2. 22
GMPGMP
MANUFACTURING ENVIRONMENTSMANUFACTURING ENVIRONMENTS
Presentation OutlinePresentation Outline
Module 1:Module 1: Introduction to GMP EnvironmentsIntroduction to GMP Environments
Module 2:Module 2: Air Conditioning System ComponentsAir Conditioning System Components
Module 3:Module 3: Types & Configurations of AC SystemsTypes & Configurations of AC Systems
Module 4:Module 4: Pressure Cascades & building LayoutsPressure Cascades & building Layouts
Module 5:Module 5: Validation, Qualification & MaintenanceValidation, Qualification & Maintenance
3. 33
GMPGMP
MANUFACTURING ENVIRONMENTSMANUFACTURING ENVIRONMENTS
Topics for this ModuleTopics for this Module
• What makes up the manufacturingWhat makes up the manufacturing
environment (not just Environmentalenvironment (not just Environmental
Control System)Control System)
• Contamination & cross-contaminationContamination & cross-contamination
• How cleanrooms are definedHow cleanrooms are defined
• Levels of ProtectionLevels of Protection ∆∆
4. 44
Module 1: Introduction to GMPModule 1: Introduction to GMP
Manufacturing EnvironmentsManufacturing Environments
• The primary objective of manufacturing in anThe primary objective of manufacturing in an
ideal GMP environment is that this should leadideal GMP environment is that this should lead
to a high quality product being produced.to a high quality product being produced.
• Manufacturing in an ideal environment not onlyManufacturing in an ideal environment not only
leads to better quality products but should alsoleads to better quality products but should also
result in :result in :
* Improved production rates.* Improved production rates.
* Operator comfort, satisfaction and safety.* Operator comfort, satisfaction and safety. ∆∆
5. 55
Factors Contributing to QualityFactors Contributing to Quality
ProductsProducts
Raw Materials
Personnel
Procedures
Validated processes
Equipment
Premises
Environment
Packing Materials
Validated processes
Equipment
Premises
Environment
The most important!
6. 66
Design considerationsDesign considerations
for a manufacturing facilityfor a manufacturing facility
Prevent
contact
with dust
Prevent
contact
with fumes
Acceptable
comfort
conditions
cross-contamination
Protect from
product
Protect from
ambient
contamination
contamination
Prevent
of staff
Correct
temperature
and humidity
Avoid
dust
discharge
Avoid
fume
discharge
Avoid
effluent
discharge
PERSONNEL
PROTECTION
PRODUCT
PROTECTION
ENVIRONMENT
PROTECTION
GMP MANUFACTURING
ENVIRONMENT
Three primary considerations to be addressed to ensure a safe and
productive manufacturing facility
7. 77
The environment comprises aspects such as:
1. Light
2. Temperature
3. Humidity
4. Air movement
5. Microbial contamination
6. Particulate contamination
Uncontrolled environments can lead to:
Product degradation & contamination
Loss of Product & Profit ∆
The manufacturing environment is
critical for product quality
PIC/S PH 1/97 (Rev.3) #3.3 & 3.12
8. 88
Contaminants are :Contaminants are :
1.1.Products or substances other thanProducts or substances other than
product manufacturedproduct manufactured
2.2.Foreign productsForeign products
3.3.Particulate matterParticulate matter
4.4.Micro-organismsMicro-organisms
5.5.Endotoxins (degraded micro-organisms)Endotoxins (degraded micro-organisms)
Cross-contamination is a particular case ofCross-contamination is a particular case of
contaminationcontamination ∆∆
What are Contaminants ?
9. 99
What is Cross-What is Cross-
Contamination ?Contamination ?
Definition of Cross-Definition of Cross-
ContaminationContamination
““Contamination of a starting material,Contamination of a starting material,
or of a product with another startingor of a product with another starting
material or product.”material or product.”
Cross – Contamination (1)
PIC/S PH 1/97 (Rev.3) Pg. 134
10. 1010
From where does Cross-ContaminationFrom where does Cross-Contamination
originate?originate?
