- [Yongjun] Welcome. My name is Yongjun Gao.
On behalf of my co-authors,
in this webinar, I will discuss and demonstrate
how to use the Clinical Relevance Approach
described in the FDA MAPPs,
for establishing impurity limits in drug substances
specifications in drug master files.
What's MAPP?
MAPP stands for the FDA CDER's Manual
of Policies and Procedures.
MAPPs are federal directives and documentation
of internal policies and procedures.
MAPPs are required by law,
and are made available to the public
to make FDA a more transparent organization.
FDA's MAPPs can be found at FDA's website.
Today, I will be talking about the two impurity
related to the MAPPS.
The first one is MAPP 5017.2:
Establishing Impurity Acceptance Criteria
As Part of Specifications for NDAs, ANDAs and BLAs
Based on Clinical Relevance.
It became effective on May 1st, 2020.
The second one is MAPP 5310.7:
Acceptability of Standards from Alternative Compendia.
It became Effective on October 13, 2017.
The purposes of these two MAPPS are two-folds.
The first purpose is to provide guiding principles
and approaches for establishing drug substance
and drug product impurity acceptance criteria
for non-mutagenic impurities in NDAs, ANDAs, and BLAS
based on the consideration of clinical relevance.
The second purpose is,
to clarify what the types of data and information are needed
when establishing impurity acceptance criteria
in drug substances and drug products.
Establishing impurity limits in drug substances.
Relevance where are the common challenges
for both of the pharmaceutical industry and the regulators,
especially when ICH guidelines don't apply.
Here, I will be using six real case examples to Illustrate
how to use the clinical relevance approach
from the two FDA MAPPs I just mentioned,
to establish impurity limits
in drug substance specifications in drug master files.
Case one:
The acceptance criterion of a specified impurity
may generally be established at up
to the ICH Q3A Qualification threshold.
If there is no other information to support
the need for a lower limit.
For example, for drug substance Dapaglifozin,
currently there's no compendial monogragh
is ICH Qualifications threshold is a .15%
based on the maximum daily dose, 10 milligram.
The acceptance criterion of each Specified impurity
in the drug acceptance can be said after that
ICH Qualification threshold of .15%.
Case two:
The acceptance criterion of a specified impurity,
should there be set at a lower than
the ICH Q3A Qualification threshold
If there is a compendial limit related to safety,
which is the lower than
the ICH Q3A Qualification threshold for the impurity.
for example, for drug substance Atorvastatin,
which is used for producing
the popular cholesterol lowering drug Lipitor.
The USP Specified Impurity
Atorvastatin 3-deoxyhept-2-enoic acid
under USP limit of .15%.
Although as is each Qualification threshold is
.15% based on the MDD: 80 milligram,
the acceptance criterion
or this impurity in the drug substance specification
should they be set at a maximum of .10%
instead of other Qualification threshold of .15%.
Case three:
The acceptance criterion of a specified Impurity
maybe established at a more than
the ICH Qualification threshold.
If that drug substance has a USP monograph
or it does not have USP monograph
but has other compendial monographs.
added monograph acceptance criterion is greater
than the ICH Qualification threshold.
For example, for the drug substance Esomeprazole sodium,
it doesn't have a USP monograph,
But it has a EP monograph.
In that EP monograph,
EP specified impurity is a controlled at a .2%,
even though ICH Qualification threshold
.15% based on the MDD: 240 milligram.
The EP limit of .2% can be considered acceptable.
It should be mentioned that,
the impurity is should there be verified,
there is no apparent at risk
for example, they did no structural alert.
The assessor, you really should verify that,
the monograph limit has been justified
by some type of data of approved product.
Case four:
acceptance criterion for a specified impurity
in a DMF reference by an ANDA or a 505(b)(2)NDA product
maybe supported side by side comparative impurity analysis
for the proposed the product and the RLD.
Just took you your example,
the drug substance Clindamycin Palmitate Hydrochloride
has a USP monograph.
However, USP has specified impurities.
On the other hand,
ICH Qualification threshold does not apply,
due to this drug substance is semi-synthetic antibiotic,
in this case, since the Nether compared monographs``
nor ICH guidelines apply.
The DMF holder can perform side-by-side
comparative impurity analysis of three batches
of the proposed drug substance and the RLD.
For example,
if impurity one was found
at the level of .5% in post the RLD samples
and in where applicants samples.
The acceptance criterion of .5%
specified impurity one at DMF can be generally justified.
It should be emphasized that,
the comparison should the be conducted on multiple batches
of the proposed the product and the RLD.
The same analytical method should be used for the analysis
and analytical methods that should be validated
to demonstrate that it is suitable for intended purpose.
Case five:
The acceptance criterion of a specified Impurity
may not be set at the ICH Qualification threshold,
if there are known safety data for the impurity based
on is a structural class.
For example,
the presence of a structural alert for mutagenicity.
For instance, for drug substance Dalfampridine
It has a USP monograph.
In the USP monograph
impurity 3,5-dibromo-4-aminopyridine
it controlled at a maximum 75 PPM.
Even though the Qualification threshold is .15%,
based on the MDD: 20 milligram,
the acceptance criterion of this impurity in DMFs
should there be a set at a maximum of 75 PPM
instead of higher ICH Qualification threshold .15%.
Case Six:
The proposed acceptance criterion
maybe supported by data or literature demonstrating that,
the impurity is a significant metabolite of drug substance.
for example, for Macitentan
it has no USP monograph
or other compendial monographs.
The ICH Qualification threshold is .15%
based on the MDD: 10 milligram.
According to the literature in clinical pharmacokinetics,
impurity ACT-132577 is a significant that metabolite
of the drug substance Macitentan,
and it has a no structure alert.
Therefore, the limit for impurity ACT-132577
can be set at ICH Qualification threshold of .15% at IMF.
It should be mentioned that,
in some cases the clinical significance metabolite
maybe subject to pharm/tox
and/or clinical pharmacology consults.
In summary,
the FDA impurity related MAPPs
provide guiding principles and approaches
for establishing drug substances impurity
acceptance criteria for non-mutagenic impurities
as part of specifications for DMFs
based on the consideration of clinical relevance.
These policies can serve as a useful tools
for both drug applicants and for the FDA assessors,
helping accelerate the drug approval processes.
Thank you for your interest.
You can send a question that regarding to this poster
to the following email by February 15th,
for including in the poster QA session, match 4th.
Follow-on webinar for both posters posters/presentations
they will be held on April 9th.
Questions Can be sent to the above email
by March 19th for the webinar.
You can also refer to the following title
that presentation on march 4th for additional information.
Thank you again.