Environmental Monitoring

Brazil-PDA

March 2020

ANVISA REGULATIONS

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 Agenda

• Contamination in Manufacturing Facilities

• What to Monitor
• Environmental Monitoring
– Regulatory Agencies
– GMP Requirements
– Total Particulate Monitoring
– Risk Assessment
– Microbial Monitoring

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 Why monitor?

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 What to Monitor in Pharmaceutical Manufacturing Environments

Microbial monitoring of manufacturing clean rooms, Restricted-Access Barrier

Systems (RABS), and isolators should include:
• Room or Enclosure Air
• Surfaces
– Manufacturing Equipment and Instruments
– Personnel garment, gloves, etc.
• Compressed Gases
• Any other materials contributing to contamination risk

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 What to Monitor in Pharmaceutical Manufacturing Environments

Air
1. Total Particulates (Inert or Nonviables plus Viables)
2. Viables
a. Settle Plates
b. Active Air Sampling

Surfaces (Viables)
1. Facilities and Instruments
2. Personnel (Gloves, garment, etc)
a. Contact Plates
b. Swabs

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 Environmental Monitoring

GMP Requirements

Regulatory Agencies & Documents

Cleanroom Grades
Classification of a Cleanroom
Monitoring of a Cleanroom

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 Regulatory Agencies and Important Organizations

EMA (European Medicines Agency) – EU

FDA (Food & Drug Administration) – USA

WHO (World Health Organization)

PIC/S (Pharmaceutical Inspection Convention and

Cooperation Scheme)

International Organization for Standardization (ISO),

Technical Committee 209 (TC 209) [ISO 14644-1]

United States Pharmacopoeia (USP) [USP 36, Chapter

<1116>”Microbiological Control and Monitoring of
Aseptic Processing Environments”, 2013]
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 Worldwide GMP

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 Enforcement of GMP Country Requirements

• Local import requirements

– Countries only permit the sale of drugs manufactured to
their accepted, current Good Manufacturing Practices
(cGMP)
– Location of the manufacturing facility does not matter

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 PIC/S

The Pharmaceutical Inspection Convention and Pharmaceutical Inspection

Co-operation Scheme (jointly referred to as PIC/S) are two international
instruments between countries and pharmaceutical inspection authorities,
which together provide an active and constructive co-operation in the field of
GMP.

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 PIC/S

• Founded November 1995

• Membership:
– 52+ Country Authorities (e.g., USA FDA)
– 4 Partners (EDQM, EMA, WHO, UNICEF)
– New members go through a detailed assessment
• Promote Global Harmonization Of GMP
• Benefits to Industry
– Reduced duplication of inspections
– Cost savings
– Export facilitation
– Enhanced market access

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 US and EU GMP Regulatory Documents

• Pharmaceutical Manufacturing
– FDA GMP: 21 CFR Parts 210/211
– EU GMP: EudraLex Volume 4 “Guidance for
Good Manufacturing Practices for Medicinal
Products for Human and Veterinary Use”
• Aseptic Processing
– FDA: “Guidance for Industry, Sterile Drug
Products Produced by Aseptic Processing”
• Sep 2004
– EU: Eudralex vol. 4 Good Manufacturing,
“Annex 1, Manufacture of Sterile Medicinal
Products”
• Mar 2009

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 Classification and Monitoring

EU and ANVISA (PIC’S) both require that

a cleanroom is classified and then
monitored

• Classification: Proving that a

cleanroom meets the required
ISO class (ISO 14644-1:2015)

• Monitoring: Continued, ongoing

verification that a cleanroom has
not shifted from “normal”
conditions (ISO 14644-2:2015)

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 EU GMP Annex 1 (PIC’S)

The EU GMP Annex 1 outlines three phases that need to be performed:

1. Classification or Certification: Each cleanroom and clean air device should

first be classified.

2. Monitoring: The cleanroom should then be monitored to verify that

conditions are maintained.

