As with any business partnership, there is an inherent level of risk and uncertainty associated with selecting a CMO for outsourcing any component of a biopharmaceutical product. Will the CMO be able to deliver on time? Will it be able to provide the regulatory guidance you need? Will its capabilities live up to its marketing hype? Often, one of the best ways to mitigate that risk is to seek references for the CMOs you are considering and solicit the wisdom of experts who have been through the CMO selection process. The latter is exactly what we have done with the following roundtable discussion. The wisdom these experts provide should prove useful to you as the trend toward increased utilization of CMOs continues to rise.
The panel includes James Bruno, managing director, Chemical and Pharmaceutical Solutions and Chemical Consultants and past president of Drug, Chemical and Associated Technologies (DCAT); Greg Troiano, senior staff engineer, process development BIND Biosciences, specializing in development, optimization, and scale-up of drug delivery technologies; and Greg Weilersbacher, principal consultant, Eastlake Quality Consulting, specializing in the design and licensing of GMP manufacturing and testing facilities and the quality systems that support GMP activities. Together they have a combined 60 years of industry experience and wisdom to offer.
What quality metrics do you utilize when building collaborations with CMOs, and why?
James Bruno of Chemical and Pharmaceutical Solutions: The best way to assess facility quality is to visit the site, meet the people, and review the records. Look at the historical position the company has with the FDA. Ask the basic questions, such as, How many times have you been inspected? When was the last inspection? What does the 483 report show? What was your response? What is the history of the QA and QC departments? What is the tenure and turnover of the personnel? Review the logbooks, a batch record, and a corrective action and preventive action (CAPA) plan. Look at their SOPs, and take at least one and follow through with it in the area it covers.
Greg Troiano of BIND Biosciences: From a quality perspective, we pay close attention to environmental monitoring (EM) excursions, out of specification (OOS) results, and handling of investigations. Obviously, you’d like to see as few excursions and OOS results as possible, but they happen. The mark of a good CMO is how it deals with these results. Conducting thorough investigations with client involvement is crucial to maintaining a good relationship and producing high-quality materials.
What new trends do you see with contract manufacturing of pharma and biopharm?
Troiano: There seems to be more focus on facility design and control with regard to microbial contamination. This includes more rigorous cleaning practices, more use of isolators (for both formulation/process work and for sterility testing), and more thought behind environmental monitoring plans. As the use of disposables has increased, there is also less shared equipment, which helps reduce the risk of cross-contamination. On the downside, there have been multiple sterile CMOs in the United States with regulatory problems, leading to a shortage of suppliers in that niche. This has resulted in more costly campaigns and longer timelines.
Greg Weilersbacher of Eastlake Quality Consulting: In the last few years, many smaller CMOs have tried to become one-stop-shops in which commercial market capabilities were added to their clinical-phase production skill sets in response to customers wanting to have one CMO for all development and commercial activities. In many cases, this diluted their expertise rather than expanded upon it. Customers have noticed this as well. I anticipate smaller CMOs returning to the core capabilities and retracting from the commercial market.
How do you assess reliability of CMOs?
Bruno: Reliability is one of the most difficult things to assess. The past record of the company is an important way to assess reliability. Things will go wrong during a project. How they dealt with past problems is a good indicator of how they are going to deal with future problems.
Weilersbacher: An accurate gauge of reliability — the ability to meet timelines and milestones — can only be truly determined through discussions with previous customers. You can start by requesting a contact list of satisfied customers from the CMO, but this will be biased in their favor. Use your network of contacts, including blogs, to find customers who can tell you whether or not the CMO has a good track record. Keep in mind, when making your CMO choice, that bad news travels faster than good news. People are less likely to report the good news.
How do you assess a CMO’s productivity?
Troiano: With only early-stage products right now, we tend to have short campaigns (two to three batches) of relatively small size (< 5000 vials/batch). So our short-term needs for capacity and productivity are not great. That said, we anticipate scale-ups and larger campaigns in the future. So, while we always ensure the CMO can fulfill our current capacity needs, we give some consideration to compatibility with our future scales. This is measured by capacity for running our bulk process, number of vials they can fill per batch, and number of vials they can lyophilize per batch.
Weilersbacher: Productivity is the CMO’s ability to deliver products or services on time. It has much to do with whether the company has overpromised in timelines and/or scientific capabilities. To assess, tour the CMO’s laboratory and manufacturing areas with an eye on the busyness factor. Are there chemists in the labs doing work, and do they look overly busy? Talk with project or lab managers to determine how many projects each chemist juggles. If each chemist is assigned three to four projects, what are the odds your development project will be completed on time? This also holds true for manufacturing campaigns.
How do you evaluate CMOs for regulatory compliance?
Bruno: For overall compliance, I conduct a plant tour. I want to see actual records and logs. Like the FDA, if it is not written down, it was not done. You need to spend some time with the people and get a feel for what they do and how many projects (and complexity) they handle on average.
Having a 483 with some observations does not concern me as much as having a 483 and not knowing how to respond or responding poorly. Too often a 483 becomes a warning letter due to poor communications and poor responses.
Troiano: We always request their audit history and ask for redacted copies of any establishment inspection reports (EIRs). In addition to reviewing the EIRs, we conduct our own audit and focus on the quality systems that most impact our processes and our products. This usually includes training, metrology, quality control sample tracking, aseptic simulation (media fill) history, and their environmental monitoring program.
How would you define CMO accessibility, and how can CMOs demonstrate they possess this characteristic?
