May 2015, page 1

Qualification and Validation - an Overview -

by Dr. Ingrid Walther

May 2015, page 2

„Qualification” Action of proving that any equipment works correctly and actually leads to the expected results. The word validation is sometimes widened to incorporate the concept of qualification.“

EU-GMP-Guide, Glossary

qualification Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results. The meaning of the word “validation” is sometimes extended to incorporate the concept of qualification. WHO Technical Report Series, No. 961, 2011

Qualification is something that has to be done additionally to GEP. It is done for those systems that have a direct impact on product quality.

ISPE Baseline Volume 5

Definitions

May 2015, page 3

Definitions

Qualification provides documented evidence that equipment is designed and works as it should:

Qualification

➩ equipment-related

Validation provides documented evidence that processes lead to product of the desired quality and safety:

Validation

➩ process-related

Example: baking oven / car

May 2015, page 4

Regulatory Background

!  WHO-Guideline, WHO Technical Report Series, No. 961, 2011 Section 4

!  EU Guide to Good Manufacturing Practice Part 1, Chapters 5 + 6 Annex 11: Computerised Systems Annex 15: Qualification and Validation, current Version 2001, new version October 2015

Part 2: GMP for Active Pharmaceutical Ingredients

!  US-FDA Regulations –  FDA 21 CFR Parts 210 and 211: CGMP-Regulations –  Process Validation, General Principles and Practice, January 2011 –  Guides for Inspection

!  GAMP 5 (Computerised Systems) !  ...further national regulations and laws

May 2015, page 5

Regulatory Background

Guidelines (no legal obligation, but should be followed):

!  PIC-Document PI 006-3 (Title: „Validation Master Plan, Installation and Operational Qualification, Non-sterile Process Validation, Cleaning Validation“, 25 September 2007)

!  ISPE Baseline, Vol. 5, Commissioning and Qualification, 2001 January 2008 – Draft for comments – no new version published yet!

Common understanding in all Regulations and Guidelines:

" Qualification and Validation activities are needed to achieve the target of reliable product quality and safe products!

May 2015, page 6

Regulatory Overview

VMP RA

DQ IQ OQ PQ PV CV Comp. Val.

EU-GMP-Guide x x x x x x x x x

WHO x x x x x x x x

PIC Document PI 006-3

x - x x x x x -

FDA-Guide-lines x - - x x x x x x

EU-GMP-Guide Part 2

Validation Policy

Identi-fication

of critical para-

meters

x x x x x x x

ISPE- Baseline

Commis-sioning

Plan / VMP

Impact Assess-

ment

En-hanced Design Review (EDR)

x x x - - -

GAMP 5 x x x x x x

New: URS is expected in EU-GMP-Guide!

May 2015, page 7 Seite 7

Different interest groups in Qualification

Qualification shall be done by interdisciplinary teams – team members have different attitudes!

Qualification QA

Engineering

Supplier

Suppliers

May 2015, page 8

GEP GMP

„Engineers ./. Pharmacists“

from: ISPE Baseline Guide on Commissioning and Qualification, 2000

Basic Idea of the Guideline: GEP ➩ GMP

May 2015, page 9

Common understanding of the GEP and GMP Regulations

"  Qualification and Validation activities are needed to achieve the target of reliable product quality and safe products!

•  ISPE Baseline, Vol. 5, Commissioning and Qualification, 2001

•  GAMP 5 (Computerized Systems)

•  ASTM E2500-7, Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment, 2007

Different Regulations – with different focuses!

GEP

GEP GMP

May 2015, page 10

Qualification and Validation Overview

DQ

IQ

OQ

PQ

VMP

Qualification Computer-Val. Validation

DQ

IQ

OQ

PQ

Method Validation

Process Validation

Cleaning Validation

Impact Assessment

Risk Analyses Risk Analyses Risk Analyses

May 2015, page 11 Seite 11

Separate responsibilities and target!

Entirety of functions of an equipment

GMP-relevant Functions

Qualification (only a part of the technical acceptance testing!)

technical documents / Technical Acceptance Testing

May 2015, page 12

Why does the split between GEP and GMP make sense?