3. Data review: The data accrued from the monitoring must be reviewed in
light of the risk to finished product quality.

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 ISO 14644-1:2015 2nd Edition
Classes of air cleanliness by particle concentration

Maximum allowable concentrations (particles/m3) for

particles equal to and greater than the considered sizes

CLASS 0.1 µm 0.2 µm 0.3 µm 0.5 µm 1.0 µm 5.0 µm

ISO 1 10
ISO 2 100 24 10
ISO 3 1,000 237 102 35
ISO 4 10,000 2,370 1,020 352 83
ISO 5 100,000 23,700 10,200 3,520 832
ISO 6 1,000,000 237,000 102,000 35,200 8,320 293
ISO 7 352,000 83,200 2,930
ISO 8 3,520,000 832,000 29,300
ISO 9 35,200,000 8,320,000 293,000

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 Cleanroom Grades

• EU Annex 1 (PIC’S) establishes 4 grades for cleanrooms:

• Grade A: Local zones for high risk operations (filling, closing, etc.)

• Grade B: The background environment of the Grade A zone

• Grade C and D: Clean areas for less critical stages

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 Cleanroom Grades, cont.

EU GMP (PIC’S)Annex 1

Grade D

Grade C
Grade B

Grade A
ISO 4.8/4.8

ISO 5/7
ISO 7/8

ISO 8/U

At Rest / In Operation
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 EU(PIC’S) Classification Table

AT REST (b) IN OPERATION (b)

(ISO) Grade Maximum permitted number of particles/m³ equal to or above(a)

≥0.5 µm(d) ≥5 µm ≥0.5 µm(d) ≥5 µm

4.8 / 4.8 A 3,520 20(e) 3,520 20(e)

5/7 B(c) 3,520 29(e) 352,000 2,900

7 /8 C(c) 352,000 2,900 3,520,000 29,000

8/U D(c) 3,520,000 29,000 not defined(f) not defined (f)

EU 2009

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 Cleanroom certifications

Certification occurs after facility construction or significant physical changes.

Certification guarantees the facility has met the requirements for a
statistically-valid maximum concentration of specified-size airborne particles.
Cleanroom certifications may occur in any of three different stages:
• As Built: a cleanroom fully constructed and operational, with all services
connected and functioning, but has no production equipment or operating
personnel
• At Rest: a cleanroom fully operational, with production equipment
installed and operating or operable, but has no personnel within the
facility.
• Operational: a cleanroom in normal manufacturing operations, including
equipment and personnel.

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 Sample locations (ISO-14644-1:2015)
Area of Cleanroom
Minimum number of
(m2)
sample locations to be
less than or equal
tested (NL)
to

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
• 5 m x 12 m = 60 m2 => 12 locations (from table) 192 21
232 22
• The cleanroom or clean zone area is divided up into a grid of 276 23

sections of near equal area, whose number is equal to the number 352
436
24
25
of sampling locations. 636 26
1000 27
• Sampling location representative of the characteristics of the >1000 See Equation A.1

section, not necessarily the center and at work height.

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 Sampling Volume per Location

• The single volume ( Vs )per location is determined by using the following

equation:
Vs = [ 20 / Cn,m ] x 1000
(expressed in liters)

• Vs is the minimum single sample volume per location, expressed in liters.

• Cn,m is the class limit (number of particles per cubic meter) for the
considered particle size specified for that class.

• 20 is the minimum number of particles needed for a statistically accurate

result.

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 Sampling Volume per Location - Example

• At each sampling location, sample a sufficient volume of air that a

minimum of 20 particles would be detected if the particle concentration
for the largest considered particle size were at the class limit for the
designated ISO class.

• Applying the formula, the single volume ( Vs )per location is calculated as:

Vs = [ 20 / 3520 ] x 1000 = 5.68 liters (for ISO-5)

(expressed in liters)

Vs = [ 20 / 35200 ] x 1000 = 0.568 liters (for ISO-6 )

(expressed in liters)

• Minimum Sample Period = 1 minute (28.3L with 1CFM particle counter)

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 EU and FDA Classification Tables

PICS

FDA

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 Additional EU Annex 1(PIC’S) Comments on
Classification

• Recertification of the cleanroom should follow the guidance given in ISO

14644-2.
– Once per year for ISO Class 6 and greater (ISO 7,8…)
– Once every six months for ISO Class 5 and cleaner (ISO4,3…)
• Note: exceptions can apply if using continuous monitoring

• The sample volume for Grade A cleanliness should be 1 m3 per sample

location.
• Portable particle counters with short length of tubing should be used
(<1m).
• Isokinetic sampling heads should be used in unidirectional flow zones.

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 Monitoring of a cleanroom, GMP guidance

EU Annex 1 (PIC’S):
• “Cleanrooms and clean air devices should be routinely monitored in
operation.”
• “Classification should be clearly differentiated from operational
process monitoring.”

