Annual Product Quality Review

(APQR)

Dr. A. Amsavelwww.bp

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“You tell me,…and I forget.

You teach me,…and I remember.

You involve me,…and I learn.”

- BENJAMINFRANKLINwww.bpha

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Introduction

• Quality Unit• APQR

– Requirement– Responsibility– Documents and data required– Preparation and evaluation– Conclusion

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ICH Q7- 2.0 Quality Management

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1. Principles– Define Responsibilities & Authorities

2. Responsibilities of Quality Unit (s)– Quality Control / Assurance, Independent of Production

3. Responsibilities of Productionactivities4. Internal Audits (self Inspection)5. Product Quality Review

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Quality Assurance responsibilities :

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Releasing or rejecting all APIs and intermediates for outsideuse

Establishing a system to release or reject raw materialintermediates, packaging and labelling materials ;

Reviewing completed batch production and laboratory control records of critical processstepsMaking sure that critical deviations are investigated and resolved;

Approving all specifications and master production instructions;

Approving all procedures impacting the quality of intermediates or APIs;

Making sure that effective systems are used for maintainingand calibrating critical equipment ;

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Questions?

• What is an annual product review?• What is the objective ofAPR?• Who is responsible?• What is procedure & reference forAPQR?• What are the data must be presented inan

annual product review?• How should an annual product reviewbe

organized?• Review and conclsion

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Annual Product Review - WHAT

Directive Statement:An Annual Product Review must be conducted for

each commercial product. The purpose of this annual review is to verify the consistency of the process, to assess trends, to determine the need for changes in specification, production, manufacturing and/or control procedures and to evaluate the need forrevalidation.

Annual Product Reviews (APRs) are important for communication between manufacturing, quality and regulatory Affairs, to enable quality improvement processes. Content and management of AnnualProduct Reviews must be established according to thisdirective.

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Reference - APQR

• US FDA –Published in 1978 GMP Guideline which was included to review the qualitystandards

• All GMP Guidelines refer the requirement ofAPQR– CFR 211.180 (e):– ICHQ7– EUGMP– WHO- GMP www.bp

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Requirement of APQR

• In USA - "Annual ProductReview“• In Europe, the EU GMP Guideline uses the

term "Product QualityReview".• Requirement or expectations are almostsame• APQR should be conducted for all commercial

product.• APQR should confirm the State ofControlwww.bp

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The US Requirements: 21 CFR 211.180 (e)

• US FDA objectives for performing the APR are to determine the need to make changes inthe– manufacturing process,– the manufacturing controls (e.g., in-process testingand

monitoring), evaluate the needs for revalidationand– product specifications.

to evaluate the compliance status of the manufacture and to identify areas ofimprovement

A review of a representative number of batches, whether approved or

rejected, and records associated with thebatch

A review of complaints, recalls, returned or salvageddrug products,

and investigations conducted under Sec. 211.192 for each drug

product.

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The Requirements for APIs in ICHQ7

2.5 Product Quality Review

2.50 Regular quality reviews of APIs should be conducted with the objective

of verifying the consistency of the process. Such reviews should normally be

conducted and documented annually and should include at least:

A review of critical in-process control and critical API test results;A review of all batches that failed to meet established specification (s); A review of all critical deviations or non-conformances and related investigations;A review of any changes carried out to the processes or analytical methods;A review of results of the stability monitoring program;A review of all quality-related returns, complaints and recalls; and A review of adequacy of corrective actions

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The Requirements for APIs in ICHQ7

2.5 Product Quality Review

2.51 The results of this review should be evaluated and an

assessment made of whether corrective actions or any

revalidation should be undertaken. Reasons for such corrective

action should be documented. Agreed corrective actions should

be completed in a timely and effective manner.www.bpha

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The EU Requirements for PQR(1)

• EUGuidelines to Good Manufacturing Practice ; MedicinalProducts for Human and Veterinary Use ; Part I ; Chapter 1Quality Management (issued on 25 October2005)

Product Quality Review1.5 Regular periodic or rolling quality reviews of all licensed medicinal products, including export only products, should be conducted with the objective of verifying consistency of the existing process, the suitability of current specifications for both starting materials and finished product to highlight any trends and to identify productand process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include atleast:

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The EU Requirements for PQR(2)

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A review of starting materials and packaging materials used for the product, especially those from newsourcesAreview of critical in- process controls and finished product resultsAreview of all batches that failed to meet established specification(s) and their investigation.A review of all significant deviations or non conformances, their related investigations, and the effectiveness of resultantcorrective and preventative actions takenAreview of all changes carried out to the processes or analytical methodsA review of Marketing Authorisation variations submitted/granted/refused, including those for thirdcountry (export only) dossiers.

