News Annual product review
Here you will find answers to the following questions:
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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).
| Documents required to carry out an annual product review |
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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 (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.
| Examples of company-internal consequences of an annual product review |
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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
- 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.
| What data must be given in an annual product review? |
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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.
| Header data in an annual product review report |
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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.
| Who approves the results of any modifications where there is a collaboration between the contract giver and contract acceptor? |
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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 |
15.F.4 Example: annual product review
Annual product review for calendar year 2004Preparation: 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 |
Annual product review for calendar year 2004Preparation: Material number: Batch designation: from to 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 Coated tablets 2.7 Average weights 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 |
Annual product review for calendar year 2004Preparation: Material number: Batch designation: from to 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. |
Annual product review for calendar year 2004 Preparation: Material number: Batch designation: from to 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. |
Annual product review for calendar year 2004 Preparation: Material number: Batch designation: from to 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. |
15.F.5 Master-SOP for the annual product review
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Logo |
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| Operating procedure |
SOP no. |
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Valid from Page x of y Facilities |
Binding for
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For information to |
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created by |
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checked by |
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approved |
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Change index - New compilation |
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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
Quality assurance
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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): |
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Yield |
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Analytical and physical data |
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Environmental monitoring |
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In-process controls |
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Stability studies |
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Deviations and their follow-up measures |
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Changes and their follow-up measures |
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Out of Specification |
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Change of supplier and |
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Reworking |
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Returns |
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Recalls |
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Complaints, trends and summaries |
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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:
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2.2 Inspection, evaluation and authorisation The annual product review, including the interim reports and recommendations, is inspected and authorised by
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The annual product review contains a further concluding evaluation of the following points: Process is in order, GMP compliant
Measures are required
Immediate measures are required
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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. |
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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. |
