Sterile | Slide 1 of 62 January 2006 Annex 6. TRS 902, 2002 Sterile Pharmaceutical Products...

Sterile | Slide 1 of 62 January 2006

Annex 6. TRS 902, 2002

Sterile Pharmaceutical Products

Supplementary Training Modules on Good Manufacturing Practice


Sterile ProductionSterile Production

Objectives

To review basic GMP requirements in the manufacture of sterile pharmaceutical products

To review air classifications for activities related to the manufacture 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


Sterile Production Sterile Production

GMP Requirements for Sterile Products

Additional rather than replacement

Specific points relating to minimizing risks of contamination

– microbiological– particulate matter– pyrogen



General Considerations

Production in clean areas

Appropriate standard of cleanliness

Filtered 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


9.1 – 9.6


Premises

Design

– Avoid unnecessary entry of supervisors and control personnel

– Operations observed from outside

In clean areas, all exposed surfaces:

– Smooth, impervious, unbroken

– Minimize shedding and accumulation of particles, microorganisms

– Permit cleaning and disinfection

– No uncleanable recesses, ledges, shelves, cupboards, equipment

– Sliding doors undesirable

– False ceilings sealed


9.6.


Premises

In clean areas, all exposed surfaces (2):– Proper installation of pipes and ducts, no recesses, no

unsealed openings– Sinks and drains avoided, and excluded in Grade A and B

areas• Where installed, design, location, maintenance• Effective cleanable traps• Air breaks preventing backflow• Floor channels open and easily cleanable


9.7 – 9.9


Premises

Changing rooms– Designed as airlocks– Effective flushing with filtered air– Separate rooms for entry and exit desirable– Hand washing facilities– Interlocking system for doors– Visual and/or audible warning system

Use filtered air supply to maintain pressure cascade

Pressure differential approximately 10 to 15 Pascales

Zone of greatest risk – immediate environment


9.9 – 9.12


Premises

Pathogenic, highly toxic, radioactive materials

Pressure cascade may be different

Decontamination procedures – air, equipment, garments

Qualification including airflow patterns– No risk to the product

Warning system to indicate failure in air supply

Pressure indicators – results regularly recorded

Restricted access – e.g. use of barriers


10.1 – 10.5


Equipment

Conveyer belts

Effective 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, water

treatment systems


10.6


Equipment

Water treatment plants and distribution system– Design, construction, maintenance– Operation and design capacity– Testing programme

Water for Injection (WFI)– Produced, stored, distributed – prevention of growth of

microorganisms– Constant circulation at temperature above 70, or not more

than 4 degrees Celsius



Environmental Monitoring - I

Microbiological

Air samples

Surface swabs

Personnel swabs



Environmental Monitoring - II

Physical

Particulate matter

Differential pressures

Air changes, airflow patterns

Clean-up time/recovery

Filter integrity

Temperature and relative humidity

Airflow velocity



Sanitation

Frequent, thorough cleaning of areas necessary

Written programme

Regular monitoring to detect resistant strains of microorganisms

Chemical disinfection

Monitoring of disinfectants and detergents

Dilutions– Clean containers, stored for defined periods of time– Sterilized before use, when used in Grade A or B areas

3.1 – 3.2



Sanitation

Monitoring of clean areas

Monitoring of personnel and surfaces after critical operations

Frequent monitoring in areas where aseptic operations are carried out

– Settle plates, volumetric air samples, surface sampling (swabs and contact plates)

– Sampling methods should not contaminate the area

Results considered when batch release is done3.3



Sanitation

Limits of detection established

Alert and action, and monitoring trends of air quality

Table 1. Limits for microbial contamination (Information only)

3.4

Grade Air sample

(CFU/m3)

Settle plates

(90mm diameter)

(CFU/4hours)

Contact plates

(55mm diameter)

(CFU/plate)

Glove print

(5 fingers)

(CFU/glove)

A < 3 < 3 < 3 < 3

B 10 5 5 5

C 100 50 25 -

D 200 100 50 -


8.1 – 8.3


Personnel

Minimum number of personnel in clean areas– Especially during aseptic processing

Inspections 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 who worked with animal tissue

materials)


