Aseptic Processing Facility

Figure 3.8: Aseptic Processing System Schematic (Sample)

This Document is licensed to

Mr. Gerardo Gutierrez, Sr.

Mexico, DF, ID number: 299643

Downloaded on: 10/5/11 2:26 PM

3.9.1 System Design Considerations

• Considerable background on product requirements and the design of HVAC systems is covered in the ISPE Baseline^® Guide for Sterile Manufacturing Facilities.

• The impact of closed barrier devices and open isolators (such as RABS) is covered in the ISPE Baseline^® Guide on Sterile Manufacturing Facilities (Reference 13, Appendix 12) and Chapter 3 of this Guide.

• Area classification requirements for bioburden-controlled processing (biotech) are covered in the ISPE Baseline^® Guide on Biopharmaceutical Manufacturing Facilities (Reference 13, Appendix 12).

• Closed wash equipment may not require room exhaust. Room pressure control may be needed if the exhaust fan can be turned on and off.

• Revisions to EU GMP Annex 1 which went into effect in 2009 suggest that capping be accomplished under Grade A conditions or if outside the aseptic space, under Grade A “airflow.” Some may interpret this as meaning that capping equipment should be in a Grade 7 (EU Grade B) room under Grade A hood. See the ISPE Baseline^® Guide on Sterile Manufacturing Facilities (Reference 13, Appendix 12), which recommends that “Grade A airflow”

is provided by a unidirectional airflow module, which provides HEPA filtered air directly to the uncapped vials until the crimp is complete.

• EU Annex 1 requires exhaust from the crimping operation. This should be located as near as possible to the crimping head(s) to minimize aluminum particulate in the capper. Contamination from the air conditioning supply system should be eliminated with properly installed and integrity tested ceiling mounted terminal HEPA filters for Grade 7/8 (EU Grade B/C).

• AHU filters – MERV 7 followed by MERV 13/14. A HEPA filter in the AHU should extend the life of the terminal HEPA filters. Draw-through AHU is acceptable if the final filter is after the fan and cooling condensate trap has sufficient height.

• RH is normally controlled by condensing cooling or by humidification. Desiccant systems are often used for dew points below 40°F (5°C).

• Outside air may be pre-conditioned and distributed from a central AHU, because of high airflow (air change) requirements.

• Infiltration of contamination from uncontrolled spaces should be minimized by the use of room pressure differentials and airlocks between air classes.

• Continuous room pressure monitoring with alarms and recording devices that indicate out of specification conditions are recommended. Rooms with stringent environmental parameters or where the product is exposed to the environment may require continuous monitoring. See the ISPE Baseline^® Guide on Sterile Manufacturing Facilities (Reference 13, Appendix 12).

• Consider automatic pressure controls to keep the spaces within specified pressure limits where process exhaust volumes can change or where doors and hatches are frequently opened or door seal integrity changes over time.

• Desiccant dehumidification with post cooling coils should be considered for low humidity room control. Low humidity and desiccant dehumidification usually are not needed, as most products are liquid.

• A dedicated air handling system is recommended to serve only the aseptic areas and to remain operational to maintain pressure control when other building systems are shut down during unoccupied periods.

This Document is licensed to

Mr. Gerardo Gutierrez, Sr.

Mexico, DF, ID number: 299643

Downloaded on: 10/5/11 2:26 PM

• HVAC systems for classified spaces should operate 24hours/day, 7 days/week. After system shutdown or setback, a protocol for returning a room to proper operating condition should be developed with QA. This does not remove the possibility of reduced airflow during idle periods.

• Ductwork should be designed per SMACNA standards (Reference 30, Appendix 12) and should be constructed for 4 inch or greater water gauge duct static pressure and SMACNA seal Class “A.”

• Ductwork should be galvanized steel except where exposed (to a minimum extent) in production areas or subject to moisture, in which case it should be a minimum 304SS stainless with cleanable finish. Cleaning materials used in the room should be considered.

• Air to an aseptic area should be supplied through ceiling mounted terminal HEPA filters. 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 (test aerosol) challenge materials upstream on the non-aseptic side of the HEPA diffusers are suggested for filter integrity testing.

• Air supplied through ceiling mounted terminal HEPA filters should be returned at floor level through multiple return duct drops. Return air in the air handling unit should be filtered through MERV 7 pleated and MERV 13 or 14 bag filters to extend HEPA filter life. Recirculation HEPA/fan units mounted below the ceiling as terminal HEPA units are not recommended (unless an alternative is unavailable), as they require service within the aseptic area and do not normally use low returns.

• The return air openings in the aseptic area should be located near the floor, preferably on at least two (2) walls and along the long dimensions of a room to ensure maximum uniformity of airflow. More return openings are better than too few. Equipment and furniture should not block return openings.

• Differential air pressure is needed to minimize infiltration of contaminants from outside the controlled space. The aseptic area should be designed for a positive pressure with all doors closed in relation to less clean adjacent areas outside the controlled space (refer to second edition of ISPE Baseline^® Guide on Sterile Manufacturing Facilities (Reference 13, Appendix 12). Gowning areas are treated as airlocks with supply and return air, and are maintained at a negative pressure relative to the controlled aseptic area and at a positive pressure relative to the outside and uncontrolled spaces. DPs are measured across airlocks. See the ISPE Baseline^® Guides (Reference 13, Appendix 12).

