Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119): Premises, equipment, utilities and personnel

On this page

• Premises
• Equipment
• Utilities
• Personnel

Premises

The manufacture of sterile drugs should take place in appropriate cleanrooms. Entry to these should be through change rooms that act as airlocks for personnel, equipment and materials. Cleanrooms and change rooms should be maintained to an appropriate cleanliness standard and supplied with air that has passed through filters of an appropriate efficiency. Controls and monitoring should be scientifically justified and effectively evaluate the state of environmental conditions of cleanrooms, airlocks and pass-through hatches.

Component preparation, product preparation and filling operations should be carried out with appropriate technical and operational separation measures within the cleanroom or facility to prevent mix-up and contamination.

Restricted access barrier systems (RABS) or isolators are beneficial in assuring required conditions and minimizing microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. The manufacturer should justify the use of alternative approaches to RABS or isolators.

There are 4 grades of cleanroom/zone:

Grade A: This cleanroom is the critical zone for high-risk operations (for example, aseptic processing line, filling zone, stopper bowl, open primary packaging or for making aseptic connections under the protection of first air). Normally, such conditions are provided by a localized airflow protection, such as unidirectional airflow workstations within RABS or isolators. The maintenance of unidirectional airflow should be demonstrated and qualified across the entire grade A area. Premises, equipment, process and procedures should be designed to minimize direct intervention by operators (for example, without the protection of barrier and glove port technology) into the grade A area.

Grade B: For aseptic preparation and filling, this is the background cleanroom for grade A (where it is not an isolator). Air pressure differences should be continuously monitored. Cleanrooms of lower grade than grade B can be considered where isolator technology is used (refer to the information on background environment for isolators in the Barrier technologies section).

Grades C and D: These are cleanrooms used for carrying out less critical stages in the manufacture of aseptically filled sterile drugs or a background for isolators. They can also be used for preparing/filling terminally sterilized products. (For details on terminal sterilization activities, refer to the Production and specific technologies page.)

In cleanrooms and critical zones, all exposed surfaces should be smooth, impervious and unbroken, to minimize the shedding or accumulation of particles or micro-organisms.

To reduce dust accumulation and facilitate cleaning, there should be no recesses that make it difficult to clean effectively. Projecting ledges, shelves, cupboards and equipment should be kept to a minimum. Doors should be designed to avoid recesses that cannot be cleaned. Sliding doors may be undesirable for this reason.

Materials used to construct the cleanroom and items used in the room should generate minimal particles. They should permit repeated application of cleaning, disinfectant and sporicidal agents.

Ceilings should be designed and sealed to prevent contamination from the space above them.

Sinks and drains should be prohibited in grade A and grade B areas. In other cleanrooms, air breaks should be fitted between the machine or sink and the drains. Floor drains in lower-grade cleanrooms should be fitted with traps or water seals designed to prevent back flow. They should be regularly cleaned, disinfected and maintained.

The transfer of equipment and materials in and out of cleanrooms and critical zones is one of the greatest potential sources of contamination. Any activities that could potentially compromise the cleanliness of cleanrooms or the critical zone should be assessed. If activities cannot be eliminated, appropriate controls should be implemented.

A unidirectional process should be followed to transfer materials, equipment and components into grade A or B areas. Where possible, items should be sterilized and passed into these areas through double-ended sterilizers (for example, through a double-door autoclave or depyrogenation oven/tunnel) sealed into the wall.

Where sterilization upon transfer of the items is not possible, a procedure that does not introduce contamination should be validated and implemented. Examples of procedures include using an effective transfer disinfection process, rapid transfer systems for isolators or, for gaseous or liquid materials, a bacteria-retentive filter.

A separate, unidirectional process should be followed to remove materials, waste and environmental samples from grade A and B areas. If this is not possible, consider moving incoming and exiting material at different times and applying controls to avoid potential contamination of incoming items.

