Process Gas and Compressed Air Systems

Gilberto Gonzalez-RiveraQA AdvisorIPR Pharmaceuticals, Inc.

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Industrial Utilities

• Water• Steam• Heat,Ventilation and Air Conditioning (HVAC)• Compressed Gases

Pharmaceutical Utilities

Compressed Gases

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Process Gas and Compressed Air

• Process gases and compressed air (PG&CA) are widely used in the development and manufacture of active pharmaceutical ingredients and also for the formulation of medicinal and investigational medicinal products.

• The control of the quality of these can therefore be critical. PG&CA systems are regulated by the Federal Drug Administration (FDA) and by the Medicines Control Agency ( MCA) in the US and Europe, respectively, to name a few.

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Regulations

• 21 CFR 211 Subpart C Buildings and Facilities

– §211.46 Ventilation, air filtration, air heating and cooling

(b) Equipment for adequate control over air pressure, microorganism, dust, humidity and temperature shall be provided when appropriate for the manufacture, processing, packing or holding of a drug product.

(c) Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas.

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Regulations

• EC Guide to Good Manufacturing Practice

– Chapter Three: Premises and Equipment

3.3 Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal product during their manufacture and storage, or the accurate functioning of equipment.

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Regulations

• EC Guide to Good Manufacturing Practice

– Chapter Three: Premises and Equipment

3.12 Production areas should be effectively ventilated, with air control facilities (including temperature and, when necessary, humidity and filtration) appropriate both to the products handled, to the operations undertaken within them and to the external environment.

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Process Gas and Compressed Air

• Generally, PG&CA systems must meet the chemical, microbial and purity requirements of the products they will potentially contact, and the requirements of the room into which they are exhausted, if applicable.

• Validation of these systems involves documenting the expected system behavior and verifying that the system performs as expected.

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Compressed Gas Uses

Type Primary Use

Compressed Air Pneumatics

Breathing/Medical Air Self-containment

Nitrogen Food Industry, gas chromatography

Oxygen Healthcare

Helium Airship, ballons, deep diving, coolant, gas chromatography

Argon Welding, ICP Spectroscopy

Carbon dioxide Soft drinks industry, fire extinguisher, dry cleaning

Hydrogen Petro-Chemical industry, gas chromatography

Natural gas Power generation, propulsion, domestic (residential)

Hydrofluoroalkanes (HFAs) Propellants, fire extinguisher, refrigerants

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Design

• Oil free air compressor

• Closed loop cooling system

• Dryer

• Copper-piping network

• Coalescing filters

• 0.5 micron filters at each product-contact point of use

• Pressure regulators

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Minumum Requirements

Characteristic Typical Acceptance Criteria

Air & Nitrogen

Pressure, min. & max. 90-110 psig

Flow, min. 10 scfm

Temperature, max. 90ºF

Purity Meets USP Monograph

Particulate1 Meets particulate class level

Microbial2 Meets limits

Dewpoint -40 ºF

Hydrocarbon Non-detectable

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Installation Requirements (IQ)

• Drawings and schematic review

• Manuals review

• Major components identification

• Major components installation

• Connections verification

• Wiring verification

• Tagging verification

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Installation Requirements (IQ)

• Utilities verification

• Plant capacity

• PC software installation (if applicable)

• Program review (if applicable)

• Supplier validation questionnaire review

• Equipment verification by a safety officer

• Calibration verification

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Operational Requirements (OQ)

• First Phase

– Verification of the functional specification for component and systems levels

• Verification that mechanical moving parts move freely

• Verification that all necessary adjustments can be performed.

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Operational Requirements (OQ)

• First Phase, continuation

• Verification that normal operating adjustments are not at the minimum or the maximum of the range.

• Low and high alarm testing.

• On/off sequences testing.

• Simulation of a power supply shut down and recovery.

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Operational Requirements (OQ)

• First Phase, continuation

– Systems level testing consists of verifying that the system delivers the required cubic feet per minute (cfm) at the specified working pressure, and is capable of achieving and maintaining the specified dewpoint.