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 GMP requirements for Monitoring

• EU (PIC’S) monitoring requirements:

– LOCATIONS: Risk-based selection of monitoring locations
– FREQUENCY:
• Continuous monitoring of critical areas (Grade A/B) (ISO5/ISO7)
• Routine monitoring of supporting cleanrooms (Grade C/D)
(ISO8/ISO9) depending on the nature of activities
– Microbial and particle monitoring are both required
– Compressed gases and ambient air must be monitored for microbial
and particle contamination. Check filter integrity.

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 Monitoring of a cleanroom

• Particle and microbial monitoring are required

• Decisions for monitoring frequency and locations are similar
– Risk-based design applies to both
– Commonly, particle and microbial points are next to each other
• Batch records must include both sets of data (V and NV), alarms,
and data on temperature, humidity, and differential pressure.

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 Monitoring – locations

EU Annex 1
• “Monitoring locations based on a formal risk analysis study and the
results obtained during classification”

Note: Risk analysis has to be described in a formal written plan that is followed. The plan
details must be rationalized and have good description.

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 Why an update of the Guideline?

• Emphasize principles of Quality Risk Management

• ICH Q8 – ICH Q9 – ICH 10 requirements officially adopted by EMA and FDA

• Streamlining and cleaning of content

• Remove ambiguities
• Hangovers from previous versions and different days
• e.g. averaging microbiological results

• Enforce the need of pharma companies to adopt state of the art:

• Include new technologies
• Single use closed systems, disposable systems
• Innovative technologies, processing and testing

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 New EU GMP Annex 1 - Scope

This Annex provides general guidance that should be used for all sterile medicinal
products and sterile active substances, via adaption, using the principles of Quality
Risk Management (QRM), to ensure that microbial, particulate and pyrogen
contamination associated with microbes is prevented in the final product.

• The New ANNEX 1 is now organized in a different way:

• A comprehensive document Map
• Index with a description of the paragraph

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 Old Annex 1 Section Number

1. Principle 12. Sanitation

2. General 13. Processing
3. Clean room and clean air device 14. Sterilization
classification 15. Sterilisation by heat
4. Clean room and clean air device 16. Moist heat
monitoring 17. Dry heat
5. Isolator technology 18. Sterilisation by radiation
6. Blow/fill/seal technology 19. Sterilisation with ethylene oxide
7. Terminally sterilized products 20. Filtration of medicinal products which
8. Aseptic preparations cannot be sterilized in their final
9. Personnel container
10. Premises 21. Finishing of sterile products
11. Equipment 22. Quality Control

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 Section Number

1. Scope 6. Equipment
Areas (other than sterile medicinal products) to apply General guidance on the design and operation of equipment.
general principles of the annex. 7. Utilities
2. Principle Guidance with regards to the special requirements of utilities
General principles as applied to the manufacture of such as water, air and vacuum.
medicinal products. 8. Production and specific technologies
3. Pharmaceutical Quality System (PQS) Discusses aseptic and terminal sterilization process approach
Highlights the specific requirements of the PQS when and different technologies such as lyophilization and Blow Fill
applied to sterile medicinal products. Seal (BFS) and their requirements. Discusses approaches to
4. Personnel product sterilization, equipment and packaging components.
Guidance on requirements for specific training, 9. Viable and non-viable environmental and process
knowledge and skills. Also gives guidance to the monitoring
qualification of personnel. Differs from section 5. Applies to ongoing routine monitoring
5. Premises for setting alert limits and reviewing trend data. Discusses
General guidance on needs of premises design and requirements of Aseptic Process Simulation.
qualification including the use of barrier technology. 10. Quality control (QC)
Discusses sterile medicinal product QC requirements.
11. Glossary explanation of specific terminology

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 New EU-GMP Annex 1 – Why an Update

•Introducing principles of Quality

Risk Management

•Over the last years,

the
•Contamination control strategy:
EU-GMP committee
• Understand facility has been working on •Reinforcing the need of
• Understand equipment the revision of the manufacturers to keep up with
• Understand process current technologies
Annex 1,
• Update based on feedback
Manufacture of
Sterile Medicinal
Products

•Reinforcing the need of •Adapted from :

manufacturers to keep up with •Regulatory update (Andrew Hopkins) 2017
current technologies:
• Single use closed systems
• Disposable systems

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 Annex 1: 2008 Vs Annex 1: 2017 - Terminology

