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Module 13 Slide 1 of 48 WHO - EDM Part Three Basic Principles of GMP Sterile Production
Module 13 Slide 1 of 48 WHO - EDM
Part Three
Basic Principles of GMP
Sterile Production
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.
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
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
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
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
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
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
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)
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
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
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
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
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
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
Module 13 Slide 16 of 48 WHO - EDM
Air Classification System
Sterile Production
Grade at rest in operation
maximum permitted number of particles/m3 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
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
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
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
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
Module 13 Slide 21 of 48 WHO - EDM
Part Three 17.24 - 17.33
Sterile ProductionEquipment
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
Module 13 Slide 22 of 48 WHO - EDM
Sterile Production
Environmental Monitoring - I
Microbiological
Air
Surfaces
Personnel
Module 13 Slide 23 of 48 WHO - EDM
Sterile Production
Environmental Monitoring - II
Physical
Particulates
Differential pressures
Air changes
Filter integrity
Temperature/humidity
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
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
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
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
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
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
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
Module 13 Slide 31 of 48 WHO - EDM
Sterile Production
Possible Issues(contd) Particulate levels/micro-organisms
Differential pressures
Air changes
Temperature/humidity
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
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
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
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
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 pyrogensvalidation (challenge tests with endotoxins)
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
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
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
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
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
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
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?
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
Module 13 Slide 45 of 48 WHO - EDM
Sterile Production
Quality Control
Environmental monitoring
Sterility testing
Endotoxin testing
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
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
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.
