The document summarizes key aspects of ISO 14644-1:2015, which provides the international standard for classifying air cleanliness in cleanrooms by particle concentration. It outlines the sampling and testing methodology used to measure airborne particle levels at different locations and classify cleanrooms into ISO classes based on particle size and concentration limits. Major changes in the updated 2015 standard include removing particle size classifications below 0.1 microns and above 5 microns, fixing the minimum number of required sampling locations based on cleanroom size, and eliminating the use of 95% confidence intervals in data analysis.
An introduction to the international cleanroom standard ISO 14644 and the 2015 revisions to Parts 1 and 2. The focus is on particulate and contamination control.
In this slide contains Investigation, reason, case study of OOS.
Presented by: K Venkatsai Preasad. (Department of pharmaceutical analysis and quality assurance).
RIPER, anantapur.
The subject of cleaning validation in active pharmaceutical ingredient manufacturing plants has continued to receive a large amount of attention from regulators, companies and customers alike.
The integration of Cleaning Validation within an effective Quality System supported by Quality Risk Management Processes should give assurance that API Manufacturing Operations are performed in such a way that Risks to patients related to cleaning validation are understood, assessed for impact and are mitigated as necessary.
It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place at this stage.
This presentation covers the requirements of Cleaning Validation for a Multipurpose API Manufactuirng Plant
This Annex describes the principles of qualification and validation which are applicable to the facilities, equipment, utilities and processes used for the manufacture of medicinal products and may also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II. It is a GMP requirement that manufacturers control the critical aspects of their particular operations through qualification and validation over the life cycle of the product and process. Any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assessed. Computerised systems used for the manufacture of medicinal products should also be validated according to the requirements of Annex 11. The relevant concepts and guidance presented in ICH Q8, Q9, Q10 and Q11 should also be taken into account.
Highlights of the guidance are given in following presentation.
An introduction to the international cleanroom standard ISO 14644 and the 2015 revisions to Parts 1 and 2. The focus is on particulate and contamination control.
In this slide contains Investigation, reason, case study of OOS.
Presented by: K Venkatsai Preasad. (Department of pharmaceutical analysis and quality assurance).
RIPER, anantapur.
The subject of cleaning validation in active pharmaceutical ingredient manufacturing plants has continued to receive a large amount of attention from regulators, companies and customers alike.
The integration of Cleaning Validation within an effective Quality System supported by Quality Risk Management Processes should give assurance that API Manufacturing Operations are performed in such a way that Risks to patients related to cleaning validation are understood, assessed for impact and are mitigated as necessary.
It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place at this stage.
This presentation covers the requirements of Cleaning Validation for a Multipurpose API Manufactuirng Plant
This Annex describes the principles of qualification and validation which are applicable to the facilities, equipment, utilities and processes used for the manufacture of medicinal products and may also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II. It is a GMP requirement that manufacturers control the critical aspects of their particular operations through qualification and validation over the life cycle of the product and process. Any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assessed. Computerised systems used for the manufacture of medicinal products should also be validated according to the requirements of Annex 11. The relevant concepts and guidance presented in ICH Q8, Q9, Q10 and Q11 should also be taken into account.
Highlights of the guidance are given in following presentation.
Contamination Control in Cleanrooms_Dr.A. AmsavelDr. Amsavel A
Basic’s of Contamination
Sources of Contamination
Environment Specification
Elements of Cleanroom Design and Qualification
Definitions
Control of Contaminations
People, Cleaning, Environment & Material
Operation, Monitoring and Control
Documents and Records
Aseptic / sterile - “ A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product”
Validation of aseptic process should be designed to provide assurance through appropriate testing that all phases and activities of the process remain sterile and it is controlled within the predetermined parameters.
Drug product, container, and closure are subject to sterilization separately, and then brought together.
Validation: Validation is a documented program that provides high degree of assurance that a specific process, method or system consistently produces a result meeting pre-determined acceptance criteria.
Discover the updates made to ISO 14644-1, and hire a team
with decades of cleanroom construction, testing, and certification experience to implement them.
Visit http://amcleanroombuild.com/ to learn more.
