Qualification: Regulatory &

Good Practice Requirements!

by
Pramote Cholayudth!
TIPA

15 June 2019 1 of 51
 Presentation Outline
n Key Words Involved in Qualification
n Regulatory Requirements on Qualification
n Inter-Relationship between URS, DQ, IQ, OQ,
and PQ
n Good Qualification Practice Requirements
n References for Qualification Practice

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Key Words

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GMP and Supporting Guidelines
Pharmaceutical Quality ICH QUALITY (Q)
System (ICH Q10) Guidelines
(Q5,Q8,Q9,Q10,Q11)
Biotech. Products,
Pharm. Develop.,
Qual. Risk, Qual. Syst.
ICH SAFETY
(S) Guidelines
Carcinogen. Stud.,
Clinical Study
Toxicity Testing, (S1,S4,S6)
Reports, Good
Clinical Practice, Biotech. Products
Clinical Trials

PIC/S GMP ICH EFFICACY

(Q, S, E, & Security)
(E) Guidelines
(E3, E6, E7-E11)
Quality, Safety, Efficacy, &
Security (ความมั่นคง Commissioning, Qualification
ปลอดภัย) and Validation
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 GMP Functions & Goals
GMP Functions GMP Activities GMP Goals
Qualification, validation,
Product Quality

Patient Protection (GMP)

quality control, monitoring
Quality (in vitro quality)
& stability study
Bioequivalence (*in vivo) Product Efficacy*
Safety (& Control contamination,
Product Safety
Biosafety) impurity, degradation prod
Protect product from Product Security
Security (&
errors e.g. mix-up, (product secured
Biosecurity)
mislabeling, etc. from all errors)
* Product efficacy is not involved in Qualification.
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Safety Functions (WHO TRS 937) & Goals
Safety Goals:
Safety Functions Safety Activities Human Protection
Protection from product
quality failure Patient Protection
Product
Protection from product (relevant to safety, not
Protection
safety failure (protected quality)
from contamination) Occupational Hygiene

Protect. from accident Personnel Protection

Personnel
Protect. from hazards (Common Goal – i.e.
Protection
Protect. from disease GMP, GEP, GLP)
Environment Avoid discharges/waste Community Protection
Protection disposal to environment (Common Goal) 6 of 51
 Key Words in Qualification Criteria
Key words in Qualification determination criteria
n Quality (คุณภาพ)
Key memory: 3+4+2
n Safety (ความปลอดภัย)
n Product protection (การปกป้องผลิตภัณฑ์ - ทุกตัวในโรงงาน)
n Personnel protection (การปกป้องบุคลากร)

n Environment protection (การปกป้องสิ่งแวดล้อม)

n Self-protection (การปกป้องตนเอง) (= การป้องกันการสูญเสีย)

n Security (ความมั่นคงปลอดภัย) Power failure/surge & overload/

fire/emergency protection
n No inside-out (ภายในห้ามออก: Local exhaust ventilation - LEV)
n No outside-in (ภายนอกห้ามเข้า: Outside Air Unit ของ HVAC)
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GMP Protection Perspective: Cleanroom
Process Shell (Cleanroom Wall)
1
Process Background (Cleanroom Air)
1 Pro 1
Uti ess
c rd s
z a
litie
s Process Environment c t Ha
(LAF) ro du 123
P
Raw Mats. Process Core
Product
1
Proc
es s Dis
ram ess
rs

