Basic Principles of GMP

Sterile Production

Part Three

Module 13

Slide 1 of 48

WHO - EDM

Sterile Production
Objectives
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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.

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Module 13

Slide 2 of 48

WHO - EDM

Sterile Production
Types of sterile products
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Terminally sterilised
® prepared, filled and sterilised

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Sterilised by filtration Aseptic preparation

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Module 13

Slide 3 of 48

WHO - EDM

Sterile Production
GMP Requirements for Sterile Products
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Additional rather than replacement Specific points relating to minimizing risks of contamination
® microbiological ® particulate matter ® pyrogen

Module 13

Slide 4 of 48

WHO - EDM

Sterile Production
General Requirements
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Production in clean areas Airlocks for entry
® personnel ® goods

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Separate areas for operations
® component preparation ® product preparation ® filling etc

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Level of cleanliness Filtered air
Slide 5 of 48
WHO - EDM

Module 13

Sterile Production
General Requirements (contd)
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Air classification: Grade A, B, C and D Laminar air flow:
® air speed (horizontal versus vertical flow) ® number of air changes ® air samples

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Conformity to standards Work station and environment Barrier technology and automated systems

Module 13

Slide 6 of 48

WHO - EDM

Sterile Production
Manufacture of sterile preparations
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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 7 of 48

WHO - EDM

Sterile Production
Classifications - I
Terminally Sterilized Products
Product type SVP and LVP SVP and LVP Others Preparation of solution C D (c losed container) C Filling of solution A/C A/C C

Part Three 17.5.1

Module 13

Slide 8 of 48

WHO - EDM

Sterile Production
Manufacture of sterile preparations
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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 9 of 48

WHO - EDM

Sterile Production
Classifications - II
Sterile Filtered Products
Product type SVP and LVP SVP and LVP SVP and LVP Other products Preparation of solution C C D (closed container) C Filling of solution A/B B/C B/C B/C

Part Three 17.5.2

Module 13

Slide 10 of 48

WHO - EDM

Sterile Production
Classifications - III
Products produced from Sterile Materials
Product type SVP and LVP SVP and LVP Other products Other products Preparation of solution A/B B/C A/B B/C Filling of solution A/B B/C A/B B/C

Part Three 17.5.3

Module 13

Slide 11 of 48

WHO - EDM

Sterile Production
Manufacture of sterile preparations
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Aseptic preparation
® Handling of materials ® All processing ® Grade A in Grade B environment or ® Grade B in Grade C environment

Module 13

Slide 12 of 48

WHO - EDM

Sterile Production
Premises
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Design
® avoid unnecessary entry

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Clean areas
® smooth, impervious, unbroken surfaces ® permit cleaning ® no uncleanable recesses, ledges, cupboards, equipment ® no sliding doors ® ceilings ® pipes and ducts Part Three ® sinks and drains

17.16 - 17.21

Module 13

Slide 13 of 48

WHO - EDM

Sterile Production
Premises
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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

Part Three 17.22 - 17.23

Module 13

Slide 14 of 48

WHO - EDM

Sterile Production
Sanitation
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Clean areas
® frequency ® SOP

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Disinfectants
® periodic alterations ® monitor microbial contamination ® dilutions, storage and topping-up

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Fumigation Monitoring
® micro and particulate matter
Slide 15 of 48

Part Three 17.34 - 17.37

Module 13

WHO - EDM

Sterile Production
Air Classification System
Grade at rest maximum permitted number of particles/m3 equal to or above 0.5 µm A B C D 3 500 3 500 350 000 3 500 000 5 µm 0 0 2 000 20 000 0.5 µm 3 500 350 000 3 500 000 not defined 5µ 0 2 000 20 000 not defined in operation

Module 13

Slide 16 of 48

WHO - EDM

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

Module 13

Slide 17 of 48

WHO - EDM

Sterile Production
Personnel
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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
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Part Three 17.10 17.15

Laundry and changes
Slide 18 of 48
WHO - EDM

Module 13

Sterile Production
Personnel
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Minimum number in clean areas
® aseptic processing ® inspection and control

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Regular training
® manufacture ® hygiene ® microbiology ® outside staff

Part Three 17.6 - 17.8

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Animal tissue and cultures of micro-organisms
Slide 19 of 48
WHO - EDM

Module 13

Sterile Production
Personnel
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Hygiene and cleanliness
® contaminants ® health checks

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SOPs : Changing and washing Jewellery and cosmetics
Part Three 17.9,17.11 17.12

Module 13

Slide 20 of 48

WHO - EDM

Sterile Production
Equipment
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Air supply:(HVAC)
® Generation and supply of filtered air under positive pressure ® Airflow patterns ® Failure of air supply ® Pressure differentials monitored and recorded

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Conveyer belts Effective sterilisation of equipment Maintenance and repairs Water treatment plants
Slide 21 of 48
WHO - EDM

Part Three 17.24 - 17.33

Planned maintenance, validation and monitoring

Module 13

Sterile Production
Environmental Monitoring - I
Microbiological
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Air Surfaces Personnel

Module 13

Slide 22 of 48

WHO - EDM

Sterile Production
Environmental Monitoring - II
Physical
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Particulates Differential pressures Air changes Filter integrity Temperature/humidity

Module 13

Slide 23 of 48

WHO - EDM

Sterile Production
Processing
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Minimise contamination No unsuitable materials e.g. live microbiological organisms Minimise activities
® staff movement

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Temperature and humidity Water sources and systems
® monitoring ® records ® action taken
Part Three 17.38-39, 17.42-43

