Textbooks and journal articles treat common cause variation as if it is an inevitable fact of nature and beyond our control: “In any production process, regardless of how well-designed or carefully maintained it is, a certain amount of inherent or natural variability will always exist. This natural variability or ‘background noise’ is the cumulative effect of many small, essentially unavoidable causes” [Emphasis added]. This attitude cuts off thoughts of trying to reduce variation. But, with some reflection, there are several ideas and techniques that can begin to help reduce common cause variation.

Aiming for and hitting the target, whether it is x, y or z, seems a simple idea, but it could be argued that it is everybody’s responsibility to know what the target is and to do everything possible to hit that target every time. One person achieving the target infrequently doesn’t help. But 400 people hitting targets a dozen times a day can have a dramatic effect on reducing variability. The target could be something as simple as setting the temperature on a dryer or as complex as a management objective. Keep in mind that a specification range is not a playground for manufacturing.

Read Lynn Torbeck’s full take on common-cause variation including advice on flexibility, operational definitions, and mistake-proofing.

ICH Q6B, approved in 1999 by the three ICH regions, outlines specifications, test procedures, and acceptance criteria for biotech products. Q6B specifically calls for structural characterization and confirmation of the amino acid sequence and composition, terminal amino acid sequences, peptide map, sulfhydryl group and disulfide bridges, and the carbohydrate structure. With the more recent passage of the ICH quality guidelines, Q8, Q9, Q10 and the pending Q11, industry has even more information (as well as more expectation) on how to conduct a risk- and quality-based analysis of these products to ensure their safety.

A series of presentations on how to conduct biopharmaceutical characterization in detail was given yesterday in Valley Forge, Pennsylvania, by SGS Life Science Services and its recently acquired M-Scan Group, which focuses on mass spectrometry and gas chromatography for chemical analysis of both small and large molecule products.

Also discussed were biosimilars, which while making headway in Europe (14 have been approved since 2006), are still awaiting an implementation plan for approval in the US. Once that plan is in place—FDA continues to promise that it will be soon—bioequivalence, interchangeability, and comparability tests will become more commonplace. In the meantime, fully understanding and characterizing one’s product—down to the tiniest and most random chromatographic peak—remains a crucial part of the process and an expectation that is here to stay.

As the unemployment rate hovers around 9.1%, the federal government needs to find ways to create jobs. Congress is debating whether a tax break on repatriated money would prompt companies to hire more workers, as I mentioned last week. Meanwhile, the Obama administration is eyeing another potential means of stimulating job growth: investing in biological research.

When he signed the America Invents Act in September, President Obama committed to developing a National Bioeconomy Blueprint by January 2012. The blueprint will describe ways to manage investment in biological research to improve the nation’s health and create the “jobs of the future.” Aside from identifying potentially productive investments in R&D, the blueprint will also describe regulatory reforms to reduce burdens on biopharmaceutical manufacturers.

Illustrating the maxim that great minds think alike, FDA is already seeking to identify and reform burdensome and inefficient regulations as part of its own initiative to stimulate biomedical innovation. At the same time, the agency plans to establish a common understanding among stakeholders to clear the approval pathway for exceptionally promising therapies. These goals are included in the agency’s recent report titled Driving Biomedical Innovation: Initiatives to Improve Products for Patients.

Biological research is the foundation of a significant portion of the American economy, as the White House website notes. The combined efforts of the president and FDA could help discover and develop new therapies. If they also encourage biopharmaceutical companies to hire new employees, they will help mitigate an urgent problem that has not yet been addressed sufficiently.

Drug shortages are an acute problem that keeps getting worse. Last year, about 211 drugs were in short supply, which was a new record. This year, the number of new drug shortages already has reached 213, according to the University of Utah Drug Information Service. As a result, many patients now have limited access to crucial drugs, such as cancer therapies and medicines for potentially lethal infections. And a Congressional committee is now investigating what appears to be an insult added to this injury.

Rep. Elijah E. Cummings (D-MD) alleges that secondary drug distributors are charging exorbitant prices for drugs that are in short supply. Allied Medical Supply, for example, has charged $990 per vial of cytarabine, a treatment for leukemia that usually costs about $12 per vial. A shortage of leucovorin, which is used to treat advanced colon cancer, has enabled Premium Health Services to charge more than $270 per vial, even though the drug’s typical price is approximately $5 per vial. On behalf of the House Committee on Oversight and Government Reform, Cummings has sent these companies letters asking how much they are making in profits on these drugs.