c har
ete
Pa roc

ges
P

123

1 Product protection, 2 Personnel protection, 3 Environment protection

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Regulatory Requirements

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 Key PIC/S Guidelines for Qualification
n Guide to Good Manufacturing Practice for Medicinal
Products: Part I
n About those who are responsible for Qualification
n Guide to Good Manufacturing Practice for Medicinal
Products: Annexes, Annex 15: Qualification and
Validation
n About URS, DQ, FAT/SAT,
n Recommendation on VMP, IQ/OQ, Non-sterile
Process Validation, Cleaning Validation
n ‘Qualification’ and ‘Validation’ is separately used
n Aide-Memoire: Inspection of Utilities
n HVAC, Pharm Water System, Compressed Air & Gas System
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 Updated PIC/S Requirements
n User Requirement Specification (URS)
n The essential elements of quality need to be built
in at this stage and any GMP risks mitigated
(reduced) to an acceptable level.
n The URS should be a point of reference
throughout the validation lifecycle.
n Design Qualification (DQ)
n The requirements of GMP compliance and URS
are to be fulfilled by Design Qualification.
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 Updated PIC/S Requirements
n Factory Acceptance Test and Site Acceptance
Test (FAT & SAT)
n FAT & SAT documents are required to support
qualification activities so that repetition is avoided
n Where appropriate and justified, documentation
review and some tests could be performed at the
FAT or other stages without the need to repeat on
site at IQ/OQ if it can be shown that the
functionality is not affected by the transport and
installation.
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 Qualification vs. Validation: PIC/S
n Qualification is applied to ‘System’ and
‘Equipment’, not validation
n Validation is applied to:
n Operation mode of system or equipment (w/ SOP)
n System e.g. HVAC/cleanroom validation
n Equipment e.g. process equipment i.e. process
validation (w/ BPR) and QC lab equipment
n Cleaning mode of process equipment (w/ cleaning
SOP) i.e. cleaning validation
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Inter-Relationship: URS, DQ, ...

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 URS vs. DQ
n DQ is intended to fulfill the followings:
n GMP requirements
n URS relevant to intended quality & use (i.e. operation mode)
n Quality: PW - quality meeting USP
n Location of use: PW - location of point of use - in which

room and corner

n Number of point of use: PW - How many points of use

n Quantity (consumption rate/amount): PW - How many

liters per day?, peak amount at what time?

n In design phase, generation/supply rate is designed to cope
with the consumption rate/amount Good Design Practice
n DQ will include URS and GDP, constructability,
functionality, etc. (but not workmanship) 15 of 51
 Is URS Hosted only by the User?
URS is hosted by URS team practically led by Q&V head:
n User requirements
n Operation mode: Intended quality and point of use list & diagram
n Cleaning mode (Cleanability)
n GMP requirements: Cont. control, clean utilities, product
protection aspect (contact & construction materials)
n Information upon request (future plan, dust/heat load, etc.)
n Operator requirements Process review & site
n Operability & Calibratability survey information, MOM
n Regeneration/fumigation/sanitizing mode
n Servicer requirements
n Installation environment requirements
n Maintenance mode (O&M manual, spare parts list)
n Q&V team requirements Maintainability
n Commissioning (FAT/SAT) & Qualification documents 16 of 51
 PAR vs. NOR
LWCL LEL Normal UEL UWCL
Operating
Range (NOR)
Δ Δ
(With SOP)

Proven Acceptable Range (PAR)

(No SOP)
Operability (NOR; Mean±2SD) = Optimized Range

LEL & UEL: Lower & Upper Extreme Limits

LWCL & UWCL: Lower & Upper Worst Case Limits
Functionality (PAR; Mean±4.5SD) >> Robust Range (Mean±3SD)
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 Qualification Matrix of System!
SOP Preparation
Draft SOP
Qualification*
Mode of Functions URS SOP Val**
DQ IQ OQ PQ
Operation mode Yes Yes Yes Yes Yes Yes Yes
Regeneration mode Yes Yes Yes Yes – Yes –
Sanitizing mode Yes Yes Yes Yes – Yes –
Calibration mode Yes Yes Yes Spare – Parts
– Yes –
Maintenance mode Yes Yes Yes – – Yes –
Safety modes (***) Yes Yes Yes Yes – Yes –
Special modes Yes Yes Yes (1) (2) – –
* To verify, ** To prove & confirm, (***) Product, personnel &
environ. & self protection, (1) Worst case, (2) NOR/Extreme case
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Qualification Matrix of Process Equipment!
Design Review SOP Preparation Draft SOP
Qualification* SOP/
Mode of Functions URS BPR
Val**
DR IQ OQ PQ
Operation mode Yes Yes Yes Yes Yes Yes PV
Cleaning mode Yes Yes Yes Yes Yes Yes CV
Calibration mode Yes Yes Yes Spare – Parts– Yes –
Maintenance mode Yes Yes Yes – – Yes –
Safety modes (***) Yes Yes Yes Yes – Yes –
Special modes Yes Yes Yes (1) (2) – –
* To verify, ** To prove & confirm, (***) Product, personnel,
environ. & self protection, (1) Worst case, (2) NOR/Extreme case
OQ/PQ: Yes – Using placebo; PV & CV: Using real products 19 of 51
Qualification Matrix of Analytical Instruments!
Design Review SOP Preparation Draft SOP
Qualification
Mode of Functions URS SOP Val
DR IQ OQ PQ
AMV
Analytical mode Yes Yes Yes Yes Yes Yes
SST
Calibration mode Yes Yes Yes Spare – Parts– Yes *
Maintenance mode Yes Yes Yes – – Yes *
Safety mode (**) Yes Yes Yes Yes – – –
SST: System suitability test, * Quarterly/annual service program
PQ: (Equipment) Performance Qualification, Analytical Method
Validation, SST: System Suitability Test, (**) Product, personnel,
environment & self 1) protection (1) UPS, stabilizer)
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Criticality Determination Criteria: Power Supply
Self-Protection Example
n Success mode (voltage supply within ±10%):
Not critical
n Off-success mode: Critical
n Power failure: Critical if loss/quality risk/error
(power gen.; UPS required)
n Power surge: Critical to all (MDB required)