•  Pharmaceutical responsibility lies with a pharmacist: He / she is obliged to ensure that all quality relevant process parameters and conditions are under control

•  Approval of Qualification documents " pharmacist / biotechnologist may not be able to evaluate ALL technical requirements

•  Technical equipment is often very complex " Fokusing on GMP-aspects in Qualification allows the view on the essential

•  In case of authority inspections: " GMPrequirements must be fulfilled and THIS must be documented (the amount of paper does NOT count!)

•  In production routine: " Formal Change Control is only required for GMP-relevant aspects

•  Reduce documentation effort by separating GEP from GMP!

GMP-compliant?

May 2015, page 13

Qualification and Validation Documents during the Life-Cycle

Combined effort between GEP and GMP " What has successfully passed the technical (GEP) testing is considered acceptable for GMP-testing!

Engineering

Routine

Production Transport/ Installation

Process- Optimi-zation

FDS / DQ PV / RV PQ-Phase SAT / IQ FAT OQ

Detail RA

Change Control / Re-Qualification

Manufa- cturing Start-up

URS

Basis RA

Re-Val.

Good Engineering Practice - GEP

May 2015, page 14

What is the basis of ASTM E2500-7?

•  „Risk- und science-based approach“ – ICH Q9

-  Risik evaluations are based on technical expertise and always target at patient safety

-  Level of effort, formalty and documentation of the QR process must be commensurate with the risk for the patient

•  critical / relevant aspects of a system must be understood

•  „Quality by Design“

•  GEP in this sense serves GMP

•  Subject Matter Experts (SMEs) participate in the entire process

•  Supplier documentation is available

•  continuous improvement process

" reduced qualification effort without compromising patient safety!

May 2015, page 15

•  idenfity critical systems

•  explain, why non-critical system have been identified as such

-  non-critical systems are under GEP-control

•  for critical systems: explain the scope of qualification

1. Step in Risk Assessment: Impact Assessment = Separation into GEP and GMP

„Impact Spectrum“ (ISPE)

ISPE Baseline: Figure 2-1

non-critical „no impact“ " GEP

critical „direct impact“ " GMP

May 2015, page 16

identify systems

„No Impact“ System

„Direct Impact“ System

develop supporting rationale

develop system boundaries

„Indirect Impact“ System

Impact on product qualify?

Linkd to DI-System?

no

no

yes

yes

Commissioning & Qualification Commissioning

GEP GEP and GMP

according to: ISPE Baseline Guide on Commissioning and Qualification, 2000

1. Step in Risk Assessment: Impact Assessment = Separation into GEP and GMP

May 2015, page 17

Technische Dokum ente

Quali fiz ierungsdokum ente

Computer-Validierungs-Rahmenplan

Designqualif izi erungs -P läne

DQ-Bericht

Konzeptstudie

Basic Engineering inkl.Hygienekonzept +

(ev. Druckstufenkonzept )

Lastenhef t

R+I-Schem ata

Leistungsverzeichnisse /Technische Anfragespezif ikation

Bestellung

Good Engineering Practi ces / Change Control

Validierungsmasterplan

Risikoanalysen

Prüfung

gegen di ese

Dokumente

Det.Eng.

ZEIT

Zusammenhang zwischen dertechnischen und der

Qualifizierungsdokumentation

Abarbei tungDQ-Pl äne

Detai l-Layouts

Prozeßablaufpläne

Funkti onsdiagram me

ProtokolleAngebotsverhandlungen

(ggf. Änderungen derAnforderungen)

Quali fiz ierungs-Rahmenplan

(3)

(3)

(3)

(3)

(3)

Einfluß auf techn.Dokumente

P flichtenheft (FS)

Beginn GM P-Change-Control

As-built -Dokumentat ion

RahmenplanRV

Risikoanalyse

P läneProzeß-

Validierung

Risikoanalyse

P läne analyt .Methoden-Validierung

P läneReinigungs--Validierung

Analyt .Methoden-validierung

Prozeß-

validierung

Reinigungs-validierung

Abschluß-bericht

Abschluß-bericht

Abschluß-bericht

Approval ( FDA / EU)

