The document discusses the requirements and procedures for conducting an Annual Product Quality Review (APQR). Key points include: - The APQR is intended to verify process consistency, assess trends, determine needed specification/procedure changes, and evaluate revalidation needs. - Regulatory guidelines like ICH Q7, FDA, and EU require annual reviews that include batch data, deviations, complaints, stability results, and corrective actions. - The quality unit coordinates the APQR using data and participation from other departments. The review is documented and approved by senior quality management.

1. Annual Product Quality Review
(APQR)
Dr. A. Amsavel

2. “You tell me,
… and I forget.
You teach me,
… and I remember.
You involve me,
… and I learn.”
- BENJAMIN FRANKLIN

3. Introduction
• Quality Unit
• APQR
– Requirement
– Responsibility
– Documents and data required
– Preparation and evaluation
– Conclusion

4. ICH Q7- 2.0 Quality Management
• 2.1 Principles
– Define Responsibilities & Authorities
• 2.2 Responsibilities of Quality Unit (s)
– Quality Control / Assurance, Independent of Production
• 2.3 Responsibilities of Production activities
• 2.4 Internal Audits (self Inspection)
• 2.5 Product Quality Review

5. Quality Assurance responsibilities :
• Releasing or rejecting all APIs and intermediates for outside use
• Establishing a system to release or reject raw material intermediates,
packaging and labelling materials ;
• Reviewing completed batch production and laboratory control records
of critical process steps
• 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 maintaining and
calibrating critical equipment ;

6. Questions?
• What is an annual product review?
• What is the objective of APR?
• Who is responsible?
• What is procedure & reference for APQR?
• What are the data must be presented in an
annual product review?
• How should an annual product review be
organized?
• Review and conclsion

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

8. Reference - APQR
• US FDA –Published in 1978 GMP Guideline which was
included to review the quality standards
• All GMP Guidelines refer the requirement of APQR
– CFR 211.180 (e):
– ICH Q7
– EU GMP
– WHO- GMP

9. Requirement of APQR
• In USA - "Annual Product Review“
• In Europe, the EU GMP Guideline uses the
term "Product Quality Review".
• Requirement or expectations are almost same
• APQR should be conducted for all commercial
product.
• APQR should confirm the State of Control

10. The US Requirements: 21 CFR 211.180 (e)
• US FDA objectives for performing the APR are to
determine the need to make changes in the
– manufacturing process,
– the manufacturing controls (e.g., in-process testing and
monitoring), evaluate the needs for revalidation and
– product specifications.
 to evaluate the compliance status of the manufacture and
to identify areas of improvement
 A review of a representative number of batches, whether approved or
rejected, and records associated with the batch
 A review of complaints, recalls, returned or salvaged drug products,
and investigations conducted under Sec. 211.192 for each drug
product.

11. The Requirements for APIs in ICH Q7
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

12. The Requirements for APIs in ICH Q7
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.

13. The EU Requirements for PQR (1)
• EU Guidelines to Good Manufacturing Practice ; Medicinal
Products for Human and Veterinary Use ; Part I ; Chapter 1
Quality Management (issued on 25 October 2005)
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 product and process improvements. Such reviews
should normally be conducted and documented annually, taking
into account previous reviews, and should include at least:

14. The EU Requirements for PQR (2)
• A review of starting materials and packaging materials used for the
product, especially those from new sources
• A review of critical in- process controls and finished product results
• A review 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 resultant corrective
and preventative actions taken
• A review of all changes carried out to the processes or analytical
methods
• A review of Marketing Authorisation variations
submitted/granted/refused, including those for third country
(export only) dossiers.

15. The EU Requirements for PQR (3)
• A review of the results of the stability monitoring programme
and any adverse trends
• A review of all quality- related returns, complaints and recalls
and the investigations performed at the time
• A review of adequacy of any other previous product process
or equipment corrective actions. For new marketing
authorisations and variations to marketing authorisations, a
review of post-marketing commitments
• The qualification status of relevant equipment and utilities,
e.g. HVAC, water, compressed gases, etc
• A review of Technical/Quality Agreements to ensure that they
are up to date.

16. Benefit or use
• Decrease the risk of out-of-specification results
• Minimize the risk of rework/reprocessing
• Decrease downtime
• Increase productivity
• Decrease the risk of product recalls
• Meet all regulatory commitments/requirements
• Improve communication between production, engineering,
quality and regulatory functions

17. Responsibilities
• It is responsibilities of QA
• Establish an SOP with responsibility and process of APQR
• Individual departments have to provide the data and
participating in the APQR process.
• Reviews should normally be conducted and documented
• The Quality Unit, as the central position, should request this
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 be involved.
• Senior Quality Management must approve the APQR.

18. Requirements
• Written procedures shall be established and it must be followed ;
• APQR must cover a one-year rolling period, but does not have to
coincide with a calendar year
• The review should normally be completed within 60 calendar days
• APQR for all products manufactured
• 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 grade produced
• For critical utilities it is recommending either to perform a separate
APR or to include a specific chapter in the APR.
• APQR must include all batches of product (accepted /rejected
/destroyed )
• APQR must address the assessment of data, documents and
electronic records reviewed

19. Preparation
• Appropriate statistical tools may be used to assess process capability
when data from a large number of batches is being reviewed.
• Where the data concludes that there is a drift in process capability ,
actions should be determined to evaluate the causes and improve
performance in the forthcoming review period.
• The review of all batches which fail to meet specification and the review
of critical deviations
• should look specifically at recurring causes and identify appropriate
actions to reduce the frequency and improve performance.

