1. MCC PRESENTATION - GMP MANUFACTURING ENVIRONMENTS
Module 1
Presented by :
Deryck Smith Consulting Engineers

2. GMP MANUFACTURING ENVIRONMENTS
Presentation Outline
Module 1: Introduction to GMP Environments
Module 2: Air Conditioning System Components
Module 3: Types & Configurations of AC Systems
Module 4: Pressure Cascades & building Layouts
Module 5: Validation, Qualification & Maintenance

3. GMP MANUFACTURING ENVIRONMENTS
Topics for this Module
What makes up the manufacturing environment (not just Environmental Control System)
Contamination & cross-contamination
How cleanrooms are defined
Levels of Protection 
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

4. Module 1: Introduction to GMP Manufacturing Environments
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. 

5. Factors Contributing to Quality Products
Raw Materials
Personnel
Procedures
Validated processes
Equipment
Premises
Environment
Packing Materials
Validated processes
The most important!
Equipment
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.
Premises
Environment

6. Design considerations for a manufacturing facility
Three primary considerations to be addressed to ensure a safe and productive manufacturing facility
GMP MANUFACTURING
ENVIRONMENT
PERSONNEL
PROTECTION
PRODUCT
ENVIRONMENT
Prevent
contact
with dust
cross-contamination
Protect from
product
Avoid
dust
discharge
Prevent
contact
with fumes
Protect from
ambient
contamination
Avoid
fume
discharge
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
Acceptable
comfort
conditions
contamination
Prevent
of staff
Avoid
effluent
discharge
Correct
temperature
and humidity

7. The manufacturing environment is critical for product quality
The environment comprises aspects such as:
Light
Temperature
Humidity
Air movement
Microbial contamination
Particulate contamination
Uncontrolled environments can lead to:
Product degradation & contamination
Loss of Product & Profit 
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.
PIC/S PH 1/97 (Rev.3) #3.3 & 3.12

8. What are Contaminants ? Contaminants are :
Products or substances other than product manufactured
Foreign products
Particulate matter
Micro-organisms
Endotoxins (degraded micro-organisms)
Cross-contamination is a particular case of contamination 
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.

9. Cross – Contamination (1)
What is Cross-Contamination ?
Definition of Cross-Contamination
“Contamination of a starting material, or of a product with another starting material or product.”
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.
PIC/S PH 1/97 (Rev.3) Pg. 134

10. Cross – Contamination (2)
From where does Cross-Contamination originate?
Poorly designed air handling systems and dust extraction systems
Poorly operated and maintained air handling systems and dust extraction systems
Inadequate procedures for personnel and equipment
Insufficiently cleaned equipment 
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
PIC/S PH 1/97 (Rev.3) # 3.14

11. Cross-contamination (3)
Contaminants
from
Environment
& Operators
Equipment
Cross
Product
Contamination is the introduction of foreign products into a drug, which does not come from another drug product.
PIC/S PH 1/97 # 5.10

12. Cross-Contamination (4)
Cross-contamination can be minimized by
Personnel procedures
Adequate premises
Use of closed production systems
Adequate, validated cleaning procedures
Appropriate Levels of Protection of product
Correct air pressure cascade 

13. 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!

14. 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 to 10 million per minute
A person walking will liberate 5000 bacteria/minute and a single sneeze can produce up to 1 million bacteria.
The manufacturing process itself can generate contaminants eg paint off equipment, dust from belt drives, etc 
Particles (squames) of 0,3 micron & greater are liberated at a rate varying between of to 10 million per minute (depending on the level of activity & the garments worn)
Patient contaminants – bone saw – trauma case patient

15. Why All the Concern About Dust?
Dust Is a Bacteria Carrier
Virus
(0,006µm to 0,03µm)
Dust carries bacteria, much like a dog carries fleas.
Dust can be categorized into 3 groups:
COARSE DUST ( microns) – settles rapidly
FINE DUST (1,0 – 50 microns) – settles slowly
ULTRA FINE DUST (< 0,5 – 1 micron) – remains suspended.
Dust Particle
(0,5µm to 500µm)
Bacteria
(0,2µm to 2µm)
Typical size relationship between
dust, bacteria and viruses

16. Airborne Contaminants
Particle sizes
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!

17. Removal of Bacteria As dust is a carrier, dust must be controlled.
Ambient bacteria is removed by filtration.
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. 