Annex 1: 2008 Annex 1 draft: 2017

• Microbial and Microbiological • Microbial and Microbiological

• 23 time in 2008 version • 68 times in 2017 version
• Risk • Risk
• 20 time in 2008 version • 92 times in 2017 version
• Document size • Document size
• 16 pages • 50 pages

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 Viable vs non viable – Scientific basics

Comment

The new Annex 1

still uses the terminology of
• In Reality the terminology “Non-viable“ is
“viable” and “non viable” misleading and may cause misinterpretations.
• “Non-viables“ are in this context “Total
particulate“

Total Particulate
= viable + non viable(inert) particles

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 Clean room qualification vs Monitoring

Comment

5.26 For initial classification the minimum

number of sampling locations can be found in • Clear reference to ISO 14644-1
ISO 14644:2015 Part 1. However, a higher • Minimum Requirements!
number of samples and sample volume is
typically required for the aseptic processing
• Even distribution
room and the immediately adjacent • Based on risk assessment and
environment (grade A/B) …, the sampling process knowledge
locations should be distributed evenly
throughout the area of the clean room. For
later stages of qualification and classification,
…locations should be based on a
documented risk assessment …

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 5µm Removal from classification

Annex 1 2008 Annex 1 2017 Draft

Maximum permitted number of Maximum permitted number of particles
particles equal to or greater than 0.5 equal to or greater than 0.5 μm
μm
ISO
At rest equal to or In operation equal
classification in
Grade greater than 0.5 to or greater than
At Rest In Operation operation/at
Grade μm per m3 0.5 μm per m3
rest

0.5 μm 5.0μm 0.5 μm 5.0μm

A 3520 3520 5/5
A 3520 20 3520 20
B 3520 352000 5/7
B 3520 29 352000 2900
C 352000 3520000 7/8
C 352000 2900 3520000 29000
Not
D 3520000 8
defined
D 3520000 29000 Not defined Not defined

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 Greater or Equal to 5 µm removal for classification

GMP Annex 1 - 2008 GMP Annex 1 - 2008

• Equal to or greater than 5um

Greater or equal to 5um particles control isn’t required during
limit provided for Classification and cleanroom classification.
Monitoring • Due to particle loss issue (same as
per the ISO 14644-1:2015)
• Monitoring Limit is still @20
particle equal to or greater then
5um for Grade A.
• Emphasize the need of set-up
Alert limit based on risk and
hystorical data.

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 Clean room qualification vs Monitoring

Comment

• 5.28 Clean room qualification (including • Do not use classification limits (ISO 14644-
classification) should be clearly 1) for Monitoring!!!
differentiated from operational process
• Grade A and B zones are treated equally
environmental monitoring.
• Bi-annual requalification is not yet
• 5.29 Clean rooms should be requalified
standard and will create difficulties and
periodically and after changes to
loss of productivity at some facilities
equipment, facility or processes based on
the principles of QRM. For grade A and B • Risk Mitigation: Use of RMM to get the
zones, the maximum time interval for zones faster back into operation
requalification is 6 months. For grades C
and D, the maximum time interval for
requalification is 12 months.

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 Quality Risk Management Methods and Tools

Below is a list of some of these tools (further details in Annex 1 and section
VIII):
❖ Basic risk management facilitation methods (flowcharts, check sheets, etc.)
❖ Failure Mode Effects Analysis (FMEA)
❖ Failure Mode, Effects, and Criticality Analysis (FMECA)
❖ Fault Tree Analysis (FTA)
❖ Hazard Analysis and Critical Control Points (HACCP)
❖ Hazard Operability Analysis (HAZOP)
❖ Preliminary Hazard Analysis (PHA)
❖ Risk ranking and filtering
❖ Supporting statistical tools

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 FMEA: Environmental Monitoring

The particle and microbiological risk assessment should be carried out by a

multidisciplinary team is divided into two steps:

➢ Step 1: Risk analysis for each phase of the production process. The purpose
of this phase is to identify, through an FMEA approach, the critical
production areas where high-risk activities are performed for the product.

➢ Step 2: Following the Risk Control from Step 1, it is possible to proceed to

Phase 2 which is intended to establish the particle and microbiological
monitoring plan by FMEA method.

