GMP steril WHO

8/18/2019 GMP steril WHO

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Module 14 | Slide 1 of 62 January 2006

Annex 6. TRS 902, 2002

Basic Principles of GMP

Sterile Pharmaceutical Products


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Sterile Production

Objectives

To review basic GMP requirements in the manufacture of sterile

pharmaceutical products

To review air classifications for activities related to themanufacture of sterile products

To review the different types of sterilization 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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Sterile Production

!P Re"uirements #or Sterile Products

Additional rather than replacement

Specific points relating to minimizing risks of contamination

microbiological

particulate matter

pyrogen


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Sterile Production

eneral $onsiderations

Production in clean areas

Appropriate standard of cleanliness

iltered air supplied

Airlocks for entry personnel and/or equipment

materials

Separate areas for operations

component preparation (containers and closures)

product preparation

filling, sterilization, etc.1.1 – 1-2


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9.1 – 9.6

Sterile Production

Premises !esign

avoid unnecessary entry of supervisors and control personnel operations observed from outside

"n clean areas# all e$posed surfaces

smooth, impervious, unbrokenminimize shedding and accumulation of particles,

microorganisms

permit cleaning and disinfection

no uncleanable recesses, ledges, shelves, cupboards,

equipment sliding doors undesirable

false ceilings sealed


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9.6.

Sterile Production

Premises %continued& "n clean areas# all e$posed surfaces %'&

proper installation of pipes and ducts, no recesses,

no unsealed openings

sinks and drains avoided, and excluded in Grade and !areas

( "here installed, design, location, maintenance

( effective cleanable traps

( air breaks preventing backflo"

( floor channels open and easily cleanable


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9.7 – 9.9

Sterile Production

Premises %continued&)hanging rooms

designed as airlocks

effective flushing "ith filtered air

separate rooms for entry and exit desirable

hand "ashing facilities

interlocking system for doors

visual and/or audible "arning system

*se filtered air supply to maintain pressure cascade

Pressure differential appro$imately +, to +- Pascals .one of greatest risk ( immediate environment


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9.9 – 9.12

Sterile Production

Premises %continued&Pathogenic# highly to$ic# radioactive materials

Pressure cascade may be different

!econtamination procedures ( air# equipment# garments

/ualification including airflow patterns

no risk to the product

0arning system to indicate failure in air supply

Pressure indicators ( results regularly recorded

1estricted access ( e2g2 use of barriers


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10.1 – 10.5

Sterile Production

%"ui&ment)onveyer belts

3ffective sterilization of equipment

Maintenance and repairs from outside the clean area

if taken apart, resterilized before use

use clean instruments and tools

Planned maintenance# validation and monitoring

equipment, air filtration systems, sterilizers, "ater

treatment systems


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10.6

Sterile Production

%"ui&ment %continued&0ater treatment plants and distribution system

design, construction, maintenance

operation and design capacity

testing programme

0ater for "n4ection %0"&

produced, stored, distributed # prevention of gro"th of

microorganisms

constant circulation at temperature above $%, or not more

than & degrees 'elsius


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Sterile Production

%nvironmental !onitorin' ( )

!icrobiolo'ical

Air samples

Surface swabs

Personnel swabs


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Sterile Production

%nvironmental !onitorin' * ))

Ph+sical

Particulate matter

!ifferential pressures

Air changes# airflow patterns

)lean up time5recovery

ilter integrity

Temperature and relative humidity

Airflow velocity


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Sterile Production

Sanitation

requent# thorough cleaning of areas necessary

0ritten programme

1egular monitoring to detect resistant strains of microorganisms

)hemical disinfection

Monitoring of disinfectants and detergents

!ilutions

clean containers, stored for defined periods of time

terilized before use, "hen used in Grade or ! areas3.1 – 3.2


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Sterile Production

Sanitation %continued&

Monitoring of clean areas

Monitoring of personnel and surfaces after critical operations

requent monitoring in areas where aseptic operations are

carried out

settle plates, volumetric air samples, surface sampling

(s"abs and contact plates)

sampling methods should not contaminate the area

1esults considered when batch release is done3.3


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Sterile Production

Sanitation %continued& 6imits of detection established

Alert and action# and monitoring trends of air quality

Table +2 6imits for microbial contamination %information only& 3.


