Rita Peters is the former editorial director of 

Pharmaceutical Technology, Pharmaceutical Technology Europe

Rita C. Peters

In mid-May, Ranbaxy Laboratories Limited, India's largest pharmaceutical company, pleaded guilty to US Department of Justice felony charges relating to the manufacture and distribution of adulterated drugs made at two of the company's manufacturing facilities in India. The company agreed to pay $500 million—the largest financial penalty paid by a generic pharmaceutical company—for violations of the US Food, Drug and Cosmetic Act (FDCA) and False Claims Act (FCA). 

Ranbaxy agreed to pay a criminal fine and forfeiture totaling $150 million. It will pay another $350 million to settle civil claims that taxpayers paid for substandard drugs used in programs such as Medicare and Medicaid. A Ranbaxy press release explained "a previously disclosed investigation by the US Department of Justice (DOJ) of data integrity and manufacturing processes at certain Ranbaxy facilities in India has been concluded." 

"While we are disappointed by the conduct of the past that led to this investigation, we strongly believe that settling this matter now is in the best interest of all of Ranbaxy's stakeholders," Arun Sawhney, chief executive officer and managing director of Gurgaon, India-based Ranbaxy, said in the statement. "The conclusion of the DOJ investigation does not materially impact our current financial situation or performance." 

Despite its confidence in the bottom line and a tagine of "Trusted Medicines. Healthier Lives." on its website, Ranbaxy USA pleaded guilty to three felony FDCA counts, and four felony counts of knowingly making material false statements to FDA, DOJ reports. The list of infractions shows problems dating to 2003. The company admitted to selling batches of adulterated drugs including Sotret, gabapentin, and ciprofloxacin; had incomplete testing records and inadequate programs to assess the stability characteristics of drugs; and had significant cGMP deviations in the manufacture of certain APIs and finished products. The company also admitted to failing to file in a timely manner required reports for batches of Sotret and gabapentin that had failed certain tests.  

DOJ reports Ranbaxy USA was aware in January 2003 that a batch of Sotret failed an accelerated dissolution stability test but continued to distribute the batch into the US for another 13 months. At various times between June and August 2007, certain batches of gabapentin were testing out-of-specification, had unknown impurities, and would not maintain their expected shelf life; the company did not notify FDA or institute a voluntary recall until October 2007. 

However, the Ranbaxy and DOJ statements tell only part of the story. An investigative report by 

magazine details "long-term criminal fraud" at Ranbaxy, and FDA's response to it " ... raises serious questions about whether our government can effectively safeguard a drug supply that last year was 84% generic ..." The article, based on interviews with former Ranbaxy employees, internal documents, regulators, and scientists, describes a pattern of invented data, falsified documents, a lack of testing, and ignorance and disregard of regulatory procedures (1). 

The article reports that some former Ranbaxy executives and FDA inspectors with knowledge of the company's manufacturing practices would not take the company's drugs. Patients did not have insider knowledge of the manufacturing problems, but trusted the medicine and the regulatory channels; some may have paid a high price for the ineffective drugs. That's a violation of trust that the drug industry and FDA must resolve. 

Articles

Ranbaxy's $500 million settlement for producing adulterated drugs and fradulent data provides a cautionary tale for patients, FDA, and drug manufacturers.

Trust in the Pill Bottle

One of the most frequent questions I receive as a publication editor is: How do I get my article published? Here is the answer to that question and more. 

) publishes peer-reviewed technical articles and expert analyses for scientists, engineers, and managers engaged in process development, manufacturing, formulation and drug delivery, API synthesis, analytical technology, packaging, IT, outsourcing, and regulatory compliance.  

Readers are PhD-level scientists, senior-level scientists, or senior production professionals specifically involved in formulation development, process development, and manufacturing of active pharmaceutical ingredients and finished drug-products; drug-delivery technologies; analytical methods development and testing; quality assurance/quality control and validation; and advances in pharmaceutical equipment, machinery, instrumentation, facility design and plant operations. 

Manuscripts accepted for peer review are published simultaneously in both 

. Peer review is double blind, where the identity of reviewers is unknown to authors and vice versa. Articles submitted for peer review may fall into four main categories: standard data-driven, novel research paper; topical literature or patent review; technical case studies/technical application notes; and science-based opinion papers. 

Technical articles and analyses, published in monthly issues and supplements, should be objective and technically relevant. An article can be a technical case study, demonstrating a problem resolution with related technical data and analysis; an explanation of a new or enhanced technology and related applications; an explanation of new compendial or regulatory standards; a topical literature review; a review of industry developments in a given area; or a review of regulatory developments and compendial requirements and related analysis.   

