Annual Product Review (APR) Product Quality Review (PQR)

1. Annual Product Review (APR)Product Quality Review (PQR)

2. 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

3. Annual Product Review - WHAT • APR for each commercial product • APR should confirm the State of Control 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.

4. 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.

5. 2. Scope This scope applies to manufacturing sites, Affiliates and subcontractors

6. 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].

7. 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 byproviding information to the site of release.

8. 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.

9. 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.

10. 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

11. 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.

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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.

18. 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) Product Quality Review 1.5 Regular periodicor rolling quality reviews of all licensed medicinal products, including export only products, should be conducted with the objective of verifying consistency of the existing process, the suitability of current specifications for both starting materials and finished product to highlight any trends and to identify product and process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least:

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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

27. 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.

28. 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 ?

29. 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 ?

30. 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 ?

31. 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 ?

32. 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)

33. The PQR should confirm the State ofControl • '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.

34. Thank You Any Questions