such as cancer vaccines. Use of recombinant expression creates the opportunity for development of platform delivery systems for a wide range of therapeutic agents. This suggests the possibility of developing platform manufacturing processes that could be used for multiple products, including those intended for early stage clinical trials. This goes against the conventio...

Single-use filtration systems are increasingly replacing traditional stainless steel filter assemblies, piping, and tanks for purification and storage of bioprocess fluids in biopharmaceutical manufacturing. Unfamiliarity with polymeric materials and the need to ensure patient safety, however, have made extractables and leachables from these new components and systems a primary concern of process developers along with specialists in quality, validation, regulatory affairs, as well as agency reviewers. A general risk-based approach to determination of extractables and leachables from disposable bioprocess equipment has been published by the Bio-Process Systems Alliance (BPSA, www.bpsalliance.org ). Detailed characterization of extractable compounds in model solvents — or leachables in drug product streams — can be generated through the use of sophisticated analytical equipment. Extractables studies show the potential for a material to contribute leachable substances into a drug product or process fluid. R...

Continually increasing bioreactor titers is placing pressure on downstream processing, especially chromatography steps, to process the greater mass of protein produced. Whereas an order of magnitude increase has been seen in titers over the last few years, no similar increase has yet been achieved in the capacity of chromatography resins. Meanwhile, the industry is coming under rising pressure to reduce manufacturing costs and the resulting cost per gram of monoclonal antibodies (MAbs) produced. Because of the specificity it offers, protein A affinity chromatography is well established and continues to be the predominant initial capture and purification step for commercial MAb purification. Although it is possible to address the increasing productivity needs through a combination of higher affinity capacity and running multiple cycles at short residence times, both attributes seldom can be maximized simultaneously. PRODUCT FOCUS: Antibodies PROCESS FOCUS: DOWNSTREAM Processing WHO SHOULD READ: PROCESS ...

Vaccines have been around a long time — longer than any other biologic medical products. Since the 1700s, when a British doctor inoculated people against smallpox using Variolae vaccinae (cowpox virus), we’ve referred to such immunizing treatments as “vaccines.” Most children in developed countries grow up knowing there will be occasional “vaccinations,” usually injections, required to get into school and stay there (which may or may not seem like a great thing, depending on who you talk to). Similarly, people from developed nations traveling to underdeveloped ones expect to undergo certain vaccinations to prevent diseases that they would most likely not be exposed to at home. In the 21st century, vaccines are a routine part of our lives. All the earliest vaccines were made using animal cell culture — some in petri dishes, some in diseased animals or humans — which produced large numbers of wild-type viruses or bacteria that could be weakened, killed, or sometimes used live as vaccines. Bacterial or tox...

Biotechnology’s mission has never been more critical. In a call to action reminiscent of President Kennedy’s challenge to place a man on the moon in the 1960s, President Obama has challenged the scientific community to seek “a cure for cancer in our time.” The challenge is tremendous, but the place to look for such a momentous and meaningful achievement is among the great minds of scientists and inside the research laboratories of biotech companies. And that is but the tip of the iceberg. This call is just one of the key scientific challenges our industry is addressing. Like the quest to cure devastating diseases, the search for clean, green sources of energy and the move to implement sustainable agriculture are among the most important scientific and technical challenges our society faces. Each day, the biotechnology industry answers these calls through groundbreaking research and innovation. Beyond the complexities of science, however, our industry faces significant barriers to the advances we want — an...