Abschluß-bericht

RahmenplanPV

Abschluß-bericht

ZEIT

Quali fiz ierungs-Abschlußbericht

IQ-P läne

OQ-P läne

Abarbei tungQuali fiz ierung

SDS / HDS

SATS / HATS

FAT

IBN / SAT

Abnahme

Prüfungnach AbschlußIQ-

Protokolle

Prüfung nach AbschlußOQ-

Protokolle

Konst rukt ion / T echn.Dokumentat ion

Pharmaunternehmen

(1) eventuell teilw. Abarbeitung IQ/OQ (Vermeidung von Doppeltestung(2) Überprüfung bei Lieferanten-Audit(3) kein zeitli cher Ablauf , wi cht ige technische Dokumente (Beispiele)

QA-Genehmigungnotwendi g

(2)

Lieferant

Installat ion derAnlage

S tabili täts-chargen

Modul test

Integrationstest

(1)

(1)

Abarbei tung

Quali tätsplan

Complex structure of Qualification and Validation work and flow of information in projects! " Organization required

May 2015, page 18

The Validation Master Plan

Validation work needs to be organised!

Implement a „Validation Project Manual“

➩ the Validation Master Plan

VMP

WHO-Requirement 4.2 The key elements of a qualification and validation programme of a company should be clearly defined and documented in a validation master plan.

May 2015, page 19

The Validation Master Plan Annex 15 EU-GMP-Guide

i. Qualification and Validation policy; ii.  The organisational structure including roles and responsibilities for

qualification and validation activities; iii.  Summary of the facilities, equipment, systems, processes on site and the

qualification and validation status;

–  equipment to be qualified –  processes to be validated ➩ summarised and compiled in a matrix format

iv.  Change control and deviation management for qualification and validation; v.  Guidance on developing acceptance criteria;

" will be presented in the presentation on Risk Analyses vi.  References to existing documents; vii.  The qualification and validation strategy, including requalification, where

applicable.

The VMP or equivalent document should define the qualification validation system and include or reference information on at least the following:

May 2015, page 20

The Validation Master Plan

Valididation Master Plan(Validation Policy)

Plant 1 / Line 1 Plant 2 / Line 2 Plant 3 / Line 3 ...

QualificationPlan

ValidationPlan

QualificationPlan

ValidationPlan

QualificationPlan

ValidationPlan

Possible VMP / QP / VP Structure

Everything described in the VMP / QP / VP must be done!

May 2015, page 21

The Validation Master Plan

i. Qualification and Validation policy (firm‘s policy, general description), e.g.:

•  Targets •  Validity (for which Project - how long?)

•  Basic Guidelines (WHO, EU- and US-FDA-cGMP-Guidelines)

•  Information about general GMP-interpretation

•  GEP issues

May 2015, page 22

The Validation Master Plan

ii. organisational structure of validation activities

•  Organisational structure / organisational charts

•  Tasks in the project: approve, check or prepare the documents

•  Names of responsible personnel

•  CVs / background •  Matrix of responsibility (Task, function: responsible, carry out the

work, support the work)

•  Description of the relationship between commissioning and qualification

•  project schedule / reference to the project schedule •  capacities / staffing

•  training needs

May 2015, page 23

The Validation Master Plan

iii. Summary of the facilities, equipment, systems, processes on site and the qualification and validation status

•  Building

•  Rooms

•  Production equipment

•  Media supply

•  Processes

•  Methods

Detailed description provides good overview ➩ High effort for changes during the project!

Impact Assessment process has to be described!

May 2015, page 24

identify systems

„No Impact“ System

„Direct Impact“ System

develop supporting rationale

develop system boundaries

„Indirect Impact“ System

Impact on product qualify?