18. Defining the Environment
What is the manufacturing environment ?
How does the manufacturing environment effect contamination and cross-contamination ?
Cleanroom concept 
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…

19. What Is a Cleanroom ?
A cleanroom is an environment where the particulate contamination & bacterial contamination are limited to prescribed levels.
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.

20. How Are Cleanrooms Classified ?
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.

21. Controlled Environment Standards-
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 -
200 -
= Uni-directional (Laminar Flow) ** = Maximum number of viable microorganisms permitted per m³.
Annex 1 # 3
CONTROLLED ENVIRONMENT STANDARDS
BS EN ISO : 1999, Federal Standard and Approximate Equivalents.

22. Facility Parameters That Need To Be Controlled
Temperature
Humidity
Air Cleanliness
An automated Building Management System is a great help in monitoring these conditions and establishing trends.
Room Pressure
Air movement
Lighting

23. How Clean Should It Be? Level of Protection Concept
Defines environmental requirements
Working to defined environments helps prevent contamination and cross-contamination
Allows production under optimal hygiene conditions
Takes into account
product sensitivity to contamination
therapeutic risk 
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.

24. 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.
ISPE : Level 1, 2 or 3 or
Cleanroom class (ISO 5, 6, etc.).
Companies : Various others such as White, Grey, Black, Green, etc.
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.

25. Manufacturing Environment requirements
Cleanroom Class Required Is Dependant on Manufacturing Process Being Carried Out !
Manufacturing Environment requirements
Cleanroom Class A / B
Cleanroom Class C
Cleanrm. Class D
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.
Others
Therapeutic risks

26. Parameters to be defined:
Levels of Protection
Parameters to be defined:
Air cleanliness requirements (filter type and position, air changes, air flow patterns, pressure differentials, contamination levels by particulate matter and micro-organisms)
Personnel and material transfer methods
Permitted operations
Building design & finishes 
All the above aspects need to be present to achieve a balanced facility.

27. Levels of Protection
All operations within a pharmaceutical facilility must be correlated to well-defined Cleanroom classes.
Example:
ISO
ISO 5U
ISO 5T
ISO 7
ISO 8
Washing of Containers X
Preparation of solution for terminal sterilization
Preparation of solutions for aseptic filling
Depyrogenisation of containers
Filling for terminal sterilization
Filling for aseptic process
Etc.
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)
U = Uni-directional
T = Turbulent
Annex 1, # 3, Pg 41

28. 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 ) 
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.

29. Parameters Influencing the Level of Protection (1)
How does an Air Handling System influence the Cleanroom Class or Level of Protection ?
Air Handling
System
Production Room
With
Defined
Requirements
Supply
Air
Outlet

30. Parameters Influencing the Level of Protection (2)
Number of particles in the air
Number of micro-organisms in the air or on surfaces
Number of air changes for each room
Air velocity
Air flow pattern
Filters ( type, position )
Air Pressure differentials between rooms
Temperature, humidity 

31. Parameters Influencing the Level of Protection (3)
Cleanroom Class
defined by
Critical Parameters
Air Handling
System
Additional Measures

32. Parameters Influencing the Level of Protection (4)
Air handling systems:
are the main tool for reaching required parameters
but are not sufficient as such
Need for additional measures such as
Appropriate gowning (type of clothing, proper changing rooms)
Validated sanitation
Adequate transfer procedures for materials and personnel 
Questions & Answers