The editors welcome subjects relevant to formulation development, process development, and manufacturing of APIs (both small molecule and large molecules) and finished drug-products (solid dosage, semisolid, liquids, parenterals drugs, topical drugs). The potential topics include drug-delivery technologies; drug substance manufacturing, scale-up, and process development; analytical methods development and testing; compliance, quality assurance, quality control, and validation; facility design, plant operation, engineering, process control and automation; quality by design, continuous processing; and emerging manufacturing approaches. 

 seeks contributions from all participants in the drug development community. Manuscripts are reviewed with the understanding that they have not been published previously, are not ghostwritten, and are not under consideration for publication elsewhere, including on the Internet.  

Peer-reviewed submissions are reviewed on a rolling basis. Depending on the manuscript, peer-reviewed articles usually take about one to two months for review, revision, and acceptance by the editors. Once accepted, an article is published within four to eight months. 

Technical, non peer-reviewed articles fit topics on the annual editorial  calendar and are typically assigned three to five months before the issue is published. If you would like to contribute an article, send an outline or abstract proposal to 

. If your topic is accepted, an editor will assign you an official deadline, approximately six weeks before the publication date.   

 and review the author's guidelines. Send me a message or give me a call at 732-346-3038. 

Wanted: Article contributions on drug and process development topics.

Pathway to Publication

The U.S. Food and Drug Administration approved updated labeling for Purdue Pharma L.P.’s reformulated OxyContin (oxycodone hydrochloride controlled-release) tablets, but also determined that it will not approve generic versions of the original OxyContin.

 The new labeling for Purdue’s reformulated OxyContin tablets indicates that the product has physical and chemical properties that are expected to make abuse via injection difficult and to reduce abuse via the intranasal route (snorting), the FDA reports.

, agency reported that because original OxyContin provides the same therapeutic benefits as reformulated OxyContin, but poses an increased potential for certain types of abuse, the agency has determined that the benefits of original OxyContin no longer outweigh its risks; original OxyContin was withdrawn from sale for reasons of safety or effectiveness. The agency will not accept or approve any abbreviated new drug applications (generics) that rely upon the approval of original OxyContin.

 The FDA approved the original formulation of OxyContin in Dec. 1995. The product was abused, often following manipulation intended to defeat its extended-release properties. Such manipulation causes the drug to be released more rapidly, which increases the risk of serious adverse events, including overdose and death, the statement explains. In April 2010, the FDA approved a reformulated version of OxyContin, which was designed to be more difficult to manipulate for purposes of misuse or abuse. Purdue stopped shipping original OxyContin to pharmacies in August 2010.

 “The development of abuse-deterrent opioid analgesics is a public health priority for the FDA,” said Douglas Throckmorton, M.D., deputy director for regulatory programs in the FDA’s Center for Drug Evaluation and Research. “While both original and reformulated OxyContin are subject to abuse and misuse, the FDA has determined that reformulated OxyContin can be expected to make abuse by injection difficult and expected to reduce abuse by snorting compared to original OxyContin.”

 The FDA has determined that the reformulated product has abuse-deterrent properties. The tablet is more difficult to crush, break, or dissolve. It also forms a viscous hydrogel and cannot be easily prepared for injection. The agency has determined that the physical and chemical properties of the reformulated product are expected to make the product difficult to inject and to reduce abuse via snorting. However, abuse of OxyContin by these routes, as well as the oral route, is still possible. The reformulated product also may reduce incidents of therapeutic misuse, such as crushing the product to sprinkle it onto food or to administer it through a gastric tube. When FDA finds that a new formulation has abuse deterrent properties, the agency has the authority to require generics to have abuse-deterrent properties also, the press statement reports.

, Purdue Pharma reported that the company was “gratified that the FDA has determined that the original OxyContin extended release tablets were withdrawn from sale for reasons of safety or effectiveness.”

 Purdue reports that the company has completed laboratory manipulation and extraction testing, pharmacokinetic and abuse “liking” studies for the reformulation of OxyContin. Additionally, it has undertaken a series of epidemiological studies to evaluate in real world settings whether the changes made to OxyContin’s formulation are resulting in a decrease in misuse and abuse and their consequences: addiction, overdose and death. Results from these studies are being reported to the FDA on an ongoing basis and have also been presented at scientific meetings and/or published in peer-reviewed medical journals, the company says.

The FDA approved updated labeling for Purdue Pharma L.P.?s reformulated OxyContin tablets, but also determined that it will not approve generic versions of the original OxyContin.

FDA Will Not Approve Generics to Original OxyContin

			In recent years, large pharmaceutical companies have launched a variety of initiatives to restock ailing pipelines and boost business performance including mergers and acquisitions, diversifying business portfolios to non-pharmaceutical products, downsizing, spinoffs, and entering the biopharmaceutical arena.

