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Ispe guidelines pdf

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The purpose of the ISPE Good Practice Guide: Process Gases is to from Parker Purification, Dehydration and Filtration Division, ayofoto.info The ISPE Technology Transfer Guide has been designed to present a standardized process and recom- US: ayofoto.info ayofoto.info or. ISPE. Good. Practice. Guide. Good. Engineering. Practice nenia diety, Civit . This ISPE Good Practice Guide aims to provide a definition and explanation of the.


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ISPE | N. Westshore Blvd., Suite | Tampa, FL | + Proposed Regulation/Guidance Document: EU Guidelines for Good. A B C D E F G H I J K L M N O P Q R S T U V W X Y Z. Active Pharmaceutical Ingredients. Active Pharmaceutical Ingredients (Second Edition) - Revision to Bulk. ISPE Good Practice Guide: Project Management for the Pharmaceutical Industry. PROJECT TYPE MATRIX: Key Activities per Life Cycle Phase. Phase. Aspects.

This is apparent in the office workplace. Use packless type for chemical exhaust applications located between the box and hood. Check for proper drainage during hot and humid periods when condensate generation is high. This measure recognizes that good layout and filtration can produce desired airborne particulate levels and recovery rates at lower than expected air change rates. HVAC controls. Doors are usually interlocked to allow only one to be open at a time.

The use of mini- environments barrier isolators, RABS, biosafety cabinets, etc. Consider the equipment heat loads where is heat generated and how is it cooled or extracted? Consider the location of utilities connection with respect to the operations to be performed. The decision of whether to use a manifold exhaust system versus one fan per hood may affect facility layout. All of the previously identified issues for consideration in the programming and layout of the facility Section 3.

The same considerations as for Room Finishes. Selection of the flooring material for the application is important, but equally important is verifying the technique and skills of the flooring installer. Often, installing test patches of the materials and the techniques being considered is the best method to evaluate their performance in a specific application.

Use floor to ceiling walls where pressure differential is important. If RH is important, then address reducing moisture migration through unsealed penetrations, door seals, and porous wall materials. Considerations in the door specifications need to address seals, windows, interlocks, construction of the door, actuation and hardware. Potent, solvents, cytotoxic, sterile?

As the components included within a system can significantly impact results, the definition of system boundaries is a critical step in a successful risk assessment.

Some examples may be: As temperature is continuously monitored by a verified system it is considered adequate to commission the heat system, and maintain it under engineering change control. The following are key design steps during the design: It is imperative that HVAC systems that affect regulated operations are designed to an end result that repeatedly meets the expectations of the regulatory body.

Product separation guidelines should be consulted when determining the boundaries of air handling systems. Separate air handling units are often used to segregate different building functions such as production, production support, warehouse, administration, mechanical areas, etc.

Within production areas, further segregation is often advisable for various unit operations, e. Manufacturing areas supporting key unit operations require maximum on-stream reliability. The air handling units supporting these areas may be configured for partial operation during routine maintenance operations to support this requirement for areas still in production. Shutdowns for routine maintenance are permissible for certain product forms, with classified spaces requiring continuous service.

Therefore, air handling units serving these less rigorous spaces may be designed accordingly. Oxygen depletion and LEL monitors may be employed as appropriate to assure that dangerous conditions do not occur, especially when recirculated air is used, in accordance with fire and building codes.

This corresponds to: HEPA filtration on the inlet air, low returns with local filtration on the outlet, high-pressure airlock, instrumentation for verification of room conditions.

When in doubt, final bulk API areas should meet the requirements for dispensing of API in the finishing facility.

Oxygen depletion and LEL monitors may be employed as appropriate to assure that dangerous conditions do not occur, especially when using recirculated systems. Such systems should also comply with fire and building codes. CNC airflow filtration with access control areas do not require low level returns but can be used if deemed necessary by the design team.

Where solvents are used, this configuration is required. Leak free connections are recommended. If processes are proven closed, recirculated air should include HEPA filtration. Alarms should be recorded at a manned workstation control room or maintenance center. Wherever possible, supply air should be directed to flow from a location near the room entrance toward the source of dust and finally out low returns mounted on the far wall.

However if air recirculation within the controlled area is required, — employ double HEPA filtration supply and return combined with semiannual filter integrity test. Filters on processes requiring PPE should be tested more frequently. Cleaning materials used in the room should be considered. These terminal HEPA filters become part of the aseptic boundary and protect the room from outside contamination.

The use of only remote bank mounted HEPA filters in the supply duct is not recommended. Access ports to introduce and monitor PAO aerosol challenge materials upstream on the non- aseptic side of the HEPA diffusers are suggested for filter integrity testing.

More return openings are better than too few. The room layout of the aseptic suite will dictate the pressure relationships to be maintained. The room with exposed product is to be maintained most positive; while ante rooms leading to this room are to be maintained successively less positive down to the zero reference level of uncontrolled areas the general building.

Only high-pressure Grade 7airlocks that have HEPA filtered supply air may have pressures higher than the aseptic filling room. A control range should be established for each room pressure level such that the pressure can float within the range and still satisfy the specified differentials. Simple facilities may be successfully balanced using only manual dampers, especially if terminal HEPA filters do not load quickly. A differential pressure gauge should be provided for each room adjacent to the remote damper controls.

An audible alarm may be provided to indicate loss of area pressure control. Where possible, terminal HEPA filters should be located directly over the exposed product, components and equipment that are not protected by UFH. Because all of the cooler central system conditioned air is not supplied over the equipment, it may be distributed to the area in a checkerboard fashion or into the local recirculating fan inlet to maintain room temperature.

The engineer should consider the heat generated from the local recirculating system fan motor. This particular oversight is quite common and can lead to serious temperature stratification and overheating in the aseptic area. Ambient air may not aspirate into the work areas along the perimeter of the unidirectional airflow barrier. The heights and filter area should deliver Class air at a velocity of 90 feet Systems in which varying flow is used as a means of controlling room temperatures are unacceptable because of their adverse effects on room pressures.

These filters contain the potentially hazardous compounds and minimize particulate "fall back" during fan failure. The gowning area should be separated from the aseptic filling room by a high pressure airlock. The de-gowning room shall be maintained negative relative to adjacent spaces on the uncontrolled side. Material leaving the aseptic filling room must be transferred via a low pressure tunnel or box. If supply is insufficient to satisfy room heat load, more exhaust EX2 may be needed.

Air from offices or technical spaces adjacent to laboratories should transfer into the laboratory. Provide a high pressure airlock where activities in positively pressurized spaces pose a threat to corridor air quality. Recirculation of this laboratory air is not acceptable. Provide propylene glycol solution, IFB coils or a reliable, alarmed, pumped chilled water coil to prevent freeze-ups. Use packless type for chemical exhaust applications located between the box and hood.

Oversized boxes yield poor airflow control and have a limited range. Laboratory hood exhaust ducts and accessories which are inaccessible should be stainless steel Laboratory hood exhaust ducts which handle large quantities of acids should be high grade stainless steel, Hastelloy, FRP or other suitable material stainless steel will corrode rapidly in the presence of high molar concentrations of Hydrochloric Acid.

The exhaust from most chemical laboratories is primarily composed of air. If necessary, use variable geometry stacks not Strobic fans to maintain velocity at reduced airflows.

Provide positionable arms such as Plymovent or Alsident for point exhaust sources which do not support hard duct connections. These supplemental point exhausts should be served by an independent exhaust box where possible or connected directly to the main with a volume damper or blast gate. Exhaust quantities should be reset upward when additional cooling is required. Where critical, connect these to the BAS. In multi-fan manifolded systems the use of emergency power for at least one fan should be considered.

Scrubbers may be required for some dedicated hoods. Actual set points and directions of flow are dependent upon the operating plan of the space and must be determined on a case-by-case basis. In colder climates, provide humidifiers in two locations within the AHU to allow the large amount of moisture to be added gradually, i. Edstrom and ATC sensors should be located adjacent to one another if possible. Exposed ductwork should be Type stainless steel with Type 4 finish Owner approval required.

Concealed exhaust ductwork from grille to above the ceiling should be stainless steel. Secondary filters should be installed prior to the reheat coil, to be replaceable with minimum disturbances to the space.

Be sure that air outlets do not overheat high stacked material. The design should consider what happens during periods of non use — is there potential for moisture to migrate from the outside environment into the system, if the outside is high humidity.

This operation should take place within the isolator so that there is no operator exposure to the VHP. The outside room should be monitored by VHP sensors as a further safety measure. The isolator air handling unit obtains supply air from the surrounding room and during different modes of operation returns to either the room or exhausts to the roof. For potent compounding, intake air during production and aeration should be taken from the room and exhausted through an independent exhaust air system.