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The EU Requirements for PQR(3)

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Areview of the results of the stability monitoring programme and any adverse trendsA review ofall quality- related returns, complaints and recalls and the investigations performed at thetimeA review of adequacy of any other previous productprocess or equipment corrective actions. For new marketing authorisations and variations to marketing authorisations, a review of post-marketingcommitmentsThe qualification status of relevant equipment andutilities,e.g. HVAC, water, compressed gases, etcA review of Technical/Quality Agreements to ensure that they are up to date.

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Benefit or use

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Decrease the risk of out-of-specificationresults Minimize the risk of rework/reprocessing Decrease downtime

Increase productivityDecrease the risk of productrecallsMeet all regulatorycommitments/requirementsImprove communication between production,engineering, quality and regulatory functionswww.bp

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Responsibilities

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It is responsibilities ofQAEstablish an SOP with responsibility and process ofAPQRIndividual departments have toprovide the data and participating in the APQRprocess.Reviews should normally be conducted anddocumentedThe Quality Unit, as the central position, should requestthis review and coordinate the necessary work. Can develop format/ check list to get information.Other departments, like Production, Engineering, Maintenance, Purchase, etc. are also need to beinvolved.Senior Quality Management must approve theAPQR.

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Requirements

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Written procedures shall be established and it must be followed ;APQR must cover a one-year rolling period, but does not haveto coincide with a calendaryearThe review should normally be completed within 60 calendardays APQR for all productsmanufacturedIn case product not manufactured in the year of review ,shall review stability and complaint, Recall & returns etc.APQR must be prepared for each water quality gradeproducedFor critical utilities it is recommending either to perform a separate APR or to include a specific chapter in theAPR.APQR must include all batches of product (accepted/rejected/destroyed )APQR must address the assessment of data, documents and electronic records reviewed

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Preparation

Appropriate statistical tools may be used to assess process capability when data from a

large number of batches is beingreviewed.

Where the data concludes that there is adrift in process capability , actions should

be determined to evaluate the causes and improve performance in the forthcoming

reviewperiod.

Thereview of all batches which fail to meet specification and the review of critical

deviations

should look specifically at recurring causes and identifyappropriate actions to

reduce the frequency and improveperformance.

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Corrective action

Equipment not functioning correctly or in need of maintenance or replacement.

Inadequate batch instructions or training ofoperators.

Process parameters so tightly defined that the equipmentis not capable of routinely

achieving the acceptancecriteria.

Inhomogeneous product or inadequate samplingprocedures.

Poor quality raw materials or lack of control of raw material suppliers.

Retest period or expirydate

Revalidation,requalification

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Review and document

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Review must include, at a minimumReview of any recommendations and actions taken from prior report"Basicstatistics" Number of batches manufactured, including partiallycompleted

batches and corresponding yields Number and percentage of batches rejected, reworked orreprocessed

and related reasons Critical in-process controls, finished product results and criticalAPI

test results www.bpha

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Review and document

• Review of "deviations from the validated state“ Areview of all batches that failed to meet established specification(s) and

their investigation

Significant/critical deviations, Out of Specification Results and relatedfailure investigations (review of adequacy and effectiveness of corrective and preventative actions taken)

Product quality complaints &ProductRecalls

Quality related issues for returned, and/orsalvaged goods

Changes effected (change control) and variations during the period (e.g. process, suppliers, equipment, critical utilities)

Changes of product specifications or methods (e.g. analytical changes,and results)

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Review and document

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Effectiveness of implementation ofCAPA out of calibrationresults;Process and analytical equipment retirement; Water quality ;Validation carried out in process and analyticalmethod; results of the stability monitoringprogram;Environment monitoring (bio-burden) in the cleanroom; Yield output variations;return goods and salvage of product; Retain sampleRegulatory issues if any

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Review and document

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TrendAnalysis Trend analysis on key in-process and release testing with graphic

representation and basic statisticsrecommended

A review of the results of the stabilitymonitoring program and trend

analysis on stabilitydata

Observations/Recommendations an conclusion Report the reviewobservations.

