Introduction to Topic #1: QbD approach for quality control and assurance of Dissolution Rate Ajaz S. Hussain, Ph.D. Deputy Director, Office of Pharmaceutical

Introduction to Topic #1: QbD approach for quality control and assurance of Dissolution Rate

Ajaz S. Hussain, Ph.D.

Deputy Director, Office of Pharmaceutical Science, CDER, FDA

ACPS Meeting, May 2005

Topic #1 ACPS Discussion Goals Seek ACPS recommendations on a proposed regulatory

tactical plan QbD based regulatory decision system for quality assurance and

control of optimal drug dissolution rate over the life cycle of a product

Are the tactical steps outlined consistent with the QbD goals we seek to achieve?

What additional steps and/or changes would you recommend to improve this plan?

What additional scientific evidence is necessary to support the development and implementation of this plan?

General considerations for identifying and developing statistical procedures

Any other specific recommendations? Prioritization?

Proposed Steps Alternate regulatory approach – suitability of dissolution

measurement system Gauge Reproducibility and Repeatability Study Using

Pivotal Clinical or Bio Lot Systems-based decision tree or establishing dissolution

rate specification Opportunities for utilizing the PAT approach for

controlling dissolution rate and development of real time quality assurance strategies

Decision tree for “design space” concept articulated in the draft ICH Q8

Develop a side-by-side comparison New and Generic Drugs and explain why the level of QA/QC confidence in the proposed approach should be higher than what is achieved under the current system

Proposed Steps

Seek ACPS recommendation at the May 2005 meeting on general considerations for identifying and developing statistical procedures

Develop a detailed proposal for a subsequent

meeting of the ACPS

Seek harmonization on the approach with other regulatory authorities (starting with ICH Q8 Part 2)

Topic #1 ACPS Discussion Goals Seek ACPS recommendations on a proposed

regulatory tactical plan QbD based regulatory decision system for quality

assurance and control of optimal drug dissolution rate over the life cycle of a product

Are the tactical steps outlined consistent with the QbD goals we seek to achieve?

What additional steps and/or changes would you recommend to improve this plan?

What additional scientific evidence is necessary to support the development and implementation of this plan?

Any other specific recommendations?

QbD & Goals? A systematic process of

defining optimal design specifications of a product, its manufacturing process and its quality control and assurance methods High degree process

understanding High confidence of low risk of

releasing a poor quality product

High efficiency through continuous learning and improvement

Intended UseRoute of administration

Patient population…..

Product Design

Design Specifications(Customer requirements)

Manufacturing Process

The Process

R&D QualityManufacturing

CMC Review

Biopharm Review

Clinical Review

Pharm/Tox Review

Process ValidationApproval

CGMPInspection

Compliance

Quality Control

Need for a “Quality System” Orientation

http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf

Quality System Requirements QS-9000Third Edition element 4.2.5—Continuous Improvement (1998).

For those product characteristics and process parameters that can be evaluated using variable data, continuous improvement means optimizing the characteristics and parameters at a target value and reducing variation around the value.

For those product characteristics and process parameters that can only be evaluated using attribute data, continuous improvement is not possible until characteristics are conforming.

If attribute data results do not equal zero defects, it is by definition nonconforming product. Improvements made in these situations are definition corrective actions, not continuous improvement.

Continuous improvement [shall be undertaken] in processes that have demonstrated stability, acceptable capability and performance.

USPXXIII 3-Stage Acceptance Rule

Step 1, 6 tablets

%5)( QXMin

No

Pass

Yes

Step 2, additional 6 tablets

Yes

No

Step 3, additional 12 tablets

Yes

No Fail

%15)(

QXMin

QX

5%-Q tablets2 than more No

%15)( ,

QXMinQX

Pass

Pass

A Recent Proposal… A step in the right direction…..

