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Table of contents
Page #
1. Patent Evaluation 2
2. Key Starting Materials 2
3. Specifications and Method of Analysis
A. Key Starting Materials 4
B. Raw Materials Specifications and Method of Analysis 4
C. In-process Specifications and Method of Analysis 5
D. Intermediates Specifications and Method of Analysis 5
4. Impurities 6
5. Impurity Profile 6
6. Analytical Method Validations 7
7. Drug Substance specifications and method 8
8. Stability 9
9. Batch Analysis 10
10. WS/RS 11
11. Container Closure System 11
12. Brief Outline of the Process 12
13. Structure Elucidation 12
14. Elaborated Process description 13
15. Process Validation 14
16. Others 14
17. Reports 15
S.
Item To be checked YES NO SLA
No.
1. Patent evaluation data
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1. Letter from Corp. R&D mentioning that in which regions
(US, Europe & Japan), the process is suitable
Patent clearance available from IPM?
2. For Starting material / KSM process
3. Patent clearance for the Intermediates
2. Key Starting Materials [KSM]
1. Is KSM being manufactured in-house or out-sourced?
2. If it is out-sourced, Source qualified as per - vendor
qualification procedure
3. Minimum 3 vendors for the starting material are available?
4. COA
5. Any variation w.r.t. Vendor COA and In-house COA.
6. Synthetic route, any Class 1 solvents are used?
7. Vendor is controlling any impurities, if yes, listed on COA?
8. If not, get the justification from Vendor? Ask him to mention
on the COA.
9. Are all the impurities available
10. Analytical methods developed used to check impurities? Is it
validated?
11. If yes, impurities are listed to what levels
12. Are we controlling internally those impurities
13. To what levels at which stages?
14. We are showing cut-off of these impurities in the stages
prior to FP.
15. If yes, LOD /LOQ are established for these impurities with
these methods.
16. If not, are we controlling these impurities [including solvents]
in the finished product.
17. If yes, LOD/LOQ for the impurities established
18. If not, we need to CONTROL!!!!!
19. Any solvent, which can result in Benzene in intermediate or
API, should be controlled.
20. Any heavy metals used in the starting materials
manufacturing process, what are they
21.
22. Impurity Profile of Key Starting Material

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23. Copies are legible
24. Protocol + report + chromatograms
25. Are all the proposed vendors considered in the impurity
profiles
26. Are all the impurities mentioned by vendor + potential
impurities of in-house process considered
27. COAs for impurities are available.
28. LOD/LOQ established
29. Are the impurities controlled or shown absence
30. Specification fixed as per impurity profile batches & trend
data, report sheet should conclude the same
31. If impurities are not shown absence, controlled in next
stages.
32. Mention the stages:
33. For the impurities which are shown absent at the

intermediate stages, we have LOD /LOQ.
34. Any unknown impurity, if yes, Limits: [RRT]
3. Specifications and Method of analysis
Raw materials and Key Starting materials specs and MOAs.
Copies are legible
3A. Key Starting Materials [KSM]
1. KSM – Identification, Assay, Purity and RS/OVI for In-house
& Vendor; If not justification
2. How many vendors are approved
3. Specifications are fixed, considering the routes from all the
vendors
4. Trend for all the batches till date is available for all the
parameters of spec and moa
5. Specs are tightened as per the trend data?
6. Impurities and solvents used by all the vendors are
considered?
7. Impurities identified - controlled if possible to the limit of
0.10% or shown absence.

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8. Possibility of isomers? If yes controlled?
9. LOD/LOQ values established for the methods
10. Any unknown impurity, if yes, Limits: [RRT]
11. KSM working standard characterization data [NMR, IR,
HPLC & Mass] should be available.
12. Special tests like SOR, Chiral purity by HPLC, isomer
monitoring method development completed.
13. Moreover tested for 3-5 batches.
14. Identification is carried out by IR
15. Justification for the control/ absence of the carry over of the
heavy metals to the API
16.
3B. Raw Material
1. RM – Identification, Assay, Purity and RS/OVI for In-house
& Vendor; If not justification
3. Possibility of isomers? If yes controlled?
4. LOD/LOQ values established for the impurities
5. Recovered solvents same spec as that virgin- otherwise
justification
6. Recovered solvent from which stream, Justification for
specs?
7. Water – HUF water final stage, earlier stages DM water.
8.
9.
3C. In-process
1 All the tests should - quantify
3D. Intermediate
1. Intermediates - Identification / Assay / Purity and RS/OVI for
In-house & Vendor; If not justification
3. LOD/LOQ values established for the impurities