8.4 – 8.6


Personnel

High standards of hygiene and cleanliness

Periodic health checks

No shedding of particles

No introduction of microbiological hazards

No outdoor clothing

Changing and washing procedure

No watches, jewellery and cosmetics


8.7


Personnel

Clothing of appropriate quality:

– Grade D

• hair, beard, moustache covered

• Protective clothing and shoes

– Grade C

• Hair, beard, moustache covered

• Single or 2-piece suit (covering wrists, high neck), shoes

• no fibres to be shed

– Grade A and B

• Headgear, beard and moustache covered, masks, gloves

• No shedding of fibres, and retain particles shed by operators


8.8 – 8.9


Personnel

Outdoor clothing not in change rooms leading to grade B and C rooms

Change at every working session, or once a day (if supportive data)

Change gloves and masks at every working session

Disinfect gloves during operations

Washing of garments – separate laundry facility

No damage, and according to validated procedures



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



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



Possible Issues (continued)

Particulate levels/microorganisms

Differential pressures

Air changes

Temperature/humidity



Two categories of manufacturing operations:

Terminally sterilized– prepared, filled and sterilized

Aseptic preparation– some or all stages

1.3



Manufacture of sterile preparations

Classification of clean areas

Manufacturing operation in an appropriate environment cleanliness level

Minimize risks – particulate and microbiological contamination – product and material

Meet classification "at rest"– (i.e. "completed installation, equipment installed and operating,

but no operating personnel present").4.1




For sterile pharmaceutical preparations:

Grade A

– Local zone, high risk operations, e.g. filling, aseptic connections

– Usually UDAF systems used

Grade B

– Background environment to grade A (in case of aseptic preparation and filling)

Grade C and Grade D

– Clean areas for less critical operations4.1


Air Classification System


Grade At rest In operation

maximum permitted number of particles/m3

0.5 - 5.0 µm > 5 µm 0.5 - 5.0 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

3.1




To reach Grade B, C and D, the number of air changes should be appropriate to the size of the area, number of personnel, equipment present

Minimum of 20 air changes per hour

Clean up time about 15-20 minutes

Good airflow pattern in the area

HEPA-filtered air

Suitable methods to determine particulate matter and micro-– e.g. EU, ISO, Japan, USA 4.1 – 4.2.




Control particulate during operation

Monitoring during operation

Alert and action limits for particulate and micro

Action taken when exceeded

Area grades should be proven (e.g. validation runs, media fills, environment, time limits – based on microbiological contamination/bioburden found)

4.3 – 4.5


Airborne particulate classification


WHO GMP US 209E US Customary ISO/TC (209) EEC GMP

Grade A M 3.5 Class 100 ISO 5 Grade A

Grade B M 3.5 Class 100 ISO 5 Grade B

Grade C M 5.5 Class 10 000 ISO 7 Grade C

Grade D M 6.5 Class 100 000 ISO 8 Grade D

4.1


4.15 – 4.16, 4.20 – 4.21


Processing

Minimise contamination – all stages including before sterilization and during processing

No unsuitable materials, e.g. live microbiological organisms

Minimize activities– staff movement controlled and methodical– avoid shedding of particles

Temperature and humidity comfortable

Containers and materials in the area


4.17, 4.18, 4.28


Processing

Validation – should not compromise the processes

Aseptic process validation: Sterile media fill (“broth fills”)– Simulate actual operation – intimate as closely as possible– Simulate worst expected condition– Use appropriate medium/media– Sufficient number of units - e.g. equal to batch size (small batches)

• acceptable limit• investigations

– Revalidation: periodic and after change

New processing procedures validated– Revalidation after significant changes– And regular intervals


4.19


Processing

Water sources, water treatment systems and treated water

Monitored regularly– Chemicals– Biological contamination– Endotoxin

Water specification

Records of results and action taken


4.22 – 4.23


Processing

Components, bulk product containers and equipment– fibre generation– no recontamination after final cleaning– stage properly identified– sterilized when used in aseptic areas

