1. Purpose
The purpose of this Guideline is to provide requirements for the content, scope and procedures for developing Annual Product Reviews and Product Quality Reviews, and also to outline recommendations on how to achieve compliance.
2. Scope and Applicability
This Guideline is applicable to all manufacturing sites sourcing Active Pharmaceutical Ingredients, Bulk Formulated Products, Drug Products and Finished Products to the US or EU, or manufactured within EU but for export only.
3. Definitions
3.1 Annual Product Review (APR)
An evaluation, conducted at least annually, to assess the quality standard of each drug product with the objective of verifying the consistency of existing process and the appropriateness of current specifications, and to highlight any trends, in order to determine the need for changes in drug product specifications or manufacturing or control procedures.
The Annual Product review is concerning drug products intended for the US market.
3.2 Product Quality Review (PQR)
Regular periodic review, normally conducted and documented annually, of an API, Bulk Formulated Product, Drug Product or Finished Product intended for the EU market or manufactured within EU but intended for export only, with the objective of verifying the consistency of existing process and the appropriateness of current specifications, to highlight any trends and to identify both product and process improvements.
For Bulk Formulated Product, Drug Product or Finished Product, the review includes verifying the appropriateness of current starting material specifications as well.
3.3 Intermediate
A material produced during steps of the processing of an API, which mustundergo further molecular change or purification before it becomes an API.
3.4 Bulk Intermediate
A material produced during steps of the processing of a Drug Substance/API, which must undergo further molecular change or purification before it becomes a Drug Substance/API.
3.5 API – Active Pharmaceutical Ingredient / Drug Substance
Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product that when used in the production of a drug becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body.
3.6 Bulk Formulated Product
A pharmaceutical product (Formulated Drug/Formulated Product) held in large intermediate or shipping containers and ready to be filled into primary containers.
3.7 Drug Product
A formulated drug packaged in its primary packaging.
3.8 Finished Product
A product, which is packaged and labeled for supply to a wholesaler, hospital, pharmacy, doctor or patient.
3.9 Product Review
For the purpose of this document, this term will be used and embraces the concepts of Annual Product Review and Product Quality Review.
3.10 EU Supplying sites
For the purpose of this guideline, this term would include any sites or Contractors, manufacturing API, Bulk Formulated Product, Drug Product or Finished Product intended for the European market, or manufactured within EU and intended for export only.
3.11 Reprocessing
Reprocessing is the act of repeating process step(s) that is (are) part of the established manufacturing process for product.
3.12 Reworking
Reworking is subjecting all or part of a batch of product that does not conform to standards or specifications to one or more processing steps that are different from established manufacturing process to obtain an acceptable quality product.
Note:
This procedure could be acceptable for an API or an API intermediate (for example recrystallizing with a different solvent).
This is generally not acceptable for a drug product; manufacture has to be done according registered manufacturing specifications.
3.13 Level 3 Deviation
A deviation from GMP or procedure with no impact on product quality.
3.14 Level 2 Deviation
An isolated event or deviation from an agreed/approved procedure or process that normally results in a rapid corrective action or establishment of such corrective actions. Alternatively, a level 2 deviation may arise as a consequence of numerous repeated level 3 deviations.
3.15 Level 1 Deviation
A deviation that may have an actual or potential adverse effect on product quality (inc. purity and identity) safety or efficacy. Alternatively, a level 1 deviation may arise as a consequence of numerous repeated level 2 deviations.
4. Responsibilities
It is the responsibility of each site performing product reviews to have procedures and systems in place describing the preparation, approval and publication of product reviews.
Where applicable, a Lead Team/Site or other responsible unit must assurethat Contract Manufactures and Contract Laboratories to fulfill the requirements in this guideline.
5. Guideline
5.1 Introduction
Product reviews are required to confirm the continued suitability and reproducibility of manufacturing and control processes, or alternatively to recommend any changes required to procedures, methods or specifications. They are therefore an integral part of the ongoing validation and provide a mechanism to help highlight any requirements for changes and revalidation.
5.2 Scope of the Product Review Report
The scope and set up of the Product Review report can be different depending on which product and market it is covering. Below is some guide to this: The Product Review report covering US products (Bulk Formulated Products, Drug Products and Finished Products) should be product or product family specific.
