Biopharmaceutical manufacturing involves large-molecule drug substances that are biologically produced using recombinant technologies such as microbial fermentation or mammalian cell culture. It is significantly more complex than the manufacturing processes for traditional small molecule drugs (SMD), which is often a matter of scaling-up a tightly controlled chemical recipe.
As a producer of biologics, a biopharmaceutical company is entrusted to make safe medicines for the public. Quite often this responsibility is delegated to an outside contracted organization. There are substantially more contract manufacturing organizations that service the SMD industry, and with less choice and a higher complexity, identifying a biologic CMO can be difficult.
Large molecule CMOs expect questions that put the spotlight on an expertise that has been won through deep experience, and which can be more difficult to identify. Any well-established CMO expects the typical generic questions about the size of their staff, their project management style, and quality record, but the complexity of biologics makes it imperative to consider some "tough" questions that need asking when seeking a more specialized large molecule CMO.
1) How will the CMC section of the IND be handled?
Get right into the nitty-gritty details. When it comes to biologics, the CMC requirement is significantly more complex for biologics. All of the manufacturing activity is going to boil down to a comprehensive Chemistry, Manufacturing and Controls (CMC) section in the biopharmaceutical company’s investigational new drug application (IND). That’s the ultimate goal, and for both commercial therapeutic products and clinical material, a CMC section grows, as drug development progresses, and will have to be filed as part of the regulatory requirement.
The CMC houses all the manufacturing results and much more – control and release of raw materials and cell banks, method of manufacture and process controls, container closure system, and quality system details – essentially all the information that has been collected on behalf of the client biopharmaceutical company, or in this case, by the CMO. Still, IND responsibility always lies with the client biopharmaceutical company.
As a biologics manufacturer, it is vitally important that the CMO you engage is going to understand what the CMC requirements are, and most importantly, be one step ahead in knowing what information is necessary to gather for that filing. The best CMO is one who can help you amass all the information and prepare and write those regulatory and compliance items for you. Look for a CMO with the personality of an experienced guide, not a follower.
2) Scale-up is almost complete. What happens next?
More often than not, a client comes to a CMO with a process they have been scaling for months or years and, often, that may be too late. Decisions that could adversely impact licensing and regulatory approvals may have already been made. The best CMOs like to see the process scale-up early, so they can help clients avoid the errors that have caused others to stumble. Early on there is still time to advise and to suggest changes.
A willingness to ask tough questions about the process of a client’s scale-up is important. While such questions at an early stage of the relationship may seem intrusive, it suggests just the opposite – a biologics CMO who understands your process deeply enough to ask the right questions. Look for the CMO who has walked EMA and FDA through their facilities as a matter of course. Ask how many times those regulatory agencies have visited and ask for the results. This is linked to choosing a CMO that has strong CMC and process development expertise, one that can provide technical and written support for regulatory filings.
3) What process used to monitor outsourced activities and maintain relationships with external suppliers and labs?
Great biologics CMOs like this question, because it separates the good from the great. How does a prospective CMO partner monitor outsourced activity and what kind of relationships do they have with external suppliers and labs? A one-way relationship will not work. Ask to see documents that reveal a strong two-way dialogue with outsourcing laboratories and other research organizations.
One example: Raw material release seems simple. The CMO buys the raw materials, but the testing for USP or EP compliance is outsourced. Some CMOs do this in-house, but these are few, since these services are expensive and time consuming. It involves more than simple procurement. All those materials have to be released, sent back out to an independent lab for ID testing, and (if USP or EP), must meet the specifications for that reagent, for example. All of this interaction requires the CMO to have forged strong relationships with these testing labs.
A great CMO will have a team or even a single individual who has more than a cameo relationship with these laboratories, and has become intimate with every step of the process. They can demonstrate their true “ownership” of these external relationships and show them as an integral part of the CMO quality system. As a follow-up question, ask a potential CMO, “How are outsourced activities integrated into the internal quality system?
4) Question the “culture of development.”
