Presentation on Aseptic Presentation on Aseptic Filling TechniquesFilling Techniques

Presented By:Muhammad SamieLecturer HIPS

“Aseptic filling Techniques: A series of actions used to minimize contamination during manufacturing of Sterile drug Products”.

“Sterile product is Said to be a Product which is free from micro-organisms and their spores”.

While to make a sterile product we need an environment which should be free from micro-organisms and the no. of Air borne particles Should be in a controlled Limit and that is known as aseptic Environment.or

“An Area with defined environmental control of Particulate and microbial count”.

The main aim of Aseptic filling techniques is to Improve Product quality

To Maintain an Aseptic filling environment we need to control the Contamination.

Contamination is of Two TypesViable Non viable

Micro-organisms Dust Particles,& Environment

Related,Spores (pyrogens) Equipment Related,

Material,

Sources of ContaminationSources of ContaminationFacilities:

Walls, Floors and CeilingPaint and CoatingsConstruction materialAir Conditioning DebrisSpills and Leaks

Peoples:Skin flakes and oilCosmetics and perfumesHairsClothing DebrisSpitting

Tools Generated:FrictionLubricationVibrationMops and Dusters

Fluids:Cleaning ChemicalsDe-ionized waterHumidity in Air

Product Generated:Aluminum ParticlesRubber gaskets

How to Control Contamination?Three main types are there to Control

Contamination Environmental Control.

HEPA Filters , HVAC System

& Fumigation of Area

Equipment Control.Sterilization & Sanitization

Individual Control.Personnel Hygiene & Aseptic Gowning

1.Environmental Control:1.Environmental Control:The Design of The Clean Room Play a major Role in Maintaining The Aseptic Area.

Different types of processes needs different cleanliness levels depending on viable and non viable count.Two major areas are there

Critical AreaLess critical / General Area

Basic design of clean room is:

Clean Room is Classified into Different Grades Clean Room is Classified into Different Grades on the Basis of No of Particulate Count.on the Basis of No of Particulate Count.

Particle Size = 0.5 - 5.0micronParticle Size = 0.5 - 5.0micron

GMP US ISO Non Viable Viable

GRADE A

CLASS 100/Ft3

5 3500/m3 <1

GRADE B

CLASS 100/Ft3

5 3500/m3 5

GRADE C

CLASS 10,000/Ft3

7 350000/m3 50

GRADE D

CLASS 100,000/Ft

3

8 3500000/m3 100

Three Entrance Areas are there:Three Entrance Areas are there:

1. Black Area (Locker Room).2. Grey Area (Change Room).3. White Area (Sterile Gowning Room).

The Clean Area should be Constructed in such a way that all Processes occurring in Aseptic Environment should be Inspected from outside

It is Ideal to ensure that the personnel flow is moving one way from gowning area to the operation area and then back from Cleanest area towards Dirtiest.

The equipment Layout and flow will also influence the Clean room design. The ideal aseptic filling system is a fully automated inline system and isolator filling system which is installed to Reduce the No of Personnel Present in the Clean Area.

Automatic vial filling machine

HVAC System:HVAC System:An essential Component of the Clean room is HVAC System. It is provided with HEPA filters and a series of Pre filters prior to HEPA filters. The heating and cooling functions are needed for environmental control and operators comfort. Ventilation function provides the necessary circulation to maintain the aseptic core by the use of +ve pressure that extends away from the core.

The comfortable working Environment is having temperature 25 degree Celsius and the relative humidity between 30% to 60% (Depending on nature of the product) to control organism growth and personnel from sweating.

HEPA filter:HEPA filter:These are the major components of LFH work

station.The pore size of HEPA filter is 0.22micron & are

capable of retaining particles up to 0.3micron.Life of a HEPA filter depends on DOP test results.They can filter organisms i.e. Yeast, Molds &

Bacteria.Air velocity of HEPA filter should be 100±20ft/min

Air Locks or Buffer zones:Air Locks or Buffer zones:To retain separate two different cleanliness levels

normally we need air locks or buffer zones.It is used for personnel or Equipments.It should consist of at least two doors.Don’t have a gowned & ungowned person in the

same air lock.Do disinfect all equipments in the air lock prior to

enter in aseptic area or an aseptically gowned person contact it.

Types of Air LocksTypes of Air Locks

Cascade Air lockCascade Air lockBubble Air lockBubble Air lockSink Air lockSink Air lock

Pass through windowsPass through windows

Laminar Flow Hood:Laminar Flow Hood:The most crucial area of a clean room is

under LFH in which the sterile drug is directly exposed to the Environment.

This technique was first introduced by an Electronics company in 1960 to control particulate contamination in electronic devices.

Very strict control of viable count is recommended under LFH.

Two types of LFH.Two types of LFH.

HorizontalVertical

Horizontal LFH is recommended to be used for sterility test (Air velocity 0.45m/s).Vertical LFH is recommended to be used for operational work (Air velocity 0.30m/s).