Contamination Control in Cleanrooms_Dr.A. AmsavelDr. Amsavel A
Basic’s of Contamination
Sources of Contamination
Environment Specification
Elements of Cleanroom Design and Qualification
Definitions
Control of Contaminations
People, Cleaning, Environment & Material
Operation, Monitoring and Control
Documents and Records
Aseptic / sterile - “ A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product”
Validation of aseptic process should be designed to provide assurance through appropriate testing that all phases and activities of the process remain sterile and it is controlled within the predetermined parameters.
Drug product, container, and closure are subject to sterilization separately, and then brought together.
Validation: Validation is a documented program that provides high degree of assurance that a specific process, method or system consistently produces a result meeting pre-determined acceptance criteria.
Discover the updates made to ISO 14644-1, and hire a team
with decades of cleanroom construction, testing, and certification experience to implement them.
Visit http://amcleanroombuild.com/ to learn more.
AAF has released a new whitepaper with a short outline on the historic development, current state and characteristics of the photometer and DPC leak testing procedures.
Pharmaceutical HVAC (Heating, ventilating, and air conditioning; also heating...Palash Das
This slide is represent the HVAC design,qualification and operational approach. As we know HVAC is important system for maintaining clean room. This presentation is made based on the requirement of Pharmaceutical Industry. All parameter are considered based on the current guidelines aspect.
ISO 14644-1.pptx.Cleanrooms and associated controlled environmentsNazim Hussain
ISO 14644 consists of the following parts, under the general title Cleanrooms and associated controlled environments:
Part 1: Classification of air cleanliness by particle concentration
Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration
Part 3: Test methods
Part 4: Design, construction and start-up
Part 5: Operations
Part 7: Separative devices (clean air hoods, gloveboxes, isolators and mini-environments)
Part 8: Classification of air cleanliness by chemical concentration (ACC)
Part 9: Classification of surface cleanliness by particle concentration
Part 10: Classification of surface cleanliness by chemical concentration
Cleanrooms and associated controlled environments provide for the control of contamination of air and, if appropriate, surfaces, to levels appropriate for accomplishing contamination-sensitive activities. Contamination control can be beneficial for protection of product or process integrity in applications in industries such as aerospace, microelectronics, pharmaceuticals, medical devices, healthcare and food.
This part of ISO 14644 specifies classes of air cleanliness in terms of the number of particles expressed as a concentration in air volume. It also specifies the standard method of testing to determine cleanliness class, including selection of sampling locations.
This edition is the result of a response to an ISO Systematic Review and includes changes in response to user and expert feedback validated by international enquiry. The title has been revised to “Classification of air cleanliness by particle concentration” to be consistent with other parts of ISO 14644. The nine ISO cleanliness classes are retained with minor revisions. Table 1 defines the particle concentration at various particle sizes for the nine integer classes. Table E.1 defines the maximum particle concentration at various particle sizes for intermediate classes. The use of these tables ensures better definition of the appropriate particle-size ranges for the different classes. This part of ISO 14644 retains the macroparticle descriptor concept; however, consideration of nano-scale particles (formerly defined as ultrafine particles) will be addressed in a separate standard.
The most significant change is the adoption of a more consistent statistical approach to the selection and the number of sampling locations; and the evaluation of the data collected. The statistical model is based on adaptation of the hypergeometric sampling model technique, where samples are drawn randomly without replacement from a finite population. The new approach allows each location to be treated independently with at least a 95 % level of confidence that at least 90 % of the cleanroom or clean zone areas will comply with the maximum particle concentration limit for the target class of air cleanliness.
What is likely to go into the revised Annex 1, including:
Terminal sterilisation vs aseptic processing
WFI produced by reverse osmosis
Guidance for media simulation trials
This remains speculative
One way AMTS is “Constructing an Intelligent Tomorrow” is through the work of our Cleanroom Performance Solutions group. In this 4-part series, our very own Emil Bordelon, a NEBB Certified Professional, outlines the four main elements of a cleanroom that are considered during the design, certification and maintenance phases.
http://amcleanroombuild.com/
Points about USFDA FS209E Monitoring of airborne particulate cleanliness. It contain some definitions and samplings procedures. Do follow the the us fda guidlines
Tiêu chuẩn ISO 14644 cho phòng sạch phần 3: phòng sạch và các môi trường kiểm soát liên quan. Xem thêm các tài liệu khác trên kênh của Công ty Cổ phần Tư vấn Thiết kế GMP EU
"Listerien-Referenzlabor: Akademischer Luxus oder Public Health Erfordernis?", 19. Oktober 2012 (AGES, Graz)
Das Nationale Listerien-Referenzlabor ist innerhalb der AGES an das "Zentrum für lebensmittelbedingte Infektionskrankheiten" / Institut für medizinische Mikrobiologie und Hygiene in Graz übersiedelt. Zum Auftakt am neuen Standort veranstaltete die AGES dieses Fachgespräch, bei dem verschiedene Aspekte in Zusammenhang mit dem potentiellen Auftreten von Listerien aktuell beleuchtet wurden. Erstmals wurden zudem die neuen Richtlinien des Europäischen Referenzlabors (EU-RL) für Listeria monocytogenes zur Harmonisierung der Probennahme vorgestellt.