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4. Trend is available for the batches manufactured till date
5. Impurities limits tightened as per the trend data?
6. If benzene or other solvents is detected in the starting
material, hence we need to check the intermediate for
residual solvents wrt benzene/ other solvents.
7. Intermediates standards are characterized.
8.
9.
4. Impurities
1. Details on Impurities Chemical names, Structural Formula
and source of the impurities
2. Impurities from KSM + Process + by Degradation are
considered
3. All the impurities considered for the study [not only the one
reported on the FP specs]
4. List of Potential impurities. [Anything other than API, that is
used in the manufacturing process]
5. KSM, RM and intermediates
Impurities from KSM,
Impurities from Raw materials
Isomers
Process related
Potential Degradation products of the drug substance
KSM
Starting Material of KSM
Intermediates
Impurities from Raw Material
11.

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12.
13. Impurities Characterization data.
14. Study of all the potential impurities, is available in the
development report??
15. List of Potential residual solvents

16.
Solvents used in the manufacturing process of KSM
Solvents used in the manufacturing process Raw materials

from various proposed vendors
Solvents used in the manufacturing process of Reagents
Recovered solvents used in the manufacturing process

5. Impurity Profile
1. Impurity profile for Finished Product with all
Chromatograms.
3. Protocol + report + chromatograms
4. Needs to carried out in accordance with ICH Q3A (R)
5. Impurity profile on minimum 3/5 batches
6. Batches with additional physical operation [milled,
micronised, etc] are considered
7. If recovered solvents are used, are there batches
considered
8. All the potential impurities are considered in the study
9. Impurities overlap is carried out / Peak purity shown
10. Methods used are same as that of validation studies and
FP specs and moa
11. LOD/LOQ for impurities mentioned
12. LOQ levels of impurities should not be more than Reporting
threshold i.e. NMT 0.05% (As per ICH guideline)
13. Are the specifications fixed on the batches considered for
impurity profile, if yes, conclusion should state that
14. If not, additional batches trend, which supports the
specification, should be enclosed.

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15.
16.
17.
6. Analytical Method Validations [45 DAYS FROM REC ALL IMPs – MV will start]
1. Copies are legible & Duly signed
2. Protocol + Report + Typical Chromatogram
3. As per the ICH guidelines ICH Q2A & B
4. Carried out as per the protocol
5. If the molecule is listed in Pharmacopoeia, compendial
methods should be considered
6. RS by HPLC - all impurities are considered
7. RS by HPLC - method same as FP spec and moa &
impurity profile
8. RS by GC - all impurities are considered
9. RS by GC - method same as FP spec and moa & impurity
profile
10. Assay- -method same as FP spec and moa & impurity
profile
11. Any other method - Chiral, should be validated
12. LOD/LOQ for impurities and drug established
13. Accuracy at the LOQ level is shown
14.
15.
16.
17.
7. Drug substance Spec and MOA
2. Effective date is mentioned
3. Duly signed
4. Spec and moa are matching
5. If the molecule is listed in Pharmacopoeia, compendial
methods should be enclosed.
6. All the potential impurities are considered and all the
potential residual solvents are listed.
7. Patent implication’s are taken in to consideration before
listing or amounting the impurities

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8. For a non-compendial drug there should be two
identification tests
9. Is the molecule chiral, if yes chiral impurity considered
10. Is the molecule polymorphic, identification by XRD is
available
11. Is it required to quantify the polymorphs are quantified
12. If yes, are they quantified
13. LOD and LOQ mentioned in the MOA
14. LOD/LOQ matching with validation values
15. Are the methods validated - RS- HPLC/GC, Assay and
chiral purity by HPLC
16. Is XRD quantification available, is the method validated
17. Are the other minerals considered - Ca / Mg contents
18. Metal catalysts - part of FP spec and moa [as per
CPMP/SWP/4446/00, table No3 Option 1]
19. If not justification report.
20. In-house spec and moa comprising of the all the tests [tests
not included in the FP spec and moa for patent reason or
some other]
21. Innovator tablets/ samples are available
22. Special tests like SOR, Chiral purity by HPLC, isomer
monitoring method development completed. Moreover
tested for 3-5 batches.
23. Trend for all the batches till date is available for all the
parameters of spec and moa
24. Specifications are tightened as per the trend data, if not
justification
25. If not, is there any commitment after how many batches we
will tighten the limits
26. RRFs and RRTs are established and considered during
calculation
27. Control of heavy metals other then ICH specified
28.
29.
30.
8. Stability
1. Brief Stability write-up