20. Corrective action
• Equipment not functioning correctly or in need of
maintenance or replacement.
• Inadequate batch instructions or training of operators.
• Process parameters so tightly defined that the equipment is
not capable of routinely
• achieving the acceptance criteria.
• Inhomogeneous product or inadequate sampling procedures.
• Poor quality raw materials or lack of control of raw material
suppliers.
• Retest period or expiry date
• Revalidation, requalification

21. Review and document
• Review must include, at a minimum
• Review of any recommendations and actions taken from
prior report
• "Basic statistics"
 Number of batches manufactured, including partially completed
batches and corresponding yields
 Number and percentage of batches rejected, reworked or reprocessed
and related reasons
 Critical in-process controls, finished product results and critical API
test results

22. Review and document
• Review of "deviations from the validated state“
 A review of all batches that failed to meet established specification(s) and
their investigation
 Significant/critical deviations, Out of Specification Results and related failure
investigations (review of adequacy and effectiveness of corrective and
preventative actions taken)
 Product quality complaints &Product Recalls
 Quality related issues for returned, and/or salvaged 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)

23. Review and document
• Effectiveness of implementation of CAPA
• out of calibration results;
• Process and analytical equipment retirement;
• Water quality ;
• Validation carried out in process and analytical method;
• results of the stability monitoring program;
• Environment monitoring (bio-burden) in the clean room;
• Yield output variations;
• return goods and salvage of product;
• Retain sample
• Regulatory issues if any

24. Review and document
• Trend Analysis
 Trend analysis on key in-process and release testing with graphic
representation and basic statistics recommended
 A review of the results of the stability monitoring program and trend
analysis on stability data
• Observations/Recommendations an conclusion
 Report the review observations.
 Recommendations from this review
• The results of the APR must be evaluated and an assessment made
whether corrective or preventive action or any re-validation is 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 be documented.

25. Data collection Volatile substances
S.No Related substances by GC
by GC
Imp-A Imp-K Sum of Methanol Toluene
impurities
% MC
%Assay
Batch number

26. Trend Chart
XXXXXX Batch Vs % of Assay
106
104
USL
102 UNSL
100
Upper limit
MEAN
%
Assay
A
y
a
s
98
LNSL
96
LSL
94
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85
Batch Number
% Assy
Mean : 99.8
Standard Deviation : 0.1
Minimum : 99.5
Maximum : 100.1
RSD : 0.1
Lower
Natural specification Limit :
Limit 99.4
Upper
( µ ± 3σ) :
Limit 100.2
98.0-102.0
Specification or Parameter Range :
%

27. Trend Chart

28. Process capability
Process consistency can be established by Cpk
Process capability index (Cpk) can be calculated as below;
SU - S L
CPk = ---------
3σ
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

29. Process consistency- Yield
Yield range : 100 -120 kg
Std deviation : 3.0
Mean : 110kg
20
Cpk = ------------ = 1.11
6*3.0
After change made in the process
Std deviation : 2.2 and mean 112 kg
20
Cpk = ------------ = 1.515
6*2.2

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

31. Stability trend
%Assay
Mean : 99.7%
Standard Deviation : 0.1%
Minimum : 99.4%
Maximum : 99.9%
RSD : 0.1%
Natural specification Limit Lower : 99.3%
Limit
Upper
( µ ± 3σ) : 100.0%
Limit
Specification or Parameter Range : 99.0 % to 100.5 %

32. Review of documents & system
Data collection and review
• Manufacturing instructions and packaging procedures
• Changes compared to the previous year
• Validation status following a change
• Batch production records
• Actual values for process parameters during production
• IPC data
• Deviations
• Yield
• Raw materials
• Test procedures
• Changes to specifications or methods compared to the previous
year
• Validation status of the test methods

33. Review of documents & system
Data collection and review
• Quality System
– Deviations
– OOS
– Failure cause analysis
• Vendor status
– Change of vendor
– Supplier qualification and approval
– Deviations, rejections of raw material
• Modification
– Changes to the facility
– Changes to machines/apparatus
– Changes to super ordinate processes

34. Review of documents & system
Data collection and review
• Quality attributes (analytical data)
– Key starting material/critical material
– Critical test result of IPC, intermediates
– Critical quality parameters of finished product/blended
– Decision on the trend- tightening of spec, CAPA, validation
requirement if any
• All quality-related returns, complaints and recalls
• Adequacy of corrective actions
• Stability data
– Changes to packaging material
– Process changes

35. Inferences from the APR
• Follow-up actions may be included but are not limited to:
 Product process improvement
 Analytical method improvements
 In-process or final product specification review
 Revalidation
 Product recall or withdrawal
 New packaging

36. Check List for APQR
• Are there any outstanding validation commitments or corrective and
preventive action plans from last APQR ?
• Are the processes in a validated state or is additional validation work
needed ?
• Is the qualification status (IQ/OQ/PQ) acceptable ?
• Are all critical aspects performing satisfactorily or are corrective/
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, and closed?

37. Check List for APQR
• Are there any significant findings concerning
– changes performed ?
– specifications or test methods ?
– deviations and non- conformances ?
– out of specification results ?
– rejected batches, quality-related returns, customer complaints, or recalls ?
– the stability monitoring program ?
– retain sample examination ?
• Are all post- marketing commitments to Authorities met ?
• Are all required Technical Agreements in place and up-to-
date ?

38. Thank You