Module 13

Slide 24 of 48

WHO - EDM

Sterile Production
Processing
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Bio-burden determination
® raw materials ® in-process materials
– LVP : filtered immediately before sterilisation – sealed vessels: pressure-released outlets

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Components, materials and containers
® fibre generation ® no re-contamination after cleaning ® stage identified ® sterilised when used in aseptic areas

Part Three 17.44-47; 17.50-17.51

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Module 13

Gas through a sterilising filter
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WHO - EDM

Sterile Production
Processing
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Validation
® new processes ® re-validation: Periodic and after change

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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 26 of 48

Part Three 17.52, 17.40

WHO - EDM

Sterile Production
Processing
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Time intervals: Components, containers, equipment
® washing, drying and sterilisation ® sterilisation and use
– time limit and validated storage conditions

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Time intervals: Product preparation
® preparation and sterilisation ® short as possible ® maximum time for each product

Part Three 17.47,17.48

Module 13

Slide 27 of 48

WHO - EDM

Sterile Production
Finishing of products
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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 28 of 48

WHO - EDM

Sterile Production
Group session 1
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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

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Describe the type of facility you would expect to find. List the typical rooms, their purpose and air classification

Module 13

Slide 29 of 48

WHO - EDM

Sterile Production
Possible Issues
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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 30 of 48

WHO - EDM

Sterile Production
Possible Issues(contd)
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Particulate levels/micro-organisms Differential pressures Air changes Temperature/humidity

Module 13

Slide 31 of 48

WHO - EDM

Sterile Production
Sterilization
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Methods of sterilization
® heat sterilization: Method of choice

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Validation
® all processes ® non-pharmacopoeia ® non-aqueous or oily solutions

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Suitability and efficacy
® part of load ® type of load ® repeated: annually and after change

Part Three 17.53 - 17.55

Module 13

Slide 32 of 48

WHO - EDM

Sterile Production
Sterilization
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Biological indicators Differentiation between sterilized and not-sterilized products
® labelling ® autoclave tape

Part Three 17.56 - 17.57

Module 13

Slide 33 of 48

WHO - EDM

Sterile Production
Sterilization by Heat
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Recording of each cycle, e.g. time and temperature
® validated coolest part ® second independent probe ® indicators

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Heating phase
® each load determined

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Cooling phase
® no contamination ® leaking containers
Part Three 17.58 - 17.60

Module 13

Slide 34 of 48

WHO - EDM

Sterile Production
Moist Heat Sterilization
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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
Part Three 17.61- 17.63

All parts of the load: Contact, time, temperature
Slide 35 of 48
WHO - EDM

Module 13

Sterile Production
Dry Heat Sterilization
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Air circulation and positive pressure in chamber Filtered air Temperature and time must be recorded Removes pyrogens
®validation (challenge tests with endotoxins)
Part Three 17.64

Module 13

Slide 36 of 48

WHO - EDM

Sterile Production
Sterilization by Radiation
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Suitable for heat sensitive materials and products
® confirm suitability of method for material ® ultraviolet irradiation not acceptable

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Contracting service Measurement of dose Dosimeters
® quantitative measurement ® number, location and calibration

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Biological indicators Colour discs
Slide 37 of 48

Part Three 17.65 - 17.67

Module 13

WHO - EDM

Sterile Production
Sterilization by Radiation
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Batch record Validation
® density of packages

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Mix-ups: Irradiated and non-irradiated materials Dose: Predetermined time span

Part Three 17.67 - 17.70

Module 13

Slide 38 of 48

WHO - EDM

Sterile Production
Sterilization by Ethylene Oxide Gas
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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

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Humidity and temperature equilibrium Monitoring of each cycle
® time, pressure ® temperature, humidity ® gas concentration
Slide 39 of 48

Part Three 17.71 - 17.76

Module 13

WHO - EDM

Sterile Production
Sterilization by Ethylene Oxide Gas
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Post-sterilization storage
® ventilation ® defined limit of residual gas ® validated process

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Safety and toxicity issues

Part Three 17.77

Module 13

Slide 40 of 48

WHO - EDM

Sterile Production
Sterilization by Filtration
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Previously sterilized containers Nominal pore size 0.22 µm or less
® remove bacteria and moulds ® not viruses or mycoplasmas

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Double filter layer or second filtration No fibre shedding or asbestos filters Filter integrity testing Time taken and pressure difference validated
Slide 41 of 48
WHO - EDM

Module 13

Sterile Production
Sterilization by Filtration
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Length of use
® one working day ® or validated

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Filter interaction with product
® removal of ingredients ® releasing substances

Module 13

Slide 42 of 48

WHO - EDM

Sterile Production
Group session 2
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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?

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Module 13

Slide 43 of 48

WHO - EDM

Sterile Production
Possible Issues
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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
Slide 44 of 48
WHO - EDM

Module 13

Sterile Production
Quality Control

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Environmental monitoring Sterility testing Endotoxin testing

Module 13

Slide 45 of 48

WHO - EDM

Sterile Production
Sterility Testing
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Samples representative of the batch
® aseptic fill
– beginning, and end of batch, or interruption

® heat sterilization
– coolest part of the load

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Last of series of control measures Adequate testing facility (e.g. Class A in B environment) Test failure: Second test subject to
® investigation:
Slide 46 of 48 – type of organism
WHO - EDM

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Module 13

Sterile Production
Pyrogen Testing
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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

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Test failures
® cause investigated ® remedial action

Module 13

Slide 47 of 48

WHO - EDM

Sterile Production
Group session 3
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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.

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Module 13

Slide 48 of 48

WHO - EDM