Understand Your Process: A Key to CMO Risk Mitigation

Eric SmartBest Practices, Manufacturing

partnership puzzle pieces shutterstock_132720506

partnership puzzle pieces shutterstock_132720506The global pharmaceutical industry outsourced an estimated $65 billion in drug manufacturing volume to contract manufacturing organizations (CMOs) in 2016, according to the research firm Mordor Intelligence. Pharmaceutical companies contract out to CMOs to reduce capital expenditures and the costs of manufacturing, to gain access to specialized manufacturing methods, and to gain redundant capacity to mitigate the risk of supply interruptions or unanticipated spikes in demand.

The advantages of contract manufacturing come with certain practical risks. Most of those risks are associated with inadequate communication and knowledge transfer between the drug’s originator and the CMO. Most are preventable.

This post is the first in a series of three on the subject of CMO risk mitigation. We approach this subject from the perspective of a sterile drug product CMO. But the principles are equally applicable to other dosage forms, as well as in API manufacturing. Our focus will be to establish methods to reduce project risks when moving from the laboratory to a GMP manufacturing setting.

In these posts we will try to help managers evaluating contract manufacturing to:

  • Determine how to work with the CMO to determine critical process parameters;
  • Explore strategies to control or eliminate process variables; and
  • Learn how to bridge the gap from lab scale to manufacturing scale.
Successful Collaboration With Your CMO

No matter how careful and comprehensive your supplier selection process is, it can give you only a high-level understanding of a supplier’s capabilities and culture. Inevitably, unknowns will remain after you’ve selected your CMO. These unknowns represent project risks.

How do you identify and mitigate these risks before you select your CMO?

  • Start with due diligence in the supplier selection process. The process must involve someone from your organization (or a consultant) with the knowledge to assess whether the supplier has the requisite skills, experience and infrastructure to carry out your project. Infrastructure is tangible; it should be the easiest of these criteria to evaluate. A site visit is critical, not only to see the facilities but to meet key personnel. And of course, ask for references from clients with similar projects.
  • Keep costs in perspective. Guard against letting the price tag of a proposal play a disproportionate role in supplier selection. The cost of a failed batch or major quality issue invariably outweighs any savings you might get from taking the lowest bid. Consider using a scorecard approach to final selection in which cost is only one of several critical factors.

Once selected, your CMO should expect to be subjected to a Quality Audit (a step that sometimes can be done during due diligence), and must be willing to sign onto a Quality Agreement that includes performance metrics. Provisions should also be put in place to allow feedback during and after project.

Risk Reduction After Project Initiation

Effective preparation can prevent surprises and generate confidence in the success of the collaboration. But how can you mitigate risks once a project is underway?

  • Set performance expectations early. Establish a set of project milestones before a project is initiated and ask for regular progress reports. These should include:
    • Target dates for key milestones (e.g. – completion of technology transfer, manufacturing readiness, batch manufacture and release dates), and
    • Specific, ideally quantifiable targets for critical quality attributes.
  • Get to know the supplier. Partake in a kickoff meeting and frequent, regular mid-project progress meetings/calls. Establish clear lines of communication. There should be a primary point of contact for the CMO – typically a project manager. Ensure you have access to other key team members and management (when necessary). Make sure that the supplier knows that communicating bad news is just as important (if not more so) as communicating good news. Strive for continuity of the team from start to finish – sometimes a change of personnel is necessary, but frequent changes increase risk (e.g., in the loss of institutional knowledge).
  • Transfer as much of your knowledge about a process as possible – as early possible. The CMO will need access to development reports, your experience from previous manufacturing (if any), and any safety information you can impart. If possible, be on site during lab-scale runs, but in any event ensure laboratory process chemists/formulators are scheduled to either participate or advise during production of the first plant-scale batch. There are, in fact, professional standards for this kind of knowledge transfer. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has developed a widely accepted model, called ICH Q10, for a pharmaceutical quality system that can be implemented throughout the different stages of a product lifecycle. Consider adopting this model.
  • Take it in stages. Consider a stage gate to assess readiness to move on to each successive step in setting up production.
  • Avoid letting a relationship become adversarial. Point out where things aren’t going the way you want. Accept responsibility for problems when they are not of the CMO’s making.

Your goal before moving to production scale should be to identify Critical Process Parameters (CPPs). CPPs are key variables affecting a production process and that when monitored, can detect changes in Critical Quality Attributes. Even in a never-before-manufactured product, CPPs should be identified prior to attempting manufacture. The next post in this series will address how these variables are identified and how to control or eliminate process variables that can affect quality. Stay tuned.

About the Author
Eric Smart

Eric Smart

Eric Smart is the Senior Advisor, Aseptic Manufacturing at Singota Solutions and President of Fountainhead Pharmaceutical Consulting. Prior to his current roles, he was President of Piramal Pharma Solutions’ aseptic manufacturing business based in Lexington, Kentucky. Eric earned his BS in Chemistry from Vanderbilt University and an MBA from the University of Maryland. After serving eight years as an officer in the United States Navy, he began a career that has spanned 24 years in the pharmaceutical contract manufacturing industry. Eric’s experience includes leadership roles in sales and marketing, operations, laboratory services and executive management at a number of contract development/manufacturing companies including roles at Albemarle, AlliedSignal/Honeywell, Organichem, AMRI and Coldstream Laboratories/Piramal Pharma Solution. Eric established Fountainhead Pharmaceutical Consulting which provides services to a wide variety of pharmaceutical, biotechnology and CMO companies in the areas of manufacturing operations, project management, vendor selection and due diligence. Most recently, Eric accepted a position with Singota Solutions as an advisor as they install and qualify a state-of-the art automated sterile fill operation.