Linkd to DI-System?

no

no

yes

yes

Commissioning & Qualification Commissioning

GEP GEP and GMP

according to: ISPE Baseline Guide on Commissioning and Qualification, 2000

1. Step in Risk Assessment: Impact Assessment = Separation into GEP and GMP

May 2015, page 25

The Validation Master Plan iii. summary of facilities, systems, equipment and processed to be validated

Equipment System Explanation

City water Only raw material for pharmaceutical water; quality defined according tonational regulations

Chilled water Only for indirect cooling; no direct contact with product or productcontacts parts; direct measurement of product temperature wherenecessary

Iced water Only for indirect cooling; no direct contact with product or productcontacts parts; direct measurement of product temperature wherenecessary

Plant steam Only for indirect heating; no direct contact with product or productcontacts parts; direct measurement of product temperature wherenecessary

Humidification for HVAC system Requirements of steam to be specified during RA ‚HVAC system‘

Waste water system Not in contact with production equipment; risk for contamination ofequipment will be covered during qualification of production equipmentand rooms

Electrical power supply / UPS - system No direct influence on product quality; reaction on failure of power supplywill be checked during qualification of equipment

Building Management System; IT – systems andtelecommunication

GMP relevant data will not be handled by these systems, only for systemcontrols; GMP relevant data will be covered by separate systems

HVAC system for packaging area To be decided during Risk analysis ‚HVAC‘ system

Example for �supporting rationale� for indirect and no impact systems

May 2015, page 26

The Validation Master Plan

iii. List of systems and processes, e.g.:

Description of Validation Activities during the Phases: •  Process transfer(from existing to new plant) •  Process Optimisation •  Cleaning Validation •  Process Validation

Similar to Qualification:

•  Operational Organisation (Organisational charts, tasks...) •  Processes to be validated (Matrix) •  Document format

May 2015, page 27

Qualification Matrix – Result of the Impact Assessment

Qualification Steps System / Equipment

RA DQ IQ IOQ OQ PQ

Formulation system incl. CIP/SIP

Formulation Tank 1

Formulation Tank 2

Diluent tank

Al-Gel diluent tank

x x x x

Weighing scales

x

x - x - - Stopper treatment unit and transfer station x x x - x x Steam autoclave x x x - x x Clean steam generation and distribution x x x - x x LF-units x x x - x x HVAC-System x - x x Environmental Monitoring System x - x - Rooms

x x

- x - x Compressed Air Generation and Distribution x x x - x x Purified Water Generation and Distribution x x - x x WFI-Generation and Distribution

x

x x - x x

The Validation Master Plan

Example to show possible structure!

May 2015, page 28

The Validation Master Plan

v. Change control and deviation management for qualification and validation;

•  Reference to existing procedure (SOP?) •  Definition of new and project specific process

–  Define project stage for start of CC –  Who has to inform about changes? –  Who has to approve the changes?

–  Deviation management may be different from routine process because deviations during qualification and validation do not impact on patient safety!

➩ Simple process for quick decisions!

May 2015, page 29

The Validation Master Plan

vi. Reference to existing documents

•  SOPs •  List of abbreviations •  Definitions •  Literature, Codes and Standards, Guidelines •  Attachments (Layouts, P&IDs)

vi. The qualification and validation strategy, including requalification, where applicable.

•  frequency of requalification •  when to revalidate

May 2015, page 30

The Validation Master Plan

Further possible and common subjects:

•  general acceptance criteria

•  how to choose and involve suppliers

•  training of personnel

•  how to carry out Risk Analyses

•  documentation format -  document structure

-  numbering system

-  example document

-  way from protocol " report

May 2015, page 31

The Validation Master Plan

The VMP

•  overview

•  official GMP-document

•  is required due to regulations

•  available to all project team members

•  read and recognised by all project team members

•  importance for equipment suppliers

The VMP is a summary document: ➩ brief, concise and clear!

May 2015, page 32

Disclaimer: •  This presentation has been prepared upon best knowledge and it presents the view and

experience of Pharma Consulting Walther.

•  The presentation reflects current guidelines, knowledge and thinking. Changes of regulatory guidelines or interpretation thereof or new regulatory expectations may change the applicability of the contents of this presentation.

•  Parts of the presentation may not be understood or misinterpreted without the verbal explanation given during the seminar.

•  Although the statements made in the presentation in general have been presented to and discussed with inspectors, a different approach may be required and adequate depending on the individual situation.

•  The information contained herein may be changed without prior notice.

Contact: Pharma Consulting Walther Dr. Ingrid Walther Rosenweg 36 61381 Friedrichsdorf – Germany +49-(0)6172-958281 +49-(0)172 654 8834 www.consulting-walther.com iw@consulting-walther.com