Reduced air speed may be used during H2O2 bio-decontamination. Air is recirculated from isolators chamber back to isolators plenum should be ducted by internal double glass windows or doors. A differential pressure device with display and alarming capabilities monitors the differential pressure between the internal zone filter plenum and the outside room pressure.

Room cooling loads for spaces in which isolators are located must take into account the heat generation by the isolator fan system s. The most common agent for decontamination of isolators is vaporized hydrogen peroxide VHP. HEPA filters should be readily changeable from outside the Isolators. A temperature measuring transmitter with display and alarming capabilities will control and monitor temperature. Design Development Design Reviews Issue for Construction Design Change control Approve Design Figure Diagram of Design Review Process Arrows missing An effective design review is dependant on the people conducting it, although most companies are now trying to develop knowledge capture systems such as: Vivarium, a formal review may be conducted, such as a FMEA, to ensure that the design is adequately robust.

A simplified version of this approach may be beneficial even for simple manufacturing facilities considering the impact of system failures on adjacent areas, to ensure that the design is robust. HVAC controls.. Maintainability Consider accessibility to key components of the system, filter maintenance requirements, filter integrity testing if required , regeneration requirements, emissions, etc.

Review and evaluate the AHU service distribution drawing and consider the following: How many AHU units zones are proposed, is the zoning based on the process requirements?

Are the temperature and humidity design and operating conditions defined? Are the systems once through or recirculating? Is the control scheme clearly defined, including monitoring and alarm requirements? Has the user defined availability requirements for the products to allow the design external conditions to be defined?

Review location of outside air intake and exhaust. Is the prevailing wind direction defined for the site, with the HVAC inlet and outlet locations defined to demonstrate no risk of recirculation? What rationale is used to divide the facility into zones? Is the location of the monitoring sensors specified such that they will give representative readings of the space conditions: For large areas, such as a warehouse multi-point mapping and monitoring may be required, for smaller areas, 1 or 2 points is generally adequate, with the reading demonstrated as representative of the areas where product is susceptible to conditions during qualification using sensors.

Consider the size of the room and the location of key process operations e. If there area multiple air handling units servicing the manufacturing area, how will failure modes affect the intended operation? Will failure of one unit increase the risk of cross contamination? Are the airlocks specified with interlocked doors? It is recommended that the design differential pressure is a minimum of 15 Pa to allow for construction issues.

Does the process require containment; if so is exhaust air filtered using safe change high efficiency filters with suitable re-filters bag-in, bag-out? If so, are the provisions in line with the area GMP operational requirements? Airflow should be designed to contain high potency compounds. For biotech facilities design shall conform to the Center for Disease Control biosafety control levels.

Are the air handling systems designed for re-circulation where appropriate, and with suitable return air filtration? What assumptions have been made to specify the position of the temperature sensor to ensure that it is representative of room conditions?

What assumptions have been made to specify the position of the humidity sensor to ensure that it is representative of room conditions? Is there a qualified system for manufacturing areas to monitor and maintain records of temperature, humidity, and airflow direction? Is there a locally mounted alarm indicator for any out of limit environmental condition - temperature, humidity, airflow direction?

If the area is classified, it is common practice to design with ceiling mounted supply grilles and return air taken at low level in the room? Is the area served a Laboratory, if so what considerations have been made for; fume hoods microenvironments, e. Does humidification use plant steam, if so does it use approved additives 21 CFR If so it should be injected before the final HEPA filter - where one is used.

Is the ductwork specified using an appropriate allowance for leakage — is it shown on the design? Are the AHUs mounted inside, if not what provision is there to protect them and the staff from the weather during maintenance? Does the specification for the AHUs include access panels and test ports to facilitate maintenance, and HEPA filter testing if required? Are AHUs designed for constant volume, and low leakage of conditioned air? Are progressive pre-filters specified — what is the basis for their selection?

What final stage filters are specified? Are all classified areas served via Note terminal filtration is preferred. H13 specified for in situ leakage testing, or H Are lockable dampers specified, and is there a requirement to record the as balanced setting in the commissioning records?

Confirm that the specification permits no interior lining of ductwork, with any sound attenuators specified using non shedding lining. What Security arrangements are there for controls? What happens in the event of power failure?

Is the ductwork made of Galvanized steel, or are there special requirements, for non classified areas does the specification limit the use of flexible ductwork to 4 feet long? Confirm that for classified areas the use of flexible ductwork is not permitted.

What are the leakage allowances — are they appropriate? The use of flexible hosing must be carefully evaluated. Maintenance requirements must be discussed as part of the review process. Does the design proposed demonstrate current best practices? How are failure modes considered? Are ceiling plenum returns proposed — if so how would the ceiling void be cleaned? How does the design consider the risk of building sickness syndrome?

Operability Challenge Response Action Are airflow directions proposed for any catering areas, to contain odor? Are there arrangements to extract from copier rooms? Is the AHU construction specified to avoid risk of external condensation?

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If not are the air handling systems designed for re-circulation where appropriate, and with suitable return air filtration? How does the design allow for future changes in the room layout in terms of sensor locations and zoning?

Maintainability Challenge Response Resolution Are the site specific requirements defined in terms of preferred suppliers? Does the specification for the AHUs include access panels and test ports to facilitate maintenance? Is the system designed with progressive filtration? How have filter grades been decided — are they a site standard? What is the bearing design life at the maximum rated fan speed?

Constructability Challenge Response Resolution Is the ductwork made of Galvanized steel, how is the internal finish specified, to ensure that the galvanizing is of good quality and finish? Does the ductwork specification limit the use of flexible ductwork to 4 feet long?

The design and construction of the equipment is intended to meet safety, product and regulatory requirements while providing environmental comfort and protection to employees. They should have robust capabilities for achieving initial, continuous, and long-term operation, ease of maintenance, and low energy use. AHU designated to operate at locations with high temperature and humidity conditions should have a true thermal break construction.

In compartments serving cooling coils or steam humidification injection, it is recommended to line this section with L SS.

It is unacceptable for exposed insulation or lining be exposed inside an air handling system serving a GMP area due to the potential of providing an area for mold propagation. The removable panel allows removal of panel using simple hand tools and avoid cutting or sawing through thermal breaks and cabinet constructed walls making removal and subsequent sealing possible.

Floor should be designed to have a capacity of psf live load, to accommodate a service mechanic working inside unit. The pan shall be double or triple sloping as to enhance total drainage. Stacked cooling coils shall have their own drain pan, with drainage into the lower coil section s.

Drain pans shall slope a minimum 1: Connections shall be piped to exterior of unit casing. Entire panel shape should be fully insulated without gaps at the peak. Roof should have a minimum slope of 1: All exterior AHUs should have perimeter roof gutter with appropriate down spouts and rain guards above all exterior access doors constructed of same materials as casings.

Positive pressure sections of the air handler shall have doors labeled as such. All access doors should have an instrument test port to allow temperature and pressure readings to be collected without drilling into cabinet during air balancing commissioning.

Interior door handles will prevent someone from being trapped inside of the unit. The mixed air becomes the supply air for the space after passing thru filtration, heating or cooling steps within the air handler. There should be a minimum of two waterproof 6-hour maximum timer light switches per AHU, one per end.

High voltage terminals shall be labeled as such. Internal power cabling shall be shielded. It is important to consider a number of items when selecting fans so they can operate smoothly over their intended life. Draw-thru units have the fan located downstream of the pre-filters, coils, and humidifier. A Class I fan offered by any particular manufacturer has a lower allowable minimum operating range than its Class II counterpart.

As a result, a Class I fan with less mechanical design strength and with less expense than a Class II fan. They should include inlet cones matched to the wheel intake rim to ensure efficient and quiet operation. The tubular design, high efficiency rotor and integral straightening vanes provide high performance using minimal space. These units should be configured for direct drive though belt driven could be used. This arrangement reduces the overall footprint of the air handler, allows design flexibility, simplifies maintenance, reduces downtime, reduces low-frequency noise rumble within the air handler, and usually saves energy, The use of multiple direct-drive fans operating in parallel improves reliability by providing redundancy.

Guidelines pdf ispe

In addition, there are no shaft bearings present, which eliminates lubrication. For multiple belt systems, belts provided should be matched sets. Entire fan assembly shall be centered in the air stream both vertically and horizontally to assure proper airflow. All fan inlets and discharges should have SS operator protective screens. Fan belt tension is extremely important during their entire life.