Dokumentation der Fachtagung mit Präsentationen:
http://www.ages.at/ages/ages-akademie/stakeholderveranstaltungen/graz-listerien-referenzlabor/
The liquid oral manufacturing plant is designed to be operated by one operator and one helper, saving on precious man-power costs. Sugar syrup and manufacturing vessels are provided with limpet coils for heating and cooling, designed for internal vacuum to facilitate transfer of sugar directly from stores to sugar syrup vessel.
Site Master File or SMF is a document in the pharmaceutical industry which provides information about the production and control of manufacturing operations. The document is created by a manufacturer.
It's a document prepared by the manufacturer containing specific and factual GMP information about the production and/or control of pharmaceutical manufacturing operations carried out at the named site and any closely integrated operations at adjacent and nearby buildings. If only part of a pharmaceutical operation is carried out on the site, the site master file need describe only those operations, e.g., analysis, packaging.
Site Master File or SMF is a document in the pharmaceutical industry which provides information about the production and control of manufacturing operations. The document is created by a manufacturer.
It's a document prepared by the manufacturer containing specific and factual GMP information about the production and/or control of pharmaceutical manufacturing operations carried out at the named site and any closely integrated operations at adjacent and nearby buildings. If only part of a pharmaceutical operation is carried out on the site, the site master file need describe only those operations, e.g., analysis, packaging.
1. ISO 14644-1:2015
CLEANROOMS & ASSOCIATED CONTROLLED
ENVIRONMENTS
PART 1: CLASSIFICATION OF AIR CLEANLINESS
BY PARTICLE CONCENTRATION
Anwar Munjewar
Quality Assurance Department
Bharat Serums and Vaccines Limited
2. ABOUT INTERNATIONAL
ORGANIZATION FOR
STANDARDIZATION■ ISO is an independent, non-governmental international organization with a
membership of 163 national standards bodies. Through its members, it brings
together experts to share knowledge and develop voluntary, consensus-based,
market relevant International Standards that support innovation and provide
solutions to global challenges.
■ What are standards?
• International Standards make things work. They give world-class
specifications for products, services and systems, to ensure quality, safety
and efficiency. They are instrumental in facilitating international trade.
■ ISO has published more than 21000 International Standards and related
documents, covering almost every industry, from technology, to food safety, to
agriculture and healthcare. ISO International Standards impact everyone,
everywhere.
3. HOW DOES ISO DEVELOP
STANDARDS?
New
Standards is
proposed to
relevant
technical
committee
Working
group of
experts start
discussion to
prepare a
working draft
1st working
draft shared
with technical
committee
and ISO CS
Draft shared
with all ISO
national
members,
who are
asked to
comment
Final draft
sent to ISO
members
ISO
International
Standards
If proposal is accepted
If standards approved by member
vote
4. ISO TECHNICAL COMMITTEE 209
Cleanroom associated with controlled environments
■ Participating Country :
22
■ Observing Country : 19
Secretariat: USA (ANSI)
Australia (SA) Kenya (KEBS)
Belgium (NBN) South Korea (KAT)
Brazil (ABNT) Netherlands (NEN)
China (SAC) Norway (SN)
Denmark (DS) Phillipense (BPS)
Finland (SFS) Portugal (IPQ)
France (AFNOR) Russian Federation
Germany (DIN) Sweden (SIS)
Ireland (NSAI) Switzerland (SNV)
Italy (UNI)
United Kingdom
(BSI
Argentina Poland
Bosnia and Herzegovina Romania
Bulgaria Saudi Arabia
Cuba Serbia
Czeh Republic South Affrica
Egypt Thailand
Hungary Turkey
India Ukraine
Iran
Jamaica
Malaysia
5. ISO PARTS & STATUS
■ Part 1: Classification of air cleanliness by particle concentration (15th Dec 2015)
■ Part 2: Monitoring to provide evidence of cleanroom performance related to air
cleanliness by particle concentration (15th Dec 2015)
■ Part 3: Test Methods (DIS 2014)
■ Part 4: Design, construction and start-up (2001)
■ Part 5: Operations (2004)
■ Part 6: Vocabulary (2006)
■ Part 7: Separative devices (clean air hoods, gloveboxes, isolators and environments)
(2007)
■ Part 8: Classification of air cleanliness by Chemical concentration (2013)
■ Part 9: Classification of surface cleanliness by Particle concentration (2012)
■ Part 10: Classification of surface cleanliness by Chemical concentration (2013)
Note: There is no Part 11 in ISO 14664, and Part 12 – Part 16 is under process(Draft).