Even if you are just interested in commercial manufacturing, ask about the “culture of development” when you interview a target CMO. Occasionally, as mentioned previously, a biotech company comes to a CMO with an unfinished or poorly designed process. It may be that since the client requires just a small amount of clinical material, they have developed their process quickly and thus, it may not be completely reliable. In this common scenario, having an eye “back” towards development when evaluating the manufacturing process can be useful for identifying simple roadblocks and solutions. The new term is CDMO (Contract Development Manufacturing Organization). A CMO partner does not need to show the bandwidth (and expense) of a full development laboratory, this subtle line of questioning is really asking about intellectual services – and process development experience. A “culture of development” mentality in a CMO manufacturing organization will view a process as a science problem first, and then as manufacturing process.
Specialized knowledge around how to run the unit operations and properly scale them, how to accurately evaluate performance, plus expertise in designing in-process controls to demonstrate that each step is performing properly, are all reasons why biotech customers, in particular, need to be very choosy about where they outsource their manufacturing. A CMO should have a team of people that has the expertise in specific biologics manufacturing processes that align with their customer base, and they should be able to support it with a strong development background.
5) What is the difference between peptide chemists and protein chemists?
This question is somewhat facetious, but will stop small molecule specialists in their tracks. Even inside the biologics world, there are significant differences in production of peptides versus large protein therapeutics. Someone who understands the nuances of the large molecule biologics world will answer this question and show that they are a CMO who has lived the process challenges, not just learned them for the initial meeting. The subtle differences between the biologics production of peptide versus protein will give rise to issues that a CMO team that is “learning on the job” has not faced before. (And this question will produce a knowing smile on the face of the large molecule teams, an excellent sign).
IS THE CMO ASKING YOU THE RIGHT QUESTIONS?
The flow of questions should be a two way street.
Early on in the selection process, a biopharmaceutical scouting team should take careful note of the questions asked of them, by the CMO. Considering the complexity of biologics manufacturing, there can be facets of the manufacturing process that some CMOs simply have not mastered. The type of probing questions posed by the CMO suggests how well they grasp the scope of the manufacturing process. This is a strong indicator that the CMO fully appreciates a client’s requirements and expectations.
To establish a successful partnership with a client, the CMO should thoroughly evaluate the request for proposal (RFP) and meet with the client to clarify any outstanding concerns. There should be an open dialogue with specific questions around process clarification. Upfront diligence in defining the scope, deliverables, and requirements of a program are an indicator that the CMO knows exactly what is being asked of them and they are certain they can deliver. So expect probing, confident questions as an excellent sign. Then, turn it around: Ask how the manufacturing, process, laboratory staff got “into biologics.” The discipline is still less than 50 years old, so finding 30+ year experienced veterans in large molecule processing is not always a given.
From the get-go, is the CMO making suggestions? Are they forthcoming with complex manufacturing issues and strategies to mitigate problems? Look for a CMO that will impress with their knowledge by being engrossed in the process from the very beginning.
A CMO that specializes in a particular biologics process as a large percentage of their business will have the correct equipment and unit processes, and investments will continue to be made in equipment that suits the niche they have chosen. This translates to advantages from a resource allocation standpoint, and advantage to the client.
Even within biologics, there is a huge difference in the equipment needed to make smaller proteins versus large proteins. As a biotech that is looking to outsource manufacturing of therapeutic products, ask questions to ensure the CMO that chosen is committed to the process required. This sort of specialized process understanding can mean the difference between success and failure.
Although a large molecule biologics CMO may be chosen to handle manufacturing, the name on the IND is not the name of the CMO. It goes without saying that when an outsourcing partner CMO ships a biologic, above all else, it must be 100% compliant. With the complexities inherent in these processes, comes a different approach to identifying and interviewing CMO candidates. A great biologics CMO will be there every step of the way and not only recognize, but anticipate, the issues. Ask these tough questions. The best and most experienced large molecule CMOs can handle it.
ABOUT THE AUTHOR
Angelo P. Consalvo is a Director of Manufacturing at Enteris BioPharma. With over 30 years experience, Angelo has been responsible for development of viable manufacturing processes for recombinant peptides and proteins originating from mammalian and microbial expression systems. He served as Director of Recombinant Process Development at Unigene Laboratories from 2009 – 2013. In 2013 he joined Enteris BioPharma, where he is heading up the recently launched contract manufacturing business for products produced exclusively in microbial expression systems. Angelo can be reached at [email protected]