RA Documents for Submission Time lines

Stability Date in is Day Zero

QA Review
Sr.
Documents Name Acceptable/
No.
Comments

Details of any outside testing/ manufacturing facility with contact

1
details and cGMP certification. (if applicable)

2 Current Starting material specification

3 Current Starting material STP

4 in-house COA of the batch (Starting material) used in exhibit batch.

Corresponding vendor COA (Starting material) of the batch used in

5
exhibit batch.

6 Each raw materials current specification

7 Each raw materials current STP

8 Each raw material representative COA (Vendor)

9 Each raw material representative COA (in-house).

Page 1 of 21
 RA Documents for Submission Time lines
Stability Date in is Day Zero
QA Review
Sr.
Documents Name Acceptable/
No.
Comments

Characterization data of KSM if available or sample is required for

10
performing characterization study

11 Current Specification for in-process control

12 Current STP for in-process control

Current Specification for intermediates for each used in final API

13
exhibit batches

Current STP for intermediates for each used in final API exhibit
14
batches

Page 2 of 21
 RA Documents for Submission Time lines
Stability Date in is Day Zero
QA Review
Sr.
Documents Name Acceptable/
No.
Comments

15 COAs of intermediates for each used in final API exhibit batches

16 Hold time study reports

Page 3 of 21
 RA Documents for Submission Time lines
Stability Date in is Day Zero
QA Review
Sr.
Documents Name Acceptable/
No.
Comments

17 Process validation protocols & reports.

18 Any additional addendum (if taken)

19 Process development report

Data for metal catalyst/reagents/possible genotoxic impurities (To

20
be outsourced)*

Any other additional data which need to be performed one time for
21
exhibit batches

Current specification of drug substance along with microbiological

22
testing

23 Current STP of drug substance.

Page 4 of 21
 RA Documents for Submission Time lines
Stability Date in is Day Zero
QA Review
Sr.
Documents Name Acceptable/
No.
Comments

Analytical method validation reports with representative

24
chromatograms for KSM

Analytical method validation reports with representative

25
chromatograms for INT

Analytical method validation reports with representative

26
chromatograms for API

27 COAs of exhibit batches in line with current specification

Current COA of reference standard & working standard along with

28 complete characterization data & qualification data of WS against
RS. Overlay IR with USPRS/ EPCRS is required.

29 WS standard COA used in method validation studies.

30 Impurity standards COAs used in method validation studies.

31 Residual solvents WS COA used in validation studies.

Container closure system, specification of primary packaging,

32 secondary, tertiary packaging along with representative vendor and
corresponding in-house COA of packaging material.

33 Food grade certificates

34 IR of packaging material against USP RS

35 Specimen label of final API

Page 5 of 21
 RA Documents for Submission Time lines
Stability Date in is Day Zero
QA Review
Sr.
Documents Name Acceptable/
No.
Comments

36 Specimen label of final API

37 Justification for the retest date (if applicable)

38 Current version master batch processing records of each stage

39 Executed batch processing records exhibit bathes of each stage

Page 6 of 21
39 Executed batch processing records exhibit bathes of each stage
RA Documents for Submission Time lines
Stability Date in is Day Zero
QA Review
Sr.
Documents Name Acceptable/
No.
Comments

40 TSE/ BSE, RSC & Melamine Certificate from Vendor

41 Post Approval Stability Commitment (PASC)

Page 7 of 21
 RA Timeline
10/20/2018
Reference
CQC review Time lines
Document Time lines
Acceptable/ Comments (IN DAYS)
Number

1. cGMP certificate not available and in given is not well enough.

10/15/2018 0
2. Outside facility agreement and audit details are not provided.

Acetone semicarbazone is KSM and specification prepared in Format GSOP-067/F-4 (Annexure-4). This
annexure-4 is applicable for the Intermediate and in-process specificaiton however for RM/PM/Rec Solvent 10/15/2018 0
annexure-1 is applicable.

Acetone semicarbazone (INPSTP/001/06):

1.Biurea content test parameter included in specification and this impurity has no impact on final API.but
Impact on this impurity has not done in Final API. (specificity was not performed with Biurea content in API) 10/15/2018 0
2. As per GSOP-067-02, PONIT NO. 5.14.3 Numbering procedure for STP in given below .XXXXX/IC/AA for
Raw material but Intermediate STP numbering system followed. (Common).

