◆ Data Integrity Problems as Main Topic of an FDA Warning Letter (17-Aug-22 ECA)
Data integrity continues to be one of the main topics during FDA inspections. One of the contributing causes for the warning letter to the American company Vi-Jon was the lack of controls to ensure the integrity of electronic data as well as insufficient access control to IT systems.
Based on an inspection which was carried out in October 2021 the FDA sent a warning letter to the American company Vi-Jon, LLC, on 31 March 2022. The company’s answers dated 3 November 2021 regarding the complaints listed in Form FDA 483 were deemed inadequate by the FDA. FDA warning letters make reference to the GMP requirements stipulated in 21 CFR Part 211. In this case the claims concerned data integrity:
Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(a))
The company’s answerThe company stated the following:
These answers of the company as regards the observations were deemed inadequate by the FDA. Why?
What does the FDA expect in the answer to this warning letter?A comprehensive, independent assessment and CAPA plan for IT system security and integrity. This includes a report that identifies design and control vulnerabilities, and appropriate remediations for each of the laboratory computer systems. This report should include but not be limited to:
SourceWarning Letter to Vi.Jon, LLC, dated 31 March 2022◆ China GMP: New Annex 13 for IMPs (24-Aug-22 ECA)
n May, the Chinese National Medical Products Administration (NMPA) published their new Annex 13 “GMP for Investigational Medicinal Products (IMPs)”, which was incorporated into the Chinese GMP guidelines on July 01, 2022.
The working group that prepared the first draft of the Chinese “Annex 13 Investigational Medicinal Products (IMPs)” was already established in 2015. The first public consultation was held in late 2018 and the second consultation period started in early 2022. The published version now contains the following 14 chapters:
So far, the guideline is only available in Chinese language and can be checked on the NMPA website. ◆ USP Article: In Vitro Test Methods for Continuous Manufacturing (31-Aug-22 ECA) 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 ManufacturingThe 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 approachesAccording 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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