1.1. Poorly designed air handling systemsPoorly designed air handling systems
and dust extraction systemsand dust extraction systems
2.2. Poorly operated and maintained airPoorly operated and maintained air
handling systems and dust extractionhandling systems and dust extraction
systemssystems
3.3. Inadequate procedures for personnel andInadequate procedures for personnel and
equipmentequipment
4.4. Insufficiently cleaned equipmentInsufficiently cleaned equipment ∆∆
Cross – Contamination (2)
PIC/S PH 1/97 (Rev.3) # 3.14
12. 1212
Cross-Contamination (4)Cross-Contamination (4)
Cross-contamination can be minimized byCross-contamination can be minimized by
1.1. Personnel proceduresPersonnel procedures
2.2. Adequate premisesAdequate premises
3.3. Use of closed production systemsUse of closed production systems
4.4. Adequate, validated cleaningAdequate, validated cleaning
proceduresprocedures
5.5. Appropriate Levels of Protection ofAppropriate Levels of Protection of
productproduct
6.6. Correct air pressure cascadeCorrect air pressure cascade ∆∆
13. 1313
How are Contaminants Removed?How are Contaminants Removed?
• By efficient filtration of supply air.By efficient filtration of supply air.
• By dilution of contaminants or flushingBy dilution of contaminants or flushing
contaminants by supplying adequate aircontaminants by supplying adequate air
quantities to the room.quantities to the room. ∆∆
More about this later!
14. 1414
Where Do Contaminants Come From?Where Do Contaminants Come From?
• Outside air carries dust which is a contaminantOutside air carries dust which is a contaminant
• People generate contaminants:People generate contaminants:
We completely shed our outer skin every 24 hrs.We completely shed our outer skin every 24 hrs.
Particles of 0,3 micron & greater are liberated at aParticles of 0,3 micron & greater are liberated at a
rate varying between of 100 000 to 10 million perrate varying between of 100 000 to 10 million per
minuteminute
A person walking will liberate 5000 bacteria/minuteA person walking will liberate 5000 bacteria/minute
and a single sneeze can produce up to 1 millionand a single sneeze can produce up to 1 million
bacteria.bacteria.
• The manufacturing process itself can generateThe manufacturing process itself can generate
contaminants eg paint off equipment, dustcontaminants eg paint off equipment, dust
from belt drives, etcfrom belt drives, etc ∆∆
15. 1515
Why All the Concern About Dust?Why All the Concern About Dust?
Typical size relationship between
dust, bacteria and viruses
Virus
(0,006µm to 0,03µm)
Dust Particle
(0,5µm to 500µm)
Bacteria
(0,2µm to 2µm)
Dust Is a Bacteria Carrier
17. 1717
Removal of BacteriaRemoval of Bacteria
• As dust is a carrier, dust must beAs dust is a carrier, dust must be
controlled.controlled.
• Ambient bacteria is removed byAmbient bacteria is removed by
filtration.filtration.
• Internal bacterial distribution can beInternal bacterial distribution can be
controlled by directional air flow andcontrolled by directional air flow and
air flushing or dilution.air flushing or dilution.
• Surface bacteria is controlled bySurface bacteria is controlled by
adherence to strict cleaning sop’s.adherence to strict cleaning sop’s. ∆∆
18. 1818
Defining the EnvironmentDefining the Environment
• What is the manufacturing environment ?What is the manufacturing environment ?
• How does the manufacturing environmentHow does the manufacturing environment
effect contamination and cross-effect contamination and cross-
contamination ?contamination ?
• Cleanroom conceptCleanroom concept ∆∆
19. 1919
What Is a Cleanroom ?What Is a Cleanroom ?
A cleanroom is an
environment where
the particulate
contamination &
bacterial
contamination are
limited to
prescribed levels.
21. 2121
Controlled Environment StandardsControlled Environment Standards
CONTROLLED ENVIRONMENT STANDARDS
BS EN ISO 1 4644-1: 1999, Federal Standard and Approximate Equivalents.
-
-
-
•= Uni-directional (Laminar Flow) ** = Maximum number of viable microorganisms permitted per m³.
