01 how to identify cqa cpp

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How to Identify Critical Quality Attributesand Critical Process Parameters

Jennifer Maguire, Ph.D.Daniel Peng, Ph.D.

Office of Process and Facility (OPF)OPQ/CDER/FDA

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FDA/PQRI 2nd Conference North Bethesda, Maryland

October 6, 2015

Opinions expressed in this presentation are those of the speakers anddo not necessarily reflect the views or policies of the FDA


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OutlineBrief introduction on Quality by Design (QbD)Example approach to identify critical quality

attributes (CQA)Example approach to identify critical materialattributes (CMA) and critical process

parameters (CPP)Illustrative examplesConcluding remarks

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What is Quality by Design (QbD)?A systematic approach to development that begins withpredefined objectives and emphasizes product and processunderstanding and process control , based on sound science andquality risk management. (ICH Q8 R2)

Systematic Approach

Predefined objectivesDefine Quality Target Product Profile (QTPP)Identify Critical Quality Attributes (CQA)

Product and processunderstanding

Identify critical material attributes (CMA*) andcritical process parameters (CPP)Establish the functional relationships that link

CMA/CPP to CQAProcess control

Develop appropriate Control Strategy, including justifications

Sound scienceScience-driven development (scientific literature,prior knowledge, DOEs etc.)

Quality risk management Risk-based development (ICH Q9)

* CMA definition will be given later.


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What is a Quality Target Product Profile(QTPP)?

ICH Q8(R2) Definition: A prospective summary of the quality characteristics of a

drug product that ideally will be achieved toensure the desired quality, taking intoaccount safety and efficacy.

TPP: labeled use, safetyand efficacy

QTPP: quality characteristicsto ensure safety and efficacy as

promised in the label


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Guidance for Industry

Q8, Q9, & Q10 Questions and Answers

The Quality Target Product Profile (QTPP)provides an understanding of what willensure the quality, safety, and efficacy of aspecific product for the patient

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EXAMP

LE QTPP

QbD for ANDAs: An Example for IR Dosage Forms. April 2012.http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdfhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdfhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdfhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdfhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdfhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdfhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf


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Points to ConsiderGuide for ICH Q8/Q9/Q10 Implementation

The Quality Target Product Profile (QTPP)describes the design criteria for the product,and should therefore form the basis fordevelopment of the CQAs, CPPs, and

control strategy.

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DefinitionsCritical Quality Attributes (CQA) – A physical, chemical, biological, or microbiological

property or characteristic that should be within anappropriate limit, range, or distribution to ensurethe desired product quality (ICH Q8)

Critical Process Parameter (CPP)

– A process parameter whose variability has an impact on a CQA and thereforeshould be monitored or controlled to ensure the process produces the desiredquality. (ICH Q8)

Critical Material Attribute (CMA)*

– A physical, chemical, biological or microbiological property or characteristic ofan input material that should be within an appropriate limit, range, ordistribution to ensure the desired quality of output material.

*CMA is not defined in ICH guidance, but used here for discussion purposes


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Approach to Identify CQAs1. Consider all DP quality attributes; physical attributes,

identification, assay, content uniformity, dissolutionand drug release, degradation products, residualsolvents, moisture, microbial limits, etc.

2. Identify a CQA based on the severity of harm to apatient (safety and efficacy) resulting from failure tomeet that quality attribute. – Identified before taking into account risk control

– Does not change as a result of risk management


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EXAMP

LE QTPP


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11QbD for ANDAs: An Example for IR Dosage Forms. April 2012.

CQA

Not a CQA

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdfhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdfhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdfhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf


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DefinitionsCritical Quality Attributes (CQA)

– A physical, chemical, biological, or microbiological property or characteristicthat should be within an appropriate limit, range, or distribution to ensure thedesired product quality (ICH Q8)

Critical Process Parameter (CPP)

– A process parameter whose variability has an impact on aCQA and therefore should be monitored or controlled toensure the process produces the desired quality. (ICH Q8)

Critical Material Attribute (CMA)*

– A physical, chemical, biological or microbiological propertyor characteristic of an input material that should be withinan appropriate limit, range, or distribution to ensure thedesired quality of output material.

