Update on and Critical Utilities for Pharmaceutical Industry … · 2016-09-02 · Maintenance of...

การประชมวชาการ เรอง Update on HVAC and Critical Utilities for Pharmaceutical Industry

วนท 29-30 สงหาคม 2559 เวลา 08.00 น.-16.30 น. หองคอนเวนชน ซ-ด ชน 1 โรงแรมแอมบาสซาเดอร สขมวท 11 กรงเทพฯ

หลกการและเหตผล การผลตยา ตองค านงถงการควบคมและปองกนการปนเปอนระหวางกระบวนการผลต โดยเฉพาะการผลต

ยาปราศจากเชอ ระบบ HVAC เปนหนงในระบบทส าคญทจะชวยลดการปนเปอนจลนทรย อนภาค ของยาจากสภาวะแวดลอมไดอยางด ในบรเวณการด าเนนการผลต ตองมการถายเทอากาศทมประสทธภาพ มสงอ านวยความสะดวกในการควบคมอากาศ ตวอยางเชน อณหภม ความชน และการกรองอากาศ ใหเหมาะสมทงตอผลตภณฑ กระบวนการ และ การด าเนนการของบคลากรทปฏบตงานอยภายในบรเวณนน และตอสงแวดลอมภายนอก การออกแบบระบบ HVAC ทดมประสทธภาพ และการบ ารงรกษาทถกตองเหมาะสมจะชวยในการควบคมปองกนการปนเปอน และประหยดพลงงานไดเปนอยางด

PIC/S GMP ไดจดแบงระดบและตรวจสอบหองสะอาด (Clean Room ) สอดคลอง ตาม มาตรฐาน ISO 14644 เพอก าหนดระดบหองสะอาดของสถานทผลต ในระดบความสะอาดแตกตางกน ซงขนอยกบประเภทของผลตภณฑและกระบวนการทผลต เพอปองกนการปนเปอน

นอกจากนระบบน า ( Water System ) และ ระบบลมอดอากาศ (Compressed Air ) กเปนระบบทส าคญในการผลตยา ทจ าเปนตองมความรความเขาใจในขอก าหนดใหม รวมถงการท า Commissioning Qualification Maintenance ของระบบเหลานดวย

วตถประสงคการเรยนร

เพอทราบและเขาใจของหลกการของระบบ HVAC รวมทงการท า Commissioning, Qualification และmaintenance

เพอทราบและเขาใจของหลกการการออกแบบ Clean Room ทมประสทธภาพ เพอทราบและเขาใจเรองของมาตรฐานใหมของ Clean Room ISO 14644 – 1& 14644 -2 (2015) เพอทราบและเขาใจเรองของ GMP the EU & PIC/S Annex 1 ทคาดวาจะมการทบทวนแกไขตาม

ISO 14644 เพอทราบและเขาใจเรองของ

o The new Ph EUR WFI monographo Specification for air quality.

เพอทราบและเขาใจเรองของ Commissioning and Qualification Maintenance of Compressed Air เพอเรยนรเทคโนโลย Building Automation System

วทยากร Mr. Gordon Farquharson and Mr. Anthony Margetts สรปการบรรยาย เปนภาษาไทย วนท 29 สค. 2559 โดย คณทศพล สนตเทวกล สรปการบรรยาย เปนภาษาไทย วนท 30 สค. 2559 โดย ภก. วรยทธ จรรศม ผทควรเขารบการอบรม ไดแก บคลากรทปฏบตงานเกยวกบการผลตยา ในหนวยงานดงน ประกนคณภาพ ควบคมคณภาพ ควบคมการผลต Validation ซอมบ ารง และออกแบบ เภสชกรทเขาอบรมตลอดระยะเวลา 2 วน ได 12 หนวยกตการศกษาตอเนอง ระยะเวลาการฝกอบรม วนท 29 - 30 สงหาคม 2559 เวลา 09.00 น. – 16.30 น. สถานท โรงแรม แอมบาสซาเดอร สขมวท 11 กรงเทพฯ คาลงทะเบยน สมาชก ISPE / TIPA คนละ 5,350 บาท ( รวมภาษมลคาเพม )

บคคลทวไป คนละ 6,420 บาท ( รวมภาษมลคาเพม )

AGENDA

Update on HVAC and Critical Utilities for Pharma

29th

- 30th August 2016

Speaker: Gordon Farquharson

1. AGENDA

29 August 2016: HVAC and contamination control ( 6 CPE )

08.00-8.50 Registration

08.50-9.00 Welcome and Opening

09.00-10.30 NEWS HEADLINES! Revised ISO cleanroom standards and future GMP changes.

Introduction

New revised ISO 14644 -1&2:2015 – Highlights of the changes.

Worked example of the revised cleanroom classification method.

10.30-10.45 Coffee Break

10.45-12.00 Anticipated revisions in the EU & PIC/S Annex 1

Cleanroom design and operation for maximum efficiency – design considerations.

Design of air systems and cooling systems for economic operation in hot and

humid climate (Zone 4B)

Understanding the influence of the air distribution system in non-UDF cleanroom design.

12.00-13.00 Lunch

13.00-14.45 Making best use of commissioning and qualification for maintenance

General principles for maintenance of GMP systems and equipment.

Maintenance of HVAC systems.


15.00-16.15 Building Automation System (BAS) (Dr. Anthony Margetts)

16.15-16.30 Q&A

16.30 Closure

30 August 2016 : Critical Utilities WFI update & Compressed Gases ( 6 CPE)

08.00-09.00 Registration

09.00-10.30 NEWS HEADLINES! The new PhEUR WFI production monograph. (Part1)

The new monograph requirements – History, background, why the change?, timing.

Comparison, new EP, USP & JP


10.45-11.00 NEW HEADLINES! The new PhEUR WFI Production monograph. (Part2)

How GMP aspects will be addressed in the revision of Annex 1 of the EU &

PIC/S GMP

Choosing a suitable WFI system

12.00-13.00 Lunch

13.00-14.45 Compressed Air (Part1)

Specification for air quality

Good design and installation practice (GEP).

Monitoring & test methods

14.45-15.00

Coffee Break

15.00-16.15 Compressed Air (Part2)

Making best use of Commissioning and Qualification information.

Maintenance of compressed air systems

16.15-16.30 Q&A

16.30 Closure

SPEAKER

UPDATE ON HVAC AND CRITICAL UTILITIES FOR PHARMACEUTICAL INDUSTRY

Monday 29th – Tuesday 30

th August 2016

Gordon Farquharson, B.Sc.(Hons), C.Eng. is a Chartered

Consulting Engineer with more than 30 years experience of quality & safety critical processes and facilities used by industries such as Healthcare, Life Science, Micro-electronics, etc. He is Principal consultant and Managing Director of Critical Systems Ltd, an international consultancy firm. In the Asian and ASEAN regions, he provides consultancy services in association with Factorytalk based in Thailand, and PharmOut based in Australia.

In recent years he has focused on technologies such as isolators, barrier technology, mini-environments, critical utility systems and bio-containment applications. He has been responsible for the development of technical solutions in product development, primary manufacturing and device and dosage form manufacturing.

Standards and regulatory compliance issues in the Pharma/Life Science sectors are a major interest and responsibility. In this context he has a high degree of expertise in the practical interpretation & application of EU/PIC-S/WHO GMPs and US FDA cGMP requirements. Experience with the variation in expectations gives an ability to dovetail the differing regulatory requirements together. In recent years, he has been heavily involved in the development of the new regulatory guidance and standards. In particular, he is active working on CEN/ISO Cleanroom & Contamination Control Standards, WHO GMP guidance and ISPE Baseline Guides. He is Chairman of BSI's LBI 30 Committee and of CEN Technical Committee 243, and is Convenor of WG1 and a UK expert working on the ISO TC209 and CEN TC243 family of contamination control standards that provide the platform for contamination control standardisation and practice in this millennium. He has recently worked with the EMeA in London to help update and improve the cleanroom classification and monitoring requirements in Annex 1 of the EU and PIC/S GMPs and has contributed writing WHO’s Pharmaceutical water GMP Guidance. He wrote the 2009 draft revision of the WHO GMP guidance on sterile products, and is active in WHO regulatory work.

He is a founding member, management committee member, past Chairman, and Honorary Member of the UK Pharmaceutical & Healthcare Sciences Society (formerly Parenteral Society), and is Editor in Chief of the European Journal of Parenteral & Pharmaceutical Sciences. He is also active in ISPE, the R3 Nordic Association, and PDA. He is a past chair of the ISPE European Education Committee and was voted ISPE International Member of the year 2001, UK Affiliate Member of the year in 2008, and recipient of the Richard B Purdy Distinguished Achievement Award 2009. He is a member of the PDA Science Advisory Board (SAB) and is an honorary senior lecturer at UCL (London) and the University of Manchester PEAT & PIAT programmes..

He lectures and teaches extensively, is an author of many papers, and contributor to books on engineering and technology applications in the life-science sector

SPEAKER

UPDATE ON HVAC AND CRITICAL UTILITIES FOR PHARMACEUTICAL INDUSTRY

Monday 29th – Tuesday 30

th August 2016

Dr .Anthony Margetts is Principle Consultant for Factorytalk’s Compliance

department and a highly experienced and leading international Pharmaceutical and Chemical engineering practitioner and project manager with +30 years working experience in the chemical/pharmaceutical/medical device industries.

As Principle Consultant, Dr Margetts leads key compliance consulting assignments. He is considered a global expert in the fields of GMP compliance and validation for the Pharmaceutical and regulated industries.

He worked for AstraZeneca (formerly Zeneca and ICI Pharmaceuticals) since 1988. He has been responsible for a variety of international projects, e.g. leading teams responsible

for technical transfers, new product introductions and preparations for international, European and US FDA pre-approval and regulatory inspections. During his time at ICI/Zeneca/AstraZeneca he managed the introduction of new medical device products, including setting up global supply chains and ensuring their compliance to international standards.

During the 1990’s he managed the introduction of new world-wide validation procedures and was the Chairman of a UK Pharmaceutical Industry Group charged with writing a Guideline on Computer Systems Validation which evolved over a number of editions and expanded from UK through Europe, USA and Japan and is now called the Good Automated Manufacturing Practice (GAMP) Guide. Dr Margetts was chairman for the editorial review of the latest version GAMP 5, published in 2008 which has now become the world wide reference for Computer Validation in the Healthcare Industries.

ISPE August 2016 1

Joint TIPA & ISPE programme

Mr. Gordon Farquharson &

Dr. Anthony Margetts

August 2016

Before we begin, there are two

very important Thai industry

milestones we need to

recognize!

These are hugely significant to Thailand, the Thai

Pharmaceutical Industry, and all of us who have an

interest and responsibility to satisfy and respect the

commitments made.

ISPE August 2016 2

ASEAN MRA

With effect from 13 March 2015, the Food and Drug

Administration (FDA) of Thailand became the 4th

Listed ASEAN Inspection Service

This is highly significant, and helps meet the

ASEAN objective of removing trade barriers for safe

and effective medicines.

ISPE August 2016 3

PIC/S

Accession of Thailand / Thai FDA to PIC/S

4 - 5 July 2016

At its meeting on 4-5 July 2016 in Manchester (UK), the PIC/S Committee invited Thailand's Food and Drug Administration (Thai FDA) to join the Scheme as from 1 August 2016. Thai FDA will become PIC/S’ 49th Participating Authority.

ISPE August 2016 4

Recognition of Thailand & Thai

FDA at ISPE Singapore Regulatory

Panel 26th August 2016

ISPE August 2016 5

Chairman

Bob Tribe

Former

TGA

Australia

Sansanee

Manchanda

Thai FDA

Boon

Meow Hoe

HSA

Singapore

Vimal

Sachdeva

WHO

Geneva

Dr. Vasiliki

Revithi

Former

EOF

Greece

Chong

Hock Sia

HSA

Singapore

Matsatoshi

Morisue

PDMA

Japan

ISPE August 2016 6

Our programme

Cleanroom Standards Update

- ISO 14644-1&2:2015

Design & Maintenance of efficient HVAC

systems

Building automation systems (BAS)

New Ph Eur WFI Specification

Design & Maintenance of efficient compressed

air systems

ISPE August 2016 7

Dr.Anthony Margetts

Chemical engineering practitioner and project manager with >35

years experience of Pharmaceutical / Life Sciences

ISPE Qualified Trainer

Principle Consultant for Factorytalk Co.Ltd.

Global expert in the fields of GMP compliance and validation for

the Pharmaceutical and regulated industries

Chairman for the editorial review of the latest version GAMP 5

Responsible for a variety of international projects :

- ISPE GAMP 5

- ISPE Thailand Vice President

- Technical transfers

- New product introductions and preparations for international,

European and US FDA pre-approval and regulatory inspections

ISPE August 2016 8

Gordon Farquharson

Chartered Mechanical Engineer with >35 years experience of

Pharmaceutical / Life Sciences

Principal Consultant & owner Critical Systems Ltd

Very active in associations including ISPE, PDA, UK PHSS.

I have been writing the ISO Cleanroom Standards for 25 years --

Chair of CEN TC 243 & Convenor of WG1 in ISO TC 209.

Contributing author of WHO’s Pharmaceutical Water GMP

guidance, and contributor to ISPE Water & Steam Baseline™

Guide.

Worked on many aspects of Sterile products GMPs.

Annex 1 EU/PIC-S.

Annex 3 WHO.

ISPE Baseline Guides

ISPE August 2016 9

You

What is your background, role, and

expertise ?