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!.1 – !.3

Sterile Production

PersonnelMinimum number of personnel in clean areas

especially during aseptic processing

"nspections and controls from outside

Training to all including cleaning and maintenance staff initial and regular

manufacturing, hygiene, microbiology

Special cases

supervision in case of outside staff decontamination procedures (e.g. staff "ho "orked "ith

animal tissue materials)


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!. – !.6

Sterile Production

Personnel %continued&

7igh standards of hygiene and cleanliness

Periodic health checks

8o shedding of particles

8o introduction of microbiological hazards

8o outdoor clothing

)hanging and washing procedure

8o watches# 4ewellery and cosmetics


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!.7

Sterile Production

Personnel %continued&)lothing of appropriate quality9Grade

( hair, beard, moustache covered ( protective clothing and shoes

Grade ' ( hair, beard, moustache covered ( single or *+piece suit (covering "rists, high neck), shoes ( no fibres to be shed

Grade and !

headgear, beard and moustache covered, masks, glovesnot shedding fibres, and retain particles shed byoperators


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!.! – !.9

Sterile Production

Personnel %continued&:utdoor clothing not in change rooms leading to Grade ; and )

rooms

)hange at every working session# or once a day %if supportive

data&

)hange gloves and masks at every working session

!isinfect gloves during operations

0ashing of garments ( separate laundry facility8o damage# and according to validated procedures


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Sterile Production

rou& session


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Sterile Production

Possible )ssues Poor design of the building

Poor design of the systems# e2g2 water# 7=A)

low of personnel

low of material

8o validation or qualification

:ld facilities not complying with current requirements


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Sterile Production

Possible )ssues %continued&

Particulate levels5microorganisms

!ifferential pressures

Air changes

Temperature5humidity


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Sterile Production

T-o cate'ories o# manu#acturin' o&erations

Terminally sterilized

prepared, filled and sterilized

Aseptic preparation

some or all stages

1.3


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Sterile Production

!anu#acture o# sterile &re&arations

)lassification of clean areas

Manufacturing operation in an appropriate environment

cleanliness level

Minimize risks ( particulate and microbiological contamination (

product and material

Meet classification >at rest>

(-hat is completed installation, equipment installed and

operating, but no operating personnel present)

.1


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Sterile Production

!anu#acture o# sterile &re&arations or sterile pharmaceutical preparations9

Grade A

local zone, high risk operations, e.g. filling, aseptic

connectionsusually 0 systems used

Grade ;

background environment to Grade (in case of aseptic

preparation and filling)

Grade ) and Grade !

'lean areas for less critical operations.1


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Air Classifcation System

Sterile Production

3.1


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Sterile Production

!anu#acture o# sterile &re&arations

To reach Grade ;# ) and !# the number of air changes should beappropriate to the size of the area# number of personnel#equipment present

Minimum of ', air changes per hour

)lean?up time about +- ( ', minutes

Good airflow pattern in the area

73PA filtered air

Suitable methods to determine particulate matter and microe.g. 1, 23, 4apan, .1 – .2.


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Sterile Production

!anu#acture o# sterile &re&arations)ontrol particulate during operation

Monitoring during operation

Alert and action limits for particulate and micro

Action taken when e$ceeded

Area grades should be proven %e2g2 validation runs# media fills#

environment# time limits ? based on microbiologicalcontamination5bioburden found&.3 – .5


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Airborne particulate classifcation

Sterile Production

.1


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.15 – .16" .20 – .21

Sterile Production

Processin'

Minimize contamination ? all stages including before sterilization

and during processing

8o unsuitable materials# e2g2 live microbiological organisms

Minimize activities

staff movement controlled and methodical

avoid shedding of particles

Temperature and humidity comfortable

)ontainers and materials in the area


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.17" .1!" .2!

