WHO sterile production in Clean Rroom Facility.ppt

WHO sterile production in Clean Room Facility

1. Module 13 Slide 1 of 48 WHO - EDM
Part Three
Basic Principles of GMP
Sterile Production

2. Module 13 Slide 2 of 48 WHO - EDM
Sterile Production
Objectives
To review basic GMP requirements in the manufacture of
sterile products
To review air classifications for activities related to the
manufacture of sterile products
To review the different types of sterilisation methods
To review quality assurance aspects in the manufacture
and control of sterile products
To consider current issues applicable in your country.

3. Module 13 Slide 3 of 48 WHO - EDM
Sterile Production
Types of sterile products
Terminally sterilised
prepared, filled and sterilised
Sterilised by filtration
Aseptic preparation

4. Module 13 Slide 4 of 48 WHO - EDM
Sterile Production
GMP Requirements for Sterile Products
Additional rather than replacement
Specific points relating to minimizing risks of
contamination
microbiological
particulate matter
pyrogen

5. Module 13 Slide 5 of 48 WHO - EDM
Sterile Production
General Requirements
Production in clean areas
Airlocks for entry
personnel
goods
Separate areas for operations
component preparation
product preparation
filling etc
Level of cleanliness
Filtered air

6. Module 13 Slide 6 of 48 WHO - EDM
Sterile Production
General Requirements (contd)
Air classification: Grade A, B, C and D
Laminar air flow:
air speed (horizontal versus vertical flow)
number of air changes
air samples
Conformity to standards
Work station and environment
Barrier technology and automated systems

7. Module 13 Slide 7 of 48 WHO - EDM
Sterile Production
Manufacture of sterile preparations
Terminally sterilised
preparation:
–Grade C: then immediate filtration and sterilisation
–Grade D: Closed vessels
–Grade A: Filling (Grade C environment) of parenterals
–Grade C: Filling of ointments, suspensions etc

8. Module 13 Slide 8 of 48 WHO - EDM
Part Three 17.5.1
Sterile Production
Classifications - I
Terminally Sterilized Products
Product type

Preparation of solution

Filling of solution
SVP and LVP C A/C

SVP and LVP D (c losed container) A/C

Others C C

9. Module 13 Slide 9 of 48 WHO - EDM
Sterile Production
Manufacture of sterile preparations
Sterilisation by filtration
Handling of starting materials
–Grade C
–Grade D: Closed vessels
–Sterile filtration into containers: Class A (in Class B environment) or
Class B (in Class C environment)

10. Module 13 Slide 10 of 48 WHO - EDM
Part Three 17.5.2
Sterile Production
Classifications - II
Sterile Filtered Products
Product type Preparation of solution Filling of solution
SVP and LVP C A/B
SVP and LVP C B/C
SVP and LVP D (closed container) B/C
Other products C B/C

11. Module 13 Slide 11 of 48 WHO - EDM
Part Three 17.5.3
Sterile Production
Classifications - III
Products produced from Sterile Materials
Product type Preparation of solution Filling of solution
SVP and LVP A/B A/B
SVP and LVP B/C B/C
Other products A/B A/B
Other products B/C B/C

12. Module 13 Slide 12 of 48 WHO - EDM
Sterile Production
Manufacture of sterile preparations
Aseptic preparation
Handling of materials
All processing
Grade A in Grade B environment or
Grade B in Grade C environment

13. Module 13 Slide 13 of 48 WHO - EDM
Part Three 17.16 - 17.21
Sterile Production
Premises
Design
avoid unnecessary entry
Clean areas
smooth, impervious, unbroken surfaces
permit cleaning
no uncleanable recesses, ledges, cupboards, equipment
no sliding doors
ceilings
pipes and ducts
sinks and drains

14. Module 13 Slide 14 of 48 WHO - EDM
Part Three 17.22 - 17.23
Sterile Production
Premises
Changing rooms
designed as airlocks
flushed with filtered air
separate for entry and exit desirable
hand washing facilities
interlocking system
visual and/or audible warning system

15. Module 13 Slide 15 of 48 WHO - EDM
Part Three 17.34 - 17.37
Sterile Production
Sanitation
Clean areas
frequency
SOP
Disinfectants
periodic alterations
monitor microbial contamination
dilutions, storage and topping-up
Fumigation
Monitoring
micro and particulate matter

16. Module 13 Slide 16 of 48 WHO - EDM
Air Classification System
Sterile Production
Grade at rest in operation
maximum permitted number of particles/m
3
equal to or above
0.5 µm 5 µm 0.5 µm 5 µ
A 3 500 0 3 500 0
B 3 500 0 350 000 2 000
C 350 000 2 000 3 500 000 20 000
D 3 500 000 20 000 not defined not defined

