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Exclusive Life Science Feature of quality by design (QbD) among all pharma manufacturers — partly because the transparency of QbD systems could illu- minate many of the now hidden or ambiguous signs of quality problems in production and prevent the need for most 483s and warning letters. James agrees: "Not only is QbD impor- tant, it is an absolute necessity. I know one company that has basically inflicted QbD on every one of its manufacturers over the past three years. As a result, its last drug-product valida- tion went incredibly smoothly. QbD is a life-cycle validation approach that the agency is pushing forward. It is the wave of the future, and if the CMOs don't get on board with QbD, they will get left behind." PREVENTION PAYOFFS Ironically, as with most measures of prevention, you may never know for certain that your efforts succeeded. Only failure pro- duces solid evidence of a measure's degree of effectiveness: success means nothing happens. So lack of evidence offers no proof of concept. But what would you rather have — the cer- tainty of failure or the uncertainty of success? The answer depends on cost. What is the cost of CMO-related regulatory problems? "A lot of the cost will depend on what stage of development you're in," James says. "For example, we had a client that had their only CMO back out of the project just as the initial clinical materials were to be prepared." For many small companies, the cost of the resulting clinical delay would likely exceed available funds, even if their clinical devel- opment could otherwise continue past the disruption. "All of a sudden, your manufacturer is gone. And it's liter- ally cost you nine months of your development timeline to go through the entire process, validating a new supplier for quality, and then transferring the process and getting the new group up to speed — just to be where you were nine months ago," James says. Supplier shutdown can also have fatal consequences for a small company beyond the financial factors. Say the company is in the middle of a Phase 3 trial when it suddenly loses its supplier. No amount of money can restart the trial after a six-month delay to resource the compound; patients have pro- gressed and many will no longer qualify. For a product already on the market, the costs of plant clo- sure and loss of supply may greatly outweigh the expense of landing a new supplier. "Certainly, there is cost in identifying and transferring the process to a new supplier at that point, but those costs are nothing compared to the cost of roughly six months of peak sales," James says. Usually, he says, there will be some lead time after finding out a supplier will not be able to supply — the period between the 483 and the warning letter or closure — in which you can transfer production to your other supplier, if you have one, and as long as you're not losing the primary supplier. The problem is that, if the market is shorted on an approved drug, patients will have to move to another therapy if available and you will permanently lose some of your market share, poten- tially costing you millions. In either case, the liability is probably less than that of a class- action lawsuit if a compromised product gets out to the mar- ket. For example, James says, "Baxter's problems with heparin will be expensive — possibly tens of millions." CALL FOR BACKUP Backup production seems the obvious way to prevent supply disruptions, of course. But it may only be possible for the largest companies, and even difficult in some cases for them, according to James. Having backup suppliers in Phase 1 or 2 is impractical for any product that requires process development, which usually continues through those stages. Unfortunately, he says, that is exactly where many small companies go wrong — choosing a sup- plier that may not be equipped to complete the process develop- ment, as James described. "Some of these small companies, if they The Trouble With Doxil (Originally published in "Unity In More Than Name" (Janssen Biotech), Life Science Leader, March 2012.) One of Janssen Biotech's key oncology products is Doxil (doxorubicin HCl lipo- some injection), which made headlines in 2011 when Boehringer Ingelheim's (BI) Ben Venue Laboratories (BVL) unit, the contract manufacturer (CMO) with sole responsibility for making the product, suddenly announced it could no longer do so. President Rob Bazemore speaks about his company's response to the crisis, its support for affected patients, and the lessons learned: BAZEMORE: Like most companies, we will always rely on strategic partnerships with CMOs, because some of these products that we make are extremely complex, difficult products to make. For ten years now, we've had the partnership with BVL without a single issue of quality or missing shipments or any other problem. Here are some lessons I have learned about what to do when a crisis occurs: • Communicate quickly and frequently with the FDA, physicians, and patients to make sure they understand the issue and its potential impact. Seek out the FDA to help you create solutions. • Provide whatever resources you can, even if it means sending your own company people to the contract manufacturer to help resolve the issue as quickly as possible. • Probably the most important lesson is to be ready to do some extraordinary things, as we've done with Doxil. We put together a program that helped us to quickly identify patients who were on the drug and who should be prioritized for receiving the drug when we had it. It prevented product hoarding and price gouging. If we had just put the available drug in the market on a monthly basis, there was no certainty that the patients who got the drug one month would be the same patients who got the drug the next month. To this day, although we could have done some things better, our response has stood the test of time, and I believe it will be a best practice example of how to handle situations like this when you can't completely supply the market with drug. The CMO Leadership Awards 2012 23