Last month 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). The list of deviations included concerns about sterility assurance, failure to monitor the manufacturing environment, failure to assure an adequate system for disinfecting aseptic processing areas and equipment, problems with the current stability testing program, failure to report a number of change controls to FDA, inadequate personnel training, and what appears to be issues with bacterial and endotoxin levels stemming from raw materials. There were more deviations, but you get the idea.
As I read through the warning letter I couldn’t help being reminded of the problems that Genzyme faced in 2009. In June 2009, Genzyme discovered a viral contamination in one of its plants that led to a shut down and clean up, which lasted three months. Two of their most successful drugs went into severe shortages – Cerezyme to treat Gaucher Disease and Fabrazyme to treat Fabry Disease. The plant shut down resulted in rationing of the drugs and only the patients most in need received treatment at partial dosing. As a result, Genzyme’s competitor Shire received Food and Drug Administration (FDA) fast track status for their experimental Gaucher Disease treatment in an effort to relieve the shortages with Cerezyme. Shire also picked up significant market share on their drug to treat Fabry Disease, which competed with Fabrazyme. Prior to the Genzyme manufacturing problems, Shire had 45% of the market, this rose to 80%. On top of lost revenue and lost market share from new competition, Genzyme also faced FDA fines. All these problems left Genzyme vulnerable and in February 2011, Sanofi-Aventis announced that they were acquiring the company.
Regrettably these scenarios are not rare. There has been an increase in the number of quality problems and a subsequent increase in warning letters has appeared over the last decade in the biopharmaceutical industry. With the pressure to keep drug costs low, some companies have adopted policies that have reduced cost while causing quality to suffer. In biopharmaceutical and vaccine manufacturing there is no room for failure. Cost cutting strategies employed today can cost companies much more in the long run, as experienced first hand by Genzyme.
This is particularly true in the area of vaccines. It is unfortunate, but vaccines have gotten a bad reputation lately. First there is the misguided, non-scientifically based fear that vaccines cause autism. Despite the fact that this concern has been disproven and the original proponents of the idea discredited, it still lingers and makes parents question whether they should have their children vaccinated on schedule. A recent study in the Journal Pediatrics studied parents in Oregon and found that an increasing number have put their children on a vaccination schedule that “delays or limits receipt of recommended vaccines.” Second, just the fact that vaccines are most often administered to children, raises safety concerns and scrutiny by the public. Lastly vaccines are administered to otherwise healthy individuals and as such the public has a lower tolerance for adverse side effects. These issues put vaccine manufacturing under a microscope and as an industry vaccine manufacturers have to do everything in their power to maintain safety that is above reproach.
Quality by Design planning and execution is one important key in CGMP manufacturing. This approach has benefited many industries and FDA adopted these principals specifically for biologic and drug manufacturing in September 2006 in their guidance “Quality Systems Approach to Pharmaceutical CGMP Regulations.” In January 2011, FDA issued the guidance “Process Validation: General Principals and Practices,” which provides an outline for their Quality by Design expectations for biologic and drug manufacturing. While these documents provide a comprehensive course for FDA’s CGMP expectations, I believe that the industry may be neglecting some available technologies that could perhaps work to reduce CGMP compliance challenges. The industry is slow to adopt new technologies because they require additional regulatory approvals, which leads to delays and additional regulatory and testing costs which can be substantial. For this reason, many manufacturing systems have not been upgraded using the best available technology, which can present risks to public health.
Several areas could be effectively addressed between FDA, European Medicines Agency (EMA) and the industry to improve biomanufacturing processes.
First would be to 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.
There was once a time when removal of these animal products would have been extremely difficult because replacement products for serum did not exist. That is not the case any longer. A new class of media supplements that are animal-free and defined allow for the reduction or removal of FBS from virus cultures. These supplements provide a way to maintain the health and productivity of cells without compromising safety. In addition many of these supplements are recombinant and provide the consistency that is lacking in animal products. This improvement in consistency can result in more efficient manufacturing and ultimately lower costs. Please see our blog “Improving Media to Increase Virus Yield in Vaccine Production,” for specific information. In addition, there are companies working on commercial animal-free vaccine media. For example in June, InVitria, was awarded a $1.5 million dollar grant “to use InVitria’s cell culture supplements to develop a novel, animal-free, defined cell culture media for the commercial production of cell-based vaccines.”
FDA also appears to be taking a tougher stance on blood derived products. They recently published a guidance that would require a warning label be added to all products containing human blood derived albumin in their manufacture. The warning would state that due to the plasma-derived source of albumin, albumin may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease and the Creutzfeldt-Jakob disease agent. Please see our recent blog “FDA Issues Guidance for Warning Labels on All Drugs Produced Using Blood Products Including Plasma-Derived Albumin,” for more information. The new warning label will heavily impact vaccine manufacturing, but it doesn’t have to because there are recombinant versions of albumin available. Today companies including Sigma, Fisher Scientific, InVitria, Sheffield Bioscience and Mediatech sell recombinant albumin that could be used to replace animal-derived versions.
A second technology that could improve biomanufacturing is the implementation of single use systems. Single use systems offer an attractive option in the area of bioreactors with some benefits that are particularly well suited to virus production. They offer similar growth and productivity to stainless steel bioreactors but are more flexible. Single use systems have a faster turnaround time between batches because there is much less cleaning and validation necessary than with stainless steel tanks. Please see our guest blog “How Single Use Systems are Improving Bioprocess Development,” for more information. Cleaning and validation can be costly and time consuming steps in the manufacturing process and can delay the next manufacturing run. They are also responsible for many issues of CGMP non-compliance.
No one should ever question the potential contributions of vaccines on public health, without them we would still have some of the deadliest and most contagious diseases on the planet including small pox, polio and measles to name a few. Perhaps even more critical to our future is the fact that new vaccines are in development to protect us against terrible diseases including HIV, West Nile Virus, Dengue Fever and Ebola and Marburg. In the Sanofi warning letter, FDA stated “Given the potential contributions of safe, pure, and potent vaccines to the public health, we encourage frequent interactions between your technical staff and FDA in an effort to help Sanofi move forward with corrective actions as rapidly as possible.” The key to maximizing vaccines’ impact on public health is to continue to provide diligent safety by implementing the best technology available to improve manufacturing safety, timeliness and efficiency so that the industry can maintain public trust and widespread vaccination compliance.
These are a couple ideas to improve CGMP compliance, there are many others.