Air Flow Pattern in LFHAir Flow Pattern in LFHHorizontal Air flowHorizontal Air flow Vertical Air flow Vertical Air flow

Pressure Differential:Pressure Differential:A very simplified illustration is the clean

room cascade type of pressure differential.

It should not be less than 0.06 IOW.10-15 pascals

2.Machine and Equipment Control:2.Machine and Equipment Control:

To complete an aseptic filling process we need to terminally sterilize the drug product, filling components, machine parts and in place equipments.Sterilization is usually done with steam autoclave, hot air oven, chemicals, filtration and radiations.

There are many considerations in the selection of your filling equipment according to the nature of sterile drug to be filled.Sterile filling of glass vials and bottles is achieved by rinsing to remove endotoxins and loose particles and then depyrogenation in hot air oven.

The small parts like filling needles, cylinders, forceps, bulk assembly, rubber tubing's and stoppers must be washed first and then wrap the parts for sterilization in autoclave.Depending on the formulation the stoppers may also be sterilized by irradiation.

Aseptic filling operation may vary from a clinical hand fill trial to a high speed filling lines.The stoppering and capping should be done as soon as possible.The sealing should be done out side the LFH to reduce particle generation from aluminum seals.

Any equipment, machine part, gloves, suits and masks that are used in the aseptic environment should be sterilized.Any type of Equipment or material that shed particles is strictly prohibited in aseptic area.Most clean rooms have telecommunication equipment to allow discussions without the need of personnel entering & exiting the operation

Material of construction also play an important role in maintaining an aseptic environment.The surfaces should be smooth, Hard and easily cleanable.The floor walls and ceiling should be continuous and provided with welded joints.Oil less compressed air should be used provided with sterile filters inside sterile core.Sterile steam and Vacuum should be used.

3.Individual Control:3.Individual Control:A room can be disinfected, an object can be sterilized, air can be filtered but we can’t sterilize a person.The personnel in the clean room are like the “double edge” sword .They are absolutely necessary to complete an aseptic process but at the same time provide the greatest microbial risk to the sterile product.

A human body constantly regenerates itself and in this process shedding a huge amount of dead skin and other particles.An average person is capable of shedding 10million particles /day.Proper personnel hygiene is necessary to work in Aseptic filling area.

Personnel entry to the aseptic Personnel entry to the aseptic area require:area require:One must have a positive thinking.Proper personal hygiene.The will to work in a precise

manner.The awareness about the critical

nature of the process.

The personnel entering the aseptic area should be properly trained.Written and qualified procedures should be available to further minimize microbial contamination.Any personnel entering the aseptic area must wear a sterilized gown.Each time you must get a new complete set of gowning component.

Disposable gowns may also be used and should be immediately discarded upon exiting the area.Sterile outer garments are usually made of synthetic or natural materials which have no or less particle shedding characteristics.

Why we need gown?Why we need gown?

To protect the product.To maintain aseptic

conditions.Compliance with GMP and

regulatory requirements

Gowning procedure:Gowning procedure:Remove the ordinary uniform except

under garments in the change room.Wear sterilized inner garments.Scrub hands and forearms with

germicidal soap to remove dirt and other contaminations.

Dry hand with hot air (don’t use towel).

Gowning should be done as follows:Gowning should be done as follows:Gloves (disinfected with alcohol).Foot wears.Hood/mask.Gown (jump suit).Shoe covers.Replace the gloves with new ones.

Before leaving the room inspect yourself in the mirror to ensure that you are gowned properly

Disinfect your hands with disinfectant and enter the aseptic area:

Remember Never touch a critical surface directly

i.e.Vials, stoppers and surfaces that are in direct contact

with the product.

Only use sterile forceps or an implement that has been sterilized to touch a critical surface.

How one should behave in a clean room?Do limit the No of peoples under LFH and in Clean

room.Don’t enter the hood unless you need it.Do keep all talking to necessary communication.Do use intercom or telephone to communicate to

some one out side the aseptic area.Do rinse your hands (gloves) with IPA after every 10-

15min while working under LFH.Do work slowly in the aseptic area.Don’t open sterile gown in the filling area.

How to assemble the machine parts?

Wipe the equipment or container with IPA before entering the LFH.

Wipe the gloves with IPA immediately after entering the LFH.

Wipe or squirt your tools with IPA to disinfect them.

Hold the tools as far away from the operating ends as possible.

Frequently disinfect the tools and gloves if working for a long time.

Keep other parts of body away from the adjustment area.

Work slowly (carefully) but efficiently.If a spill occurs wipe up it immediately.

Micro contamination is very small and surfaces and environment that looks clean

and sterile may not be…

SoHow we can consider an environment to

be aseptic?Environmental monitoring is the process to

ensure that the clean room is under control for potential viable and non

viable contamination.

Surface air sampler (weekly for 10min).Settle plate method (Daily for 01hr).Contact plate method/swab test.Uniform count/gloves.Particle counting for Non viable particles

(monthly).Qualitative test for Disinfectant

(monthly).Air Changes in Aseptic area (6 months)

Surface Air Sampler

Settle plate method

Contact plate method

Contact plate method

Airborne particle counter