ANNUAL PRODUCT REVIEW

(APR)
WHO/PICS

Maria Masood
(Manager Quality Support)
 QUESTIONS?
 What is an Annual Product Review?
 What is the objective of APR?
 Reference / Guidelines
 Who are all responsible?
 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 ?
 Approval and Archiving
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 confirm the State of Control of product,

manufacturing process, and quality.

 Requirement or expectations are almost same
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 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.
 REFERENCE / GUIDELINES
 All GMP Guidelines refer the requirement of APQR
 CFR 211.180 (e)

 ICH Q7 (2.5) for API

 PICS (PP-PE 009-15 Part I ,1 May 2021 )

 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
 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…)
 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.
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;
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
 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.
 PIC/S 2021GUIDELINE
1.10 Regular periodic or rolling quality reviews of all authorized medicinal
products, including export only products, should be conducted with the objective of
verifying the consistency of the existing process, the appropriateness 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:

 (i) A review of starting materials including packaging materials used in the product,
especially those from new sources and in particular the review of supply chain
traceability of active substances;
 (ii) A review of critical in-process controls and finished product results;
PIC/S 2021GUIDELINE
 (iii) A review of all batches that failed to meet established
specification(s) and their investigation;
 iv) A review of all significant deviations or non-conformances,
their related investigations, and the effectiveness of resultant
corrective and preventive actions taken;
 (v) A review of all changes carried out to the processes or
analytical methods;
 (vi) A review of Marketing Authorization variations submitted,
granted or refused, including those for third country (export only)
dossiers;
 vii) A review of the results of the stability monitoring programe
and any adverse trends;
PIC/S 2021GUIDELINE
 (viii) A review of all quality-related returns, complaints and
recalls and the investigations performed at the time;
 (ix) A review of adequacy of any other previous product
process or equipment corrective actions;
 (x) For new Marketing Authorizations and variations to
Marketing Authorizations, a review of post-marketing
commitments;
 (xi) The qualification status of relevant equipment and
utilities, e.g. HVAC, water, compressed gases, etc;
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
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
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 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.
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.
BENEFIT OR USE
 Meeting the regulatory commitments and requirement
 Help to minimize the OOS result and deviation

 Minimize the risk of rework or reprocessing

 Decrease downtime

 Increase productivity

 Decrease the risk of product recall

 Improve communication between

production,engineering,quality and regulatory functions
RESPONSIBILITIES
Officer Quality Support
 Preparation of APR schedule.

 Collection and preparation of all data and information required as per

SOP.
 Preparation of summary / report.

 Co-ordination and tracking of all corrective actions identified in the

APR.
MANGER QUALITY SUPPORT (MQS)
 Review of data and reports.

 Identification and verification of corrective actions.

 Ensuring the conduction of APRs.

 Ensure the completion of Product/Process related recommendation and

corrective actions identified in the APR.

APPROVAL OF APR

HEAD OF QUALITY ASSURANCE (HOQA)

ASSOCIATE DIRECTOR PRODUCTION (ADP)
DIRECTOR QUALITY OPERATIONS (DQO)
 Approval of APR schedule.
 Approval of APRs and summary / reports.
 REQUIREMENTS
 The Annual Product Review must cover a one-year rolling period, If the
production is less than 3 batches per year, an annual product review must
still be conducted and this review can include a review performed on the 2
or 3 preceding production years.
 The Annual Product Review must include all batches of product whether
they were accepted or rejected or destroyed during manufacture.
 For active pharmaceutical ingredients, the Annual Product Review
includes the manufacturing critical steps.
 REVIEW AND PREPARATION OF APR:
Collect data and tabulated parameters for review and
documentation
 Number of batches manufactured, including partially completed batches
and corresponding yields.
 Number and percentage of batches rejected and related reasons.

 Number and percentage of batches reworked or reprocessed and related

reasons.
 Critical in-process controls, finished product results and critical API test
results.
 A review of all batches that failed to meet established specification(s) and
their investigation.
 REVIEW AND PREPARATION OF APR:
 Significant/critical deviations, Out of Specification Results and related
failure investigations (review of adequacy and effectiveness of corrective
and preventative actions taken).
 A review of the adequacy of all corrective actions

