Cleanrooms and Containment Guidelines: Validation Perspectives€¦ · 18 Perspective on GMP vs. GEP GMP purpose of cleanroom or containment is to protect products via providing process

1September 19, 2016

Cleanrooms and Containment

Guidelines: Validation Perspectives

by

Pramote Cholayudth

[email protected]

Thai Industrial Pharmacist Association (TIPA)

2

Quality Management

System (QMS): ICH Q10

GMP Reg. & Reg. Guide.

(Q, S, E, Security)

GMP Regulations & Supporting Guidelines

Cleanroom

Validation

Adopted from John C. Berridge,

PhD, Pfizer: Quality by Design – A

Modern System Approach: An

Industry Perspective

Biotech. Products,

Pharm. Develop.,

Qual. Risk, Qual. Syst.

ICH Quality (Q)

Guidelines (Q5, Q7,

Q8, Q9, Q10, Q11)

Carcinogen. Stud.,

Toxicity Testing,

Biotech. Products

ICH Safety (S)

Guidelines

(S1, S4, S6)Clinical Study

Reports, Good

Clinical Practice,

Clinical Trials

ICH Efficacy (E)

Guidelines (E3,

E6, E7-E11)

Q: Quality

S: Safety

E: Efficacy

3

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)

4

HVAC/Cleanroom C&Q&V Reference Hierarchy

ISPE Pharm. Engineering Journals, etc.

(Published Papers, Workshops, Forums, SMEs)

NEBB, ISPE Baseline Guides

(HVAC, Sterile & Non-Sterile Facilities)

ISO 14644, ASHRAE, EN

(Cleanroom & Filter Standards)

PIC/S, WHO, ICH

(HVAC Qualification)

Law Thai’s

Approaches & Strategies

Industry Guidances

Industry Standards

Regulatory Guidelines

Law

C: Commissioning

Q: Qualification

(DQ, IQ, OQ & PQ)

V: Validation

5

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

6


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

7


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 2-

9 test locations

8


Industry Standards: (cont’d)

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 14644-

1, and

The title changes to ‘Part 2: Monitoring to

provide evidence of cleanroom performance

by air cleanliness by particles’

9


Industry Standard: (cont’d)

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

10

Recognized Approaches:

Streamlining Approach

Leverage Approach (ASTM E2500, ISPE

C&Q)

Risk-Based Approach

Science-Based Approach


11

Cleanroom Environment (WHO TRS # 937)

SYSTEM VALIDATION

SYSTEMS

Avoid Effluent

Discharge

Avoid Fume

Discharge

Avoid Dust

Discharge

Acceptable Comfort

Conditions

Prevent Contact with Fumes

Prevent Contact with Dust

Correct Temperature &

Humidity

Protect from Product Cross-Contamination

Contamination

(Product & Staff)

PRODUCT

PROTECTION

PERSONNEL

PROTECTION

ENVIRONMENT

PROTECTION

GMP MANUFACTURING

ENVIRONMENT

SYSTEM VALIDATION

SYSTEMS

Avoid Effluent

Discharge

Avoid Fume

Discharge

Avoid Dust

Discharge

Acceptable Comfort

Conditions

Prevent Contact with Fumes

Prevent Contact with Dust

Correct Temperature &

Humidity

Protect from Product Cross-Contamination

Contamination

(Product & Staff)

PRODUCT

PROTECTION

PERSONNEL

PROTECTION

ENVIRONMENT

PROTECTION

GMP MANUFACTURING

ENVIRONMENTCleanroom/Containment

environment is intended

to provide protection to

product i.e. maintain

product quality.

Containment system

is also intended to

control spread of bio-

contaminants i.e.

control biohazards.

12

Shell-Like Containment Control ConceptRef.: WHO TRS # 937

Praphon Angtrakool, Thai FDA

13

Process Protection Layers: Validation Perspective

Process Background (Cleanroom Air)

Process Boundary

Process Core Raw Mats.

Product

Process Utilities

Product Hazards

Process Shell (Cleanroom Panel)

(Aseptic Core)

Process Discharges

Proce

ss

Param

eter

s

14

Biocontainment System: BSL-3

Secondary Biocontainment

Primary Biocontainment

±0

What view would you prefer to this figure?

Bird-eye, naked-eye, zoom in, zoom out or

microscopic view?

15

Perspective on Qualification & Validation Timeline

URS: User Requirement Specification

DQ: Design Qualification

IQ: Installation Qualification

OQ: Operational Qualification

PQ: Performance Qualification (multi-function)

EquipmentPQ

VMP

Please note difference

between Q (w/o SOP)

& V (w/ SOP)

16

Process Validation

Qualification Engineering IQ

& OQ

Precommissioning & Commissioning

Construction

Engineering Design

Good Engineering Practice

(ISO 9000)

Client Engineering Approval

Client QA Approval

Client QA Audit

International Congress

February 2002

International Congress

February 2002

Perspective on Shared Responsibility:

Engineering vs. QA (GEP vs. GMP)

17

Facility URS

is Driven by

Process URS

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

GMP Facility Design is Driven by GMP Process Design

Facility Design is Driven by Process Design

Perspective on DesignThe processes will include

manufacturing, cleaning,

washing, sterilization,

fumigation, facility flows

(personnel, material, product),

waste treatment and so on.

Facility is driven

by Process.Design review comprises

process & facility design.

18

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 (บริบท; risk & surrounding factors)

involved into account e.g. air change (dust load, O2),

room temperature (heat load), %RH (moisture load)

19

History of HVAC and EU Annex 1 Requirements

Parameters 1983 1993 19972002 -

2008Current

Particles Yes Yes Yes Yes Yes

Air pressure

differential

0.06 inch

water g.

Not

specific

10-15

pascals

10-15

pascals

10-15

pascals

Air change

rate

Not

specific> 20 /hr

Related

to oper.

Related

to oper.

Related

to oper.

HEPA

filtrationYes Yes Yes Yes Yes

Clean up

time

Not

specific

Short

period

15-20

min.

15-20

min.

15-20

min.

R A Walker, ISPE North West Region

20

Perspective on HVAC/Cleanroom Q&V Requirements

Modes of HVAC/Cleanroom

Functions

Q&V Requirements

DQ IQ OQ PQ Val

Operation mode (air quality

tested via test parameters)Yes Yes Yes Yes Yes

Cleaning mode (cleanroom) Yes Yes Yes Yes Yes

Fumigation mode Yes Yes Yes – –

Safety mode (product,

personnel & environ. protection)Yes Yes Yes – –

Calibration mode Yes Yes – – –

Maintenance mode Yes Yes – – –

21

# Test Parameters Test Procedures

1 Airborne particle count

(verify air cleanliness)

Dust particle counts to be carried out and result printouts

produced.

In accordance with ISO 14644-1 Annexes B through F

and ISO 14644-3 Annex B1

2 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

3 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.


4 Airflow velocity (verify

unidirectional flow or

containment condition)

Air velocities for containment systems and unidirectional

flow protection systems to be measured.


Cleanroom/Containment Validation Requirements

22


5 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.


6 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

7 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.



23


8 Airflow visualization

(verify airflow pattern)

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.



24

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

25

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 non-

normal 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

26

95% UCL for Particle Count

27

Other Perspectives on Cleanroom Validation

Room condition design criteria – WHO

guideline

Air differential pressure (cleanrooms, airlocks)

Room temperature

% Relative Humidity

28

Any Question?

Documents

Cleanrooms and Containment Guidelines: Validation Perspectives€¦ · 18 Perspective on GMP vs. GEP GMP purpose of cleanroom or containment is to protect products via providing process