Sterile Products Sterile Products LabLab

PHT 434PHT 434

Sterile Sterile AreaArea

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Definitions Definitions Sterilization: Sterilization: refers to any process that effectively refers to any process that effectively

kills or eliminates living microorganisms. It is not kills or eliminates living microorganisms. It is not absolute. It is acceptable when it achieves killing absolute. It is acceptable when it achieves killing effect of 10effect of 10-6-6 i.e. every 1 million sterile items have a i.e. every 1 million sterile items have a chance for only 1 item to be non-sterile. chance for only 1 item to be non-sterile.

Clean roomClean room: has a controlled level of : has a controlled level of contamination that is specified by the number of contamination that is specified by the number of particles per cubic meter at a specified particle particles per cubic meter at a specified particle size.size.

Laminar flow:Laminar flow: An airflow moving in a single An airflow moving in a single direction and in parallel layers at constant velocity direction and in parallel layers at constant velocity from the beginning to the end of a straight line from the beginning to the end of a straight line vector. vector.

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Definitions Definitions

HEPA filters: HEPA filters: High Efficiency Particulate Air: remove at least 99.97% of airborne particles 0.3 µm in diameter.

ULPA filtersULPA filters: Ultra Low Particulate Air: : Ultra Low Particulate Air: remove at least 99.999% of airborne particles 0.12 µm in diameter.

Airlock: Airlock: A small room with interlocked doors, constructed to maintain air pressure control between adjoining rooms (generally with different air cleanliness standards).

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Definitions Definitions Bioburden: Bioburden: The total number of The total number of

microorganisms associated with a specific item microorganisms associated with a specific item prior to sterilization.prior to sterilization.

Colony Forming Unit (CFU):Colony Forming Unit (CFU): A A microbiological term that describes the microbiological term that describes the formation of a single macroscopic colony after formation of a single macroscopic colony after the introduction of one or more microorganisms the introduction of one or more microorganisms to microbiological growth media. One colony to microbiological growth media. One colony forming unit is expressed as 1 CFU.forming unit is expressed as 1 CFU.

Endotoxin:Endotoxin: A pyrogenic product (e.g., A pyrogenic product (e.g., lipopolysaccharide) present in the bacterial cell lipopolysaccharide) present in the bacterial cell wall. Endotoxin can lead to reactions in patients wall. Endotoxin can lead to reactions in patients receiving injections ranging from fever to death.receiving injections ranging from fever to death.

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Methods of sterilization:Methods of sterilization:

Terminal sterilizationTerminal sterilization The product, container, and closure have low The product, container, and closure have low

bioburden, but they are not sterile. bioburden, but they are not sterile. The product in its final container is then The product in its final container is then

subjected to a sterilization process such as subjected to a sterilization process such as heat or irradiation. heat or irradiation.

Aseptic conditionsAseptic conditions The drug product, container, and closure are The drug product, container, and closure are

first subjected to sterilization methods first subjected to sterilization methods separately, as appropriate, and then brought separately, as appropriate, and then brought together.together.

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Buildings and FacilitiesBuildings and FacilitiesClean rooms classification Clean rooms classification

systemssystemsThree classification system:Three classification system: 1- US Federal Standard 209E1- US Federal Standard 209E

Measuring unit: max particles/ftMeasuring unit: max particles/ft33

Class 100, 1000, 10000, 100000Class 100, 1000, 10000, 100000 Class 100 means: not more than 100 particles of size Class 100 means: not more than 100 particles of size

≥≥0.5 0.5 m present in one ftm present in one ft33 2- 2- ISO 14644-1ISO 14644-1

Measuring unit: max particles/mMeasuring unit: max particles/m33

Class ISO 5, ISO 6, ISO 7, ISO8Class ISO 5, ISO 6, ISO 7, ISO8 Class ISO 5 means: not more than 3500 particles of size Class ISO 5 means: not more than 3500 particles of size

≥≥ 0.5 0.5 m present in one mm present in one m33

3- 3- European GMP:European GMP: Measuring unit: max particles/mMeasuring unit: max particles/m33

Class A, B, C, DClass A, B, C, D Class A means: not more than 3500 particles of size Class A means: not more than 3500 particles of size ≥≥

0.5 0.5 m present in one mm present in one m33

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Buildings and FacilitiesBuildings and FacilitiesClean rooms classification Clean rooms classification

systemssystems in the 3 classification systems:in the 3 classification systems:

Class 100 = ISO 5 = Class AClass 100 = ISO 5 = Class A Class 1000 = ISO 6 = Class BClass 1000 = ISO 6 = Class B Class 10,000 = ISO 7 = Class CClass 10,000 = ISO 7 = Class C Class 100,000 = ISO 8 = Class DClass 100,000 = ISO 8 = Class D

Class 100 = ISO 5 = Class A: contain less Class 100 = ISO 5 = Class A: contain less than 1 CFU/mthan 1 CFU/m33 (CFU/ft (CFU/ft33))

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Buildings and FacilitiesBuildings and Facilities Critical Area (class 100) (ISO 5) Critical Area (class 100) (ISO 5)

(Class A)(Class A) Operations:Operations:

1- Sterile 1- Sterile ingredients ingredients additionsadditions

2- filling2- filling 3- closure3- closure

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Buildings and FacilitiesBuildings and Facilities Supporting Clean AreasSupporting Clean Areas

Function as zones in which non-sterile Function as zones in which non-sterile components, formulated products, in-components, formulated products, in-process materials, equipment, and process materials, equipment, and container/closures are prepared, held, container/closures are prepared, held, or transferred. or transferred.

