Good Guide

15.F Annual product review

An annual product review is a yearly evaluation of the production and quality control data of a preparation. The analysis of this data (e.g. from correlations, trends, deviations, unexpected variability, etc.) results in valuable indications regarding the validation status of the manufacturing process (chapter 7 Process Validation). On the one hand, the annual product review serves as "ongoing validation" and, on the other hand, the data and results obtained are important prerequisites for continuous improvement (CIP). Another important function of the annual product review is to ensure that all the instructions, specifications and procedures currently used still correspond to the details in the submission file for marketing authorisation.

CFR 211.180 (e) basically specifies that the quality standard of every product must be evaluated at least once a year based on the current specifications and records to determine whether modifications to product specifications, manufacturing instructions or control procedures are required.

Numerous documents must be evaluated to determine whether this is the case (see figure 15.F-1).

As well as the batch records for all manufactured batches (including rejected and destroyed batches), the manufacturing instructions and test procedures that they are based on are also taken into consideration. Even the secondary documentation, that is, documents regarding the used raw materials (specification, supplier, order, receipt, sampling, quality control, storage), apparatus (operation, cleaning, qualification, calibration, maintenance) and rooms

Here you will find answers to the following questions:

� What is an annual product review? � Which documents are required for an annual product review? � What consequences can a company draw from the annual product review? � What data must be presented in an annual product review? � How should an annual product review be organised? � Who approves the results or any modifications to an annual product review report

where there is a collaboration between the contract giver and contract acceptor?

Figure 15.F-1 Documents required to carry out an annual product review

Documents required to carry out an annual product review

� Manufacturing instructions and packaging procedures � Batch production records and batch packaging records � Test procedures � Certificates of analysis and test protocols � Test protocol for raw materials � Sampling plans and reports � Modification documents � Quality deviations � Complaints and recalls � Stability data

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(monitoring, hygiene plans) must be taken into consideration.

The CFR also requires complaints, recalls, returns, destructions and observations from the batch record reviews to be analysed.

As there are no clear statements regarding the scope and content of an annual product review, it is important to set out company-internal regulations in the form of an SOP.

A considerable amount of work is required for an annual product review in order for it to provide more than just general statements and recognise actual dependencies e.g. between manufacturing parameters (e.g. dependencies between the breaking strength and disintegration of a tablet - the influence of disintegration on dissolution). For this, process parameters and analysis results must be contrasted even down to the level of individual values.

To keep the amount of work within acceptable limits during the annual product review, "for some kinds of data (e.g. analytical tests results, yields, environmental controls, etc.) it is recommended that records be kept in a manner permitting trend evaluation" in the current year of production (EU GMP Guideline, chapter 6.9).

Storing the batch documentation systematically will also considerably reduce the amount of work for the annual product review. The "quick retrievability" of documents and raw data required by GMP is thus also checked during the annual product review.

Weaknesses

� in the documentation system (e.g. too many, scattered storage locations, lack of labelling of originals and copies, lack of cross references to raw data, traceability of raw data, etc.),

� in the documentation (e.g. overwriting, blank fields, missing reasons for modified entries, transfer errors) or

� in the change control program (e.g. not all changes have been recorded or evaluated, deficiencies in the implementation of follow-up measures, etc.),

which are uncovered by the annual product review should be immediately rectified by corrective measures, such as improved storage organisation (check of the SOP on which this is based) and training.

Figure 15.F-2 gives as an example a few measures which a company could implement as the result of the findings of the annual product review.

Figure 15.F-2 Examples of company-internal consequences of an annual product review

Examples of company-internal consequences of an annual product review

� Process optimisation � Revalidation � Adaptation of manufacturing or control procedures � Amendments or authorisation changes � Improvement to batch documentation storage (retrievability) � Continuous, systematic gathering of specific process data and analysis values for



15.F.1 Documents required for an annual product review

All documents which directly or indirectly refer to the manufacture and control of a preparation in the period concerned must be investigated.

The following lists the most important aspects which must be checked for the individual document types.

� Manufacturing instructions and packaging procedures � Version � Changes compared to the previous year � Measures as part of change control � Validation status following a change

� Batch production records and batch packaging records � Actual values for process parameters during production and packaging � IPC data � Deviations � Yield � Raw materials

� Test procedures � Version � Changes to specifications or methods compared to the previous year � Measures as part of change control � Validation status of the test methods

� Certificates of analysis and test protocols � Averages, individual values and raw data � Deviations � OOS � Failure cause analysis

� Test protocols for raw materials � Supplier qualification � Deviations, rejections

� Sampling plans and reports � Deviations � Qualifications of the operator taking the sample

� Modification documents � Changes to the building (zonal concept, ventilation, etc.) � Changes to machines/apparatus (software updates, additional control points,

etc.) � Changes to superordinate processes (change control, OOS, validation master

plan, etc.) � Deviations in quality (internal complaints)

� Cause analysis and follow-up

permanent validation or statistical process control (SPC) � Strict change control programs � Monitoring of implementation measures for approved changes � Improvement of discipline for managing protocols � Improvement of complaint processing � Recording of conclusions as a training topic



� complaints and recalls � Cause analysis and follow-up

� Stability data � Changes to packaging material � Process changes � Recipe changes � Does the current data support the stability declared in the submission file for

marketing authorisation?

