In July, the Food and Drug Administration (FDA) issued a warning letter to Sanofi Pasteur, S.A. regarding April inspections at their facilities in Marcy l’Etoile, France and Toronto, Canada. The warning letter summarized an extensive list of “significant deviations” from Current Good Manufacturing Practices (cGMP). Please read our blog “Reducing cGMP Compliance Challenges is Key to Public Vaccine Confidence and Industry Success,” for more details.

Novartis has also experienced a fair share of attention from the FDA recently. According to a recent Forbes article, Novartis received a warning letter for “significant violations” at two United States manufacturing facilities. In addition, Novartis recently conducted a self-cGMP investigation and discovered a data-handling discrepancy in their Rosia, Italy facility that caused some vaccines to be held for several months. Regrettably these scenarios are not rare, the Forbes article identifies several other companies that have received warnings from FDA regarding quality and cGMP concerns, including Johnson & Johnson, Hospira, and Merck KGgA.

The FDA is not the only group raising concerns about pharmaceutical manufacturing quality. Last week, Reuters published a special report titled “China’s “Wild East” Drug Store.” The article outlines many problems associated with the purchase of active pharmaceutical ingredients (API) from some companies operating in China. In many instances the manufacturing of APIs in China is not cGMP compliant and due to regulatory loopholes many escape regulation entirely. APIs manufactured by these companies are at best substandard and at worst deadly. In 2008, 149 Americans died due to Heparin that contained a contaminated API sourced from porcine intestine and manufactured in China. Many pharmaceutical companies also fight the counterfeit manufacturing and selling of their products into the global market by these same Chinese companies. Recent counterfeit versions of Avastin have entered the global market from China.

Unfortunately these aren’t the only instances of raw material or API quality problems from China, in fact, there is a history for this type of substandard quality. In 2007, pet food that contained raw materials contaminated with melamine and sourced from China caused widespread pet food recall and some pet deaths. In 2008, dairy products and livestock feed from China were found to contain melamine. Melamine raises the protein content of products; so inexpensive ingredients can pass for more expensive concentrated proteins. Earlier this year gelatin sourced from China and sold for drug capsule manufacturing was found to be industrial grade instead of food grade. Recently one company in China was found to be using “gutter oil” (recycled food grease) for antibiotic API manufacturing instead of the acceptable soybean oil.

While these violations certainly do not represent all API or raw material manufacturing in China, it is a cause for concern. With 70-80% of all APIs manufactured in China or India, companies that purchase APIs and raw materials must conduct full due diligence prior to using these ingredients. The United States and Europe are safer because of an established quality system and FDA and European Medicines Agency (EMA) oversight, however no country or company is immune to purchasing sub-standard ingredients from unscrupulous suppliers. That said, in countries in the developing world, such as Africa, low quality pharmaceutical ingredients are an even bigger problem. The World Health Organization (WHO)’s coordinator for Quality Assurance and Safety in Medicines, Lembit Rago, was quoted in the Reuter’s article as saying, “There is falsification of APIs going on, we know it.”

Regulators in the US and Europe are working to institute additional regulations on APIs and raw materials, but admittedly this is difficult to manage. EMA will employ a “Falsified Medicines Directive” next year that will require drug companies to prove the purity of the ingredients they use regardless of where they are sourced. Holding pharmaceutical companies responsible may be the only way to ensure that pharmaceuticals don’t contain poor quality ingredients. Ultimately pharmaceutical companies selling the final products have the most to lose if there are product recalls or lawsuits associated with contamination.

It is clear that the buck stops with the pharmaceutical company both from the perspective of regulatory bodies and consumers. Everyone knows that quality is key, but how can biopharmaceutical companies of significant size ensure high quality, cGMP compliant manufacturing at each step of their supply chain? Here are some ideas:

Go Animal-Free. Animal– Free Certficate

Eliminate all animal products from manufacturing and formulation. Many problems with respect to contamination are a result of problems with raw materials and too often these raw materials are sourced from animals. Animal-derived products always carry a risk of contamination from adventitious agents, such as viruses and prions. Not only are animal sourced products a safety risk, but also they simply are no longer necessary ingredients in manufacturing. Most animal sourced proteins traditionally used in manufacturing are either available in recombinant form or can be replaced by a synthetic. These products carry an Animal-Free Certificate or Declaration as part of their qualification and some provide this declaration with each Certificate of Analysis (CofA). Today companies including Sigma, Fisher Scientific, InVitria, Sheffield Bioscience and Mediatech sell recombinant albumin and transferrin. Other commonly used proteins including insulin, aprotinin and trypsin are also available in recombinant form. Please see our recent blog titled “Defined Supplements – The Role of Recombinant Proteins in Biopharmaceutical Manufacturing,” for more details. Each of these products will stipulate that no animal components are used as the biomanufacturing host or in the biomanufacturing. In addition, it is typical that there are no animal components exposed to process or packaging equipment used in Animal-free facilities. The highest standards require a dedicated animal-free biomanufacturing facility that has not been exposed to animal components.

Don’t Cut Corners– if it sounds too good to be true… it probably is

Never before has there been so much emphasis and pressure to cut healthcare costs. However this can’t be done at the expense of regulatory compliance or final product quality. The key to cutting costs is to adopt new technologies that improve manufacturing. For example, better cell culture ingredients can increase product yield. Improved clone selection tools can help engineer better performing cell lines thereby increasing yield. Single use systems can cut cleaning and validation time, allowing more manufacturing runs per year. New state of the art bioreactors allow more control over culture conditions that can result in improved yield and reduced run time. Lastly improved filtration systems can ensure more yield is captured in downstream, thus improving product quality and yield. These are just a few examples of ways to improve manufacturing and reduce cost without sacrificing quality or cGMP compliance.

Know the Source – Country of Origin Declarations

Another key factor in protecting quality is selecting raw material suppliers from countries with an established quality system that share the same commitment to quality. Regular vendor audits and source-verification with Country of Origin declarations on each Certificate of Analysis (CofA) has become the standard for high quality cGMP manufacturers. It does not matter if your manufacturing process is impeccable, if raw materials are not manufactured with the same care, you could be introducing major problems into your manufacturing process. It is critical to find suppliers that use dedicated facilities, cGMP, and that use materials in their manufacturing that are also of the highest quality.

A commitment to quality across the supply chain and through the entire manufacturing process is an important part of maintaining high quality final products. In an industry where maintaining physician and patient trust is critical to long-term business value, there is no room for error. What do you think are the most important considerations in maintaining quality throughout the entire manufacturing process?