2. An Overview
Annual Product Quality Review (APQR)
Guidelines / Requirement
Responsibility
Procedure
Documents and Data Required
Preparation, evaluation and documentation
Eg. Trend Charts, process capability
Recommendation and Conclusion
3. Questions?
What is an Annual Product Review?
What is the objective of APR?
Who are all responsible?
How Procedure has to be prepared? How Procedure has to be prepared?
What are the data must be presented in an annual
product review?
How should an Annual Product Review be organized?
How to prepare the report ?
Recommendation and conclusion
4. APR, PQR or APQR
USA: “Annual Product Review”
Europe, the EU GMP Guideline uses the term "Product
Quality Review".
APQR should be conducted for all commercial product. APQR should be conducted for all commercial product.
APQR should confirm the State of Control of product,
manufacturing process, and quality.
Requirement or expectations are almost same
There are few differences, it is explained subsequently
5. Purpose of Annual Product Review
The purpose of Annual Product 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. This is toprocedures and to evaluate the need for revalidation. This is to
be conducted for each commercial product.
Annual Product Reviews 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 GMP
requirement / directive.
6. Reference / Guidelines
All GMP Guidelines refer the requirement of APQR
CFR 211.180 (e)
ICH Q7 (2.5) for API
PICS (PP-PE 009-14 Part I & PE 009-12 API-Part II) PICS (PP-PE 009-14 Part I & PE 009-12 API-Part II)
WHO- GMP TRS 986- Annex-2 (PP) TRS957,
Annex 2 (API).
EU GMP EudraLex - Volume 4 : Part-2 GMP for APIs and
Part-1, Volume 4 : EU GMP for Medicinal products
Chapter 1
7. Requirement: 21 CFR 211.180 (e)
• US FDA requirement for APR is to evaluating, at least annually, the
quality standards of each drug product to determine the need for
changes in drug product specifications or manufacturing or control
procedures.
the manufacturing controls (Critical process parameter, quality attributes
yield etc…)yield etc…)
evaluate the compliance status of the manufacture and to identify areas
of improvement or need for revalidation
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.
8. Requirement: ICH Q7 for APIs
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;
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;
9. Requirement: ICH Q7 for APIs
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 A review of adequacy of corrective actions
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.
10. Requirement: EU GMP
EU Guidelines to Good Manufacturing Practice: Medicinal Products
for Human and Veterinary Use ; Part I Quality Management
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
11. Requirement: EU GMP
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
Note: The requirements mentioned in red is different from ICH Q7 and same as WHO
TRS and PICS guideline
12. Requirement: EU GMP
A review of all changes carried out to the processes or
analytical methods
A review of the results of the stability monitoring programme
and any adverse trendsand any adverse trends
A review of all quality- related returns, complaints and recalls
and the investigations performed at the time
A review of Marketing Authorisation variations submitted/
granted/ refused, including those for third country (export
only) dossiers.
13. Requirement: EU GMP
A review of adequacy of any other previous product process or
equipment corrective actions. For marketing authorisations like
new, variation or 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.
14. Benefit or Use
Meeting the Regulatory Commitments and Requirements
Help to minimize the OOS results and deviations
Minimize the risk of Rework or Reprocessing
Decrease downtime
Increase productivity
Decrease the Risk of Product Recalls
Improve communication between production,
engineering, quality and regulatory functions
15. Responsibilities
Responsibilities lies with 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.
Production, Engineering , Maintenance , Purchase, etc. are also
need to be involved.
Senior Quality Management must approve the APQR.
16. SOP for APR
Written procedures shall be established and it must be
followed ;
Procedure must cover at least one-year rolling period. Can be on calendar
year
The review all products manufactured and should be completed within 60 The review all products manufactured and should be completed within 60
calendar days
In case product not manufactured in the year of review, shall review stability
and complaint, Recall & Returns etc.
1. Review all batches manufactured (accepted /rejected /destroyed)
2. The review of all batches which fail to meet specification and the review of
critical deviations in the production, Laboratory facility etc
3. Assessment of data, documents and electronic records in the review
17. SOP for APR
4. Review of the starting materials used and change of vendor of KSM
5. Review of the In-process control test results, quality attributes of
intermediate and final product.
