1. CONVALIDA E QUALIFICA: I NUOVI ORIENTAMENTI DELL’ANNEX 15 Anna Fumagalli Labochim 19 aprile 2016

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3. R EFERENCE Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 EudraLex - Volume 4 - EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 15: Qualification and Validation (October 2015) ICH Q8, Q9, Q10 and Q11 EudraLex - Volume 4, Part I, relationship to Part II EudraLex - Volume 4 - Annex 11 FDA – Guidance for Industry – Process Validation: General Principles and Practices (January 2011) EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1: Guideline on process validation for finished products -information and data to be provided in regulatory submissions (February 2014) EMA/CHMP/ CVMP/ SWP/169430/2012 – Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (November 2014) 3

4. A NNEX 15 «Q UALIFICATION AND VALIDATION » H ISTORY Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 First issue: July 2001 EMA/INS/GMP/705397/2012 Concept paper on revision of Annex 15 of the GMP guide: Nov 2012 Draft release: February 2014 Final version release: March 2015 effective from 01 st of October 2015 4

5. C OMPARISON Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 155

6. W HAT ARE THE CHANGES ? Key change: reference to ICH Q8/Q9/Q10/Q11 Use of concepts such as Quality by Design, Risk Assessment and Quality Systems. References made to validate computerised systems according to Annex 11 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 156

7. W HAT ARE THE CHANGES ? Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 157 NEW SECTIONS ADDED Transport verification Packaging validation Qualification of the utilities Validation of the test methods

8. W HAT ARE THE CHANGES ? Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 158 The term “validation” has been replaced with “qualification and validation” to reflect the true intent of the Annex 15

9. P RINCIPLE Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 Annex 15 contains the requirements for qualification and validation of processes, equipment, utilities and facilities used to manufacture pharmaceutical products. May be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II 9

10. P RINCIPLE Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 The root principles address a product / process lifecycle which should be accompanied by qualification and validation activities. In addition, it is now highlighted that changes should also assess the influence on the validation status or "control strategy". 10

11. G ENERAL Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 There is a brand new section ("General") in which a "justified and documented" risk analysis (as part of the quality risk management approach) should be the basis for decision making regarding the scope and depth of the qualification/ validation activities. Retrospective validation is no longer an acceptable approach 11

12. G ENERAL Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 According to the last section of this chapter "data supporting qualification and/or validation studies which were obtained from sources outside of the manufacturers own validation program may be used provided that this approach has been justified and that there is adequate assurance that controls were in place throughout the acquisition of such data" 12

13. P LANNING, ORGANIZATION AND LIFE CYCLE APPROACH Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 VMP should describe: Qualification/validation strategy, Roles and responsibilities, List of systems/processes and current qualification/validation status Guidance for acceptance criteria. VMP no longer needs to include: Protocol and report template Scheduling and planning information 13

14. P LANNING, ORGANIZATION AND LIFE CYCLE APPROACH Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 Qualification /validation activities performed by trained personnel following approved procedures Qualification/validation personnel should report as defined in the pharmaceutical quality system not essential to be a quality management or a quality assurance function. 14

15. P LANNING, ORGANIZATION AND LIFE CYCLE APPROACH Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 The importance of Quality Risk Management is evident Risk assessment to be repeated if further knowledge and understanding is gained from any changes during the project phase or during commercial production. Incorporate appropriate checks to ensure the integrity of all data obtained 15

16. G OOD D OCUMENTATION P RACTICES Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 Prepare validation protocols which defines the critical systems, attributes and parameters and the associated acceptance criteria Documents may be combined together, where appropriate e.g. installation qualification (IQ) and operational qualification (OQ). Any significant changes to the approved protocol during execution should be documented as a deviation and scientifically justified 16

17. G OOD D OCUMENTATION P RACTICES Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1517 If validation protocols are delivered by third parties, the manufacturer has to confirm their suitability and compliance with the internal procedure before any approval.

18. G OOD D OCUMENTATION P RACTICES Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1518 Releases of validation steps part of the release of the validation report, or summarised on a document. Something new: Conditional approval to proceed to the next stage "given where certain acceptance criteria or deviations have not been fully addressed and there is a documented assessment that there is no significant impact on the next activity."

19. Q UALIFICATION ACTIVITIES Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1519

20. Q UALIFICATION ACTIVITIES Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1520 All stages from initial development of the user requirements should be considered. Specifications for new facilities, systems or equipment should be defined in a user requirements specification (URS) and/or a functional specification. This should help building in quality at this stage and minimising GMP risks. The URS should be "a point of reference" throughout the validation life cycle.

