By Kevin Wall, principal consultant and owner, Cincero Consulting
Choosing the right contract development and manufacturing organization (CDMO) is the most important factor leading to the success of drug product development. Small and virtual companies outsource their product and process development as well as their manufacturing. It is the CDMOs that execute the projects. They have the biggest impact on your overall success. To be successful, you must look past the opening presentation, the facility walk-throughs, and even the compliance audit. I am a firm believer in the team approach to vendor selection. You need the right people asking the right questions if you are to make a wise decision. The vendor needs to be well-rounded and well-staffed, and your selection team should be the same. Here are three things to consider when selecting a CDMO.
1. Does it have adequate human capital?
No project proceeds right the first time, on budget and on time, unless the people executing the project have sufficient expertise in sufficient quantity. Great facilities with a compliant QMS are very important, but they are not the prime factors that ensure success. It is the people at the CDMO who have the biggest impact on project success. You cannot simply audit your way into selecting the best CDMO. You must assess both the skills of the people and their capacity to take on new projects.
When it comes to skills, great CDMOs will anticipate your needs. For example, one European CDMO had a deviation on analytical transfer due to a new impurity being identified. By the time we came to work in America, they had already proposed a tentative impurity structure and examined other lots to see if the impurity was present. Our ability to act quickly and to assess the magnitude of problem was facilitated by the CDMO knowing what to do and acting accordingly. The quality management system (QMS) and facilities did not drive those results. The competence and decision-making ability of the people running the facility and QMS did.
Having competent people is not enough. There should be enough competent people to execute your project. I had CDMOs that passed the quality audit and had people who interviewed well in person. However, the bandwidth of the key individuals was stretched, resulting in delays on critical path items. Investigations took longer than needed. Reports were not right-first-time. The best of people will create substandard work when stretched too thin. In one case, the CDMO only had one analytical method expert who could troubleshoot problems and draw scientific conclusions. He had too many projects demanding his time. Our project suffered, and it was not because of the scientist. He simply had too many tasks.
I make it a point to assess the following on my audits:
- Do the validation records and investigations demonstrate competent scientific thought?
- Are they timely?
- Do they have a backlog in investigations?
- How many senior scientists and engineers do they have in relation to the project load?
- Will your project be the proverbial straw?
2. Do they understand quality risk management?
Quality by Design has become expected in regulatory submissions. Identifying critical quality attributes and critical variability is the heart of the control strategy and writing the chemistry and manufacturing controls (CMC) section. Every CDMO sales presentation has slides on the company’s approach to Quality by Design. You need to remove the bows and ribbons and take a deeper look. Is there substance behind the buzzwords?
You can assess their risk management understanding by examining their equipment qualifications. Do they follow the ISPE approach to direct impact and indirect impact systems? Risk management principles should be woven into their records, from installation qualification through performance qualification. They should have a well-documented, risk-based approach to cleaning validation. Did they identify and challenge difficult to clean locations and process materials? The facility monitoring program should follow a risk-based approach as well. The sampling locations and intervals should be data-based and take process risk into account. The important factor is gauging the CDMO’s understanding and application of risk management principles. These system records do not have customer proprietary information and therefore should be available for your review.
I want to see tangible examples of how they identify critical process variability. They should provide examples of experiments they typically run. How have they identified critical parameters in projects like yours? What challenges did they overcome? When reviewing investigations, look for a risk-based approach to analyzing the data. Do they correlate the data to the critical quality attributes, even if they are not formally defined? Do they execute purposeful experiments? Is there a documented rationale for the plan? Does the rationale make scientific and risk-based sense, or does it seem like trial and error?
If this seems like a job interview, then good. You got my point. It is one of the most important job interviews you can conduct.
3. Can they meet your analytical development needs?
By far, analytical development is the number one reason projects fall behind schedule. The amount of time and resources needed to properly execute an adequate analytical program is often grossly underestimated. I want to make sure the important message is clear. The overall project success will rise or fall based on the validity of the analytical methods. The analytical methods generate the data the development scientists use to plan experiments. They generate the data to characterize the product. They produce the data used in investigations. They generate the data used to release product. They support the regulatory submission. It surprises me how many times the difficulty of analytical development is underestimated. The common question in all projects is: How much analytical validation is needed at a given phase of development? I like to answer with, “How much project risk are you willing to take and how are you going to prove the methods are fit-for-phase?” Problems arise when teams try to cut corners to shave time off the development schedule. Firms struggle with when to spend money on a project. That can lead to delays in beginning analytical activities. When schedules get crunched, analytical development can become one of the casualties. Hence, the competence of the CDMO to effectively develop and validate methods is critical. Will the project take on extra risk because the CDMO does not have enough capacity? The CDMO must have enough available capacity to meet the rigors of the project timeline.
Your CDMO is the one developing and executing these methods. Can they execute the things needed, when needed? Look beyond the obvious, such as linearity, accuracy, robustness, and specificity. For example:
- Do they have the bandwidth and expertise to generate chemical markers for validation?
- Are they managing their marker production, or are you?
- When can they qualify reference standards? Do they have a process?
- Do they have the capacity to properly store all the reference standards?
- Are they competent to deliver the reference standards to your other labs that need them?
- Do they have a pattern of qualifying standards at the last minute before they either run out of time or reach the retest date?
If you can only check one thing, understand how the CDMO executes analytical transfer, either as the sending laboratory or receiving laboratory. If they treat analytical transfer as a check-the-box exercise, move on. My favorite nightmare was when the sending and receiving labs did not use the same qualified reference standard. The two labs did not have equivalent detectors (the validation did not account for differences in detection methods). The receiving lab did not integrate the baseline the same way as the sending lab. I could go on and on, but you get the point. The CDMO must be able to address the details of analytical transfer.
Choosing a CDMO is the most important task on your development timeline. It is a decision that has lasting impact on your success. I believe in spending money where it matters most, giving the biggest upside and mitigating the biggest downside. Choosing the right CDMO is the place to spend the money. So, choose wisely.
About The Author:
Kevin Wall is principal consultant and owner of Cincero Consulting. He has worked with five virtual pharmaceutical companies to move eight of their drug substance and drug product projects through development. He applies “fit for phase GMP” from Phase 1 to commercialization. Wall’s process for identifying critical quality attributes (CQAs) and critical process parameters (CPPs) forms the basis for the CMC section of the regulatory submission (ICH Q11). He led the Johnson & Johnson development and global deployment of quality by design (ICH Q8) and quality risk management (ICH Q9) in pharmaceutical development and operations. He helped define and deploy Janssen’s risk-based qualification and process validation systems (ICH Q7). You can contact Wall at 817-915-0822 or firstname.lastname@example.org, or visit his YouTube channel, cGMP Made Easy.