Used in clean areas, passed through double-ended sterilizers or use triple wrapping

Gas used to purge solution or blanket a product – passed through a sterilizing filter


4.26, 5.3


Processing

Bioburden monitored– Products: Before sterilization– Working limits established– Solutions to be filtered before filling (especially LVP)– Pressure release outlets – hydrophobic microbiological air

filters

Starting materials – microbiological contamination should be minimal

Monitored as per specification


4.23 - 4.24


Processing

Time intervals: Components, bulk containers, equipment

Washing and drying and sterilization; and sterilization and use– As short as possible– Time limit validated

Time intervals: Product

Start of preparation of solution and sterilization (filtration)– As short as possible– Maximum time set for each product



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 (and indicate the choice of sterilization process).

What are the key features you should find in each sterilization situation?

Discuss the relevance, need, and the extent of qualification and validation required.



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


5.1 – 5. 2


Sterilization

Methods of sterilization:– Moist or dry heat– Irradiation (ionizing radiation)– Sterilizing gaseous agents (e.g. ethylene oxide)– Filtration with subsequent aseptic filling

Whenever possible: Terminal sterilization by heat in their final container - method of choice


5.4 – 5.5


Sterilization

Validation – All sterilization processes– Special attention when non-pharmacopoeia methods are used– Non-aqueous or oily solutions

Before the method is adopted – its suitability and efficacy demonstrated with desired conditions:

– All parts of the load– Each type of load– Physical measurements and biological indicators (where

appropriate)– Verified at least annually and after change– Records maintained


5.6 - 5.7


Sterilization

For effective sterilization:

Whole of the material subjected to the treatment

Biological indicators:

Additional method of monitoring

Storage and use, quality checked through positive control

Risk of contamination


5.8 - 5.9


Sterilization

Differentiation between sterilized and not-yet-sterilized products

Each basket/tray or other carrier, properly labelled– Name of material– Batch number– Sterilization status

Use of autoclave tape

Sterilization records for each run – approved as part of the batch release procedure


6


Terminal Sterilization

Sterilization by heat

Sterilization by moist heat

Sterilization by dry heat

Sterilization by radiation

Sterilization by gases and fumigants


6.2 – 6.3



Sterilization by heat

Recording of each cycle, e.g. time and temperature chart– Temperature: validated coolest part– Check from second independent probe– Additional chemical or biological indicators

Heating phase: Sufficient time for the whole load– Determined for each load

Cooling phase: After sterilization cycle– Precautions to prevent contamination– Sterilized cooling fluid/gas


6.4 – 6.6

Sterile ProductionSterile ProductionTerminal Sterilization

Sterilization by moist heat (heating in an autoclave)

Water-wetable materials only, and aqueous formulations

Temperature, time and pressure monitored

Temperature recorder independent of the controller

Independent temperature indicator

Drain – temperature recorded from this position

Regular 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

Quality of the steam – no contamination


6.7



Sterilization by dry heat

For non-aqueous liquids, dry powders

Air circulation in the chamber

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

HEPA filtered air supplied

When removing pyrogens, challenge tests

– validation (using endotoxins)


6.8 – 6.10

Sterile ProductionSterile ProductionTerminal Sterilization

Sterilization by radiation

Suitable for heat-sensitive materials and products– confirm suitability of method for material– ultraviolet irradiation not acceptable

Contracting service – ensure validation status, responsibilities

Measurement of dose during procedure

Dosimeters independent of dose rate– quantitative measurement– number, location and calibration time-limit

Biological indicators only as additional control

Radiation sensitive colour discs


6.10 – 6.13



Sterilization by radiation (2)

Information forms part of the batch record

Validation to cover effects of variation in density of packages

Handling procedures to prevent misidentification of irradiated and non-irradiated materials

Each package to have a radiation-sensitive indicator

Total radiation dose administered within a predetermined period of time


6.14 – 6.20



Sterilization by gases and fumigants

Only when no other method is suitable

e.g. ethylene oxide, hydrogen peroxide vapour

Validation: Also prove the gas has no damaging effect on product

Time and conditions for degassing (specified limits) - residue

Direct contact with microbial cells essential– Nature and quantity of packaging materials

