Update on and Critical Utilities for Pharmaceutical Industry … · 2016-09-02 · Maintenance of...
Transcript of 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.
14.45-15.00 Coffee Break
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
10.30-10.45 Coffee Break
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
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
ISPE 2016 3 August 2016
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.
5 ISPE 2016 August 2016
Status of ISO 14644-1 & 2
ISPE 2016 6 August 2016
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.
ISPE 2016 7 August 2016
ISO TC209 wg1 Timeline
ISPE 2016 8 August 2016
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 !
ISPE 2016 9 August 2016
ISO 14644-1 revisions
ISPE 2016 10 August 2016
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
11 ISPE 2016 August 2016
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
ISPE 2016 13 August 2016
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
ISPE 2016 August 2016
The new classification table
ISPE 2016 15 August 2016
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
18 ISPE 2016 August 2016
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 .
ISPE 2016 21 August 2016
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
22 ISPE 2016 August 2016
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
24 ISPE 2016 August 2016
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
25 ISPE 2016 August 2016
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
26 ISPE 2016 August 2016
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
27 ISPE 2016 August 2016
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
28 ISPE 2016 August 2016
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
29 ISPE 2016 August 2016
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
ISPE 2016 31 August 2016
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.
32 ISPE 2016 August 2016
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.
33 ISPE 2016 August 2016
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
Questions / Discussion
Contact: Gordon Farquharson
Critical Systems Ltd
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1
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.
2
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.
3
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
1
Worked Example
ISO 14644-1 & 2:2015 Understanding and applying the changes
By Gordon Farquharson
Chair BSI LBI/030; Chair CEN TC243;
Convenor ISO TC209 WG1
August 2016
ISPE 2016 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.
ISPE 2016 2 August 2016
The example facility.
A Pharma cleanroom
ISPE 2016 3 August 2016
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
Diffused non-UDF airflow
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
Diffused non-UDF airflow
August 2016
The essential dimensions of the
facility
ISPE 2016 5 August 2016
Number and position of
sampling locations
ISPE 2016 6 August 2016
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.
ISPE 2016 11 August 2016
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
ISPE 2016 13 August 2016
Particle size
ISPE 2016 14 August 2016
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
ISPE 2016 15 August 2016
The classification table
ISPE 2016 16 August 2016
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 .
ISPE 2016 19 August 2016
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.
ISPE 2016 20 August 2016
Sample volume determination
ISPE 2016 21 August 2016
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.
ISPE 2016 22 August 2016
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.
ISPE 2016 23 August 2016
Sample volume Grade B ‘At Rest’
Grade B ‘At Rest’
ISO 5; 3520 parts/m3 ≥ 0.5 5.68 litres
ISO M(29≥ 5.0); at rest & operational; LSAPC 690
litres
Sample volume required at each sampling location
the most demanding from:
2 litres; 1 min = 28.3 litres; 5.68 litres; or 690 litres.
If we only consider particles ≥ 0.5 micron, then sample
volume = 28.3 litres.
ISPE 2016 24 August 2016
Sample volume Grade B
‘Operational’
Grade B ‘Operational’
ISO 7; 352000 parts/m3 ≥ 0.5 5.68 litres
ISO 7; 2930 parts/m3 ≥ 5.0 8.37 litres
Sample volume required at each sampling location
the most demanding from:
2 litres; 1 min = 28.3 litres; 5.68 litres; or 8.37 litres.
If we only consider particles ≥ 0.5 micron, then sample
volume = 28.3 litres.
ISPE 2016 25 August 2016
Summary of the testing
ISPE 2016 26 August 2016
Summary Table of sampling
requirements
ISPE 2016 27 August 2016
Undertaking the sampling
ISPE 2016 28 August 2016
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.
ISPE 2016 29 August 2016
Example data
ISPE 2016 30 August 2016
Evaluating the data
ISPE 2016 31 August 2016
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?
ISPE 2016 32 August 2016
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
Questions / Discussion
Contact:
Gordon Farquharson
Critical Systems Ltd
1
Anticipated Revision of
Annex 1 of the EU & PIC/S
GMPs By Gordon Farquharson
Chair BSI LBI/030; Chair CEN TC243;
Convenor ISO TC209 WG1
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
ISPE 2016 3 August 2016
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 !!!!
August 2016 ISPE 2016 4
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.
August 2016 ISPE 2016 6
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).
ISPE 2016 7 August 2016
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
ISPE 2016 8 August 2016
Dealing with old issues
Averaging is not acceptable!
