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of the regulators by taking an even tougher approach, pointing out problems that could grow more serious if ignored."
Before getting into what you should do after a problem occurs, James emphasizes what you should do before it happens. "Prevention is always the best course, and the best thing a sponsor can do is audit the facility regularly and have a good quality agreement. You really need to focus on the CMO Quality unit's standard operating procedures. Change control and reporting to sponsor are also very important." Prevention of CMO-related regulatory problems is a chain of observations and prepa- rations that extend from the beginning to the end of the supply chain. If you wish to avoid regulatory problems, not just react to them, you will not wait for them to occur but make it your business to know your CMO inside and out. CMOs naturally have a duty to keep their pharma clients informed of problems, as well as a broad interest in doing so. After all, their business depends on satisfying customers; 483s are public, and a fair number of the problems they herald may be expected to come home to roost, possibly harming the CMO's reputation. (Find 483s at www.fda.gov/AboutFDA/CentersOffices/officeofGlobalRegulatoryOperationsand Policy/ORA/ORAElectronicReadingRoom/default.htm.) Unfortunately, however, because some CMOs are not always candid, you cannot count on being informed in every case unless you insist on it. Commonly, because 483s and warning letters are specific to a given product, another company using the same CMO for other products may not see them. Even if your contract with the CMO stipulates that it share all 483s and warning letters it receives, take steps to ensure that happens.
Sometimes, a CMO inadvertently fails to inform the sponsor — as when it makes a change for one client but does not realize the change affects another client. "There has to be a good change control system in place," says James. "That's very critical. The CMO project managers need to know who they should inform about such changes. I don't think there is anybody who has a really good system for that, at least not that I've come across yet."
For ongoing prevention, James says regular communication between you and your CMO has no substitute. In the best cases he has seen, the responsible managers on both sides hold weekly or biweekly teleconferences to go over everything from process development to production schedules. During early runs, the companies have some- one on site to supervise and report back any issues that might arise. Even with the best communication, however, he says that analytical tests can com- plicate matters, mainly by delaying problem identification and sometimes limiting candor. Too often, he says, the CMO fails to follow through with the client, believing
Who Is Brian James?
Brian James, MBA, Ph.D., is now a VP of operations at Rondaxe, a firm that audits and advises pharma manufacturing operations and companies. He has broad devel- opment expertise that includes API, drug product, and CMO sourcing, and he is well experienced with regulatory issues that arise between drug sponsors and their CMOs. At Rondaxe, he oversees project management, API synthesis design, and API/formu- lation sourcing support to clients. He manages and oversees projects ranging from pre-IND (investigational new drug) chemistry development to prelaunch validation and material sourcing for late-stage clinical trials. Previously, Dr. James was associ-
ate director, global actives and intermediates, Bristol-Myers Squibb (BMS) Company, and before that, senior scientist, technical operations planning and sourcing, and Chemical Development Laboratories, at BMS. He earned his Ph.D. in chemistry at the University of California and his MBA at LeMoyne College.
The CMO Leadership Awards 2012 21
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