1. As per specification no. ST/INT/001/05 one test of Biurea content (wt% by HPLC) (NMT 2.5%) given but in
COA's test results are not reported.
2. AS1SR001 (Pre-validation) batch was used to manufacture NF1SR006 batch and this batch was
consumed to manufacture final API batch NFTSR006 (Validation with recovered solvent). 10/15/2018 0
3. In COA page of page not given.
4. COA format is not hormonised. (Format no., Title of format).
5. COA was not prepared as per SOP QCD-S008/F12.

Not Provided 10/15/2018 0

All specifications are not provided. Follwings are not provided:

2-Furaldehyde, Methanol, Hydrochloric Acide, Acetic Anhydride, Potable Water, Mixed IPR Acetic acid (NF2), 10/15/2018 0
IPR acetic acid.
1. Acetic Anhydride: STP not available
10/15/2018 0
2. Conc. Nitric Acid: STP not available

1. Acetic acid : Vendor COA not proper legible. 10/15/2018 0

1. All representative COA are not provided. Follwings are not provided:
2-Furaldehyde, Methanol, Hydrochloric Acide, Potable Water, Mixed IPR Acetic acid (NF2), IPR acetic acid.
2. Retest period (date) of COA is not inline with specification.
3. Option of Expiry/Retest date not ticked for thyl Chloroacetae, Hyflow, Sodium carbonate. 10/15/2018 0
4. Vendor name is not matching in COA with validation report for Nitric Acid and Sulfuric acid.
5. Purified Water COA: Limit of description is not inline with the specification. In COA additional information of
tastless.

Page 8 of 21
 RA Timeline
10/20/2018
Reference
CQC review Time lines
Document Time lines
Acceptable/ Comments (IN DAYS)
Number

Not Provided 0

In-process specification of 5-Nitro-2-furfural diacetate (FD2) not provided 10/20/2018 0

In-process STP of 5-Nitro-2-furfural diacetate (FD2) not provided 10/20/2018 0

Available and OK 10/15/2018 0

Distilled 2-Furaldehyde (INPSTP/005/01): Chromatographic purity test, solution stability not mentioned in
STP (After AMV completion).
5-nitro-2-furfural diacetate:
Nomenclatures of 5-nitro-2-furfural diacetate was not harmonized in all stage (eg. 5-nitro-2-furfural diacetate
(Intermediate, NF-1) 5-Nitrofuraldehyde diacetate, Nitrofuraldehyde diacetate (Final API) 5-nitro-2-
furfuraldehydrate diacetate in (in process, NF-1).
5-nitro-2-furfural diacetate (INPSTP/003/04): 10/15/2018 0
1. LOD value not mentioned
2. Solution stability not mentioned
Nitrofurantoin Crude (INPSTP/009/01):
1. As per Specification water content by drying at 140 c but define in STP water content BY KF
Nitrofurantoin Crude (Step-1):
AMV not performed for Chromatography test but it is part of specification.

Page 9 of 21
 RA Timeline
10/20/2018
Reference
CQC review Time lines
Document Time lines
Acceptable/ Comments (IN DAYS)
Number

1. In batch no. FD2SR004, test name is wrong, 5-Nitrofuroic 2-furoic acid istead of 5-Nitro-2-furoic acid.
2. Result reporting is not hormonised in batch no. FD2SR009 result reported as BLD for 2-furfuraldehyde and
in batch no. FD2SR010 result reported as BDL for 5-nitro-2-furoic acid.
3. In batch no. FD2SR010 option for retest/ expiry is not ticked.
4. Retest period is 90 days as per specification ST/FNT/009/01, and as per GSOP-066 retest to be assigned
from manufacturing date but during review of the COA's, retest period is assigned from date of release
instead of date of manufacturing.
5. Validation batches of NF1 released delay details are as below
NF1SR003:
Date of Mfg: 16-04-2018
Date of release: 23-08-2018 10/15/2018 0
NF1SR004:
Date of Mfg: 01-06-2018
Date of release: 12-09-2018
NF1SR005:
Date of Mfg: 03-06-2018
Date of release: 12-09-2018
NF1SR006:
Date of Mfg: 06-07-2018
Date of release: 19-07-2018
Post validation batch is released before the validation batches.

1. Hold time study summary report given instead of hold time study report.
2. Frequency of testing given monthly in FD2 and Days in NF2 (wet cake).
3. Validation batches of NF1, initial results are not given in summary report.
4. For NF1 hold time study 1 month and 2 month results are released before initial results.
5. 5-nitro-2-furfural diacetate (FD2) (ST/INT/003/04): As per AMV report (R-AMV-NFD-003-17) LOQ Value
10/20/2018 0
of -nitro-2-furfural diacetate-0.03 %, but Hold time report for Batch no-FD2SR005,total impurity reported
0.01 instead of BQL.
6. Nitrofurantoin monohydrate (Step-II) (ST/FP/006/03): As per AMV report (R-AMV-NFT-002-17) LOQ
Value of Nitrofurazone-0.004 %, but Hold time report for Batch no-NF2SR005, Nitrofurazone impurity
reported BDL instead of BQL in initial result.