Special attention should be incorporated, especially when installing new V- belts. Once the new belt s have operated for a short time, they most likely will need to be readjusted due to belt wear-in. Improper under- tensioning will result in premature failure and increased energy usage. They should have a primer with at least one coat of industrial strength or epoxy paint finish to eliminate rusting. For centrifugal fans a drain connection should be included, located at the bottom of the fan housing for draining any fluids that may accumulate.

All wheels are both statically and dynamically balanced.

Guidelines pdf ispe

A shaft seal should be included to reduce leakage and protects the bearings from a contaminated air stream. Automatic bearing lubricators should be installed to increase bearing life and reduce maintenance. Recommend lubricator installed directly to bearing housing.

Lubricators should be sized to supply lubricant for a minimum of 6 months without refill or replacement. The vendor needs to work closely with the lubricator supplier to provide the proper lubricant and device for the intended operation of the air handler.

The lubricator should not be mounted or activated until the fan is put into full operation, to eliminate automatic, excessive lubrication and damage. The inlet cone of the fan is used as the flow nozzle. The vibration limits shall be 2. The balance quality grade for impellers shall be no greater than G2. Balance readings shall be taken by electronic type equipment in the axial, vertical, and horizontal directions on each of the bearings.

A shaft grounding system or isolated bearings should be installed to prevent bearing failures caused by induced electrical current. The advantage of the VFD in lieu of variable inlet guide vanes include better volume control, energy usage, less maintenance, soft start of fan motor reducing the in-rush of electrical current and stress on the fan, and positive control feedback to the building automation.

Invertors should include line and load reactors to eliminate motor failure. The advantages include non-slip operation, longer life, less maintenance, little to no belt shedding, single sync. The one disadvantage is that it will possibly produce higher noise levels.

To maximize the intent of exhausting unwanted contaminants, the inlets to the exhaust system should be as close to the point of generation as possible. The exhaust plume height shall be great enough to avoid re-entrainment of exhaust air into air inlets or onto roof and to disperse the exhaust. The effective stack height should be used when analyzing design issues. Factors impacting the wake flow requirements include: Exhaust from the hoods, BSC, or process equipment can be accomplished by ducting each piece of equipment to a dedicated fan or by manifolding the ducts to a centralized fan system.

However, when only a few hoods exist or hood locations are remote from one another or for specific applications, then individual dedicated fans will probably be more applicable. Automatic dampers shall be strategically installed so as to not cause exhaust air to be drawn back down into the building or short cycled from an idled companion fan.

This may include acoustical silencer nozzles and roof sound barriers. These include the preferred mixed-flow impeller combines the benefits of axial flow and centrifugal flow fans or the centrifugal fan. All metal surfaces shall be coated with an epoxy for protection against weather, UV, and chemical vapors. Fans and accessories shall have internal drain systems to prevent rainwater from entering building duct system.

Replacement of any of these components shall not require removal of the fan from the system or exposing maintenance, service personnel to the potentially contaminated interior of the fan. All steam coils should be fitted with vacuum breakers. Water system velocities should be kept between 2 and 6 fps 0. Should fluid speed reduce toward laminarity, this can result in reduced sensible and latent heat transfer capacity. All coil performances should be designed and achieve rating in accordance with ARI Std.

Cooling coil face velocities shall be fairly uniform with actual velocity hot spots being no greater than fpm 2. Steam and hot water coils should have a maximum face velocity of fpm 3. Preheat steam and hot water coils should consist of no less than 2 rows to provide lower downstream face temperature variation. Include full port shut-off valves with hose connection with cap and chain. All cooling coils should be coated to enhance heat transfer and reduce biological growth.

When clean steam is required for humidification, sanitary tri-clamp connection control valves and thermostatic steam traps, along with other components made of L SS, should be used. Modulating steam control valves should be included to provide accurate control. A wye strainer should be installed upstream of the control valve to provide it from dirt.

Connections should be piped to exterior of unit casing. Humidifier ductwork sections shall be pitched downstream of the humidifier to a drain. Select low face velocity coils to reduce air pressure drop and improve dehumidification performance. The circulating fluid is pumped to transfer heat from the warm mixed air to the off coil cold supply air.

The run-around system reduces the cooling load on the main cooling coil; reheat is provided by the heat picked up by the circulating fluid in pre-cooling coil instead of by an external source of expensive energy.

For bigger systems, an expansion tank with air vent may be needed. The typical design consists of a refrigerant loop with two connected heat exchangers placed upstream evaporator coil section and downstream condenser coil section from the cooling coil.

As the air passes through the first heat exchanger it vaporizes the refrigerant and is pre-cooled. The air then passes through the second heat exchanger and is reheated, which liquefies the refrigerant, causing it to flow back to the first heat exchanger. The heat pipe system is hermetically sealed, uses a wicking action, and requires no pump. The increased dehumidification capacity provided by heat pipes allows for a smaller cooling system.

The secondary coil furnishes the sensible cooling of part of the relatively cool and dry return air. A portion of the return air may bypass the secondary coil and mix with the cooled return air stream. These two air streams are then mixed into supply air with appropriate temperature and humidity. Dual-path systems decouple sensible cooling and latent cooling for easy control of the supply air temperature and humidity.

The OA cooling coil should be sized for peak latent load, while the RA cooling coil should be sized for peak sensible load. They can be configured to condition part or all of the incoming air. The main factors, which influence this, include percentage of outside air, outside and space relative humidity levels, and the quantity of air flow for the conditioned spaces.

Both solid and liquid desiccants are used in cooling systems, but solid desiccants are the most widely used for HVAC operations. Water is adsorbed or held on the surface of the material and in the pores.

However, the addition of a desiccant wheel will increase the pressure drop, fan power and maintenance, and an additional motor is required to rotate the wheel. This extra energy usage must be counted accordingly. Desiccant systems should use low- cost surplus heat, waste heat or solar heat for desiccant reactivation. Side access for wheel and filter replacement and maintenance should be provided. The dehumidifier should be a fully factory assembled package unit, complete with desiccant rotor, desiccant rotor drive assembly, reactivation heat source, filters, motors, fan s , access panels, volume dampers, dust-tight electrical enclosure, and all component auxiliaries as recommended by the manufacturer for safe, unattended automatic operation.

The unit should be fully automated and equipped with differential pressure gauges and temperature transmitters, which measure and display the pressure drop across the desiccant wheel and the reactivation and pre-cooling air discharge temperatures. The casing should be welded, gasketed, and sealed to be air and vapor tight at design pressures and airflows.

The dehumidifier should have full-face seals on both the process air entering and the process air leaving sides of the wheel. These should seal the entire perimeter of both air streams as they enter and leave the wheel. The seals should have a minimum working life of 25, hours of normal operation.

These include: The following is intended to be an overview of various filtration levels. It does not discuss in detail the construction of the filters themselves, since extensive detailed technical information is readily available from filter manufacturers. The efficiency of the filters should be sufficient to keep the internal components coils, fan and the AHU itself relatively clean over an extended period of time, so they can perform as intended. Terminal filtration, which is located at the room perimeter ceilings and walls is intended to provide both the cleanest air possible supplied into the room and when required, to capture air particulates generated by the processes served by the air handler and carried through the return ductwork.

Consideration should be made to make sure that all the air travels through the filters and does not bypass around the filters or the grid. Filters should be front-loaded to eliminate air bypass.

EN approx. These comparisons of filter rating systems are only approximate as the test methods are different. K type filters are Since the different grading systems are based on different challenge materials and sizes and use different measurement methods, comparisons between the different grading systems are not exact.

While the following table is an approximate comparison between filters classified by the different systems and is helpful in understanding relative performance of the various filter classes, the specific standard relevant to the requirements for your application must be quoted to avoid confusion.

EU type approx. Its intent to capture larger 3 microns and larger particulates insects, vegetation typically introduced into an air handler from the outside air. It is also used as a pre-filtration to extend the life of Level II filtration.

These filters should have a seamless sealing gasket preferred or a silicon gel seal on the downstream side of the filter to form a positive seal to eliminate air bypass around the filter perimeter. Permanent upstream and downstream media protective screens media guards should be included to prevent physical damage to the filter media. Individual HEPA filters should be able to be replaced without disruption of adjacent filters. H14 These filters should have a silicone gel seal on the downstream side of the filter to form a positive seal to eliminate air bypass around the filter perimeter.

They are positioned at the entry ceiling of the room and provide clean air into the space. The body of the module is solidly constructed of cleanable rigid material such as stainless steel or aluminum with the exposed trim being stainless steel.

It should be designed for room side filter replacement. They are fabricated structural plenums that house the air inlet opening, filters, dampers, challenge dispersion manifold, test ports, optional sprinkler system, and an integral grid for support of gel seal filled framed filters, flush mounted lighting and perforated grill.

