Annual Product Reviewby

Umer Al-Fasial

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Quality Assurance in Pharmaceuticals

It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use.

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Key Functions of Quality Assurance

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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.

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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.

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Scope

This scope applies to manufacturing sites, Affiliates and subcontractors

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▪ Individual departments, such as, Supply Chain, Engineering, Production, Quality and Compliance, Pharmacovigilance and Regulatory Affairs are responsible for providing data and participating in the Annual Product Review process

Responsibilities

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Requirements

▪ 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

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Requirements (Cont.)

▪ 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. 9

Requirements (Cont.)

▪ An Annual Product Review must be prepared for each water quality grade produced at each site

▪ 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

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APR 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 and related reasons

▪ Number and percentage of batches reworked or reprocessed and related reasons

▪ Critical inprocess controls, finished product results and critical API test results 11

APR must include, at a minimum (Cont.)

▪ 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

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APR must include, at a minimum (Cont.)

▪ 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

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APR must include, at a minimum (Cont.)

▪ 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

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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 revalidation 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.

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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 suitable period and made available (upon request) during internal or external audits by Regulatory Authorities.

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Checklist to prepare the APR

▪ Are there any outstanding validation commitments or corrective and preventive action plans from last PQR/APR ?

▪ 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 specifications or test methods ?

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Checklist to prepare the APR (Cont.)

▪ 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 ?

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Checklist to prepare the APR (Cont.)

▪ 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 nonconformance?

▪ Are there any significant findings concerning data trending of the manufacturing

process, starting materials, or packaging materials ?

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APR Principles

▪ 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 interbatch) because these trends are not obvious from single batch data

▪ 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)

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APR 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

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Take Home Message

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Questions

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