- Hi, my name is Mahmut Levent.
I'm going to present a poster
on list of relevant quality guidances
and common deficiencies
observed during Drug Master file review.
I would like to mention
that this presentation is (indistinct)
by Sad Ahmed.
Purpose and objective.
This presentation is intended
to provide a non-exhaustive list of relevant guidances
and discuss common deficiencies
to improve submission quality.
Poster is organized by CTD sections.
Each session includes commonly observed deficiencies
and relevant guidance that are helpful
to address deficiencies.
Section S.1.
Guidances.
Drug Master File guidance for industry.
ANDAs, pharmaceutical solid polymorphism:
chemistry, manufacturing
and controls information.
Examples of deficiencies.
The general properties section S.1 fails
to contain all relevant information.
Please provide chilarity, polymorphism,
hygroscopicity, melting range for the drug substance.
Please provide a letter of authorization
for each referencing application in module one
section 1.4 of your DMF.
Section S.2.
Here are some of the guidances.
Process validation.
General principles and practices.
Q11, development and manufacturer of drug substances.
Q11, questions and answers.
Q7, good manufacturing practice
for active pharmaceutical ingredients
Q8(R2), pharmaceutical development.
Q9, quality risk management.
Examples of deficiencies for section S.2.
Please provide a statement
that your manufacturing facilities are
in compliance with applicable cGMP requirements.
Include all contract labs cGMP statement.
Please revise your synthetic scheme
to include chemical structures
with reagents, solvents
and reaction conditions as appropriate.
Potential impurity X is expected
in your manufacturing process.
Please discuss your control strategies for it
with supporting data as necessary.
Please provide summary of your process validation
for the manufacturing process
such as validation, batch description,
starting material analysis, IPCs,
intermediate and final API analysis in a tabular format.
Section S.3.
Here are the guidances.
M7(R1), assessment and control
of DNA reactive mutagenic impurities in pharmaceuticals
to limit potential cardiogenic risk.
Q3A, impurities in new drugs substances.
ICH Q3C, residual solvents.
Q3D, elemental impurities.
ANDAs, impurities in drug substances.
Here are the examples.
In your manufacturing process,
for example X, Y, and Z are plausible impurities.
Please discuss your control strategy for these impurities
and their downstream derivatives.
Please include them to the specification
with the justifiable limits if needed.
Please comment on the following possible process
or degradation impurities
and demonstrate that if present,
the related substances test method would detect them
so that they can be controlled appropriately.
Section S.4.
Here are some of the guidances.
Q6A, specifications.
Test procedures and acceptance criteria
for new drug substances and new direct products:
chemical substances.
Q6B, specifications.
Test procedures and acceptance criteria
for biotechnological, biological products.
Q2B, validation of analytical procedures.
Other helpful information,
USP 43-NF 38.
General chapters, 621, chromatography.
Examples of deficiencies.
Please revise the limit
of any individual unspecified impurity acceptance criterion
in your drug substance release and stability specifications
to not more than 0.1%
to be aligned with ICH Q3A.
Per USP 621
where there is not a monograph available,
the RSD for assay determined by table one RSD requirements.
Please re-evaluate the RSD the requirements
for the assay tests
and provide the updated system suitability
Section S.5.
Guidance.
Analytical procedures and methods validation
for drugs and biologics.
Other helpful information,
USP 43-NF 38, general chapter 11.
Reference standards.
Examples of deficiencies.
Please provide qualification
of your in-house reference standard
against USP reference standards if available.
Please provide the source, lot number, COA
for the primary reference standard
or working reference standard
for each of the following identified impurities.
Section S.6.
Here are the guidances.
CFR, code of federal regulations, title 21.
Q1A(R2). Stability testing
of new drug substances and products.
Other helpful information.
USP monographs.
Examples of deficiencies.
Please revise the storage temperature
on the drug substance label
to USP controlled room temperature
or 20 Celsius to 25 Celsius degrees
with excursions permitted
between 15 Celsius to 30 Celsius degrees.
Or provide long-term stability data
that supports a 30 Celsius degree storage temperature.
Please align your caution statement
with 21 CFR 201.122(a)
to contain caution for manufacturing,
processing or repacking. RX only.
Section S.7.
Here are the some of the guidances.
Q1A(R2), stability testing
of new drug substances and products.
Q1B, photostability testing
of new drugs substances and products.
Q1C, stability testing
for new drugs and products.
Q1D, bracketing and matrixing designs
for stability testing of new drug substances and products.
Q1E, evaluation for stability data.
ANDAs, stability testing
of drug substances and products.
ANDAs, stability testing
of drug substances and products.
Questions and answers.
Example of deficiency.
They acknowledge you have provided six months of accelerated
and 12 months of long-term stability data
from the three validation batches.
Please clearly indicate the retest state
for your drug substance.
Resources.
ICH website,
FDA guidance documents,
USP website.
And conclusion.
The goal is to be able to deem the DMF submissions adequate
in the first cycle.
It is possible to limit the review cycles
and a number of ICH and FDA guidances are available.
DMF holders are encouraged
to consult the FDA guidances document page.
For the spot we received
we would like to thank Dr. Ramnarayan Randad,
Dr. Erin Skoda,
Dr. Wei Liu.
Thank you for your attention.
Please send questions regarding this poster
to a DMFworkshop2021@fda.hhs.gov
by 2/15/2021
for inclusion in the poster question and answer session
on March 4th, 2021.
Follow on webinar
for both posters, presentations
on April ninth, 2021.
Questions can be sent to the above email
by 3/19/2021 for the webinar.
Please refer to to the following posters
for cross-referenced materials.
Administrative process, V.Selvan.
Please refer to the following presentations on March 3rd
for additional information.
Effective communication strategies
by D. Skanchy.