Sterile Production

Processin' =alidation ( should not compromise the processes Aseptic process validation9 sterile media fill %@broth fills&simulate actual operation # intimate as closely as possiblesimulate "orst expected conditionuse appropriate medium/mediasufficient number of units, e.g. equal to batch size (small batches)

( acceptable limit ( investigations

revalidation5 periodic and after change8ew processing procedures validated

revalidation after significant changesand regular intervals


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.19

Sterile Production

Processin'

0ater sources# water treatment systems and treated water

Monitored regularly

chemicalsbiological contamination

endotoxin

0ater specification

1ecords of results and action taken


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.22 – .23

Sterile Production

Processin')omponents# bulk product containers and equipment

fibre generation

no recontamination after final cleaning

stage properly identified

sterilized "hen used in aseptic areas

*sed in clean areas# passed through double?ended sterilizers or

use triple wrapping

Gas used to purge solution or blanket a product ( passedthrough a sterilizing filter


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.26" 5.3

Sterile Production

Processin' ;ioburden monitored

products5 before sterilization

"orking limits established

solutions to be filtered before filling (especially 678) pressure release outlets # hydrophobic microbiological air

filters

Starting materials ( microbiological contamination should be

minimal

Monitored as per specification


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.23 - .2

Sterile Production

Processin' Time intervals com&onents, bul/ containers, e"ui&ment

0ashing and drying and sterilizationB and sterilization and use

as short as possible

time limit validated

Time intervals &roduct

Start of preparation of solution and sterilization %filtration&

as short as possiblemaximum time set for each product


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Sterile Production

rou& session 2)onsidering the same factory as in the previous group session#

discuss the process of sterilization

6ist all the items that will need to be sterilized %and indicate the

choice of sterilization process&

0hat are the key features you should find in each sterilization

situationC

!iscuss the relevance# need# and the e$tent of qualification andvalidation required


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Sterile Production

Possible )ssues

Autoclave ? no pressure gauge

Autoclave ? no temperature recorder

Autoclave ? superheated steam)lean room ? pressure differentials

3$posure for settle plates

"nterlocks turned off

1usty 6aminar airflow cabinets73PA filters not checked regularly


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5.1 – 5. 2

Sterile Production

SteriliationMethods of sterilization

moist or dry heat

irradiation (ionizing radiation)

sterilizing gaseous agents (e.g. ethylene oxide)

filtration "ith subsequent aseptic filling

0henever possible9 terminal sterilization by heat in their final

container ? method of choice


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5. – 5.5

Sterile Production

Steriliation=alidationall sterilization processesspecial attention "hen non+pharmacopoeial methods are

used non+aqueous or oily solutions

;efore the method is adopted ( its suitability and efficacydemonstrated with desired conditionsall parts of the load each type of load physical measurements and biological indicators ("here

appropriate)verified at least annually and after change records maintained


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5.! - 5.9

Sterile Production

Steriliation!ifferentiation between sterilized and not?yet?sterilized products

3ach basket5tray or other carrier# properly labelled

name of material

batch number sterilization status

*se of autoclave tape

Sterilization records for each run ( approved as part of the batch

release procedure


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6

Sterile Production

Terminal Steriliation

Sterilization by heat

Sterilization by moist heat

Sterilization by dry heat

Sterilization by radiation

Sterilization by gases and fumigants


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6.2 – 6.3

Sterile Production

Terminal SteriliationSterilization by heat

1ecording of each cycle# e2g2 time and temperature chart

temperature5 validated coolest part

check from second independent probe

additional chemical or biological indicators

7eating phase9 sufficient time for the whole load

determined for each load

)ooling phase9 after sterilization cycle

precautions to prevent contamination

sterilized cooling fluid/gas


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6. – 6.6

Sterile Production


Sterilization by moist heat %heating in an autoclave&

0ater?wettable materials only# and aqueous formulations

Temperature# time and pressure monitored

Temperature recorder independent of the controller

"ndependent temperature indicator

!rain ( temperature recorded from this position

1egular leak test when vacuum is part of the cycle

Material allows for removal of air and penetration of steam

All parts of the load in contact with steam/uality of the steam ( no contamination