Raise your hands for each that applies:

QA

QC

Validation

Production management

Engineering

Supplier

Cleanroom expert

Pharma critical utilities expert

ISPE August 2016 10

Let’s get started

ISPE August 2016 11

Questions / Discussion

Contact: Gordon Farquharson

Critical Systems Ltd

[email protected]

CRI ICAL

S

Y

S

T

E

M

S

CRI ICAL

S

Y

S

T

E

M

S

Let’s get started

1

Review - Revision of

EN/ISO 14644-1 & 2 Revised standards approved in December 2015

By Gordon Farquharson

Chair BSI LBI/030; Chair CEN TC243;

Convenor ISO TC209 WG1

August 2016

ISPE 2016 August 2016

Agenda The status of ISO 14644-1 & 2.

The challenge of improving ISO 14644-1:1999

Timeline for the new standards.

ISO 14644-1 New – classification by table.

New – number of sample locations.

Update to sequential sampling procedure.

Handling Ultrafine particles – now in Nano-particle monitoring standard.

Keeping the concepts of Macro-particles

Test methods update.

Revision of ISO 14644-2 Change to a standard for monitoring only.

The monitoring plan.

Guidance about critical parameter monitoring.

ISPE 2016 2 August 2016

Background to the revisions


Why were the revisions to

ISO 14644-1:1999 needed?

At the systematic review in 2005, P-nations decided they wanted to improve standard. In particular:

Review the standard against current best practice.

Improve clarity of some parts of the specification e.g. ‘Sequential Sampling”.

Reconsider the statistical model– consider removing the need to evaluate the 95% UCL for 2-9 test locations.

Improve sensitivity to different classes of cleanliness (this was not achieved in the end).

4 ISPE 2016 August 2016

Why were the revisions to

ISO 14644-2:2000 needed?

This standard has to be kept in parallel with the revision of 14644-1.

Existing standard has defined intervals between re-classification tests – Out of date concept with modern monitoring systems.

Concept in title is not considered correct today Cleanrooms and associated controlled environments — “Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1”

Part 2: Monitoring to provide evidence of cleanroom performance by air cleanliness by particles (ACP)

To become a monitoring standard only.


Status of ISO 14644-1 & 2


Very important !!!!! Status of ISO 14644-1 & 2

On 15th December 2015, ISO 14644-1:1999 & ISO 14644-2:2000 were replaced by the 2015 versions.

This means: ISO 14644-1:1999 ISO 14644-1:2015

ISO 14644-2:2000 ISO 14644-2:2015

These are voluntary standards invoked in contracts and our pharma GMP guidance (e.g. US FDA 2004 APG & EU/PIC-S Annex 1).

In the GMPs they are referred to as ISO 14644-1 (no date). This means always the latest/current version.

We understand that EMA will allow 12 months to comply; no word yet from US FDA.

Making the transition. I suggest the following: Have a clear policy in your business.

Trial the new ISO 14644-1:2015 classification process ASAP prior to full implementation using your change control procedure.

Review your monitoring programme vs ISO 14644-2:2015 and implement changes using your normal change control procedure.


ISO TC209 wg1 Timeline


ISO TC209 WG1 Timeline

(10 years + in the making!)

Revised International Standard published on 15th December 2015 ISO 14644-1&2:2015 Published as an EN ISO standard in parallel Will be published as national standards

progressively e.g. ISO ANSI (USA), BS EN ISO (UK), etc.

FDIS enquiry vote passed 27 October 2015 2nd DIS enquiry PASSED vote in November

2014 1st DIS enquiry PASSED vote December 2010,

but had numerous questions and requested changes.

Start of revision 12th Nov 2005 !


ISO 14644-1 revisions


Change from:

Classification by Formula (+ table to illustrate)

TO Classification by Table

+ Formula for Intermediate Sizes

Keep decimal classes; but now just 0.5 steps (1.5; 2.5;

etc.). More logical related to particle counter size

discrimination capability.

Remove ≥ 5.0 micron limit for ISO 5 (29) & ISO 5.5

Key change - ISO 14644-1:2015 The basis for classifcation


ISO Formula

– retained for intermediate

particle sizes only

ISO Cn = 0.1 2.08 x 10N(class) D

( )

12 ISPE 2016

For example if you needed a class

concentration limity for ≥ 0.4 micron

August 2016

The

formula

illustrated

by an

Informative

Table

Old - EN/ISO 14644-1:1999 Classification by Particles


14

Transition to New - ISO 14644-1:2015

Class Table Remove 29/m3 ISO 5

class limit ~

Counting uncertainty

Very Low

values deleted

Low values have

sample size warning


The new classification table


16

Now closer to OLD US Fed Std 209E Classification by Table (Particles)

No ≥5.0m

limit in old

Class 100 ISPE 2016 August 2016

The new decimal class table in

ISO 14644-1:2015

ISPE 2016 17

Concentration of particles (particles/m3) a

ISO classification number (N) 0,1 0,2 0,3 0,5 1,0 5,0

ISO Class 1,5 [32] b d

d d d e

ISO Class 2,5 316 [75] b [32] b

d d e

ISO Class 3,5 3 160 748 322 111

d e

ISO Class 4,5 31 600 7 480 3 220 1 110 263

e

ISO Class 5,5 316 000 74 800 32 200 11 100 2 630

e

ISO Class 6,5 3 160 000 748 000 322 000 111 000 26 300 924

ISO Class 7,5

c c c

1 110 000 263 000 9 240

ISO Class 8,5

c c c

11 100 000 2 630 000 92 400

Examples of intermediate decimal air cleanliness classes

by particle concentration (only 0.5 class steps allowed)

August 2016

This proposed change is not a major impact on the principle of

classification .

Helps prevent poor selection of size vs class.

Means Annex 1 Grade A and B clearly outside the ISO Class

system!

See later how this is dealt with!

Major discussions

Good science of particle counting removes ≥ 5 micron limit for ISO5

REMEMBER that the table doesn’t represent typical distribution of particles

in a cleanroom.

How to deal with Annex 1 or the EU/PIC/S GMP. Big influence from EU and

PIC/S GMP nations.

ISO 14644-1:2015 changes Impact


The proposal is to use adapted macro-particle descriptor concept –

See Annex C7.

ISO 14644-1:2015 & EU + PIC/S Annex 1 Impact

19 ISPE 2016

Class limit of 20 parts ≥

5.0 micron is also

outside scope of the

standard

Class limit of 29 parts ≥ 5.0

micron outside scope of

standard –

≥ 5.0 micron cannot be used

for an ISO5 classification

The GMP Grade table from Annex 1.

August 2016

Using the macro-particle descriptor for 5

micron particles in ISO 14644-1:2015

GMP should use the macro-particle concept for

Grade A 20 particles/m3 @ ≥ 5.0 micron

Grade B “at rest” 29 particles/m3 @ ≥ 5.0 micron

We use this terminology

ISO M (20;≥ 5.0); LSAPC

ISPE 2016 20

M =

Macroparticles

20 =

Class limit

from GMP

5.0 =

Considered

particle size

LSAPC = Light

scattering

airborne

particle counter

August 2016

This is how we would define Annex 1

Grade A & B using ISO 14644-1:2015 An extrapolation of the Macro-particle concept.

Grade A

ISO 5; at rest & operational; ≥ 0.5

ISO M(20≥ 5.0); at rest & operational; LSAPC

Grade B

ISO 5; at rest; ≥ 0.5, and ISO M(29≥ 5.0); at rest, LSAPC.

ISO 7; operational; ≥ 0.5 & 5.0 .


Simplification: The 95% UCL Evaluation for 2-9 locations has been removed.

Each sampling location now evaluated independently. All locations must comply for room or zone to comply.

There is a ‘Look-up’ table for the number of sampling locations required. Based on ensuring 95 % level of confidence that at least 90 % of the

cleanroom or clean zone will comply with the class limit.

Will increase the number of locations up to 1000m2. For > 1000m2, very similar to the current Area rule.

Placement of sampling locations: Even distribution, at representative locations In N-UDF cleanrooms with non-diffused airflow, avoid placement directly

under HEPA filter supply air terminals.

Key change - ISO 14644-1:2015 Improved sampling statistics


23

ISO 14644-1:2015

Required minimum sampling locations

1. Determine the number of sample locations NL from table A1.

2. Divide the room/zone into NL equal areas.

3. Select representative sampling locations in each zone (not under undiffused HEPA filter terminals).

4. Take a sample at each location (sample size as existing standard).

5. Average at each location if multiple samples are taken.

6. If all measured particle concentrations (or averages) comply with the class limit, the classification is met.

7. For larger rooms >1000m2, extrapolate the location density from the 1000m2 requirement – equation A.1.

ISPE 2016

Area of cleanroom (m2) less than

or equal to

Minimum number of sample locations

to be tested (NL) 2 1 4 2 6 3 8 4 10 5 24 6 28 7 32 8 36 9 52 10 56 11 64 12 68 13 72 14 76 15

104 16 108 17 116 18 148 19 156 20 192 21 232 22 276 23 352 24 436 25 636 26 1000 27

> 1000 See Equation A.1

Table A.1 — Sample locations related to cleanroom area

August 2016

ISO 14644-1:2015

Number sampling locations comparison

0

20

40

60

80

100

120

2 4 6 8

10

12

14

16

18

26

28

32

34

36

38

52

54

58

74

78

96

116

138

176

200

300

500

100

0

200

0

500

0

100

00

Min

imu

m N

um

ber

of

sa

mp

le p

oin

ts

Size of Room, m2

Comparison of the number of Sample Points: current and proposed

1999

Square

Root

rule

2015

look-up

To deal with very

large cleanrooms,

extrapolate the

location density

above 1000 m2


This is an important change to the basic mechanics of

classification.

Organisations will have to redefine their classification

sampling plans & data evaluation.

Does not affect Real-time monitoring.

Discussions

How to select the locations – can be randomised or fixed.

You can add locations to deal with Risk-Based requirements.

Allows re-test at same locations after a repair or remediation.

Can now deal with unusually large cleanrooms > 1000 m2

ISO 14644-1:2015 changes Impact


Change

Sequential sampling retained.

Now Annex D

The specification in old Annex F is

difficult to follow and has improved

presentation and explanation.

Impact

The clarified specification of sequential sampling would assist its use for classification of clean-zones with low particle concentrations limits.

Limited change - ISO 14644-1:2015 Sequential sampling


Change

Ultrafine Descriptor.

In reality we don’t classify by

this size range, we monitor

critical control points.

Removed to a new standard

(ISO 14644-12) dealing with

nano-particle cleanliness

monitoring in cleanrooms and

associated controlled

environments.

Impact

No impact on life-sciences industry.

Particle measurement technology changing fast.

Micro-electronics and nano-technology industries need flexibility to develop separate new standards.

Key change - ISO 14644-1:2015 Ultrafine or nano-scale particles


Change

ISO TC 209 decided that each classification or monitoring standard needs to have its own test method and test instrument guidance on-board.

Better than in a separate standard.

Makes revision of standards easier to keep coordinated.

Annex F imported from ISO 14644-3 with some updating.

Most important reference is ISO 21501-4:2007.

Impact

No direct impact on users.

Makes each standard more complete and

easier to use.

ISO 14644-3 will now only deal with the

support tests for cleanrooms e.g.:

Installed fFilter leak

Airflow velocity and volume

Pressurisation

ISO 21501-4:2007 describes a calibration

and verification method for a light scattering

airborne particle counter (LSAPC), which is

used to measure the size and particle

number concentration of particles

suspended in air. The light scattering

method described in ISO 21501-4:2007 is

based on single particle measurements.

The typical size range of particles

measured by this method is between 0,1

µm and 10 µm in particle size.

Key change - ISO 14644-1:2015 Test methods and instruments


Now on to 14644-2:2015 revision Quick summary in the time available

This standard will now just focussed on MONITORING !

The title has changed:

From ISO 14644-2:2000 Cleanrooms and associated controlled environments

Part 2: Specifications for testing and monitoring to prove continued

compliance with ISO 14644-1

To ISO 14644-2:2015 Cleanrooms and associated controlled environments

Part 2: Monitoring to provide evidence of cleanroom performance related

to air cleanliness by particle concentration


Change

Tables of frequency removed; guidance retained in text.

Annual classification required, and after modifications, or after monitoring deviation and rectification.

Annual classification is the default minimum monitoring required, but interval can be extended if automated monitoring system provides satisfactory data.

Monitoring should include: Air cleanliness

Pressure differential

Airflow velocity in UDF

Airflow volume in non-UDF.

Impact

This change will make it easier to use RISK BASED decision making about testing frequency.

Means if GMPs need to be specific, they can in the context of the ISO guidance.

e.g. In Pharma sector, US FDA’s 6 monthly leak testing of HEPA filters in the aseptic core.

Key change - ISO 14644-2:2015 Test Frequencies

30 ISPE 2016

Note:

The UK version of ISO 14644-2:2015 has an additional informative ‘National Annex’ to provide those relying more on periodic testing with some test frequency guidance.

August 2016

UK’s BS EN ISO 14644-2:2015

– National Annex


ISO 14644-2:2015 Essential principles

Normative requirements

The minimum requirement is to undertake annual

classification using ISO 14644-1:2015. Frequency

can be extended if a real-time monitoring system

is used.

Requires “Demonstration of control” by:

Having a documented approved monitoring plan.

Implementing the plan.

Recording and acting on the results of the monitoring.


ISO 14644-2:2015 Informative

Annexes

Guidance provided

Airborne particle monitoring systems.

Pressure differential monitoring systems.

Air velocity and volume monitoring systems.

Generally specifies matters to consider when

specifying and configuring such

systems.

Not prescriptive or limiting.