The Product Review report covering EU products or products manufactured in EU but intended for export only (Bulk Formulated Products and Drug Products) may be grouped by product type, e.g. solid dosage forms, liquid dosage forms, sterile products, etc.
The Product Review report covering API may be grouped in a similar way as the report covering EU products. The Product Review report covering EU Finished Product packaging steps may be grouped by packaging line or packaging type. If a site is supplying both EU and US, a combined report should be considered for products using the same process and master formula, see also section 5.4.2.
5.3 Report Frequency and Timing
The Annual Product Review Report for US products must be composed annually, whenever there is manufacture. The Product Quality Reviews for EU products should normally be conducted and documented annually. Other review frequencies could be acceptable provided a documented rationale is available. The Product Review Report should normally be completed 3 months after the last day of the review period.
5.4 Content of the Product Review Report
The table below outlines which areas must be included in the product review, depending on scope of operations and if products are supplied to or from EU, and/or US.
* For primary packaging and other packaging steps that could affect product quality
** If applicable
Sections of the product review could be combined when practical.
Regular trend reports produced for other purposes (for deviations, complaints, stability, validation, etc.) could be referenced. Critical trends and conclusions from these should be evaluated with all other information in the Product Review.
5.4.1 Summary
A short summary section must be written on completion of the review, to appear at the beginning of the report. The summary must briefly describe: Time period and batches covered by the review. Reference to completion of any recommendations from the previous review Significant points evident from the review Conclusions and recommendations including explanations of key points, a statement of validation status and recommendations for any changes The summary must be written in English.
5.4.2 Batches reviewed
All batches that have a final release decision within the review period must be included in the review. Batches of Active Pharmaceutical Ingredients, Bulk Formulated Products, Drug Products and Finished Products must be covered.
All batches manufactured according the same process and the same Master Formula must be included in the review, irrespective of which markets they are supplied to. For example, even though the specifications may be different, if products are supplied to EU, ROW (Rest of the World) and US and manufactured according the same manufacturing process and the same recipe (Master Formula), the report (or reports) must include a review of all batches for those markets.
A check must be undertaken to ensure the review does not duplicate, or exclude, any batches made since the previous review. On-plant rejected batches not submitted for analysis must be included. Where a site is manufacturing more than one stage, it may choose to generate a single product review to cover all stages.
For newly commercialized products, the first product review should include all batches from the date of first release to the first anniversary of that release. Batches manufactured for Clinical studies only should not be included in the product review.
5.4.3 Starting and Packaging Materials
For EU supplying sites, key quality parameters for starting material and packaging material must be included in the review of the Bulk Formulated Product, Drug Product or Finished Product. For starting materials, include API and key excipients. For packaging materials, include primary and other packaging materials that could affect the quality of the product(e.g. blister foils).
5.4.4 Analytical data
Selected key data from in-process and product (API, Bulk Formulated Product, Drug Product, Finished Product) testing must be collated and reviewed against specification limits, in a manner to facilitate detection and explanation of any trends or isolated high/low results.
All registered (regulatory) tests must be included, but the inclusion of non-registered tests is optional. Where practical, graphical representation of data should be undertaken. Statistical interpretation of data, if used, should be clearly explained and justified.
A summary of the data reviewed and a review of acceptance limits must be undertaken. In case adverse trends or other problems are identified, a thorough investigation must be undertaken, including changes and deviations that could be related to the problem.
Any remedial actions taken and recommendations must be documented. For EU supplying sites, include review of critical in-process controls (for API, Bulk Formulated Product, Drug Product, Finished Product).What constitutes a critical in-process control should be defined per product or product type.
5.4.5 Changes
A listing and status summary of changes, introduced during the period of review must be produced. For changes to manufacturing process or analytical methods, all changes must be included in the review. The cumulative effect of all individual changes should be considered.
Conclusions must be made on any effects of introducing these changes on product quality and validation status. This section should provide a reference to the Manufacturing Change Management (MCM) system for changes impacting on regulatory compliance in the international supply chain.
5.4.6 Stability data
All data from ongoing stability programs and stability programs finalized during the review period must be reviewed and conclusions made to confirm that data continues to support the defined product shelf life. A summary of any stability failures must be included, summarizing any remedial actions ongoing or further recommendations. The sites performing the stability studies and analyzing the samples should do this review.