6. Review of process parameters and output or yield
7. Review of all quality related returns, complaints and recalls and the7. Review of all quality related returns, complaints and recalls and the
investigations performed
8. Review the stability data and adverse trends if any
9. Result of verification of reserve samples
10. Equipment addition or retired, Qualification/requalification, calibration&PM
11. Review of any changes carried out in the processes equipment ,
specifications or analytical methods, facility,
18. SOP for APR
12. Review of action taken for the recommendation of the previous
year PQR
13. Review of adequacy of corrective actions implemented and
effectiveness
14. Review the critical utilities like HVAC, water, compressed gases
o Result of Environment monitoring/ Bio-burdon
o Water test results- conductivity, TOC trend etc
o If it is common utilities, it can be documented separately.
15. Review of technical agreements and ensure it is updated.
All the above details shall be covered in the SOP. Prepare trend
data, statistical analysis with conclusion and recommendation
19. Review and Preparation of APR
Collect the data and tabulate the selected parameters,
for review and documentation. Example
o Key starting material /Critical material
o Critical quality parameters of finished product/blended
o Batch No, test parameters, test result of intermediates & API
o Critical in-process controls & test results, process parameters
o No. of batches manufactured, and corresponding yields
o No. Or % of batches rejected, reworked or reprocessed
o No. of Batches under OOS, non-conformance / deviation
o Quantity or No. of Complaints, returns etc
20. Review of Documents & System
Data collection and review
Manufacturing instructions and packaging procedures
Changes in the process and validation status after change
Batch Production Records
Process parameters: actual and standard
IPC test data, deviations, Yield, Cpk, IPC test data, deviations, Yield, Cpk,
Equipments change
Environment monitoring
Quality Control Data
Changes to specifications or methods
Validation status of the test methods
Analytical Instruments& equipment Qualification, calibration
Deviation or incident
21. Review of Documents & system
Data collection and review
Quality Management System:
Deviations, OOS, Failure cause analysis
Customer complaint, Returns, recalls
Reprocess, rework / salvage of material
Vendor status :
Change of vendor, qualification and approval
Deviations, rejections of raw material
Facility :
Change of facility, utility , HVAC, compressed gases etc
Requalification of HVAC, temperature, differential pressure
environment monitoring - bio-burden and deviation if any
22. Review and Preparation of APR
Review of Stability data / Hold time data
Adverse trend if any
Changes to packaging material or Process
Review of Water system: Changes, qualification, chemical andReview of Water system: Changes, qualification, chemical and
microbial trend, deviation if any
Review of technical agreements with contact manufacturing, testing
Lab and service providers ensure it is updated
Result of verification of reserve samples and report deterioration if
any
Regulatory: Issues and annual update requirement if any
23. Conclusion and Recommendations
Prepare the detailed report for each elements and present the required
data, trend chart , review all the data, report the observation based on
the findings. Report the conclusion and recommendation based on the
overall review.
Observations/Recommendations and conclusion Observations/Recommendations and conclusion
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,
The results of the APR must be evaluated and an assessment made
whether corrective or preventive action or any re-validation is necessary.
Rationale for such CAPAs must be documented.
24. Conclusion and Recommendations
State of validation, consistency of process parameter & quality attributes.
Any spike or OOT in the data have to explained and justified
Following are the examples for recommendation, but not limited to:
Product process improvement
Analytical method improvements Analytical method improvements
Revision of specification
In-process or final product specification review
Revalidation, Requalification
Product recall or withdrawal
New packaging
Training
Vendor control
Calibration and maintenance
25. How to Collect Data, Preparation,
Review and Documentation of APR:
A Practical ApproachA Practical Approach
26. Organizing Documents
List the documents and Records to be reviewed
Arrange all the relevant documents, BPRs, Test records log
books, calibration, computer system, data from external
source as required
QMS documents, deviations, failures/ nonconformity,
Complaints, investigation and CAPA reports Change control ,
Returns, Recalls, etc
Validation, Qualification, Stability data, Utility data, etc
Prepare the template for entering the data
Use check list to prevent the missing data
27. Check List for APQR
Is there any outstanding Validation commitments from last PQR
or corrective and preventive action plans?