Conclusion

ISPE 2016 34

I hope you found this review of the main changes to ISO 14644-1&2:2015 useful.

Make sure you understand the important changes:

ISO Classes 1-9 will be defined by a table. The basic classes don’t change!

There will be changes to the details of undertaking cleanroom classification.

Look out for when regulators will expect you to change.

Trial the impact and plan implementation of the revised standards.

August 2016




[email protected]

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15thDecember2015MajorrevisionsofISO14644Parts1and2arefinallypublishedinDecember2015ByGordonFarquharson,ConvenorISOTC209wg1ISOstandardsarereviewedatfiveyearlyintervals.InthecaseofISO14644Parts1and2,whichwerefirstpublishedin1999and2000,thereviewswereinitiatedin2005inaccordancewithnormalpractice.ADIS(draftinternationalstandard)wasproducedforeachofthesePartsin2010andalthoughvotingwasinfavourofapprovingbothstandards,thereweresomanycommentsreceivedwiththevotingthatthoseresponsible(WG1ofISOTC209)decidedthatasecondDISenquiryandvotewasrequired.ThissecondDISvoteclosedinNovember2014witharesoundingpositivevotetoprogressthroughtheFDISstagetofinalpublication,whicheventuallytookplaceinDecember2015.ThechangesfromtheoriginalstandardsarecomprehensivelyexplainedintheIntroductionstothetwostandards,whicharereproducedbelow.Ihaveaddedasmallnumberofcommentswithfurtherexplanationsandtheseareinsquarebrackets.TheUKeditionofISO14644-2:2015,prefixedBSENISO,hasanimportantadditionalAnnexthatrecommendsspecificintervalsforcleanroomtests.TherationaleforthisadditionalAnnexisthattestingintervals,whichwereconsideredtobeausefulpartoftheoriginalstandard,havenotbeenincludedinthe2015revision.Itwasalsoanopportunitytoreviewandrevisethetestingintervalsandtoincludealltestsrelevanttocleanrooms,includingthosefromISO14644-3.AllthisisexplainedintheUKNationalForeword.TheAnnexisinformativeandnotnormativeandmightbeconsideredusefulguidanceoutsidetheUK.ItishoweveronlyavailablefromBSIintheUKedition,BSENISI14544-2:2015.Manyyearsofworkhavegoneintoabsorbingandreconcilingthestronglyheldviewsoftheexpertswithnumerousmeetingsindifferentpartsoftheworld.AsConvenorofWG1Iwouldliketoexpressmyprofoundthankstoalltheexpertswhocontributedwiththeirwell-arguedviewsanddiscussedthosepatientlyinthemeetingsuntilwefinallyarrivedatwhatweallbelievearereallyusefulrevisionsofthesetwostandardsthatareattheheartofcleanroomtechnology.GordonFarquharson,December2015ExtractsfromtheintroductionstothestandardsISO14644-1:2015Cleanroomsandassociatedcontrolledenvironments—Part1:ClassificationofaircleanlinessbyparticleconcentrationIntroductionCleanroomsandassociatedcontrolledenvironmentsprovideforthecontrolofcontaminationofairand,ifappropriate,surfaces,tolevelsappropriateforaccomplishingcontamination-sensitiveactivities.Contaminationcontrolcanbebeneficialforprotectionofproductorprocessintegrityinapplicationsinindustriessuchasaerospace,microelectronics,pharmaceuticals,medicaldevices,healthcareandfood.ThispartofISO14644specifiesclassesofaircleanlinessintermsofthenumberofparticlesexpressedasaconcentrationinairvolume.Italsospecifiesthestandardmethodoftestingtodeterminecleanlinessclass,includingselectionofsamplinglocations.

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ThiseditionistheresultofaresponsetoanISOSystematicReviewandincludeschangesinresponsetouserandexpertfeedbackvalidatedbyinternationalenquiry.Thetitlehasbeenrevisedto“Classificationofaircleanlinessbyparticleconcentration”tobeconsistentwithotherpartsofISO14644.ThenineISOcleanlinessclassesareretainedwithminorrevisions.Table1definestheparticleconcentrationatvariousparticlesizesforthenineintegerclasses.[ThisTableisnormativeandpredominantandsupersedestheformulathatwasnormativeinISO14644-1:2000].TableE.1definesthemaximumparticleconcentrationatvariousparticlesizesforintermediateclasses.Theuseofthesetablesensuresbetterdefinitionoftheappropriateparticle-sizerangesforthedifferentclasses.ThispartofISO14644retainsthemacroparticledescriptorconcept;however,considerationofnano-scaleparticles(formerlydefinedasultrafineparticles)willbeaddressedinaseparatestandard.[Table1differsfromthatinISO14644-1:2000inthatsomeofthesingledigitparticleconcentrationshavebeenremovedastestingforsuchlowconcentrationswasconsideredtobeimpracticalforreasonsthatareexplainedinthenotestothetable].Themostsignificantchangeistheadoptionofamoreconsistentstatisticalapproachtotheselectionandthenumberofsamplinglocations;andtheevaluationofthedatacollected.Thestatisticalmodelisbasedonadaptationofthehypergeometricsamplingmodeltechnique,wheresamplesaredrawnrandomlywithoutreplacementfromafinitepopulation.Thenewapproachallowseachlocationtobetreatedindependentlywithatleasta95%levelofconfidencethatatleast90%ofthecleanroomorcleanzoneareaswillcomplywiththemaximumparticleconcentrationlimitforthetargetclassofaircleanliness.Noassumptionsaremaderegardingthedistributionoftheactualparticlecountsovertheareaofthecleanroomorcleanzone;whileinISO14644-1:1999anunderlyingassumptionwasthattheparticlecountsfollowthesamenormaldistributionacrosstheroom,thisassumptionhasnowbeendiscardedtoallowthesamplingtobeusedinroomswheretheparticlecountsvaryinamorecomplexmanner.Intheprocessofrevisionithasbeenrecognizedthatthe95%UCLwasneitherappropriatenorwasappliedconsistentlyinISO14644-1:1999.Theminimumnumberofsamplinglocationsrequiredhasbeenchanged,comparedwithISO14644-1:1999.Areferencetable,TableA.1,isprovidedtodefinetheminimumnumberofsamplinglocationsrequiredbasedonapracticaladaptationofthesamplingmodeltechnique.Anassumptionismadethattheareaimmediatelysurroundingeachsamplinglocationhasahomogeneousparticleconcentration.Thecleanroomorcleanzoneareaisdividedupintoagridofsectionsofnearequalarea,whosenumberisequaltothenumberofsamplinglocationsderivedfromTableA.1.Asamplinglocationisplacedwithineachgridsection,soastoberepresentativeofthatgridsection.Itisassumedforpracticalpurposesthatthelocationsarechosenrepresentatively;a“representative”location(seeA.4.2)meansthatfeaturessuchascleanroomorcleanzonelayout,equipmentdispositionandairflowsystemsshouldbeconsideredwhenselectingsamplinglocations.Additionalsamplinglocationsmaybeaddedtotheminimumnumberofsamplinglocations.Finally,theannexeshavebeenreorderedtoimprovethelogicofthispartofISO14644andportionsofthecontentofcertainannexesconcerningtestingandtestinstrumentshavebeenincludedfromISO14644-3:2005.TherevisedversionofthispartofISO14644addressesthe≥5µmparticlelimitsforISOClass5inthesterileproductsannexesoftheEU,PIC/SandWHOGMPsbywayofanadaptationofthemacroparticleconcept.TherevisedversionofthispartofISO14644nowincludesallmattersrelatedtoclassificationofaircleanlinessbyparticleconcentration.TherevisedversionofISO14644-2:2015nowdealsexclusivelywiththemonitoringofaircleanlinessbyparticleconcentration.

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Cleanroomsmayalsobecharacterizedbyattributesinadditiontotheclassificationofaircleanlinessbyparticleconcentration.Otherattributes,suchasaircleanlinessintermsofchemicalconcentration,maybemonitoredandtheattribute’sgradeorlevelmaybedesignatedalongwiththeclassificationoftheISOClassofcleanliness.Theseadditionalattributesdonotsufficealonetoclassifyacleanroomorcleanzone.ISO14644-2:2015Cleanroomsandassociatedcontrolledenvironments—Part2:MonitoringtoprovideevidenceofcleanroomperformancerelatedtoaircleanlinessbyparticleconcentrationIntroductionThisrevisionofISO14644-2emphasizestheneedtoconsideramonitoringstrategyinadditiontotheinitialorperiodicexecutionoftheclassificationofacleanroomorcleanzoneinaccordancewithISO14644-1:2015,5.1.Themonitoringactivityprovidesacontinuingflowofdataovertime,therebyprovidingamoredetailedviewoftheperformanceoftheinstallation.Potentialbenefitsgainedfrommonitoringare—fasterresponsetoadverseeventsandconditions,—abilitytodeveloptrendsfromdataovertime,—integrationofdatafrommultipleinstruments,—enhancedknowledgeofinstallationandprocess,whichallowsformoreeffectiveriskassessment,and—improvedcontrolofoperationalcostsandproductlosses.ISO14644-2specifiestherequirementsofamonitoringplan,basedonriskassessmentoftheintendeduse.Thedataobtainedprovideevidenceofcleanroomorcleanzoneperformancerelatedtoaircleanlinessbyparticleconcentration.Insomecircumstances,relevantregulatoryagenciesmayimposesupplementarypolicies,requirementsorrestrictions.Insuchsituations,appropriateadaptationsofthemonitoringproceduresmayberequired.Afteramonitoringplanisinitiallyestablishedandimplemented,itmaybenecessarytorevisetheplanwhensignificantchangesaremadetotheinstallationorprocessrequirements.Itisalsoprudenttoconductperiodicreviewsofamonitoringplanbasedondataobtainedandexperienceinuse.Endofdocument

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Worked Example

ISO 14644-1 & 2:2015 Understanding and applying the changes

By Gordon Farquharson



August 2016


Agenda We’re going to look in more detail about the revised

classification process in ISO 14644-1:2015.

I’ll use a pharma life-sciences cleanroom example.

Run through the process.

Explain some of the reasons for the changes.

Number of sampling locations.

Positioning sampling locations.

Sample volume.

Taking the sample (what if there is a problem?).

Evaluating the data.


The example facility.

A Pharma cleanroom


Industrial Integrated Vial Line

ISPE 2016 4

We’ll focus on this room only

Vial washing room EU Grade C

ISO 7 (at rest)≥0.5 & 5.0

ISO 8 (operational) ≥0.5 & 5.0

Diffused non-UDF airflow

Filling room Room - EU Grade B

ISO 5;at rest; ≥0.5

& ISO M(29≥5.0); at rest; LSAPC

ISO 7;operational;≥0.5 & 5.0


Aseptic core areas – EU Grade A

ISO 5;at rest & operational;≥0.5

& ISO M(20≥ 5.0); at rest & operational; LSAPC

UDF

Capping room EU Grade D

ISO 8 (at rest)≥0.5 & 5.0

No operational limit


August 2016

The essential dimensions of the

facility


Number and position of

sampling locations


First – define the different

cleanliness zones

ISPE 2016 7

Grade B

Grade B

Grade A Transfer Grade A Fill

Grade

A

Holding

August 2016

8

ISO 14644-1:2015

Required minimum sampling locations

1. Determine the number of sample locations NL from table A1.

2. Divide the room/zone into NL equal areas.

3. Select representative sampling locations in each zone (not under undiffused HEPA filter terminals).

4. Take a sample at each location (sample size as existing standard).

5. Average at each location if multiple samples are taken.

6. If all measured particle concentrations (or averages) comply with the class limit, the classification is met.

7. For larger rooms >1000m2, extrapolate the location density from the 1000m2 requirement – equation A.1.

ISPE 2016

Area of cleanroom (m2) less than

or equal to

Minimum number of sample locations

to be tested (NL) 2 1 4 2 6 3 8 4 10 5 24 6 28 7 32 8 36 9 52 10 56 11 64 12 68 13 72 14 76 15

104 16 108 17 116 18 148 19 156 20 192 21 232 22 276 23 352 24 436 25 636 26 1000 27

> 1000 See Equation A.1

Table A.1 — Sample locations related to cleanroom area

August 2016

Number of sampling locations

Use the look-up table A.1.

Grade B room

Region #1 8 m2 4

Region #2 19.35 m2 6 (7)

Total 27.35 m2 7

Grade A areas

Filling zone 6 m23

Transfer zone 5 m23

Holding zone 2.65 m22

ISPE 2016 9

One needs to decide if to

consider separate zones

within the room

OR

The total area

August 2016

Second – Divide into equal sections

ISPE 2016 10

Section

Grade B

Section Grade

B

Grade

A Trans

Grade A

Fill

Grade A

Holding

Section

Grade B

Section

Grade B

Section

Grade B

Section Grade

B

Section

Grade B

Section

Grade B

Section

Grade B

Section

Grade B Section

Grade B

Grade

A Trans

Grade

A Trans Grade

A Fill

Grade

A Fill

August 2016

Placing sampling locations

Within each section, select a sampling location

considered to be representative of the characteristics of

the section.

Position the particle counter probe in the plane of the

work activity or another specified point.

Additional sections (and associated sampling locations)

may be added to facilitate subdivision.

For non-UDF cleanrooms, locations directly below un-

diffused HEPA filter air supplies may not be

representative of the room.