15.F.2 Annual product review report

Those documents named above which are required for the annual product review give rise to a multitude of results and information. This must be summarised in a report:

� All analytical results obtained from the certificates of analysis must be recorded and evaluated. The results must be included as averages or individual values, depending on the test item.

� It is absolutely necessary to evaluate all changes to a preparation in an annual product review. This primarily relates to all changes to the manufacturing and testing procedures. The reason for these changes and the follow-up measures that are implemented (e.g. requalification) must be documented.

� The yields at the individual manufacturing stages must be recorded. Losses at critical production stages must be evaluated for possible risk. Yields that fall below the tolerance range must be explained.

� As well as the yields, the results of the in-process controls also play an important role. Dependencies, e.g. between breaking strength and disintegration or disintegration and dissolution of tablets, must be tested and illustrated. Deviations from in-process control results must be described and the resulting measures explained.

� All internal and external complaints, as well as the affected measures must be presented in order to prevent complaints of a similar kind in the future.

� All changes to the procurement of starting materials must be documented. This primarily applies to changes in suppliers or to raw material specifications. If results with the changed starting materials are already available at the time of the evaluation, these results should be taken into consideration. The results of ongoing long-term stability studies must be reported and annotated.

� If additional stability testing is required during the course of a calendar year due to changes in the raw material specifications, supplier, manufacture or packaging materials, the results must be documented in a report.

Figure 15.F-3 Basic content of the annual product review report

What data must be given in an annual product review?

� Results from the certificates of analysis � Changes to a preparation � Yield control � In-process control results � Deviation from specifications � Analysis of the complaints situation � Change to starting material specifications � Results of stability testing



An annual product review report must also satisfy the formal requirements for GMP conforming documents (see chapter 15.B GMP-conforming documentation). The information given in the header (see figure 15.F-4), a well-defined structure, clearly laid-out contents and a summary of the most important statements and conclusions all contribute to the readability of the report.

Ultimately, the annual product review report should not only serve to fulfil legal requirements, but should also be used as a useful internal status report ("validation barometer").

The annual product review report must not only be signed and authorised by the author, but also by the responsible persons, in this case specifically the Heads of Production and Quality Control as well as the Head of Quality Assurance.

15.F.3 Collaboration with a contract manufacturer

This section refers to the specific situation of collaboration between a contract giver and a contract acceptor. Once the report has been completed, the contract acceptor or contract manufacturer cannot directly adopt the results for subsequent production. The contract acceptor must forward the results to the contract giver or the holder of the authorisation in the form of a recommendation. The contract acceptor may only adopt the authorised results once he has written authorisation or agreement from the contract giver. In a functioning change process, the authorised changes to the manufacturing instructions must also be authorised and signed by the contract giver as a matter of course.

15.F.4 Example: annual product review

Figure 15.F-4 Header data in an annual product review report

Header data in an annual product review report

� Name of the preparation � Material number of the preparation � Batch designation of the evaluated batches � Calendar year � Date of creation � Version number

Figure 15.F-5 Distribution of tasks between the contract acceptor and the contract giver

Who approves the results of any modifications where there is a collaboration between the contract giver and contract acceptor?

Contract acceptor compiles the report - results - changes - recommendations

Contract giver tests results - analysis/change recommendations - authorisation

Contract acceptor changes the manufacturing instruction

Contract giver authorises the manufacturing instructions

Figure 15.F-6 Cover sheet of an annual product review report Annual product review for calendar year 2004



Preparation:

Material number:

Batch designation: from to

Version:

Created on:

Author:

Objective:

The annual product review records and evaluates all batches of the "sample tablets" preparation during the calendar year 2004.

The evaluation includes the in-process data, the analytical results for the final product, the physical results and the general production data. The procedural changes implemented and changes in the starting material manufacturers are reviewed with regard to their effects on the final product. Deviations from the process are recorded and evaluated. There is a summary of all batches and any deviations from specifications and of all batches for which external complaints were received.

Authorisation of the annual product review

Head of Production: Date/signature

Head of Quality Control: Date/signature

Quality assurance: Date/signature

Development: Date/signature

Client authorisation: Date/signature

Figure 15.F-7 Contents of an annual product review Annual product review for calendar year 2004

Preparation:

Material number:


Version:



Created on:

Author:

Contents

1.0 Overview of batches 2004

2.0 Analysis of the physical and chemical results

Tablet cores

2.1 Dimensions 2.2 Breaking strengths 2.3 Disintegration 2.4 Friability 2.5 Loss on drying 2.6 Determination of content

Coated tablets

2.7 Average weights 2.8 Dimensions 2.9 Breaking strength 2.10 Disintegration 2.11 Determination of content

3.0 Analysis of the production data

4.0 Analysis of the process changes

5.0 Deviations from the manufacturing specifications

6.0 Analysis of the batches that do not conform to the specifications

7.0 Recommended measures for the year 2005

8.0 Diagrams

Figure 15.F-8 Example 1 for graphical presentation Annual product review for calendar year 2004

Preparation:

Material number:


Version:



Created on:

Author:

Presentation example for average weights of the

cores

It is useful to analyse the batches and to use a graph to show the various average weights of all manufactured batches.

