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Basic Principles of GMP

Sterile Production

Part Three

Module 13 Slide 1 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 2 of 48 WHO - EDM


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

● Sterilised by filtration

● Aseptic preparation

Module 13 Slide 3 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 4 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 5 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 6 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 7 of 48 WHO - EDM


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

Part Three 17.5.1

Module 13 Slide 8 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 9 of 48 WHO - EDM


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

Part Three 17.5.2

Module 13 Slide 10 of 48 WHO - EDM


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

Part Three 17.5.3

Module 13 Slide 11 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 12 of 48 WHO - EDM


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
Part Three 17.16 - 17.21
➤ sinks and drains

Module 13 Slide 13 of 48 WHO - EDM


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

Part Three 17.22 - 17.23

Module 13 Slide 14 of 48 WHO - EDM


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

Grade at rest in operation


maximum permitted number of particles/m3 equal to or above
0.5 µm 5 µm 0.5 µm 5µ
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 16 of 48 WHO - EDM


Sterile Production

Comparison of Various Codes

Comparison of different classification systems


WHO US US ISO/TC EEC
cGMP Customary 209E 209 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 17 of 48 WHO - EDM


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
Part Three 17.10 -
➤ Grade B 17.15
– masks, gloves
● Laundry and changes
Module 13 Slide 18 of 48 WHO - EDM
Sterile Production
Personnel
● Minimum number in clean areas
➤ aseptic processing
➤ inspection and control
● Regular training
➤ manufacture
➤ hygiene
➤ microbiology
Part Three 17.6 - 17.8
➤ outside staff
● Animal tissue and cultures of micro-organisms

Module 13 Slide 19 of 48 WHO - EDM


Sterile Production
Personnel

● Hygiene and cleanliness


➤ contaminants
➤ health checks
● 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
● 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 Part Three 17.24 - 17.33

● Planned maintenance, validation and monitoring


● Water treatment plants
Module 13 Slide 21 of 48 WHO - EDM
Sterile Production
Environmental Monitoring - I
Microbiological

● Air
● Surfaces
● Personnel

Module 13 Slide 22 of 48 WHO - EDM


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

Module 13 Slide 23 of 48 WHO - EDM


Sterile Production
Processing
● Minimise contamination
● No unsuitable materials e.g. live microbiological
organisms
● Minimise activities
➤ staff movement
● Temperature and humidity
● Water sources and systems Part Three 17.38-39,
➤ monitoring 17.42-43

➤ records
➤ action taken
Module 13 Slide 24 of 48 WHO - EDM
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
Part Three 17.44-47;
➤ stage identified 17.50-17.51
➤ sterilised when used in aseptic areas
● Gas through a sterilising filter
Module 13 Slide 25 of 48 WHO - EDM
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
Part Three 17.52, 17.40
➤ revalidation: periodic and after change

Module 13 Slide 26 of 48 WHO - EDM


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
Part Three 17.47,17.48

Module 13 Slide 27 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 28 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 29 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 30 of 48 WHO - EDM


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

Module 13 Slide 31 of 48 WHO - EDM


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 Part Three 17.53 - 17.55

Module 13 Slide 32 of 48 WHO - EDM


Sterile Production
Sterilization
● 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
● 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 Part Three 17.58 - 17.60

Module 13 Slide 34 of 48 WHO - EDM


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
Part Three 17.61- 17.63
● Penetration of steam, quality of steam
● All parts of the load: Contact, time, temperature

Module 13 Slide 35 of 48 WHO - EDM


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)

Part Three 17.64

Module 13 Slide 36 of 48 WHO - EDM


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 Part Three 17.65 - 17.67

● Colour discs
Module 13 Slide 37 of 48 WHO - EDM
Sterile Production
Sterilization by Radiation
● Batch record
● Validation
➤ density of packages
● 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
● 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 Part Three 17.71 - 17.76
➤ temperature, humidity
➤ gas concentration
Module 13 Slide 39 of 48 WHO - EDM
Sterile Production
Sterilization by Ethylene Oxide Gas
● Post-sterilization storage
➤ ventilation
➤ defined limit of residual gas
➤ validated process

● Safety and toxicity issues

Part Three 17.77

Module 13 Slide 40 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 41 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 42 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 43 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 44 of 48 WHO - EDM


Sterile Production
Quality Control

● Environmental monitoring
● Sterility testing
● Endotoxin testing

Module 13 Slide 45 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:
Module 13 Slide 46 of 48 WHO - EDM
– type of organism
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 47 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.

Module 13 Slide 48 of 48 WHO - EDM

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