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 Failure Mode Effects Analysis (FMEA)

1. Identify the functions of your scope. Ask, “What is the purpose of this system, design,
process or service?
2. For each function, identify all the ways failure could happen
3. For each failure mode, identify all the consequences on the system, related systems,
process, related processes, product, service, customer or regulations
4. Determine how serious each effect is. This is the severity rating, or S. Severity is usually
rated on a scale from 1 to 10, where 1 is insignificant and 10 is catastrophic.
5. For each failure mode, determine all the potential root causes
6. For each cause, determine the occurrence rating, or O. This rating estimates the
probability of failure occurring for that reason during the lifetime of your scope.
Occurrence is usually rated on a scale from 1 to 10, where 1 is extremely unlikely and 10 is
inevitable.
7. For each cause, identify current process controls.

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 Failure Mode Effects Analysis (FMEA)

8. For each control, determine the detection rating, or D. This rating estimates how
well the controls can detect either the cause or its failure mode after they have happened
but before the customer is affected. Detection is usually rated on a scale from 1 to 10,
where 1 means the control is absolutely certain to detect the problem and 10 means the
control is certain not to detect the problem (or no control exists)

9. Calculate the risk priority number, or RPN, which equals S × O × D

RPN = S x O x D

These numbers provide guidance for ranking potential failures in the order they should be
addressed. Identify recommended actions. These actions may be design or process changes to
lower occurrence. They may be additional controls to improve detection. Also note who is
responsible for the actions and target completion dates.

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 Monitoring – frequency

EU Annex 1
• Grade A: Continuous monitoring required during setup and
operation
• Grade B: Recommend same as Grade A; frequency can be reduced
• Grade C, D: In accordance with principles of quality risk
management

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 Monitoring – sample volume

EU Annex 1
• “It is not necessary for the sample volume to be the same as that used for
formal classification of cleanrooms”

Not required to have cubic meter samples during continuous monitoring

• 1-minute sample periods are typical during continuous monitoring

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 Monitoring – special applications

• Powder filling
EU (PIC’S) acknowledge difficulty of monitoring close to fill point, but
both require monitoring prior to filling
– Recommendation:
• Monitor particles before and after filling. Monitor differential
pressure throughout.
• Monitor surrounding area, with frequency depending on the
barrier
• Dangerous product (cytotoxic, radioactive)
– Same as powder filling – monitor particles before and after filling
– Negative pressure isolator increases the importance of monitoring
the surrounding area.

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 Monitoring – compressed gas

EU Annex 1 (PIC’S)
• “Non-combustible gases should be passed through micro-organism
retentive filters.”
• “The integrity of critical gas and air vent filters should be confirmed
after use. The integrity of other filters should be confirmed at
appropriate intervals.”

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 Environmental Monitoring Summary

• GMPs require room classification, then monitoring.

• Design of monitoring systems should be based on a formal risk analysis.

• Microbial and particle contamination (viable and non-viable) must be

monitored in air and compressed gas.

• Critical areas (Grade A/B, ISO 5) should be monitored continuously.

• Supporting areas (Grade C/D, ISO 7/8) can be tested periodically with
portables or manifolds.

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 Classification And Monitoring Differences

Classification Monitoring
Frequency 6 months or annual Daily, weekly, monthly,
or continuous
Number of positions By formula Risk Analysis

Sample Volume By formula Based on grade of

room

Pass/Fail Criteria By table By need for trend info

or control
Reporting format By standard In form needed for
rapid understanding

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 ANVISA
The next three slides are from a
presentation given by ANVISA

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 •NEW GMP in Brazil: RDC 301 - INSTRUÇÃO NORMATIVA Nº 35/2019 Article 21
•Online Particle counting (monitoramento contínuo de partículas não viáveis)
•Art. 21.Para as áreas de Grau A, o monitoramento de partículas deve ser
realizado ao longo de toda a duração dos processos críticos, incluindo a
•Tex montagem do equipamento, exceto quando justificado pela presença de
to contaminantes no processo que danificariam o contador de partículas ou
representariam um perigo, como por exemplo organismos vivos e riscos
radiológicos,
• Vigência em onde
18 nesses
meses. casos, o monitoramento ao longo das operações
de preparação do equipamento, antes das situações impeditivas, deve ser
• Gerenciamento de risco definindo:
realizado
a) Processos assépticos (Montagem e conexão de filtros, alimentação de
consumíveis (tampas), acumulação de frascos ou ampolas, envase,
fechamento etc...)
b) Posições de amostragem ideais para a detecção de falhas
correlacionadas a particulado carreado pelo fluxo de ar (distância
máxima de 1ft). As posições devem minimizar ao máximo o
comprimento e as curvas do tubo de amostragem, e devem favorecer o
raio das curvaturas. (PDA – Points to consider to asseptic processing
Part 1)
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 •NEW GMP in Brazil: RDC 301 - INSTRUÇÃO NORMATIVA Nº 35/2019
•Article 21 – Particle Monitoring in Grade B
•Art. 22.Um sistema similar de monitoramento deve ser utilizado para
áreas Grau B, contudo a frequência de amostragem pode ser reduzida.
•Tex •§1ºA extensão do monitoramento da área Grau B correlaciona-se com a
to efetividade da segregação desta com a área Grau A que circunda.