Humidity and temperature equilibrium

Monitoring of each cycle with biological indicators– time, pressure– temperature, humidity and gas concentration


6.21



Sterilization by gases and fumigants (2)

Post-sterilization storage – controlled manner– Ventilated conditions– Defined limit of residual gas– Validated process

Safety and toxicity issues



Terminally sterilized products

4.6 – 4.7

Grade

Preparation Remark

D Components and product Ensure low microbial and particulate count

C Product at unusual risk of

microbial contamination e.g. product actively supports microbial growth, or is held for a long period of time before sterilization, or is not prepared mainly in closed containers

C Filling before sterilization -



Terminally sterilized products

4.8 – 4.9

Grade

Preparation Remark

A in C background

Filling before sterilization if product at unusual risk of contamination from environment

e.g. slow filling operation, or Wide neck containers, or Exposure for a few seconds before sealing

C Preparation and filling Ointments, creams, suspensions, emulsions



Aseptic processing and sterilization by filtration

Aseptic processing

Objective is to maintain the sterility of a product, assembled from sterile components

Operating conditions so as to prevent microbial contamination

What do you think are the aspects that require careful attention? 7.1 – 7.2



Aseptic processing and sterilization by filtration

Aseptic processing (2)

Careful attention to:

Environment

Personnel

Critical surfaces

Container/closure sterilization

Transfer procedures

Maximum holding period before filling7.3



Aseptic preparation

4.10, 4.11, 4.14

Grade

Preparation Remark

D Components after washing C Preparation of solutions to be

sterile filtered later in the process

A (in B

background)

Preparation and filling of sterile ointments, creams, suspensions, emulsions

When the product is exposed and filtered



Aseptic preparation

4.10 – 4.13

Grade

Preparation Remark

A (in B

background)

Sterile starting materials and components

(Unless subjected to sterilization or filtration through a microorganism retaining filter later in the process)

A (in B

background)

Preparation of solutions (if not to be sterile filtered later)

A (in B

background)

Handling and filling of aseptically prepared products,

A (in B

background)

Handling of exposed sterile equipment

A (in B

background)

Transfer of partially closed containers, before complete stoppering

e.g. in freeze drying (Grade B environment if in sealed transfer trays)



Sterilization by filtration

Through a sterile filter of 0,22 µm or less, into previously sterilized containers

– remove bacteria and moulds– not all viruses or mycoplasmas

Consider complementing with some degree of heat treatment

Double filter layer or second filtration advisable, just before filling - no fibre shedding or asbestos filters

Filter integrity testing immediately after use– also before use if possible

7.4 – 7.7



Sterilization by Filtration (2)

Validation to include– Time taken to filter a known volume– Pressure difference to be used across the filter

Significant differences to be noted and investigated, recorded in batch records

Integrity of gas and air vent filters checked after use, other filters at appropriate intervals

7.7



Sterilization by Filtration (3)

Same filter not used for more than one working day, unless validated

No filter interaction with product, e.g.– removal of ingredients– releasing substances into product

7.8 – 7.9



Quality Control

Samples for sterility testing should be representative

From parts of the batch, most at risk– Aseptic filling – at beginning and end of batch filling, and after

interruptions– 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

Batch processing records, sterility testing records, environmental records should be reviewed

2.1 -2.2



Quality Control

Endotoxin testing for injectable products– Water for injection, intermediate and finished product

Always for large volume infusion solutions

Pharmacopoeia method, validated for each product

Failure of the test – investigation

Corrective action 2.3



Finishing of products

Containers closed by means of validated methods

Samples checked for integrity

Maintenance of vacuum (where applicable) checked

Parenteral products inspected individually

Visual inspection under suitable and controlled conditions:– illumination and background– eyesight checks of operators– allowed frequent breaks

Other methods:– validated, and equipment performance checked at intervals– results recorded

11.1 – 11.3



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.

Sterile | Slide 1 of 62 January 2006 Annex 6. TRS 902, 2002 Sterile Pharmaceutical Products...

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