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

FPP assessment: approaches and considerationsWondiyfraw Z. Worku

Assessors training

Copenhagen, January 2011

FPP assessment: Approaches &

Considerations | January 20112 |

Talk pointsTalk points

Dossier assessment– 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



Dossier assessment/evaluationDossier 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.



Dossier assessment/evaluationContd

Dossier assessment/evaluationContd

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



General approaches for the assessorGeneral 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



General approaches, contdGeneral 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




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




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




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, Drugs @ FDA, National DRA web sites)




– 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




– 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




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



API specification & retest periodAPI 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)



API specification & retest period, contdAPI 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



Development pharmaceuticsDevelopment 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



Development pharmaceutics, contdDevelopment 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



Development pharmaceutics, contdDevelopment 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



Formulation, manufacturing process and controls

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



Formulation, Mfg and controls-contdFormulation, 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



Formulation, Mfg and controls-contdFormulation, 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



Initial proposedInitial proposed

Wet granulation



Comment to the applicantComment to the applicant



RevisedRevised



Process validationProcess 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”



Process valdn-contdProcess 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



Process valdn-contdProcess 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



Example-tabletExample-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 monitoringManufacturing steps Sampling and testing stages

Uniformity of drying



ExcipientsExcipients

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



Excipients, contdExcipients, 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)



Finished product specificationFinished 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



Finished product spec, contdFinished 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




– 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)




– 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)




• 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



Analytical methods and validationAnalytical 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



Analytical methods and Valdn, contdAnalytical 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



Analytical methods and Valdn, contdAnalytical 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



Reference standardsReference 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)



Reference standards, contdReference 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



Container closure systemContainer 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).



Container closure system, contdContainer 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



Stability dataStability 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)



Stability data, contdStability 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



Samples and product labellingSamples 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



Example 1Example 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?



Example 2Example 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?



Example 3Example 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.



Some points to re-emphasizeSome 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



Additional materialAdditional material

Presentation on

– Quality assessment and the assessment report

• by Lynda Paleshnuik– On PQ web site, under trainings (Kampala Uganda,

23-27 February 2009)

FDA's Q and A guide on question based review (QbR)



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