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Session 6 Microbiology
Biocontamination Control
– Challenges in Food, Healthcare and Life Science
o Introduction
o Irish Cleanroom Society
o ICS & VCCN
o Ireland & Life Sciences
o Biocontamination Control
o Environmental Monitoring
o EN ISO 14698 Update
o CEN 243 New Work Item (Approved May 2015)
o EU Annex 1 Revision/Update 2015
Presentation Content
2
o Industries such as Food manufacture, Healthcare and Life Science need better guidance and science to help improve our Health, Safety and Wellbeing
o Biocontamination control, like the unseen enemy of micron size particles in Cleanrooms is complex
o Microbiologists are dealing with living microorganisms that are not easy to observe, recover and measure
o Current science of EM using Lag indicators of CFUs is a blunt instrument
Summary Points
3
o Real time measurement of airborne particles using laser particle counters has enabled classification of cleanrooms
o Real time measurement of Microorganisms is still not practical and reliable (RMM/IMD techniques are improving)
o There is a real need for better scientific methods
o The ICS and VCCN within the ICCCS are working on this at ISO TC 209 and CEN 243
o CEN 243 has voted to form a new working group on Biocontamination and revise EN ISO 14698
Summary Points
4
CEN Biocontamination Control WGo Working Group made up of Subject Matter Experts from
Food, Healthcare and Life Science
o Primarily Microbiologists but aided by professionals from many backgrounds including measurement and metrology, certification and engineering controls
o Conor Murray (Convenor) & Rebecca Walden (Secretary)
o Countries nominating experts from The Netherlands, Ireland, France, Germany, Switzerland, UK, Denmark, Sweden, Italy
o Expect contributions from other EU countries once started
o Observers to be invited from original ISO TC 209 WG2
o First meeting in Dublin late June/early July ‐ 3 yr programme
5
Electronics/Cleantech
Engineering
Dairy/ FunctionalFoods
Ingredients,Beverages andFood TechnologyConsumer Food,Seafood andHorticulturePrimary Meats
Food
Medtech
•devices
•diagnostics
Medical Sub‐Supply
Pharma/Vet Pharma
Chemicals
Manufacturing
Healthcare/Pharma
Services
Lifesciences
Key Manufacturing Sectors for Ireland
• Critical to Ireland’s economy & recovery
• Sustains about 206,000 direct jobs split almost evenly between indigenous and overseas employers
• Supports at least as many people again in indirect jobs
• Provides employment across a wide range of occupations and skills levels
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Ireland & Life Sciences
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Change Drivers in Ireland
EN/ISO Standards & GMPs
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ISO 14664 & 14698 StructureTotal
ParticlesViable
BiocontaminationChemical
Nano-particles
ACC
SCC
Airborne
Surface
ACP
SCP
ACN ?
SCN ?
ACV
SCV
TotalParticles
Viable Biocontamination
Chemical Nano-
particles14698-1 14698-214698-1 14698-2
Surface
Airborne 14644-1
14644-9
14644-8
14644-10
14644-?
14644-?
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ISO 14644 & 14698 Flow Chart
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11
ISO 14644 & 14698 Flow Chart
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12
EN/ISO Standards & GMPs
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EN ISO 14644-1 & EU GMP- Annex 1 March ‘09
14
At Rest In Operation
Grade Max Particles greater than or equal
to the stated sizes Microbiological
0.5 5.0 0.5 5.0 Air
sample cfu/m3
90mm settle plate
cfu/4hr
A 3 500 20 3 500 20 <1 <1
B 3 500 29 350 000 2 900 10 5
C 350 000 2 000 3 500 000 20 000 100 50
D 3 500 000
20 000 Not defined
Not defined
200 100
Classification EC FDA Activities
ISO Class 5 Grade A Critical Aseptic preparation and filling, filling of open ampuls and bottles
ISO Class 5 Grade B Controlled Surrounding of class A, transfer of aseptic products in closed receptacles
ISO Class 7 Grade C Controlled Preparation of solutions, when unusually at risk
Filling of finally sterilized products
Surrounding of isolators (closed cabinets)
ISO Class 8 Grade D Controlled Preparation of solutions to be filtered by consequent sterile filtration
Production without open substances
Primary package
Washing of parts, handling of components after washing
UNC - Uncontrolled Laboratories, administration, technical areas, workshops, storage etc.