ISPE 2016 9 August 2016
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.
ISPE 2016 10 August 2016
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??
ISPE 2016 11 August 2016
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
August 2016 ISPE 2016 12
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??
August 2016 ISPE 2016 13
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.
August 2016 ISPE 2016 14
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.
ISPE 2016 15 August 2016
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.”
August 2016 ISPE 2016 16
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.
August 2016 ISPE 2016 17
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
August 2016 ISPE 2016 18
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.
August 2016 ISPE 2016 19
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.
ISPE 2016 20 August 2016
Questions / Discussion
Contact: Gordon Farquharson
Critical Systems Ltd
CRI ICAL
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August 2016 ISPE 2016 1
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
ISPE 2016 2 August 2016
Air Handling Systems
The conditions we have to deal
with
ISPE 2016 4 August 2016
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.
ISPE 2016 5 August 2016
What are we talking about ?
Zone 4b conditions Summer
Bangkok
Summer
London
Inside
normal
factory
Inside
Low RH
factory
Understanding the basic
Psychrometrics
ISPE 2016 7 August 2016
Understanding the basic
Psychrometrics
ISPE 2016 8 August 2016
Optimum configuration of
systems
ISPE 2016 9 August 2016
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
ISPE 2016 12 August 2016
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.
ISPE 2016 13 August 2016
Duplicate – separate outside air
pre-treatment
ISPE 2016 14 August 2016
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
ISPE 2016 15 August 2016
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
ISPE 2016 19 August 2016
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.
ISPE 2016 20 August 2016
Two options – A liquid desiccant, and solid desiccant
loaded on a wheel for dehumidification
The return of liquid desiccant dehumidification &
improved desiccant wheels
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
The return of liquid desiccant dehumidification &
improved desiccant wheels
Questions / Discussion
Contact: Gordon Farquharson
Critical Systems Ltd
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August 2016 ISPE 2016 1
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
ISPE 2016 2 August 2016
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
August 2016 ISPE 2016 3
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.
ISPE 2016 4 August 2016
The decay of small particles in a
non-UDF cleanroom
A classic asymptotic decay curve
ISPE 2016 5 August 2016
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
August 2016 ISPE 2016 6
Non-UDF Air mixing
What really happens !
ISPE 2016 7 August 2016
Whyte et Al showed us what
happens with poor air distribution
ISPE 2016 8 August 2016
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).
ISPE 2016 9 August 2016
So how much supply air is
needed
ISPE 2016 10 August 2016
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.
ISPE 2016 11 August 2016
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.
ISPE 2016 12 August 2016
Placing sampling locations in
non-UDF cleanrooms
ISPE 2016 13 August 2016
New ISO 14644-1:2015 has clear
requirements
ISPE 2016 14 August 2016
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
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
Diffused non-UDF airflow
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
Diffused non-UDF airflow
August 2016
The simple plan of the facility
ISPE 2016 16 August 2016
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
ISPE 2016 18 August 2016
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
Questions / Discussion
Contact: Gordon Farquharson
Critical Systems Ltd
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August 2016 ISPE 2016 1
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 2016 2 August 2016
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.
ISPE 2016 3 August 2016
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.
ISPE 2016 5 August 2016
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.
ISPE 2016 6 August 2016
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.
ISPE 2016 7 August 2016
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
ISPE 2016 8 August 2016
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
ISPE 2016 9 August 2016
Granulation Room before the
explosion
August 2016 ISPE 2016 10
Granulation Room after the
explosion
August 2016 ISPE 2016 11
Centre of the explosion - Gearbox and
belt drive under granulator bowl
August 2016 ISPE 2016 12
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 !
August 2016 ISPE 2016 13
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.
ISPE 2016 14 August 2016
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.
ISPE 2016 15 August 2016
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.
ISPE 2016 16 August 2016
And finally in this general
section
ISPE 2016 17 August 2016
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!
Questions / Discussion
Contact: Gordon Farquharson
Critical Systems Ltd
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August 2016 ISPE 2016 1
Maintenance of GMP HVAC
Systems
Gordon Farquharson
August 2016
Planned Maintenance is best!
ISPE 2016 2 August 2016
ISPE 2016 3 August 2016
ISPE 2016 4 August 2016
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
ISPE 2016 5 August 2016
PPM –Consumables
Periodic – time based maintenance:
Air filter replacement
Fan belts – adjust tension or replace.
