USP Article: In Vitro Test Methods for Continuous Manufacturing

Continuous manufacturing (CM) of medicinal products is a young, spreading type of modern production of medicinal products. Unlike classical batch manufacturing, the processes run continuously, i.e. dosing and product withdrawal are uninterrupted and continuously monitored. The development of control strategy or process control through continuous monitoring is already described in some documents. The situation is somewhat different with the release testing methods. A Stimuli article published in Pharmacopeial Forum 48(4) of the USP describes how this could be implemented in future.

Requirements for Continuous Manufacturing

The regulatory requirements for the quality of the product during CM remain the same as for conventional batch manufacturing. The release of a medicinal product, which is usually tested by means of dissolution, is a specific quality characteristic for bioavailability and is relevant for release. Using this method, significant changes in the formulation or manufacturing process that could affect the in vivo property can be detected. A correlation between in vivo and in vitro can also be used to make statements about bioavailability.

However, the applicability of the dissolution test in continuous processes is strongly limited. The dissolution test is time-consuming and can take 1-3 hours, in the case of delayed-release tablets even much longer. Inline testing is therefore not possible, and atline difficult to implement. Another difficulty is the high variability of this test method. In any case, physical samples would have to be taken and examined. Since continuous processes require a larger amount of data to describe the product quality, an even larger amount of samples would need to be taken than in conventional batch processes.

In a conventional batch process, sampling of dissolution samples and batch release testing is usually done after production. Testing is performed on a mixed sample according to well-defined and specified sampling requirements as per USP <711> or Ph. Eur. 2.9.3.
However, in a continuous process, production is scheduled and the concept of a " mixed sample" is quite different from a conventional batch process. There are no well-defined guidelines for mixed samples in a CM process, and the expectations of authorities in different countries may vary. The ICH guideline (Q13), which is expected to be final soon, even excludes release testing.

Release testing methods for products that have been manufactured using a continuous process should have real-time or near-real-time capability, ideally non-destructive.

Two basic approaches

According to the USP article, there are two basic approaches: The first consists of on- or at-line testing, such as at-line dissolution for very soluble medicinal products, which could be done by measuring disintegration.

The second approach is to use data obtained during CM/continuous monitoring to define a non-destructive surrogate test. By establishing a correlation between dissolution and other methods or process parameters, documented control of these parameters during manufacturing can eliminate the need for conventional dissolution testing.

In order to use alternative dissolution testing methods for OSD dosage forms and enable RealTimeRelease, the article recommends that the dissolution mechanism should first be closely examined. This dissolution mechanism depends not only on the solubility, shape and particle morphology of the medicinal product, but may also depend on the manufacturing process and the selection and properties of excipients. This should be used as a guide for the selection of a possible surrogate test or dissolution model.

The article "In Vitro Performance Tests for Continuous Manufacturing: The Impact on the Current Compendial Framework from the Viewpoint of the USP New Advancements in Product Performance Testing Expert Panel" in PF 48(4) is available free of charge after registration.

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