PHCT 401 Aseptic Processes & Techniques · 2017-01-12 · PHCT 401 Aseptic Processes & Techniques...

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PHCT 401 Aseptic Processes & Techniques Principles of Aseptic Techniques Aseptic Processing Sterility Testing Laminar flow air cleaning Quality Control Tests Personnel

Transcript of PHCT 401 Aseptic Processes & Techniques · 2017-01-12 · PHCT 401 Aseptic Processes & Techniques...

Page 1: PHCT 401 Aseptic Processes & Techniques · 2017-01-12 · PHCT 401 Aseptic Processes & Techniques Principles of Aseptic Techniques Aseptic Processing ... Steps in Aseptic Room Air

PHCT 401

Aseptic Processes & Techniques

Principles of Aseptic Techniques

Aseptic Processing

Sterility Testing

Laminar flow air cleaning

Quality Control Tests

Personnel

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Principles of Aseptic Techniques

Overview

• Certain pharmaceutical products must be sterile

• Parenteral preparation o Injections

o Intravenous infusions

o Non-injectable sterile fluids Urological (bladder) irrigation solutions

Peritoneal dialysis & Haemodialysis solutions

• Ophthalmic preparations o Eye drops/Oint

o Eye lotions

o Contact lens solution

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• Dressings

• Implants

• Two categories of sterile products

Terminally Sterilized (TS) – can be sterilized in

their final containers

Non-Terminally Sterilized (NTS) – cannot / will

not be sterilized in their final containers.

Principle

‘Starting with sterile materials and equipments, it

is possible to produce a sterile product if strict

precautions are taken to avoid microbial

contamination’

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• Methods used, collectively described as “Aseptic Technique”

• Aseptic manufacturing procedures available for different types of products.

• Awareness of aseptic handling procedures to be adopted to minimize risk of product contamination.

• Those who have cause to open, use or dispense sterile products e.g Hospital Pcy

• Manufacturing under conditions that do not permit entry of contaminating µorganisms

Aseptic Manufacturing Processing

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Asepsis

“A state of control attained by using an

aseptic work area and performing activities

in a manner that precludes microbiological

contamination of the exposed sterile

product”

Aseptic Processing

“the processing of drug components (drug,

containers, excipients etc.) in a manner that

precludes microbiological contamination of

the final sealed product”

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Aseptic processing:

“A method of producing sterile products in which sterile bulk product or sterile raw materials are compounded and filled into sterile containers in a controlled environment, in which the air supply, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels”

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

• Operating conditions so as to prevent microbial contamination.

• Combination of various simple techniques and processes.

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• Spoilage of medicines due to microbial

contamination is undesirable

• Various consequences

Financial loss – main

Risk of initiating infection (though uncommon)?

More important in terms of

oRisk to the patient

oPossible loss of life

Financial implications of product-related infections

Additional treatment costs

Product recalls

Possible litigation & damage to reputation

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Understanding Aseptic processes & techniques

• Understand various sources of contaminating microorganisms in the production or work area

Personnel o Skin and respiratory tract flora

oMicrobial transfer from operators

Atmosphere - air

Water

Raw materials

Packaging materials

Equipment

Buildings oWalls & ceilings

o Floors &drains

o Doors, windows & fittings

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• Quality of pharmaceutical products refers to ‘fitness for purpose’

• Product should not only have the desired therapeutic properties

• Safe for administration by intended route

• Sterile products – free from microbes

• Others like oral preparations, need not be sterile

Free from indicator pathogens that can be contracted through the oral route

• Greater attention paid to quality of sterile product

• Reflects additional Quality assurance required

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• In demonstrating quality, tests carried out to detect the absence of quality

• Sterility Test

o Sampling products at random

o Testing for presence of microorganisms

o Samples taken should be representative of the whole population –Sampling Technique

o Absence of microorganisms will only allow you to estimate the statistical probability that the batch sampled is sterile.

o All products should therefore be manufactured in a suitable environment

By procedure that minimizes the possibility of microbial contamination occurring

Building quality into the product

At the end of the manufacturing process, tests can be performed as additional measure, since

Quality is not inspected into the product

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Application of Aseptic Techniques & Processes

Techniques designed to prevent accidental contamination of sterile materials & pure cultures from the environment during handling

• Pharmaceutical manufacturing

• Foods & cosmetics

• Pure cultures of microorganisms used in Pharmaceutical biotechnology

Recombinant human insulin

Production of immunological products- vaccines

Production of antibiotics

Careful handling to prevent accidental contamination of pure stock

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Aseptic technique involve procedures such as:

• Use of sterile apparatus & materials at all

times

• Use of proper closures & containers

• Wrapping of apparatus for sterilization

• Flaming of necks of containers in Bunsen

burner flame

• Minimal exposure of materials during handling

• Spraying & swabbing of benches & work area

with a suitable disinfectant

• Washing & scrubbing of hands

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Keeping the operator’s dirt and germs out of the sterile cleanroom environment and away from sensitive products and processes is the main objective of the sterile cleanroom suit

Automated Hand-Washing System

•Use of protective clothing-to keep all clothing

parts together

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Carrying out operations within/under special handling

cabinets equipped with filtered air.

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Wearing of protective clothing

• Clothing worn must be made from non-

shedding materials: terylene a suitable fabric

• Proper head gears/wears

• Rubber or plastic gloves

• Face masks to prevent the release of droplets

must be worn by operators in the aseptic

areas for production of especially NTSP

• Prevents airborne contamination of both

microbial and particulate matter.

• Clothing that are close fitting at the neck, wrist

and ankles more suitable

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• Clothing should be used once a day

• Fresh headwear, overshoes and powder-free

gloves should be provided for each working

session.