21. Q UALIFICATION ACTIVITIES Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1521 Factory acceptance tests (FAT) are new, and site acceptance tests (SAT) have been included in the draft. For equipment with novel or complex technology, the FAT is binding ("should be evaluated at the vendor prior delivery"). On the contrary, the use of SAT is mentioned as "may be" option.

22. Q UALIFICATION ACTIVITIES Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1522 Installation qualification (IQ) (Equipment, Facilities, Utilities, Systems) Operational qualification (OQ) (following or combined with IQ (IOQ)) Performance qualification (PQ) (following IQ and OQ or combined with OQ or Process Validation) Generally, the section on the qualification of established (in-use) facilities, systems and equipment has disappeared.

23. RE-QUALIFICATION Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1523 The term “revalidation” has been replaced with “re-qualification”: Equipment Facilities Utilities Systems

24. P ROCESS V ALIDATION Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1524 Applicable to the manufacture of all pharmaceutical dosage forms. Used in conjunction with the current EMA guideline on Process Validation for Finished Products. Robust product development process required to enable successful process validation

25. P ROCESS V ALIDATION Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1525 Manufacturing processes may be developed using a Traditional approach Continuous verification approach Hybrid approach Retrospective validation is no longer an acceptable approach Concurrent validation can be used under exceptional circumstances

26. P ROCESS V ALIDATION Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1526

27. P ROCESS V ALIDATION Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1527 Critical Quality Attributes and Critical Process Parameters: important for ensuring the validated state and acceptable product quality Process validation should establish whether these can be consistently met by the process Data from process and product development form the basis for informative process validation. Research and Development data used in process validation must be GMP-compliant.

28. T RADITIONAL APPROACH Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1528 It must be shown that the process consistently delivers the defined quality. Classic three-batch approach is accepted, but this is only a minimum requirement. This must subsequently be documented with informative data (representative number of batches, standard range, batch size as in routine production).

29. C ONTINUOUS VERIFICATION APPROACH Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1529 The approach known as «continuous process verification (CPV)» is brand new and can be used only for processes already developed in accordance with QbD. CVP should be based on a “science based control strategy for the required attributes for incoming materials, critical quality attributes and critical process parameters to confirm the product realization"

30. H YBRID APPROACH Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1530 A hybrid of the traditional approach and continuous process verification approach could be used where there is substantial amount of product and process knowledge Could be used for any validation activities after changes and during ongoing process verification.

31. O NGOING P ROCESS VERIFICATION Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1531 The term «ongoing process verification» (OPV) has been introduced. Together with the product quality review (PQR), OPV will replace revalidation.

32. C LEANING V ALIDATION Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1532 Cleaning validation more detailed: use of quality risk assessment, toxicological evaluation automated cleaning processes. The visual check for cleanliness is an important criterion for acceptance, but exclusively visual monitoring is not acceptable. The requirement of three consecutive cleaning procedures for cleaning validation has been replaced by a risk-based assessment for the specification of the necessary number of validation runs.

33. NEW SECTIONS Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1533 Transport verification This is intended to ensure that products are transported in compliance with the approval dossier and specification. Transport routes must be clearly specified. For example, seasonal fluctuations, delays, data logger malfunctions, etc. must be included and their influence on product quality analyzed.

34. NEW SECTIONS Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1534 Packaging validation This applies to the critical process parameters (e.g. temperature, speed, sealing pressure) in primary packaging that potentially have a direct influence on the product. Validation should encompass the entire range of operations.

35. NEW SECTIONS Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1535 Qualification of the utilities This includes water, steam, air and gases, for example. Direct (e.g. heating, ventilation, air- conditioning) or indirect (e.g. heat exchanger) product contact must be subjected to risk assessment in order to keep control over the effects in the event of faults.

36. NEW SECTIONS Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1536 Validation of the test methods The analytical methods used for qualification, validation and cleaning must be validated. Here reference is made to EU GMP Part 1. For microbial testing, the validation should confirm that the product itself does not promote bacterial growth. Likewise, the validation of wipe tests in cleanrooms should show that the cleaning agents used do not influence the result.

37. C HANGE C ONTROL Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1537 The «Change Control» section has been expanded to include new content. The change process is an important part of knowledge management within the framework of the pharmaceutical quality system. When Design space is used the impact on changes to the design space as registered in MA should be considered Assess need for any regulatory actions

38. C HANGE C ONTROL Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1538 Review supporting data to confirm that the impact of change has been demonstrated prior to final approval. Perform an evaluation of the effectiveness of change to confirm that the change has been successful

39. C ONCLUSION Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 1539 Overall, this reform is a big step toward standardization. The concepts described in ICH Q8, Q9, Q10 and Q11 must be explicitly taken into account. With an integrated life cycle concept, QRM and contemporary PV approaches, Annex 15 has responded to practical experience and harmonization goals, including those of the FDA

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