Annual Product Review

(APR)
Product Quality Review
(PQR)
 The Overview
• WHAT is an APR and WHY do we need it
• Scope, Glossary and Responsibilities
• The Requirements
 Basic requirements
 What must be in the APR, at a minimum
 Additional Local Requirements (EU, CFR, ICH Q7
for APIs)
 What may be included
 Approval and Archiving
• Helpful Checklist to prepare the APR/PQR
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.

• APR for each commercial product

• APR should confirm the State of Control

 Annual Product Review - WHY
• "Reviews" are a critical element of any Quality
Management System. Regular reviews of process
and quality system performance is necessary to
ensure product quality.

• All regulatory authorities require "reviews“ which

may be called
 "Annual Product Review“ (US GMP term), or
 "Product Quality Review“ (EU GMP term)

• Expectations regarding contents and objectives

are more or less the same.
 2. Scope

This scope applies to manufacturing

sites, Affiliates and subcontractors
 3. Glossary
Annual Product Review (APR)

• Periodic review of the product’s production documents,

release data, stability data, product complaints, etc. to
establish trends and determine any issues

• A report must be issued to Senior Site Management on an

annual basis

• Annual Product Reviews are applicable to commercial

products [such as API, intermediate for API, pharmaceutical
product (i.e. drug product) and medical devices].
 4. Responsibilities (1)
• Senior Site Quality Management at manufacturing site or
External Manufacturing Unit that releases the active
pharmaceutical ingredient (API), pharmaceutical product
(i.e. drug product) or medical device is responsible for
ensuring that an Annual Product Review and the report
for the Annual Product Review are completed and issued

• Where semi-finished product is processed in multiple

sites, all sites involved must participate in the Annual
Product Review process by providing information to the
site of release.
 4. Responsibilities (2)
• Individual departments, such as Industrial Technologies,
Purchasing, Engineering, Manufacturing, Information
Solutions, Quality and Compliance, Pharmacovigilance and
Regulatory Affairs are responsible for providing data and
participating in the Annual Product Review process

• Senior Site Quality Management or External Manufacturing

Unit (as applicable), Senior Site Production Management and
Senior Site Management must approve the Annual Product
Review Report

• The resulting report must be distributed at least to Senior Site

Management with critical deviations reported to the Global
Head of Quality and Compliance.
 4. Responsibilities (3)
New Statement in Version 3 (Feb. 2008):

• Where the marketing authorisation holder is not the

manufacturer, their respective responsibilities is defined in a
quality agreement in place between the various parties

• The Qualified Person responsible for the final batch

certification must ensure that the annual product review is
performed on a yearly basis in a timely manner and is accurate

• In case of anomaly/deviation found, the information of the

marketing authorization holder is performed in accordance
with the requirements of the current directive "Quality Alert
Management.
 5. Requirements (1)
• Each site must have written procedures, which must be
followed when conducting Annual Product Reviews.

• The Annual Product Review must cover a one-year rolling

period, but does not have to coincide with a calendar year

• The review should normally be completed within sixty (60)

calendar days of the period close and must in all cases be
completed within ninety (90) calendar days of the period close

• 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
 5. Requirements (2)

• The number of batches to be considered is the number of batches

manufactured during the agreed annual period. The Annual Product
Review must include all batches of product whether they were
accepted or rejected or destroyed during manufacture

• The Annual Product Review report must address the assessment of

data, documents and electronic records reviewed

• For active pharmaceutical ingredients, the Annual Product Review

includes the manufacturing critical steps

• Annual Product Reviews are to take into account previous reviews.