Hauck, W.H., Foster, T., Sheinin, E., Cecil, T., Brown, W., Marques, M. and Williams, R.L. Oral Dosage Form Performance Test: New Dissolution Approaches. Pharm. Res. 22: 182-187 (2005) Conclusions

(a) hypothesis testing, with clear delineation of consumer and producer risks (b) testing by variables as opposed to testing by attribute (c) a tolerance interval approach to set acceptance criteria (d) more flexible study design

But …. Several challenges first need to be addressed (e.g., measurement system and robust estimates of variability) and then it will be essential to find an appropriate balance between statistics and pharmaceutical science One has to start with pharmaceutical science discussion before

developing an appropriate statistical tool


Corrective Actions Provide the leverage for Continuous Improvement?

A case of an Approved and Validated product follows….


This can be catastrophic for the business and availability ofImportant drugs

A Warning Letter

Inability to resolve Out of Specification Observations…

Undermines the credibility of decision system Raises questions - adequacy of the current

decision system Increases the risk of releasing unacceptable

quality product to the consumer Contributes to the low efficiency

CAPA: Challenges

Difficult questions faced by Difficult questions faced by Manufacturing Groups and RegulatorsManufacturing Groups and Regulators……•• IfIf we chose to use a calibrator tablet for a we chose to use a calibrator tablet for a

Gauge R&R study....Gauge R&R study....

•• σσ22(Total for Calib.)(Total for Calib.)

•• = = σσ22(Calib.)(Calib.) + + σσ22

C*MeasurementC*Measurement

•• What is the measurement for the Calibrator and what What is the measurement for the Calibrator and what is its variability?is its variability? σσ22

(C*Measurement)(C*Measurement)

•• Since Since σσ22(Calib.)(Calib.) is not known; we have to use is not known; we have to use σσ22

(Total for (Total for Calib.)Calib.)

•• σσ22Total for ProductTotal for Product = = σσ22

ProductProduct + + σσ22Total for Calib.Total for Calib.

Hussain, A.S. Biopharmaceutics and Drug Product Quality:Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests Performance Tests for Drug Products, A Look Into the Future. for Drug Products, A Look Into the Future. USP Annual Scientific Meeting"The Science of Quality“. September 26–30, 2004

Difficult questions faced by Difficult questions faced by Manufacturing Groups and RegulatorsManufacturing Groups and Regulators……•• Assumption of independent variable?Assumption of independent variable?

•• Another aspect Another aspect –– is the measurement capability for a is the measurement capability for a Calibrator tablet representative of the drug product? Calibrator tablet representative of the drug product? What if there are differences such as disintegration What if there are differences such as disintegration mechanism and buoyancy between the Calibrator and mechanism and buoyancy between the Calibrator and the drug product? the drug product?

CAPA: Challenges


Need for improvement is not just limited to CAPA We need to be confident on our analyses of

Surveillance samples Consumer complaints Other investigations

Is the Current Approach to “Calibration” Adequate?

Dissolution Experience at the FDA Division of Dissolution Experience at the FDA Division of Pharmaceutical AnalysisPharmaceutical Analysis

•• Dissolution testing with USP Apparatus 1 and 2 Dissolution testing with USP Apparatus 1 and 2 requires diligent attention to details: mechanical requires diligent attention to details: mechanical and chemicaland chemical

•• Dosage forms can respond differently to small Dosage forms can respond differently to small variations in apparatus set up or degassing variations in apparatus set up or degassing

•• Large differences in dissolution results are possible Large differences in dissolution results are possible unless all parameters are carefully controlled unless all parameters are carefully controlled

•• Differences in reproducibility can often be traced Differences in reproducibility can often be traced to improper mechanical calibration and/or to improper mechanical calibration and/or degassing degassing Cindy Buhse

Director, Division of Pharmaceutical AnalysisFDA/CDER/OPS/OTR


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We faced significant challenges in our analysis: Unexpected inter-laboratory differences that highlighted limitation of the current calibration procedure“We are at a loss to explain the difference between DPA’s and PHI-DO’s initial results. ………………..We further contend that the Helium sparging does not remove dissolved air as well as the vacuum procedures and therefore could account for the additional 5 or 6% increase in the dissolution results. And finally, for this formulation basket wobble can significantly increase the dissolution values.”