Recommendations from thisreview

The results of the APR must be evaluated and an assessment made whether corrective or preventive action or any re-validationis necessary.A conclusion statement must be written to assess if the product consistently meets its quality attributes, and if not, what actions need to be taken.Rationale for such CAPAs must bedocumented.

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Data collectionS.No

Batch number% MC

%Assay

Related substances by GC

Imp-A Imp-K Sum of impurities

Volatile substances by GC

Methanol Toluene

54 XXYYZZZ 0.28 100.1 0.06 0.00 0.00 0.10 0.00

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TrendChart%Asay

XXXXXX Batch Vs % of Assay106

1 4 7 10 13 16 19 22 25 28

% Assy

MeanStandard Deviation Minimum MaximumRSD

Natural specification Limit

( µ ± 3σ)

Specification or Parameter Range

104 USL

102 UNSL

100 MEAUNpper limit

98Assay

LNSL96 LSL

9431 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85

Batch Number

: 99.8: 0.1: 99.5: 100.1: 0.1

LowerLimit : 99.4

Upper Limit : 100.2

: 98.0-102.0%

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TrendChart

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Processcapability

Process consistency can be established by CpkProcess capability index (Cpk) can be calculated as below;

SU-SL

CPk = ---------3σ

x - SL

or CP=---------

One sided specification SU– x

CPk=----------3σ 3σ

1.33 ≤CPk Satisfiable enough

1.00 ≤CPk < 1.33 Adequate

CPk <1.00 Inadequate

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Process consistency-Yield

Yield range : 100 -120kg Std deviation : 3.0Mean : 110kg

= 1.1120

Cpk =------------6*3.0

After change made in theprocess

and mean 112kg

= 1.515

Std deviation : 2.220

Cpk =------------6*2.2

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Normal distribution

Normal Distribution:µ ± σ = 68.3% µ± 2σ = 95.4% µ± 3σ = 99.7%

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Stability trend

%Assay MeanStandard Deviation MinimumMaximum RSD

Natural specification Limit LowerLimitUpperLimit

: 99.7%: 0.1%: 99.4%: 99.9%: 0.1%

: 99.3%

: 100.0%( µ ± 3σ)

Specification or Parameter Range : 99.0 % to 100.5 %

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Review of documents & system

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Data collection and reviewManufacturing instructions and packagingprocedures

• Changes compared to the previousyear• Validation status following achange

Batch production records• Actual values for process parameters duringproduction• IPCdata• Deviations• Yield• Rawmaterials

Test procedures• Changes to specifications or methods compared tothe previous

year• Validation status of the testmethods

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Review of documents & system•

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Data collection and review

Quality SystemDeviationsOOS– Failure cause analysis

Vendor status– Change of vendor– Supplier qualification andapproval– Deviations, rejections of rawmaterial

Modification– Changes to the facility– Changes to machines/apparatus– Changes to super ordinate processes

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Review of documents & systemData collection and review

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Quality attributes (analytical data)– Key starting material/critical material– Critical test result of IPC,intermediates– Critical quality parameters of finishedproduct/blended– Decision on the trend- tightening of spec, CAPA,validation

requirement if any

All quality-related returns, complaints andrecalls Adequacy of correctiveactionsStability data– Changes to packaging material– Process changes

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Inferences from the APR

• Follow-up actions may be included but are not limitedto:

Product process improvement Analytical method improvements

In-process or final product specificationreview Revalidation

Product recall or withdrawal

New packagingwww.bp

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Check List forAPQR

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Are there any outstanding validation commitments or correctiveand preventive action plans from last APQR?Are the processes in a validated state or is additional validationwork needed ?Is the qualification status (IQ/OQ/PQ) acceptable?Are all critical aspects performing satisfactorily or arecorrective/ preventive action plans required?Are there any significant findings concerning data trending of the manufacturing process, starting materials, or packaging materials?Are all change controls implemented, and closed? Communicated to the relevant customers and regulatory agencies?Are all change controls, deviations, OOS investigation, complaints are reviewed, investigated, CAPA implemented, andclosed?

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Check List forAPQR

• Are there any significant findingsconcerning– changes performed ?– specifications or test methods?– deviations and non- conformances ?

– out of specification results?

– rejected batches, quality-related returns, customer complaints, orrecalls ?

– the stability monitoring program?

– retain sample examination ?

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Are all post- marketing commitments to Authorities met ?Are all required Technical Agreements in place andup-to-date ?

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ThankYou

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