Airlocks should be designed to provide physical separation, minimize microbial and particle contamination of the different areas, and used when material and personnel move between different grades. Wherever possible, airlocks used for personnel movement should be separated from those used for material movement. Where this is not practical, consider moving the personnel and materials at different times.

Airlocks should be flushed effectively with filtered air to ensure that the grade of the cleanroom is maintained. The final stage of the airlock should, in the "at rest" state, be of the same cleanliness grade (viable and total particle) as the cleanroom into which it leads.

The use of separate change rooms for entering and leaving the grade B area is desirable. Where this is not practical, consider time based separation of ingress and egress activities. Where the CCS indicates that the risk of contamination is high, separate change rooms for entering and leaving production areas should be used.

Airlocks should be designed as follows:

• Personnel airlocks: Areas of increasing cleanliness used for entry of personnel (for example, from grade D to grade C to grade B areas). In general, hand washing facilities should be provided only in the first stage of the changing room, not in changing rooms directly accessing the grade B area.
• Material airlocks: Used for materials and equipment transfer.
  • Only materials and equipment that have been included on an approved list and assessed during validation of the transfer process should be transferred into the grade A or B areas through an airlock or pass-through hatches. Equipment and materials intended for use in the grade A area should be protected when moving through the grade B area. Unapproved items that require transfer should be pre-approved as an exception. Appropriate risk assessment and mitigation measures should be applied and recorded as per the manufacturer's CCS. They should include a specific disinfection and monitoring program approved by quality assurance.
  • Pass-through hatches should be designed to protect the higher-grade environment, for example, by flushing with an active filtered air supply.
  • The movement of material or equipment from lower-grade or unclassified areas to higher-grade clean areas should be cleaned and disinfected in keeping with the risk and in line with the CCS.

Entry and exit doors for all pass-through hatches and airlocks (for material and personnel) should not be opened at the same time. For airlocks leading to grade A and B areas, an interlocking system should be used. For airlocks leading to grade C and D areas, a visual and/or audible warning system should be operated as a minimum. Where required to maintain area segregation, there should be a time delay between when the interlocked doors close and open.

Cleanrooms should be supplied with a filtered air supply that maintains a positive pressure and/or an airflow relative to the background environment of a lower grade under all operational conditions. The filtered air supply should flush the area effectively. Adjacent rooms of different grades should have an air pressure difference of at least 10 Pascals (guidance value). Particular attention should be paid to protecting the critical zone.

The recommendations for air supplies and pressures may need to be modified where certain materials, such as pathogenic, highly toxic or radioactive products or live viral or bacterial materials, must be contained. Modifications may include positively or negatively pressurized airlocks that prevent the hazardous material from contaminating surrounding areas. For some operations, it may be necessary to decontaminate facilities (for example, cleanrooms and heating, ventilation, air conditioning (HVAC) systems) and treat the air leaving a clean area. Where containment requires air to flow into a critical zone, the source of the air should be from an area of the same or higher grade.

Airflow patterns within cleanrooms and zones should be visualized to demonstrate that:

• there's no ingress from lower- to higher-grade areas
• air doesn't travel from less clean areas (such as the floor) or over operators or equipment that may transfer contamination to higher-grade areas

Where unidirectional airflow is required, visualization studies should be done to determine compliance. For information on grades of cleanroom/zone, refer to the Premises section. For information on design of technology and processes, refer to the Barrier technologies section.

When filled, closed products are transferred to an adjacent cleanroom of a lower grade via a small egress point. Airflow visualization studies should demonstrate that air does not ingress from the lower-grade cleanrooms to the grade B area. Where air movement is shown to be a contamination risk to the clean area or critical zone, corrective actions, such as design improvement, should be implemented. Airflow pattern studies should be conducted both "at rest" and "in operation" (for example, simulating operator interventions) and the video recordings of airflow patterns retained. The outcome of these studies should be documented and considered when work is undertaken to establish the environmental monitoring program for the facility.

Indicators of air pressure differences should be fitted between cleanrooms and/or between isolators and their background. The CCS should consider set-points and air pressure differences that have been identified as critical.

