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.
MCC PRESENTATION - GMP
Presented by :
Deryck Smith Consulting
Introduction to GMP Environments
Air Conditioning System Components
Types & Configurations of AC Systems
Pressure Cascades & building Layouts
Validation, Qualification & Maintenance
Topics for this Module
What makes up the manufacturing
environment (not just Environmental
Contamination & cross-contamination
How cleanrooms are defined
Levels of Protection ∆
Module 1: Introduction to GMP
• The primary objective of manufacturing in an
ideal GMP environment is that this should lead
to a high quality product being produced.
• Manufacturing in an ideal environment not only
leads to better quality products but should also
result in :
* Improved production rates.
* Operator comfort, satisfaction and safety. ∆
Factors Contributing to Quality
The most important!
for a manufacturing facility
Three primary considerations to be addressed to ensure a safe and
productive manufacturing facility
The manufacturing environment is
critical for product quality
The environment comprises aspects such as:
Uncontrolled environments can lead to:
Product degradation & contamination
Loss of Product & Profit ∆
PIC/S PH 1/97 (Rev.3) #3.3 & 3.12
What are Contaminants ?
Contaminants are :
1. Products or substances other than
2. Foreign products
3. Particulate matter
5. Endotoxins (degraded micro-organisms)
Cross-contamination is a particular case of
Cross – Contamination (1)
What is CrossContamination ?
Definition of Cross Contamination
“Contamination of a starting material,
or of a product with another starting
material or product.”
PIC/S PH 1/97 (Rev.3) Pg. 134
Cross – Contamination (2)
From w here does Cross-Contamination
1. Poorly designed air handling system s
and dust extraction systems
2. Poorly operated and maintained air
handling system s and dust extraction
3. Inadequate procedures for personnel and
4. Insufficiently cleaned equipment ∆
PIC/S PH 1/97 (Rev.3) # 3.14
PIC/S PH 1/97 # 5.10
Cross-contamination can be minimized by
1. Personnel procedures
2. Adequate premises
3. Use of closed production systems
4. Adequate, validated cleaning
5. Appropriate Levels of Protection of
6. Correct air pressure cascade ∆
How are Contaminants Removed?
• By efficient filtration of supply air.
• By dilution of contaminants or flushing
contaminants by supplying adequate air
quantities to the room. ∆
More about this later!
Where Do Contaminants Come From?
• Outside air carries dust which is a contaminant
• People generate contaminants:
We completely shed our outer skin every 24 hrs.
Particles of 0,3 micron & greater are liberated at a
rate varying between of 100 000 to 10 million per
A person walking will liberate 5000 bacteria/minute
and a single sneeze can produce up to 1 million
• The manufacturing process itself can generate
contaminants eg paint off equipment, dust
from belt drives, etc ∆
Why All the Concern About Dust?
Dust Is a Bacteria Carrier
(0,006µm to 0,03µm)
(0,5µm to 500µm)
(0,2µm to 2µm)
Typical size relationship between
dust, bacteria and viruses
Removal of Bacteria
• As dust is a carrier, dust must be
• Ambient bacteria is removed by
• Internal bacterial distribution can be
controlled by directional air flow and
air flushing or dilution.
• Surface bacteria is controlled by
adherence to strict cleaning sop’s. ∆
Defining the Environment
• What is the manufacturing environment ?
• How does the manufacturing environment
effect contamination and crosscontamination ?
• Cleanroom concept
What Is a Cleanroom ?
A cleanroom is an
Controlled Environment Standards
•= Uni-directional (Laminar Flow)
** = Maximum number of viable microorganisms permitted per m³.
Annex 1 # 3
CONTROLLED ENVIRONMENT STANDARDS
BS EN ISO 1 4644-1: 1999, Federal Standard and Approximate Equivalents .
Facility Parameters That
Need To Be Controlled
How Clean Should It Be?
Level of Protection Concept
Defines environmental requirements
Working to defined environments h elps prevent
contamination and cross-contamination
Allows production under optimal hygiene conditions
Takes into account
• product sensitivity to contamination
• therapeutic risk ∆
Many Different Standards In Use
Levels of Protection & Cleanroom Class
definitions currently in use.
EC, PIC/S, TGA, WHO, etc. : A, B, C, D.
US FDA :
Critical and Controlled or
Class 100, 1000, etc.
Level 1, 2 or 3 or
Cleanroom class (ISO 5, 6, etc.).
Various others such as White, Grey,
Black, Green, etc.
Cleanroom Class Required Is Dependant on
Manufacturing Process Being Carried Out !
Cleanroom Class A / B
Cleanroom Class C
Cleanrm. Class D
Levels of Protection
Parameters to be defined :
1. Air cleanliness requirements (filter type
and position, air changes, air flow
patterns, pressure differentials,
contamination levels by particulate matter
2. Personnel and material transfer methods
3. Permitted operations
4. Building design & finishes ∆
Levels of Protection
All operations within a pharmaceutical facilility must be
correlated to well-defined Cleanroom classes.
Washing of Containers
Preparation of solution for terminal sterilization
Preparation of solutions for aseptic filling
Depyrogenisation of containers
Filling for terminal sterilization
Filling for aseptic process
U = Uni-directional
T = Turbulent
Annex 1, # 3, Pg 41
Levels of Protection
Based on the Cleanroom Class Requirements,
various Levels of Protection have to be
created, including :
Correlation between process operations and Cleanroom classes
Type of operation permitted in each Level of Protection zone
Definition of Cleanroom class (Contaminant parameters, building
materials, room requirements, air handling systems )
Requirements for personnel and material in the different classes
(clothing, training, type of materials, etc. )
Requirements on entry conditions for personnel and material
(change & clean-down procedures ) ∆
Parameters Influencing the
Level of Protection (1)
How does an Air Handling System influence
the Cleanroom Class or Level of Protection ?
Parameters Influencing the
Level of Protection (2)
1 Number of particles in the air
2 Number of micro-organisms in the air or on
Number of air changes for each room
Air flow pattern
Filters ( type, position )
Air Pressure differentials between rooms
Temperature, humidity ∆
Parameters Influencing the
Level of Protection (3)
Parameters Influencing the
Level of Protection (4)
Air handling systems:
• are the main tool for reaching required
• but are not sufficient as such
Need for additional measures such as
Appropriate gowning (type of clothing, proper
Adequate transfer procedures for materials and
Questions & Answers