DMF section 3.2.S.4 - Control of drug substance

The DMF in CTD format consists of 7 sections. In this video, we will talk about section 3.2.S.4, which will describe how the manufacturer performs the quality control of the API. This section is divided in 5 parts - specification, methods, validations, batch analysis, and justification of specification.

The information needs to be coherent throughout these different subsections and also in line with the previous DMF sections. For example, if the impurity section describes that a certain impurity is controlled in the API specification, this should be reflected here.
We don't want any surprises here regarding the control of impurities, because in theory everything was already well explained in the previous section, so we know what to expect.

This section starts with the API specification - that is, all the tests which are performed in routine for each batch of the API which is produced, to decide whether or not that batch is approved.
If the DMF complies with a certain pharmacopoeia, a comparison with the API pharmacopoeial monograph is done here, and this means that if the API is tested with the tests described in the monograph, it will pass. So even if the specification limits are tightened in relation to the monograph limits, we can also consider that it complies with the pharmacopoeia.

Each one of these tests is done through a method, an analytical procedure, and these need to be described in the section that follows. Even if some tests are outsourced, the complete procedure needs to be described.

Analytical methods need to be validated, and the analytical validation will be provided next.
For pharmacopoeial APIs, if the method is exactly as described in the monograh, the v
alidation may be only partial. However when there are differences, the method is considered in-house, and a complete validation will be needed.
The ICH guideline that should be followed is Q2. This guideline explains which parameters need to be part of the validation, depending on the purpose of the method. For example, identification tests only need to demonstrate specificity. On the other hand, tests for quantifying impurity levels need to have a complete validation with all the parameters shown on this table.
In case impurities are controlled as unspecified impurities, the validation should demonstrate the capacity of the method to detect such impurities - even if a pharmacopoeial method is used to control in-house impuriities.

After the validations, batch analysis results are presented for the 3 batches that were used for the process validation, which were tested using this specification and these methods that were described. In case any test is only performed for a specific customer, for example particle size, it may not be part of the certificates of analysis presented within the DMF, although its method and validation will be necessary for that customer.

Finally, we will also see a justification for each test which is part of the specification, describing why it was chosen for the quality control of that API, and why these limits are considered acceptable. Are the limits based on any pharmacopoeial monograph or ICH guideline? Is there any qualification study for impurities with limits higher than the qualification threshold as per ICH Q3A?
If this is the case, another regulatory submission may be needed, so that this study be assessed by a team specialized in toxicology.
Also, in case the microbiological analysis test is not part of the API specification, a justification for its absence needs to be presented, in line with the principles of ICH Q6A.

And this was section 3.2.S.4.
The next video will be about section 3.2.S.5, which is about the reference standards. Stay tuned!

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