Incorporate guidelines and standards

To help prevent manufacturing deviations, manufacturers can put into practice key points from the International Conference on Harmonization's quality-trio guidelines (Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System), advises Parexel's O'Hara. "I would suggest that companies take the time to understand the guidelines, train their staff, and have a good implementation plan," she says. "The deviation system is just one of many valuable Quality system tools a company should use to encourage continuous improvement, which helps not only the compliance of the company but also the bottom line.

The ICH quality-trio guidelines are also pushing drug manufacturers and regulators to focus more on corporate responsibility when it comes to managing risk and potential manufacturing deviations, according to PRTM's Prutow. A key message from ICH Q8, Q9, and Q10, says Prutow, is that "quality, safety and compliance should not to be limited to the domain of the quality unit and compliance organizations. Rather, the ICH tripartite emphasizes that executive management must be effective at preventing risks from spreading. Furthermore, the tripartite takes risk well beyond the product itself to the broader supply and business domains making an enterprise risk approach more important for all pharmaceutical companies, especially when they face threats in areas that may not have originally been expected (i.e. wooden pallets causing issues at Johnson & Johnson).

The ICH quality-trio also incorporates the concept of knowledge management, an idea that has been the topic of many industry forums and conferences during the past several months. Information can be used to a drug manufacturer's benefit, according to experts. "Companies collect data, track and trend deviations and complaints, and monitor CAPAs, but in many cases, that's all that's done," says Parexel's O'Hara. Taking these data and actually analyzing them can yield valuable information. For example, a company might group deviations into similar problem types and root causes and use that grouping to determine whether a deviation is occurring in the same department, during the same shift, or when using a certain piece of equipment or certain part of the process, she explains.

In the case of a recall

In day-to-day manufacturing, an automated CAPA process can be interfaced with a knowledge management repository to maximize access to the data and minimize the need for re-entering data into multiple systems, recommends Pfizer's Kentrup. "A well-integrated CAPA system can be invaluable with regard to overall product-knowledge management by providing access to information regarding the issues that have been addressed in one central repository or via a single link."

Knowledge management can also play a role when a company is manufacturing multiple products that share specific components or processes, says PRTM's Prutow. "One best practice is the use of virtual dynamic centers of excellence, or user communities, which allow sharing of practices and opportunities across a specified area, such as validations or aseptic practices. The centers of excellence ensure knowledge of issues and best practices across the company," he explains.

Finally, involvement of management is crucial for several reasons, says Parexel's O'Hara. Management is ultimately responsible for how the company responds to risks and the actions taken has the authority and responsibility to provide the resources (e.g., financial, staff) to ensure that the company produces a product that is safe and effective (and in a safe and compliant environment) and can encourage the engagement of staff, which aids in ensuring success from the design of a product to a finished product. These three factors encourage staff to anticipate issues, and to voice their thoughts as to why or how a deviation occurred and aid in CAPA. Their knowledge and experience is invaluable in the deviation and CAPA systems processes.

Don't overlook the supply chain

Beyond the manufacturing floor, it's crucial for quality teams to pay attention to raw-material sources and potential supply-chain gaps at the international level. For example, explains Jian Liu, PhD, associate professor of the Eshelman School of Pharmacy at the University of North Carolina. Liu has researched extensively the heparin contamination of 2008, which was largely the result of a shortage of pigs (their intestines are used to manufacture the blood-treatment product).

It should not have been a surprise to drug companies that "the worldwide production of heparin exceeds 100 tons/year, which is isolated from 500 to 700 million pigs, and that the entire US pig production is only about 60 to 65 million/year," says Liu. When the pig shortage started to gain traction, manufacturers should have been looking for potential counterfeit problems. A key lesson learned from this incident, says Liu, is that, "Manufacturers must monitor the quality of products from suppliers and have adequate controls in place to prevent the counterfeits, especially those highly sophisticated counterfeit products (i.e., such as the oversulfated chondroitin sulfate used in the heparin contamination).

In order to reduce risks associated with material sources, industry and regulators might also consider enforcing "high purity standards," says Liu, For example, after the heparin crisis, FDA and the US Pharmacopeia worked to revise the heparin monographs to contain higher purity standards. Such standards, however, can be a double-edged sword, he says, because excessively high purity can narrow profit margin and hurt honest suppliers.