6. SCOPE
■ Only particle populations having cumulative distributions based on threshold
(lower limit) particle sizes ranging from 0.1 µm to 5.0 µm are considered for
classification purposes.
■ Light scattering (discreet) airborne particle counters (LSAPC) is the basis
for the determination of the concentration of airborne particles equal to and
greater than the specified sizes, at designated sampling locations.
■ ISO 14644 does not provide for the classification of particle populations that are
outside the specified lower threshold particle size range 0.1 µm to 5.0 µm.
■ An M descriptor may be used to quantify populations of macroparticles
(particles larger than 5 µm).
■ The standards also allow the addition of location to the minimum number of
sampling locations.
■ Calculation for Number of location changed and 95% UCL completely
removed.
8. Method for Classification of Air
Cleanliness by Particle Concentration
■ Apparatus: Light Scattering Airborne Particle Counter (LSAPC)
■ Establishment of Sampling locations:
– Drive the number of sampling locations from the Table 1
– Positioning the sampling locations
– Sampling locations for large cleanrooms or clean zone
– Establishment of single sample volume and sampling time per locations
– Processing of results
– Interpretation of result
10. A.4.2 Positioning the sampling locations
Use the minimum number of sampling locations NL derived from the Table 1
Divide the whole cleanroom or clean zone into NL section of equal area
Select within each section a sampling location considered to be
representative of the characteristics of the section
Additional sampling locations may be selected for locations considered
critical
A.4.3 Sampling locations for large cleanrooms or clean zone
When the area of a clean room is greater than 1000 meter square.
𝑁 𝐿 = 27 𝑥
𝐴
1000
NL- is the minimum number of sampling locations to be evaluated
A- is the area of the clean room in meter square.
11. A.4.4 Establishment of single sample volume and sampling
time per locations
At sample location, sample a volume of air sufficient to detect a minimum of 20
particles if the particle concentration for the largest selected particle size were at the
class limit for the designated ISO class
Single sample volume:
𝑉𝑠 = (
20
𝐶𝑛,𝑚
) x 1000
Where,
Vs – is the minimum single volume per location (expressed in liters)
Cn,m – is the class limit (number of particles per cubic meter) for the largest
considered particle size.
20 – is the number of particles that could be counted if the particle concentration
were at the class limit.
12. A.6 Processing of results:
A.6.1 Recording of results:
– Record each sample measurements as the number of particles in each single
sample volume.
– When two or more single sample volume are taken at a location, calculate and
record the average number of particles per location at each considered particle
size.
– For particle counters with concentration calculation mode, the manual
evaluation may not be necessary. (i.e. counts per litter to counts per cubic
meter)
A.6.2 Interpretation of result:
– If an out-of-specification count found at a location due to an identified abnormal
occurrence, then that count can be discarded and noted as such on the test
report and a new sample taken.
– If an out-of-specification count found at a location is attributed to a technical
failure of the cleanroom or equipment, then cause should be identified, remedial
action taken and resting performed of the failed sampling location, the
immediate surroundings locations and any other locations affected. The choice
shall be clearly documented and justified.
13. ISO 14644-1:2015(E) ANNEX
■ Annex A – Reference Method For Classification Of Air Cleanliness By Particle
Concentration
■ Annex B – Examples Of Classification Calculations
■ Annex C – Counting And Sizing Of Airborne Macroparticles (M descriptor)
■ Annex D – Sequential Sampling Procedure : NA
■ Annex E – Specification Of Intermediate Decimal Cleanliness Classes And
Particle Size Thresholds : NA
■ Annex F – Test Instruments : NA
14. Why Does the Pharmaceutical Industry
Love 5.0 μm particles?