Critical air pressure differences should be continuously monitored and recorded. A warning system should be in place to instantly indicate and warn operators of any failure in the air supply or reduction of air pressure differences (below set limits for those identified as critical). The warning signal should not be overridden without assessment and a procedure developed outlining the steps to be taken when a warning signal is given. Where alarm delays are set, these should be assessed and justified within the CCS. Other air pressure differences should be monitored and recorded at regular intervals.

Facilities should be designed to allow observation and supervision of production activities from outside the grade A and B areas (through windows or remote cameras with a full view of the area and processes). This requirement should be considered when designing new facilities or refurbishing existing facilities.

Barrier technologies

Isolators or RABS, which are different technologies, and the associated processes, should be designed to provide protection, by separating the grade A environment from the environment of the surrounding room. The hazards introduced from entry or removal of items during processing should be minimized and supported by high capability transfer technologies or validated systems that robustly prevent contamination and are appropriate for the respective technology.

The design of technology and processes that are in place in the critical zone should ensure that appropriate conditions are maintained to protect the exposed product during operations.

• Isolators:
  • The design of open isolators should ensure grade A conditions with first air protection in the critical zone and unidirectional airflow that sweeps over and away from exposed products during processing.
  • The design of closed isolators should ensure grade A conditions with adequate protection for exposed products during processing. Airflow may not be fully unidirectional in closed isolators where simple operations are conducted. However, any turbulent airflow should not increase risk of contamination of the exposed product. Where processing lines are included in closed isolators, grade A conditions should be ensured with first air protection in the critical zone and unidirectional airflow that sweeps over and away from exposed products during processing.
  • Negative pressure isolators should only be used when it's essential to contain the product (for example, radiopharmaceutical products) and specialized risk control measures should be applied to ensure the critical zone is not compromised.
• RABS:
  • The design of RABS should ensure grade A conditions with unidirectional airflow and first air protection in the critical zone. A positive airflow from the critical zone to the supporting background environment should be maintained.

The background environment for isolators or RABS should ensure the risk of transferring contamination is minimized.

• Isolators:
  • The background environment for open isolators should generally correspond to a minimum of grade C. The background for closed isolators should correspond to a minimum of grade D. The decision on the background classification should be based on a risk assessment and justified in the CCS.
  • Key considerations when performing the risk assessment for the CCS of an isolator should include, for example, the:
    • bio-decontamination program
    • extent of automation
    • impact of glove manipulations that may potentially compromise 'first air' protection of critical process points
    • impact of potential loss of barrier/glove integrity
    • transfer mechanisms used and
    • activities such as set-up or maintenance that may require the doors to be opened before the final bio-decontamination of the isolator
  • Where additional process risks are identified, a higher grade of background should be considered unless appropriately justified in the CCS.
  • Airflow pattern studies should be performed at the interfaces of open isolators to demonstrate the absence of air ingress.
• RABS:
  • The background environment used for aseptic processing should correspond to a minimum of grade B and airflow pattern studies should be performed to demonstrate the absence of air ingress during interventions, including door openings if applicable.

The materials used for glove systems (for both isolators and RABS) should be shown to have appropriate mechanical and chemical resistance. The CCS should indicate how frequent gloves should be replaced.

• Isolators:
  • Leak testing of the glove system should be performed using a methodology demonstrated to be suitable for the task and criticality. Testing should be done at defined intervals. In general, glove integrity testing should be done, at a minimum, at the beginning and end of each batch or campaign. Additional glove integrity testing may be necessary depending on the validated campaign length.
  • Glove integrity monitoring should include a visual inspection associated with each use and following any manipulation that may affect the integrity of the system.
  • For manual aseptic processing activities where single unit or small batch sizes are produced, the frequency of integrity verification may be based on other criteria, such as the beginning and end of each manufacturing session.
  • Integrity/leak testing of isolator systems should be performed at defined intervals.
• RABS:
  • Gloves used in the grade A area should be sterilized before installation and sterilized or effectively bio-decontaminated by a validated method before each manufacturing campaign. If exposed to the background environment during operation, disinfection using an approved methodology following each exposure should be completed. Gloves should be visually examined with each use and tested for integrity at periodic intervals.