Page 10 of 21
 RA Timeline
10/20/2018
Reference
CQC review Time lines
Document Time lines
Acceptable/ Comments (IN DAYS)
Number

5-Nitro-2-Furfural Diacetate (FD2):

1. In first report it is KSM of Nitrofurantoin however in addendum report it is not, but justification for the same
is not given.
2. Reason for validation is different in protocol and report and its addendum.
3. Process flow diagram is not inline with process.
4. CPP is addition ratio but in obervation ratio not given during operation. 10/30/2018 0
With Recovered Solvent
1. PPQP-ST-026-00: Validation approach given Prospective with one batch.
2. Non critical process parameter evaluation not carried out, however in recommendation mentioned that all
process parameter meets with in the specified limit in BPR.
3. CPP is addition ratio but in obervation ratio not given during operation.

Report: On page no. 10 of 15, for the operation no. 16, following are the observations:
a. End temperature is wrong in all batches 20.6˚C, 29.8˚C, 28.6˚C instead of 26.4˚C, 36.3˚C, 31.7˚C
respectively.
b. Vacuum 684 mmHg instead of 608 mmHg for batch no NF1SR003.
NF2 and NFT report not provided
1. Addendum to Process Validation Report, 5-Nitro-2-furfural Diacetate (FD2)
2. Addendum to Process Validation Report, 5-Nitro-2-furfural Diacetate (FD2) with recovered solvent. 0
3. Addendum to process validation report of NF-1

Not Provided 10/30/2018 0

Not Provided 0

Not Provided 0

1. Self life and market done "NA" on header.

10/30/2018 0
2. Microbial testing is not part of specification.

Nitrofurantoin monohydrate (FPSTP/005/04): As per Revision history of STP, some Method parameter are
change for Residual solvent, but impact on previous batches not done (eg. Change parameter –split ratio, 10/15/2018 0
injection time,Neddle flush time )

Page 11 of 21
 RA Timeline
10/20/2018
Reference
CQC review Time lines
Document Time lines
Acceptable/ Comments (IN DAYS)
Number

Analysed by & checked by sign not legible in Attached chromatogram & Chromatogram not legible.
10/15/2018 0
(Scanning document)

Analysed by & checked by sign not legible in Attached chromatogram & Chromatogram not legible.
10/15/2018 0
(Scanning document)

Analysed by & checked by sign not legible in Attached chromatogram & Chromatogram not legible.
10/15/2018 0
(Scanning document)

Not Provided 10/30/2018 0

Complete characterization data & qualification data of WS against RS. Overlay IR with USPRS/ EPCRS not
10/20/2018 0
provided

R&D Controlled stamp not available in std.COA. eg. Nitrofurantoin monohydrate (NFT-NH/17/0526/026) , 5-
10/15/2018 0
nitro-2-furfural diacetate(IMP17002800)

Scanning Std COA not proper legible 10/15/2018 0

Not Provided 10/15/2018 0

Provided and OK 10/15/2018 0

Provided and OK 10/15/2018 0

Not Provided 0

Not Provided 10/15/2018 0

Page 12 of 21
 RA Timeline
10/20/2018
Reference
CQC review Time lines
Document Time lines
Acceptable/ Comments (IN DAYS)
Number

Not Provided 10/15/2018 0

Not Provided 0

Not Provided 0

FD2 BPR:
1. SAP Checklist not attached with BPR.
2. Potable and Purified Water material code not avaialble in BPR.
3. In apge no 15 & operation no 19, addition is to be maintain in ratio approx ~7:1 (This is Critical Process
Parameter). But in BPR no any recording available to ensure that how much ratio they had maintained
during operation. Ratio racording is not part of BPR.
4. Page no 16 & operation no 20-23, Sodium carbonate addition done to maintain pH (limit 3-4). But used qty
for maitaining of pH is not part of BPR. Hence how to ensure actual qty used for pH maintainng.
5. CF bag intactness checking is not part of BPR before start of filtration operation. In batch no. FD2SR004,
remark was given in BPR that during feeding operation (page no 20 operation no 32) material pass through
CF bag. So how to ensure that why material pass through & what was the bag intactness before use. 10/15/2018 0
6. CFML tank details not part of BPR.
7. Optional instructions are not specified or ticked in BPR
E.g. Cleaning as per frequency/ Product change over cleaning
8. Candle filter (CRFC01) is part of BPR but not in BPR equipment list.
9. Set point not given for dryer temperature and RPM of reactor.
10. Validation samples for additional testing as part of validation protocol send from the Centrifuge but in BPR
sample send remark not available.
11. As per Process flow diagram given in BPR Sparkler filter SPFC01 is part of BPR but in BPR sparkler is
not used, hence PFD is not matching with the actual process.
12. Scanned documents are not legible (IPR slip, Stamp, Signature & Date, page cut from side).