5.4.7 Deviations
All significant deviations recorded during the period of review and their investigationsmust be included in the review. Include at least Level 1 deviations in the review process.Include trending of Level 1 and Level 2 deviations. For EU supplying sites, include a review of the effectiveness of resultant corrective and preventive actions taken. This could be reviewed as part of regular deviation trend analysis and a reference to such report included.
5.4.8 Reprocessed and reworked batches
All batches reprocessed and reworked must be included in the review. The reason for reprocessing or reworking and the success of procedures undertaken must also be reviewed.
5.4.9 Rejected batches
A listing of all batches rejected, (either from failing to meet established specification, in-process testing or other reasons), must be compiled. The reason for the rejection must also be included. Conclusions must be drawn relating to underlying trends for rejections. Established specification is the external registered specification.
5.4.10 Complaints
All complaints reported during the period of review must be categorized, (i.e. medical, quality of manufacture, justified/not justified etc.),and an evaluation undertaken of any trends or links to a common cause. This could be reviewed as part of regular complaint trend analysis and a reference to such report included. A comparison of numbers and category with the previous review must be undertaken. Any remedial actions ongoing or further recommendations must be highlighted. Product Defect Notifications raised by other sister sites and affecting the drug product must be included in the review.
5.4.11 Recalls, Stock Recoveries, Field Alerts
Recalls, stock recoveries and Field Alerts (for US products only) must be included in the review. Include all investigations in the review.
5.4.12 Returned and Salvaged goods
A list of all returned and salvaged US product lots including each lots final disposition must be included in the review.
5.4.13 QA Agreements
For EU supplying sites, include a review of QA Agreements with Contractors of Bulk Formulated Products and Drug Products.
5.4.14 Qualification Status of Relevant Equipment and Utilities
For EU supplying sites of Bulk Formulated Products, Drug Product and Finished Products, include qualification status of relevant manufacturing equipment and services, e.g. HVAC, water, compressed gases, etc. It is recommended to include equipment with direct product impact. The qualification status can where appropriate be reviewed per production area rather then per product.
5.4.15 Marketing Authorization Variations
For EU supplying sites of Bulk Formulated Products, Drug Product and Finished Products, a listing of all marketing authorization variations submitted / granted / refused must be compiled.
5.4.16 Post-marketing Commitments
For EU supplying sites of Bulk Formulated Products, Drug Product and Finished Products, a listing of all post-marketing commitments must be compiled.
5.4.17 Other
It might be relevant to add in conclusions from trend reports for e.g. water systems or environmental monitoring, major changes in SOPs and Master Batch Records etc. Sites may also choose to include other activities where this is practical.
5.4.18 Comparison with Previous and Related Reviews
Comparisons of data with previous and, when relevant, related product reviews must be undertaken for each section. A comparison of the product reviews with the previous product reviews must be undertaken and summarized in the first page summary.
5.4.19 Conclusions and Recommendations
The conclusions must include explanations of key points evident from the review, a statement of validation status and recommendations for any changes and/or revalidation.
5.5 Contract Manufacturer or Contract Laboratory
The QA Agreement between the company and a Contractor must include a section On Product Reviews. Copies of a Contractor’s Product Review report must be available at the Lead Team/Site (or other responsible unit).. The sponsor company must review and agree to any conclusions made by the Contractor in the Product Review. If a sponsor manufacturing site and a contractor both are supplying the same API or drug product the review must cover this fact, see also section 5.4.2.
5.6 Product Review SOP
5.6.1 Content and format of the Product Review Report
It is recommended to include templates in the product reviews SOP to support complete and consistent reports. It is recommended to write the product reviews in English, but at least the summary section must be written in English. The SOP should for example define where raw data is to be filed, which standard regular reports can be used, etc.
5.6.2 Review, Approval and follow-up of actions
Formal review and acceptance of the product review’s content, conclusions and recommendations should be jointly undertaken by the site Manufacturing, Technical support and QA managers, or delegated senior manager within these functions. The responsibility for the final approval of product reviews lies with the QA manager or the Qualified Person. An agreed action plan, including names and target dates should be generated and there should be a follow up process to track agreed action to completion.
5.6.3 Archiving
The Product Review report should be archived by QA and kept for local use only, for example during an authority inspection. It is not intended for submission to authorities.