FDA recommends that the area FDA recommends that the area immediately adjacent to the aseptic immediately adjacent to the aseptic processing line meet, at a minimum, processing line meet, at a minimum, Class 10,000 (ISO 7) standards. Class 10,000 (ISO 7) standards.

An area classified at a Class 100,000 An area classified at a Class 100,000 (ISO 8) is appropriate for less critical (ISO 8) is appropriate for less critical activities (e.g., equipment cleaning).activities (e.g., equipment cleaning).

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Buildings and FacilitiesBuildings and Facilities Clean Area SeparationClean Area Separation

1- Positive pressure differential 1- Positive pressure differential between rooms of different classes.between rooms of different classes.

2- Use of a double-door, airlocks or 2- Use of a double-door, airlocks or integrated sterilizer helps ensure integrated sterilizer helps ensure direct product flow, often from a direct product flow, often from a lower to a higher classified area.lower to a higher classified area.

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Buildings and FacilitiesBuildings and FacilitiesAir FiltrationAir Filtration

Class A:Class A: HEPA-filtered air HEPA-filtered air

should be should be supplied atsupplied at a velocity a velocity

sufficient to sweep sufficient to sweep particles away particles away from the from the filling/closing area filling/closing area

maintain maintain unidirectional unidirectional airflow during airflow during operationsoperations

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Buildings and FacilitiesBuildings and FacilitiesAir FiltrationAir Filtration

Class A:Class A: Membrane filters can be used to filter

a compressed gas to meet an appropriate high-quality standard.

These filters are often used to produce a sterile compressed gas to conduct operations involving sterile materials, such as components and equipment

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Buildings and FacilitiesBuildings and FacilitiesDesignDesign

Aseptic processes are designed to minimize exposure of sterile articles to the potential contamination hazards of the manufacturing operation.

Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures, or the surrounding environment.

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Buildings and FacilitiesBuildings and FacilitiesChanging roomChanging room

Changing rooms leading into class A and B environment should be designed as airlocks.

There should be physical separation of the different stages of changing to minimize microbial and particulate contamination of clean room clothing.

Changing rooms for all classes should be flushed effectively with filtered air.

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Buildings and FacilitiesBuildings and FacilitiesChanging roomChanging room

The final stage of the changing room should be the same grade as the area into which it leads.

The use of separate changing rooms for entering and leaving clean areas is sometimes desirable.

In general, hand washing facilities should be provided only in the first stage of the changing rooms.

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EquipmentsEquipments

should be appropriately designed should be appropriately designed to facilitate ease of sterilization. to facilitate ease of sterilization.

should not obstruct airflow and, in should not obstruct airflow and, in critical areas, its design should not critical areas, its design should not disturb unidirectional airflow.disturb unidirectional airflow.

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PersonnelPersonnel

cGMP trainingcGMP training Gowning: Gowning:

SterilizedSterilized Non- sheddingNon- shedding cover skin and hair (cover skin and hair (face-masks, hoods,

beard/moustache covers, protective goggles, and elastic gloves are examples of common elements of gowns ) )

Keep the entire body out of the path Keep the entire body out of the path of unidirectional airflowof unidirectional airflow

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PersonnelPersonnel

Keep the Keep the entire body out entire body out of the path of of the path of unidirectional unidirectional airflowairflow

Number of Number of personnel per personnel per areaarea

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Components, containers, Components, containers, closuresclosures

It is important to characterize the microbial content (e.g., bioburden, endotoxin) of each component that could be contaminated and establish appropriate acceptance limits.

Pre-sterilization preparation of glass containers usually involves a series of wash and rinse cycles. These cycles serve an important role in removing foreign matter.

They should be subjected to sterilization and depyrogenation processes.

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New featuresNew features

Blow/fill/seal technologyBlow/fill/seal technology Blow/fill/seal units are purpose Blow/fill/seal units are purpose

built machines in which, in one built machines in which, in one continuous operation, continuous operation, containers are formed from a containers are formed from a

thermoplastic granulate, thermoplastic granulate, filled with the sterile formulationfilled with the sterile formulation and then sealed. and then sealed.

all by the one automatic machine.all by the one automatic machine.