1. FPP assessment: approaches and considerations
Wondiyfraw Z. Worku
Assessors training
Copenhagen, January 2011

2. Talk points Dossier assessment General assessment approaches
Why do we assess dossiers
Where does it fit
General assessment approaches
Approaches for specific dossier sections (quality part)
Section by section recommendations
Points to re-emphasize

3. Dossier assessment/evaluation
Dossier assessment is an objective, scientific, written analysis of information relevant to prequalification of a dossier. It provides an account of all necessary points, in summary, of studies and findings related to efficacy, safety quality. It documents both the applicant’s and reviewer’s evidence-based findings, as well as the decisions taken regarding the dossier.

4. Dossier assessment/evaluation Contd
At the centre of a medicine regulatory system
Establish the achieved and desired safety, efficacy and quality profile for a certain product
Assumes genuineness of submitted information

5. General approaches for the assessor
Treat assessment as investigative work
To establish the current quality of the product
To help improve the quality further
To ensure consistency/reproducibility
We also need justifications for our comments
Guidance documents
Summarize available data and discuss the background

6. General approaches, contd
Look for details but don't get lost
There is never enough time
Know when and where to go deeply/lightly
Be pragmatic
Avoid nice to knows

7. General approaches, contd
Dossier sections are not isolated to each other
Aim to do the full assessment in one go. Minimize interruptions
Take notes as you go through your assessment
If you are first assessor don't leave decisions to the second assessor.
Any issue you are uncomfortable with, highlight it in the report and seek advice from colleagues and the second assessor

8. General approaches, contd
Don't forget to record in the report of what you have done
Record in the report reference /version numbers of signed and dated documents
Avoid copying too much data from the dossier, better to summarize it in your own words
Any data that looks suspicious, draft a communication to the inspectors

9. General approaches, contd
Need to know the dossier well before you start the actual assessment (assessment preparation)
New/existing applicant
New/existing product for the programme
New/existing product for the applicant
Get available public regulatory information of approved products (eg. EPAR, FDA, National DRA web sites)

10. General approaches, contd
Collect relevant articles
Collect available monographs for the API and FPP including drafts
Check how the API information is submitted
Check screening/preassessment notes
Check the Efficacy/Safety assessment status
Check key API properties: solubility, polymorphism, stability or sensitivity to environmental conditions
Proposed process: complicated/less complicated
Dosage form: complicated/un complicated

11. General approaches, contd
Any known compatibility issues
Whether applicant has already manufactured commercial validation batches and data is part of the submission
Re-familiarize your self with alerts and internal guidelines
In case of additional data assessment,
Majority of the above considerations also work here
Good to quickly go through the previous assessment reports (at minimum the most recent)
Try to understand the rationale behind each question and the requirements thereof

12. General approaches, contd
When ever available, the bio batch, bio waiver or clinical batch is our reference
We need to understand critical attributes of this batch and compare these with those proposed for production batches.
API specification
Formulation
Manufacturing process specifics and controls
FPP specification

13. API specification & retest period
Recommendations
Review the physico-chemical properties of the API
Identify the FPP applicant's specification
Identify your reference specifications
Pharmacopoeial monograph, CEP
APIMF approved specifications
Any additional in-house test that may be needed (example PSD)
Your assessment of the API information (if API assessment is part of the FPP dossier)
Look for COAs for the API batches used in the submission batches (especially the biolot)

14. API specification & retest period, contd
Check methods and consider the need for additional validation:
adopted from the APIMF holder or pharmacopoeia,
in house
Give attention to special notes by the APIMF assessor
Give attention to foot notes
Identify types and sources of reference substances
Retest period: if already assigned by the APIMF assessment, inform the same to the FPP applicant
If FPP manufacturer wants shorter retest period, we accept this

15. Development pharmaceutics
Why do we need it as a regulatory submission?
To ensure that applicant has sufficient understanding of the product attributes and the manufacturing process
To give us better understanding of key product and process attributes (to help the review)
In certain cases, annual product review report may be considered a substitute

16. Development pharmaceutics, contd
Read and understand the whole development report; in the mean time try to answer the following:
What are the target profile/attributes of the product
Which drug substance characteristics affect performance and stability of the FPP
The purpose of each excipient and proposed amounts
Is there evidence of API-excipient compatibility
Why the preferred process over the others
Has the formulation been optimized

17. Development pharmaceutics, contd
What are the critical steps and parameters
How does the desk designed, lab tried and piloted formulation and process translates to a production/commercial manufacturing
Is the proposed dissolution method satisfactory
Is the proposed container closure system suitable and safe
Overages and justifications
Is there a need for tablet scoring and supporting data provided
Microbiologic attributes
Additional considerations for injectables & other dosage forms
etc

