Before this program, according to the agency, some firms submitted multiple and delayed written responses to Form 483 observations, sometimes over many months. Because FDA reviewed all of these responses before making a decision on whether to issue a warning letter, the process delayed enforcement  and compliance. Now, however, FDA “will not ordinarily delay the issuance of a warning letter in order to review a response to an FDA 483 that is received more than 15 business days after the FDA 483 was issued,” according to an announcement in the Federal Register.

If a response to a Form 483 is received after 15 business days, FDA says it does not plan to “routinely include a response on the apparent adequacy of the firm’s corrective actions in the warning letter.” Instead the agency “plans to evaluate the response along with any other written material provided as a the direct reponse tot he warning letter.” FDA maintains the discretion to issue a warning letter regardless of whether any responses are received.

The program appears to apply the 15-day limit regardless of the number of observations on the Form 483. One hopes this program will help add a greater level of urgency, especially in situations that apparently have not been taken seriously until a warning letter has been issued. I do not want to think some firms may have deliberately delayed compliance by submitting their responses weeks apart, but I can see how the assumption can be made. On the other hand, investigating the cause of some observations and developing a corrective action can be a time-consuming process such that delayed and multiple responses are not uncommon. One hopes, then, this program will be a good first step toward achieving the tough, no-nonsense enforcement the agency needs without also overburdening the industry.

“Most of the genes that we’ve identified as diabetes risk genes to date reduce the function of the pancreas, specifically of beta cells in the pancreas that make insulin,” explained Dr. Robert Sladek of McGill University and the Génome Québec Innovation Centre in a McGill University release. Sladek is also a corresponding author of the paper in the September 6 issue of  Nature Genetics that describes this discovery. “IRS1 has to do with the function of the other tissues in the body. Rather than reduce production of insulin, this gene reduces the effect of insulin in muscles, liver and fat, a process called insulin resistance.”

“IRS1 is the first inside the cell that gets activated by insulin,” said Sladek in the release. “It basically tells the rest of the cell, ‘hey, insulin is here, start taking in glucose from the blood!’ If IRS1 doesn’t work, the whole process is disrupted.”

The team also discovered the genetic “trigger” that prevents the IRS1 gene from working properly.  Interestingly, the single-nucleotide-polymorphism (SNP) does not actually lie within the IRS1 gene, but “it’s about half-a-million base pairs away,” recounts Sladek in the release.

Understanding that widely different genetically based mechanisms may underlie diabetes may someday help drug developers tailor therapies to specific subpopulations of diabetics. These are the types of breakthroughs the industry has been waiting for; the links between genetics, biology, and medicine are becoming ever more refined. Those who predicted that the benefits of genomics would become apparent within the decade are being proven correct.

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For example, recent advances in therapeutic biologics have raised the need for a greater understanding of how the body fights infectious diseases at the most fundamental level. One of the most elusive parts of this understanding is the inner workings of ribosomes, those parts of the cell responsible for producing proteins. Scientists attribute the difference between human and bacterial ribosomes as the reason antibiotic drugs selectively attack the bacteria. Viruses such as hepatitis C and polio use the ribosomes of their human host cells to produce proteins beneficial to the virus.

“Inside the ribosome, antibiotics and viruses are using chemistry to either fight or promote disease,” said Jamie Cate, one of the study co-authors and a University of California, Berkeley, associate professor in chemistry and molecular and cell biology in a university press release.

Cate, who conducted the work with research specialist Wen Zhang and graduate student Jack Dunkle, both co-lead authors of the study, in his lab at UC Berkeley, is then quoted in the University release as asking “But what sort of chemistry? The short answer is that we have a lot still to learn. Once we find out, that knowledge could lead to more effective antibiotics, or new treatments against devastating diseases like hepatitis C. We know what goes in and what comes out of ribosomes, but we’re only beginning to learn about what is going on in between.”

Cate and a team of researchers this week said they have used X ray crystallography to take a peek inside this “black box.” Their technique produced images of nanoscale movements of ribosomes as they interact with transfer RNA (tRNA) and messenger RNA (mRNA). Their research showed these interactions were much more complex, undergoing several steps in their spatial arrangement, than previously thought. Researchers say, however, until further advancements in imaging technologies, only snapshots of the movement are possible.

