Annual Product Quality Review

Annual Product Quality Review

 Introduction
The APQR (Annual Product Quality Review) is an estimation carried out yearly or to be
conducted at regular period of time to evaluate every drug product’s quality standard or
quality assessments of all registered medicinal pharmaceutical products, with the vision to
justify the constancy of the current method and to check the correctness of the existing
qualifications and to focus on any trends in order to decide the necessity for modification of
any manufacturing procedures (or) the specifications of drug product (or) the control
techniques

This is a useful quality development tool to improve the constancy of manufacturing

procedure and complete characteristic of the product. This is done by taking into account the
comprehensive review of product information and capturing styles that will help to conclude
the deficiencies and possible developments of the process and Procedures and will reveal if
 Annual Product Quality Review

Annual Product Quality Review

there is no significant modification should be done to the manufacturing procedure (or) to the
system. The Annual Product Quality review approves that the process (or) the system is
constantly producing material (or) Product meeting its qualifications; normally revalidation
is not needed.

 Product Quality Review

It is defined as a rolling quality (or) the regular periodic reviews of all approved medicinal
products, which include the products to be shipped. The annual product review should be
organized with the objective of confirming the constancy of current process, the correctness
of existing specifications for both starting materials and the finished products to highlight
any trends and to identify the product and process improvements.

 Role of Annual Product Quality Review

 Annual Product Quality Review should

 Verify the constancy of the current manufacturing processes.

 Determine the quality and process faults of the products.
 Regulate the faults and possible developments of the methods and procedures.
 Determine analytical results and trend of yield
 Highlight the manufacturing parameters of the product.
 The quality of raw materials and packing materials which is used for the product.
 Specify the material quality.
 Help to determine the quality and the consistency of the product.
 Review the results of finished products and in-process parameters.
 Review the final product quality by using trend of yield for every batch.
 Determine the product defects by using out of specification parameter.
 Determine the batch rejection of the product if any of the product batches have failed.
 Be helpful in the determination of stability study, trend analysis and the product
stability.
 Determine the process revalidation and if there is any improvement made previously.
 Review the corrective and preventive actions and their impact on the quality of the
product.

 Significance of APQR

 The annual product quality review should verify the current manufacturing process
consistency and minimizing the risks for the pharmaceutical products which are
helpful for Pharmaceutical companies for the consistent development of product
quality for yearly basis.
 The annual product quality review should determine the process defects and the
quality of products. It should also determine the improvements that are possible for
the manufacturing processes and the analytical methods.
 The annual product quality review should highlight the product’s manufacturing
parameters, yield trend and the analytical results. It is also helpful in the
identification of the product or the process defects.
 The annual product quality review should analyse the raw material and the packing
material quality which are used for product. Mainly the APQR should indicate the
material quality.
 Annual Product Quality Review

Annual Product Quality Review

 The annual product quality review should verify the current qualifications,
appropriateness for both starting materials and the finished products to identify the
improvements in the product and the process and to highlight any styles.
 The product defects should be determined by using OOS (out of specification) and the
actions that are prospective then the possible risks which should protect the product
quality.
 The annual product quality review should contain information regarding the batches
that are rejected.
 The annual product quality review should contain the results of stability study for on-
going and the long term stability of the marketed product and the bulk product that
should be done.

 Preparation of APR (Annual Product Review)