It prevents hazardous airborne materials from escaping into the surrounding atmosphere. It is typically positioned at the perimeter near floor of the room where the material is generated.

Studies problem have determined that this failure is due to the migration of unbonded polymer components out of the gel matrix, forming a slimy liquid on the surface of the gel. Factors which contribute to this include: Urethane gels are not recommended as replacements for silicone gels in pharma cleanroom applications that will be exposed to cleaning and sanitizing chemicals, since their performance is affected by those chemicals as well as being affected by aerosol challenge materials such as PAO and DOP.

Reducing the amount of aerosol challenge to which the filters are exposed will also reduce the risk of gel degradation. Fading of color does not appear to affect seal integrity. This often occurs with filters that had previously passed a factory efficiency and scan test. It has been observed worldwide and is not limited to one filter or paper manufacturer.

Further, it appears to be limited to HEPA not ULPA filters and to applications in which thermo-pneumatic hot-block aerosol generators were used for testing. Studies into the nature of this problem have resulted in determining that the following factors are crucial to understanding and avoiding the bleed-through problem: Although HEPA filters are often efficiency tested at 0.

Thus, HEPA filters which may pass an integrity scan test in the factory with a Laskin nozzle generator at 0. It is important the filter supplier know the field test challenge method to be used so the appropriate filter paper can be provided. Many issues can be avoided by simply stating the efficiency of the filter at the filter's MPPS.

Increasing the velocity will decrease both the filter efficiency and the MPPS for that filter. Fr example, testing a specific filter for efficiency and integrity at fpm face velocity and then field integrity testing at fpm will likely result in different results, Filter performance should be specified for the intended face velocity.

This may occur when: Stainless steel should be used when corrosion and continual cleaning occur. There shall be no interior insulation. Ductwork needs to be adequately supported so as to easily carry the weight of ductwork and insulation along with in-line equipment and controls. If noise is a concern in- line silencers should be installed. If vibration is an issue, flexible support and connections should be considered.

When flexible ductwork is required to tie the branch into the terminal air device, its length should be keep to a minimum and should not exceed 10 feet 3 m. Provide sufficiently sized duct access doors at appropriate locations to equipment e. To preclude air leakage all ductwork shall be sealed with approved fire and smoke rated sealant in accordance with NFPA or UL or equivalent.

Ductwork leak testing percentages will vary from site-to-site, air system, and areas served. Recommendations include the following performances for various applications. Damper blade movement can be either parallel or opposed. Opposed blade dampers operate such that adjacent blades rotate in the opposite direction from each other. It is preferred to orientate the physical location of the outdoor air and return air entry points into the mixing plenum to direct the air streams into each other.

Outside air inlet velocities shall prevent drawing in of rain recommended maximum of 3. For areas that experience significant snow, openings shall be equipped with a degree gooseneck inlet sized for a maximum of 1. All louvers shall be drainable and be constructed of anodized aluminum or stainless steel with SS hardware, and include SS bird screens.

It is advisable to select a storm louver for outside air intakes that meet those rare occasions for unseasonable weather to avoided pulling moisture into system.

Low leakage dampers should have vinyl seals that are mechanically attached not glued to the damper blade and jamb seals to prevent leakage around the ends of the damper blades. Dampers should be made of corrosion-resistant materials of aluminum or SS. There are local and regional codes that provide minimum distances and these requirements must be followed. Proper positioning is vital for providing good distribution and a sweeping action of the air from the supply to the return side of the space to deliver uniform air patterns to cleanse the environment and displace contaminants.

For clean room operation, stainless steel is preferred to eliminate corrosion and rusting, which can occur to other materials and finishes that can occur during wash downs using aggressive cleaning agents.

Refer to the Filtration section for more detail. They can be mounted inside air ducts and placed adjacent to cooling coils and condensate drip pans where biological growth can easily occur and lead to energy losses due to heat transfer reduction caused by fouling.

When microbes bacteria, bacterial spores, viruses, yeast, mold and mold spores are exposed to sufficient doses of UVC light, their DNA is destroyed, causing cell death or making replication cell division impossible. The optimal microorganism frequency killing occurs at the Many variables air flow, humidity, distance of microorganism to the UV light and time take place in a real world environment that will influence the dosage needed to cause microbial inactivation when exposed to the UV radiation.

The system shall be safeguarded against accidental UV exposure. Air temperature is a consideration when specifying a cooling coil irradiation UV system, as the temperature inside the lamp is directly related to the UV output obtained. Robust design and construction of HVAC equipment will increase their reliability and maintainability to perform properly from the start up of the operation and will continue beyond their normal anticipated life when they are properly maintained.

Vivariums are extremely sensitive operations with long-term studies that require reliable and redundant systems, so as to achieve steady environmental conditions. Ideally the fan power should be reduced with load variable air flow.

If this is not possible, then the systems should be designed to reduce airflow during unoccupied periods for all or part of the system. This is also relevant for values of air change rates and pressure differentials.

Similarly the external design conditions should also be investigated, to avoid over sizing of systems resulting in less than optimal performance and added project and operational costs.

As previously indicated, reduced energy costs should be significantly greater than that, which would occur from the increased capital costs over the life of the building. If this is unavoidable, use VFD control of the fan or pump. The low average pressure drop translates into reduced fan power and then into energy savings.

Also good filtration results in cleaner coils and equipment to optimize heat transfer and reduced frequency of equipment wash down. This can be reduced dramatically by using direct driven fans when possible. When the outside ambient temperature conditions are lower than the inside space temperature, increased draw of the cooler and less humid outside air will reduce cooling energy that would otherwise come from mechanical cooling.

An outside air economizer is a collection of air dampers and controls that allows the outside air to be drawn into the air handler. Typically, this is setup as an all or no situation, meaning that when comparing the inside to outside conditions, the condition that is most favorable to cause the lower energy usage would apply.

If another air handler is serving an adjacent area, it is possible for room pressure excursions to occur due to the changing air quantities as a result of varying positions of dampers in the HVAC system. The use of the economizer in areas that require pressurization control must be carefully evaluated to adopt. The control and use of outside air should be carefully evaluated to avoid additional air quality conditioning, resulting in a substantial energy penalty.

Supply and exhaust ducting configuration is important and needs to be routed to be adjacent at the heat recovery device. Certain vapors in the exhaust stream may be retained in the wheel, to be released into entering fresh air. Supply and exhaust ducting configuration is important and needs to be routed to be adjacent. Reduced heating demand will reduce mechanical heating equipment sizing and operating costs.

Is best applied where heating requirements are dominant. Additional fan power is required due to increased airside static pressure.

Pdf ispe guidelines

The recovered heat will reduce demand from mechanical heating equipment resulting in possible downsizing and reduced operating costs. Care must be taken during the installation and startup in order to preclude operational and maintenance problems. It is not intended to be all-inclusive, and the user should consult with the equipment manufacturer for specifics and procedures that are more detailed.

There are a number of installation and startup items specific to the air handler itself that are presented in this section. Internal equipment fans, coils, dampers, filters, etc. It is strongly recommended that an experienced rigger supervise the lifting and installation of the equipment.

If the unit is to be stored for more than one month prior to startup, equipment with bearings shall have their shafts manually rotated every two weeks to not cause premature bearing failure and redistribution of the lubricant.

It is to be mounted on a rigid, level foundation for proper alignment of the fan and drive equipment, freedom from excessive vibration and for the removal of condensate. Minimal sealant should be applied to produce a clean, smooth and level bead surface.

The interior of air handler shall be wiped down to remove any residual oil and grease. Listen for unusual noise and inspect for increased vibration and overheating of bearings.

Following a short period of operation, the belts will need to be re-tensioned. If automatic lubrication units have been installed, they should be activated only at the time of startup.

Check location of wheel in relation to fan inlets and be sure fan housing is not distorted. Electrically jog the fan to check for proper rotation. Ductwork shall have the installation quality of achieving zero leakage. Their location can cause undue air contaminants to reenter the building through air intakes along with producing noise that could be an annoyance to surrounding businesses and residential communities. Guide wires supports will need to be evaluated for inclusion onto stacks to ensure adequate support.

The coil fins should be combed after installation to foster good air distribution and heat exchange. It is recommended that piping have shut off valves and union fittings to facilitate coil removal, should repairs be necessary.

If carryover occurs, then the following resolutions are available: Access panels should be located up and downstream of the humidifier for servicing. Do not place the steam distribution manifold where visible discharge mist will impinge directly on a metal surface.

