Pharmaceutical companies historically have had confidence in the safety of their nonsterile drugs. The products are made through processes generally regarded as reliable and well established. But developments during the past several years have led many industry professionals to question whether these dosage forms are being produced in a state of control.
In September 2001, Greenstone Brand glyburide tablets were recalled because raw materials used to make them had been contaminated with fungal organisms. Drugmakers gradually perceived a trend of similar problems during the years following that incident. The most recent, and high-profile, example occurred in April 2010, when Johnson & Johnson recalled lots of children’s liquid medications, including Tylenol and Benadryl. This recall was prompted by the discovery that raw materials used to make the products had been contaminated with gram-negative bacteria.
Other factors have increased attention to contamination in nonsterile drugs as well. The industry has noted a growing emphasis on inhaled formulations and dermatological products, both of which carry potentially higher risks to the patient than other dosage forms. In addition, the patient base has expanded to include more individuals with potentially compromised immune systems, such as infants and elderly people, than before.
These considerations have helped generate broad support among manufacturers for enhancing environmental-monitoring programs and finding ways to reduce the risk of microbial contamination in nonsterile manufacturing suites. The US Pharmacopeia (USP) Expert Committee on Microbiology is nearing completion of an informational chapter that will provide general guidance on the development of an environmental-control program for nonsterile production suites. And the International Organization for Standardization’s working group 209 is rewriting the ISO 14698 standards for biocontamination control.
Although drugmakers have begun to perform environmental monitoring in their nonsterile manufacturing facilities, many companies are uncertain about how to interpret the data and develop alert and action levels, says Leonard W. Mestrandrea, principal consultant at Mestrandrea Consulting and chair of the aforementioned USP subcommittee. The industry should record the types and numbers of microorganisms that it identifies in its environmental-monitoring programs and evaluate the information on a quarterly basis, he says. This strategy could provide guidance, based on scientific rationale, for assessing and controlling the risk of contamination.
Not everyone is convinced that the problem is urgent, however. “I don’t think a scientific reason for increased emphasis on nonsterile product monitoring has been established,” says James E. Akers, president of Akers Kennedy and Associates. Given that companies monitor aseptic environments, it might seem logical that they should monitor nonsterile product environments as well, but “it would be the rare nonsterile product that would require comprehensive microbiological monitoring,” says Akers. “Fundamentally, microbial risk to the patient in the use of nonsterile products is low. There may be good reason to make certain nonsterile drugs administered to high-risk patient categories in controlled environments, but generalizing this requirement to all nonsterile drugs would simply add to the cost of these products with no real public-health benefit.”
For this reason, “the consensus among expert microbiologists is that microbiological environmental-control level recommendations would be of little benefit for the vast majority of nonsterile products,” says Akers. Many in the industry question the need to change the current practice of nonsterile drug manufacturing. Some fear that if companies tightened their controls, it would trigger a “regulatory spiral” that inevitably would increase environmental monitoring with no real benefit to the manufacturer or the end user, says Akers.
Good quality programs do not require activities unless they have value to the end user, and the question of contamination in nonsterile manufacturing suites should be analyzed thoroughly from a risk- and science-based perspective, says Akers. Any requirements should be based on data derived from assessment of risk and should result in well-designed processing systems with control points defined to mitigate risk. “The focus should be on reducing risk in processing, not on bug hunting,” says Akers.
So far, no regulatory authority has set formal microbial-control standards for the manufacture of nonsterile dosage forms. FDA’s policy is that individual firms must establish the environmental controls necessary for these products, according to a spokesperson for the agency’s Division of Manufacturing and Product Quality. Even after USP publishes its informational chapter titled “Microbiological Control Programs for Manufacturing Non-Sterile Pharmaceutical Drug Product,” individual companies will be free to strengthen their own monitoring regimes or not, according to their own judgments. The debate about the need for enhanced control and monitoring of nonsterile products likely will continue, but both sides seem to agree that decisions ultimately should be based on an analysis of products’ risk to the patient.