n Power trip: Critical if loss/quality risk/error (UPS

required)
n Power instability: Critical if loss/quality risk/error

(stabilizer required) 21 of 51
History of HVAC and EU Annex 1 Requirements
R A Walker, ISPE North West Region
2002 -
Parameters 1983 1993 1997 Current
2008
Particles Yes Yes Yes Yes Yes
Air pressure 0.06 inch Not 10-15 10-15 10-15
differential water g. specific pascals pascals pascals
Air change Not As required As required As required
> 20 /hr
rate specified ISPE: 6-20 (D), 20-40 (C), 40-60 (B)
HEPA
Yes Yes Yes Yes Yes
filtration
Clean up Not Short 15-20 15-20 15-20
time specified period min. min. min.
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Good Qualification Practice

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 Qualification and Validation Phases

Construc/on$/$ Process$
URS$ DQ$ Installa/on$ IQ$ OQ$ PQ$ Valida/on$

Valida(on+(Process+
Equipment*PQ*
Qualifica(on+(System/Equipment):+No+SOP+ PQ):+with+SOP/BPR+

URS: User Requirement Specification

DQ: Design Qualification
IQ: Installation Qualification
OQ: Operational Qualification
PQ: Performance Qualification
MQ: Maintenance Qualification
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 ‘How to Do’ in Qualification
(How to Do = Principles + Practices + Procedures)
n Concept to do (criticality determination) = Principles
n Approach to do (risk-based approach) + Practices

n Descriptive procedure (e.g. Qualification Plan)

n Step-by-step written procedure* (Protocol)
n Strategy to do (manage use of approach & resource)
n Descriptive procedure
n Step-by-step written procedure* (Protocol)
n Protocol development, protocol execution & report
preparation Concept: แนวคิด, Approach: แนวทางปฏิบัติ
Note:- Principle: หลักการ, Practice: หลักปฏิบัต,ิ
Procedure: วิธีปฏิบัต,ิ * วิธีปฏิบัติเป็นขั้นตอน (= Protocol)
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Q&V Documentation Hierarchy

Level 1
Guidelines Validation Goal
Validation Objective
Level 2 Validation Strategy
Validation Master Plan Validation Approach
Level 3
User Requirement Specification
(URS) & Req. Traceability Matrix (RTM)
Level 4
Qualification/Validation Plan – Test Plan
& Qualification Matrix (QM)
Level 5
Qualification/Validation Protocol – Test Protocol

Level 6
Supplier Documentation (O&MM, FAT & SAT – Test Cases/Scripts)

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 Subject Matter Expert (SME)
n SME is recognized by ASTM E2500-07: Standard
Guide for Specification, Design, and Verification of
Pharmaceu-tical and Biopharmaceutical
Manufacturing Systems and Equipment
n The guide is in line with ICH Q8 and ICH Q9

Definition:
n Subject matter experts (SMEs) (ผู้เชี่ยวชาญเฉพาะทาง)

are individuals with specific expertise and

responsibility in a particular area or field (for
example, quality unit, engineering, automation,
development, operations, and etc.). 27 of 51
 Comparison of Skill Levels!
Levels of Expectation Levels of Skills
Answer ‘What if’ question Subject Matter Expert (SME)
Answer ‘Why’ question FDA, QA & Validation