*CMA is not defined in ICH guidance, but used here for discussion purposes


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Linking Patient - Product - Process

Product

Patient

Formulation/Process

Clinical Outcome(Safety & Efficacy )

Critical QualityAttributes

(CQA)

Critical Material Attributes(CMA)

Critical Process Parameters

(CPP)


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Example Approach to Identify MaterialAttributes and Process Parameters

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Useful tools:Risk assessment, prior knowledge, established science…..


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Example Approach to Identify MaterialAttributes and Process Parameters

Intermediate CQAs: Blend Uniformity

Process Variables:1. Particle size distribution2. Loading level3. Number of revolutions

Drug Product CQAs:Content Uniformity


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Identifying Potentially High Risk MAs or PPs

17Yu et al, Understanding Pharmaceutical Quality by Design, The AAPS Journal, 2014 , 16(4) 771- 783

Special considerations for unique DS/DP properties – e.g. RH can be potentially high risk for a hygroscopic formulation


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Example Approach to Determine Criticality

Once potentially high risk variables are identified:Identify levels or ranges of these potentially high riskattributes and/or parameters.Design and conduct experiments, using DOE whenappropriate.Analyze the experimental data to determine if a

material attribute or process parameter is critical. – If variability has an impact, then need to monitor and/or control

Develop a control strategy.

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Key Points from EMA-FDA QbD PilotPilot program aimed at a parallel assessment of CMC sectionswhich are relevant to QbDThe fact that a risk of failure is mitigated by applying a robustproactive control strategy should not allow for theunderestimation of assigning criticality.

Agencies are amenable to the applicant using their ownterminology in the pharmaceutical development section tocommunicate development findings

However, in the 3.2.P.3.3 “Description of the ManufacturingProcess and Process Controls” and 3.2.P.3.4 “Control ofCritical Steps and Intermediates” sections, the description ofall parameters that have an impact on a CQA should beclassified as critical. 19


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Criticality

I n c r e a s e

d R i s k

I n c r e a s e

d C

o n

t r o

l

1. Continuum2. Focus on the vital few3. The control strategy ( the

established range ) isimportant

4. If underlying assumptionschange, then criticality canchange

What's in a name? That which we call arose by any other name would smell assweet. – William Shakespeare


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Schematic Flow Diagram for Identification of

CMAs/CPPs

Is variableshown to beor likely to bepracticallysignificant?

Can the CQA beimpacted byformulation andprocess variables?

No or low potential

NoYes

Yes

Does studiedrange captureintendedvariability?

Yes*

No

* Changes to the range may impact criticality and need to be re-assessed!


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Illustrative Examples

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Example-1

A fixed-dose combination IR tablet: – API-1: ~80% of the tablet weight

– API-2: ~1% of the tablet weight – Diluent (microcrystalline cellulose): ~ 14% of the

tablet weight

– Other excipients: disintegrant, colorant, andlubricant

– Content Uniformity (CU) of API-2 is a high risk CQA

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P r o c e s s F l o w D i a g r a m


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Process Understanding and ControlProcess understanding: – Ranked all blending steps as medium risk; hence, no

development study was conducted

– Provided testing results of one lab scale batch (4-quart V-blender, 1.2 kg) and exhibit batch (20 cu. ft. 184 kg)

Applicant’s control strategy: fix all MAs and PPs for allblending steps

Agency’s comment: All MAs and PPs are potentiallycritical due to limited characterization of the sourcesof variability and inadequate understanding of theimpact of CMAs and CPPs on the drug product CQAs