17. Module 13 Slide 17 of 48 WHO - EDM
Comparison of Various Codes
Sterile Production
Comparison of different classification systems
WHO
cGMP
US
Customary
US
209E
ISO/TC
209
EEC
Annex I GMP
A M 3.5 100 ISO 5 A
B M 3.5 100 ISO 5 B
C M 5.5 10 000 ISO 7 C
D M 6.5 100 000 ISO 8 D

18. Module 13 Slide 18 of 48 WHO - EDM
Part Three 17.10 -
17.15
Sterile Production
Personnel
Outdoor clothing
Appropriate to air grade
Grade D
–hair, beard and shoes
Grade C
–hair and beard
–suit covering wrists, neck
–no fibres
Grade B
–masks, gloves
Laundry and changes

19. Module 13 Slide 19 of 48 WHO - EDM
Part Three 17.6 - 17.8
Sterile Production
Personnel
Minimum number in clean areas
aseptic processing
inspection and control
Regular training
manufacture
hygiene
microbiology
outside staff
Animal tissue and cultures of micro-organisms

20. Module 13 Slide 20 of 48 WHO - EDM
Part Three 17.9,17.11 -
17.12
Sterile Production
Personnel
Hygiene and cleanliness
contaminants
health checks
SOPs : Changing and washing
Jewellery and cosmetics

21. Module 13 Slide 21 of 48 WHO - EDM
Part Three 17.24 - 17.33
Sterile Production
Equipment
Air supply:(HVAC)
Generation and supply of filtered air under positive pressure
Airflow patterns
Failure of air supply
Pressure differentials monitored and recorded
Conveyer belts
Effective sterilisation of equipment
Maintenance and repairs
Planned maintenance, validation and monitoring
Water treatment plants

22. Module 13 Slide 22 of 48 WHO - EDM
Sterile Production
Environmental Monitoring - I
Microbiological
Air
Surfaces
Personnel

23. Module 13 Slide 23 of 48 WHO - EDM
Sterile Production
Environmental Monitoring - II
Physical
Particulates
Differential pressures
Air changes
Filter integrity
Temperature/humidity

24. Module 13 Slide 24 of 48 WHO - EDM
Part Three 17.38-39,
17.42-43
Sterile Production
Processing
Minimise contamination
No unsuitable materials e.g. live microbiological organisms
Minimise activities
staff movement
Temperature and humidity
Water sources and systems
monitoring
records
action taken

25. Module 13 Slide 25 of 48 WHO - EDM
Part Three 17.44-47;
17.50-17.51
Sterile Production
Processing
Bio-burden determination
raw materials
in-process materials
–LVP : filtered immediately before sterilisation
–sealed vessels: pressure-released outlets
Components, materials and containers
fibre generation
no re-contamination after cleaning
stage identified
sterilised when used in aseptic areas
Gas through a sterilising filter

26. Module 13 Slide 26 of 48 WHO - EDM
Part Three 17.52, 17.40
Sterile Production
Processing
Validation
new processes
re-validation: Periodic and after change
Aseptic process: Sterile media fill (“broth fills”)
simulate actual operation
appropriate medium/media
sufficient number of units
–acceptable limit
–investigations
revalidation: periodic and after change

27. Module 13 Slide 27 of 48 WHO - EDM
Part Three 17.47,17.48
Sterile Production
Processing
Time intervals: Components, containers, equipment
washing, drying and sterilisation
sterilisation and use
–time limit and validated storage conditions
Time intervals: Product preparation
preparation and sterilisation
short as possible
maximum time for each product

28. Module 13 Slide 28 of 48 WHO - EDM
Sterile Production
Finishing of products
Validated closing process
Checks for integrity
Maintenance of vacuum (where applicable) checked
Parenteral products: Individual inspection
illumination and background
eyesight checks
breaks
validation

29. Module 13 Slide 29 of 48 WHO - EDM
Sterile Production
Group session 1
You are asked to visit a factory producing the following
product lines:
Injections in ampoules and vials, including insulin, vaccines and
heat-stable pharmaceuticals.
Sterile eye ointment
Describe the type of facility you would expect to find.
List the typical rooms, their purpose and air classification

30. Module 13 Slide 30 of 48 WHO - EDM
Sterile Production
Possible Issues
Poor design of the building
Poor design of the systems e.g. water, HVAC
Flow of personnel
Flow of material
No validation or qualification
Old facilities not complying with current requirements

31. Module 13 Slide 31 of 48 WHO - EDM
Sterile Production
Possible Issues(contd)
Particulate levels/micro-organisms
Differential pressures
Air changes
Temperature/humidity

32. Module 13 Slide 32 of 48 WHO - EDM
Part Three 17.53 - 17.55
Sterile Production
Sterilization
Methods of sterilization
heat sterilization: Method of choice
Validation
all processes
non-pharmacopoeia
non-aqueous or oily solutions
Suitability and efficacy
part of load
type of load
repeated: annually and after change