 All companies should have a written procedure for APQR process and should
recommend that the review should be done for all batches that are manufactured from
1st January to 31st December. Then all batches should include both approved and
rejected batch products. This is the written procedure and made mandatory by
majority of the GMP regulatory bodies.
 The annual product review report configuration should be different based on specific
documentation of the company and different types of products.
 A standard template should be followed by the company to ensure that all the
required aspects should be evaluated.
 Since annual product review is a progressing document, it must contain only few
sections consisting of nominal necessities to elaborate the document with an agenda
consisting of data or information appropriate to the product.
 The report of an APQR should contain the following information.
 The testing results of finished and half finished products should contain the following
information.
 The review of a reworked/reprocessed batch and then the reason for the
rework/reprocess of the batches.
 Critical in-process controls.
 Yield review and quality review of the failed batches CAPA & OOS should be taken.
 Changes are proposed, and then certified and further implemented that would
indirectly or directly related to the product, in-case if a change control is raised
related to a multi-product facility should be mentioned in the APQR review report of
all the products that are manufactured in the facility.
 Effectiveness of CAPA, deviations, and Corrective and preventive actions are taken
against each deviation on the later manufactured batches.
 It involves the issues regarding the previous year APR and unresolved issues.
 It contains information regarding the recalls, return of goods and complaints which
are noted for the products.
 The review of a retained sample.
 The CAPA effectiveness should be mentioned in the previous year records of APR.
 The analytical (or) process Validation methods should get caused if any changes are
made.
 The updates (or) the regulatory filings should be made in current drug master file
(DMF) with the changes made.
 Repacking made
 The qualifications of the critical equipment.
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Annual Product Quality Review

 In any station, if any investigation outcomes related to stability studies found, it
should be addressed properly.
 The quality agreements should be made for product.
 The review of a starting packaging materials and starting materials which are used
for the product.
 A comment must be there after every numbered sub-section followed by an overall
summary of the report.
 The annual product review document should be finally reviewed by each department,
approved by the quality and authorized by the management. Figure 1 explains The
Relationship of Annual Product Review to Quality System.

 Need of APQR for the manufacture and controlling of pharmaceuticals and API’s
 Annual Product Quality Review

Annual Product Quality Review

 The USFDA recommended a necessity for preparation of printed summary for every
drug product. This was done on Feb 13th, 1976 by modifying GMP of products.
 The intention behind this suggested GMP necessities were to deliver consistent
processes for the drug industrialist for the purpose of reviewing required standards
for quality regarding every drug products.
 Later FDA received many comments from companies regarding objection to printed
summary preparation. This made FDA to revise its proposal which allowed every
industry to launch processes that helped to evaluate the quality standards of drug
products, by revising the records which are required by the GMP on a yearly basis.
 This led to publication of CGMP regulations for the drug products.
 From the time of this publication, the 21 CFR Part 211.180(e) is being referred as
PAR (Product Annual Review) or the APR (Annual Product Review).
 FDA proposed Q7A GMP Guidance for API in August 2001.
 These regulations were proposed by the Expert team of ICH.
 In October 2005, these regulations were introduced as part of EU GMP Guidelines.
 The above regulation specifies the PQR (Product Quality Review) for API.
 European Union Good Manufacturing practices Guidelines offer information that
supports GMP principles in EU.

 Contents of APQR

The annual product review should be annually organized and recorded, by taking
information of earlier reviews, and should include the following information.

 The review should include raw materials and packing materials which are used for
the product, especially which are bought from the new sources.
 The review should include all information regarding the batches that are unsuccessful
to meet the specification
 The review should contain an information regarding all changes should be carried
out to the analytical methods or the procedures.
 The review should contain information related to results of adverse trends and
stability monitoring programme.
 The review should contain information regarding the results of critical in-process
parameters and finished products.
 A review which contains all recalls, complaints, investigations and quality-related
returns should be performed at the time of review
 A review should include all non-conformances (or) significant deviations, the
effectiveness of the CAPA should be taken and related investigations.
 A review should include marketing authorised variations which are granted (or)
submitted (or) refused for the third person (country)/ for export only.
 The condition of relevant utilities and the relevant equipment, e.g. compressed gases,
HVAC and water, etc.
 A review should contain an adequacy of corrective actions of equipment (or) any
other process done for the product previously. .
 A review which contains commitments for Post marketing, authorisations which are
used for the new marketing and variations due to marketing authorities.

