DMF CHECKLIST DRUG : Table of contents
Page #
1.
Patent Evaluation
2
2.
Key Starting Materials
3.
Spec Specif ific icat atio ions ns and and Meth Method od of An Anal alys ysis is
2
A. Key Starting Materials
4
B. Raw Materials Specifications and Method of Analysis C. In-process Specifications and Method of Analysis
4 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.
Batch Analysis
10
10.
WS/RS
11
11.
Container Closure System
12.
Brief Outline of the Process
12
13.
Structure Elucidation
12
14.
Elaborated Process description
13
15.
Process Validation
16.
Others
14
17.
Reports
15
S. No.
Item
9
11
14
To be checked
YES
NO
SLA
1. Patent evaluation data
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REGULATORY AFFAIRS
P age 1 of 16
DMF CHECKLIST DRUG : S. No. 1.
Item
To be checked
YES
NO
SLA
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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REGULATORY AFFAIRS
P age 2 of 16
DMF CHECKLIST DRUG : S. Item No. 23. Copies are legible
To be checked
YES
NO
SLA
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 Trend for all the batches till date is available for all the parameters of spec and moa
4. 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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REGULATORY AFFAIRS
P age 3 of 16
DMF CHECKLIST DRUG : S. Item To be checked No. 8. Possibility of isomers? If yes controlled? 9.
YES
NO
SLA
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. 2.
RM – Identification, Assay, Purity and RS/OVI for In-house & Vendor; If not justification Impurities identified - controlled if possible to the limit of 0.10% or shown absence.
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? Water – HUF water final stage, earlier stages DM water.
7. 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
2.
Impurities identified - controlled if possible to the limit of 0.10% or shown absence.
3.
LOD/LOQ values established for the impurities
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REGULATORY AFFAIRS
P age 4 of 16
DMF CHECKLIST DRUG : S. Item To be checked No. 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.
YES
NO
SLA
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] List of Potential impurities. [Anything other than API, that is used in the manufacturing process]
4. 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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REGULATORY AFFAIRS
P age 5 of 16
DMF CHECKLIST DRUG : S. No. 12.
Item
To be checked
YES
NO
SLA
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.
2.
Copies are legible
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 If recovered solvents are used, are there batches considered
7. 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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REGULATORY AFFAIRS
P age 6 of 16
DMF CHECKLIST DRUG : S. No. 15.
Item
To be checked
YES
NO
SLA
16. 17. 6. Analytical Method Validations 1.
[45 DAYS FROM REC ALL IMPs – MV will start]
Copies are legible & Duly signed
2.
Protocol + Report + Typical Chromatogram
3.
As per the ICH guidelines ICH Q2A & B
4. 5.
Carried out as per the protocol 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.
Copies are legible 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
1.
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REGULATORY AFFAIRS
P age 7 of 16
DMF CHECKLIST DRUG : S. Item To be checked No. 8. For a non-compendial drug there should be two identification tests 9.
YES
NO
SLA
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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REGULATORY AFFAIRS
P age 8 of 16
DMF CHECKLIST DRUG : S. Item To be checked No. 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. 8.
Are these decided based on forced degradation studies? Stability data
9.
Stab data with the material supplied to customers
YES
NO
SLA
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] 16. Copies are legible 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, H 2O2, acid, base, etc.] 22. Photostability study needs to be initiated as per ICH Q1B 23. 24. 25. 26. . 9. Batch analysis 1.
Copies are legible
2.
COAs for three consecutive batches
3.
Product name same as DMF name
4.
Results with in the specs
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REGULATORY AFFAIRS
P age 9 of 16
DMF CHECKLIST DRUG : S. Item To be checked No. 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. 8.
Retest period in line with the commitment. Manufactured as per the process enclosed in the DMF
9.
LOD/LOQ taken in consideration
YES
NO
SLA
10. Duly signed 11. 12. 13. 14. 10. WS and RS 1.
Copies are legible
2.
Effective date is marked
3.
Duly signed
4. 5.
Name same as that of DMF Name 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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REGULATORY AFFAIRS
P age 10 of 16
DMF CHECKLIST DRUG : S. Item To be checked No. 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'
YES
NO
SLA
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
5.
Copies are legible
6.
Should include - codes, Chemical names, Quantities & Inprocess controls [without abbreviations]
7. 8. 9. 10. 11. 13. Structure Elucidation Copies are legible 1. 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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REGULATORY AFFAIRS
P age 11 of 16
DMF CHECKLIST DRUG : S. Item To be checked No. 9. If molecule has morphs, Polymorphism of the drug is discussed? [Or at least a separate report is available]
YES
NO
SLA
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. 18. Copies are legible 19. The standard and allowed ranges for in-put raw materials 14. Elaborated process description 2.
Expected and Theoretical yields 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
1.
5. 6.
Blank BPRs
7. 8.
Executed BPRs : Copies are legible
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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REGULATORY AFFAIRS
P age 12 of 16
DMF CHECKLIST DRUG : S. No.
Item
To be checked
YES
NO
SLA
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. 7.
As per protocol 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 20. Customer specific? 21. 22. Sifting 23. Any Sifting carried out till date? 24. Customer specific? 25. 26. 27. 28. Report on changes 1.
A report on Significant variations between the Lab &
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REGULATORY AFFAIRS
P age 13 of 16
DMF CHECKLIST DRUG : S. No.
Item
To be checked
YES
NO
SLA
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. 6. S
Standard batch numbering system In-house batch numbering system
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 21. Environmental treatment of chemicals facilities
RA will provide
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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REGULATORY AFFAIRS
P age 14 of 16
DMF CHECKLIST DRUG : S. No. 29.
Item
To be checked
YES
NO
SLA
30. 31. 32. 17. Reports 1.
2.
Cut-off 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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REGULATORY AFFAIRS
P age 15 of 16
DMF CHECKLIST DRUG : S. No.
Item
To be checked
YES
NO
SLA
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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REGULATORY AFFAIRS
P age 16 of 16