33. Module 13 Slide 33 of 48 WHO - EDM
Part Three 17.56 - 17.57
Sterile Production
Sterilization
Biological indicators
Differentiation between sterilized and not-sterilized
products
labelling
autoclave tape

34. Module 13 Slide 34 of 48 WHO - EDM
Part Three 17.58 - 17.60
Sterile Production
Sterilization by Heat
Recording of each cycle, e.g. time and temperature
validated coolest part
second independent probe
indicators
Heating phase
each load determined
Cooling phase
no contamination
leaking containers

35. Module 13 Slide 35 of 48 WHO - EDM
Part Three 17.61- 17.63
Sterile Production
Moist Heat Sterilization
Water wettable materials
Temperature, time and pressure monitored
Recorder and controller independent
Independent indicator
Drain and leak test
Removal of air
Penetration of steam, quality of steam
All parts of the load: Contact, time, temperature

36. Module 13 Slide 36 of 48 WHO - EDM
Part Three 17.64
Sterile Production
Dry Heat Sterilization
 Air circulation and positive pressure in chamber
 Filtered air
 Temperature and time must be recorded
 Removes pyrogens
validation (challenge tests with endotoxins)

37. Module 13 Slide 37 of 48 WHO - EDM
Part Three 17.65 - 17.67
Sterile Production
Sterilization by Radiation
Suitable for heat sensitive materials and products
confirm suitability of method for material
ultraviolet irradiation not acceptable
Contracting service
Measurement of dose
Dosimeters
quantitative measurement
number, location and calibration
Biological indicators
Colour discs

38. Module 13 Slide 38 of 48 WHO - EDM
Part Three 17.67 - 17.70
Sterile Production
Sterilization by Radiation
Batch record
Validation
density of packages
Mix-ups: Irradiated and non-irradiated materials
Dose: Predetermined time span

39. Module 13 Slide 39 of 48 WHO - EDM
Part Three 17.71 - 17.76
Sterile Production
Sterilization by Ethylene Oxide Gas
Only when no other method is practicable
Effect of gas on the product
Degassing (specified limits)
Direct contact with microbial cells
Nature and quantity of packaging materials
Humidity and temperature equilibrium
Monitoring of each cycle
time, pressure
temperature, humidity
gas concentration

40. Module 13 Slide 40 of 48 WHO - EDM
Part Three 17.77
Sterile Production
Sterilization by Ethylene Oxide Gas
Post-sterilization storage
ventilation
defined limit of residual gas
validated process
Safety and toxicity issues

41. Module 13 Slide 41 of 48 WHO - EDM
Sterile Production
Sterilization by Filtration
Previously sterilized containers
Nominal pore size 0.22 µm or less
remove bacteria and moulds
not viruses or mycoplasmas
Double filter layer or second filtration
No fibre shedding or asbestos filters
Filter integrity testing
Time taken and pressure difference validated

42. Module 13 Slide 42 of 48 WHO - EDM
Sterile Production
Sterilization by Filtration
Length of use
one working day
or validated
Filter interaction with product
removal of ingredients
releasing substances

43. Module 13 Slide 43 of 48 WHO - EDM
Sterile Production
Group session 2
Considering the same factory as in the previous group
session, discuss the process of sterilization.
List all the items that will need to be sterilized.
What are the key features you should find in each
sterilization situation?
Which aspects would be subject to validation?

44. Module 13 Slide 44 of 48 WHO - EDM
Sterile Production
Possible Issues
Autoclave - no pressure gauge
Autoclave - no temperature recorder
Autoclave - superheated steam
Clean room - pressure differentials
Exposure for settle plates
Interlocks turned off
Rusty Laminar airflow cabinets
HEPA filters not checked regularly

45. Module 13 Slide 45 of 48 WHO - EDM
Sterile Production
Quality Control
Environmental monitoring
Sterility testing
Endotoxin testing

46. Module 13 Slide 46 of 48 WHO - EDM
Sterile Production
Sterility Testing
Samples representative of the batch
aseptic fill
–beginning, and end of batch, or interruption
heat sterilization
–coolest part of the load
Last of series of control measures
Adequate testing facility (e.g. Class A in B environment)
Test failure: Second test subject to
investigation:
–type of organism
–batch records, environmental monitoring records

47. Module 13 Slide 47 of 48 WHO - EDM
Sterile Production
Pyrogen Testing
Rabbit method
LAL test (endotoxin monitoring)
Injectable products
water, intermediate, finished product
validated pharmacopoeia method for each type of product
always for water and intermediates
Test failures
cause investigated
remedial action

48. Module 13 Slide 48 of 48 WHO - EDM
Sterile Production
Group session 3
Considering the same factory as in the previous group
sessions, devise a plan for monitoring of the facility.
List the parameters to be tested, tests to be used,
acceptance criteria and frequency of testing.