GMP Comparison– EN ISO & EU/& FDA
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3,520,000 832,000 29,300
ISO 9 35,200,000 8,320,000 293,000
ISO 8
35,200 8,320 293
ISO 7 (Class 10,000) 352,000 83,200 2,930
ISO 6 (Class 1,000) 1,000,000 237,000 102,000
352 83
ISO 5 (Class 100) 100,000 23,700 10,200 3,520 832 29
ISO 4 10,000 2,370 1,020
4
ISO 3 1,000 237 102 35 8
ISO 2 100 24 10
0.5 um 1 um 5 um
ISO 1 10 2
0.1 um 0.2 um 0.3 um
CLASS Number of Particles per Cubic Meter by Micrometer Size
EN ISO 14644-1:1999
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o “In Grade A and B zones, the monitoring of the ≥5.0 μm particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure.”
o “... consecutive or regular counting of low levels (of ≥5.0 μm) is an indicator of a possible contamination event and should be investigated.”
o Particles ≥5.0 μm could be skin particles carrying biocontamination
Annex 1 & Aseptic Processing- 5μm Particles & EU GMPs
17
3,520,000 832,000 29,300
ISO 9 35,200,000 8,320,000 293,000
ISO 8
35,200 8,320 293
ISO 7 (Class 10,000) 352,000 83,200 2,930
ISO 6 (Class 1,000) 1,000,000 237,000 102,000
352 83
ISO 5 (Class 100) 100,000 23,700 10,200 3,520 832 29
ISO 4 10,000 2,370 1,020
4
ISO 3 1,000 237 102 35 8
ISO 2 100 24 10
0.5 um 1 um 5 um
ISO 1 10 2
0.1 um 0.2 um 0.3 um
CLASS Number of Particles per Cubic Meter by Micrometer Size
EN ISO 14644-1:20XX- 5um limit & EU GMP Annex 1
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WG01 and (2nd) ISO DIS 14644-1.1:2014 position:
Remove 29 Class limit & use Macro descriptor instead
M (20 ≥ 5.0µm); LSAPC; At Rest
Biocontamination Control
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o Food Manufacture
o Healthcare
o Life Sciences
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Food Manufacture- Cross Contamination
o Increasingly food manufacturers are turning to Cleanrooms to control airborne contamination and increase product shelf life
o Food industry Cleanrooms are clearly less “clean” than those found in sterile pharmaceutical applications BUT……
o The requirements for the Food Processing Cleanroom vary depending on the food being produced
o The dry process in a Bakery pose less of a risk than wet processes in Dairy. Even in Dairy the requirements for fluid milk will generally be less than for yogurt or cultured milk, where bacterial activity is more intense
Food Manufacture - Cleanrooms
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o Food processors will usually consider Cleanroom technology because they are concerned with the spread of bacteria, yeasts and moulds that can grow in the moist conditions of process areas and are carried by air currents throughout the food plant
o The objective is to keep the air in the immediate vicinity of the food being processed free from microbial contaminants
o This can reduce or eliminate the need for:
o pasteurisation or flash freezing process stages or
o unnecessary addition of preservatives
Food Manufacture - Cleanrooms
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o This will lead to a better and hopefully a healthier food product:
o Lower Costs of production (higher yield)
o Low Microbial content
o No Micorbial contamination
o Increased Shelf life
o Improved Freshness
Food Manufacture - Cleanrooms
23 24
Healthcare- HAIs & Infection Control
o Biocontamination Control rather a Cleanroom
o Infection Control
o Cross Contamination
o Isolation (Immunocompromised)
o Sterility
o Cytotoxics
o Biosafety
o Instrument Sterilisation (Prions)
Healthcare – Cleanrooms?
