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Annual Product Quality Review


Dr. A. Amsavel



“You tell me,

…and I forget.

You teach me,

…and I remember.

You involve me,

…and I learn.”





• Quality Unit

– Requirement

– Responsibility

– Documents and data required

– Preparation and evaluation

– Conclusion



ICH Q7- 2.0 Quality Management

• 1. Principles

– Define Responsibilities & Authorities

• 2. Responsibilities of Quality Unit (s)

– Quality Control / Assurance, Independent of Production

• 3. Responsibilities of Productionactivities

• 4. Internal Audits (self Inspection)

• 5. Product Quality Review



Quality Assurance responsibilities :

• 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 processsteps

• Making 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 ;




• 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

• Review and conclsion



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.



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):






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


• APQR should confirm the State ofControl



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



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


 A review of any changes carried out to the processes or analytical


 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


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.



The EU Requirements for PQR(1)
• EUGuidelines to Good Manufacturing Practice ; Medicinal

Products for Human and Veterinary Use ; Part I ; Chapter 1
Quality Management (issued on 25 October2005)

Product Quality Review

1.5 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:



The EU Requirements for PQR(2)
• A review of starting materials and packaging materials used for the

product, especially those from newsources
• Areview of critical in- process controls and finished product results
• Areview 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 taken

• Areview of all changes carried out to the processes or analytical

• A review of Marketing Authorisation variations
submitted/granted/refused, including those for thirdcountry
(export only) dossiers.



The EU Requirements for PQR(3)
• Areview of the results of the stability monitoring programme

and any adverse trends
• A review ofall quality- related returns, complaints and recalls

and the investigations performed at thetime
• A 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-marketingcommitments

• The qualification status of relevant equipment andutilities,
e.g. HVAC, water, compressed gases, etc

• A review of Technical/Quality Agreements to ensure that they
are up to date.



Benefit or use
• Decrease the risk of out-of-specificationresults

• Minimize the risk of rework/reprocessing

• Decrease downtime

• Increase productivity

• Decrease the risk of productrecalls

• Meet all regulatorycommitments/requirements

• Improve communication between production,engineering,
quality and regulatory functions




• It is responsibilities ofQA
• Establish an SOP with responsibility and process ofAPQR
• Individual departments have toprovide the data and

participating in the APQRprocess.
• Reviews should normally be conducted anddocumented
• The 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.



• 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 calendaryear

• The review should normally be completed within 60 calendardays
• APQR for all productsmanufactured

• In 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 gradeproduced
• For 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

18 electronic records reviewed



 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

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


 should look specifically at recurring causes and identifyappropriate actions to

reduce the frequency and improveperformance.



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

 Retest period or expirydate




Review and document

• Review must include, at a minimum
• Review 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



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




Review and document

• 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 sample

• Regulatory issues if any



Review and document
• 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.



Data collection
Volatile substances

S.No Related substances by GC
by GC

Imp-A Imp-K Sum of Methanol Toluene

% MC

Batch number


54 XXYYZZZ 0.28 100.1 0.06 0.00 0.00 0.10 0.00



XXXXXX Batch Vs % of Assay


102 UNSL

100 MEAUNpper limit





31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85
1 4 7 10 13 16 19 22 25 28 Batch Number

% Assy

Mean : 99.8
: 0.1

Standard Deviation
: 99.5

: 100.1

: 0.1

RSD Lower

Natural specification Limit Limit 99.4

( µ ± 3σ) Limit 100.2


Specification or Parameter Range %







Process consistency can be established by Cpk

Process capability index (Cpk) can be calculated as below;

CPk = ———

One sided specification
SU– x x – SL

CPk=———- or CP=———
3σ 3σ

1.33 ≤CPk Satisfiable enough

1.00 ≤CPk < 1.33 Adequate

CPk <1.00 Inadequate



Process consistency-Yield

Yield range : 100 -120kg

Std deviation : 3.0

Mean : 110kg

Cpk =———— = 1.11


After change made in the process

Std deviation : 2.2 and mean 112 kg

Cpk =———— = 1.515



Normal distribution

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



Stability trend

Mean : 99.7%
Standard Deviation : 0.1%
Minimum : 99.4%
Maximum : 99.9%
RSD : 0.1%

Natural specification Limit : 99.3%


( µ ± 3σ) Upper : 100.0%

Specification or Parameter Range : 99.0 % to 100.5 %



Review of documents & system
Data collection and review

• Manufacturing 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

• Validation status of the testmethods



Data collection and review
Review of documents & system

Quality System


– Failure cause analysis

Vendor status
– Change of vendor

• – Supplier qualification andapproval

– Deviations, rejections of rawmaterial

– Changes to the facility

– Changes to machines/apparatus

– Changes to super ordinate processes


Data collection and review
Review of documents & system

• 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 correctiveactions

• Stability data
– Changes to packaging material

– Process changes



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 packaging



Check List forAPQR

• 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?



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 ?

• Are all post- marketing commitments to Authorities met ?

• Are all required Technical Agreements in place andup-to-
date ?