Third – Select a representative

sampling location in each area

ISPE 2016 12

Section

Grade B

Section Grade

B

Grade

A Trans

Grade A

Fill

Grade A

Holding

Section

Grade B

Section

Grade B

Section

Grade B

Section Grade

B

Section

Grade B

Section

Grade B

Area 1

Grade B

Section

Grade B Section

Grade B

Grade

A Trans

Grade

A Trans Grade

A Fill

Grade

A Fill

★ ★ ★ ★

★ ★

★

★ ★ ★

★

★

★ ★ ★ ★

★ ★ ★

August 2016

Influence of supply air distribution

and mixing


Particle size


Choosing particle size to consider

Your choice – outside regulated industry.

Regulated industry (our example):

Annex 1 EU GMP

Requires we consider ≥ 0.5 & 5.0 microns

US FDA 2004 Aseptic Processing guidance

Requires we consider ≥ 0.5 microns only


The classification table


The proposal is to use adapted macro-particle descriptor concept –

See Annex C7.

EU + PIC/S Annex 1 – 2 particle sizes

17 ISPE 2016

Class limit of 20 parts ≥

5.0 micron is also

outside scope of the

standard

Class limit of 29 parts ≥ 5.0

micron outside scope of

standard –

≥ 5.0 micron cannot be used

for an ISO5 classification

The GMP Grade table from Annex 1.

August 2016

Using the macro-particle descriptor for 5

micron particles in ISO 14644-1:2015

GMP should use the macro-particle concept for

Grade A 20 particles/m3 @ ≥ 5.0 micron

Grade B “at rest” 29 particles/m3 @ ≥ 5.0 micron

We use this terminology

ISO M (20;≥ 5.0); LSAPC

ISPE 2016 18

M =

Macroparticles

20 =

Class limit

from GMP

5.0 =

Considered

particle size

LSAPC = Light

scattering

airborne

particle counter

August 2016

This is how we would define Annex 1

Grade A & B using ISO 14644-1:2015 An extrapolation of the Macro-particle concept.

Grade A

ISO 5; at rest & operational; ≥ 0.5

ISO M(20≥ 5.0); at rest & operational; LSAPC

Grade B

ISO 5; at rest; ≥ 0.5, and ISO M(29≥ 5.0); at rest, LSAPC.

ISO 7; operational; ≥ 0.5 & 5.0 .


US FDA 2004 Aseptic Guide – 1

particle size

Clean Area

Classification

(0.5 um particles/ft3)

ISO

Designation

b

> 0.5 mm

particles/m3

Microbiological

Active Air Action

Levels (cfu/m3 )

c

Microbiological Settling

Plates Action Levels

(diam. 90mm; cfu/4

hours) c, d

100 5 3,520 1e 1e

1000 6 35,200 7 3

10,000 7 352,000 10 5

100,000 8 3,520,000 100 50

a. All classifications based on data measured in the vicinity of exposed materials/articles

during periods of activity.

b. ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in

multiple industries. An ISO 5 particle concentration is equal to Class 100 and

approximately equals EU Grade A.

c. Values represent recommended levels of environmental quality. You may find it

appropriate to establish alternate microbiological action levels due to the nature of the

operation or method of analysis.

d. The additional use of settling plates is optional.

e. Samples from Class 100 (ISO 5) environments should normally yield no microbiological

contaminants.


Sample volume determination


Sample volume calculation

No change from ISO 14644-1:1999

Based on counting at least 20 particles per sample if

you were at the class limit of the largest considered

particle size (this case ≥ 5.0 micron).

Formula A.2 defines this:

+ at least 2 litres

+ at least 1 minute

Remember particle counters can sample at different rates:

28.3 (=1 cfm), 40, 50 & 100 litre/min, so the sampling time

can vary.

In the following example I’ll choose 28.3 litre/min.


Sample volume Grade A

Grade A ‘At Rest’ & ‘Operational’

ISO 5; 3520 parts/m3 ≥ 0.5 5.68 litres

ISO M(20≥ 5.0); at rest & operational; LSAPC 1000

litres

Sample volume required at each sampling location

the most demanding from:

2 litres; 1 min = 28.3 litres; 5.68 litres; or 1000 litres.

If we only consider particles ≥ 0.5 micron, then sample

volume = 28.3 litres.


Sample volume Grade B ‘At Rest’

Grade B ‘At Rest’


ISO M(29≥ 5.0); at rest & operational; LSAPC 690

litres



2 litres; 1 min = 28.3 litres; 5.68 litres; or 690 litres.




Sample volume Grade B

‘Operational’

Grade B ‘Operational’





2 litres; 1 min = 28.3 litres; 5.68 litres; or 8.37 litres.




Summary of the testing


Summary Table of sampling

requirements


Undertaking the sampling


Sampling procedure Set up the particle counter as per manufacturer’s

instructions, including a zero count check.

Ensure normal conditions are established for the selected occupancy state.

Sample the required air volume as a minimus.

If an ‘out of spec’ result is attributed to an abnormal occurrence, the count can be discarded. The event must be recorded in the test report.

If an ‘out of spec’ result can be attributed to a technical system or equipment failure, then once rectified, the failed sampling location can be retested. The event must be recorded in the test report.


Example data


Evaluating the data


Evaluating the data in accordance with

ISO 14644-1:2015the new way

Consider the Grade A filling machine RABS.

3 sampling locations.

The evaluation of the 95% UCL is now not required.

We have different sample numbers at the different locations (3; 1; & 2 samples).

Ensure counts are converted to parts/m3

Calculate the mean at each location.

x is mean at each location: 1676; 1235; 1532 part/m3

Does each location comply?

That’s it……. PASS, YES or NO?


Conclusion

ISPE 2016 33

I hope you found this review of the classification process in ISO 14644-1:2015 useful.

The part most need to focus on is the identification and documentation of the rationale for selecting the sampling locations.

The evaluation of the data is simplified for 2-9 locations.

For most cleanrooms and clean air devices, there is more testing due the the need for some more locations.

August 2016


Contact:

Gordon Farquharson


[email protected]

1

Anticipated Revision of

Annex 1 of the EU & PIC/S

GMPs By Gordon Farquharson



August 2016

August 2016 ISPE 2016

Agenda Sources of information.

Remember the last revision in 2007!

What has changed since then?

Will it be different as a joint EMA + PIC/S exercise?

New material & subjects.

Some of the areas that need to be updated:

Correction or errors.

New cleanroom standards.

Maturation of technologies & practice.

Timeline…........

August 2016 ISPE 2016 2

Information sources

Comments submitted on the position paper dated

March 2015.

Comments submitted by ISPE, France A3P, CEN

TC243, UK PHSS.

Presentations by Andrew Hopkins – MHRA and

Rapporteur for the EMA/PICs joint revision process.

PHSS Annual meeting London September 2015.

ISPE Europe Annual Meeting Frankfurt March 2016.

Some personal observations


Annex 1 – Last revision Revision completed December 2007.

Into operation 1st March 2009 for most; and 1st March 2010 for the

vial capping changes.

Major changes were:

Alignment with EN ISO 14644-1:1999 (the old 5m issue); Media

simulation update; changes to bio-burden testing; and capping of vials.

Also failed to properly align with ISO 14644-1:1999, and introduced

some very poor wording.

This version was transferred into PIC/S; but, required a Q&A paper to

clarify various matters (e.g. “Grade A air supply”).

http://www.picscheme.org/publication.php?id=8

Now it’s time for another go !!!!


Annex 1 – The current revision

process

In 2012, the German (ZLG) presented a concept

statement on revision the the EMA IWG.

Work started February 2015.

Joint EMA & PIC/S process (first time).

Initial joint “concept paper” issued by EMA & PIC/S

dated 20th March 2015

(EMA/INS/GMP/735037/2014).

There was no substance about the revision in the

so called “concept paper”. August 2016 ISPE 2016 5

Annex 1 – Nature of the

issues/subjects identified so far….... Typographical errors.

Update to accommodate revisions to EN ISO 14644-1 & 2:2015/16.

Update to accommodate the PIC/S Annex 1 Q&A clarification document.

Deal with lack of clarity in some clauses.

Deal with the bad science (hopefully).

Fill gaps in information.

Update to recognize the maturing of some technologies & practices since 2007.

Some new areas – WFI & biofilms.

Deal with industry & regulatory concerns.


What do we know about the

contents and structure so far? Refresh the requirement of all GMPs….we need to keep up

to date whatever the GMP says!

Will only consider sterile products (no application of Annex 1 to non-sterile products).

The existing structure and sections will be retained. It will be a revision, NOT a re-write!

Will be better organised:

Have cleanliness classes and levels more clearly defined. Will better explain “Grade A air supply”.

Everything to do with environmental monitoring will be together; and improve the definition of the approach for lower grade areas (B, C & D).


Environmental monitoring Will all be in one place.

Essential part of QRM. Viable

Non-viable

Media process simulations Large scale & campaign or “tail-gate” simulations.

Small scale.

Essential to understand the risks process/product/facility

Levels and knowledge Setting levels

NO AVERAGING in the text !

Trending


Dealing with old issues

Averaging is not acceptable!


Averaging at a location over time isn’t ok!

When the limit for a micro level is <1, then we need to look at frequency of occurrence.

Today, microbiologists are of the opinion that our traditional micro methods aren’t sensitive enough to differentiate between 0 and 10 cfu.

Technical matters requiring better

description or new guidance

Ensure QRM approach is adequately addressed.

Focus on keeping operators away from the product; update approach to newer technologies Isolators & RABS.

Address the new EP Monograph for WFI and fill the GMP gaps….... ..........

New section on biofilms.

Address closed process systems:

Sterilise in place.

Integrity proving.

Small batch size issues – media process simulations.


Why some of the new guidance?

Bio-films:

These seem to be a high profile with some inspectors !

Where has this come from? Water systems?

Closed process systems?

Guidance on WFI:

EMA has major concerns about the new EP WFI Monograph allowing membrane technologies.

They think the GMP bio-contamination controls necessary for RO/UF to be acceptable are quite complex.

GJF suggests - Maybe there should be a separate Annex on Pharma Water systems…based on WHO guidance??


Biofilm Control (multiple points of attack)

Avoid

incubation

Temperature

conditions

Periodic

sanitisation

Chemicals or heat

Ensure

Smooth

surfaces

Limit

bug

source

Continuous flow

in pipe ~ 1.5 m/s

Apply UV light for

planktonics


Typo & unclear examples

So, what does

this mean?

0.45 +/- 20%,

or a range?

Where is the

working

position?

Not even in English!

Maybe it works in

Franglais??


Dealing with New standards –

EN ISO 14644-1:2015

(approved on the 15th December 2015)

These values will be clearly outside the revised EN ISO standard.

There is a rationale in the standard to extrapolate the use of the

Macro-particle descriptor (see Annex C7).

Good science would remove these levels.


The 5 micron problem It seems that EU Inspectors are still convinced that

monitoring ≥ 5.0 micron particles is a good indicator of deterioration in the performance of UDF clean air systems.

This is contentious !

Many scientists like Ljunqvist & Reinmuller, and Whyte & Eaton would challenge this !

It is possible that revised Annex 1 will remove the ≥ 5.0 micron limit from classification of Grade A & B, and retain it for real-time monitoring.

This would help the integration of the revised ISO 14644-1:2016 standard.


Maturing technology example –

Isolators & RABS 21. The utilization of isolator technology to minimize human interventions in processing

areas may result in a significant decrease in the risk of microbiological contamination of

aseptically manufactured products from the environment. There are many possible

designs of isolators and transfer devices. The isolator and the background environment

should be designed so that the required air quality for the respective zones can be

realised. Isolators are constructed of various materials more or less prone to puncture

and leakage. Transfer devices may vary from a single door to double door designs to

fully sealed systems incorporating sterilization mechanisms.

Today, we would see Isolators and RABS as essential

technology that should at least be considered.

Perhaps the revised Annex 1 should say?

“The utilisation of barrier technologies, RABS and

Isolators can improve the sterility assurance during open

aseptic processing, and should be considered when

selecting the environmental control solution.”


Maturing technology example – closed

& single use process systems

The evolution of closed systems, including

disposables/single-use, requires some improved

guidance because the risks are different:

CIP & SIP (clean-in-place; sterilise-in-place)

Integrity of aseptic connection devices.

Integrity of closed systems.


Confusion examples 51. Changing rooms should be designed as airlocks and used to provide

physical separation of the different stages of changing and so minimize

microbial and particulate contamination of protective clothing. They should be

flushed effectively with filtered air. The final stage of the changing room should

, in the at-rest state, be the same grade as the air into which it leads. The use

of separate changing rooms for entering and leaving clean areas is sometimes

desirable. In general hand washing facilities should be provided only in the first

stage of the changing rooms.

Is this clear to you? An

even greater problem in

many PIC/S nations in

Asia


How to proceed and help ensure we

have good regulatory guidance

Understand the impact of the PIC/S input.

Historically PIC/S has followed the EMA – is the relationship

changing?

Remember PIC/S has a January 2010 “Recommendation”

document (PI 032-2) to deal with many of the issues in the

current Annex 1 http://www.picscheme.org/publication.php?id=8 .

Our industry should identify where issues and new

requirements exist.

Look closely at the technical proposals, and make

constructive comments via standards bodies and industry

associations.


Anticipated timeline

Presented to PHSS by Andrew Hopkins (MHRA) in

September 2015 and updated to ISPE in March

2016 .

Working party develops a draft by end September 2015.

Complete documentation by end December 2015.

4 months editing.

Present to EU IWG and PIC/S by April 2016.

First public review 3rd Qtr 2016 possibly.





[email protected]

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Design of HVAC Systems in Hot

& Humid (Zone 4b) regions

Gordon Farquharson

August 2016

agenda

The outside air conditions we have to deal with

(Zone 4b).

Optimum configuration of air handling systems:

Outside air pre-treatment principles.

Configuration options.