Yesterday I read about one interesting approach to the successful lyophilization of a nanodrug. Scientists at AlphaRx (Markham, Ontario), a small biopharmaceutical company, say they have lyophilized the company’s inhalable Zysolin nanomedicine (a Tobramycin compound for the adjunctive treatment of Gram-negative pneumonia). Joseph Schwarz, the company’s chief scientist has called this “a technological milestone” for the nanomedicine industry, noting that “It is well known that many FDA-approved ingredients used in nanomedicine formulations cannot be readily lyophilized.” According to the release, Schwarz identifies this difficulty as “the major obstacle” to the therapeutic development of nanomedicines. The company now plans to move on to clinical batch material manufacturing.

One of the objectives behind the US Food and Drug Administration’s science-based approach to drug manufacture is gaining better process understanding, making the link between drug quality and critical process attributes. It is of a fortunate coincidence, then, that at the same time the industry is gaining this understanding, formulators are presenting the industry with the unique challenges from nanoparticle-based products.

For example, researchers at the Retinoblastoma Program in the Vision Center at Children’s Hospital Los Angeles have developed what may be more effective method of locally treating retinal and vitreous diseases. A presentation given last week by A. Linn Murphree, MD, director of the program, at the Association for Research in Vision and Ophthalmology Summer Eye Research Conference described a “episcleral drug reservoir,” a tiny silicone cup that could be filled with a drug and sealed to the outer surface of the eyeball.

The delivery system could provide localized delivery of drugs to treat macular degeneration, diabetic retinopathy, uveitis, endophthalmitis, and retinoblastoma, according a press release. Currently, drugs for these diseases are administered systemically with an intravenous drip or by an injection into the eyeball. For retinoblastoma (a cancer), avoiding systemic delivery would prevent the loss of bone marrow that is crucial for maintaining the immunity to fight infection.

Murphree’s research team is currently developing a protocol for Phase I/II clinical trials in humans.

A key to the insulin release and delivery is that the pH level of the skin, usually 7.4, reaches a more basic level when it is healing, according to a release by the team directed by Dean Ho, assistant professor of biomedical engineering and mechanical engineering at Northwestern. “It’s a tricky problem because proteins, even small ones like insulin, bind so well to the nanodiamonds. But, in this case, the right pH level effectively triggers the release of the insulin.”

The next step in the study is to incorporate the nanodiamond-insulin clusters into gels for clinical trials. Other possible formulations may include ointments, bandages, and sutures. Ho’s group is also studying the use of nanodiamonds to release a chemotherapy agent, Doxorubicin, to fight cancer and to disperse some insoluble drugs in water.

If your research team is working toward finding alternative routes to deliver therapeutic proteins, PharmTech would be glad to hear from you.

Wyeth’s chairman, Bernard Poussot, stated in a release the deal will bring added resources to the company’s biopharmaceutical division as well as to its human, consumer, and animal healthcare divisions. But some industry observers have speculated that Pfizer may sell off Wyeth’s consumer healthcare units. Last week, the European Commission approved the $68 billion deal but required the companies to divest its animal healthcare businesses.

The dwindling number of new chemical entities and the shrinking number of small-molecule blockbusters have made expansion into biologics a necessary strategy. Still uncertain, however, is the effect these shifts will have in employment. Observers have speculated whether the Pfizer-Wyeth deal will include a repeat of the job cuts Pfizer imposed after its mergers with Warner-Lambert in 2000 and Pharmacia in 2003. Pfizer claims the Wyeth deal will be different. The focus, it says, is on building a strong biopharmaceutical unit, not cutting costs. Job cuts will be relatively minimal at 15% (or 20,000 jobs), and the number of sites will most likely be reduced from 46 to 41.

Perhaps the greatest uncertainty is whether the Wyeth deal will echo results from the Warner Lambert agreement, under which Lipitor became the world’s best-selling drug, or will it flake like the Pharmacia deal, under which Celebrex nose-dived Pfizer’s stock?