Do not locate the intake and outlet for the process and reactivation air streams too close together to avoid short cycling, which will lesson the overall dehumidification capacity. Once construction of the building and spaces has been completed, these filters shall be removed and replaced with clean filters. The filters shall be stored in such a manner as to prevent damage or intrusion of foreign matter. Storage should be indoors, under roof and be thoroughly protected from moisture.

Pallets of filters that have been damaged or broken down should not be accepted without a thorough inspection and appropriate comments noted on the shipping documentation.

Unpack the filter and thoroughly inspect for damage. Exercise extreme caution to avoid damaging the filter media. If the media is damaged and has any visible holes, do not install filter. Protection of the ductwork during construction and access to and around it must be adequately provided; otherwise, damage to the ductwork will result in loss of airflow transmission and increased air pressure and velocity. In addition, insulated ductwork that has been compromised will result in condensation and rusting and loss or gain in heat.

Self piercing zip screws are preferred when there is concern for loose contamination fragments inside the ductwork. Ductwork penetrations of the duct wall should be performed in a manner to maintain ductwork interior cleanliness. Failure to follow these practices can result in sharp metal fragments being blown into the delicate HEPA filter media causing nuisance filter integrity failures. A simple check list can be developed.

The following are recommended leakage percentage for various operations: Blow down will not flush the system of metal fragments as a result of poor ductwork cleanliness quality control. Inspect drive linkages so they are secure and will operate without binding over their full range of travel. This is to protect personnel from UV exposure. UV installations should minimize escape of the light through direct or indirect transmission.

In addition, warning signs should be placed in the area to advise personnel. If the ballast is installed externally to the duct then heating is usually not an issue. Oil from fingerprints will permanently etch glass of emitter and weaken structure. If necessary clean emitter using isopropyl alcohol and lint free wipe.

The Owner needs to review the site on a regular schedule to verify design intent, construction quality and integration of systems occur as planned.

The following identify just some of the construction issues. The following items should be checked, noted and resolved during walk throughs. Door floor sweeps are not recommended for swinging doors due to their accumulation of dirt, scratching of floor, and maintenance. In addition, this action will increase maintainability of the equipment. If this is not controlled, extensive time and repetitive cleanup steps will be required, which will affect the commissioning and qualification of the building and HVAC systems.

At this time equipment, walls, floors should have been wiped down, floors swept and vacuumed. Inadequate maintenance will eventually lead to unexpected and extended shutdowns. It will also lead to underperformance for maintaining the various environmental temperature, humidity, air quality, air flow and pressurization aspects required for good cGMP facilities.

This allows maintenance personal to order parts, schedule manpower, and plan multiple repairs during a scheduled shutdown. The goal of PdM is to proactively correct machinery degradation before significant deterioration occurs to a critical component or equipment item. Equipment is susceptible to unplanned catastrophic failure that interrupts production operations, causes risk to product, and results in reactive repairs that are more expensive than planned repairs.

Spent materials, extra parts and trash could give a regulatory inspector the impression of sloppy maintenance practices. Contaminants in HVAC systems can take many forms. Common contaminants include dust particles viable and non-viable , active bacterial or fungal growth, debris from HVAC components rust, belt shedding, grease , insulation, mold spores, and other items. For these reasons good housekeeping practices need to be followed. A cleanliness inspection should consider all components within the unit such as filters, heating and cooling coils, condensate pans, condensate drain lines, humidification systems, acoustic insulation, fans, fan compartments, dampers, door gaskets and general unit integrity.

Though prefilters are installed, they are not intended to remove all air particulates. Dirt accumulation can lead to microbial growth. Typically the units are washed down with a solution that will kill microorganisms, while at the same time eliminating grease and oil, which may have been dispersed from bearing and other lubricated joints. Check for proper drainage during hot and humid periods when condensate generation is high.

This can lead to lower air delivery by the unit, sweating and infiltration of dirt. Additionally, return fans provide semi-conditioned air back to air handling units Fans have several components, which if not properly maintained will lead to diminished airflow capacity and eventual failure.

They include the fan housing, wheel, bearings, belts, guards and motor. These will eventually result in increased vibration and noise and possible catastrophic failure and a life threatening condition. If present and not removed, the desired airflow volume may not be achieved. In addition, dirt accumulation on the fan impeller will become unbalanced, causing vibration and overloading of the shaft and motor bearings resulting in catastrophic failure i.

Personnel need to have proper training and services provided from bearing manufacturers and lubrication vendors are recommended. One item in particular, belt tension, is one of the most common root causes for premature failure.

The following provides several important steps to follow: Re-check the belt tension and adjust as necessary. If the motor or bearings are hot, the belt tension may be too high. A run-in consists of starting the drive and letting it run under full load for up to 24 hours. After the belts have run-in, stop the belt drive and check the belt tension. Running the belts under full load for an extended period of time will seat the V-belts into the sheave grooves.

Adjust the belt tension as necessary. Since tension in V-belts will drop after the initial run-in and seating process, failure to check and re-tension the belt will result in low belt tension, belt slippage and reduction of airflow. Properly maintained. Since motors are expensive to purchase and their operating costs are high e. Wipe, brush, vacuum or blow accumulated dirt from the frame and air passages of the motor. Heat reduces insulation life and eventually causes motor failure.

Do NOT over-lubricate. The changes in humidity are due to the process. The heat gains and losses to and from the space are through the usual mechanisms of heat transfer.

Airflow can entrain particles of product. If building conditions are significantly different from those outside and the fabric of the building does not have sufficient integrity. Though differential pressure is commonly used as a control of contamination between two rooms. These may be due to solar gain. Both the quality temperature.. This stems from the need to 13 QQ: When comparing the effective ventilation rates of various designs.

In order to understand what equipment is needed to achieve this at the HVAC system level. Ventilation is responsible for the transport of airborne particles. HVAC systems are not a substitute for good process. HVAC can not clean surfaces that are already contaminated. HVAC can contribute to the control of temperature. This explores the effects of physical layout geometry. Pharmaceutical HVAC can help control contaminants within a space. Pharmaceutical HVAC is one tool in preventing unwanted environmental contaminants from adversely affecting a product and to prevent products from contaminating one another.

It can also assist in limiting operator exposure to potent pharmaceutical compounds. Several systems have been promulgated for the classification of space. Airlocks serve other purposes as well: The orientation of these airflows can aligned so as to protect product or personnel by sweeping across one or the other or both on its way from the supply terminal to the extract point. Contamination control is generally achieved by filtering the incoming air.

To bridge the gap between the various standards. Local supply or extraction can also assist in contamination control by creating a local environment that excludes or removes particulate. These rooms control traffic into and out of a space through a series of interlocked doors to assure that a door to the space is always closed. It should not be used for other facilities.

See the appropriate Baseline Guide for specific air quality information. Annex 1. Volume lV. October These air change rates often drive decisions regarding room size and airflows. When considering the design of classified first consider the requirement for 20 expressed in the FDA Sterile Guide. Now the room sees an air change every minutes. If we would supply 1 air change per hour CFM of clean air. This 1 CFM creates an air change every minute.

Now put the same process into a cubic foot volume and keep the airflow at 1 cfm. If we purge the volume with 1 cubic foot per minute of clean air. The airborne particle levels depend more on a number of factors. Little is said about the relationship between these rates and the classification of the space. To explain this difference: Assume a 1 cubic foot volume with a process inside it that generates Hood air is not as clean as HVAC supply air.

With clean air supply of 20 air changes per hour. Cleanliness of dilution air assumed to be negligible in pharma due to HEPA filtration As is demonstrated elsewhere. Taking the example above. This measure recognizes that good layout and filtration can produce desired airborne particulate levels and recovery rates at lower than expected air change rates.

The entire flow from the hood will likely not be available to add into air change calculations. Since air leaving the space served by the hood is often orders of magnitude cleaner than the room it leaks into. Quantity of dilution air supplied to the space cubic volume per time 3. Even though the hood might be rated as Grade 5 class the air leaving the work space has collected additional contaminants from equipment and people outside the critical zone.

Particles generated inside the space 2. In many respects the added flow from the hood not only reduces airborne particles in its path.

Only areas near the airflow path will see the added dilution. A simplified method neglecting the orifice coefficient for the opening to calculate the expected velocity of airflow from a given pressure is: A velocity of FPM will contain light powders and bioburden One method to control this direction of airflow is by controlling the relative pressurization of adjacent spaces or the Differential Pressure DP between the spaces.

An in-depth knowledge of psychrometrics is impossible 19 QQ: VP is pressure difference in inches w. A is area of the opening in square feet. Q is airflow in CFM — We can breakdown velocity as being volume divided by area. Assuring that air is always flowing in the desired direction through the cracks in building construction door gaps.

