Cleanrooms and Containment

Guidelines: Validation Perspectives

by
Pramote Cholayudth
cpramote2000@yahoo.com
Thai Industrial Pharmacist Association
(TIPA)
September 19, 2016 1

GMP Regulations & Supporting Guidelines

Quality Management
System (QMS): ICH Q10
Biotech. Products,
Pharm. Develop.,
Qual. Risk, Qual. Syst.

Clinical Study
Reports, Good
Clinical Practice,
Clinical Trials

Q8, Q9, Q10, Q11)

Q: Quality

Carcinogen. Stud.,
Toxicity Testing,
Biotech. Products

GMP Reg. & Reg. Guide.

(Q, S, E, Security)

Adopted from John C. Berridge,

PhD, Pfizer: Quality by Design A
Modern System Approach: An
Industry Perspective

ICH Quality (Q)

Guidelines (Q5, Q7,

ICH Safety (S)

Guidelines
(S1, S4, S6)

S: Safety
E: Efficacy

ICH Efficacy (E)

Guidelines (E3,
E6, E7-E11)
Cleanroom
Validation
2

Defining Presentation Title

Cleanrooms and Containment Guidelines:
Validation Perspectives

The title is intended to share a validation point

of view, by the speaker as a validation
specialist (SME*), on Cleanrooms and
Containment Guidelines

* SME: Subject matter expert (this term was

introduced in ASTM E2500)
3

HVAC/Cleanroom C&Q&V Reference Hierarchy

Law

Law

Regulatory
Guidelines

Thais

Industry Standards
Industry Guidances
Approaches & Strategies

PIC/S,
WHO, ICH
(HVAC Qualification)

C: Commissioning
Q: Qualification
(DQ, IQ, OQ & PQ)
V: Validation

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)
4

References: HVAC/Cleanroom
GMP Regulations:
In the Thai FDA GMP Regulations (BE 2554):
Chapter 14 (Manufacture of Sterile Medicinal
Products) describes cleanroom requirements for
sterile production and quality control facilities
(corresponding to PIC/S Annex 1)
Chapter 12 (Qualification and Validation) also
describes qualification of facilities (i.e. HVAC and
cleanroom) and utilities (corresponding to PIC/S
Annex 15)

References: HVAC/Cleanroom
Regulatory Guidelines:
PIC/S GMP Annexes (updated on 1 October
2015)
Annex 1: Manufacture of Sterile Medicinal
Products (not revised)
Annex 15: Qualification and Validation (revised
and expanded) already translated (by the
speaker) and to be implemented in the near future

References: HVAC/Cleanroom
Industry Standards:
ISO 14644-1: 2015 (15 October 2015)
New classification by table
New number of sample locations i.e. no more
square root of the area in square meters
Updated sequential sampling procedure
Test methods updated
One of the reasons to revise is to reconsider the
statistical model i.e. withdraw the 95% UCL for 29 test locations

References: HVAC/Cleanroom
Industry Standards: (contd)
ISO 14644-2: 2015 (15 October 2015)
Change to a standard for monitoring only
Monitoring plan
Guidance about critical parameter monitoring
Revision is made to be in parallel with ISO 146441, and
The title changes to Part 2: Monitoring to
provide evidence of cleanroom performance
by air cleanliness by particles

References: HVAC/Cleanroom
Industry Standard: (contd)
ASTM E2500: Standard Guide for
Specification, Design, and Verification of
Pharmaceutical and Biopharmaceutical
Manufacturing Systems and Equipment

Leverage approach and subject matter expert

(SME) was introduced

Industry Guidances:
ISPE Good Practice Guide: HVAC
ISPE Baseline Baseline Guide: C&Q

References: HVAC/Cleanroom
Recognized Approaches:
Streamlining Approach
Leverage Approach (ASTM E2500, ISPE
C&Q)
Risk-Based Approach
Science-Based Approach

10

Cleanroom Environment (WHO TRS # 937)

Cleanroom/Containment
environment is intended
to provide protection to
product i.e. maintain
product quality.
Containment system
is also intended to
control spread of biocontaminants i.e.
control biohazards.

GMP MANUFACTURING
ENVIRONMENT

PRODUCT
PROTECTION

Contamination
(Product & Staff)

PERSONNEL
PROTECTION

Prevent Contact
with Dust

ENVIRONMENT
PROTECTION

Avoid Dust
Discharge

Protect from
Product CrossContamination

Prevent Contact
with Fumes

Avoid Fume
Discharge

Correct
Temperature &
Humidity

Acceptable
Comfort
Conditions

Avoid Effluent
Discharge

SYSTEMS

SYSTEM VALIDATION

11

Shell-Like Containment Control Concept

Ref.: WHO TRS # 937

Praphon Angtrakool, Thai FDA

12

Process Protection Layers: Validation Perspective

Process Shell (Cleanroom Panel)

Process Background (Cleanroom Air)
Pro
c
Uti ess
litie
s

Process Boundary

Raw Mats.

Process Core

P
Pa roc
ram ess
ete
rs

(Aseptic Core)

d
o
r
P

H
t
c
u

s
d
r
za

Product
Proc
e ss

Disc

harg
es

13

Biocontainment System: BSL-3

What view would you prefer to this figure?

Bird-eye, naked-eye, zoom in, zoom out or
microscopic view?