Prophylaxis compliance and not pharmaceutical quality was the reason

DPA/CDER/FDA Memo B. J. Westenberger, 17 October 2003

Equally important is the need to Better understand the sources of variability in

product performance and quality so as to establish the most appropriate design specifications that support continuous improvement and address

increasing complexity of product designs Develop measurements systems for products

intended for non-oral route of administration and novel drug delivery systems

Develop and implement globally harmonized proactive regulatory decision systems For example: ICH Q6A and draft ICH Q8

Example: Pharmaceutical Development & Dissolution Specification Without pharmaceutical development information

Decision focus only on dissolution test data Test often used for both “in-process control” and final product

testing Decision characteristics focus only on “mean”

Variability managed indirectly -“discriminating” test conditions and “tight” procrustean acceptance criteria

Leads to a deterministic interpretation of specification (ignores the impact of random variability)

“Specifications are Standards” – can not be risk-based “Event Trees” not “Decision Trees”

Difficult to resolve “out of specification” observations Post-approval changes and optimization or continuous

improvement difficult

Dissolution specification without pharmaceutical development information

Test 1

Test 2

Mean DissolutionProfiles (n=6)

Pivotal clinical lots

“Discriminating test”

FDA

75%

Applicant

Dissolution Test Problems:False +ives and -ives

15 min 30 min 45 min AUC CmaxRef 95 96 98 100 100B 96 97 97 104 95C 62 84 92 84 55D 82 94 95 88 87E 103 103 103 112 120F 13 35 53 100 102

Test/Ref. Mean

I. J. MacGilvery. Bioequivalence: A Canadian Regulatory Perspective. In, Pharmaceutical Bioequivalence. Eds. Welling, Tse, and Dighe. Marcel Dekker, Inc., New York, (1992)).

Differences between US & Japan?

*Due to ACS restrictions on discussing specific drugs, names of drugsavailable in open literature have been erased.

Differences between US & Japan?

Due to ACS restrictions on discussing specific drugs, names of drugs available in open literature have been blocked.

ICH Q6A: Goal and Characteristics of Pharmaceutical Quality Decision System “The quality of drug substances and

drug products is determined by their design, development, in-process controls, GMP controls, process validation, and by specifications applied to them throughout development and manufacture.”

Characteristics

Goal

Life-cycle

What is the ICH Q8 What is the ICH Q8 Opportunity?Opportunity?

Specifications

In process controls

Development

Design

Process validation

GMP Controls

ICH Q6A ICH Q6A Decision CharacteristicsDecision Characteristics

“…where the provision of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.”

ACPS May 2005

1995 1997 2000

SUPAC DissolutionIVIVC

BCSICH Q6A

2004, PAT & draft ICH Q8

Current State

Desired State

ACPS Discussion

The Measurement System Cindy Buhse

Overview of Current Regulatory Decision process Mehul Mehta and Vibhakar Shah

Current state of science Lawrence Yu

Basis of the proposed Tactical Plan Ajaz Hussain

ACPS recommendations for improving and/or modifying the proposed plan

Corrective Actions and Preventive Actions

““Special Cause” or “Common Special Cause” or “Common Cause”Cause”

Stable- Yes; Capable?

Reduce “Common Cause”Variability

Unstable

Corrective ActionsEliminate “Special Cause”

Frequent,MajorOOS

Minor,Occasional

OOS


Identifying Sources of Variability

Process Capability and Measurement Process Capability and Measurement Capability: Dissolution TestCapability: Dissolution Test

•• When we evaluate process capability by When we evaluate process capability by measuring variability in the product measuring variability in the product producedproduced

•• Total variability Total variability σσ22TotalTotal

•• Assuming independent variable (if not independent Assuming independent variable (if not independent for example interaction between measurement and for example interaction between measurement and product a covariance term needs to be included)product a covariance term needs to be included)

•• σσ22TotalTotal = = σσ22

ProductProduct + + σσ22MeasurementMeasurement

•• σσ22MeasurementMeasurement = = σσ22

RepeatabilityRepeatability + + σσ22ReprodicibilityReprodicibility


CAPA: Steps necessary

© Light Pharma

Process Capability: If you can’t measure it, you can’t improve it

Process Capability Roadmap:

1Has MeasurementSystem capability

been verified?