25
o Operating Theatres
o Isolation Wards
o Immunocompromised Wards
o Pharmacy (CIVAS & Cytotoxics)
o Central Sterilisation Services Departments
o Biosafety Laboratories
Healthcare – Biocontamination Control
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o Uncontrolled People variability and contact!
o HAIs (Hospital Acquired Infections)
o Patient Microorganism flora/population
o Patient resistance to infection
o Staff and Visitor Microorganism flora/population
o Unknown infectious risks
Healthcare – Biocontamination Control
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o Complex People interactions & variability
o Inadequate guidance compared to Life Science GMPs
o Difficult to regulate effectively
o Inadequate funding models
o Adequate HVAC & Engineering controls
o Significant mcirobiological challenges
o Personnel (Staff and Visitor) training
o Cleaning & Decontamination regimes
o Balancing conflicts between Product Protection ‐ Personnel Protection ‐ Cross Contamination
Healthcare – Biocontamination Control
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Life Sciences- Sterile & Non Sterile
o Sectors
o Pharma (Small Molecule)
o Biopharma (Large Molecule)
o Medical Devices
o Applications
o Aseptic
o Terminal Sterilisation
o Non Sterile
Life Science – GMP Cleanrooms
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Environmental Monitoring
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Environmental Monitoring
Environmental Monitoringo Environmental monitoring is different to environmental
control
o Cleanrooms and clean areas are assessed through an environmental monitoring programme
o Environmental Monitoring:
o Assess cleanliness
o Physical assessment of airborne particles
o Checks on Temperature, Relative Humidity, Differential Pressure, etc
o Collection of data relating to the numbers and types of Microorganisms present on surfaces, in the air and from people
EN ISO 14698 -1 & -2: 2003
- Biocontamination WG 02
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EN ISO 14698 -1 & -2: 2003
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o ISO 14698 not in line with ISO 14644
o No Tables of Classification
o Not up to date with Risk Assessment & Risk Management techniques (eg ICH Q9 QRM)
o No Check Lists of “Things to Consider”
o Not up to date with technology advances in Rapid Microbiological Methods (RMM) & Instantaneous Microbiological Detection (IMD) (eg ATP/Bioluminescence)
EN ISO 14698 Issues
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o Cannot “Monitor a process into Control”
o Not enough clarity on differences, issues and guidance on Aseptic vs Non Sterile applications
o Not enough guidance on Airborne vs Surface biocontamination risks and control
o Overall seen as not easy to read & use
EN ISO 14698 Issues
37
IS O/TC 2 09 N 187 Re solutions from ISO/TC 20 9 Mee ting 9-10 Nov em be r 2007 Résolutions de l' ISO/T C 209 (19ème réunion, 9 et 10 Novembre 2007) Re solution 1 IS O/TC 209 reso lves th at WG 2 co mmence s work on these two documents :
a. Classification of airb orne bioconta minatio n in c leanroo ms, inc luding metho ds of measure ment a nd their valida tion.
b. Classification of surf ace biocontaminatio n in c le anroo ms, including method s of measure ment a nd their valida tion.
At t he appropriate time during the de velopment of these docu ments, the position of IS O 14 698
Parts 1 a nd 2 sh ould b e cons idered, as wel l as a Risk Manage ment Standard. (All in fa vor)
ISO TC 209 - Work Items WG02
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o Current measurement ‘technologies’ limited to orders of magnitude resolution, especially in low density populations
o Species recovered using these technologies limited due to incubation methodology (inc media, temperature, pH, aerobic/anaerobic, etc.)
o “Environmental microbiologists recent research indicate that some species are inter-dependant & one species will not culture successfully without the presence of the other”
EN ISO 14698 Challenges- Limitations of Quantitation
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o People are the greatest source of biocontamination
o Unpredictability and uncertainty of Human behaviour
o “80% of the species found in the human upper respiratory tract cannot be recovered”
EN ISO 14698 Challenges- Diversity of People
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o Below limit of resolution for current technologies
o i.e. 1 cfu recovered may be indicative of 1cfu or perhaps >10cfu, impossible to accurately and repeatably determine
o Risk of false positives high due to likelihood of accidental contamination during collection and incubation
EN ISO 14698 Challenges- Issues in clean spaces
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o In some cases, all species are considered harmful
o In some cases there is ‘background counts’ of cfu of species considered ‘normal and non-harmful’
o In some cases, some species are considered ‘objectionable’ and are not tolerated at all
o Significant differences and challenges between Food (Biocontamination), Healthcare (Infection Control) and Life Sciences
EN ISO 14698 Challenges- Process/ Application Specific
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o CD 14698:2014 after 5 years – over 300 comments
o Fundamental differences in expert opinions from
different industries on the role of/need for
Classification for harmonisation/guidance
o Seoul October ’14 ‐ Could not agree on a way
forward and WG 02 CANCELLED
ISO 14698- WG 02 Position at Seoul, Oct 2014
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o WG 02 work done inc CD retained on record
o Recognised valuable scientific work done on:
o Structure and Principles of Establishing Control and thenDemonstrating Control
o Things to Consider/Check Lists
o Risk Assessment/QRM (ICH Q9)
o Critical Control Points/QbD (ICH Q10) and EM
o Comparison and comparability of traditional methods ‐ Airbornesamplers inc d50 number
o New Rapid Microbiological Methods (RMM)
ISO 14698- WG 02 Position at Seoul, Oct 2014
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o ISO 14698 -1 & -2:2003 – remain as is
o Systematic review after 5 years (2019)
o Could exclude search for Classification Tables
o CEN 243 Initiative- New Work Item for an EU
Biocontamination Control passed MAY 13th
o US sponsored NWIP to work on new 14698-9
Healthcare ONLY (add to existing -1 & -2) –
vote closes mid July
ISO 14698 - What happens next?