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Operational Requirements (OQ)

• Second Phase

– Air Quality testing

• Viable particles

• 0.1 colony-forming units per cubic feet (cfu/ft3)

• Non-viable particles

• less than 9,000 parts per cubic feet (ppcf) for 0.5 micron particulates

• Hydrocarbon content

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Performance Qualification

• System Testing– Pressure

– Flow

– Purity

– Hydrocarbon

– Dewpoint

– Particulate

– Microbial

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System Testing - Pressure

• If there is a pressure or flow specification at a point-of-use, that point-of-use should be tested.

• One cannot assume that because the correct pressure appears at one drop in a room, it applies to all drops in the room.

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System Testing - Flow

• The flow rate of each point-of-use should be measured to verify that user requirements are met.

• Performing this test to each drop also provides visual check for large pockets of stagnate water in the pipeline. – Condensate may form in the lines during initial

installation of the system, or after an old portion of an existing system has not been used for an extended period.

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System Testing - Purity

• If claims are made about the purity of the gas, then testing should be performed to demonstrate that the appropriate specifications are met.

• The methods used to obtain the sample and to demonstrate purity should be carefully documented and reproducible.

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System Testing - Hydrocarbon

• The most common test use Draeger tubes (or equivalent) to indicate the approximated level of contamination.

• Hydrocarbon measurements should be taken near the source during maximum load conditions to ensure that minimum system requirements are met. They should be tested at points-of-use where product will be contacted.

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System Testing – Dew Point

• The equipment used to measure dewpoint includes chilled mirror, moisture level conversions and others.

• It is important that the dewpoint measurement be taken at the correct temperature and pressure.

• Measurements taken at other pressures and temperatures must be converted to ensure that the system specifications are met.

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System Testing - Particulate

• Most standard particle counters can be used to measure particulate levels in process gas.

• Flow must also be carefully controlled during measurement. Particle counters are usually designed to pull the sample at 0.1 or 1.0 cfm.

• Compliance: Federal Standard 209E

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System Testing - Microbial

• An agar plate can be easily and aseptically placed into an atrium for sample capture.

• The amount of air that passes over the agar plate should match that of a typical room air sample, usually at least 40 liters.

Note: A sampling atrium pull samples directly from the process gas line

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Definitions

– Cleanroom – a room designed, maintained and controlled to prevent particulate and microbiological contamination of drug products. Such a room is assigned, and reproducibly meets, an appropriate air cleanliness classification.

– Cleanzone – an area with a defined particulate and microbiological cleanliness standard.

– Dewpoint – is the temperature at which the liquid and gaseous phases of a material present in a gas, such as water in air, are in equilibrium at a given gas pressure. In other words, the dewpoint temperature, or dewpoint, is the temperature at which the liquid water, or dew, evaporates at the same rate at which it condenses.

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Cleanroom Standards

• Federal Standard 209E Airborne Particulate Cleanliness Classes in Clean Rooms and Clean Zones –U.S. General Service Administration and approved for use by all U.S. agencies. In the absence of an international standard, FS 209E was broadly used internationally.

• ISO 14644-1 Cleanrooms and associated controlled environments Part 1: Classification of airborne particulates

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Standards Conversions

ISO 14644-1 Fed Std. 209E ISO Class English Metric

1 2 3 1 M1.5 4 10 M2.5 5 100 M3.5 6 1,000 M4.5 7 10,000 M5.5 8 100,000 M6.6 9

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Cleanroom Classifications

Number of particles per cubic meter by micrometer size Class

0.1 0.2 0.3 0.5 1 5

ISO 1 10 2 - - - -

ISO 2 100 24 10 4 - -

ISO 3 1,000 237 102 35 8 -

ISO 4 10,000 2,370 1,020 352 83 -

ISO 5 100,000 23,700 10,200 3,520 832 29

ISO 6 1,000,000 237,000 102,000 35,200 8,320 293

ISO 7 - - - 352,000 83,200 2,930

ISO 8 - - - 3,520,000 832,000 29,300

ISO 9 - - - 35,200,000 8,320,000 293,000

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Compressed Air Systems