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GMP or QSR for Combination Products?

One of the biggest challenges in manufacturing a combination product is figuring out when to apply the medical device Quality System Regulation and when to apply the drug Good Manufacturing Practices. Linda Alexander, president of Alquest Inc., said it's pretty straightforward during the phases where different components are made separately. Apply the QSR when making the device and apply GMPs when making the drug or biologic. But, she said, the decision is much more difficult once one reaches the phase of manufacturing the overall product.

She spoke in March at the PharmaMedDevice conference held in Philadelphia. A draft guidance published in 2004 offers some advice, but it is still up to the manufacturer to sort out which parts of the QSR apply and which parts of the drug GMPs apply, Alexander said. "You must justify what you choose to follow, especially in areas where they conflict," she said. She said device manufacturers who may not have experience with the drug GMPs will need to keep the following provisions in mind, as they differ quite a bit from what's in the QSR: * 21 CFR 211.84: Testing and approval or rejection of components, containers, and closures. Identity tests (preferably United States Pharmacopoeia) must be performed on all components, containers, and closures that come in. They cannot be used until they have been tested and released for use by the quality control department. * 21 CFR 211.103: Calculation of Yield. Manufacturers must specify or estimate expected yields, and state them in the batch record. A firm must designate one person to calculate them and another to verify them. Any deviation must be corrected to prevent recurrence. * 21 CFR 211.137: Expiration Dating. Drug products must bear an expiration date determined by stability testing (for more on stability testing, see below). It must appear on the labeling. * 21 CFR 211.165: Testing and Release for Distribution. Tests to determine the identity and strength of each active ingredient must be performed on each batch. Tests to ensure the drug is free of objectionable microorganisms must also be performed on each batch. The accuracy, sensitivity, specificity, and reproducibility of test methods must be established and documented. * 21 CFR 211.166: Stability testing. "It's kind of like shelf-life testing, but not," Alexander said. One crucial difference is that accelerated-aging tests may not be used in lieu of real-time tests. Accelerated-aging tests can only be used to support tentative expiration dates, pending the outcome of the real-time studies. The tests must be performed using the same package that will be used on the marketed product. * 21 CFR 211.167: Special Testing Requirements. Drug products purported to be sterile or pyrogen-free must undergo tests to prove that. This section also has provisions relating to ophthalmic ointments and controlled-release dosages. * 21 CFR 211.170: Reserve Samples. Manufacturers must retain a sample of product that is representative of each lot. The amount of samples kept must be at least twice the quantity necessary for all tests required to determine whether the active ingredient meets its established specifications, except for sterility and pyrogen testing. The purpose is to help diagnose a cause in case of a recall. The problem is that an individual medical device is usually much more expensive than an individual package of drugs, so the reserve-sample requirement can be quite burdensome for combination-device manufacturers. "It could mean holding onto millions of dollars worth of product if you're dealing with something like a drug-eluting stent," said Alexander. "That does not make any sense. Especially since what they're really looking for is the degradation of the drug." Michael Gross, prinicpal consultant of Chimera Consulting and a member of the Combination Products Coalition, said the issue is "totally unresolved," and FDA appears to be dealing with it on a case-by-case basis. -- Erik Swain

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