 Product quality complaints

 Product Recalls

 Critical regulatory issues

 Changes effected (change control) and variations during the period (e.g.
process, suppliers, equipment)
 REVIEW AND PREPARATION OF APR:
 Changes of product specifications or methods (e.g. analytical changes,
and results)
 Process Validation Status
A review of the results of the stability monitoring program and trend
analysis on stability data
Trend Analysis
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.
APPROVAL AND ARCHIVING
 Annual Product Reviews will be reviewed, assessed, and
approved by Senior Site Quality Management, Site
Production Management and Senior Site Management.
 The approved documents must be archived by quality
support department and made available (upon request)
during internal or external audits by Regulatory
Authorities.
THE PQR SHOULD CONFIRM THE
STATE OF CONTROL
 'Validated status' based on assessment of process
performance (critical / relevant process information,
trends) Closure of any deviation from the validated
state, especially changes, batch failures / OOS /
deviations, or complaints / recalls Confirmation that
the product is stable Confirmation that specifications
and acceptance criteria are still suitable to assure
product quality.
PREPARATION OF TREND CHARTS
 Trend Analysis: Perform the trend analysis of release test
parameters with graphic representation with basic statistical
data
 Appropriate statistical tools may be used to assess process
capability for large number of batches
 Mean, Maximum, Minimum, Standard Deviation, %RSD

 If any drift in process ,out of trend, evaluate the causes and

take appropriate action and improve performance
 Highnoon Laboratories Limited
Annual Product Review
Inhibitol 30 mg Caspules
Table-1
01-Nov-2019 to 31-Oct-2020

Avg. wt. with Dissolution

Yield Avg. wt. Assay
Sr. No. Batch No. Mfg. Date Expiry Date shell
0.1 N HCl Buffer pH 6.8
97 - 100 % 353 ± 3% 436 g ± 3 % NMT 10% NLT 80% (Q) 90.0 - 110.0%

1 200582 01-02-2019 31-01-2022 98 354 431 0.1 105 97.4

2 200583 01-02-2019 31-01-2022 99 356 434 0.5 95 99.5

3 201669 01-03-2019 28-02-2022 99 355 438 0.5 95 98.0

4 202008 01-03-2019 28-02-2022 99 351 427 0.0 95 103.1

5 202906 01-03-2019 28-02-2022 99 354 436 0.0 95 99.8

6 202907 01-06-2019 31-05-2022 99 355 437 0.1 107 100.0

7 203586 01-06-2019 31-05-2022 99 354 436 0.1 107 97.2

Mean 99 354 434 0.2 100 99.3

Min. 98 351 427 0.0 95 97.2

Max. 99 356 438 0.5 107 103.1

STDEV 0.513 1.508 3.746 0.214 6.139 2.019

RSD 0.52 0.43 0.86 104.75 6.14 2.03

Cp 0.98 2.34 1.16 NA NA 0.83

Cpu 0.70 2.11 1.34 15.26 NA 1.77

Cpl 1.25 2.58 0.99 NA 0.81 1.53

Cpk 0.70 2.11 0.99 15.26 0.81 1.53

PARAMETERS
PROCESS CAPABILITY
UCL represents upper LCL represents lower control
control limit on a control limit.
chart
USL represents upper LSL represents lower
acceptance limit acceptance limit
 Highnoon Laboratories Limited
Annual Product Review

Inhibitol 30mg Capsules

Table-2

01-Nov-2019 to 31-Oct-2020

Raw Material Components Summary

Period Revision Change

Raw Materials Code Manufacturer Supplier RMS # Revision Effective Date
Summary

Precise Chemipharma (Pvt) QD6-QA-RMS-

Lansoprazole Pellets 4500042 PRECISE 3 Dec, 2016 No changes during the review period
Ltd. L0701

Capsule Inhibitol 30mg 5050012

SUHEUNG Suheung Vietnam Co., Ltd QD7-QA-050012 5 Oct, 2016 No changes during the review period
#1 Printed A
 Highnoon Laboratories Limited
Annual Product Review
Inhibitol 30mg Capsules
Table-3
01-Nov-2019 to 31-Oct-2020

Packaging Material Components Summary

Effective Period Revision Change
Packaging Materials Code Manufacturer Supplier PMS # Revision
Date Summary

Carton Sale Inhibitol 30 5060048 QD7-QA- No changes during the review

T&T Track & Tie Printers 7 Dec, 2017
mg Capsules C 060048 period

Foil Inhibitol 30 mg 5120043 Jiangsu Zhongjin QD7-QA- Revised due to Addition of

JIANGSU 7 Oct, 2020
Capsules 124 mm A MataiMedcinal 120043 Microbial Test

Insert Inhibitol 30 mg 5130029 QD7-QA- No changes during the review

Printech Printech 6 Jun, 2016
Capsules A 130029 period

Label Shipper Inhibitol QD7-QA- No changes during the review

5140202 Printech Printech 1 Mar, 2016
30 mg 140202 period

PVC Transparent 134 Misr Packaging QD7-QA- No changes during the review
5160001 MISR 3 Mar, 2018
mm Materials Co. 160001 period

Shipper Combine 5180157 Bulleh Shah QD7-QA- No changes during the review
BULLEH 2 Jan, 2016
Highnoon A Packaging (Pvt) Ltd. 180157 period
Thank You