Decontamination methods (cleaning and bio-decontamination, and, where applicable, inactivation for biological materials) should be appropriately defined and controlled. The cleaning process before the bio-decontamination step is essential. Any residues that remain may inhibit the effectiveness of the decontamination process.

Evidence should be available to demonstrate that the cleaning and bio-decontamination agents used do not have an adverse impact on the product produced within the RABS or isolator.

• For isolators:
  • The bio-decontamination process of the interior should be automated, validated and controlled within defined cycle parameters, and include a sporicidal agent in a suitable form (for example, gaseous or vaporized form). Gloves should be appropriately extended with fingers separated to ensure contact with the agent. Methods used (cleaning and sporicidal bio-decontamination) should render the interior surfaces and critical zone of the isolator free from viable microorganisms.
• For RABS:
  • The sporicidal disinfection should include the routine application of a sporicidal agent using a validated method. The method should include all areas of the interior surfaces and ensure the environment is suitable for aseptic processing.

Cleanroom and clean air equipment qualification

Cleanrooms and clean air equipment such as unidirectional airflow units (UDAFs), RABS and isolators should be qualified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state to minimize the risk of contaminating the product or materials being handled. Appropriate cleanliness levels in the "at rest" and "operational" states should be maintained.

Cleanrooms and clean air equipment should be qualified using methodology in accordance with the requirements of either of the following:

• Guide to validation – Drugs and supporting activities (GUI-0029) (Health Canada)
• PIC/S Annex 15 – Qualification and validation (PIC/S)

Cleanroom qualification (including classification) should be clearly differentiated from operational environmental monitoring.

Cleanroom and clean air equipment qualification is the overall process of assessing the level of compliance of a classified cleanroom or clean air equipment with its intended use.

As part of the qualification requirements of Health Canada's Guide to validation – drugs and supporting activities (GUI-0029) (or alternatively PIC/S Annex 15 – Qualification and validation), the qualification of cleanrooms and clean air equipment should include (where relevant to the design/operation of the installation):

• installed filter system leakage and integrity testing
• airflow tests for volume and velocity
• air pressure difference test
• airflow direction test and visualization
• microbial airborne and surface contamination
• temperature measurement test
• relative humidity test
• recovery test
• containment leak test

Reference for the qualification of cleanrooms and clean air equipment can be found in the ISO 14644 series of standards.

Cleanroom classification is part of the cleanroom qualification. It's a method of assessing the level of air cleanliness against a specification for a cleanroom or clean air equipment by measuring the total particle concentration. Classification activities should be scheduled and conducted to avoid any impact on process or product quality. For example, initial classification should take place during simulated operations and reclassification during simulated operations or aseptic process simulation (APS).

For cleanroom classification, the total of particles equal to or greater than 0.5 and 5 µm should be measured. This measurement should be performed both at rest and in simulated operations in accordance with the limits specified in Table 1.

Table 1: Maximum permitted total particle concentration for classification

Grade	Maximum permitted number of particles/m3 equal to or greater than the tabulated size
	≥ 0.5 µm		≥5.0 µm
	At rest	In operation	At rest	In operation
A	3,520	3,520	Not specifiedFootnote a	Not specifiedFootnote a
B	3,520	352,000	Not specifiedFootnote a	2,930
C	352,000	3,520,000	2,930	29,300
D	3,520,000	Not predeterminedFootnote b	29,300	Not predeterminedFootnote b
a Classification including 5 µm particles may be considered where indicated by the CCS or historical trends. Return to footnote a referrer b For grade D, "in operation" limits are not predetermined. The manufacturer should establish these limits based on a risk assessment and routine data where applicable. Return to footnote b referrer

For classification of the cleanroom, the minimum number of sampling locations and their positioning can be found in ISO 14644 Part 1. For the aseptic processing area and background environment (grade A and B areas, respectively), additional sample locations should be considered and all critical processing areas such as the point of fill and container closure feeder bowls should be evaluated. Critical processing locations should be determined through a documented risk assessment process and knowledge of the process and operations being performed in the area.