45
CEN 243
- European Biocontamination
Working Group
46
CEN Biocontamination Control WGo Working Group made up of Subject Matter Experts from
Food, Healthcare and Life Science
o Primarily Microbiologists but aided by professionals from many backgrounds including measurement and metrology, certification and engineering controls
o Conor Murray (Convenor) & Rebecca Walden (Secretary)
o Countries nominating experts from The Netherlands, Ireland, France, Germany, Switzerland, UK, Denmark, Sweden, Italy
o Expect contributions from other EU countries once started
o Observers to be invited from original ISO TC 209 WG2
o First meeting in Dublin late June/early July ‐ 3 yr programme
47
Challenges to Addresso There are fundamental differences between the needs of
different stakeholders in Food, Life Sciences and Healthcare
o This may require a different approach and guidance in each case
o Microbiological contamination is hugely variable and is normally a function of how a cleanroom is used and particularly the people involved rather than predetermined performance characteristics
o A continuum of biological cleanliness might be helpful
48
Challenges to Addresso Getting an understanding of the underlying risk and the WHY
for microbiological cleanliness across industries is very important
• Slavishly following Tables of Classification or Monitoring levels because they have been told to, without understanding the actual risk to their process from the defined levels of microbiological contamination is not good science
• The inherent variablity of people, the huge variety of species of interest in most cases and limitations in measurement technologies are significant obstacles to progress
49
Challenges to Addresso The regulated Sterile Medicines industry has long established
guidance that must be integrated and any revision cannot be in conflict with existing industry regulation
o There is a new and evolving science of RMM/IMD
o The limits in the classification tables are based on current technology and don’t seem to make enough allowance for changing recovery efficiencies that may be associated with emerging technologies (RMM/IMD)
o Is real time measurement is ready for practical application?
o Allow good science to prevail & get enough experts with the competencies and skills required to do a deep dive into the science involved, inc new and evolving technologies
50
o Is this is a stand alone Biocontamination Control standard or part of the 14644 Cleanroom series where the Cleanroom is fundamentally based on total particle concentrations in air and all other attributes are treated as secondary is number one on my list.
• ISO and CEN standards need to be very simple and specify the basics of biocontaminaton control in terms of what must be considered.
• Determining the Scope of the Stndard and what is Normative vs Informative are very important early stage decisions
Challenges to Address
51
CEN 243 Biocontamination Control WG
1. Risk Management & Control inc ICH QRM, HACCP, etc
2. Principle of Establishing control and then Demonstrating control (EM)
3. Setting limits in establishing control & setting levels in demonstrating control (EM)
4. Independent review and comparison of current measurement metrology, inc d50 number
52
CEN 243 Biocontamination Control WG
5. Advances in the science, application of suitability of RMM/IMD inc measurement metrology
6. A review of different industries including Food, Life Sciences and Healthcare and whether classification tables are possible and appropriate in each case
7. Check Lists of things to be considered in biocontaminationcontrol
8. Improved structure for ease of use and application
9. Use the parts of the current ISO 14698 – 1 & ‐2 that are still appropriate
53
EN ISO 14698 – New Structure?