Understanding

Wisdom
Knowledge
Answer ‘How’ question PD & QC

Inform.
Answer ‘4W’ question Head
Answer ‘none’ of questions Data*
* Operator, 4W: Who, What/Which, Where, When
PD & QC Managers, QA & Validation Manager, FDA Inspector
Credit: Russel Ackoff – He indicates that the first four categories of skills relate to the
past; they deal with what has been or what is known. Only the fifth category, WISDOM,
deals with the future because it incorporates vision and design. With wisdom, people
can create the future rather than just understand the present and past.
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7 Steps To Become A Subject Matter Expert!
Authenticity
SME
Be Genuine
Be A Decision
Maker
Share Your Subject
Matter Expertise
Participate on Social Media

Try Out Your Own Ideas

Continue Educating Yourself
Build A Foundation of Knowledge
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The Cone of Learning!

Think Over (Digest) / Imagine

95% of what we TEACH
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 ASTM E2500-07 Highlight
n Alternative to ISPE Baseline Guide Vol. 5
Commissioning & Qualification
n Complexity, cost, time
n Replaces Design Qualification with Design Review
by Subject Matter Experts
n Risk Assessments by Subject Matter Experts (SMEs)
n Eliminate Impact Assessment
n Replaces sequential Commissioning and
Qualification with ‘Verification’
n Not bound by the formal IQ, OQ, & PQ phases
n E2500 puts focus on critical areas that affect Product
Quality and Patient Safety 31 of 51
 ASTM E2500-07 Highlight
n Verification is a systematic approach to verify that
manufacturing systems, acting singly or in
combination, are fit for intended use, have been
properly installed, and are operating correctly. This is
an umbrella term that encompasses all types of
approaches to assuring systems being fit for use
such as commissioning (FAT) and qualification,
verification, system validation, or others.
n No more Commissioning, Qualification, and Design
Qualification
n For PIC/S compliance, Qualification Review Report is
required
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ASTM E2500-07 Element: Leverage Approach

PT: Performance Testing

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Commissioning and Qualification Plans (Leverage Approach)
User Functional &
SMEs Requirements Risk Assessment Detail Design
Specification Specifications

Verification Plan (Using Traceability Matrix Gateway)

Factory Site Installation/ Performance

Acceptance Acceptance Operational Qualification
Tests Tests Qual. Tests Tests
Commissioning Leverage → Qualification

Verification Summary Report (Enhanced Turn-Over Package – ETOP)

GMP Operation and Process

& Cleaning Validation
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 Commissioning vs. Qualification (Leverage Approach)
IC: Installation Commissioning
OC: Operation Commissioning Magnitude of Leverage
PC: Performance Commissioning
IQ: Installation Qualification
OQ: Operation Qualification Magnitude of Work Done
PQ: Performance Qualification
Verification

User Requirement
Specifications PQ
Verification PC
Design & Construction

Qualification
Functional
Specifications
Verification OC
OQ

Design
Specifications IC
IQ
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 ‘Design and Qualification’ V-Model
GMP/FDA Technical/User The Model
Requirements Requirements SOP (Draft)

User Requirement Demonstrate Fitness for Intended Use Performance

General URS Configured in

Specifications Qualification
Traceability Matrix

Verif
y Rand
om Us
e
Funct. Design Verify Critical** Operational
Specifications Functions Qualification

Detail Design Verify Critical** Installation

Specifications Components Qualification

Design System/Equip Critical Aspects

Qualification* Fabrication Determination
Direct Impact System/Equipment Traceability Matrix
* GMP, Safety, URS, Risk
Assessment, Gap Analysis **Critical to Quality, Safety & Security
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 V-Model Cross Verification Matrix
(V1 for URS_1)
Reqmnt Traceability Matrix Qualification Reqmnt Matrix
URS FDS DDS IQ OQ PQ
URS_1 FDS_1.1 DDS_1.1.1 IQ_1.1.1 OQ_1.1 PQ_1
DDS_1.1.2 IQ_1.1.2
FDS_1.2 DDS_1.2.1 IC_1.2.1 OC_1.2
DDS_1.2.2 IC_1.2.2
DDS_1.2.3 IC_1.2.3
All IQ & OQ are executed after installation & operational
commissioning (IC & OC).