Is process in a validated state or revalidation needed ?
Is the qualification / Requalification of Equipment adequate?
Are there any significant findings from the data/trend in the
manufacturing process, starting materials, or packaging materials ?
Are all change controls implemented, and closed?
Any annual update to be submitted regulatory agencies?
Are all change controls, deviations, OOS investigation, complaints
are reviewed, investigated, CAPA implemented, and closed?
Is corrective/ preventive action is adequate and effective ?
28. Check List for APQR
Are there any significant findings related to the following
changes performed ?
specifications or test methods ?
deviations and non- conformances ?
out of specification results ? out of specification results ?
rejected batches, quality-related returns, customer complaints, or
recalls ?
the stability data monitoring ?
retain sample examination ?
Are all post- marketing commitments to Authorities met ?
Are all the Technical Agreements in place and up-to-date ?
29. Review of Deviations
Review of “Deviations from the Validated state”, investigation
and CAPA
A review of all batches that failed to meet established
specification(s) and their investigation
Significant/critical deviations, Out of Specification Results and Significant/critical deviations, Out of Specification Results and
related failure investigations.
Review for adequacy and effectiveness of corrective and
preventative actions
Changes effected and variations during the period (e.g. process,
suppliers, equipment, critical utilities)
Changes of product specifications or methods (e.g. analytical
changes, and results)
30. Preparation of Trend Charts
Trend Analysis: Perform trend analysis for the result of in-process,
release test parameters and results of the stability monitoring with graphic
representation with basic statistical data.
Prepare control chart, other types of chart
Appropriate statistical tools may be used to assess process capability for Appropriate statistical tools may be used to assess process capability for
large number of batches.
Mean, maximum, minimum, standards deviations, six sigma, %RSD
If any drift in process, out of trend, evaluate the causes and take
appropriate action and improve performance
Review specifically at recurring causes and identify appropriate actions to
reduce the frequency and improve performance.
33. Process Capability
Normal Distribution:
µ ± σ = 68.26%
µ ± 2σ = 95.44%
µ ± 3σ = 99.73%µ ± 3σ = 99.73%
µ is mean value; σ is standard
deviation
The capability of the process to
meet the specifications
determined by stability of the
process, the range of variation
and the process aim point
34. Normal distribution
Normal
Process Capability for strength
LSL = 114.0, Nominal = 115.0, USL = 116.0
24
Histogram follows NORMAL DISTRIBUTION Process
meets the Specification, consistent and capable
Normal
Mean=114.978
Std. Dev.=0.238937
Cp = 1.41
Pp = 1.40
Cpk = 1.38
Ppk = 1.36
K = -0.02
114 114.4 114.8 115.2 115.6 116
strength
0
4
8
12
16
20
24
frequency
DPM = 30.76
35. Process Capability Index
Process Capability Index Calculation;
Cpk = (SU – SL)/ 6 σ (σ- Standard deviation,
If Specification is one sided
Cp
SU- Upper spec limit
SL- Lower spec limit
X- Base value of one side
(σ- Standard deviation,
Cpk = (SU – X)/ 3 σ
Cpk = (X - SL)/ 3 σ
(σ- Standard deviation,
# CPk Value Process Capability
1 1.33 ≤ Cpk Satisfiable enough
2 1.00 ≤ Cpk < 1.33 Adequate
3 Cpk < 1.00 Inadequate
36. Process Capability Index (Cpk)
Assumption- Chemical process-A
give Yield range:100 -120kg,
Standard deviation : 3.4 and mean
is 12kg. Calculate the process
capability
20
Cp = -------
6*3.4
Assumption- Chemical process-A give
Yield range: 100 -120 kg; Mean is
111kg and standard deviation : 2.2.
Calculate the process capability
20
Cp = -------
6*2.2Cp = -------
6*3.4
Cp= 0.98
Process in not capable, there is
inconstant
Cp = -------
6*2.2
Cp = 1.52
Process is capable & constant