M opening. A psychrometric chart is used to identify conditions of air and to illustrate the process of achieving the desired state of the controlled space. Latent heat is the heat required to evaporate the moisture which the air contains. See Appendix for psychrometric chart discussion. Sensible heat shows on the psychrometric chart as a horizontal line. The colder the air. For example. If any two properties of the air mixture are known.

When this moist air reaches a level at which it can not hold any more moisture. Air-water vapor mixtures have interrelated psychrometric properties that can be plotted on a psychrometric chart. Addition or removal of sensible heat will cause the measured temperature to rise or fall.

Latent heat appears on the psychrometric chart as a vertical line. The air around us is a mixture of dry air and water vapor. HVAC equipment serving GMP areas are intended to work in conjunction with associated controls and sequences of operation systems to: Dampers are used to regulate airflow to certain rooms.

Air diffusers are usually located to distribute the air as uniformly as possible through out a space. A louver may also be found in return air ductwork at room interfaces. It is common practice to divide a manufacturing area into zones. Other factors that are 23 QQ: It is easier to make modifications to parts of the facility in future and upgrade a small unit than change a large single unit Use of multiple units allows for easier separation of areas within a multi-product concurrent manufacturing plant.

The decisions regarding AHU system zoning are very important as a factor in subsequent facility commissioning. The use of multiple smaller units might make air balancing easier The use of multiple smaller units means that the main distribution ducts are smaller. A percentage of the air is either discarded or lost through leakage to adjacent areas. This category is much more common — the room supply air is made up of a percentage of treated outside air mixed with some of the air extracted from the space.

Lower risk of cross contamination of products from another room via HVAC Exhaust fan may be located remote from the AHU making duct routing simpler As there are less concerns about the ductwork noise in the extract ductwork. It may be interlinked to a once-through or recirculated air supply system.

Disadvantages of this system: Makeup air is pulled from surrounding spaces. Used alone. The two approaches have distinctive characteristics. Add some combinations. The advantage of this is that the unit is often smaller. When configuring units in parallel. Automatic isolation dampers and variable fan drives assist in managing these factors. This 27 QQ: This is particularly useful when heat loads are particularly high and supply air temperature must be as cold as possible.

Another advantage is that if the drain trap on the cooling coil runs dry. Shown below are a few examples of design concepts commonly used. It is not advisable to follow a blow through unit immediately with a set of HEPA filters unless special precautions are included to prevent moisture carryover from the cooling coil. The term describes the relationship of the fan to the coils in the air handling unit.

The use of parallel units is common practice where large areas are being conditioned. One advantage of this type of unit is that it allows the AHU discharge temperature to be at the cooling coil discharge air temperature. The disadvantage. This is a useful concept to use to gain improved accuracy. The design must include provisions for maintaining a wetted drain trap.

Recirculating AHU: Here will establish a lexicon of design components. One precaution with draw through units is that if the drain trap is dry. To illustrate the possible options. Prefilter or Prefilter and Intermediate Filter Filters are typically provided upstream of coils in an air handler to protect the coils from fouling with dirt or debris.

These systems may also employ a bypass damper to decrease pressure drop across the coil when energy recovery is not advantageous. This is particularly important if the downstream system has volume control boxes on both the supply and return. These coils are typically upstream of all other coils and may be placed upstream of the filters if used to melt snow in cold climates. It also allows the return air to be diverted to exhaust when outside air conditions are closer to desired discharge conditions than return air.

Energy Recovery Coil Once through air systems. The return air can be directed to exhaust or to recirculate. Mixing Box This pieced of equipment is also common in recirculating air systems.

This fan allows return pressure and flow to be managed independently from the supply. In very cold environments the mixed air may be subjected to a turbulence inducing device to assure thorough mixing and avoid stratification. Preheat Coil Once through air systems. When employed in an AHU. However care must be taken to assure that excessive relative humidity or liquid water droplets do not damage the dehumidifier.

If latent cooling is expected drainage of these coils is a key design issue and mist eliminators may be employed to eliminate carryover of liquid water droplets that condense on the coil.

In this second application they operate below chilled water temperature and are typically filled with refrigerant or a low temperature brine of water and glycol ethylene or propylene. They are also employed downstream of cooling coils to provide additional latent heat removal. The choice of desiccant may vary. Cooling Coil Cooling to maintain environmental conditions is common. These devices are typically downstream of the heating coil and may even be mounted in ductwork where turbulence and high velocity promote absorption of water vapor.

Humidifier Once through air systems. These coils do not typically impose a large pressure drop so a bypass damper would be unusual. These coils do impose a large pressure drop so a bypass damper can be employed. These coils are always upstream of cooling coils. The dehumidifier is often located downstream of the cooling coil as they work most efficiently when airstream relative humidity is high but within desired limits. These coils can eliminate both sensible and latent heat and can be upstream or downstream of the fan.

These coils do not typically impose a large pressure drop.

ISPE Good Practice Guide - HVAC

Recool Coil These coils are only commonly installed downstream of dehumidifiers to eliminate sensible heat from the supply air. This fan provides the motive force for distribution of air throughout the air handling system. Three types of airlock pressure arrangements are indicated below: These filters provide assurance of air quality with reference to particulate downstream of all air handling operations and are particularly valuable in protecting terminal filters from fouling with dirt or debris and in providing filtration for classified spaces.

These coils are always downstream of cooling coils. Supply Fan All air systems will utilize a supply fan. Final Filter Filters may be provided as the last treatment step in an air handler. This is of particular interest in systems that employ fan drive belts which shed particulate into the airstream. If there are requirements for both area cleanliness classification and product containment. If protecting non-sterile processing areas not classified a lower pressure is acceptable.

There may be different pressure drops across each door due to building tolerances. Pressure differential will drop momentarily while one door is opened.

For unclassified areas the minimum suggested pressure differential is 0. In no case should pressure differential reverse.. The pressure differential is measured across the airlock. Normal design pressure differential between classifications should be 0. Airlock 0. Acceptable 0. Doors are usually interlocked to allow only one to be open at a time.

Clean-Contained Space 0. The positive pressure airlock provides a robust means of segregating areas using positive airflow. Bubble Airlock 0. The minimum operational differential between areas of the same classification 33 QQ: Bubble Airlock - 0.

Unclassified Space 0" w. A similar leakage calculation is discussed in the article. Pharmaceutical Engineering. Note that corrections are to be applied for design pressure differentials using the formula contained in Figure Airlocks for Biopharmaceutical Plants. Doors may be provided with a provision for operable floor sweeps which drop down as the door closes. Figure See the Appendix This scheme should be adopted only when airlocks are not possible. In most cases. Common practice is to design for a 0.

Door frames may include continuous seals which would reduce leakage required to maintain the desired pressure.. Pressure may be maintained across doors between air classes when no airlocks are present.

Where double doors are used in the facility. Door grilles should be avoided unless part of a pressure scheme without airlocks as discussed in the Appendix. Because of this. Volume Number 2.

This method provides a conservative leakage number. This calculation must be based on the design pressure differential established in the project documents and not on some rule of thumb method. Door seals are the primary path of room air leakage. It is also sometimes necessary to have directional air flows for operational reasons without a measurable pressure differential.

The airflow leakage rate should be calculated for each room. To calculate leakage through these and other fixed openings use the formula. The HVAC design engineer should consult with the facility architect to assure specifications are adequate for pressurization requirements.

A good rule-of-thumb is to size the return for half the supply air flow into the room. Interstitial Space. In some cases the calculated room leakage may exceed the minimum air change rate for small rooms such as airlocks.

For this reason it is a good engineering practice to put a tighter specification on the supply air volume. All signals are sent to the control system where differentials are 35 QQ: In these instances the total supply air to the space must match the calculated leakage.

While both have been used successfully. Two methods of measurement are commonly applied to monitor room pressure relationships. In applying this approach. DRAFT FOR REVIEW For information monitoring. There are two basic types of displacement air distribution.

In a dilution design, room air is mixed continuously with supply air to help achieve uniform air temperatures within the space. In areas where temperature uniformity is the only factor, aspirating-type diffusers are used to allow turbulent mixing of room air with supply air.

Aspirating-type diffusers are not acceptable in any of the clean classified rooms. Even though non-aspirating diffusers do not eliminate turbulent air patterns in the room, using non-aspirating diffusers in clean rooms reduces the mixing effect. The particulate level in the room can be reduced with dilution by increasing the air-change rate of clean air supply.

Dilution distribution with non-aspirating diffusers typically perforated face plate over the terminal HEPA media is acceptable to clean classified areas up to ISPE In a displacement design, room particulates are displaced by clean terminal HEPA filtered unidirectional air. This design requires continuous HEPA coverage at the ceiling and properly sized and located low level return or exhaust grills.