54
EN ISO 14698 – Establish Control
55 56
EN ISO 14698 – Test Methods
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EN ISO 14698 – Demonstrate CEN 243 Biocontamination Control WG
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CEN 243 Biocontamination Control WG
o EU GMP Annex 1 deals with the manufacture of Sterile Medicinal Products
o Annex 1 does not address Medical Devices
o EU Medical Devices Directive (MDD) 93/42/EEC Essential Requirement 8.5: ‘Devices intended to be sterilised must be manufactured in appropriately controlled (e.g. environmentally) conditions’
o EN ISO 13485 along with EN ISO 14971 emphasise risk based assessment but there is no clear guidance on GMP
59
CEN 243 Biocontamination Control WG
o Guidance is extracted from EU Annex 1 in the absence of any other clear guidance
o Guidance is extracted from EU Annex 1 (Paragraph 17 on Page 4 along with further guidance in Paragraphs 28 ‐ 35 on Pages 6 & 7.
60
EMA Annex 1 – Classification Tables
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EU GMP Annex 1
- Concept Paper 2015
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EMA Concept Paper Revision of Annex 1 EMA Annex 1 ‐ Last Update
Annex 1 Update in 2008 included:
o Classification of the environmental cleanliness of clean rooms
o Guidance on media simulations
o Guidance on capping of vials
o Bioburden monitoring prior to sterilisation
64
EMA Annex 1 ‐ Last Update
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EMA Annex 1 Update – WHY?o The Annex‐1 "Manufacture of Sterile Medicinal Products"
guideline was developed before the implementation of ICHQ9 and ICHQ10
o Guidance will be provided pertinent to the level of use of QRM principles offering a systematic approach to the management of risk in sterile and non‐sterile manufacturing facilities.
o ICHQ10 will be expanded upon as part of the Annex‐1 update to include discussion points on the pharmaceutical quality life cycle in order to obtain a state of control, the realisation of product quality and to facilitate continual improvement over the entire life cycle.
66
EMA Annex 1 Update Timeline 1
o Agreed by GMP/GDP IWG and PICs ‐ January 2015
o Start of public consultation ‐ 5th February 2015
o End of consultation (deadline for comments) ‐ 31st
March 2015
o Discussion PIC/S Committee ‐May 2015
67
EMA Annex 1 Update Timeline 2
o Discussion in GMDP / IWG ‐ June 2015
o Discussion with other working parties ‐ June to September
2015
o Proposed date for release of draft guideline ‐ October 2015
o Deadline for comments ‐ April 2016
o Re‐discussion with GMDP / IWG ‐ June 2016
o Re‐discussion with PIC/S Committee ‐ July 2016
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EMA Annex 1 UpdateAnnex 1 topics for revision in 2015:
o how ICHQ9 and ICHQ10 will be expanded upon and how this will link into PIC/S Annex 15 "Qualification & Validation and Annex‐20 "Quality Risk Management" not currently in the EU code of cGMP
o requirements for environmental controls of non‐sterile manufacturing facilities
• inaccuracies and ambiguity in relation to GMP expectations
69
EMA Concept Paper Revision of Annex 1
o The scope and title of the guideline should therefore be broadened to encompass these references but it is stressed that this is a clarification of current practices and that no new expectations will be created
• The current guideline does not reflect the advances in the manufacture of sterile medicinal products; the revised guideline will embrace the use of new technologies to prevent detrimental impact on product and also to encourage the introduction of new technologies that are not currently covered
70
EMA Annex 1 ‐ Differential Pressure
o Currently Annex‐1 clause 53 states the requirement to have 10‐15Pa pressure differential between adjacent rooms of different grades.
o However there is no requirement to have pressure differentials between cleanrooms of the same classification.
o Annex‐1 does address this issue by stating that "A filtered air supply should maintain a positive air pressure and an airflow relative to the surrounding areas under a lower grade under all operational conditions and should flush the area effectively" (Ref‐ Annex‐1, Clause‐53, 2008).
71
o Best Practice is that airflow should cascade from the most critical cleanroom zones to the least critical cleanroom zone
o In reality it is challenging to maintain 100% compliance in operational state
o Challenges that impact pressure differentials include:
o operational use i.e. equipment in use
o staff walking in and out of cleanroom zones
o pre and post cleaning of the GMP cleanroom
o HVAC and Atmospheric changes (weather changes can all impact pressure differentials in your cleanroom environment )
EMA Annex 1 ‐ Differential Pressure
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o In a dynamic cleanroom of the same grades there may be ocassions when there are momentary drops below the required 10‐15Pa. Guidance is required as to what is an acceptable regain time limit before it becomes a quality issue.
o Factors to be considered here should include operations taking place in the adjacent cleanroom locations, proximity of the critical grade C and B locations to grade D and uncontrolled zones, environmental monitoring controls in place, i.e. particle monitoring in the location.