STOP! Do not compute

Proc. Cap. statistics.Improve the Meas. System.

No

2Is the process stableor unstable via SPC?

Yes

STOP! Do not compute

Proc. Cap. statistics.Investigate special causes.Improve process stability.

3Is the data normal “enough” via theNormality Test?

STOP!Transform data.

No4Compute

Cpk

Yes

Unstable

Stable

0Challenge

Specs!

p-value < 0.05p-value > 0.05

Gage R&R& Calibration

SPC Charts

Scott Tarpley, UK Arden House 2004


CAPA: ChallengesIn an OOS Situation In an OOS Situation –– the question the question is what went wrong?is what went wrong?

•• Repeatability Repeatability –– inherent precision of the test inherent precision of the test procedure (did this change?)procedure (did this change?)

•• Reproducibility Reproducibility –– different operator, different different operator, different time period, different environment,time period, different environment,…… (is this a (is this a problem?)problem?)

•• Destructive sample Destructive sample –– what should we use to what should we use to evaluate repeatability and reproducibility?evaluate repeatability and reproducibility?

•• A USP Dissolution Calibrator Tablet? A USP Dissolution Calibrator Tablet? •• Tablets from clinical batch?Tablets from clinical batch?

–– Statistical approaches are available for ensuring Statistical approaches are available for ensuring appropriate sample of reference appropriate sample of reference

••Difficult questions; a need exists for further Difficult questions; a need exists for further discussion on this topicdiscussion on this topic


CAPA: Challenges

Difficult questions faced by Difficult questions faced by Manufacturing Groups and RegulatorsManufacturing Groups and Regulators……•• IfIf we chose to use a calibrator tablet for a we chose to use a calibrator tablet for a

Gauge R&R study....Gauge R&R study....

•• σσ22(Total for Calib.)(Total for Calib.)

•• = = σσ22(Calib.)(Calib.) + + σσ22

C*MeasurementC*Measurement

•• What is the measurement for the Calibrator and what What is the measurement for the Calibrator and what is its variability?is its variability? σσ22

(C*Measurement)(C*Measurement)

•• Since Since σσ22(Calib.)(Calib.) is not known; we have to use is not known; we have to use σσ22

(Total for (Total for Calib.)Calib.)

•• σσ22Total for ProductTotal for Product = = σσ22

ProductProduct + + σσ22Total for Calib.Total for Calib.


Difficult questions faced by Difficult questions faced by Manufacturing Groups and RegulatorsManufacturing Groups and Regulators……•• Assumption of independent variable?Assumption of independent variable?

•• Another aspect Another aspect –– is the measurement capability for a is the measurement capability for a Calibrator tablet representative of the drug product? Calibrator tablet representative of the drug product? What if there are differences such as disintegration What if there are differences such as disintegration mechanism and buoyancy between the Calibrator and mechanism and buoyancy between the Calibrator and the drug product? the drug product?

CAPA: Challenges


CAPA: Challenges

Options for reducing Options for reducing σσ22ProductProduct??

•• Reduce Reduce σσ22ProductProduct

–– Often during development the same or similar Often during development the same or similar dissolution test method is used to generate the dissolution test method is used to generate the average average ““responseresponse”” dissolution profiles for identifying dissolution profiles for identifying and optimizing formulation and process conditionsand optimizing formulation and process conditions•• Are any relevant information on Are any relevant information on ““variabilityvariability”” available in the available in the

development reports?development reports?

•• Caution: Observed variability in the production Caution: Observed variability in the production setting can be setting can be ““common causecommon cause”” variability and variability and attempts to alter processing parameters without attempts to alter processing parameters without good information can create a bigger problemgood information can create a bigger problem


Documents

Introduction to Topic #1: QbD approach for quality control and assurance of Dissolution Rate Ajaz S. Hussain, Ph.D. Deputy Director, Office of Pharmaceutical