Page 13 of 21
 RA Timeline
10/20/2018
Reference
CQC review Time lines
Document Time lines
Acceptable/ Comments (IN DAYS)
Number

NF1 BPR:
1. SAP picklist not attached.
2. Unit of measurement in BPR is not matching with SAP picklist.
For Example:
a. For Black LDPE bag in BPR 2 No. but in SAP picklist it is 0.182 kg.
b. For Sodium Methoxide in BPR 193.7 kg but in SAP picklist it is 199.691 L.
3. In Batch No. NF1SR005, SAP picklist quantity and BPR quantity for the FD2 is not matching in decimals.
In BPR, FD2SR007 qty. is 25.595 Kg and in picklist it is 25.590 Kg and FD2SR008 qty. is 24.405 Kg and in
picklist it is 24.410 Kg.
4. Scanned documents are not legible (Stamp, Signature & Date).

NF2 and NFT BPR not provided

Not Provided 10/15/2018 0

Not Provided 0

Page 14 of 21
 Product: Nitrofurantoin Monohydrate

RA Review Status of RA
Actual date
Acceptable submission as Remark
sent
/Comments on 04-10-2018

10/16/2018 U/RA Review cGMP certificate is not avilable till,

10/16/2018 U/RA Review

10/16/2018 U/RA Review

10/16/2018 U/RA Review

10/16/2018 U/RA Review

10/16/2018 U/RA Review

10/16/2018 U/RA Review

10/16/2018 U/RA Review

Page 15 of 21
 RA Review Status of RA
Actual date
Acceptable submission as Remark
sent
/Comments on 04-10-2018

10/16/2018 U/RA Review

10/16/2018 U/RA Review

10/16/2018 U/RA Review

10/16/2018 U/RA Review

Page 16 of 21
 RA Review Status of RA
Actual date
Acceptable submission as Remark
sent
/Comments on 04-10-2018

10/16/2018 U/RA Review

10/16/2018 U/RA Review

Page 17 of 21
 RA Review Status of RA
Actual date
Acceptable submission as Remark
sent
/Comments on 04-10-2018

Process validation report shall be finalised

10/16/2018 U/RA Review after completion of analysis of all four
validation batches

10/16/2018 U/RA Review

10/16/2018 U/RA Review

Process development report is not available, It

shall be taken from R&D as process
development is a part of PD lab/R&D

as per RA recommendation XRD shall be

carried out from external laboratory

Cuurent available specification is without

microbial testing, if microbial testing is requried
10/16/2018 U/RA Review
as a part of specification then it shall be
revised

10/16/2018 U/RA Review

Page 18 of 21
 RA Review Status of RA
Actual date
Acceptable submission as Remark
sent
/Comments on 04-10-2018

10/16/2018 U/RA Review

Urea and Biurea content of NF-1 is to be

10/16/2018 U/RA Review
carried out till now

10/16/2018 U/RA Review Partical size distribution AMV is under process

All four batches are under analysis till date,

hence after analysis COA shall be provided

Characteristion data of RS is avilable in MRC

10/16/2018 U/RA Review
R&D, we will take from them

10/16/2018 U/RA Review

10/16/2018 U/RA Review

10/16/2018 U/RA Review

We are releasing Packaging material, In IR

test based on Vendor COA, inhouse Ir test is
not available

Page 19 of 21
 RA Review Status of RA
Actual date
Acceptable submission as Remark
sent
/Comments on 04-10-2018

BPR to be revised as optional purification for

acetic acid content to be removed

10/16/2018 U/RA Review

Page 20 of 21
 RA Review Status of RA
Actual date
Acceptable submission as Remark
sent
/Comments on 04-10-2018

10/16/2018 U/RA Review

Stability study shall be initiated after analysis

and approval of all for batches.

Page 21 of 21