The biggest cause of drug shortages, according to FDA, is manufacturing quality problems. Fortunately for us, FDA just awarded a multimillion-dollar grant to the National Institute for Pharmaceutical Technology and Education (NIPTE) to improve drug development and manufacturing. NIPTE, a not-for-profit research organization, will use the money for various projects that could help manufacturers better understand their products and processes. For example, NIPTE will seek to develop analytical methods that can characterize complex molecules and enhance control of product quality. The group also will investigate specialized manufacturing techniques for low-dosage and high-toxicity products.

By improving manufacturing quality, NIPTE’s work could help reduce the number of future drug shortages that patients must endure. And FDA will soon provide recommendations for avoiding and mitigating drug shortages. FDA’s efforts are a good sign that it takes the problem seriously, but for many patients, relief cannot come too soon.

Concern about pharmaceuticals in our water supply has been in the public consciousness for a few years now. In 2009, the Environmental Protection Agency found traces of various drugs in fish caught in rivers that receive effluent from wastewater-treatment plants. The drugs were believed to come from doses that people had excreted or flushed down the toilet. In response, FDA updated its guidelines for disposing of drugs. New research, however, shows another potential source of drugs in our waterways.

French scientists investigated fish called wild gudgeon that lived upstream and downstream of a steroid-manufacturing facility owned by sanofi. About 60% of the fish downstream of the facility had both male and female sexual characteristics, as opposed to 5% of the population upstream. Researchers identified pollutants such as diuretics and anti-inflammatory agents in the river. The fish’s abnormalities could prevent them from breeding and also signal problems in other species.

“People think drug release is regulated, but it’s not,” said Joakim Larsson, a pharmacologist at the University of Gothenburg in Sweden, to Nature. But this lack of oversight may end: the European Commission is now considering whether to set limits on common drugs (e.g., ibuprofen and the contraceptive ethinylestradiol) in waterways.

Setting limits might prove difficult, however. Scientists have not yet determined safe limits for many pharmaceuticals in the aquatic environment, or how widespread the problem is, according to Susan Jobling, an aquatic ecotoxicologist at Brunel University in London who spoke to Nature.

The French researchers’ findings certainly are alarming, but regulators won’t have a solid basis for any decisions until more information comes to light. I’m encouraged that sanofi is cooperating with regulatory agencies, researchers, and ecological associations to investigate the scope and root of the problem. In the meantime, the pharmaceutical industry would do well to keep this story in mind, and perhaps review whether it can reduce the potential risks of its waste-disposal procedures.

Also see my previous posts about pharmaceuticals in water:

“Water without Side Effects”

“Hope for Bipolar Fish”

Understanding critical quality attributes will help Pfizer develop robust design spaces and, ultimately, achieve real-time release, said Gerry Migliaccio, senior vice-president of network performance for Pfizer Global Supply, according to In-Pharma Technologist. Migliaccio made his remarks at a meeting of FDA’s Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. Using QbD as a basis, and process analytical technology to establish manufacturing controls, Pfizer believes it will be able to reduce quality-control costs, achieve real-time release, and quickly get a return on its investment.

But not all companies are rushing to adopt QbD. Manufacturers of small-molecule generic drugs fear that spending the extra initial time and effort to adopt QbD could prevent them from being the first to file an application for their products. “If you’re not first to file, you may as well be last,” said Yatindra Joshi, vice-president of generics R&D for Teva, at the same FDA meeting. Consequently, some generic-drug manufacturers aren’t willing to gamble that the benefits of QbD will outweigh the profits lost by not being first to file.

If Pfizer and other heavyweights adopt QbD, it could boost patients’ confidence in the safety and efficacy of marketed drugs. But patients would benefit even more if generic-drug manufacturers felt freer to pursue this initiative. By making some elements of QbD mandatory in filings, FDA could “level the playing field,” said Joshi. This idea seems like one plausible solution that could be of advantage to the industry and consumers alike.

For FDA’s evaluation of the QbD program so far, please watch for Pharmaceutical Technology’s September issue, in which CDER’s Helen Winkle and Moheb Nasr analyze the initiative’s present and future.

EMA published guidelines for follow-on biologics in 2005, and FDA has been studying its peer’s approach. So far it appears that FDA will follow EMA’s strategy of taking a product-specific approach to approving follow-on biologics. “Given the complex nature of biologics, it’s unlikely that a ‘one size fits all’ systematic assessment of biosimilarity can be developed,” wrote Janet Woodcock, director of the Center for Drug Evaluation and Research, and her colleagues in The New England Journal of Medicine. The agency will likely examine not only the manufacturing process for the therapies, but also the populations for whom the drugs are intended.

Companies that hope to enter this potentially lucrative market have argued that analytical characterization methods have improved to the point where they can establish similarity between a branded and a follow-on product. Some firms have argued that these methods could reduce the need for clinical trials. But FDA does not seem convinced that characterization methods have advanced far enough. Rather, “additional animal and clinical studies will generally be needed for protein biosimilars for the foreseeable future,” they wrote in the article, but “the scope and extent of such studies may be reduced further if more extensive fingerprint-like characterization is used.”