 Regulatory characteristics for the preparation of APQR

 Parameters to be reviewed
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Annual Product Quality Review

 Ware house review
 Production review
 Micro review
 Quality control review
 Quality assurance review

 Ware house review

 During the ware house review identify all the starting materials and the packing
materials which are used for product.
 The review should include the approval of packing material and their release and the
rejections.
 The review includes all the deviations, analytical tests and the changes that are made
for the specifications.

 Production review

 The review which contains the product description and the master formula record
description.
 The review which contains information regarding the equipment’s which are used for
the manufacturing and for packing purpose.
 The review which contains information regarding the classification of the
manufacturing area and the flow diagram for the process.
 The review which contains information regarding the qualification status of utilities,
equipment’s and the processes.

 Quality control review

 The review which contains information regarding the written procedure should be
there for the process and the production controls and to assure the quality, purity,
strength and the identity of the drug product. If there should be any procedure
changes then it should be reviewed and approved by quality units.
 The review which contains information regarding the out of specifications, out of
trend and the laboratory incidents of the drug products.
 The review which contains an on-going (or) the long term stability for the marketed
drug products and the bulk products.

 Quality assurance review

 The review which contains information regarding the corrective and preventive
actions that are taken, investigations and the process deviations.
 The review should be done for the market complaints, quality related returns, product
recalls, rejected batches, repacking batches, control samples, post marketing
commitments and the marketing variations.

 Six Areas are listed below

 Legal: The regulatory notices and Market authorisation.

 External: Returns, recalls, complaints and the adverse events.
 Processes: Process validation, changes and controls.
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Annual Product Quality Review

 Product: Failures, OOS, Product testing, stability and retention samples.
 Quality Control: Test methods, changes and product specification.
 Events: Product related Corrective and preventive action and the incidents

 Product Quality Review by Various Regulatory Agencies

 European Commission

The quality reviews of an active pharmaceutical ingredient should be regularly organized

with an objective to verify the process constancy. Such type of reviews would be annually
organized and should be recorded which include following information.

 A review which includes the test results of critical active pharmaceutical ingredients
and the critical in-process parameters.
 A review which includes the information regarding the adequacy of corrective
actions.
 A review which contains the information related to complaints, recalls, and all quality
related problems.
 A review which contains information regarding any changes are made to the
analytical methods (or) processes.
 A review which includes that batches that are unsuccessful to meet the established
specifications.
 The review which includes the stability monitoring program results.
 A review which contains information regarding the non-conformances (or) the critical
deviations and their related investigations.

The results which are obtained from the review which should be evaluated and made an
assessment whether there should be undertaken any revalidation (or) corrective action. The
reasons which are documented for the revalidation and the corrective actions which are
taken. Those corrective actions that are agreed should be completed in an effective and
timely manner.

 Periodic Review of the Validated Systems

The systems and the processes that will be evaluated regularly to confirm that the systems or
the processes which should still be operated in an effective way. The Significant variations
are not made to the processes and the systems. The quality review should also confirm that
the system (or) the process is consistent and product is meeting its requirements. Thus,
normally there is no need for the revalidation
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Annual Product Quality Review

 the procedures for time line APQR

 The FDA requires annual frequency for APQR, which should be mentioned in all the
three guidance documents and the Good Manufacturing Practice regulations.
 The APQR should require an account which should be maintained for previous
reviews.
 The European Union and Food and drug administration should require the yearly
frequency for PQR/PAR that information should be mentioned in three guidance
document and the GMP regulations.
 The FDA should not allow the review frequency which may go on an extension
annually, regarding the number of batches that are produced during the period of 12
month’s
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Annual Product Quality Review

 As per WHO

The rolling quality (or) regular periodic reviews are conducted with an objective and with a
view to verify the existing process consistency and to check that the current specifications
appropriateness, then to identify the improvements which are made for both process and the
product.