■ EU inspectors maintain that large particles are potential carriers (hitch-hikers) of, or
are viable organisms themselves. If these particles are present in an aseptic
environment, they represent an increased risk of contamination of the sterile
product. Most ISO Class 5 (Grade A) clean zone shave counts of zero or one on the
>= 5 μm size channel. Viable microorganisms, whose individual sizes are generally
less than 1 μm, tend to form in pairs, chains, and clusters. These colony forming
units together often have a size greater than 5 μm. Therefore, a particle counter is
like the “canary in a coal mine”, because it provides an early warning of a potential
problem.
■ It is worth while noting that USFDA cGMP 2004 does not require measurement of
5um particles in ISO Class 5.
15. Counting and Sizing of Airborne
Macroparticles – M Descriptor
■ The test method describe the measurement of airborne particles with a threshold
size ≥ 5 µm in diameter(macroparticles).
■ The number of sampling location, location selection and quantity of data required
should be in accordance with A.4.
■ M descriptor format:
“ISO M (a;b); C”
Where,
a- is the maximum permitted concertation of macroparticles (in cubic meter)
b- is the equivalent diameter associated with the specified method for
measuring macroparticles.
c- is the specified measurement method.
Example : To express an airborne concentration of 29 particles per cubic meter in the
particle size range ≥ 5 µm using LSAPC
“ ISO M (29; ≥ 5 µm ); LSAPC”
16. Annex A of ISO 14644-1:2015
■ Clause A.2 Apparatus Requirements, under A.2.2 Instrument Calibration
specifies that the particle counter shall have a valid calibration certificate, the
frequency and method of calibration should be based upon ISO 21501-4
■ Old ISO14644 specified calibration be performed by suitable method. New
revision recognises some of the older particle counters (ex. those manufactured
prior to 2011) cannot be calibrated to all of the required tests in ISO21501-4
■ Some details of this new calibration standard are given in the next two slides, a
detailed presentation is available from the author.
17. ISO 21501-4 Calibration
■ Parameters that will now be required
– Size Calibration (Using NIST traceable particles)
– Size Verification
– Counting Efficiency (50% and 100%)
– Size resolution (equal to or less than 15%)
– False Count Rate (1 or less in 15 minutes)
– Maximum Concentration (before coincidence loss)
– Flow Rate (Uncertainty of 5% or less)
– Sample Time (Uncertainty of 1% or less)
– Response Rate (0.5% or less)
– Calibration Interval ( not to exceed 1 year)
– Test Report (minimum information required)
18. Summary
ISO14644-1:1999 ISO14644-1:2015
Title Change
Part 1 : Classification of air cleanliness
Part 1 : Classification of air cleanliness by particle
concentration
Ultra and Macro (U,M) Descriptors
Smaller than 0.1 microns defined as U, >than 5
microns defined as M.
Smaller than 0.1 micron particles will no longer
exist in ISO 14644-1. This issue addressed in
ISO 14644-12 (Air cleanliness by nanoparticles).
Annex A Informative (Graphical Illustration of
classes)
Annex A (normative) Reference method for
determination of classification
Table E.1 of Annex E provides permitted
intermediate air cleanliness classes in increments
of 0.5 (3.5, 4.5, 5.5etc.)
No graphical illustration
19. Summary
ISO14644-1:1999 ISO14644-1:2015
ISO Class 5, 5.0 micron – 29 Particles No more Class 5, 5.0 micron size
Sample Numbers and Locations
Square-root method for sample numbers.
Grid for sample locations
Table A.1. (Fixed numbers). Sections of equal
area, within each section select location
representative of characteristics of the section
Apparatus for Particle Count
DPC = Discrete Particle Counter
LSAPC = Light Scattering Airborne Particle
Counter
ParticleSizes in Classification Table
ISO Class 1: 0.2 um = 2 particles
ISO Class 2: 0.5 um =4 particles
ISOClass 3: 1.0 um = 8 particles
ISO Class 5: 5.0 um = 29 particles
Since it is possible to classify a cleanroom at one
particle size only, these low table values are
removed and cannot be used for classification.
95% Upper Confidence Limit
>1 & <10 sample points, 95% UCL should be 95% UCL removed completely