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.