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2. Stability packing should simulate FP packing
3. Re-test period, Justified based on the stab data.
4. Stability Specifications and Method of Analysis.
5. Stability packing is same as finished product packing
[commercial packing]
6. Stability spec same as that of FP [whatever test that are
included]
7. Are these decided based on forced degradation studies?
8. Stability data
9. Stab data with the material supplied to customers
10. Have we dispatched material to the customer with some
additional physical parameters?? If yes have we initiated
stab on it?
11. Have we initiated the stability at all the conditions – as per
core SOP
12. Current retest period is based on the stability data
13.
14.
15. Stability indicative methods [Specificity studies]
17. Protocol + Report + Chromatograms
18. RS by HPLC and Assay by HPLC specificity carried out
19. Degradation: Min 2/5 % Max 30%
20. As per ICH
21. Specificity studies to be carried out [water, H2O2, acid, base,
etc.]
22. Photostability study needs to be initiated as per ICH Q1B
23.
24.
25.
26. .
9. Batch analysis
2. COAs for three consecutive batches
3. Product name same as DMF name
4. Results with in the specs

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5. Batches are with the same batch size being mentioned in
the DMF
6. As per the current version of FP spec and moa
7. Retest period in line with the commitment.
8. Manufactured as per the process enclosed in the DMF
9. LOD/LOQ taken in consideration
10. Duly signed
11.
12.
13.
14.
10. WS and RS
2. Effective date is marked
3. Duly signed
4. Name same as that of DMF Name
5. All the tests as per the FP specs
6. All the tests are matching For ex. Solubility in the same
media
7. IF the drug is polymorphic or chiral, specific tests should be
included.
8. Preparation procedure,
9. The procedure is the one which is used for the preparation
of the WS/RS
10. Characterization
11. The data based on which its confirmed that it is WS / RS.
12. Packing and Storage details for WS and RS.
Provided
13.
14.
15.
16. .
11. Container and Closure system
1. Detailed description for FP packing
2. Specs and MOAs for Packing materials -
Copies are legible

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3. Same as in which drug will be dispatched / maintained in the
stab condition
4. .COA are matching wrt the tests
5. COA – packing materials
Vendor COA should mention 'as per the FDA 21 CFR
155.1720'
6.
7.
8.
12. Brief outline of the Process
1. All the chemicals used in the manufacturing process
mentioned
2. Are recovered solvents are used in the manufacturing
process?
3. Batches manufactured with reprocessing procedure?
4. Process Flow Diagrams
6. Should include - codes, Chemical names, Quantities & In-
process controls [without abbreviations]
7.
8.
9.
10.
11.
13. Structure Elucidation
2. Structure Elucidation report carries the same name as drug
- DMF
3. Same chemical name & structure as DMF / Merck Index.
4. The same polymorph or hydrate is discussed in the report &
confirmed
5. Chirality / melting range / other characteristics are same as
that of FP spec and moa
6. Elemental analysis report is enclosed
7. Elemental Analysis report: +0.3% rule is followed
8. Optically active molecules are discussed wrt their rotation.

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9. If molecule has morphs, Polymorphism of the drug is
discussed? [Or at least a separate report is available]
10. Exact differentiating 2-theta value mentioned?
11. Based on this value is it confirmed that molecule is of this
form?
12. If molecule is hydrate form, Hydrates are discussed?
13. Exact temperature is mentioned?
14. Based on this value is it confirmed that molecule is of this
form?
15.
16.
17.
19. The standard and allowed ranges for in-put raw materials
14. Elaborated process description
1. Expected and Theoretical yields
2. BPR of the max batch size
3. Drying, milling, sieving and Blending and sampling.
4. Also, the process with which material supplied to the
customer
5.
6. Blank BPRs
7. Executed BPRs :
9. Is the process same as that of Process validation?
10. One set of Executed Batch Production Records (trail
order).
11. Blending BPR (For each blending size).
12. Milling BPR (For each PSD requirement).
13.
14.
15. Batch Sizes
16. Maximum Batch size for In-house, Dispatch batches and
typical packing size-Same as the current BPR
17.
18.