Annex 1 # 3
200
22. 2222
Facility Parameters ThatFacility Parameters That
Need To Be ControlledNeed To Be Controlled
TemperatureTemperature
Humidity
Air Cleanliness
Room Pressure
Air movement
Lighting
23. 2323
How Clean Should It Be?How Clean Should It Be?
Level of Protection ConceptLevel of Protection Concept
1.1. Defines environmental requirementsDefines environmental requirements
2.2. Working to defined environments helps preventWorking to defined environments helps prevent
contamination and cross-contaminationcontamination and cross-contamination
3.3. Allows production under optimal hygiene conditionsAllows production under optimal hygiene conditions
4.4. Takes into accountTakes into account
• product sensitivity to contaminationproduct sensitivity to contamination
• therapeutic risktherapeutic risk ∆∆
24. 2424
Many Different Standards In UseMany Different Standards In Use
Levels of Protection & Cleanroom ClassLevels of Protection & Cleanroom Class
definitions currently in use.definitions currently in use.
EC, PIC/S, TGA, WHO, etc. :EC, PIC/S, TGA, WHO, etc. : A, B, C, D.A, B, C, D.
US FDA :US FDA : Critical and Controlled orCritical and Controlled or
Class 100, 1000, etc.Class 100, 1000, etc.
ISPE :ISPE : Level 1, 2 or 3 orLevel 1, 2 or 3 or
Cleanroom class (ISO 5, 6, etc.).Cleanroom class (ISO 5, 6, etc.).
Companies :Companies : Various others such as White, Grey,Various others such as White, Grey,
Black, Green, etc.Black, Green, etc.
26. 2626
Levels of ProtectionLevels of Protection
Parameters to be defined:Parameters to be defined:
1.1. Air cleanliness requirements (filter typeAir cleanliness requirements (filter type
and position, air changes, air flowand position, air changes, air flow
patterns, pressure differentials,patterns, pressure differentials,
contamination levels by particulate mattercontamination levels by particulate matter
and micro-organisms)and micro-organisms)
2.2. Personnel and material transfer methodsPersonnel and material transfer methods
3.3. Permitted operationsPermitted operations
4.4. Building design & finishesBuilding design & finishes ∆∆
27. 2727
Levels of ProtectionLevels of Protection
All operations within a pharmaceutical facilility must beAll operations within a pharmaceutical facilility must be
correlated to well-defined Cleanroom classes.correlated to well-defined Cleanroom classes.
Example:Example:
ISO 14644-1 ISO 5U ISO 5T ISO 7 ISO 8
Washing of Containers X
Preparation of solution for terminal sterilization X
Preparation of solutions for aseptic filling X X X
Depyrogenisation of containers X
Filling for terminal sterilization X
Filling for aseptic process X
Etc.
U = Uni-directional
T = Turbulent
Annex 1, # 3, Pg 41
28. 2828
Based on the Cleanroom Class Requirements,Based on the Cleanroom Class Requirements,
various Levels of Protection have to bevarious Levels of Protection have to be
created, including:created, including:
1.1. Correlation between process operations and Cleanroom classesCorrelation between process operations and Cleanroom classes
2.2. Type of operation permitted in each Level of Protection zoneType of operation permitted in each Level of Protection zone
3.3. Definition of Cleanroom class (Contaminant parameters, buildingDefinition of Cleanroom class (Contaminant parameters, building
materials, room requirements, air handling systems )materials, room requirements, air handling systems )
4.4. Requirements for personnel and material in the different classesRequirements for personnel and material in the different classes
(clothing, training, type of materials, etc. )(clothing, training, type of materials, etc. )
5.5. Requirements on entry conditions for personnel and materialRequirements on entry conditions for personnel and material
(change & clean-down procedures )(change & clean-down procedures ) ∆∆
Levels of Protection
29. 2929
Parameters Influencing theParameters Influencing the
Level of Protection (1)Level of Protection (1)
Air Handling
System
Production Room
With
Defined
Requirements
Supply
Air
Outlet
Air
How does an Air Handling System influence
the Cleanroom Class or Level of Protection ?