Cleanroom classification should be carried out in the "at rest" and "in operation" states.

• The "at rest" state is the condition where the installation of all utilities is complete, including any functioning HVAC, with the main manufacturing equipment installed as specified but not operating and without personnel in the room.
• The "in operation" state is the condition where the installation of the cleanroom is complete, the HVAC system fully operational, equipment installed and functioning in the manufacturer's defined operating mode, with the maximum number of personnel performing or simulating routine operational work.
• The total particle limits given in Table 1 for the "at rest" state should be achieved after a "clean-up" period once operations and line clearance/cleaning activities have been completed. The "clean-up" period (guidance value of less than 20 minutes) should be determined during the qualification of the rooms, documented and adhered to in procedures to reinstate a qualified state of cleanliness if disrupted during operation.

The speed of air supplied by unidirectional airflow systems, including the location for air speed measurement, should be clearly justified in the qualification protocol. Air speed should be designed, measured and maintained to ensure that appropriate unidirectional air movement protects the product and open components at the working position (for example, where high-risk operations occur and product and/or components are exposed). Unidirectional airflow systems should provide a homogeneous air speed in a range of 0.36 to 0.54 m/s (guidance value) at the working position, unless otherwise scientifically justified in the CCS. Airflow visualization studies should correlate with the air speed measurement.

The microbial contamination level of the cleanrooms should be determined as part of the cleanroom qualification. The number of sampling locations should be based on a documented risk assessment and the results obtained from room classification, air visualization studies, and knowledge of the process and operations for the area. The maximum limits for microbial contamination during qualification for each grade are given in Table 2. Qualification should include both "at rest" and "in operation" states.

Table 2: Recommended limits for microbial contamination

Grade	Air sample cfu/m³	Settle plates (diam. 90 mm), cfu/4 hoursFootnote a	Contact plates (diam. 55 mm), cfu/plate
A	< 1	< 1	< 1
B	10	5	5
C	100	50	25
D	200	100	50
a Settle plates should be exposed for the duration of operations and changed as required after a maximum of 4 hours. Exposure time should be based on recovery studies and should not allow desiccation of the media used. Return to footnote a referrer
Notes: All methods indicated for a specific grade in the table should be used for qualifying the area of that specific grade. If a method tabulated is not used or alternative methods are used, the approach taken should be appropriately justified. Limits are applied using cfu throughout the document. If different or new technologies are used that present results in a manner different from cfu, the manufacturer should scientifically justify the limits applied and, where possible, correlated to cfu. For the qualification of personnel gowning, the limits given for contact plates and glove prints in Table 6 should apply. Sampling methods should not pose a contamination risk to manufacturing operations.

The requalification of cleanrooms and clean air equipment should be carried out periodically following defined procedures. At a minimum, requalification should include the following:

• cleanroom classification (total particle concentration)
• integrity test of final filters
• airflow volume measurement
• verification of air pressure difference between rooms
• air velocity test

Note: For grades B, C and D areas, the air velocity test should be performed according to a risk assessment documented as part of the CCS. However, it is required for filling zones that have unidirectional airflow (for example, when filling terminally sterilized products or background to grade A and RABS). For grades with non-unidirectional airflow, a measurement of recovery testing should replace velocity testing.

Maximum time intervals for requalification are:

• 6 months for grade A and B areas
• 12 months for grade C and D areas

Appropriate requalification consisting of at least the above tests should also be carried out after:

• completion of remedial action to rectify an out-of-compliance equipment or facility condition
• changes to equipment, facility or processes

The change management process should be used to determine the significance of a change. Examples of changes to be considered include the following:

• interruption of air movement that affects installation
• change in design of the cleanroom or the operational setting parameters of the HVAC system
• special maintenance that affects installation (for example, changing final filters)

Disinfection

Disinfecting the cleanrooms is particularly important. Cleanrooms should be cleaned and disinfected thoroughly in accordance with a written program.