The quality review of a product should be considered as a tool and helps in surveying the
quality status of the manufacturing processes, including collection of the starting materials.
Such type of reviews should be conducted every year and must be documented. According to
the NRA and the international recommendations and requirements may include:

 All changes made

 The starting materials
 The results of quality monitoring and the quality control
 The in-process controls which are critical
 The complaints and the recalls
 The content of information regarding the findings that are obtained during the
inspections and the internal audits and corrective actions that are implemented
 Review of the information regarding the errors, significant deviations and all non-
conformances and corrective actions that are implemented.
 Review of all the look-back cases.

 PIC/S - Quality Management

The given inherent variability in many of the products and the biological substances, having
the steps that helps to raise the process robustness and thereby decreasing the process
variability and should improve the reproducibility at various stages of lifecycle of product
and should be reassessed by the product design during the review of a product quality.
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Annual Product Quality Review

The rolling quality reviews (or) the regular periodic reviews of all the certified medicinal
products, including the transport products, the review should be organized with an objective
to verify the constancy of the current process, and to check the correctness of the existing
specifications for both the starting materials and the finished products, to identify the
improvements in the process and the product. Such type of reviews should be organized and
should be recorded yearly, taking into consideration of the earlier reviews, which should
include the following information.

 The review which includes the starting materials and the packing materials which are
used for the product, particularly those are bought from the different sources.
 The review which includes any contractual arrangements ensures to check that if they
are up to date.
 The review which contains the results of in-process controls and the finished
products.
 The review which contains information regarding the changes which are carried out
for the analytical methods (or) the processes.
 The review which contains information regarding all the batches that are
unsuccessful to meet the established requirement and should be their examination.
 The review which contains information regarding the non-conformances (or) the
significant deviations and their related investigations, and their effectiveness of the
resultant CAPA which are taken.
 The review which includes the information regarding the results of adverse trends and
stability program monitoring.
 The review which includes the variations in the marketing authorization that is
granted (or) submitted or rejected, and including for the third party (export) dossiers.
 The review which includes all the information regarding the complaints, recalls, and
returns, quality related problems and then the investigations that are done.
 The review which includes an adequacy if any of the previous product (or) the process
(or) the corrective actions which are taken for the equipment.
 The review which contains information regarding the new marketing authorization
and the changes in the marketing authorizations, and a review should be done for the
post marketing.
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Annual Product Quality Review

 The review which includes the qualification status of the relevant equipment and their
utilities, e.g. water, compressed gases and HVAC.

 Annual Product Quality Review by ICH Q7

 The quality reviews for the active pharmaceutical ingredients should be done
regularly and the reviews should be organized with an objective to verify the process
constancy. These types of reviews should be annually organized and should be
recorded which includes the following information.
 The review which includes the results of Active pharmaceutical ingredient tests and
the in-process controls which are critical.
 The review which includes that what are the corrective actions that are taken for the
adequacy.
 The review which includes all the information regarding the complaints, recalls,
returns which are related to quality related problems.
 The review which includes the stability monitoring program results.
 The review which includes the information regarding the batches that are
unsuccessful to meet the established specifications.
 The review which includes the information regarding the changes that are carried out
for the analytical methods (or) the processes.
 The review which contains information regarding the non conformances (or) critical
deviations and their related investigations.

The results which are obtained from the review that should be assessed and evaluated.
Whether the corrective actions (or) the re validations those are undertaken. The reasons for
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Annual Product Quality Review

the corrective actions that are undertaken that are documented. Then the agreed actions that
are taken are completed on time and in an effective manner.

 Annual Product Review report format

The report of an APR should contain the following information

 The cover page should include the title of APR, Products that are covered and the
signatures of APR reviewers and the approvers.
 APR subsection should contain the element reports which are documented during the
analysis of each element and it acts as a document which contains data.
 The APR summary should contain integrated analysis of APR element reports and
overall rating of APR.
 The list of corrective and preventive actions that are taken and their result.

 Annual Product Reviews Rating’s

 Acceptable – The risk assessment may not be warrant.

 Satisfactory – The risk assessment should not warrant.
 Acceptable with conditions – The risk assessment should be performed.
 Unacceptable – The risk assessment should be performed and then the notification is
sent to the regulatory agencies and should consider as a part of mitigation and
communication.