Primary Biocontainment
Secondary Biocontainment
14

Perspective on Qualification & Validation Timeline

VMP

Equipment PQ

URS: User Requirement Specification

Please note difference
DQ: Design Qualification
between Q (w/o SOP)
IQ: Installation Qualification & V (w/ SOP)
OQ: Operational Qualification
PQ: Performance Qualification (multi-function)
15

Perspective on Shared Responsibility:

Engineering vs. QA (GEP vs. GMP)
International Congress
February 2002

Process
Validation
Qualification
Engineering IQ
& OQ
Client
Engineering
Approval

Client QA
Approval

Precommissioning
& Commissioning
Construction

Client QA
Audit

Good
Engineering
Practice
(ISO 9000)

Engineering Design
16

Perspective on Design
Facility is driven
by Process.
Design review comprises
process & facility design.

Facility URS
is Driven by
Process URS

The processes will include

manufacturing, cleaning,
washing, sterilization,
fumigation, facility flows
(personnel, material, product),
waste treatment and so on.

Facility Design is Driven

by Process Design
GMP Facility Design is Driven by
GMP Process Design
GMP-Based GEP Facility Design is Driven by
GMP Process Design
17

Perspective on GMP vs. GEP

GMP purpose of cleanroom or containment is
to protect products via providing process
boundary, background and surrounding
GEP purpose of cleanroom or containment is
to design to deliver functions of cleanroom or
containment system to meet the GMP purpose

Such GMP-based GEP design will take all the

contexts ( ; risk & surrounding factors)
involved into account e.g. air change (dust load, O2),
room temperature (heat load), %RH (moisture load)

18

History of HVAC and EU Annex 1 Requirements

R A Walker, ISPE North West Region

2002 Parameters
1983
1993
1997
2008
Particles
Yes
Yes
Yes
Yes
Air pressure 0.06 inch Not
10-15
10-15
differential
water g. specific pascals pascals
Air change Not
Related Related
> 20 /hr
rate
specific
to oper. to oper.
HEPA
Yes
Yes
Yes
Yes
filtration
Clean up
Not
Short
15-20
15-20
time
specific
period
min.
min.

Current
Yes
10-15
pascals
Related
to oper.
Yes
15-20
min.
19

Perspective on HVAC/Cleanroom Q&V Requirements

Modes of HVAC/Cleanroom
Functions

Operation mode (air quality

tested via test parameters)
Cleaning mode (cleanroom)
Fumigation mode
Safety mode (product,
personnel & environ. protection)
Calibration mode
Maintenance mode

Q&V Requirements
DQ IQ OQ PQ Val
Yes

Yes

Yes

Yes

Yes

Yes
Yes

Yes
Yes

Yes
Yes

Yes

Yes

Yes

Yes

Yes

Yes
Yes

Yes
Yes

20

Cleanroom/Containment Validation Requirements

#

Test Parameters

Test Procedures

Airborne particle count Dust particle counts to be carried out and result printouts
(verify air cleanliness) produced.
In accordance with ISO 14644-1 Annexes B through F
and ISO 14644-3 Annex B1

Air differential
pressure (verify non
cross-contamination)

Log of pressure differential readings to be produced or

critical plants should be logged daily, preferably
continuously. A 15 Pa pressure differential between
different zones is recommended.
In accordance with ISO 14644-3 Annex B5

Airflow volume (verify

air change rate)

Airflow readings for supply air and return air grilles to be

measured and air change rates to be calculated.
In accordance with ISO 14644-3 Annex B4

Airflow velocity (verify Air velocities for containment systems and unidirectional
unidirectional flow or
flow protection systems to be measured.
containment condition) In accordance with ISO 14644-3 Annex B4
21

Cleanroom/Containment Validation Requirements

#

Test Parameters

Test Procedures

Filter leakage (verify

filter integrity)

Filter penetration tests to be carried out by a competent

person to demonstrate filter media, filter seal and filter
frame integrity. Only required on HEPA filters.
In accordance with ISO 14644-3 Annex B6

Containment leakage
(verify absence of
cross-contamination)

Demonstrate that contaminant is maintained within a

room by means of:
room air pressures
airflow direction smoke tests
In accordance with ISO 14644-3 Annex B5 & B8

Recovery (verify
cleanup time)

Test to establish time that a cleanroom takes to recover

from a contaminated condition to the specified cleanroom
condition. Should not take more than 15 min.
In accordance with ISO 14644-3 Annex B13

22

Cleanroom/Containment Validation Requirements

#

Test Parameters

Airflow visualization
(verify airflow pattern)

Test Procedures
Tests to demonstrate air flows:
from clean to dirty areas
do not cause cross-contamination
uniformly from unidirectional airflow units
Demonstrated by actual or video-taped smoke tests.
In accordance with ISO 14644-3 Annex B7

23

Perspective on Validation
Basically we validate success mode, not
failure mode, of the operation mode of the
systems, equipment and processes
So if failed, breakdown maintenance (repair)
mode will play the role
After repaired, validation maintenance mode will
go on

E.g. change control and other GMP activities

24

Perspective on Particle Count Validation

Calculation of 95% UCL for the particle count
data in ISO 14644-1: 1999 is based on Central
Limit Theorem stating that the average data of
non-normal data is normal
Note that the particle data is not only nonnormal but also splashed/scattered rather than
turbulent data
Withdrawal of 95% UCL calculation in the new
version is justified and more realistic
PIC/S sample volume NLT 1 m3

25

95% UCL for Particle Count

26

Other Perspectives on Cleanroom Validation

Room condition design criteria WHO

guideline
Air differential pressure (cleanrooms, airlocks)
Room temperature
% Relative Humidity

27

Any Question?

28