18. Formulation, manufacturing process and controls
To ensure that the formulation and mfg process for the commercial batches
are sufficiently detailed regarding inputs, processing sequence, process parameters, equipment details and other factors which may affect batch to batch reproducibility/consistency
are inline with the ones developed and used in the production of the clinical/bioequivalence/biowaiver batch/es
Any difference should be known and justified

19. Formulation, Mfg and controls-contd
Recommendations:
Go through the batch record for the clinical batch and take note of key process parameters, equipment types, in process results
Demand further details if necessary, example: granulation parameters
Take the proposed blank master production record, ensure equivalence of composition, excipient grades, details of the process, as described above, may be by page to page comparison
Any difference should be understood and justified in light of reproducibility; consider variation and SUPAC requirements as necessary
Also discuss differences with 2nd assessor and possibly bio assessors

20. Formulation, Mfg and controls-contd
If required comment on a need for revision of the master record
Also check that the narrative and process flow charts provided in the dossier are reflective of what's provided in the BMRs
Highlight the reference observations in the assessment report (to help the subsequent assessment)
Check if proposed controls including frequencies are satisfactory
If the bio study has been rejected, request for batch record of the new bio/clinical batch

21. Initial proposed
Wet granulation

22. Comment to the applicant

23. Revised

24. Process validation
If available at the time of assessment, preliminary process validation data provides further assurance to the assessor that proposed mfg method can provide reproducible batches as the clinical batch.
confirms what is already known
A good validation exercise supplemented with robustness studies provides additional assurance that the manufacturer has good understanding and control of the product and its attributes.
Should be pushed to the “edge of failure”

25. Process valdn-contd Recommendations
Ensure that process parameters and other variabilities are representative of those proposed for production batches
Provide particular attention to the specific steps where sampling and testing is made
Not all specific step needs to be evaluated by sample analysis but at least the process parameters should have been monitored and understood as these will affect the down stream results

26. Process valdn-contd
Ensure extensive sampling than normally required for in process testing
Try to interpret and understand reported results
Consider improvements to the protocol, such as the need for
additional sampling points,
Individual vs composite sample testing
robustness studies
Where applicable for comparative dissolution profile studies

27. Example-tablet Dispensing Sifting and dry mixing Granulation Drying
Blending
Lubrication
Compression
Coating
Content uniformity on individual samples
Content uniformity on individual and composite samples, blend properties, LOD
In process (including robustness studies) and pooled sample testing
In process and pooled sample testing including dissolution profile
Weight checks
Sifting and mixing parameters
Wet and dry granulation parameters
Tray or FBD parameters
Blending parameters and equipment
Lubrication parameters & equipment
Compression parameters and equipment
Coating parameters and equipments
Process monitoring
Manufacturing steps
Sampling and testing stages
Uniformity of drying

28. Excipients Need to have good quality and safety as the API
Most are well established
For the purpose of PQ, we have clearly stated in our guideline that novel excipients are not acceptable
Recommendations
Ensure presence of specifications for every excipient used
For colourants, ensure that these are permitted
For proprietary coating materials, ensure that qualitative composition is provided

29. Excipients, contd
For flavours, ensure that these are permitted and a qualitative composition is provided
For excipients of animal or plant origin ensure that the necessary TSE/BSE free certification/declaration is provided
Depending on the dosage form and formulation requirement, consider the need for additional in house tests (example, MLT, endotoxin, particle size, bulk density)

30. Finished product specification
Just one of the control mechanisms
Quality by design
Control of raw materials
Process monitoring and in process testing
Final product testing
etc
Should be relevant and realistic
Should be signed and dated
Can be viewed as a contractual agreement

31. Finished product spec, contd
Recommendations
Remind your self of the product attributes
Visit your notes from previous sections
Outline common and specific additional tests
Identity, potency, purity, performance and microbiologic tests
Consider a need for additional identification test for the API
Identification test for non active excipients but which may have safety importance such as colours
Identification and potency tests for preservatives, antioxidants
Limit tests for residual solvents

32. Finished product spec, contd
Check all available pharmacopoeial monographs (including drafts), identify additional tests that may need to be considered
Identify release, shelf/regulatory and/or stability specifications
Identify periodic testing proposals and ensure that the necessary support is provided
If additional data, compare the spec against the previous version (to identify any unsolicited changes)

33. Finished product spec, contd
For related substances,
if pharmacopoeial, ensure that all the specified and unspecified degradants are controlled by the applicant's specification/analytical methods
If non pharmacopoeial, try to identify potential identified impurities that need to be controlled and ensure that the analytical method is demonstrated as capable of controlling these degradants
Acceptance limits
If pharmacopoeial ensure that the product meets the requirements of your recognized pharmacopoeia (including the general monograph requirements)