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19.
20.
21.
15. Process Validation
1. Process Validation
2. Carried out? On the current batch size, process, facility,
Raw materials [out-source]
3. All the critical parameters mentioned in the Development
report considered and scale-up experience
4.
5. Drying Validation
6. As per protocol
7. How many batches carried out
8. Drying time fixed its ‘+’ and not range.
9.
10.
11. Blending Validation
12. Any blending carried out till date?
13. As per protocol
14. Customer specific?
15.
16.
17. Milling Validation
18. Any Milling carried out till date?
19. As per protocol
21.
22. Sifting
23. Any Sifting carried out till date?
25.
26.
27.
28. Report on changes
1. A report on Significant variations between the Lab &

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commercial process (Changes during Scale-up).
2. A report on Manufacturing Process Development
16. Others
1. Should be detailed, considering the parameters checked
2. If not, otherwise provide justification
3.
4. Final Product Batch numbering system.
5. Standard batch numbering system
6. In-house batch numbering system
S
7. Dispatch batch numbering system
8. With milling how the batch number will appear and without
milling
9.
10.
11. Elaborated description for Final Product Packing and
Labeling
12. Same as the proposed [container closure] and stability
conditions
13.
14. Write-up on Reserve samples. RA will provide
15. Number of years the sample is stored
16.
17. Write-up on Complaints file. RA will provide
18. Number of years the documents are stored
19.
20. Environmental assessment include RA will provide
21. Environmental treatment of chemicals facilities
22.
23. Product Label with storage conditions
24. Copy is legible
25. Product name as the DMF name
26. Proposed Storage conditions
27. NDC mentioned
28.

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29.
30.
31.
32.
17. Reports
1. Cut-off
2. Cut-off solvents absence study at final Product by using
Final Stage method of analysis [if the method of analysis is
different from Final stage MOA, then that Method of
analysis should be Validated].
3. All the solvents coming from the KSM or the process, but
not checked in the FP, a cut-off report shown for these
solvents
4. The methods used for this activity should have LOD/LOQ
values established
5. For the impurities arising from the KSM and from the
process, should be checked in the subsequent stages or
should be controlled in the FP
6. If not report should be generated
7. If Benzene derivative solvents are being used (like
Toluene, Hexane, Heptane, etc.,), then Benzene absence
at Final stage should be shown and Benzene should be
part of Method validation study.
8. Usage of metal catalysts [including starting materials] : Any
used should be controlled otherwise justification report is
available.
9.
10.
11. Engineering diagrams for packing drums
12. DRUM - with dimensions, as per dimensions final packaging
13.
14.
15. Batch cycle times for each stage.

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For info
16.
17. Drug Description
18. Write-up on Polymorphism
Is it polymorphic product?
19. If yes - Mixture or particular form.
20. Is the drug name comprises of the Form?
21. What about the other forms?
22. Do we have method to detect other forms?
23. Can we quantify other forms with the current method?
24. Write-up on Potential Isomerism
Is it chiral molecule
25. If yes, are we controlling other isomers?
26. Is method available?
27. LOD/LOQ established
28. Any other type of isomerism?
29. If yes, report on absence of other isomers
30. pH, pKa, Solubility at various pH , Partition Coefficient,
Higroscopicity studies data, Aqueous and non-aqueous
solubility profile of the API
31. For KRM, Intermediates and Pharma.
32. Cleaning methods should be available
33. PSD method development and optimization [no Class 1
solvent is used]
34. Holding studies completed
35. Metal ion content [Pb, As, Ni, etc] for out sourcing labs
36.
37.
38.
* If answer to any of the question is NO, then a scientific justification [supported by Chemistry &
analytical data] needs to be produced.
Or
Needs to be discussed with concerned departments, which ever is applicable.

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33. For the impurities which are shown absent at the

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Impurities from KSM,

Impurities from Raw materials

Potential Degradation products of the drug substance

Starting Material of KSM

Impurities from Raw Material

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15. List of Potential residual solvents

Solvents used in the manufacturing process Raw materials

Solvents used in the manufacturing process of Reagents

Recovered solvents used in the manufacturing process

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