Large warehouse spaces, however, may see hot and cold spots with poor air distribution. GMP spaces and cleanrooms require more stringent methods. The use of non-aspirating diffusers on the face on terminal HEPA filters may improve airflow patterns. Within mixed airflow rooms, airflow patterns should be from clean side of the space to the less clean.

Therefore, HEPA supplies should be located on the clean side and low wall returns should be located on the opposite side of the room. Returns should be generously sized with a maximum grille face velocity of no more that FPM. Ductwork should be sized for a maximum pressure drop or 0. The elbow and connecting ductwork, up to an elevation of 5 feet above the floor, should be Type or L stainless steel.

Typical Low Wall Return Figure Typical Low Wall Return Return air ducts located in stud wall spaces need not be insulated within the walls. Insulation shall terminate at the top of the wall. The mechanical engineer should consult with the facility Architect to assure that, where needed, wall cavities are adequate to contain low wall returns.

Such calculations should be performed by only qualified HVAC professionals, There may be independent control units — e. This option provides a low purchase and installation cost. A picture of a typical control unit is shown below. However there is no ability to monitor the system performance. The controller may also have the capability of providing alarms. Hart or Foundation Fieldbus.

This is a proprietary packaged system typically comprising of a number of local independent control panels. The large scale use of these systems has reduced the cost significantly. This type of system is the most expensive to install. The cost typically limits the use of this type of system to process operations at present. Figure — to be added 2. The software is held within the control system which communicates with the devices. This type of system is more expensive.

Fully pneumatic controls are available but seldom used with large installations and BMS. Installation is simple. In order to get the best response time the converter should be as close as possible to the actuator. The actuators can be supplied as fail open. For some instruments accuracy and repeatability are important.

These units typically have a faster response time than an electric or electronic unit. The pneumatic system is also ideal for hazardous areas requiring intrinsically safe installations. The parameters usually requiring monitoring include: The system is naturally proportional control — i.

There is a lot of difference between domestic and commercial building type sensors and industrial type units. Thus three point calibration verification may be justifiable. These provide more linear control with better pressure recovery and turndown. For specialized applications such as the monitoring of unidirectional air flow protection devices laminar flow hoods hot wire anemometers are used.

Vane anemometers are commonly used for commissioning as they tend to have an averaging affect over the fan area compared to the spot reading from the hot wire unit.

The difference in pressure signal between the two sets of tubes is proportional to the square of the mean velocity in the airway. It should be noted that the usual function of the grid is not to get an accurate reading. In order to get an accurate reading the installation should have straight duct runs equivalent times the duct diameter upstream and downstream of the flow grid.

For classified spaces. Because flow sensing is not dependent on the square root of pressure. Its performance is independent of the ductwork design. This may be done using a flow grid — The Grid consists of a row of tubes with closed ends. Due to the square law operating principle. Another system gaining popularity is the fan venturi meter. By connecting the output tubes to a suitable instrument. A similar grid system uses hot wire anemometer elements.

The three port valve was once the industry standard. There are two types of control valve. The characteristic should be chosen with respect to the application of the valve.

Valve characteristic The valve characteristic is the ratio of flow through the valve to the valve lift opening at a constant differential pressure. The installed characteristic is the relationship between the flow and valve lift in the system where it is installed. Where the pressure drop across the valve decreases with increasing flow the EP valve will produce a more desirable linear characteristic.

There are three main types of valve characteristic: The Linear valve has a flow rate directly proportional to the amount it is open. The equal percentage valve is more commonly used in two port applications.

One of the most basic instruments is the Magnehelic gauge. Valve Authority This is defined as the percentage of total system pressure drop assigned to the valve. If the latter is small in comparison to the former the valve will have less ability to control effectively. Differential Pressure There are pressure: If the valve normal operating condition results in operation in a near closed condition control can be erratic.

This device is also available with a switch output.

The use of a pressure switch to detect: Flow failure of a fan not usually necessary if the system has flow monitoring Detection of high pressure across a filter or filter set. An alternative is a simple device using a colored ball mounted in an inclined tube. The detection of low differential pressure between rooms to provide an indication of the incorrect airflow direction non sterile areas. When specifying these units be careful to consider the operating pressure range.

Liquid and gas expansion systems are used for self acting controllers and switches. Output is commonly mA. The sensors used industrially to monitor relative humidity now are generally units which measure the change in capacitance between two plates due to the variation in humidity. For example if the conditions are 18 — 25 degrees C. Colony Forming Units for classified spaces It is now common practice in the industry to validate the monitoring system sensors. This approach provides the quality organization with a record of the conditions from a validated system.

These vary depending on the product. Other alarms often for the same variable at a worse condition may indicate that operating conditions have exceeded the specified states and production need to take action with the process to ensure product quality is not compromised.

The raw material sits in a hopper typically near a supply register. These alarms need to be relayed to the appropriate business unit. As the equipment generates a significant amount of heat the air change rate is high — typically around 20 times per hour.

It may be necessary to study the relationship between worst conditions in the room and the mixed condition in the return duct. Many alarms will provide early warning to the facility engineering staff of an unusual state requiring some attention or adjustment.

There are also a number of options to consider for Differential Pressure. When considering sensor locations also consider the process as seen by the product — for example consider a typical tablet compression room. The traditional location for the monitoring sensor was in the common return air duct — this is still a good location. The most critical area is the feed hopper. Standard Deviation. The control contactor can be wired so that an alarm is given if the unit goes into overload.

This may be by an audible and or visual indication — e. With the new generation of accelerometers it is cost effective to monitor the performance of rotating equipment to ensure early detection of system wear due to vibration. It is a good practice to set this action alarm at the extreme conditions.

Fan speed or current draw. The motor current can be monitored The motor temperature can be monitored Vibration or acoustic output may be monitored. This engineering alarm may come from the validated monitoring system. The airflow from the fan can be monitored using an in duct device.

The sensors can be wired to a BMS. With current data logging systems this may be in the form of a continuous chart.

It may be preferred to have an actual record. The engineer needs to review the risk and potential impact of system failure considering all of the potential modes of failure. But a better recourse is to redesign the system or process to reduce the risk. The instrument needs to be mounted so that it is easy to calibrate. Thus the cost of the equipment installed may be higher than in equivalent plant in other industries.

The instrument specification and mounting need to consider any local cleaning required It is best to keep pneumatic control lines as short as possible. The benefit of providing a clear definition of the potential impact of system failure is that it can influence and justify the allowable budget for the system.

These requirements present Engineers with a unique set of challenges which vary from system to system. The industry is open for audit. The potential impact of redundancy will not only influence the HVAC system design and maintenance but also the design requirements for the supporting utilities — for example. If the cost and likelihood of failure is high. External conditions. The scope of the analysis may include business as well as quality aspects — simplistically put if the system fails.

There may be benefits from grouping the environmentally critical areas within the building. The capital and operating costs of this more complex system are likely to be higher. These considerations are on top of the conventional considerations balancing capital and operating costs.

How much variation is acceptable. If the facility is to kept operable days a year then the plant needs to be sized to handle the peak external design conditions.

Many believe that if they specify closer operating ranges. If it is acceptable to have a a few percent downtime during peak seasons. A low cost poorly insulated facility will mean a corresponding increase in the operating cost and capital cost of the HVAC system.

A well developed design will keep the influence of major heat loads outside the conditioned area. Having specified these closer tolerances the system must be commissioned to operate to meet these specifications.

Other factors will affect the system economics: Table to go in!! When reviewing potential solutions. Maintenance costs as discussed below extend over the entire facility life. Ductwork design based on static regain. It may use a high efficiency flat belt drive instead of the traditional Vbelts to improve energy efficiency.

Filter selection — the optimum selection of pre-filtration systems will balance labor cost. Fan — the fan may be direct drive. Chillers cooled using cooling tower water rather than air cooled condensers. Another example would be the drive belt — V-belts have a significantly shorter life than a flat belt.

They are not as energy efficient as a flat belt though. The unit may suffer from high air leakage. Chilled water cooling vs. Similarly systems which use the measurement of enthalpy to vat the amount of fresh air may be economic.

The cost of routinely calibrating instrumentation should not be overlooked — it may be cost effective to have one calibrated differential pressure switch across a bank of filters. The potential impact of system failure will not only potentially influence the HVAC system design and maintenance but affect design of the supporting utilities.

Grouped lubrication points will minimize costs. In a poor environment there will be corrosion on the fin material. Copper tube with polyester coated aluminum fins or Copper tube with electro tinned copper fins A fan specification with a long design bearing life will allow for extended operating periods without maintenance.

