CONVALIDA E QUALIFICA I NUOVI ORIENTAMENTI DELLANNEX 15

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

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REFERENCE • Eudra. Lex - Volume 4 - EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 15: Qualification and Validation (October 2015) • ICH Q 8, Q 9, Q 10 and Q 11 • Eudra. Lex - Volume 4, Part I, relationship to Part II • Eudra. Lex - Volume 4 - Annex 11 • FDA – Guidance for Industry – Process Validation: General Principles and Practices (January 2011) • EMA/CHMP/CVMP/QWP/BWP/70278/2012 -Rev 1: 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) Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 3

ANNEX 15 «QUALIFICATION AND VALIDATION» HISTORY • 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 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 4

COMPARISON Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 5

WHAT ARE THE CHANGES? Key change: reference to ICH Q 8/Q 9/Q 10/Q 11 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 15 6

WHAT ARE THE CHANGES? NEW SECTIONS ADDED • Transport verification • Packaging validation • Qualification of the utilities • Validation of the test methods Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 7

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

PRINCIPLE 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 Eudra. Lex, Volume 4, Part II Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 9

PRINCIPLE 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". Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 10

GENERAL 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 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 11

GENERAL 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" Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 12

PLANNING, ORGANIZATION AND LIFE CYCLE APPROACH 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 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 13

PLANNING, ORGANIZATION AND LIFE CYCLE APPROACH 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 14

PLANNING, ORGANIZATION AND LIFE CYCLE APPROACH 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 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 15

GOOD DOCUMENTATION PRACTICES 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 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 16

GOOD DOCUMENTATION PRACTICES If validation protocols are delivered by third parties, the manufacturer has to confirm their suitability and compliance with the internal procedure before any approval. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 17

GOOD DOCUMENTATION PRACTICES 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. " Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 18

QUALIFICATION ACTIVITIES Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 19

QUALIFICATION ACTIVITIES 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 20

QUALIFICATION ACTIVITIES 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 21

QUALIFICATION ACTIVITIES • 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 22

RE-QUALIFICATION The term “revalidation” has been replaced with “re-qualification”: • Equipment • Facilities • Utilities • Systems Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 23

PROCESS VALIDATION 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 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 24

PROCESS VALIDATION 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 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 25

PROCESS VALIDATION Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 26

PROCESS VALIDATION 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 27

TRADITIONAL APPROACH 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). Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 28

CONTINUOUS VERIFICATION APPROACH The approach known as «continuous process verification (CPV)» is brand new and can be used only for processes already developed in accordance with Qb. D. 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" Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 29

HYBRID APPROACH 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 30

ONGOING PROCESS VERIFICATION The term «ongoing process verification» (OPV) has been introduced. Together with the product quality review (PQR), OPV will replace revalidation. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 31

CLEANING VALIDATION 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 32

NEW SECTIONS 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 33

NEW SECTIONS 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 34

NEW SECTIONS 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 35

NEW SECTIONS 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. Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 36

CHANGE CONTROL 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 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 37

CHANGE CONTROL • 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 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 38

CONCLUSION Overall, this reform is a big step toward standardization. The concepts described in ICH Q 8, Q 9, Q 10 and Q 11 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 Anna Fumagalli, 19 Aprile 2016 – Convalide e qualifica: i nuovi orientamenti dell’Annex 15 39

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