Prostate cancer remains one of the most common cancers and the second-leading cause of cancer death in American men, according to the American Cancer Society. So far, treatments for prostate cancer include drugs that affect the entire body, instead of only cancer cells. Work by a team of researchers at Purdue University offers hope they have found a new method of not only finding and targeting these cancer cells, but also carry therapeutic drugs directly to the site of infection.

The scientists have synthesized what they have termed a homing device: a molecule that finds and penetrates prostate cancer cells. The molecule attaches to a protein that is only present in 90% of all prostate cancers (prostate-specific membrane antigen, or PSMA). If the targeting molecule could be linked to new drugs being designed to destroy the vasculature of solid tumors, says Philip Low, professor of Biochemistry, then the method would kill the cancer cells directly and the vasculature that feeds the tumors.

Scientists have for many years looked to monoclonal antibodies as molecular homing devices. But the Purdue scientists used a rational-design approach. They developed their homing molecule after studying the PSMA structure in computer models.

The team also has developed imaging agents for body scans that can be linked to and be carried by the molecule. Currently, only one imaging agent for prostate cancer cells has been approved by the US Food and Drug Administration. The research team says it hopes to enter its radioimaging application into clinical trials this fall.

 A successful targeted drug delivery system would be a giant step not only in the fight against cancer but also in providing some relief to those who endure the painful side effects associated with existing therapies.

In his plenary address, Jim Thomas, PhD, vice-president of the process and product development group at Amgen, spoke about the benefits and challenges of QbD principles in biologicals. He set the scene by quoting a recent article that predicted that in 2014, 7 of 10 top selling drugs will be biologicals. Moreover, biotechnology drugs will account for 50% of the top 100 drugs in 2014, compared with 11% in 2000 (versus conventional drugs). But, said Thomas, the challenges were many. The costs of drug development and treatment are high. Intellectual property issues and the growth of follow-on biologics will have to be addressed. In addition, he listed at least 25 major attributes of molecules that, if modified, would have an effect on a molecule’s pharmacokinetics. “We need to pay attention to these attributes because of concerns over safety, efficacy, and stability,” said Thomas. The long-term solution, he said, is innovation, specifically in formulation, better production methods, and in deliverying protein therapeutics. “Innovation will be key to future success,” said Thomas, who then discussed in detail Amgen’s work in antibodies, peptibodies, and avimers as examples.

Amgen is working with the US Food and Drug Administration and other companies to understand how to apply the philosophies of QbD in they way they develop protein therapeutics, particularly “based on a fundamental understanding of the science of building quality into the molecule.” The process, said Thomas, starts with a core design knowledge (”what works and what doesn’t”), which must then incorporate what he referred to as “systematic learning” or “buckets of information” that include analytics (including top-down mass spectrometry), biological aspects, and the process itself. The keys are trying to link an knowledge of the molecule with analytics and then linking the analytical characterization of the molecule to the biology to define the critical quality attributes.

The main challenge in doing this, says Thomas, is that there will be a significant initial investment to apply QbD to biologics, but these costs should decrease for platform modalities. The application of QbD to nonplatform molecules will be much more costly. An investment in high-throughput technologies is necessary, he said. Other challenges include the need for sophisticated knowledge of antigen systems, linking molecular structure to biological attributes, and applying risk-management tools to help define the design space. Thomas said Amgen is taking “gradual steps” in applying QbD in it’s processes and will “soon” have evidence of QbD in its regulatory filings.

An afternoon session in process analytical chemistry echoed much of these challenges and future benefits of implenting QbD. In a session titled “What can the Biopharmaceutical Industry Learn from the Use of QbD in Small Molecule Production,” Mel Koch, PhD, of the University of Washington’s Center for Process Analytical Chemistry (CPAC) reviewed the fundamental principles of QbD and how the advancements in measurement science (miniaturization, new materials, data processing, etc.) have helped trigger the need for implementing these principles in bioprocessing. Areas of interest, said Koch, include the characterization of media, nutrient quality, sampling, and microfermentation for optimizing bioprocesses.

A keen eye on science and built-in quality … biotechnology is indeed on the verge of great innovation.