Thus, with reasonable assurance, we can adjust a process to meet certain parameters and expect a product that resembles past lots. These monitors are a godsend to production managers. When PAT reaches its true efficiency, there will no longer be OOS (out of specification) investigations, simply because no lots will ever be OOS.
While the process itself is of great value to control, it is important to keep the purpose of the process in mind: to deliver the proper medicine, in the proper dosage form, to patients. Whether we are making simple aspirin for headaches or immune suppressants for liver transplants, we are making medicine, not potato chips! Two key features are part and parcel of the finished product: it must contain the correct amount of (pure) drug substance AND it must deliver it in the proper fashion.
The correct amount of API (active pharmaceutical ingredient) is critical. In fact, most of our release testing focuses on the assay of the API. Another important test measures how quickly it releases from its matrix. While we design immediate-release products to explode in the stomach and release the drug all at once, controlled-release forms are more complicated. These are designed to deliver a controlled and metered amount of the active to a specific part of the GI tract over a specified amount of time.
After an innovator produces a new drug and establishes the release rate for efficacy, generic manufacturers will attempt to mimic this pattern with their products. Why make them the same? They mimic the innovator profile to ensure the delivery (hence bioequivalence) of their drug substance. Currently, one of the best ways to measure this release rate in the QC lab is dissolution.
Just what is dissolution and why does it matter? Dissolution is placing a single, solid dosage form (sdf) in a controlled (usually aqueous) environment and, via various measurements, observing the rate at which it releases into the solvent. In one configuration, a paddle agitates the solvent with the sdf at the bottom of the vessel, allowing the drug to dissolve in a gentle, reproducible manner. Another method is to place the sdf in a small basket, which is spun to effect dissolution.
During product development, studies are performed to correlate this dissolution rate with blood levels in clinical trials. This in vivo/in vitro correlation shows that dissolution reasonably measures what the sdf does in a patient. Does the blood level reach a therapeutic, ineffective or toxic level?
On the other hand, this test, when used as a QC tool, indicates whether a batch of product, placed on stability testing, will release in a manner similar to the clinical studies. It is merely a prediction, not truly an assay.
In itself, thats not a bad thing. Surely companies cannot perform thousands of clinical trials to measure blood levels of all drug lots and all stability time points. If it were even physically possible, cost and time factors would place the retail cost of drugs beyond most peoples reach. So, we are left with a QC tool called dissolution. Considering we have not been producing bad products, it must work.
However, recall that dissolution is a prediction with a tenuous correlation to reality (i.e. bioavailability). NIR is used to predict a method that is, in itself, a prediction. Having used NIR to predict dissolution (under controlled, limited circumstances) since the late 1980s, I have found that an amazing number of parameters affect the rate of release: particle size (API, excipients), moisture (amount, location), hardness of the tablet, cluster sizes of drug, etc., etc.
Much work is being done, using wonderful techniques such as chemical imaging, to elucidate which factors affect release rates and why. However, we are in the Kitty Hawk stage as far as 100% predictability of dissolution using NIR. When I read reports of a 13-factor PLS equation being used to predict dissolution times, I have great trepidation. In some cases, we are approaching astrology, not science.
My conclusions are simple: NIR is a tool. Like any other tool, it has limitations, one of which is lack of a direct reference material. We have a long way to go before we can consider abandoning final testing completely. The major improvements in PAT will be: months of warehouse time obviated, tons of materials NOT destroyed, and eventually, better products produced. In the meantime, we need to keep repeating: Drugs are not potato chips. After whittling the process time from months to days, how much can a few hours of lab time cost?