• Each area should have an air supply and return with dampers to permit proper balancing. 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 anterooms leading to this room are to be maintained successively less positive down to the zero reference level of uncontrolled spaces (the general building). Where potent product is open-filled and may become airborne, a high-pressure containment airlock that meets the filling room air grade may have pressure 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 continue to satisfy the specified differentials.

• The manual/remote gauges and controls or automatic controls should be mounted in a common panel outside the controlled space. An audible alarm may be provided to indicate loss of area pressure control. This alarm may be a manual reset type and equipped with a hard copy printout that indicates the out-of-range alarm.

• Unidirectional airflow serves as a barrier between product and microbial and particulate contamination generated by the equipment and personnel within an aseptic area. Where components and equipment are not protected by unidirectional airflow, terminal HEPA filters should be located directly over the exposed product.

This Document is licensed to

Mr. Gerardo Gutierrez, Sr.

Mexico, DF, ID number: 299643

Downloaded on: 10/5/11 2:26 PM

• When the central system air conditioning air quantity required to maintain room conditions is not sufficient to provide adequate air changes for recovery or protection over the product, components, and equipment, a supplemental (“local”) HEPA filtered air recirculating system may be employed. The cooler central system conditioned air may be distributed into the local recirculating AHU or UFH (preferably at the fan inlet) to maintain room temperature. The heat generated from the local recirculating system fan motor should be considered;

failing to do so can lead to serious temperature stratification and overheating in the aseptic area. Fan-filter (HEPA) units may add protection or air changes to speed recovery when inlets are ducted to create return airflow from low level.

• Airflow patterns within the workspace (inside the UFH) should be uniform with minimum turbulence. Ambient air may not aspirate into the work areas along the perimeter of the unidirectional airflow barrier. The hood filter area should deliver ISO 5 air at a target velocity of 90 feet per minute (0.45 m/sec) with uniformity within plus or minus 20%, measured just below the filter face (6 to 12 inches, 15 to 30 cm). Velocity at the work height also should be measured although it may measure close to zero if it is far from the filter face. The optimal filter face velocity should be determined during qualification of the UFH using airflow visualization (“smoke testing”). The performance of the UFH should be monitored and alarmed (current sensing relay). See the ISPE Baseline^® Guide on Sterile Manufacturing Facilities (Reference 13, Appendix 12).

• Room temperatures should be controlled by maintaining constant airflow through a cooling/dehumidification coil (humidity control), and possibly modulating a heating coil for temperature control. Systems that vary cool airflow to control room temperatures are not recommended because of adverse effects on room pressures.

• The HVAC system may be required to quickly return room conditions after sanitization. Sanitizing chemicals and frequency and duration of sanitizing may have an effect on HVAC materials.

• Since a Grade 5 room requires a very large treated airflow to create the unidirectional condition, air from the Grade 5 room is normally recirculated rather than exhausted with some excess supply air to create room DP. A Grade 5 (Grade A) room would be unusual; the Grade 5 area is usually a UFH or RABS inside a Grade 7 (Grade B) room. See the ISPE Baseline^® Guide on Sterile Manufacturing Facilities (Reference 13, Appendix 12).

• Dampers on return air may be modulated to maintain room pressure, while CV units on supply air help maintain constant flow to the room (particularly when there is no high-efficiency final filtration in the AHU).

• A desiccant dehumidifier may be required for aseptic liquid filling facilities.

This Document is licensed to

Mr. Gerardo Gutierrez, Sr.

Mexico, DF, ID number: 299643

Downloaded on: 10/5/11 2:26 PM

3.9.2 Aseptic Powder Potent Compounds

Figure 3.9: Aseptic Potent Powder Processing System Schematic with Pretreatment (Sample)

This Document is licensed to

Mr. Gerardo Gutierrez, Sr.

Mexico, DF, ID number: 299643

Downloaded on: 10/5/11 2:26 PM

• Processes should be contained in isolators with dedicated HVAC for the containment enclosure.

• Where the process leaks into a room, protect the HVAC system and other rooms on the system from hazardous compounds by using non-recirculating primary air conditioning systems.

• The exhaust or return air ducts may be kept clean with HEPA filters protected from physical damage with a pre-filter or equivalent. These filters should be located within the room where properly gowned and protected personnel can service them. Frequent filter change out or active room pressure controllers may be needed to offset loading of return air filters.

• If return filters are located remote from the room where open processing occurs, they should be housed in a high containment bag-in/bag-out filter housing and identified as such. These filters contain the potentially hazardous compounds and minimize particulate “fall back” during fan failure.

• Gowning areas should be supplied with HEPA filtered air and maintained at a negative pressure relative to the controlled aseptic area and at a positive pressure relative to the uncontrolled spaces. Local regulations may prefer two-stage gowning. The gowning area should be separated from the Grade 7 (EU Grade B) aseptic filling room by a high pressure Grade 7 (Grade B) airlock.

• The de-gowning area should be separated from the aseptic filling room by a low-pressure airlock. The de-gowning room shall be maintained negative relative to adjacent spaces on the uncontrolled side.

• Material entering the aseptic filling room should be transferred via a HEPA filtered, high-pressure tunnel, box, or sterilizer. Contaminated material leaving the aseptic filling room should be transferred via a low-pressure tunnel or box.

• If aseptic product is a powder, very low RH may be required. Minimize leakage into the AHU after the dehumidification step (blow-through AHU is preferred).