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6.7

Sterile Production


Sterilization by dry heat

or non?aqueous liquids# dry powders

Air circulation in the chamber

Positive pressure in chamber to prevent entry of non?sterile air

73PA filtered air supplied

0hen removing pyrogens# challenge tests

validation (using endotoxins)


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6.! – 6.10

Sterile Production

Terminal SteriliationSterilization by radiation

Suitable for heat?sensitive materials and productsconfirm suitability of method for material ultraviolet irradiation not acceptable

)ontracting service ( ensure validation status# responsibilities

Measurement of dose during procedure

!osimeters independent of dose ratequantitative measurement number, location and calibration time+limit

;iological indicators only as additional control

1adiation sensitive colour discs


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6.10 – 6.13

Sterile Production

Terminal SteriliationSterilization by radiation %'&

"nformation forms part of the batch record

=alidation to cover effects of variation in density of

packages7andling procedures to prevent misidentification of

irradiated and non?irradiated materials

3ach package to have a radiation?sensitive indicator

Total radiation dose administered within a predeterminedperiod of time


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6.21

Sterile Production

Terminal Steriliation Monitoring of each cycle with biological indicators time, pressure

temperature, humidity

gas concentration

Sterilization by gases and fumigants %'&

Post?sterilization storage ( controlled manner

ventilated conditions

defined limit of residual gas

validated process Safety and to$icity issues


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Sterile Production

Terminall+ sterilied &roducts

.6 – .7


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Sterile Production

Terminall+ sterilied &roducts

.! – .9


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Sterile Production

Ase&tic &rocessin' and steriliation b+ #iltration

Aseptic processing

:b4ective is to maintain the sterility of a product# assembled

from sterile components

:perating conditions so as to prevent microbial contamination

0hat do you think are the aspects that require careful attentionC

7.1 – 7.2


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Sterile Production

Ase&tic &rocessin' and steriliation b+ #iltration Aseptic processing %'&

)areful attention to9

3nvironment

Personnel

)ritical surfaces

)ontainer5closure sterilization

Transfer proceduresMa$imum holding period before filling

7.3


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Sterile Production

Ase&tic &re&aration

.10" .11" .1


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Sterile Production

Ase&tic &re&aration

.10 – .13


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Sterile Production

Steriliation b+ 1iltration Through a sterile filter of ,#'' Dm or less# into previously

sterilized containers

remove bacteria and moulds

not all viruses or mycoplasmas)onsider complementing with some degree of heat treatment

!ouble filter layer or second filtration advisable# 4ust before filling? no fibre shedding or asbestos filters

ilter integrity testing immediately after use

also before use if possible

7. – 7.7


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St il P d ti


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Sterile Production

5ualit+ $ontrolSamples for sterility testing should be representative

rom parts of the batch# most at risk

aseptic filling + at beginning and end of batch filling, and afterinterruptions

heat sterilized # coolest part of the load

Sterility of the batch ensured through validation

validated sterilization cycle

media fill

Sterility test procedure as per pharmacopoeia# and validated for

each product;atch processing records# sterility testing records# environmental

records should be reviewed2.1 -2.2

St il P d ti


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Sterile Production

5ualit+ $ontrol3ndoto$in testing for in4ectable products

"ater for inection, intermediate and finished product

Always for large volume infusion solutions

Pharmacopoeia method# validated for each product

ailure of the test ( investigation

)orrective action

2.3

St il P d ti


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Sterile Production

1inishin' o# &roducts)ontainers closed by means of validated methods Samples checked for integrity

Maintenance of vacuum %where applicable& checked

Parenteral products inspected individually

=isual inspection under suitable and controlled conditions illumination and background

eyesight checks of operators

allo"ed frequent breaks

:ther methods

validated, and equipment performance checked at intervals

results recorded 11.1 – 11.3

St il P d ti


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Sterile Production

rou& session 4)onsidering the same factory as in the previous group sessions#

devise a plan for monitoring of the facility

6ist the parameters to be tested# tests to be used# acceptance

criteria and frequency of testing

Documents

GMP steril WHO