Low RH applications


Air Handling Systems

The conditions we have to deal

with


The outside conditions

Hot (dry bulb 38 oC)

Humid (wet bulb 35 oC, % RH, moisture content)

Polluted with particles (dust, aerosols, biological

material)

Common problems:

Poorly sealed building – contaminated air gets in.

AHUs (air handling units) cannot deal with the moisture

load on cooling coils (flooding).

AHU filters block very quickly.


What are we talking about ?

Zone 4b conditions Summer

Bangkok

Summer

London

Inside

normal

factory

Inside

Low RH

factory

Understanding the basic

Psychrometrics


Understanding the basic

Psychrometrics


Optimum configuration of

systems


Central AHU Particles

Moisture

Cooling

Z

C

ZC = Zone control

Air volume & reheat

Z

C

Z

C

Z

C

Z

C

Z

C

Systems Configuration – Single

AHU

Zonal AHU Fine control Temp,

RH, Particles

Zonal AHU Fine control Temp,

RH, Particles

ZC

ZC = Zone control

H14 Terminal HEPA

Heater

F7 pre-filter

ZC ZC ZC ZC ZC

ZC

Systems Configuration – Separate

Outside Air treatment

The principles – separate outside

air pre-treatment


AHU - Outside air treatment

AHU – Recirc Department AHU – Recirc Department

Acknowledgement: Diagrams

adapted from ISPE HVAC GPG

Principles explained AHU – Outside air

Treats all the outside make-up air.

Quantity based on pressurisation, fresh-air need, make-up for exhaust, internal humidity control requirements.

Cools and dehumidifies.

Filters 99% of airborne particles (short pre-filter life)

Protects the department AHUs.

Much more thermally efficient than single AHU solutions.

AHU – Recirculation for department Treats all the air for the department.

Typical 80-90% recirculation.

Can include local exhaust for contaminated air streams.

Final filtration stages – cleanroom and cross-contamination control requirements.


Duplicate – separate outside air

pre-treatment


AHU - Outside air treatment 1

AHU – Recirc Department AHU – Recirc Department

AHU - Outside air treatment 2

Under extreme situations (highly contaminated outside air,

consider duplicate Outside Air AHUs – Allows live filter

maintenance without loss of air supply.

Acknowledgement: Diagrams adapted from ISPE

HVAC GPG

Cooling coil design is critical


AHU Cooling Coil - critical

Coil constructed from copper

tubes with bonded copper fins

If coil is subject to potentially

corrosive cleaning materials,

then consideration should be

given to protective coating &

‘Tinning’

With condensate collection tray

(stainless steel) to allow free

flow of condensate with water

seal trap

Special consideration for the

avoidance of moisture carry

over

A

ACCESS

DOOR

ACCESS

DOOR

AC

CE

SS

SE

CTIO

N

FI LL CAP

FALL

A

A IR MIX ING BOX

RETURN AIR

D.X . RE FRIGERANT

CHILLED WA TER

INLET

FRESH

A IR

AHU Cooling Coil - Condensate

Trapping

Material - Transparent glass is available

CLEAN OUT

FALL

CHARGE TRAPACCESS TO

DRAIN TRAY

MIN 50mm

MIN Pmm

+ 40mm

POSITIVE PRESSURE IN AHU

= + Pmm wg

CLEAN OUT

+ 40mm

MIN 0.5Pmm

MIN Pmm

= - Pmm wg

NEGATIVE PRESSURE IN AHU

DRAIN TRAY

FALL

CHARGE TRAPACCESS TO

+ 50mm

Example - Drains and Traps

Good Engineering

Practice

Glass traps can

be easily

inspected

Collect condense

from cooling coils

Provide traps from

drain pans

Ensure traps are

full at all times

Low %RH Applications


The need for low relative humidity,

and how to get there

Say typically 22 oC db, 20% RH.

Effervescent moisture sensitive product.

You cannot reach this low level of moisture content using cooling coils.

You need a desiccant adsorb the water from the air.

As the water is absorbed by the desiccant, heat is released.

To desorb the water, heat is needed to drive it out of the desiccant.


Two options – A liquid desiccant, and solid desiccant

loaded on a wheel for dehumidification

The return of liquid desiccant dehumidification &

improved desiccant wheels



Kathabar

http://www.kathabar

.com/

24

Desiccant Dehumidifier

Maximise pre-cooling

Consider heat recovery on

the regeneration cycle

Eliminate cross air stream

leakage

Prevent air flow without

regeneration as the material

could become saturated

Type of regeneration control

& heat source

Main design considerations

for a chemical de-humidifier






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Efficient Cleanroom HVAC Design

Non-Unidirectional Airflow systems

Gordon Farquharson

August 2016

agenda

Contamination control techniques

UDF

Non-UDF

Why is air-change rate a bad concept?

Effective non-UDF systems.

How much supply air is needed?

Impact on classification locations – ISO 14644-

1:2015


Basic contamination control

principles

Uni-directional

displacement of contaminants in air

Non-Unidirectional

dilution of contaminants in air

0,30-0.45 m/s

Air flow patterns


Recovery time vs Air changes per

hour Many still rely on a rule of thumb for air changes per

hour – the magic 20!

Annex 1 (PIC/s) does not, and uses recovery time.

WHY ? Because the effectiveness of non-UDF systems

relies upon:

Having enough clean supply air,

And achieving good mixing of the air in the room with the clean supply air.


The decay of small particles in a

non-UDF cleanroom

A classic asymptotic decay curve


0

50000

100000

150000

200000

250000

300000

350000

400000

0 50 100 150 200 250 300 350 400 450 500

Co

nce

ntr

atio

n (

/m3)

Time (s)

EU GMP Annex 1, Grade B Decay by 1/2 Life

In Op

ISO 7

350,000

At Rest

ISO 5

3,500

Time

175000

87500

43750

21875

10937

5468

2734

7# half-life

decays are

required to go

from ISO7--5

Part

icle

s/m

3 7 1/2-lives in

15 mins, needs

28 ac/hr


Non-UDF Air mixing

What really happens !


Whyte et Al showed us what

happens with poor air distribution


Whyte et Al showed us what

happens with poor air distribution

CFD used to compare the two configurations.

Both designs are poor, but

The left hand diagram shows more effective mixing and

a more even distribution of contamination/cleanliness.

The right hand diagram has a super-clean location

under the supply filter, and poor mixing of air in the

room. (there would also be comfort problems due to a severe

downdraught from the supply).


So how much supply air is

needed


How much supply air is needed ?

To satisfy Annex 1, we must do 2 calculations:

1. The steady state class limit – how much clean supply air do I need to dilute the source strength of contamination in the room?

2. The recovery time – How many air changes do I need to achieve my target recovery time?

Which is the greatest?

In a recent example, the following result was obtained for a PIC/S Grade B room:

Steady state supply air requirement 3.3 m3/sec = 40 ac/hr.

Recovery time: Assume 15 mins for 2 log reduction in particles; would require 18.4 ac/hr; and by applying a typical ventilation effectiveness allowance would require 27 ac/hr.

Therefore in this case the steady state winds.


How much supply air is needed ?

Remember that you also have to take into account

the following:

The amount of air required for cooling.

The air quantity to compensate for pressurisation.

Any air to compensate for exhaust air flows.


Placing sampling locations in

non-UDF cleanrooms


New ISO 14644-1:2015 has clear

requirements


Industrial Integrated Vial Line

ISPE 2016 15

We’ll focus on this room only

Vial washing room EU Grade C

ISO 7 (at rest)≥0.5 & 5.0

ISO 8 (operational) ≥0.5 & 5.0


Filling room Room - EU Grade B

ISO 5;at rest; ≥0.5

& ISO M(29≥5.0); at rest; LSAPC

ISO 7;operational;≥0.5 & 5.0


Aseptic core areas – EU Grade A

ISO 5;at rest & operational;≥0.5

& ISO M(20≥ 5.0); at rest & operational; LSAPC

UDF

Capping room EU Grade D

ISO 8 (at rest)≥0.5 & 5.0

No operational limit


August 2016

The simple plan of the facility


The sampling locations

ISPE 2016 17

Grade

A Trans

Grade A

Fill

Grade A

Holding

Grade

A Trans

Grade

A Trans Grade

A Fill

Grade

A Fill

★ ★ ★ ★

★ ★

★

★ ★ ★

★

★

★ ★ ★ ★

★ ★ ★

August 2016

Some sources of information


Ensuring the air supply rate to a cleanroom complies with

the EU GGMP and ISO 14644-3 recovery rate requirements

W Whyte1, N Lenegan2 and T Eaton3 1 School of Engineering, University of Glasgow, Glasgow G12 8QQ 2Energy and Carbon Reduction Solutions, Ashton-Under-Lyne, Lancashire, OL5

0RF 3AstraZeneca, Macclesfield, Cheshire, SK10 2NA




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Principles

Maintenance of GMP Systems

Gordon Farquharson

August 2016

agenda What is a GMP system?

Maintenance approvals & reviews

Planned Preventative Maintenance (PPM)

Emergency maintenance

Like-for-like replacement

Dealing with wear and tear

Performance information from C & Q work

Using technology


ISPE Maintenance GPG

Published in 2009.

Lots of risk based guidance.

Provides summary of GMP requirements, including guidance on:

Maintenance programme

Work Order management

Work completion

Emergency work.


Why maintenance is required

GMP Compliant Maintenance Programming

The Second Law of Thermodynamics tells us that

equipment wears out.

All things go from order to disorder.

The facility or equipment, including packaging and filling

equipment, that was validated last month is in a different

condition this month.

In order to maintain the validated state, regular

compensation for this "wearing out" must be applied via

Preventive Maintenance

A GMP System is…..... One that has been engineered within GEP.

One that has a direct impact on product quality.

One that has gone through all the Qualification protocols (coordinated with a planned commissioning programme).

One that is approved by QA (and supporting SMEs).

One that has a plan for reacting to performance deviations.

One where critical parameters are monitored.


Maintenance approvals & reviews

Maintenance plan approved by engineering & QA.

Maintenance personnel approved (in/out house).

Controlling a maintenance activity on a GMP System:

Initiation of task approved.

Work undertaken.

Work reported and approved (including spares use).

System approved for use again.

Periodic review of maintenance history – feedback may change frequency or scope.


Planned Preventative Maintenance

A routine task.

Defined procedure.

Mostly replacing consumables, cleaning, inspections.

Clear objective is the avoidance of unplanned interruptions.

Usually recommended by system vendor.

Approved spares list.

Competent operatives.

Reported task.

Periodic review.


Emergency Maintenance

Things go wrong!

Unplanned maintenance is High Risk for a GMP

system:

Emergency shut-down

Spares not available immediately

Desperate to get system UP

again


Like-for-like replacement

Minimises risk.

Reduces qualification requirement (provided that we

can show the system is working as previously

qualified).

Can be an equivalent part from an alternative

source.

Sadly, occasionally things go wrong


Granulation Room before the

explosion


Granulation Room after the

explosion


Centre of the explosion - Gearbox and

belt drive under granulator bowl


So what went wrong?

Solvent vapour in the technical zone under the

machine

Poor ventilation of zone

Wrong drive belts purchased and fitted by the firm

Right size,

Right rating,

Not Anti-static

NOT Like-for-Like !


Dealing with wear and tear All engineering equipment and systems deteriorate with

time.

PPM programmes should always have an element of observation for wear and tear.

Problems should be reported and addressed as soon as possible.

Examples of things to look for:

Drips and leaks.

Corrosion and wear.

More examples will be in the HVAC and Compressed air maintenance presentations.


Performance information from C&Q

In maintenance and testing programmes, it is very

important to use actual system performance

information rather than theoretical design

information.

This information comes from:

System commissioning tests and test reports.

Qualification (OQ & PQ) test results.

Integrated C&Q test results.


Using technology – Many opportunities

Computerised maintenance and calibration systems:

Database for listing items,

Scheduling,

Storing SOPs and maintenance instructions,

Storing reports,

Looking for trends.

Condition monitoring:

Real-time monitoring of critical performance attributes.

Predicting end of life or failures before they happen.

See examples in the HVAC and Compressed air presentations.


And finally in this general

section


Common maintenance challenges Equipment documentation is not readily accessible

It is essential that all the documentation for a piece of

equipment/system should be in the hands of the maintenance

team as part of the “hand-over” or “turn-over” to the customer.

This documentation includes:

The manufacturer’s operation manual

The manufacturer’s installation manual

The manufacturer’s service manual

Details of the Commissioning and Qualification state of the equipment,

e.g., settings used, and outputs achieved.

Any maintenance records

Any work instructions or procedures covering the use & maintenance of

the equipment

Engineering drawings

Process and instrument diagrams

Common maintenance challenges

Maintenance is not considered during equipment/system

design & purchase process

The maintenance department is often at the bottom of the list

when it comes to selecting new equipment.

The production engineers and product development scientists

base their selection purely on criteria such as output and ease

of cleaning.

The ease and impact of maintenance also need to be on the list.

Make maintenance information part of the project

delivery – use payment milestones to focus

attention!




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Maintenance of GMP HVAC

Systems

Gordon Farquharson

August 2016

Planned Maintenance is best!


Agenda – HVAC maintenance

Planned preventative maintenance (PPM)

Consumables

Condition - Wear and tear

Functional tests

Performance

Performance information from C & Q work

Using technology – automated condition monitoring


PPM –Consumables

Periodic – time based maintenance:

Air filter replacement

Fan belts – adjust tension or replace.

Coil face cleaning.


PPM – Wear & Tear

abc


PPM – Functional tests

Stroke actuated valves and dampers to ensure free

movement.