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 V-Model Cross Verification Matrix
(V2 for URS_2)
Reqmnt Traceability Matrix Qualification Reqmnt Matrix
URS FDS DDS IQ OQ PQ
URS_2 FDS_2.1 DDS_2.1.1 IC_2.1.1 OC_2.1 PQ_2
DDS_2.1.2 IC_2.1.2
FDS_2.2 DDS_2.2.1 IQ_2.2.1 OQ_2.2
DDS_2.2.2 IC_2.2.2
DDS_2.2.3 IC_2.2.3
All IQ & OQ are executed after installation & operational
commissioning (IC & OC).

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 Traceability Matrix
Traceability Matrix Model 1 (Short)
Taken from RTM & QRM Table
URS # URS Description
IQ Test Plan OQ Test Plan PQ Test Plan
URS_01 IQ_1.1.1 OQ_1.1 PQ_01
IQ_1.1.2
URS_02 IQ_2.2.1 OQ_2.2 PQ_02

Traceability Matrix Model 2 (Full)

Taken from Risk Assessment Table
URS
Description URS FDS DDS IQ Test OQ Test PQ Test
RA #
# # # Plan Plan Plan

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 Perspective on Shared Responsibility:
Engineer vs. Pharmacist (GEP vs. GMP)
International Congress
February 2002
Client QA Client QA
Process Approval Audit
Validation
Qualification
Engineering IQ
& OQ
Client Precommissioning Good
Engineering & Commissioning Engineering
Approval Practice
Construction (ISO 9000)
Engineering Design

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References

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Equipment IQ: Pharm Equip Validation

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Equipment OQ: Pharm Equip Validation

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Equipment IQ (with Software): PEV

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Equipment OQ (with Software): PEV

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Facility Design Reference Hierarchy
Law
Thai’s
PIC/S,
WHO, EU
(Facility, Utility, HVAC)
ISO, ASHRAE, EN, etc.
(ISO 14644 & 8573, Filters)
NEBB, ISPE Baseline Guides
(ISPE BG Vol. 2, 3, 4 & 5, HVAC, TT, PQLI)
ISPE Pharm. Engineering Journals, etc.
(Published Papers, Workshops, Forums, SMEs)
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HVAC Qualification Reference Hierarchy

Law
Thai’s
PIC/S,
WHO, ICH
(HVAC Qualification)
ISO 14644, ASHRAE, EN
(Cleanroom & Filter Standards)
NEBB, ISPE Baseline Guides
(HVAC, Sterile & Non-Sterile Facilities)
ISPE Pharm. Engineering Journals, etc.
(Published Papers, Workshops, Forums, SMEs)
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PW/WFI Qualification Reference Hierarchy

Law
Thai’s
PIC/S,
WHO, ICH
(Water System Qual.)
ASTM A380, USP, BP
(Passivation, Water Quality)
ISPE Baseline Guides
(C&Q, Water & Steam Systems)
ISPE Pharm. Engineering Journals, etc.
(Published Papers, Workshops, Forums, SMEs)
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Pure Steam Qual. Reference Hierarchy
Law
Thai’s
PIC/S,
WHO, ICH
(Utility Qualification)
EN 285, USP, BP
(Steam Quality, Water Quality)
ISPE Baseline Guides, PDA TR
(C&Q, Water&Steam Systems, PDA TR # 1)
ISPE Pharm. Engineering Journals, etc.
(Published Papers, Workshops, Forums, SMEs)
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CDA Qualification Reference Hierarchy
Law
Thai’s
PIC/S,
WHO, ICH
(Utility Qualification)
ISO 8573, USP, BP
(CDA Quality Std., Micro. Test)
ISPE Baseline Guides
(C&Q, Compressed Gas Systems)
ISPE Pharm. Engineering Journals, etc.
(Published Papers, Workshops, Forums, SMEs)
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Equipment Qual. Reference Hierarchy
Law
Thai’s
PIC/S,
WHO, FDA
(Qualification)
ASTM E2500
(Pharm & Biopharm Syst/Equip)
ISPE Baseline Guide
(Commissioning & Qualification)
ISPE Pharm. Engineering Journals, etc.
(Published Papers, Workshops, Forums, SMEs)
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