• Contagem pelo procedimento de monitoramento de partículas, via

contadores portáteis.

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 •NEW GMP in Brazil: RDC 301 - INSTRUÇÃO NORMATIVA Nº 35/2019
•Articles 32, 35 and 36 – Environmental Monitoring of viables (partículas viáveis)

• Grau A – Monitoramento frequente durante toda a operação.

• Grau B – Monitoramento durante a operação .
• Graus C e D – Monitoramento por frequência definida em
Gerenciamento de Risco.
• Necessidade de estabelecimento de limites de alerta (quando possível) e
ação para todas as áreas.

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 Particle counting

• Typically monitoring for 0.5 µ and 5.0 µ

• Higher likelihood of 0.5 µ particles
• Very few particles at 5.0 µ
• Due to small quantities of particles present how to view the data
• Raw data
• Number of counts obtained
• Normalized
• Number of counts per unit of volume

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 0.5 µ Data

• Higher number of counts typically

• Can use traditional statistical methods
• Gather enough data prior to establishing limits
• Typically during media fill
• Revisit after months of data
• Revise if changes occur to the process

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 Data analysis – Initial Qualification and Routine Monitoring

• Particle alarms are often set to the maximum permitted concentration of

particles determined from Table 1 of ISO 14644-1.

• Classification table makes a good first step, but facilities should be

reviewing their data routinely (quarterly, annually) and setting these based
on actual data

• Classification limits are not the same as monitoring limits…

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 Particle data interpretation (0.5 µm)

Activity patterns Process signature

• Manufacturing shifts • Recipe flow
• Work flow • Sequencing

•95% UCL
• (SD x 2)
•Operationa
l Average

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 Data interpretation guidance

• For 0.5 µm particle data:

• A 95% confidence limit should be established for the actual events during
production
• Should be done during media fills while operators are following SOPs in ‘normal’
operations
• The limits found, typically, will be less than the class limits (i.e., may be less than
the Grade A or ISO 5 limit)

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 Different approaches

Cubic foot for monitoring

• Do not totalize 36 minutes of data then update
• Will miss significant events or run for too long with problems
• Rolling average
• Excursions will be masked by 1/36 of the event
Preferred
• Perform normalization
• Multiply the value by 35.3 to get normalized data.
• Will see events very clearly.
▪ Realize value is multiplied by 35.3

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 5.0 µ Data

• Typically few particles

• Difficult to perform statistic
• Continuous
• Frequent
• N of M sampling (number of
events per time in minutes)

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 Particle data interpretation (5.0 µm)

5.0 µm – Periodic data patterns to consider

N:m = 3:10
Continuous Frequent
Where t = 1 min

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 Data interpretation guidance

• For 5.0 µm particle data:

• In critical areas, single 5.0 µm events need to be tracked
• In this instance, a number of events-per-unit-time should be used
• Frequency is estimated to be no more than 3 events in any 10 minutes to create
an action (n:m = 3:10), and potentially 2:10 events for an alert
• Actual operations will determine limits

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 ISO Standards

EU Annex 1 says:
“This guidance does not lay out detailed methods for determining the
microbiological and particulate cleanliness of air, surfaces, etc. References
should be made to other documents such as the EN/ISO Standards.”

ISO 14644 – Cleanrooms and Controlled Environments

Defines cleanroom classes, certification methods, frequency, etc.

ISO 14698 – Biocontamination in Cleanrooms

Defines biological monitoring programs, choosing a sampling device, etc.

ISO 21501 – Particle Counters

Defines particle counter performance characteristics and calibration

ISO 8573 – Compressed Air

Defines compressed air contaminants, purity classes, test methods

63

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Dave Crance
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