EMA Annex 1 ‐ Differential Pressure
73
EMA Annex 1 – EM & Non Sterileo Environment controls for Non‐Sterile Facilities is not very well
defined in the PIC/S code of cGMP or the EU code of cGMP
o Annex‐9 "Manufacture of Liquids, Creams and Ointments" does state that closed systems is recommended to protect the product from contamination and that production areas should be well ventilated with filtered air (Ref PIC/S cGMP Annex 9, Clause 1)
o Clear guidance is required for microbiological monitoring, particle monitoring (if required), and pressure cascades defined for non‐sterile facilities
74
EMA Annex 1 – ICH Q9o Annex 15 Clause 1, only references that a risk based approach
should be taken for validation activities and does not really go into the mechanics of risk assessment
o If Annex 1 is going to be an expansion of ICHQ9 then QRM principles may be built into the qualification stages of a new process as part of the URS
o QRM principles may also be built into the methodology as stated in ICHQ9 and preferred methods used for example FMEA or HACCP
o Clarification of the requirements of QRM principles of air pressure differentials between cleanroom grades of the same classification to be included for grade‐C and grade‐B.
75
EMA Annex 1 – ICH Q9
o PIC/S code of cGMP has already updates guidance with the implementation of Annex‐20 "Quality Risk Management”
o Any update needs to make sure what is already referenced in the other annexes and chapters of the code of cGMPpertinent to PIC/S and the EU is not lost and that all of the sections which reference QRM principles and quality management are integrated
o Updated guidance should clearly state how the risk rationale and methodology should be used, implemented and at what stage of the product life cycle this is required
76
• The update may give an expansion not just on the quality life cycle of the finished product but also of other quality management systems.
• ICH Q10 has good definitions of change management systems and CAPA systems for process improvements
• Existing guidance does not define very well both practices as change management is only discussed in Annex15, clause 44 & 45 and implies change management is only necessary for validation activities. Change management is actually a much more broader concept
EMA Annex 1 – ICH Q10
77
o Clarification on the minimum requirements for environmental controls of Non‐Sterile facilities should be included
o The use of an effective CAPA system is hardly referenced at all in the code of cGMP and is only discussed in Chapter 1, clause 1.4 Product Quality Review (PIC/S cGMP) and clause 1.4 Pharmaceutical Quality System (EU cGMP)
o Updated guidance should clarify how the product quality life cycle should be recorded and how this will link into the PQR process
EMA Annex 1 – ICH Q10
78
o Industries such as Food manufacture, Healthcare and Life Science need better guidance and science to help improve our Health, Safety and Wellbeing
o Biocontamination control, like the unseen enemy of micron size particles in Cleanrooms is complex
o Microbiologists are dealing with living microorganisms that are not easy to observe, recover and measure
o Current science of EM using Lag indicators of CFUs is a blunt instrument
Summary Points
79
o Real time measurement of airborne particles using laser particle counters has enabled classification of cleanrooms
o Real time measurement of Microorganisms is still not practical and reliable (RMM/IMD techniques are improving)
o There is a real need for better scientific methods
o The ICS and VCCN within the ICCCS are working on this at ISO TC 209 and CEN 243
o CEN 243 has voted to form a new working group on Biocontamination and revise EN ISO 14698
Summary Points
80
CEN Biocontamination Control WGo Working Group made up of Subject Matter Experts from
Food, Healthcare and Life Science
o Primarily Microbiologists but aided by professionals from many backgrounds including measurement and metrology, certification and engineering controls
o Conor Murray (Convenor) & Rebecca Walden (Secretary)
o Countries nominating experts from The Netherlands, Ireland, France, Germany, Switzerland, UK, Denmark, Sweden, Italy
o Expect contributions from other EU countries once started
o Observers to be invited from original ISO TC 209 WG2
o First meeting in Dublin late June/early July ‐ 3 yr programme
81
Thank You for Your Attention
82