The batch production records or the certificates of analysis form the basis of the analysis.

Figure 15.F-9 Example 2 for graphical presentation

Annual product review for calendar year 2004

Preparation:

Material number:


Version:

Created on:

Author:

Presentation of the average breaking strength of the

cores:

It is also advisable to show the relationships between the breaking strengths of the individual batches as a graph. Additional inspections should be used to check the influence of the breaking strength on disintegration or on release.

Figure 15.F-10 Example 3 for graphical presentation



15.F.5 Master-SOP for the annual product review

Annual product review for calendar year 2004

Preparation:

Material number:


Version:

Created on:

Author:

Example of the presentation of yields:

The total yield or the yields at the individual manufacturing stages can be used to show the yields.

Where there is a collaboration between contract giver and contract acceptor, consideration of the yields does not only concern GMP, because the number of items supplied forms the basis for invoicing.

Figure 15.F-11 Master-SOP for the annual product review

Company name Logo

Operating procedure SOP no.

Title Annual product review

Valid from

Page x of y

Facilities Replaces SOP no.

Binding for

� Material characteristics � Production



� Quality control � Quality assurance � Engineering

For information to

created by

checked by

approved

Change index

- New compilation

1. Introduction

1.1 Background/objectives

The annual product review looks back at production and quality control data to assess changes, trends and weaknesses.

The SOP sets out the requirements for compiling the annual product review. It describes the scope and content, responsibilities, time specifications, important key words and authorisation procedures.

1.2 Relatedness to other regulatory information

EU GMP Guideline, chapter 6.9 21 CFR 211.180 (e)

1.3 Definition

Annual product review

Examination of the history of the manufacture and testing of a product over a manufacturing year.

1.4 Scope and responsibilities

The annual product review includes all medicinal products manufactured in the pharmaceutical company, including contract manufacturing.

The Heads of Production, Quality Control and Engineering

arrange that

� all relevant data and documents for their area of responsibility are made available. � develop recommendations and corrective measures based on the existing data and

reports. � evaluate and authorise the results together with Quality Assurance.

Quality assurance



� collects and evaluates the necessary data and information in accordance with the SOP, compiles the summary report and makes it available.

� ensures authorisations and scheduling for necessary remedial action. � is responsible for the annual compilation of the annual product review in accordance

with the SOP.

2 Implementation

2.1 Data collection, responsibilities

Quality Assurance compiles a list of all the products manufactured in the period concerned and distributes it to all the areas responsible for collecting the data. These complete the list in the time specified by Quality Assurance.

The following individual data for all manufactured, rejected or destroyed batches must be determined and consolidated (· specialist function responsible):

Yield � Production and engineering

Analytical and physical data � Quality control

Environmental monitoring � Quality control

In-process controls � Production, Quality control, Engineering

Stability studies � Quality control

Deviations and their follow-up measures � Quality assurance

Changes and their follow-up measures � Quality assurance

Out of Specification Results, trends and summaries

� Quality control

Change of supplier and resulting measures

� Quality assurance and material characteristics

Reworking � Quality assurance

Returns � Quality assurance and material characteristics

Recalls � Quality assurance

Complaints, trends and summaries � Quality assurance

All data must be prepared in tables and/or graphs so that results, deviations and trends are immediately recognisable.

The following reports must be compiled by Quality Assurance:

� Detailed summaries with references to available interim reports and single value data

� List of all quality-relevant data and deviations with references to interim reports and any existing single value data

� Records of necessary measures, as well as action plans, responsibilities for these and their scheduling

� Measures status with regard to previous annual product reviews

2.2 Inspection, evaluation and authorisation



The annual product review, including the interim reports and recommendations, is inspected and authorised by

� the head of the specialist function concerned and those responsible for the required corrections,

� the Head of Production � the Head of Quality Control � the Head of Quality Assurancwe

The annual product review contains a further concluding evaluation of the following points:

Process is in order, GMP compliant

� That is, the reported data does not demonstrate anything unusual, the process functions and is valid.

Measures are required

� The review has shown that some measures are required. The process functions as it is and is valid.

Immediate measures are required

� The review has shown that significant corrections are required. The process is out of control, an inspection is required including an assessment of the products that are already on the market.

2.3 Archiving

Archiving is carried out by Quality Assurance.

2.4 Distribution

The specialist functions concerned and those responsible for the required correction should receive copies of all authorised annual product reviews.

Summary

The annual product review is a structured procedure in which all information, changes and dependencies that have arisen during a calendar year with regard to the manufacture and control of a preparation are detected, evaluated and documented and in which suggestions for improvements are formulated.

Although a large amount of time is required to compile an annual product review, its significance will also be high due to the generally large number of batches analysed in comparison to the three validation batches.

At the same time, the annual product review offers the opportunity to critically examine the functions of internal systems, such as change controls, documentation, storage, investigation of deviations, OOS procedures and the processing of complaints.