Coil face cleaning.
ISPE 2016 6 August 2016
PPM – Wear & Tear
abc
ISPE 2016 7 August 2016
PPM – Functional tests
Stroke actuated valves and dampers to ensure free
movement.
Test function of control
loops.
ISPE 2016 8 August 2016
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.
ISPE 2016 9 August 2016
PPM – Cleanroom Performance
testing guidance Guidance can be found in ISO 14644-2:2015; and
more in BS EN ISO 14644-2:2015
ISPE 2016 10 August 2016
ISPE 2016 11 August 2016
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.
ISPE 2016 12 August 2016
Predictive techniques
ISPE 2016 13 August 2016
Thermal imaging
Fixed or portable.
Continuous or periodic
Predictive techniques
ISPE 2016 14 August 2016
Vibration monitors
Fixed.
Continuous monitoring.
Permanently mounted accelerometers
Avoid catastrophic failures
and finally…........
ISPE 2016 15 August 2016
Finally – remember the
human side !
An
impossible
job leads to
poor quality
!!
Questions / Discussion
Contact: Gordon Farquharson
Critical Systems Ltd
CRI ICAL
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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
Connecting Pharmaceutical Knowledge ispe.org
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
Connecting Pharmaceutical Knowledge ispe.org
EMS - Trend Reports
Connecting Pharmaceutical Knowledge ispe.org
“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
Connecting Pharmaceutical Knowledge ispe.org
Warehouse
Connecting Pharmaceutical Knowledge ispe.org
'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?
Connecting Pharmaceutical Knowledge ispe.org
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
Connecting Pharmaceutical Knowledge ispe.org
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)
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• Room Classification
• Room Temperature Ranges
• Room Humidity
• Room Pressurization Requirements
• Air Exchange Requirements
URS - Process Requirements
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
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
Connecting Pharmaceutical Knowledge ispe.org
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
Supplier knowledge and technical expertise
Verification Specification
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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
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
Connecting Pharmaceutical Knowledge ispe.org
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
Supplier knowledge and technical expertise
Verification Specification
Connecting Pharmaceutical Knowledge ispe.org
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
Supplier knowledge and technical expertise
Verification Specification
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.
Connecting Pharmaceutical Knowledge ispe.org
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
Supplier knowledge and technical expertise
Verification Specification
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.
Connecting Pharmaceutical Knowledge ispe.org
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
Supplier knowledge and technical expertise
Verification Specification
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)
Connecting Pharmaceutical Knowledge ispe.org
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
Supplier knowledge and technical expertise
Verification Specification
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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
Connecting Pharmaceutical Knowledge ispe.org
• 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
August 2016 ISPE 2016 1
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.
August 2016 ISPE 2016 2
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 ?
August 2016 ISPE 2016 3
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.
August 2016 ISPE 2016 4
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)
August 2016 ISPE 2016 5
Reverse Osmosis in the Ph.
Eur “Monograph for Water for
Injections”
Overview of the change
August 2016 ISPE 2016 6
Pharmacopoeial monographs – Bulk
waters don’t change
August 2016 ISPE 2016 7
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.
August 2016 ISPE 2016 8
Summary of the change in
position 2002-2015
ISPE 2016 9 August 2016
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).
August 2016 ISPE 2016 10
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.
August 2016 ISPE 2016 12
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.
August 2016 ISPE 2016 13
Reverse Osmosis in the Ph.
Eur “Monograph for Water for
Injections”
Some more detailed notes of the
review and revision process
August 2016 ISPE 2016 14
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
August 2016 ISPE 2016 15
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.
August 2016 ISPE 2016 20
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
August 2016 ISPE 2016 21
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
Ph Eur WFI Action 2: 2011
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.
August 2016 ISPE 2016 23
Ph Eur WFI Action 3: 2013
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.
August 2016 ISPE 2016 24
Ph Eur WFI Action 4: 2013
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)
August 2016 ISPE 2016 25
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).
August 2016 ISPE 2016 26
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
August 2016 ISPE 2016 28
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
August 2016 ISPE 2016 30
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
August 2016 ISPE 2016 31
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
August 2016 ISPE 2016 32
Remember the distillation
options
ISPE 2016 33 August 2016
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
August 2016 ISPE 2016 34
Vapour Compression Distillation
August 2016 ISPE 2016 35
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
August 2016 ISPE 2016 36
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
August 2016 ISPE 2016 37
Biofilm and the microbial
contamination risk
The main scope of the WFI GMP
Guidance in revised Annex 1
ISPE 2016 38 August 2016
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.