Ultimately, we won’t be able to predict the shape of the follow-on biologics industry in the US until FDA publishes its final guidance. Large-molecule therapies are more complex than small-molecule products, and it remains to be seen how burdensome the agency’s approval requirements will appear to the industry. Firms will have to weigh regulatory costs against the potential future profits before taking the plunge into this new market.

Before ICH Q3B, there was ICH Q6A, harmonized in 1999, which addresses testing container-closure systems for extractables (mainly in parenteral products) and when tests can be eliminated based on developmental and stability data.

In early 2002, the Product Quality Research Institute (PQRI) E&L working group, representing industry, academia, and FDA, introduced a threshold concept to qualify E&L in nasal and inhalation products based on total daily intake rather than the percentage of API. FDA used the paper to shape its own guidance on the subject in July 2002. The European Medicine Agency’s Committee for Medicinal Products for Human Use followed suit in 2005. PQRI issued additional proposed safety thresholds and best practices for qualification of E&L in nasal and inhaled products in September 2006, and since then, many in industry have questioned whether the PQRI approach can be applied to other dosage forms.

Finally, if one turns to the pharmacopeia, USP offers chapter <87> on biological reactivity, <661> on containers-plastics, and <1031> on biocompatibility of materials, while Ph.Eur. 3.1 and 3.2 guidance documents focus on raw material extractions and finished containers. There are also guidance and standards documents from FDA, ISO, and other regulatory bodies on this topic. Currently EU and US leachable levels are slightly different with the EU approach similar to ICH Q6A and the FDA approach a bit more stringent.

With so many disparate standards for qualifying and testing for E&L, it’s no wonder that industry may be slightly confused. For those interested in learning more about current regulatory expectations, Pharmaceutical Technology is hosting a free webinar on the subject on June 22, 2010 and June 24, 2010. Be sure to listen in.

Sources

-J. Fleitman, Allergan, “Extractable/Leachable Testing and Regulatory Requirements for Opthalmic Dosage Forms,” presentation to AOAC-SCS/WCDG,Nov. 5, 2009.

-D.J. Ball, “Derivation and Justification of Safety Thresholds,” presentation to PQRI L&E Workshop, 2006.

See related articles
Extractables and Leachables: An Overview of Emerging Challenges

The Importance of Leachables and Extractables Testing for a Successful Product Launch

The McDonalds recall is the fourth cadmium-related recall issued by CPSC this year for children’s products. Cadmium is one of the four major toxic elements of concern in consumer products. Together with lead, arsenic, and mercury, these make up “the big four” heavy metals that pose the greatest threat to our health.

The pharmaceutical industry has been reworking guidelines for limits and testing methods in an attempt to keep tabs on heavy metals. As Managing Editor Angie Drakulich discussed in her post last week, FDA recently focused its attention on the amount of lead contamination in dietary supplements. Legislation is under review in the Senate that could give FDA the power to regulate supplements and better control the amount of heavy metals they contain. Additionally, the US Pharmacopeia and ICH are working to update guidelines relating to heavy metals and keeping them out of pharmaceutical products.

For more on heavy metals testing requirements, register for Pharmaceutical Technology’s webcast scheduled for next week on June 14 and 17.

On Friday, the US Treasury released details about its Therapeutic Discovery Project Program, which was created by the Affordable Care Act to support small pharmaceutical and biopharmaceutical companies’ research efforts. The program’s goals are to promote the development of new therapies, create US jobs, and increase US firms’ competitiveness.

Companies with 250 employees or fewer can apply for tax credits worth as much as 50% of the cost of qualifying research investments. Each company could earn a maximum credit of $5 million. To provide an immediate boost to the industry, the credit will cover research investments made in 2009 and 2010. To startup firms that have not yet become profitable and thus cannot take advantage of a tax credit, the Treasury will offer grants.

On Friday, the Internal Revenue Service published guidance that explains how firms can apply to have their research projects certified as eligible for the credit. Projects must show “significant potential to produce new therapies, address unmet medical needs, reduce the long-term growth of healthcare costs, and advance the goal of curing cancer within the next 30 years,” according to a statement from the US Treasury. The application period begins on June 21, 2010 and lasts through July 21, 2010.

It’s heartening to see the US government try to encourage the development of new treatments, especially in a difficult economy. With luck, the industry’s pipelines and the country’s patients will both benefit. The Therapeutic Discovery Project Program should remind industry of just how valuable R&D scientists are, and I hope it encourages small firms to hire more of them. The program might just put a spring back in the step of these researchers.