COURSE NUMBER: 6.
ANDA QUERIES AND RESOLUTION
1
6.6 ANDA QUERIES AND RESOLUTION
Introduction
• After the submission of the ANDA, USFDA may raise any Queries / Gaps / Deficiency /
Additional Information / Clarification regarding the submission and will contact the company
(Through US agent) regarding it.
• The company should respond to the query with proper justification and within the stipulated
timeline. Failure to provide correct response or crossing the stipulated timelines carries the
risk of further delay of approval or Protocols, etc.. of the submission.
even rejection
• There are different types through which query management takes place.
2
6.6 ANDA QUERIES AND RESOLUTIONA
Back Ground
• In October 2012, with the implementation of Generic Drug User Fee Amendments (GDUFA I),
the FDA initiated a program to act on received ANDAs within previously agreed timeframes.
• As part of this undertaking, the FDA instituted the use of multiple types of letters regarding
queries, request for information, deficiencies. These are:
➢ Information Request (additional information to complete review)
➢ Discipline Review Letter (Possible deficiencies
Protocols, etc.. observed during mid point of review).
• At the end of review, FDA will issue either:
➢ Approval Letter
➢ Complete Response Letter (All deficiencies)
➢ Tentative Approval Letter
3
6.6 ANDA QUERIES AND RESOLUTION
Refuse to Receive (RTR)
• The ANDA is verified in an initial review and would be Refused to Receive (RTR) if any
of the following deficiencies are observed in initial checking:
1. Application form is not complete (Form FDA 356h)
2. eCTD format not maintained
3. If ANDA fees not paid
4. Lack of designated US agent Protocols, etc..
5. KSM for API is not justified (in DMF)
6. Excipients are exceeding the limit as prescribed in Inactive Ingredients Database (IID)
7. Inadequate Stability data with stipulated time period (6 months Accelerated and months
long term data). If significant change observed in Accelerated, months intermediate stability
data required
8. Commercial Blank BMRs and executed Exhibit batch records should be submitted
9. Inadequate Method validation / verification data for each analytical tests for both Drug
substance and drug product
10. Score line difference between RLD and Generic 4
6.6 ANDA QUERIES AND RESOLUTION
Queries
• USFDA will provide responses and queries to the ANDA in the following manner:
1. Information Request (IR)
2. Deficiency Response Letter (DRL)
3. Complete Response Letter (CRL)
Protocols, etc..
5
6.6 ANDA QUERIES AND RESOLUTION
1. Information Request (IR)
• Information Request (IR) is a letter sent to an applicant during an application assessment to
request further information or a clarification that is needed or would be helpful for completion of
the ANDA review / Discipline review.
Discipline means: Quality, Chemistry, Labeling, Bioequivalence etc. Review for each discipline is
carried out by subject experts for each discipline inside CDER.
• It is provided as soon as any information is required to complete the discipline review.
Protocols, etc..
• The applicant can receive multiple IRs (from multiple disciplines or same discipline) during the
review period.
• Timeline is provided to provide the required information, generally 7 – 15 Days. Response to each
received IRs should be provided within the timelines.
• If extension is required for response, application for extension should be provided within 7 days of
receiving IR letter.
6
6.6 ANDA QUERIES AND RESOLUTION
2. Deficiency Response Letter (DRL)
• Deficiency Response Letter (DRL) is a letter sent to an applicant during an application
assessment to inform the applicant of possible deficiencies observed during the ongoing
assessment.
• It is submitted at the conclusion of a particular Discipline review.
Discipline means: Quality, Chemistry, Labeling, Bioequivalence etc.
• It is generally issued at the mid point of the ANDA
Protocols, etc.. review process.
• Multiple DRLs may be possible from a discipline.
• Timeline is provided to provide the response to the DRL, generally 30 Days.
• DRLs are issued so that the applicant can start working on the deficiencies soon enough.
• It is not considered as a final response of USFDA.
• The unresolved DRLs can be a part of the final Complete response Letter (CRL) which will
contain all the final deficiencies.
7
6.6 ANDA QUERIES AND RESOLUTION
3. Complete Response Letter (CRL)
• Complete Response Letter (CRL) is the final letter sent by the agency to the applicant
which states that the ANDA cannot be approved in its current form, due to the complete set of
deficiencies which are provided thereafter.
• It is provided at the end of review by the multi-disciplinary review team.
• It is not considered as a rejection of application.
• It is considered as a course-correction method
Protocols, etc..and will contain recommendations and
suggestions to correct the deficiency.
• Timeline is provided to provide the response to the CRL is 1 year.
• If the applicant is not able to provide the complete response to CRL, it should provide an
application for extension of review period. The application for extension should contain:
➢ Reason for not providing the complete response within the stipulated 1 year period.
➢ Progress made so far with respect to the response activities.
➢ The required extension period.
8
6.6 ANDA QUERIES AND RESOLUTION
3. Complete Response Letter (CRL)
• Based on the justification provided, agency will provide the required extension.
• Deficiencies in CRL are classified as Major and Minor.
Protocols, etc..
9
6.6 ANDA QUERIES AND RESOLUTION
Examples of Common Deficiencies
• A quality and error free submission will result in First cycle approval of the ANDA. If
deficiencies are observed, it can lead to multiple cycle reviews and delays in ANDA approval.
• Each submission must take into account all the learnings and deficiencies encountered during
earlier submissions and strive for continual improvement.
• Common Deficiencies observed are:
1. Specification provided are not suitable
Protocols,justified
etc.. and not based on batch analysis data.
2. Labeling updates particularly in RLD or in USP, literature etc. are not updated.
3. The sub-contract facilities are failing in regulatory inspections: Drug substance, Drug
substance intermediate, Contract testing labs, CROs etc.
4. Deficiencies in providing data on impurities, elemental impurities (ICH Q3D), Genotoxic
impurities.
5. Undesired polymorphic form observed
6. Presence of NDMA (N-Nitrosodimethylamine) and other N-nitrosamine impurities in drug
substance.
10
6.6 ANDA QUERIES AND RESOLUTION
Examples of Common Deficiencies
• Common Deficiencies observed are:
7. Physical description of the product not comparable to Reference Listed Drug (RLD)
including functional score.
8. Justification of overages/overfill (if any) not provided.
9. Comprehensive PDR should be submitted which should include:
➢ Reference Product characterization
Protocols, etc..
➢ Quality Target Product Profile (QTPP)
➢ Critical Quality Attributes (CQAs)
➢ Critical Material Attributes (CMAs)
➢ Critical Process Parameters (CPPs)
➢ Drug-excipient compatibility studies
➢ Other scientific studies (DOE study, tablet split study, extractable-leachable study,
elemental risk assessment for FP, etc.)
11
6.6 ANDA QUERIES AND RESOLUTION
Examples of Common Deficiencies
• Common Deficiencies observed are:
10. Manufacturing process flowchart should include all input materials, unit operations, in-
process controls and in-process tests.
11. Differences in results between vendor’s COA and Drug Product manufacturer COAs (if
any) not justified appropriately.
12. Proposed specification shouldProtocols,
be supported
etc.. by exhibit batches data and RLD (wherever
applicable). Wherever possible, the limits should be tightened on the basis of 6-months
stability data in order to avoid FDA deficiency asking for tightening.
13. Full validation/method equivalency of in-house methods should be provided along with
method transfer if the release testing site is different from the validation site.
14. Justification for low yield and CAPA not provided.
12
QUESTIONS
13
THANK YOU
14