Bruno: There is a thin line between accessibility and interfering. It is important that there is a team leader or key contact on both sides. I am doing a project now, and the CMO provided a list of the key contacts with titles and contact information. Have weekly or biweekly calls. If the calls are planned properly, you can cover things quickly. Have an agenda in advance of the call. The better prepared the CMO, the more comfortable the sponsor. I like companies that schedule routine visits with not only the salesperson, but the technical manager, product manager, and management.
Weilersbacher: All CMOs promote they are focused on meeting the customer’s needs for accessibility. Their ability and willingness to live up to this claim is usually found when a problem is encountered during the manufacture or testing of the product. I would prefer being notified about an issue from a CMO in real time, as it happens, rather than hearing about it weeks or months later when it is too late for me to provide input on resolving the issue.
When selecting a CMO, where does cost rank in the selection process?
Troiano: Unless the cost difference is extremely different (>2x), cost is a much smaller consideration than quality, reliability, and technical capabilities.
Weilersbacher: It is rare when price does not factor into the selection process. Whether you work for a large or small company, you still have to live within a budget. Due to the worldwide economic crisis, many CMOs try to underquote their competitors to the point of selling products/services for less than cost. These are the companies to watch out for. What are you willing to sacrifice in the quality of the product or in customer service by going with the lowest bidder?
What are some of the frustrations you have had going through the CMO selection process?
Bruno: CMOs sometimes forget who is paying the bill. Sponsors forget they went to the CMO for their expertise. Sometimes you need to take a step back. CMOs will often want to do everything their way and forget the sponsor has a set of needs and wants. Some sponsors are very shortsighted and forget there are things that should be done now, e.g. analytical development or methods validation, and try to delay it. Process development without strong analytical development can quickly become an issue.
Weilersbacher: One of the biggest frustrations is that many CMOs have marketed themselves as having capabilities they really do not possess. For example, a CMO that is an expert in fill/finish also states it is a formulation guru. Sometimes this is the case, but often the CMO does a great job at aseptically filling vials, but if the formulation crashes, it looks to the customer for help. In my experience, I have had to bring in external formulation experts to fix problems that a CMO could not handle. A CMO should not promise more than it can deliver.
What could CMOs do to make the selection process easier on pharmaceutical and biopharma companies?
Bruno: I am not sure if there is anything that can actually make the whole process easier. For one thing, every company does it differently, and every sponsor is different. I think the CMOs need to clearly define what they are trying to do and how they are going to do it. If both sides understand the situation, the better it will be in the long run.
Troiano: From a selection perspective, if they all listed their full set of capabilities on their website it would be easier to develop a list of potential CMOs. During the interview process, I’d like to be able to get a better sense of how they will manage the nuances of the project. One of the biggest problems we’ve had once the work gets going are small tasks that they are responsible for that slip through the cracks. If not managed right, these things could easily lead to a manufacturing campaign delay.
In addition to good old common sense, our panel of experts has the following recommendations for the CMO selection process. Troiano advises using quality and technical questionnaires with prospective CMOs prior to sending an RFP. This will help your company weed out CMOs who may not meet your needs due to an analytical requirement, capacity, or some other special requirement. In addition, Troiano suggests focusing on the specifics of your product that are not routine.
Weilersbacher recommends meeting with all of the CMO members who will be personally involved with your specific project. These include the scientists and manufacturing and QA/QC staff who will actually produce, test, and release your product. These are the people who will make your project happen. Connect with these folks, and establish a comfort level. These are the ones who will truly give you a good CMO experience.
During an initial evaluation, Bruno recommends defining the process first. To do this, build a strong technical team with a mix of personalities who can work together. Next, make sure the CMO has the right resources and equipment to do the job. Then, evaluate the overall stability of the company, including the tenure of the team members who will be directly involved in your project.
Words Of Wisdom
James Bruno, Greg Troiano, and Greg Weilersbacher have a combined 60 years’ worth of experience in the life sciences industry and have been heavily involved in the CMO selection process. Here is their advice to those involved in the CMO selection process.
Bruno suggests staying involved. “Too often, one side lets the other start to take control. It is important that both the CMO and the sponsor have regular and continuous contact. This means more than regular phone calls. You need to be there periodically. I can never say it enough — this is about communication,” he advises.
Weilersbacher recommends focusing on the CMO’s capabilities and redundancies. “Dig beyond the generic sales pitch, and ask the questions,” he states. Weilersbacher suggests asking, “How many times has the CMO successfully manufactured a product like yours? Can the CMO provide you with a few references from satisfied customers whom you can call? When a specialized piece of equipment breaks, which it will, does the CMO have redundant equipment available to use as backup? Are scientific staff members on-site and available to assist with problems with blending, formulations, equipment, and filling, or will this technical expertise have to be outsourced?”
Troiano believes you need to focus internally before looking externally. “The first thing you need to do is get internal alignment on what your outsourcing needs are,” he says. “Rigorously define the scope and scale of what you want to outsource and why. Then, generate a detailed RFP with all of your requirements and the services you are looking for from a CMO. This includes development, manufacturing, quality control, product storage/distribution, and any regulatory support. Prior to sending the RFP, gather as much information from the prospective CMO via its website, phone calls, and references. Try to narrow the list of potential CMOs to five or fewer before sending out the RFPs. Also, in addition to your quality audit, you should do a separate technical visit to focus on your process and any unique needs your product may have,” he concludes.