If a biologics (API) batch for clinical study use was already manufactured, does the FDA still require sterility test if it wasn’t tested before it was used in the manufacturing process of the drug product? If yes, the risk of drug contamination increases. Would they still require a sterility test, or is a passing a test of zero bioburden conducted prior to (drug product) manufacturing sufficient? Drug contamination can occur when taking the drug through the sterility testing room because the package will go through vigorous cleaning processes using harsh chemicals. Then, when the drug is ready for packaging, these harsh chemicals may break through and contaminate the drug product.

The first part is the easy part. Any product for parenteral use should be sterile, whether it’s in clinical trials or not.
Yes, under an IND, the first concern would be safety, so yes, the sterility test would be required for that. The other concern when talking about the manufacturing steps is that it wasn’t clear where they wanted to apply the sterility test. Was it at various points along the manufacturing or was it for the final product? The biologics regulations are very specific. If you have a discrete bulk, prior to filling that bulk product there should be a separate sterility test, and then an additional sterility test after it’s filled in the final container. For the biologics product, it’s two parts. There seems to be an implication in the question that passing a sterility test means the product is sterile. That’s not necessarily true or the best way to look at it. The best way to look at it, whether you’re making clinical products or marketed products, is that they’re supposed to be handled in a manner that keeps them from becoming contaminated; processed, especially near the end, by methods that have been validated, such that you have a high degree of assurance that the product in the vial is sterile and the test merely confirms that. To think that passing the sterility test is the only thing that’s necessary to assure that the product is sterile is oversimplifying the problems.
For some small volume parenteral operations, when the solution is sterilized and put into a sterile tank, that whole process is validated in order to assure the sterility of the sterile bulk solution. Often, once that has been validated, during routine manufacturing it is highly possible that the manufacturer may not sample the bulk solution because they always run the risk of contaminating it. That’s perfectly acceptable, as long as they have adequately validated that process. That is a common thing in small volume and other parenteral manufacturing. The situation in CBER drug products is a little bit different because of the two-part sterility test. One is the requirement to do a sterility test on the final product. But, again, if there is a discrete bulk, that would have to undergo a sterility test, as well. That is something that is required under the regulations.