Check list [ DMF ]

DMF CHECKLIST DRUG :

Table of contentsPage #

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. No.

Item To be checked YES NO SLA

1. Patent evaluation data

/tt/file_convert/551e4149497959e4398b47bf/document.doc REGULATORY AFFAIRS P age 1 of 16


S. No.


1. Letter from Corp. R&D mentioning that in which regions (US, Europe & Japan), the process is suitablePatent 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



S. No.


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.



S. No.


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



S. 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.

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

6.



S. No.


7.

8. Impurities Characterization data.

9. Study of all the potential impurities, is available in the development report??

10. List of Potential residual solvents

11. 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.



S. No.


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



S. No.


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



S. 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. 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



S. 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. 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



S. 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 materialsVendor 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.



S. No.


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.



S. No.


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 &



S. No.


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

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.

29.



S. No.


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.For info



S. No.


16.

17. Drug Description

18. Write-up on PolymorphismIs 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 IsomerismIs 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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Check list [ DMF ]