30. 3030
Parameters Influencing theParameters Influencing the
Level of Protection (2)Level of Protection (2)
11 Number of particles in the airNumber of particles in the air
22 Number of micro-organisms in the air or onNumber of micro-organisms in the air or on
surfacessurfaces
33 Number of air changes for each roomNumber of air changes for each room
44 Air velocityAir velocity
55 Air flow patternAir flow pattern
66 Filters ( type, position )Filters ( type, position )
77 Air Pressure differentials between roomsAir Pressure differentials between rooms
88 Temperature, humidityTemperature, humidity ∆∆
31. 3131
Parameters Influencing theParameters Influencing the
Level of Protection (3)Level of Protection (3)
Cleanroom Class
defined by
Critical Parameters
Air Handling
System
Additional Measures
32. 3232
Parameters Influencing theParameters Influencing the
Level of Protection (4)Level of Protection (4)
Air handling systemsAir handling systems::
• are the main tool for reaching requiredare the main tool for reaching required
parametersparameters
• but are not sufficient as suchbut are not sufficient as such
Need for additional measures such asNeed for additional measures such as
Appropriate gowning (type of clothing, properAppropriate gowning (type of clothing, proper
changingchanging rooms)rooms)
Validated sanitationValidated sanitation
Adequate transfer procedures for materials andAdequate transfer procedures for materials and
personnelpersonnel ∆∆∆∆
Questions & AnswersQuestions & Answers
Editor's Notes
Production environment is not just ECS – lots of aspects affect the air quality such as:
Building and equipment finishes
Staff discipline
Building layout
Production processes
All factors contributing to a quality medicine must be seen as interactive.It is not possible to neglect any of them, as they mutually influence each other.
There are no independently operating systems.
We will be paying the most attention to Product Protection as this is the most important from an inspector’s point of view.
We will only briefly look at Personnel Protection and Environment Protection
Some environmental factors have a direct influence on a product: (these factors also have practical operator considerations, such as light is required to see, etc.)
Light, for light sensitive products (photo-degradation)
Temperature, for temperature sensitive products (many injectables, vaccines)
Humidity, often for capsules and always for effervescent tablets. The higher the temp & RH the greater the proliferation of bacteria.
Air movement, affecting contamination & cross-contamination
Microbial contamination can lead to the destruction of the product and to grave accidents in the case of injectables or sterile products
Particulate contamination is critical in injectable forms
These factors, if not properly controlled, can lead to:
Product degradation
Product contamination
Loss of product & profit
Cross contamination can lead to sensitisation or allergic reactions. In the case of highly potent drugs, it can lead to grave accidents.
Temp, humidity and air movement will be discussed in more detail in later modules.
What are contaminants?
Contaminants are in fact the presence of anything in the manufactured product which should not be there.
Contaminants can be:
Products or substances other than product manufactured (eg. products resulting from air pollution)
Foreign products, such as metal parts from equipment, paint chips,etc.
Particulate matter, especially dangerous in injectables
Micro-organisms – a particular problem for sterile products.
Endotoxins: Even if killed by thermal treatment, micro-organisms are degraded to endotoxins and can cause damage.
Contaminants can originate from:
Environment (particles, micro-organisms, dust containing other products)
Equipment (residues of other products, oil, particles, rust, gaskets, metal) and can be brought into the product by air movements.
Definition of Cross-Contamination
Definition according to the PIC/S Guide to GMP for Medicinal Products. (Yellow box at bottom of various slides will refer to the PIC/S guide)
In other words, Cross-Contamination is the presence in a particular product of small, traceable quantities of other pharmaceutical products manufactured
at the same time in the same premises
previously on the same equipment or in the same premises
Cross-Contamination is thus only concerned with the presence of traces of products manufactured in-house !
Adequate analytical detection is important to detect traces of contamination:Validated analytical methods, especially developed for detection purposes, may be necessary to detect cross-contamination.
An absence of cross-contamination being detected may just mean the absence of adequate analytical procedures.