 Annual Product Review report approval

The final APR report summary should be approved and signed by:

 The Quality Assurance Manager

 The Regulatory affairs manager
 Production manager
 Other groups who may be affected if any changes are occurred.

 CONCLUSION/SUMMARY

Thus, Annual product Quality Review (APQR) is an estimation carried out annually to
measure the quality standard of each drug product with the view to verify the constancy of
current process and to check the correctness of existing specifications to manufacture the
pharmaceutical product. Thus, it is necessary to study the regulatory requirements for the
preparation of APQR to manufacture the pharmaceutical product according to the Good
manufacturing practice (GMP) requirements and which is safe and effective to the public.
Hence, to study the regulatory requirements is essential. APQR not only required for GMP
and also required for the quality improvement of the pharmaceutical product. It is designed
to minimize the risks involved in any pharmaceutical production. APQR is a written report
which is required for every drug product based on data which should be collected annually.
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Annual Product Quality Review

APQR is annual product Quality review. It also known as annual product review (APR),
product quality review (PQR), Periodic product review (PPR). APQR is the documented
evidence provides review of product on annual basis for the quality purpose. It include
review, collection and summarized data of batches manufactured in one year and provide
recommendation for product, method, process based on the final conclusion of APQR. APQR
provide statistical trend data of all test parameter, process. Which help to identify the action
required to improve the process or method of testing.

Annual product review (APR) is an evaluation conducted annually to assess the quality
standard of each drug product with a view to verify the consistency of existing process and to
check the appropriateness of current specifications and to highlight any trend in order to
determine the need to change any drug product specifications or the manufacturing processes
or control procedures.

 Annual Product Quality Review (APQR) is an evaluation which is prepared according to

the CGMP requirements of different regulatory authorities. A Good Manufacturing
Practice ensures that the products are consistently produced and controlled according to
quality standards. Annual Product Quality Reviews not only are required by GMP but also
required for robust quality improvement for manufacturing the pharmaceutical product.

 Difference between APQR / APR / PQR

Basically some of industry use wording APR, some of APQR and Some of PQR.

There is no such big difference between them. Only definition and wording difference.

USFDA used Annual product review (APR) word in their guideline.

WHO, PICs, ICH Q7, EU GMP used Product Quality Review (PQR).

What are the guidelines?

Below are the some guidelines

1. 21 CFR 211.180 (e) (USFDA)

2. ICH Q7
3. EudraLex Volume 4 Good manufacturing practice (EU GMP)
4. PIC/S, Guide to Good manufacturing practice for Medicinal products, Part I,
Chapter 1
5. WHO forty-fifth report point no: 2.5

 Content of Annual Product Quality Review

1. Objective
2. Scope
3. Action from previous APQR
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Annual Product Quality Review

4. Product description ( Brief product review category of product and therapeutic use
etc)
5. Drug formula as per dosage form (starting raw material and packing material their
quantity)
6. Vendor details of the raw material and packing material (details about new vendor
qualified, vendor rejection, no. of consignment received etc.)
7. Details of batches (Number of batches manufactured, yield of batches, reprocessed,
reworked batches etc.)
8. Stability data of Product ( data on which product shelf life is decided and cover the
batch kept for stability on yearly basis including previous year of batches)
9. Critical process parameters (Identified critical process parameter for that product
mentioned)
10. In process test results (LOD, friability, disintegration test, hardness etc., all test
procedure as per in process test specification)
11. Finished product testing results (cover all testing parameter as per specification)
12. Retention/Control Sample samples
13. Details of Out of specification
14. Details of change control
15. Details of Deviation
16. Details of Out of trend
17. Details of Out of calibration
18. Details of control sample
19. Details of market complains
20. Details of validation
21. Details of product returns
22. Details of product recall
23. Calculate Cp and Cpk (process capability index)
24. Recommendation
25. Conclusion
26. Abbreviation