 5. Requirements (3)
• An Annual Product Review must be prepared for each
water quality grade produced at each site

• New Statements in Version 3 (Feb. 2008):

• If one quality of water is only used for one product ,

the data concerning this water can be included in the
APR of the corresponding APIs

• For critical utilities it is recommending either to

perform a separate APR or to include a specific
chapter in the APR of the corresponding APR
 Review must include, at a
minimum (1)
• 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 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
 Review must include, at a
minimum (2)
• 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)

 A review of the adequacy of all corrective actions

 Product quality complaints

 Product Recalls
 Review must include, at a
minimum (3)
• Review of "deviations from the validated state“

 Product Recalls
 Critical regulatory issues
 Quality related issues for returned, and/or salvaged
goods
 Changes effected (change control) and variations
during the period (e.g. process, suppliers, equipment)
 Changes of product specifications or methods (e.g.
analytical changes, and results)
 Process Validation Status
 Review must include, at a
minimum (4)
• 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

 From any official inspectorate which directly concern and relate

to the product under review (i.e. not observations/
recommendations which relate to general quality system issues)

 New recommendations from this review

 Further Requirements
• Additional items must be added to the APR/PQR in
line with local regulatory requirements (e.g. EU GMP
Chapter 1). All of these topics to be covered by the
review must be stated in a site procedure.

• The results of the APR must be evaluated and an

assessment made whether corrective or preventive
action (CAPA) 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.
 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)
 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.
 The EU Requirements for PQR (3)
• 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.
 The EU Requirements for PQR (4)
• 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.
 The EU Requirements for PQR (5)
• 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.
 The EU Requirements for PQR (6)
Subcontractors and Technical Agreements

The manufacturer and marketing authorisation holder, where different,

should evaluate the results of this review and an assessment should be made
whether corrective and preventative action or any revalidation should be
undertaken. Reasons for such corrective actions should be documented.
Agreed corrective and preventative actions should be completed in a timely
and effective manner. There should be management procedures verified
during self-inspection. Quality review may be grouped by product type, e.g.
solid dosage forms, liquid dosage forms, sterile products, etc. where
scientifically justified.

Where the marketing authorisation holder is not the manufacturer, there

should be a technical agreement in place between various parties that defines
their respective responsibilities in producing the quality review. The Qualified
Person responsible for the final batch certification together with the marketing
authorisation holder should ensure that the quality review is performed in a
timely manner and is accurate.
 The US Requirements:
21 CFR 211.180 (e)
• … data … used for 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

 A review of a representative number of batches,

whether approved or rejected, and, where applicable,
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.
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

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.
 What may be included in the
APR
• Follow-up actions may be included but are not limited
to:

Product process improvement

Formulation improvement
Analytical method improvements
In-process or final product specification
review
Revalidation
Product recall or withdrawal
New packaging
 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 for a

minimum of 11 years and made available (upon
request) during internal or external audits by
Regulatory Authorities.
 Helpful Checklist to prepare the PQR
(1)
• Are there any outstanding validation
commitments or corrective and preventive
action plans from last PQR ?

• Are the processes in a validated state or is

additional validation work needed ?

• Is the qualification status (IQ/OQ/PQ)

acceptable ?
 Helpful Checklist to prepare the PQR
(2)
• Are all critical aspects performing satisfactorily or are
corrective/preventive action plans required ?

• Are there any significant findings concerning

specifications or test methods ?

• Are there any significant findings concerning data

trending of the manufacturing process, starting
materials, or packaging materials ?

• Are there any significant findings concerning deviations

and non- conformances ?
 Helpful Checklist to prepare the PQR
(3)
• Are there any significant findings concerning
changes performed ?

• Are there any significant findings concerning out

of specification results ?

• Are there any significant findings concerning

rejected batches, quality-related returns,
customer complaints, or recalls ?
 Helpful Checklist to prepare the PQR
(4)
• Are there any significant findings concerning
the stability monitoring program ?

• Are there any significant findings concerning

retain sample examination ?

• Are all post- marketing commitments to

Authorities met ?

• Are all required Technical Agreements in place

and up-to-date ?
 PQR Principles should be
followed
• Focus on evaluation and assessment of data and
information
 Create a meaningful list of facts and data
• Reviews should focus on mid- and long-term
trends (e.g. intra- and inter-batch) because these
trends are not obvious from single batch data
 Therefore, make a connection to the previous report
• One element of a meaningful review is the
verification of selected original records (e.g. batch
record, test records)
 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.
Thank You

Any Questions