Test function of control

loops.


PPM – Performance

Critical functions

Air flow volume – non-UDF systems.

Air velocity – UDF systems.

HEPA filter leak test.

Classification of air cleanliness (ISO 14644-1:2015).

Cleanroom related tests.


PPM – Cleanroom Performance

testing guidance Guidance can be found in ISO 14644-2:2015; and

more in BS EN ISO 14644-2:2015



Predictive maintenance Condition monitoring – real-time measurement of a

condition to give early detection of failure or prediction of a normal end-point.

Example of normal end point – disposable filter life Measure Rate of ventilation filter fouling.

Look at rate of filter Dp increase;

Know max Dp;

Predict end-point; send alert messages.

Avoid excessive replacement.

Early Warning of failure Vibration detection.

Hot-spots in controls panels.

Leak detection.


Predictive techniques


Thermal imaging

Fixed or portable.

Continuous or periodic

Predictive techniques


Vibration monitors

Fixed.

Continuous monitoring.

Permanently mounted accelerometers

Avoid catastrophic failures

and finally…........


Finally – remember the

human side !

An

impossible

job leads to

poor quality

!!




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BUILDING AUTOMATION

SYSTEM BAS

CASE STUDY

By Dr. Anthony Margetts

Connecting Pharmaceutical Knowledge ispe.org

• Building Management System (BAS)

• Building Automation System (BAS)

− A BAS or BAS is a computer-based control system to

control and monitor mechanical and electrical

equipment such as ventilation, lighting, power, fire &

security systems.

• Facility Monitoring System (FMS)

− An FMS notifies and record any alarm conditions that

may arise during the course of production

BAS, BAS, FMS


Room Conditions • Temperature

• Humidity

• Room pressure

• Airflow

Utilities • Status

• Flow

• Pressure

• Temperature

Processing Rooms

& critical utilities

All areas and

Utilities

Utilities

Inputs Outputs

Monitoring report

for critical rooms

Includes critical alarms

Control of mechanical &

electrical equipment

Screen reports

for utilities

EMS

BAS

BAS & EMS


EMS - Trend Reports


“The alarm system that communicates, records, and

controls alarms such as air balance and temperatures

for production, warehouse and testing areas lacked

validation documentation”

“There is no written procedure in place for, nor is there

any testing performed, for the environmental monitoring

system…..”

Regulator - Observations


Warehouse


'When you open a Microsoft Excel 5.0 spread-sheet that

contains exponential formulas in Word 6.0 the formulas

are incorrect by a factor of 10’

Why We Validate?


BAS – Specify & verify

Configure Modules

Configuration

Testing

Functional

Testing

Requirements

Testing User Requirements

Specification

Functional

Specification

Configuration

Specification

Regulated

Company

Supplier

Prim

ary

R

esp

on

sib

ility

Supplier

QMS

Supplier knowledge and technical expertise

Verification Specification

Provided by the Supplier


New section!

• This section is new to Annex 15 and states that "the specification

for new facilities, systems or equipment should be defined in a

URS and/or a functional specification”

• This is a significant change as the current version of Annex 15

does not mention a specification phase.

• The URS should be written with quality elements in mind, as well

as minimizing GMP risks and "should be a point of reference

throughout the validation life cycle".

• URS is now a GMP requirement

The User Requirements

Specification (URS)


• The BAS provides the environmental controls &

monitoring of the Superclean Sterile Products

Manufacturing Facility

• This facility will be used to manufacture and package

sterile hospital infusion products

URS - Use


• The 10,000 m2 facility will consist of

• 20 clean rooms

• With controlled temperature, humidity and pressure

• Occupying 2000 m2 for manufacturing

• 5000 m2 for packaging

• 8000 m2 for warehouse

URS - Capacity


• Room Classification

• Room Temperature Ranges

• Room Humidity

• Room Pressurization Requirements

• Air Exchange Requirements

URS - Process Requirements


• Temperature

• Humidity

• Room pressure

• Airflow

• Air change rates

• For each measurement :

- Measurement Range: __°C to __°C ± __

- Setpoint Range: _____°C to ______°C

- Control Tolerance: ±_____°C

URS - Measurements


• Monitoring, alarming, point trending, point

adjustments, and overrides.

• Data shall be sampled and logged at frequencies from

____sec. to ______sec.

• Capable of system scheduling such as night setback,

morning warm-up, etc.

• The BAS shall be capable of allowing manual

operation

URS - Operation


• Alarm Log, recording when an alarm condition starts,

when the alarm is acknowledged, by whom the alarm

is acknowledged, and when the alarm condition is

removed.

• How to react to alarms, can product quality be

affected?

• “Informational Messages” shall notify the operator and

take no further action.

URS - Alarms & Warnings


• User interface access levels

• Frequency of data point collection

• Hardcopy/electronic data collection requirements

• Data retention time on the system

• Data storage media

• Security for data and operator access provided by

(User ID/Password, & Card Reader)

URS – Data security and Access


• Set point, alarm, trend changes and code changes.

• Changes to user-defined programs and associated

changes

• User identification, full name linked to the user

identification/password, old value replaced, new

value implemented, and date and time.

• Audit trail protected from changes

• Audit file backup, restoration

URS - Audit Trail


• Does the BAS control temperature, humidity, pressure?

• Does the BAS monitor temperature, humidity, pressure?

• Is there a separate FMS system ?

• Do the environmental parameters affect product quality?

• Does the BAS control airflow to classified air space?

• Are there alarms in system, how to react to alarms, can product quality be affected?

• Are electronic records from the BAS used for product release?

• Does the BAS control or monitor WFI or clean steam?

• If make a change do we need QA approval?

Important Questions for the BAS


Setting Alarms

Design

Target

Operating Range - Validated

Acceptance Criterion

Normal Operating Range

Alert* Point Alert Point

Source: ISPE Baseline® Guide for OSD Facilities

Alarm (Action) Point Alarm (Action) Point

Allowance

for

Instrument

Error


User Requirements Specification

Configure Modules

Configuration

Testing

Functional

Testing

Requirements

Testing User Requirements

Specification

Functional

Specification

Configuration

Specification

Regulated

Company

Supplier

Prim

ary

R

esp

on

sib

ility

Supplier

QMS



Provided by the Supplier

URS

•Definition of use of system BAS or FMS

•Definition of capacity

•Specification of process requirements

•Measurement

•Operation, normal, night, holiday

•Definition of mimics (screens)

• Definition of user access

•Definition of data security

•Definition of alarms and trips

•I/O Database, I/O schedule

•Definition of Hardware

•Application reports - configuration

specification

•Definition of loop diagrams. •Definition of critical parameters


• Definition of use of system, BAS or FMS • Definition of capacity • Specification of process requirements • Measurements • Definition of user access & data security • Definition of mimics (screens) • Definition of audit trail • Definition of alarms and trips • I/O Database • Definition of Hardware • Application reports - configuration specification • Definition of loops. • Definition of critical parameters and loops

BAS - URS


Integrate with Validation

Documentation (as appropriate)

SUPPLIER

Functional Specification

(Traceable to URS)

USER/(CONSULTANT if applicable)

Master Validation Plan User Audit of Supplier • User Initiates

Proposal

• Quality Plan • Project Plan

Equipment Validation Plan • Explanation to Supplier

(Living Document)

User Requirements Specification (URS)

(Living Document)

Proposal Analysis

Detailed Design

Documentation

(traceable to Functional Specification) Review Functional Specification

Review Detailed Design

System Acceptance Test

Specifications (IQ/OQ) • Hardware • Software

Review System

Acceptance Test Specifications

System Acceptance

Testing and Results

(User Witness Optional)

Maintenance & Support

Documentation

Approval

Approval

Approval

“BASELINE” EQUIPMENT ACQUISITION MODEL


Risk Assessment – When to assess

Risk?

Configure Modules

Configuration

Testing

Functional

Testing

Requirements

Testing

User Requirements

Specification

Functional

Specification

Configuration

Specification

Regulated

Company

Supplier

Prim

ary

R

esp

on

sib

ility

Supplier

QMS




BAS – Risk Assessment

Configure Modules

Configuration

Testing

Functional

Testing

Requirements

Testing

User Requirements

Specification

Functional

Specification

Configuration

Specification

Regulated

Company

Supplier

Prim

ary

R

esp

on

sib

ility

Supplier

QMS



Key Points: Risk Assessment

• use of system

• capacity

• process requirements

• measurement

• operation SOPs

• alarms

• user access

• data security

• audit trail

•Should be traceable to the URS.


BAS – Risk Assessment

Configure Modules

Configuration

Testing

Functional

Testing

Requirements

Testing

User Requirements

Specification

Functional

Specification

Configuration

Specification

Regulated

Company

Supplier

Prim

ary

R

esp

on

sib

ility

Supplier

QMS



Key Points: Risk Assessment & Design Reviews of :

• Definition of mimics (screens)

• Definition of alarms and trips

• I/O Database, I/O schedule

• Definition of Hardware

• Application specific configuration specification

• Definition of loop diagrams.

• Definition of critical loops and parameters

• Should be traceable to the URS.


BAS – Configuration Testing

Configure Modules

Configuration

Testing

Functional

Testing

Requirements

Testing

User Requirements

Specification

Functional

Specification

Configuration

Specification

Regulated

Company

Supplier

Prim

ary

R

esp

on

sib

ility

Supplier

QMS



Key Points:

Testing specifications should be traceable to

the configuration specifications/ associated

Design Specifications and URS.

Scope of testing activities influenced by the

Risk Assessment

• mimics (screens)

• security

• alarms and trips

• I/O database,

• hardware

• application specific configuration

• loops

• critical loops /critical parameters)


BAS – Testing

Configure Modules

Configuration

Testing

Functional

Testing

Requirements

Testing

User Requirements

Specification

Functional

Specification

Configuration

Specification

Regulated

Company

Supplier

Prim

ary

R

esp

on

sib

ility

Supplier

QMS



Key Points:

• Procedures for use of system (SOPs)

• Verification requirements

• Verification of Operation including alarms

• Verification of user access

• Verification of data security

• Change controls


• Formal, documented evidence that the system will consistently perform according to its predetermined design and performance specifications

All requirements have to be tested:

• Use of system

• Capacity

• Process requirements

• Measurements

• Operation

• Mimics (screens)

• User access & data security

• Audit trail

• Alarms and trips

• I/O Database,

• Hardware

• Application specific configuration

• Loop diagrams.

• Critical loops and parameters

All requirements have to be tested

Testing


• The following is a general checklist to ensure appropriate

test coverage of the installed system :-

• Power failure testing especially

− Prevention against loss of critical data or loss of control

action

− Ease of controlled restart.

• System access and security features.

• Audit trails and logging of critical actions including manual

interactions.

• Manual data entry features, input validation.

• Electronic signature features.

• Alarms and error messages

User Testing Activities (1)

Tony Margetts GAMP5


• Critical calculations.

• Critical parameters

• Transfer of critical data into other packages or

systems for further processing

• Backup and restore.

• Data archival and retrieval.

• Ability to deal with full plant operation

30

User Testing Activities (2)

Tony Margetts GAMP5


• Review and approve validation plan

• Approval of definition of critical parameters

− Concept of CPP and CQA ( eg. humidity – hardness)

• Review and approval of :-

− Critical acceptance criteria

− Correct operation – user testing

− Correct procedures and training

− Data handling (data storage and reports)

• Review and approve validation report

Role of QA

Tony Margetts GAMP5


• Equipment Qualification determines that the equipment is

suitable for its intended use ( this is sometimes called DQ,

IQ, OQ )

• Use risk assessment and /or design review to confirm that

all process requirements and critical aspects are specified

and included in acceptance criteria ( can be a called DQ)

• A checklist of critical aspects and their acceptance criteria

can be used to confirm all these aspects have been

checked based on supplier testing; completion and sign off

of these checklists can be the final verification report (this

can be called IQ/OQ )

Practical Verification


• Validation plan – specify what to validate

• Specification and verification documentation – use

the supplier as much as possible

• Risk assessment – how much validation

• Test results – does it work

• Change Control procedure

• Control of data (access, data security, audit trail)

• Maintenance procedures including backup

• Operating procedures and periodic review

• Validation report

Summary


• Validation

• Risk Management

• Personnel

• Suppliers

• Data

• Accuracy Checks

• Data Storage

• Printouts

• Audit trails

• Change Control

PICS Annex 11 : Data

• Periodic Evaluation

• Security

• Incident Management

• Electronic signature

• Batch release

• Business Continuity

• Archiving


WFI - New Ph Eur production specification.

- Choosing appropriate production technology

Gordon Farquharson August 2016

My agenda today

• Why this is an important debate.

• Pharmacopoeia updated position.

• The ‘basic’ options available today.

• EP and Annex 1 – the connection.

• Making the right choice - identification and

option selection.


Why is this an important debate?

In the old days before Risk and Science Based thinking was the

vogue, life was simple:

For WFI we most often chose ONE way-

Pharmacopoeias specified Distillation as the production method.

We usually chose final purification by Multi-effect still.

Generate WFI hot ~ 80 degC

Store hot.

Circulate hot.

Cool as required – in the process or by the water system.

Now it is more complex: WHY ?


Why more complex?

• General push for less prescription where possible.

• Technology develops and gives us more acceptable options.

• Risk & science based thinking in the GMPs allows us to make

choices.

• Energy and sustainability thinking is considered.

• Risk-based thinking is difficult – particularly in emerging markets.

In theory, we have freedom to identify options and risks and

make an informed choice. Are we all qualified to do this?

Technologies are improving fast (but often are more complex).