34. Finished product spec, contd
Ensure that your specific requirements are met, e.g. Assay at release
For additional tests (such as related substances and residual solvents) apply ICH requirements
For tests whose limits can be justified by batch analysis/stability results (except those for which the pharmacopoeial monograph includes specific limits), check if proposed limits are reflective of the observed results
Dissolution, metabolite impurities, water content/LOD, antioxidants, preservatives

35. Analytical methods and validation
Most of the data in the dossier depends on reliability and reproducibility of the analytical methods
Recommendations:
before proceeding with the validation details go through the proposed method & try to understand
how standard and sample solutions are processed
take note of concentrations of sample and standard solutions
if pharmacopoeial compare with the appropriate monograph
see how analytes particularly impurities are determined

36. Analytical methods and Valdn, contd
As you evaluate the validation data,
Check if sample/std concentrations taken are relevant to the method being validated
Check if results were correctly determined, eg RRF
If method is in-house while a pharmacopoeial monograph is available, check if the method is demonstrated as capable of controlling all potential degradants specified in the pharmacopoeia

37. Analytical methods and Valdn, contd
Check the supporting/representative chromatograms
Check if there is a need to include in the method details a precautionary note to the analyst
Check if proposed SS criteria are adequate
see whether the RRT and RF values of the specified degradants included in the method are appropriate

38. Reference standards
To ensure validity of the standard used to produce the dossier data and for future use
When there is no official RS, applicant may receive the standard from the API supplier or may prepare one in-house (qualification)
If official RS exists then check if the WS has been qualified against the official RS (calibration)

39. Reference standards, contd
Recommendations
Try to establish the type and source of the standard
Check the characterization/qualification data preferably for lots of the standard lots used in the validation studies
Establsih Identity, potency and purity
Other details better be left for the inspectors

40. Container closure system
One of the major product attributes
Recommendations
We need to understand the components and establish
Components in immediate contact with the product (Primary components)
Secondary functional components
Measuring devices
Secondary components
ensure that specifications are inline with general pharmacopoeial monograph requirements (depending on the dosage form).

41. Container closure system, contd
consider further aspects depending on the dosage form and stability concerns (which may have been partly addressed as part of development pharmaceutics)
Extractables/leachables
Moisture and air permeation
Biological activity tests
Contaminants (for rubber elastomers)
Dose reproducibility for measuring devices

42. Stability data
To ensure that the product quality as achieved at release can also be maintained throughout a reasonable product shelf life
Recommendations:
Start with the protocol
specification and analytical methods
batch type and packaging
testing plan
future plans (ongoing and stability on production batches)

43. Stability data, contd While assessing the stability data
Check if all reported results are within acceptable limits
Try to visualize any visible trend or variability (intra and inter batch)
Summarize the data indicating any trend, variability of OOS
When there are trends, variabilities, or OOS go back to the relevant other sections of the dossier
Conclude if the data is sufficient to support a shelf life
When ever appropriate ask for updated data instead of communicating an extrapolated shelf life
Consider if there is a need for revision of the protocol for commitment batches

44. Samples and product labelling
Submitted samples are primarily for visual evaluation of the product and its labels
ensure that these are representative of the product as presented in the dossier
As quality assessors, we only need to comment on quality related aspects of the labels,
Section 1.0, 2.0, 3.0 and 6.0
Occasionally also section 4.2(posology and administration)
WHOPAR
Make sure that in your assessment reports/QIS, information vital for WHOPAR preparation are clearly spelled out, e.g. ink composition for capsules shell

45. Example 1
Assume that you are preparing to start an assessment of a new application (quality part). As part of your preparation you have noticed that the BE data submitted had already been assessed and considered not acceptable. What does this tells you and how will this affect your assessment? Would you start a full assessment of the dossier?

46. Example 2
Assume that you are assessing an API specification as used by an FPP manufacturer. The APIMF approved specification is based on a BP/EP monograph, while the FPP manufacturer's specification is based on USP monograph
As FPP assessors what issues do you need to consider?

47. Example 3
Assume that you are assessing control of degradation products of a certain FPP (as part of the FPP specification). It's noted that applicant is using an in- house developed method for control of degradants while a monograph exists in one of the recognized pharmacopoeias. Please describe your approaches in determining acceptability or non acceptability of the proposed controls.

48. Some points to re-emphasize
We are always under time pressure
We need to be pragmatic
Biobatch/clinical batch records
heart of the quality assessment
Process details and end points
Example: Wet granulation
API/FPP specifications and other signed records
Should be clear and changes should be known
Always re-familiarize your self with requirements, alerts, and internal guidance

49. Additional material FDA's Q and A guide on question based review (QbR)
Presentation on
Quality assessment and the assessment report
by Lynda Paleshnuik
On PQ web site, under trainings (Kampala Uganda, February 2009)
FDA's Q and A guide on question based review (QbR)

50. Thank you