25Knowledge is power ! - Francis Bacon


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Example -2An Extended–Release (ER) CapsuleAPI: 100 mg – highly soluble, excellent chemical

stability, no polymorphismManufacturing Process: – Seal-coated sugar sphere core

– API coated pellets – ER polymer coated pellets – Encapsulation and packing

Dissolution is a high risk CQA 26

SugarSphereCore

API coat

ER coat

Seal coat


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ER Polymer Layer FormulationER polymer layer: – Polymer-1 (release controlling, water insoluble) – Polymer-2 (pore former, water soluble) – Plasticizer B – ColorantFormulation feasibility studies – Trial with IR pellets + ER pellets (abandoned) – Effect of Polymer 1 viscosity – Effect of Polymer 2 type – Effect of plasticizer type: Plasticizer A vs. B

(hydrophobic vs. hydrophilic)

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Formulation Optimization

One-factor-at-a-time (OFAT) approach – Polymer-2 quantity

– Polymer-2 viscosity – ER layer coating weight gain

Applicant’s conclusion: No impact on

dissolution; hence, these factors are not criticalAgency’s comments: Any interaction? How’sthe range justified? Coating process variability?

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Further StudiesER layer coating weight gain andPolymer-2 viscosity have stronginteraction.Both factors are critical!

Control strategy:

– Using fixed amount of Polymer-1 and Polymer-2

– Tighten the Polymer-2 viscosityto the studied ranges instead ofcompendial limits

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B: Viscosity

Di s s o

@ 4 h

A: ER layer coating weight gain

Don’t use insufficiently powered studies to force a favorable conclusion ofnon-criticality. The narrow range of ‘non-critical process parameter’ is still

potentially critical .


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Summary of MAs and PPs Evaluated

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Process Development

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So What is Critical?The applicant’s conclusion: – No critical process parameters, intermediates or

process steps have been identified within theranges studied during development.

The Agency did not focus so much on theterminology, but…Paid a lot of attention to the studied ranges andverified if these ranges are captured in thecontrol strategy, process description, and

master batch record…. 33


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Example-4Oral IR tablet: 2.5 mg and 5 mg

Drug substance: BCS high solubility, non-hygroscopic, onlyone crystalline form known, excellent chemical stability

API loading: 2.4%Diluents: microcrystalline cellulose (~40%) and lactosemonohydrate (~50%)

Other excipients: disintegrant, wetting agent, and lubricant

Manufacturing Process: – blending, screening, lubrication, roller compaction, milling,

blending and lubrication, compression, and film-coating

Content Uniformity is a high risk CQA35


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Process Understanding and Control Strategy

In-line NIR method todetermine BU and blendingendpoint

At-line NIR method for tabletAssay and CU (Large N)

Other traditional in-process

controls: ribbon density,ribbon thickness, core tabletweight & hardness

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So What is Critical?Flexible for input material attributes and processparametersAgency looked carefully at the NIR method,model development, validation, lifecyclemaintenance planThe established NIR method, instrument details,spectral acquisition and sampling, spectral dataprocessing, calculation/reporting and theacceptance criteria are included in P.3.4 “ Controls

of Critical Steps and Intermediates ”. 37


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Impact on Post-Approval ChangesLevel 1: flexible input materialattributes and process parameters;real-time automatic controls assurethat CQAs consistently conform to

the established acceptance criteriaLevel 2: flexible material attributesand process parameters within theestablished design spaceLevel 3: any significant change inthese MAs and PPs warrantsregulatory oversight

38Yu, et al. Understanding Pharmaceutical Quality by Design, The AAPS Journal, 2014, 16(4): 771-783

Control Strategy Implementation Options


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Concluding RemarksSystematic approach, begin with the end in mindIdentify CQAs based on patient's needs: safety andefficacyUse science- and risk-based approach to identifymaterial attributes and/or process parameters thatmay impact CQAsPrioritize development studies and focus on the vitalfew potentially high risk material attributes andprocess parametersEstablish an appropriate control strategyConsider discussing lifecycle management plans

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Acknowledgements

Christine MooreRobert IserRapti MaduraweNaiqi YaUbrani Venkataram

01 how to identify cqa cpp

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