Knowledge of performance is improving – rapid OR real time

quality attribute testing – Conductivity, TOC, TVC, endotoxin.


Pharmacopoeias updated position.

The Pharmacopoeias for water for pharmaceutical use are

dominated by:

EP - European Pharmacopoeia

USP – US Pharmacopoeia

JP – Japanese Pharmacopoeia

Right now, the EP required that the final stage of

purification for WFI be distillation (will change in 2017).

USP requires distillation or a process of equivalent

capability (how to interpret this?).

JP allows distillation Distillation or RO + UF (Ultrafiltration)


Reverse Osmosis in the Ph.

Eur “Monograph for Water for

Injections”

Overview of the change


Pharmacopoeial monographs – Bulk

waters don’t change


Changes to the EP

Purification method for WFI

After much review and debate, the new

revision to the EP will allow Distillation or

certain membrane technology.

However it is very likely that there will be

additional GMP guidance in a revised Annex 1 of

the EU GMP (2016).

Note: Within the Pharmacopoeias, there is no differentiation

between Multi-effect or Vapour Compression distillation

processes.


Summary of the change in

position 2002-2015


EMA position about WFI in 2002

Decided that RO based systems were not as robust

as distillation.

Recommended to EP Commission that monograph

remain with distillation for WFI.

Recommended to EP that monograph remain with

membrane technology being allowed for HPW

(highly purified water).


Reasons for EMA position in 2002

Reviewed evidence and found:

RO & associated technologies lacked robustness of

distillation.

Most successful systems seemed to use a combination RO,

UF and Ozone/Heat sanitisation with an effective

management control.

Membrane fouling was a risk (scaling & microbial).

Membrane integrity failure was a risk.

Lack of effective validation and monitoring of the membrane

process.

Hence NO change recommended. August 2016 ISPE 2016 11

EP thinks again in 2015

EP prepares a paper proposing a revision of the EP based on a European Pharmaceutical Commission endorsement in June 2013.

Based on the EDQM, EMA Inspectors Working Party investigations undertaken in 2010.

It notes that membrane methods are not RO alone. Most systems include:

RO + CEDI + UF + microbiological controls using Ozone and thermal sanitisation techniques.

Reference was also made to the micro-electronics industry:

Here it was found that systems were:

Bigger

More consistently and heavily used – better water turn-over.

Low lower conductivity and TOC limits than WFI seemed to be more bacteria static.


EP reaches a conclusion in 2015 The production part of the monograph will change.

The specifications for the quality attributes (CQA) of WFI will NOT change.

Purification method will include options RO or Distillation based.

Users will be reminded that a successful system requires:

That the manufacturer (the Pharma Co) is responsible for consistent production of

water of the quality prescribed.

Some additional GMP Guidance will be required. Not part of the Ph Eur

monograph.

GMP requires that the Pharma Co be responsible for:

Design

Operation

Maintenance

Qualification

Validation

Monitoring

As a consequence when implemented, HPW will disappear.


Reverse Osmosis in the Ph.

Eur “Monograph for Water for

Injections”

Some more detailed notes of the

review and revision process


Ph Eur sources and acknowledgements

Dr Susanne KEITEL, Director

European Directorate for the Quality of Medicines & HealthCare

Council of Europe

EDQM colleagues:

Emmanuelle Charton

Thomas Hecker

Mihaela Buda

Dr Ged Lee, Chair of the Ph. Eur. WAT Working Party

All specialists of the Ph. Eur. WAT Working Party


Note: The European Directorate

for the Quality of Medicines &

HealthCare (EDQM) is a

directorate of the Council of

Europe that traces its origins and

statutes to an international treaty

enabling an international

cooperation for the elaboration of a

common pharmacopoeia.

3 waters in the old Ph Eur WAT

Monographs

Water,purified (Ph.Eur.0008)

PW

WaterforInjections (Ph.Eur.0169)

WFI

Water,highlypurified (Ph.Eur.1927)

HPW

DEFINITION

for preparation of

Medicines other than those that are required to be both sterile and apyrogenic, unless otherwise justified and authorised

for preparation of

Medicines for parenteral administration (bulk WFI) and for dissolving or diluting substances

intended for use where

Water of high biological quality is needed, except where WFI is required

DrKeitel ©2016 EDQM, Council of Europe. All rights reserved.


WFI history in Ph Eur

1969

Ist Ed. Purified Water

Physico/chem tests

1973

WFI introduced

Distillation only

1983

2nd Ed. WFI changes

Distillation only

1997

3rd Ed. WFI changes

LAL introduced

1999

Monitoring changes

initiated

2000

3rd Ed. Rev to production section

(TOC, Conductivity, Bioburden)

2002

4th Ed. HPW added, no

change to WFI

CHMP/CVMP – Guidance

on quality of water for

pharma use adopted.

2008

Regulatory event. RO used for WFI

production for Vet product

2008

Reflection paper on WFI by RO.

Regulatory concerns expressed about

biofilm and microbial safety

2009

135th Session of the Ph Eur Commission.

Ph Eur requested to take lead on changing the

WFI monograph

2016

New production WFI

monograph published

2017

New production WFI

monograph published


Ph Eur WFI Action 1: 2010

RO Technology survey Objective To gather data and information to support responses.

Specific questions about the system, maintenance, biofilm, membrane efficiency.

Many companies reported favourably: RO not sufficient alone – RO part of purification pathway coupling

several purification modules/steps.

Additional microbial treatment includes UV light, heat and ozone.

System design features to help avoid biofilm.

Regular sanitisation regime needed (heat/chemicals).

Systems used – great diversity Degasser, softening, ultrafiltration.

Filtration – softener – RO – EDI – UF.

Softener – microfiltration - - 3 x RO.

Double pass RO. August 2016 ISPE 2016 22


EDQM expert workshop Objective

Is there sufficient data to re-open the NON-distillation debate?

Review the need for a new WFI monograph.

Provide discussion platform for industry and regulators.

Identify the implications for the monographs and general chapters.

Experience from pharma companies. Critical parameters for microbial control:

Adherent bio-film a big risk. Essential to consider roughness, flow rates, dead-legs, and the evolution of membrane technologies.

Feed-water quality (avoid surface water sources).

Evolution of membranes, specifically those tolerant to thermal sanitisation.

Sanitisation strategies (thermal and chemical).

Close monitoring of membrane ageing.

Position of the PH Eur Commission.

Progress in the development of water purification technology has to be considered.

Issue a mandate to the Ph Eur water w/p to review WFI Monograph (0169), including the need for additional on-line monitoring.



Reflection paper from Ph Eur WAT WP

Summarised the current status of alternative production techniques, based on

scientific and technical evidence.

Reviewed all the evidence supporting a revision to the WFI monograph.

Also refers to the USP and JP.

USP “- distillation or a purification process proven to be equal to or superior to

distillation.”

JP allows distillation OR RO followed by UF.

Recognises the microbial concerns…...

But concludes not neccessarily an issue provided control mechanisms are in

place.

Properly operated membrane systems, initial water pre-treatment, disigns to

minimise bio-film, continuous in-process control, and increased use of rapid

microbial enumerationand identification techniques.



Decision in June 2013 At 146th Session of the European Pharmacopoeia Commission

Endorses the Reflection Paper on WFI.

Agreement to work on revision of the WFI production Monograph

(0169).

Acknowledgement that design, failure mode, and maintenance of

water systems are critical to ensuring appropriate quality of water

is consistently produced.

AND

That is is necessary for the GMP & GDP Inspectors Working

group (EMA) and the CHMP/CVMP Quality working group to

jointly agree roles and responsibilities in ensuring satisfactory

water system performance. (need for GMP guidance)


Ph Eur Action 5: 2016

The new WFI Monograph (0169) Revised 0169 was adopted during the 154th meeting of Ph Eur

Commission on 15-16th March 2016.

Will be published in Ph Eur supplement 9.1, and will become

effective in April 2017.

Allows Reverse Osmosis linked with other purification techniques:

Expectation that the membrane based approach will be equal or

better than distillation.

Not just water quality, but also robustness of the system.

The supervisory authority must be informed before

implementation.

GMP guidance will be included in the new Annex 1 of the EU

GMP (currently in revision August 2016).


The new WFI Monograph (0169)

Water for injections in bulk

PRODUCTION

Water for injections in bulk is obtained from water that complies with the regulations on

water intended for human consumption laid down by the competent authority or from

purified water.

It is produced either:

- by distillation in an apparatus of which the parts in contact with the water are of

neutral glass, quartz or a suitable metal and which is fitted with an effective device

to prevent the entrainment of droplets; the first portion of the distillate obtained

when the apparatus begins to function is discarded and the distillate is collected; or

- by reverse osmosis, which may be single-pass or double-pass, coupled with other

suitable techniques such as deionisation and/or ultrafiltration.

Correct operation monitoring and maintenance of the system are essential.

In order to ensure the appropriate quality of the water, validated procedures, in-process

monitoring of the electrical conductivity, and regular total organic carbon and microbial

monitoring are applied. August 2016 ISPE 2016 27

EP and Annex 1 – the connection.

There is now likely to be a stronger link between the EP

and the GMP (EU GMP Annex 1):

When the EP permits WFI by membrane (RO+UF), the

GMP Annex 1 will reinforce that a successful system will

require effective control of the process, including:

QRM principles.

Microbial control, with a strong focus on bio-film risk.

Full use of quality attribute testing.

Effective monitoring of physical process parameters

such as flow, pressure, temperature, etc


So now we can see the available

WFI production options in Ph Eur

from April 2017

Note:

Now means better alignment with the USP & JP

Distillation is still the reference or bench-mark!

WFI - So what is IN and OUT?

RO + EDI

Multi-effect

Vapour compression


Possible options available - WFI

Make it Store it Circulate it Use it

ME Distillation

80 degC

80 degC 80 degC 80 degC

(cool at use)

VC Distillation

70 degC

20 degC

+Micro control

periodic thermal

sanitisation

Or

80 degC

20 degC

Micro control

periodic thermal

sanitisation

Or

80 degC

20 degC

Or

80 degC

RO + DI + UF

20 degC

Micro control

periodic thermal

sanitisation

20 degC

Micro control

periodic thermal

or Ozone

sanitisation

20 degC

Micro control

periodic thermal

or Ozone

sanitisation

20 degC


Skid Mounted HPV & WFI Water Generator

Typical unit purification steps (all capable of thermal sanitisation): Softening.

Chlorine removal.

Reverse osmosis.

Continuous Electro-deionisation.

Ultra-filtration


Remember the distillation

options


Multiple Effect Distillation

FEEDWATER

IN

BLOWDOWN

OUT

CONDENSATE

OUT

DISTILLATE

PUMP

STEAM

IN 6-8 barG

EVAPORATOR

DEMISTER

VENT OUT

COOLING WATER

OUT

COOLING WATER

IN

DISTILLATE

OUT

150 C

EFFECT

1

EFFECT

2

EFFECT

3 CONDENSER

120 C 115 C

110 C

0.7 bar


Vapour Compression Distillation


Vapour Compression Distillation

DISTILLATE

COOLER

FEEDWATER

IN

BLOWDOWN

OUT

CONDENSATE

OUT

STEAM

IN

DISTILLATE

OUT

BLOWDOWN

COOLER

DECARBONATOR

COMPRESSOR

EVAPORATOR DISTILLATE

PUMP

RECIRC

PUMP

FEED

HEATER

VENT OUT

DEMISTER


Distillation Options

Some Specific Differences

Feed water needs to be close to purified water

Cooling water is required

Separate condenser is used

No compressor required

Distillate and blowdown pumps usually not required

Plant steam @ 6-8 barg

Electrical requirements are minimal

ASME coded pressure vessels

Feed water deionised

No cooling water required

No separate condenser

Compressor is required

Distillate and blowdown pumps are required

Plant steam at 2.4-3.1 barg

More electrical requirements for compressor

drive

Not a ASME coded vessel

Multi-Effect Vapor Compression


Biofilm and the microbial

contamination risk

The main scope of the WFI GMP

Guidance in revised Annex 1


The likely scope of WFI GMP

Guidance in Annex 1

We know from the EP Commission discussions that EMA inspectors want some additional controls over and above the revised EP Monograph 0169.

The additional requirements are: Must advised the regulatory authority of the intention to use

WFI by membrane technology.

Comply with the GMP guidance (to be found in revised Annex 1).

The GMP guidance will focus on the risks associated with biofilms, and identify the principles of control measures that should be considered. Will not be prescriptive about the detail.


Biofilm Formation

Mark Wiencek, Rohm & Haas Company, Spring House, PA 19477


Biofilms Can Shed In Water

Flow


Biofilm Control (multiple points of attack)

Avoid

incubation

Temperature

conditions

Periodic

sanitisation

Chemicals or heat

Ensure

Smooth

surfaces

Limit

bug

source

Continuous flow

in pipe ~ 1.5 m/s

Apply UV light for

planktonics


WFI System - Typical

“Thermal sanitisation example” • Applies to:

• 1. The RO membrane based purification system components.

• 2. The storage tank and distribution loop system

• Assume ambient temperature storage and circulation of water (at 15-20 oC ideally).

• Typical sanitisation cycles:

• 1. Purification • weekly 3 monthly; heat to 70 oC; hold 1 hr; cool to operating temperature.

• Usually a 2-3 hr total cycle time.

• 2. Storage & distribution • Monthly 3 monthly; heat to 75-80 oC; hold 2 hrs; cool to operating temperature.

• Usually a 5-6 hr total cycle time.

• Note:

• a) Actual cycle times and frequencies are specific for particular systems, in specific

situations.

• B) Energy saving measures cab be added e.g. water volume reduction before loop

sanitisation cycle.