ISPE 2016 39 August 2016
Biofilm Formation
Mark Wiencek, Rohm & Haas Company, Spring House, PA 19477
August 2016 ISPE 2016 40
Biofilms Can Shed In Water
Flow
August 2016 ISPE 2016 41
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
August 2016 ISPE 2016 42
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.
August 2016 ISPE 2016 43
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.
August 2016 ISPE 2016 44
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.
August 2016 ISPE 2016 45
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.
August 2016 ISPE 2016 46
Making the decision about
system selection.
Choosing the best option for
you.
August 2016 ISPE 2016 47
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.
August 2016 ISPE 2016 49
Assessment techniques Brainstorm aspects to consider
Suggest Ishikawa (fishbone) diagrams.
Aspects to
consider when
choosing an
appropriate WFI
system
Meet WFI spec
Capital cost
August 2016 ISPE 2016 50
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
August 2016 ISPE 2016 51
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
August 2016 ISPE 2016 53
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.
August 2016 ISPE 2016 61
Questions / Discussion
Contact: Gordon Farquharson
Critical Systems Ltd
CRI ICAL
S
Y
S
T
E
M
S
CRI ICAL
S
Y
S
T
E
M
S
August 2016 ISPE 2016 1
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!’
August 2016 ISPE 2016 3
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
August 2016 ISPE 2016 4
Compressed Air
August 2016 ISPE 2016 5
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.
August 2016 ISPE 2016 6
Uses for Compressed Air in
Pharmaceutical Manufacture
Motive air for machines
Breathing air
Product Direct Impact - “GMP” air
Process air
Analytical air
August 2016 ISPE 2016 7
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”
August 2016 ISPE 2016 8
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
August 2016 ISPE 2016 9
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
August 2016 ISPE 2016 10
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
August 2016 ISPE 2016 11
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 ?
August 2016 ISPE 2016 12
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
August 2016 ISPE 2016 13
Removal of Contaminants
Solids
Cyclones
Filtration
Water
Vapours
Condensation followed by separation
Sorption (absorption or
adsorption)
Oil
Gases
Adsorption
August 2016 ISPE 2016 14
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
August 2016 ISPE 2016 15
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.
August 2016 ISPE 2016 17
HDPE Plastic
Socket fusion ISPE 2016 18 August 2016
Butt fusion Electro-fusion
HDPE Plastic
ISPE 2016 19 August 2016
Double Ferrule Compression
Fittings
August 2016 ISPE 2016 20
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.
August 2016 ISPE 2016 21
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
August 2016 ISPE 2016 22
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.
August 2016 ISPE 2016 23
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.
August 2016 ISPE 2016 24
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)
August 2016 ISPE 2016 25
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.
August 2016 ISPE 2016 26
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.
August 2016 ISPE 2016 28
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 ?
August 2016 ISPE 2016 29
ISPE 2016 30 August 2016
And finally – testing and
monitoring
ISPE 2016 31 August 2016
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
ISPE 2016 32 August 2016
Moisture test method
The presence of moisture contaminants can be
established by the test method specified in ISO
8573-3:1999.
Dewpoint meters:
Built in.
Hand held portable
ISPE 2016 33 August 2016
Particle test method
The presence of particle contaminants can be
established by the test method specified in ISO
8573-4:2001.
Airborne particle counter (LSAPC).
Filter collection and microscopic counting.
ISPE 2016 34 August 2016
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.
ISPE 2016 35 August 2016
Gaseous content test
The presence of gaseous contaminants can be
established by the test method specified in ISO
8573-5:2001.
Gas chromatograph is the reference test method.
ISPE 2016 36 August 2016
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
ISPE 2016 37 August 2016
Questions / Discussion
Contact: Gordon Farquharson
Critical Systems Ltd
CRI ICAL
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CRI ICAL
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August 2016 ISPE 2016 1
“Update on HVAC and Critical
Utilities for Pharma”
Gordon Farquharson
August 2016
Questions / Discussion
Contact: Gordon Farquharson
Critical Systems Ltd
CRI ICAL
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CRI ICAL
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August 2016 ISPE 2016 1
“Update on HVAC and Critical
Utilities for Pharma”
Gordon Farquharson
August 2016
Questions / Discussion
Contact: Gordon Farquharson
Critical Systems Ltd
CRI ICAL
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Y
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T
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CRI ICAL
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