There are options for the specification of this item. Some companies specify their own arbitrary air change rates — this is not a good practice. For Class In order to define the actual air change rate required the designer must consider the following interrelated factors: Significantly higher air change rates are normally needed for Class For example: There may be a benefit in assuming air change rates to use as a basis for establishing an initial project concept cost used to determine the viability of a project.

This is generally not true. Recovery and use of cooling coil condensate Reuse of cooling tower blow down water 57 QQ: Some of the areas to consider are provided below: Cleaning and disposal cost. Refer to 2. The cost of putting in a system capable of higher air change rates than those actually required is significant both in terms of the capital and system operating costs.

As discussed earlier. To be successful in delivering such a design. It is important to clearly establish the required levels of cleanliness for any particulate. This will require collaboration with the user and the quality unit in determining which are the critical operating parameters and thus the environmental requirements which must be provided by the facility design. Even small incremental increases in the level of cleanliness and the amount of classified space can result in relatively large increases in the initial cost of the facility and ongoing operating costs.

The HVAC engineer plays a key role throughout the design process in helping the project team understand the implications of excessive requirements on the cost of the project and the ongoing operating costs of the facility. In addition to the cGMP related user requirements. The risk assessment can be combined with an economic analysis to arrive at a facility and HVAC system which will have the lowest total cost of ownership.

Once user requirements are established. In the pharmaceutical industry. This defining of user requirements is the most critical step in the design process and has the greatest impact on the size and complexity of the facility. This includes a risk assessment of alternative engineering solutions that can meet the user requirements.

After detailed design is completed. At certain points in the design process. These regulatory requirements identified in the Baseline Guides from such governing bodies as the FDA. In addition to the cGMP quality regulatory requirements. Decisions and commitments made in the early phase of project planning are often too costly to change as the project advances to final design and then to execution phase.

HVAC costs. Process — Critical environmental parameters that must be achieved and maintained. These include applicable local building. Assembling programming data for a facility early in the design process is critical to the successful operation. For HVAC systems in a pharmaceutical environment. It is important to ensure that user requirements are well understood and properly applied. Quality — Regulatory guidance and quality principles to guide decision making on HVAC parameters that can have product impact.

It is accepted practice to copy HVAC criteria from one facility to another similar facility — as long as the rationale for the original criteria is well understood.

The HVAC designer should carefully consider each of these variables when proposing criteria and avoid using "industry norms" or "accepted industry practices" without an understanding of the variables involved.

In either case. Although there may not be any restrictions from a process viewpoint In the case of performance based information. User requirements can either be in the form of performance based information that describes an operation and sets expectations or strict criteria where critical HVAC parameters are well defined.

It could unnecessarily drive up qualification and ongoing maintenance costs. If these concepts are not well understood or established procedures or practices do not recognize this methodology. Well defined and accepted procedures should be in-place or agreed upon when defining the user requirements that would allow the single HVAC system to have a lower total cost of ownership.

The baseline guides that would apply to this section include the following: Non-shaded areas are HVAC parameters that do not normally have product impact and are not used to set criteria. The following chart depicts at-a-glance the typical HVAC parameters that would generally apply to each facility type. Product Type. One suggested method will be provided in the form of a matrix in which the individual components of the HVAC system preheat coil.

Oral Solid Dosage Forms. Terminally Sterilized. These components will require additional attention via qualification and may require higher levels of redundancy to avoid business impact. Individual HVAC parameters are discussed in the following section with an emphasis on establishing the minimum requirements to achieve "compliance".

These are areas in which the HVAC engineer and the project programmer must coordinate their knowledge and experience to avoid future problems in the construction. Environmental Classification.

There are a number of ways to address this. This logic could be extended to determine which components should be under cGMP change control. Solvent Issues. Determining what should be monitored — every room or select rooms. Methodology in determining appropriate alarm delays.

Guidance on how to monitor. This looks to be light… why discuss just temperature? Access to field instruments for calibration. There may be special considerations in the layout and adjacencies for projects employing prefabricated modular construction. It is important to establish User Requirements before beginning layout and design. In general. The locations and considerations for HVAC and utilities equipment. For AHU maintenance. What are the maintenance philosophies for the facility i.

Building configuration H x W x L may affect the location of central services and how they are distributed.

Determine if there are there special requirements for temperature or RH for specific rooms freezers. Understand the requirements for maintenance. HVAC system zoning. The impact of HVAC on programming and layout will vary by the type of facility.

The flow of materials. You not only need access around the AHU for equipment removal. Will major equipment be located in basement. DH wheels. It is especially important to identify critical parameters versus controlled parameters. Within the room: Consider the locations of people. SISPQ risks… Special considerations with hydrogen operations The requirements of local codes and standards may need special attention in the design and construction of prefabricated modules.

The materials address. The following are additional areas in which the HVAC engineer and the project architect must also coordinate their knowledge and experience to avoid future problems in the construction..

When facility modules are fabricated in a different jurisdiction than the location of the facility. The use of minienvironments barrier isolators.

Issues related to codes and standards: Egress and other safety considerations Must understand risks associated with various layout and programming issues i. Consider the equipment heat loads where is heat generated and how is it cooled or extracted? Consider the location of utilities connection with respect to the operations to be performed. Room HVAC system must be designed as an integrated system in rooms with fume hoods.

Must be cleanable. The decision of whether to use a manifold exhaust system versus one fan per hood may affect facility layout. All of the previously identified issues for consideration in the programming and layout of the facility Section 3.

Determining User Requirements critical parameters versus controlled parameters What codes and standard apply? Use floor to ceiling walls where pressure differential is important. Environmental cleanliness classifications Materials to be used in the process: Impact of HVAC on programming and layout will vary by the type of facility.

Major equipment in basement. The same considerations as for Room Finishes. Requirements for testing. Consider a commissioning test to verify room tightness i. Egress and other safety considerations 68 QQ: Locations and considerations for HVAC and utilities equipment.

If RH is important. Selection of the flooring material for the application is important. Considerations in the door specifications need to address seals.

The construction methodology for the facility is another key area in which the architect and the HVAC design engineer must coordinate their designs. Approaches and technologies for product containment. Use of airlocks to separate areas of different requirements cleanliness. The risk assessment process may be used to determine: Must understand risks associated with various layout and programming issues i.

As the components included within a system can significantly impact results. The contents of this file would include as applicable: Some examples may be: There are a number of approaches to performing a risk assessment.

As the HEPA filter integrity is not continuously monitored.

ISPE- HVAC.pdf

As verified system it system. Based on the above examples. The monitoring systems for airflow. The shading is in the wrong place. The air handling units supporting these areas may be configured for partial operation during routine maintenance operations to support this requirement for areas still in production. Define the type of facility and the operational requirements of each area within the facility.

The following are key design steps during the design: Within production areas. Define the design criteria for each area within the facility. Provide a means to control the systems so that design criteria are met.

Manufacturing areas supporting key unit operations require maximum on-stream reliability. Certain parts of a facility may be subject to regulatory compliance. Develop a set of HVAC systems that meets the design criteria with an appropriate balance of cost and risk. Assure that the systems meet the design criteria. Air handling systems should be designed to achieve physical separation in order to prevent cross contamination. It is imperative that HVAC systems that affect regulated operations are designed to an end result that repeatedly meets the expectations of the regulatory body.

Separate air handling units are often used to segregate different building functions such as production. Product separation guidelines should be consulted when determining the boundaries of air handling systems.

Shutdowns for routine maintenance are permissible for certain product forms. Manufacturing rooms should be protected from migration of contaminants or solvent vapors via the use of pressure or tracking differentials. Air systems may recirculate with the OA necessary to maintain pressure relationships.

Oxygen depletion and LEL monitors may be employed as appropriate to assure that dangerous conditions do not occur. Where solvents are handled. Provide explosion proof or intrinsically safe electrical components in the exhaust air stream. Unidirectional flow hoods UFH that have recirculation should be supplied with a small percentage of fresh air to offset fan heat. Humidification should be considered for cold climates where static control is a concern.

Heating coils may not be required for systems in warm climates. Dehumidification and post cooling coils should be considered for low humidity room control or for facilities with limited cooling capacity. Risk assessment should be performed to determine need for fan redundancy parallel fans or fan walls If required.

Provide LEV for containment devices. Provide all spark-proof exhaust equipment serving process areas. When in doubt. Risk assessment should be performed to determine fan redundancy parallel fans or fan walls Unidirectional flow modules LFU that have recirculation should be supplied with a small percentage of fresh air to offset fan heat.

This corresponds to: HEPA filtration on the inlet air. Provide LEV for any containment devices. Such systems should also comply with fire and building codes.