WFI System - Typical

“Ozone sanitisation example” • Applies to:

• 1. The storage tank and distribution loop system only.

• Note: The RO membrane based purification system components can only be thermally sanitised.

• Assume ambient temperature storage and circulation of water (at 15-20 oC ideally).

• 2 Ozone use options:

• Full time ozonised tank, intermittent ozonised loop.

• Sanitise loop when no demand, kill ozone (high intensity UV) when

water is used.

• Intermittent ozonised tank & loop.

• Periodic validated cycle daily monthly.


Real-time on-line water quality

• Today we monitor our systems on-line for

TOC

Conductivity

Temperature, Flow & pressure

• For microbiological purity we still have to rely on Grab-

sample testing, and wait 5 days !

• For endotoxin testing we rely on off-line testing.

• Therefore, we alert and alarm deviations immediately for

some CQAs and after a delay for others.

• New Annex 1 may recommend the use of On-line

microbial monitor for membrane WFI systems.


Rapid micro methods for water

• In 2014, the first systems hit the market.

• Often called instantaneous microbiological detectors (IMD) or light induced

fluorescence (LIF). LIF is a spectroscopic technique capable of high

sensitivity in the detection of compounds that fluoresce.

• ‘On-line’ systems Give immediate results, and automatically collect samples

for identification (traditional methods).

• Very similar to the techniques used for IMD in air.

• Fluorescence is the luminescence that

occurs with the absorption of radiation at

one wavelength followed by the emission

of radiation at a different wavelength.

• Substances that typically fluoresce may

be referred to as fluorophores.


Making the decision about

system selection.

Choosing the best option for

you.


Risk & Opportunities – Choosing the

best option • Some use of risk and option assessment.

• The application:

WFI for a parenteral dosage form formulation will be considered more

critical than WFI for a biotech buffer, media, or elluent.

• Many judgements qualitative:

USP equivalent or better purification capability

Reliability (some data (& confidence) from semi-conductor industry)

QA and Regulatory confidence/risk. Regulators and B2B.

Qualification burden

• Some quantitative

Capital cost

Running cost – energy & maintenance

Carbon liberation August 2016 ISPE 2016 48

Some aspects to consider • Ability to deliver water to the required quality specification.

• Ph Eur and GMP compliance.

• Reliability & robustness of system.

Not just the purification….....

Includes purification, storage and distribution.

• QC cost....

Testing.

Likely frequency and cost of deviations.

• Capital cost.

• Running cost.

• Availability of utilities.

• Technical support of equipment and utilities.

• Regulatory & partner firm approvals.


Assessment techniques Brainstorm aspects to consider

Suggest Ishikawa (fishbone) diagrams.

Aspects to

consider when

choosing an

appropriate WFI

system

Meet WFI spec

Capital cost


Ishikawa example

Aspects to

consider when

choosing an

appropriate

WFI system

Meet WFI spec

Capital cost Energy running

cost

Purification

reliability

Failure

detection

Spares supply

Storage &

distribution micro

reliability

Maintenance

intervals

Regulatory

issues

Pre-treatment

criticality


Kepner Traego analysis - A scoring

approach to choosing best option Example

considerations

Multi-effect

distillation

Membrane Vapour

compression

distillation

Capital cost

Running cost

Purification

reliability

Pre-treatment

criticality

Ability to meet

water spec

Micro control in

purification

Micro control in

storage and

distribution

Total August 2016 ISPE 2016 52

Filling in the scores Example

considerations

Multi-effect

distillation

Membrane Vapour

compression

distillation

Capital cost 1 3 2

Running cost 1 3 2

Purification

reliability

3 1 2

Pre-treatment

criticality

1 2 3

Ability to meet

water spec

3 3 3

Micro control in

purification

3 1 3

Micro control in

storage and

distribution

3 2 2

Total 15 15 17


Some references Advances in vapor compression technology for the production of

USP WFI. Gsell, Nunez, and Smith-Palmer. ISPE Pharmaceutical Engineering March/April 2013,

Vol 33, N0 2.

Methods of producing WFI. Brush and Zoccolante. ISPE Pharmaceutical

Engineering July/August 2009, Vol 29, No 4.

Water systems utilizing mutiple effect and vapor compression

technologies compared. George Gsell. ISPE Pharmaceutical Engineering March/April 2004,

Vol 24, No 2.

EMEA (now EMA): Note for guidance on quality of water for

pharmaceutical use. CPMP/QWP/158/01 & EMEA/CVMP/115/01; London May 2002.

Reliability study for membrane processed WFI. Kojima, Okada, Sasaki, Oba,

Fujise, Kusuyama. PDA Journal of GMP & Validation in Japan Vol 13, No 2; 2011.

Background document for revision of monograph Water for injections

(0169), based on the Reflection Paper endorsed by the European Pharmacopoeia Commission at its

146th Session, June 2013.





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Compressed air

Specification, systems, and

testing

Gordon Farquharson

August 2016

Piped Gases for Pharma

applications This presentation focuses on compressed air

The ISPE ”Good Practice Guide” is helpful!

The special issues of a gas

system

Rather like water systems

When a direct impact on product quality – in contact

with the products, container/closure system, or product

contact surfaces:

› We don’t test and release it in batches like other

materials.

› We need to be certain of the following:

‘Every time we open the valve, we need to be

assured that the Quality is correct!’


Designer - Planning a Gas

System 1

• Establish the required quality of the direct impact gas

2

• Identify the point of use/s of gas system and supply rates. Provide analysis of the potential gas generating/storage equipment to match demand.

3 • Establish the supply rates and provide analysis of the potential

gas generation/storage/distribution equipment to match demand.

4 • Review future system flexibility requirements

5 • Identify potential locations of generation and distribution

equipment and utility requirements

6 • Evaluate distribution routing options

7 • Establish the requirements for installation, commissioning and

validation


Compressed Air


Compressed air is an important service which is used in the majority of

pharmaceutical manufacturing facilities

The design of the compressed air system needs to be appropriate

for its application

cGMPs are silent about specific quality requirements

The key issues are outlined in this presentation

Water & oil in compressed air present the greatest risks to

product.


Uses for Compressed Air in

Pharmaceutical Manufacture

Motive air for machines

Breathing air

Product Direct Impact - “GMP” air

Process air

Analytical air


Specifications and Standards

There are no GMP requirements stated for air

quality.

Must avoid any unacceptable

product contamination.

An important ISO Standard exists

• ISO 8573, parts 1-7, under the general title “Compressed Air”


ISO 8573 - Compressed Air

• Contaminants and Quality Classes ISO 8573-1:2010

• Test methods for Aerosol Oil Content ISO 8573-2:2007

• Test methods for Measurement of Humidity ISO 8573-3:1999

• Test methods for Solid Particle Content ISO 8573-4:2001

• Test methods for Oil Vapour and Organic Solvent Content ISO 8573-5:2001

• Test methods for Gaseous Contaminant Content ISO 8573-6:2003

• Test methods for Viable Microbiological Contaminant Content ISO 8573-7:2013


Source Quality Compressed Air Be aware a standard exists.

Quality

Class

PARTICULATE

Max number of particles per m3

WATER

Pressure Dewpoint

OIL &

OIL VAPOR

0.1-0.5

micron

0.5-1.0

micron

1.0-5.0

micron °F °C mg/m3

0 As specified by the user or equipment manufacturer and more stringent than class 1.

1 100 1 0 -100 -70 0.01

2 100000 1000 10 -40 -40 0.1

3 - 10000 500 -4 -20 1

4 - - 1000 37.4 3 5

5 - - 20000 44.6 7 -

6 - - - 50 10 -

ISO 8573-1: 2010 Air Quality Classes


Compressors - Points to

Consider Source air contamination

Compressors are noisy

Compressors require regular maintenance

Compression process creates heat

Security of the compressed air supply - back-up

Lubricated or oil-free compressors are the basic options available

Need to dry the air to prevent condensation

Need to prevent contamination

• Supply/Source

• Distribution


Typical Compressed Air System

Air Source

Screen/Silencer

Compressor Compressor

Re

ce

ive

r/

Kn

ocko

ut

Pot

Y

Dryer Dryer

Vent

Prefilter Re

ce

ive

r(s)

Receiv

er

Filter(s)

Aftercooler

‘GMP’ User

Point of Use Filter

HP Ring Main

User ?


Typical Compressed Air

System

Typical materials of construction:

Pipework

• galvanised carbon steel

• copper

• high density polyethylene

• thin walled stainless steel

Receivers

• galvanised carbon steel

• carbon steel


Removal of Contaminants

Solids

Cyclones

Filtration

Water

Vapours

Condensation followed by separation

Sorption (absorption or

adsorption)

Oil

Gases

Adsorption


Use of Filtration

• Filter for each critical application

• Filter for each ‘Clean’ sub-loop or branch

• 0.22 µm absolute filter – Test by water intrusion method.

• Pre-filtration may be required ?

• Point of use filter in SS and all pipework downstream is SS


Distribution & use of

Compressed Air

Piping materials

Galvanised mild steel.

Primary distribution

(particle shedding

risk).

Stainless steel

compression fittings.

Primary distribution.

Final distribution after final filtration & regulation.

Plastics.

Primary distribution.

High Density Polyethylene

Orbitally welded

stainless steel.

Final distribution after final filtration

& regulation.

When fittings are undesirable

externally.

Where pipework is sterilised.


HDPE Plastic

Socket fusion ISPE 2016 18 August 2016

Butt fusion Electro-fusion

HDPE Plastic


Double Ferrule Compression

Fittings


Orbitally welded 316L SS

Unacceptable weld taken from an operating pharmaceutical plant.

This weld has defects which include lack-of- penetration, misalignment,

a huge crevice, and discoloration due to poor internal gas purge. This weld

would is clearly unacceptable.

Orbital weld on 316L electropolished stainless steel. Full penetration with a

uniform crevice-free inner weld bead with good alignment. The internal was purged with argon. This

weld would be acceptable.


Quality Instrumentation

Dewpoint monitor -100° to +20°C dewpoint in compressed air and other gas streams.

Digital display

Pressure compensated readout

Multiple engineering unit display

Alarm relays and scalable 4-20 mA output

Calibration traceability


Distribution system design

The distribution system is the link between supply, storage, and demand.

The distribution system will allow the required air to flow with minimum pressure drop. The pressure drop should never exceed 0.05 – 0.15 bar (1-2 psi).

To reduce pressure drop effectively, a loop system with two-way flow can be used.

Alternative distribution configurations can be used satisfactorily.


Grid Layout

A typical grid-system layout using a centrally located air compressor.

Air from the receiver goes to a large header pipe that runs down the centre of the plant or department.

Branch lines from the header go to separate areas where working drops come down to specific machines.

This is a very flexible arrangement for making future additions.


Loop – Ring Main

Typical loop piping system.

The compressor and receiver are at a central location.

The oversized loop around the periphery of the plant or department adds storage and allows flow with low pressure drop.

It also allows for short bursts of high-volume flow to any section because flow in the loop is bi-directional.

(Another way to get short high-volume flows with any of these piping systems is to install extra receiver tanks at or near areas that need such flow)


Maintenance - Leakage

Preventive maintenance is essential.

Leaks are one of the biggest maintenance

issues and can be very expensive. For example, one 6mm dia opening will waste 2.8 m3/min at 6 bar.

This is equivalent to running an 18 kW

compressor. Also, it places additional stress on the

the compressors.


Finally - System Qualification

ISPE Commissioning & Qualification Baseline® Guide should be applied.

Risk based.

The purpose is to differentiate the product quality critical aspects of the system.

Identify Direct Impact System or Parts of System

• GEP applies to everything (GEP applies to safety of pressurised systems).

• Qualification to the direct impact parts.

• Direct impact system has critical and non-critical components.


System Boundaries for Qualification

Control & monitor Air Input

Quality here

Air Source

Screen/Silencer

Compressor Compressor

Re

ce

ive

r/

Kn

ocko

ut

Pot

Y

Dryer Dryer

Vent

Prefilter Re

ce

ive

r(s)

Receiv

er

Filter(s)

Aftercooler

‘GMP’ User

Point of Use Filter

HP Ring Main

User ?



And finally – testing and

monitoring


Oil test methods

The presence of oil contaminants can be

established by the test method specified in ISO

8573-2:2013.

Volumetric/gravimetric method using a coalescing filter.

Draeger tube systems. https://www.youtube.com/watch?v=gqTs_csxBPE


Moisture test method

The presence of moisture contaminants can be


8573-3:1999.

Dewpoint meters:

Built in.

Hand held portable


Particle test method

The presence of particle contaminants can be


8573-4:2001.

Airborne particle counter (LSAPC).

Filter collection and microscopic counting.


Oil vapour & Organic solvent test

The presence of oil vapour & organic solvent

contaminants can be established by the test method

specified in ISO 8573-5:2001.

Draeger type tubes for oil vapour.

Gas chromatograph

is the reference test

method.


Gaseous content test

The presence of gaseous contaminants can be


8573-5:2001.

Gas chromatograph is the reference test method.


Microbial Testing Methods

The presence of microbiological contaminants can be established by

the test method specified in ISO 8573-7:2013.

Impaction to Agar method

Example - Pinnochio sampler - Video

https://www.youtube.com/watch?v=WX2vnywqhBg





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“Update on HVAC and Critical

Utilities for Pharma”

Gordon Farquharson

August 2016




[email protected]

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Update on and Critical Utilities for Pharmaceutical Industry … · 2016-09-02 · Maintenance of...

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Transcript of Update on and Critical Utilities for Pharmaceutical Industry … · 2016-09-02 · Maintenance of...