By Mark Moody, VP of Analytical Science, Merrimack Pharmaceuticals
Biologics manufacturing is complex, and it’s worth remembering that this complexity provides many opportunities for bad things to happen – with big consequences. At some point most biomanufacturing companies will have to deal with these sorts of problems, and a successful response to “big problems” requires effective leadership to direct the focused and coordinated efforts of many people in the organization.
Viral contaminations of bioreactors are rare but are high-impact events that illuminate the key factors of a successful response to big problems. Although often unreported, some of these contaminations have made the headlines, illustrating the potentially severe consequences from these types of events. First, there is a potential risk for patients, if not a direct risk from the virus, then from the indirect impacts of drug shortages. Second, there are the risks to the company. Dealing with the contamination can shut down production, divert the focus of employees, and lead to difficult conversations with regulatory authorities and investors.
The Path To Successful Resolution
In 2009, Merrimack Pharmaceuticals experienced a viral contamination, and the lessons learned from successfully resolving the problem demonstrate that, at a high level, there are three factors that can affect the problem: the quality systems that guide and document the work, the science and technology that can identify the root cause and mitigate risks, and most importantly — the people in the organization and how they work together in high-stress situations.
There has been much written on the subject of risk assessment, mitigation, and corrective and preventive actions (CAPAs). And while there are variations on how companies organize these processes, it is very important to follow the systems that your QA department has in place, as the FDA has issued many warning letters for not following established procedures. We have developed an integrated approach of emergency response, risk analysis, root cause determination, and CAPAs. This system utilizes tools such as failure mode and effect analysis (FMEA) for the multidimensional analysis of the risk to patients, the risk to the environment and the community, the impact on the drug supply, and the impact on the company. This analysis needs to be revisited and updated as new information is learned.
It should be noted that, due to different perceptions of harm and different knowledge of the facts, achieving a shared understanding of risk among diverse stakeholders is difficult. Reaching the most accurate understanding — and not a “consensus” assessment — is vitally important. This leads to a strategic question: Who should be on the response teams? With high-impact problems, there can be a desire to include all the stakeholders, but it is often better that the team that guides the response be limited rather than inclusive. If too many people are included who are not functional experts, the team will spend a lot of time on education, or worse, get led down the wrong path. It is important to keep all stakeholders informed, but they don’t need to be part of the process of working toward a solution. The key factor when setting up the teams is to emphasize expertise.
Merrimack’s core team consisted of fewer than a dozen people representing QA, manufacturing, quality control, clinical, and regulatory functions. An honest and systematic evaluation of the knowledge and experience of the team will identify any gaps, which can be filled with knowledge from consultants and guidance from professional associations. This assessment led Merrimack to include a consultant virologist who had worked on similar problems at other companies. Additionally, the teams should include skilled facilitators to help the team stay focused and ensure good chemistry among the team members while they work through this high-stress event.
While the teams are being assembled, it is essential to gain a commitment from senior management to empower the teams to carry out their work. A clear system for decision making should be outlined to determine who has responsibility and authority, and a communication plan should be developed to clarify what is communicated, when it is communicated, and who gets the information. Proactive formation of an emergency response team and development of a generic response plan will increase the likelihood of a quick and successful resolution.
Finally, everyone involved — the teams, the stakeholders, and senior management — should approach the problem with a positive attitude and the understanding that a properly supported team will reach a successful resolution.