Cross-contamination is a sure indication of bad practices, as it shows that there is insufficient control over
Design of premises and systems quality
Air handling and dust extraction systems
Operation and maintenance of air handling and dust extraction systems
Procedures for cleaning of equipment and for restriction of movement of personnel
Procedures for cleaning of premises
Contamination is the introduction of foreign products into a drug, which does not come from another drug product.
Particles (squames) of 0,3 micron & greater are liberated at a rate varying between of 100 000 to 10 million per minute (depending on the level of activity & the garments worn)
Patient contaminants – bone saw – trauma case patient
Dust carries bacteria, much like a dog carries fleas.
Dust can be categorized into 3 groups:
COARSE DUST (50-500 microns) – settles rapidly
FINE DUST (1,0 – 50 microns) – settles slowly
ULTRA FINE DUST (< 0,5 – 1 micron) – remains suspended.
The smallest particle visible with the human eye is about 10 micron in size
Just because you cant see it does’nt mean the dust is not there!
Before proceeding further we need to look at how we define the Manufacturing Environment. What is the air quality required and how do we quantify this?
Rather than refer to the Manufacturing Environment – we would like to use the more generic term of “cleanroom”, which could refer to the production area, sampling area, Q& A Labs. Etc…
In the next slide we will look at how the air cleanliness defined.
People often mistakenly refer to a cleanroom classification by a filter efficiency.
Be sure that the air particle tests are correctly carried out. There are very specific procedures laid down for carrying out particle counts. Ask for Mapping points!
It is possible to get a very good particle count by sampling the air directly below an air inlet, but this gives a totally false reading as it is not representative of the room condition.
The next slide gives a comparison of various international cleanroom standards as well as well as recommended bacterial limits.
Give origin of Class 100 etc. (imperial)
Be sure to specify full criteria i.e. “as-built’, “at rest” or “operational” You need this 2nd criteria. Without specifying this it is like saying your car does 150!! Is that m/s, furlongs/fortnight or km/h.
Bacterial limits = max no of viable organisms permitted per m3
An automated Building Management System is a great help in monitoring these conditions and establishing trends.
We need to have a measure for defining different levels of cleanliness. For instance manufacture of open product must obviously be cleaner than Secondary Packing where product is closed – but how do we define this?
Having the zones classified ensures that we operate in the correct environment to prevent contamination and cross-contamination.
There are may different standards in use today. The recommendation is to adopt the new ISO standards to define the Level of Protection or Cleanliness.
The illustation shows that the manufacturing environmental requirements, as defined in the definition of the cleanroom zones, increase with the therapeutic risk.
The Level of Protection classes are classified as a function of the product sensitivity to contamination (e.g. aseptically filled products are handled in a higher class than terminally sterilised products) and to the therapeutic risk (stricter environment for injectables, as injectables enter directly into the bloodstream without the additional protection given by the stomach and intestinal barriers ).
In order to obtain a constant and well-defined quality level, it is necessary to have well-defined requirements for the cleanroom zones.
Level of Protection classes are referred to as Class A, B, C, etc. in the EC countries, whereas other countries may refer to Class 100, 1000, etc or ISO Class 5, 6, 7, etc. These different classes will be discussed later in this module.
All the above aspects need to be present to achieve a balanced facility.
ISO 5U refers to an ISO class 5 with uni-directional airflow (equates to an EU Class A). Uni-directional airflow is the term which is currently set to replace all reference to Laminar airflow in GMP guides.
ISO 5T refers to Turbulent airflow (EU Class B or US Class 100 turbulent flow)
The manufacturers should have a Level of Protection Concept for their factories, stating:
Correlation between process operations and Cleanroom classes, as shown in the table of the previous slide
Type of operation permitted in each hygiene class
Definition of Levels of Protection classes (parameters, building materials, room requirements, HVAC systems)
Requirements for personnel and material in the different classes (clothing, training, type of materials allowed in the respective classes, etc.)
Requirements on entry conditions for personnel and material (change procedures, when to change clothing, etc.)
The Levels of Protection concept can be part of the Site Master File.