			Whatever the approach, pharmaceutical companies want balanced portfolios with programs at various stages and risk profiles, says Melinda Richter, founder and CEO of San Francisco-based Prescience International in a 

			To date, most Big Pharma companies have partnered or acquired assets of biopharmaceutical companies with products in late-stage development, says Richter. However, as the availability of late-stage development opportunities shrink and the landscape becomes more competitive, Big Pharma is turning to more early-stage partnerships with academia and early-stage companies.

			It is attractive to for the pharmas to go after early-stage companies because “by nature, they are smaller, they are nimbler, and they are willing to take the risks that the large pharmas just can’t. These small companies have to swing for the fences and they have to win. Pharmas have a lot to protect. They have to be more conservative,“ says Richter.

			More scalable innovation opportunities are another part of the story, says Richter.

			For example, last year, Merck announced a $90 million, seven-year commitment for the California Institute for Biomedical Research (Calibr), an independent, not-for-profit organization established to accelerate the translation of basic biomedical research to innovative new medicines.

			However, for hands-on research, startup companies need laboratory and office space, as well as specialized equipment. Janssen Labs, located on the West Coast Research Center of Janssen Research & Development in La Jolla, Calif., offers short-term leases on wet laboratory and office space.  Tenants also have access to core research facilities and instruments.

			The facility, operated by Prescience International, has a “no strings attached” policy. Janssen R&D does not take an equity stake or first right of refusal in the work of tenants, protecting the entrepreneurial rights of startup companies that choose independence.

			Janssen Labs and Calibr are two options offered by Big Pharma that will be explored in the session “And Now for Something Completely Different: How Will Pharma Access External Early-Stage Innovation?” at the 2013 BIO International convention on April 23, 2013.

In recent years, large pharmaceutical companies have launched a variety of initiatives to restock ailing pipelines and boost business performance including mergers and acquisitions, diversifying business portfolios to non-pharmaceutical products, downsizing, spinoffs, and entering the biopharmaceutical arena.

Big Pharma Leverages Early-Stage Risk with Innovative Options

America's biopharmaceutical companies are using biological processes to develop 907 medicines and vaccines targeting more than 100 diseases, according to a 

 released today by the Pharmaceutical Research and Manufacturers of America (PhRMA).

The report includes biologics in human clinical trials or under review by FDA such as 338 cancer therapeutics that target several different types of solid tumors, leukemia and lymphoma; 134 vaccines for infectious diseases; 71 medicines for autoimmune diseases including lupus, multiple sclerosis, and rheumatoid arthritis; and 58 treatments for cardiovascular disease.

Among the biologic medicines in development are a genetically-modified virus-based vaccine to treat melanoma; a monoclonal antibody for the treatment of asthma; an antisense therapy for the treatment of leukemia; a recombinant fusion protein to treat Type II diabetes.

The report lists the product name, sponsor, product category, indication, and development phase. 

America's biopharmaceutical companies are using biological processes to develop 907 medicines and vaccines targeting more than 100 diseases, according to a new report.

More than 900 Biologics in Development

While the number of patent filings at the European Patent Office (EPO) in 2012 increased by 5.2% over 2011, pharmaceutical-based patents remained flat, and biotechnology patents dropped slightly.

 The EPO reports 5377 filings for pharmaceutical patents in 2012, compared to 5364 in 2011. Biotechnology-based patents dropped 4.3% from 5550 in 2011 to 5309 in 2012.

 Last year, the EPO received a total of 257744 patent filings from all over the world. The number of filings originating from the 38 EPO member states reached a new peak in 2012, beating the previous record set in 2008. The EPO also published 65687 granted patents, 5.8% more than in 2011 (62115).

 “The growth of filings from European businesses is a clear indication that industry here has opted to innovate its way out of the economic crisis," EPO President Benoît Battistelli 

. "The patent filings of today are shaping the innovations of tomorrow. These results confirm that Europe is not only a prime location for R&D activities but also valued as a stronghold of innovation by both technology generating and exporting companies."

  More than one-third of all filings came from the 38 EPO member states. The top five countries in 2012 were the US (24.6%), Japan (20.1%), Germany (13.3%), China (7.3%), and Korea (5.6%). The most active European countries after Germany were France (4.7%), Switzerland (3.2%), the UK (2.6%) and the Netherlands (2.5%). 

 With 2.3% growth, the number of filings from Europe has recovered well from the slight decline in 2011 (-0.9%). The steepest growth rates, however, again came from Chinese (+11.1%), Korean (+9.3%) and Japanese (+9.1%) companies. Asian countries accounted for more than half of total growth. 

 The EPO also published a new record of granted patents: 65687. Almost half went to European companies.

While the number of patent filings at the European Patent Office in 2012 increased by 5.2% over 2011, pharmaceutical-based patents remained flat, and biotechnology patents dropped slightly.