Four Pillars of a robust Aseptic Processing

• Personnel Training &Monitoring

• Environmental Monitoring

• Facility Design HVAC Validation

• Process Simulation (Media Fills)

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Sterility Testing

• Required for all sterile products

• Not overriding control to cover all short-

comings

• Adequate attention must be paid to every

stage in the production process

Adequate premises

Sterilizing equipment and process

Skilled and trained personnel etc

• Building quality into the product

• ST is actually the detection of the absence of

quality!

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• Sterility does not detect all known living forms

• Official tests for sterility detects gross contamination

with most common organisms (including pathogens)

• Most probable contaminants limited to bacteria and

fungi.

• No test for viruses

• Difficulty in culturing viruses

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Design of Sterility Tests

Critical considerations

Sampling – method should give the greatest

probability of picking up an infected unit within the

batch.

Batch

Container Unit

Volume of medium

Inhibitory substances in the product

Product should not affect the ability of the medium to

support growth.

Added product not > 10% of the volume of medium. B.P

Details from U.S.P.

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Media – appropriate to support likely contaminant

Bacteria

Fungi – modified

Inactivation

Of preservatives

Any constituent with AMA activity

Inactivation aids recovery of contaminants

Inactivators

• Not inhibitory to growth promoting property of

medium

• Should not interfere with nutritive quality of the

medium

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Methods of inactivation

• Dilution

• Inactivation by constituents

• Destruction or inactivation / antagonization by

addition of sterile inactivators.

• Physical removal by filtration.

Other critical consideration

• Controls

• Incubation conditions

• Interpretation of results

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Controls

• Two major controls against which to check

conclusion from the test series.

• Negative Control

Sterility of the media used

Checked by including un-innoculated bottles from

the same batch as that used in the test

• Positive Control

Growth promoting properties of the batch

Inactivation of inhibitory substances in the product

Demonstrated by including an exact set with same

quantities of test substance (sample) in the same

volumes of the batch of test media

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Reporting Sterility Testing Results

CODE SAMPLE NUTRIENT

MEDIUM

CONTROL

OREGANISM

EXPECTED

RESULT

ACTUAL

RESULT

AET Sample Thioglycolate No Organism - ve

ANT Sample Thioglycolate No Organism -ve

FGT Sample SDM No Organism - ve

AET PC No Sample Thioglycolate S. aureus + ve

ANT PC No Sample Thioglycolate Clostridium + ve

FGT PC No Sample SDM Candida + ve

AET NC No Sample Thioglycolate No Organism - ve

ANT NC No Sample Thioglycolate No Organism -ve

FGT NC No Sample SDM No Organism - ve

KEY

AET = Aerobic Test

ANT = Anaerobic Test

FGT = Fungal Test

PC = Positive Control

NC = Negative Control

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Laminar Flow Air Cleaning

• Providing the environment for aseptic manufacturing

• Cleanrooms with specific requirements

• Two major types

• Differentiated by their method of ventilation.

Turbulently ventilated cleanrooms (‘nonunidirectional’)

Unidirectional flow cleanrooms (originally known as

‘laminar flow’

The unidirectional type of cleanroom uses very much more

air than the turbulently ventilated type,

Gives a superior cleanliness. w.

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Non-unidirectional Airflow

Figure shows a turbulently

ventilated room receiving clean

filtered air through air diffuses in

the ceiling. This air mixes with the

room air and removes airborne

contamination through air extracts

at the bottom of the walls. The air

changes are normally equal to, or

greater than, 20 per hour, this

being much greater than that used

in ordinary rooms, such as in

offices. In this style of cleanroom,

the contamination generated by

people and machinery is mixed

and diluted with the supply air and

then removed.

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Unidirectional Airflow The horizontal flow cleanroom uses the same filtration airflow technique as the downflow, except the air flows across the room from the supply wall to the return wall. One major limitation of the horizontal flow design is that the downstream contamination in the direction of airflow increases.

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Steps in Aseptic Room Air Filter

• Air intake

• Pre-filtration

• Temperature regulation

• Humidification

• HEPA filtration

HEPA - High Efficiency Particulate Air filters

Can remove 99.97% of airborne

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Air intake

• From environment – high up

• Away from polluted area of town & chimneys

Pre-filtration

• Through a pre-filter

• Set of coarse filters next to the air intake

• Removes large particles (≥5µm)

Temperature regulating/adjustment

• Regulates air temperature to ambient

• If too cold, heats up

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Humidification

• Prepare air of required humidity

• Incoming air passed through system of fine atomized

spray of de-mineralized water

HEPA filtration

• Final filtration step

• Air forced through high efficiency air filters

• Removes 99.97% of airborne particles of 0.3µm size

• Particles 0.3µm size most difficult to filter

• Considered MPPS (Most Penetrating Particle Size)

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Airflow Control

• Vertical laminar flow

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Personnel

• High standards of personal hygiene

• Most common source of contaminants in

sterile drug products.

• Large numbers of microbes

• Healthy population known as reservoir of

many microbes.(pathogens)

• Shed numerous ‘viable’ & ‘non-viable’

particles into environment

• Free from communicable diseases & open

lesions on exposed body surfaces.

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• Organisms carried on (larger) skin particles.

• Adherence to high standards of cleanliness

ensured by

Adequate hand-washing facilities

Protective garments – head gears,

gloves

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Appropriate training of all staff before being

permitted to enter the Aseptic Manufacturing

area

Fundamental Training Topics

Principles of cGMP

Practice & theory of assigned task

Aseptic technique

Microbiology

Gowning proficiency – training, observation.

Specific SOPs covering aseptic

manufacturing area operations.

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Laminar Flow Air Cleaning

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