For disinfection to be effective, prior cleaning to remove surface contamination should be performed. Cleaning programs should effectively remove disinfectant residues. More than 1 type of disinfecting agent should be used to ensure that where they have different modes of action, their combined usage is effective against bacteria and fungi. Disinfection should also include using a sporicidal agent periodically.

There should be regular monitoring to assess the effectiveness of the disinfection program and detect changes in types of microbial flora (for example, organisms resistant to the disinfection regime currently in use).

Validation studies should demonstrate the suitability and effectiveness of disinfectants in the specific manner in which they are used and on the type of surface material, or representative material if justified. Such studies should also support the in-use expiry periods of prepared solutions.

Disinfectants and detergents used in grade A and B areas should be sterile before they are used. Disinfectants used in Grade C and D should be sterile where determined in the CCS. Disinfectants and detergents that are diluted/prepared by the sterile drug manufacturer should be done in a manner that prevents contamination and be monitored for microbial contamination.

Dilutions should be kept in previously cleaned containers (and sterilized where applicable) and should only be stored for the defined period. If the disinfectants and detergents are supplied "ready-made," then results from certificates of analysis or conformance can be accepted subject to appropriate vendor qualification.

Where fumigation or vapour disinfection (for example, vapour-phase hydrogen peroxide) is used for cleanrooms and associated surfaces, the effectiveness of the fumigation agent and dispersion system should be understood and validated.

Equipment

A written, detailed description of the equipment design should be available (including process and instrumentation diagrams as appropriate). This should form part of the initial qualification package and be kept up to date.

Equipment monitoring requirements should be defined in "user requirements specifications" and during early stages of development and then confirmed during qualification. Process and equipment alarm events should be acknowledged and evaluated for trends. The frequency at which alarms are assessed should be based on how crucial they are, with those that are critical reviewed immediately.

As much as is practicable, equipment, fittings and services should be designed and installed so that operations, maintenance and repairs can be performed outside the cleanroom. If maintenance has to be performed in the cleanroom, and the required standards of cleanliness and/or asepsis cannot be maintained, then precautions should be considered. These could include restricting access to the work area to specified personnel and generating clearly defined work protocols and maintenance procedures. Additional cleaning, disinfection and environmental monitoring should also be considered. Equipment that must be sterilized should be carried out, wherever possible, after complete reassembly.

The cleaning process should be validated to be able to:

• remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used
• minimize chemical, microbial and particulate contamination of the product during the process and before disinfection

For aseptic processes, direct and indirect product contact parts should be sterilized. Direct contact parts are those that the product passes through, such as filling needles or pumps. Indirect product contact parts are equipment parts that do not contact the product but may come into contact with other sterilized surfaces where the sterility is critical to the overall product sterility. Examples of indirect product contact parts are stopper bowls and guides, and sterilized components.

All equipment such as sterilizers, air handling systems (including air filtration) and water systems should be subject to qualification, monitoring and planned maintenance. Upon completion of maintenance, their return to use should be approved.

The potential impact of unplanned maintenance of equipment critical to the sterility of the product should be assessed and recorded.

A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt is continually sterilized (for example, in a sterilizing tunnel).

Particle counters, including sampling tubing, should be qualified. The manufacturer's recommended specifications for tube diameter and bend radii should be considered. Tube length should typically be no longer than 1 m unless justified, and the number of bends should be minimized.

Portable particle counters with a short length of sample tubing should be used for classification purposes. Isokinetic sampling heads should be used in unidirectional airflow systems, oriented appropriately and positioned as close as possible to the critical location to ensure that samples are representative.

Utilities

The nature and extent of controls applied to utility systems should be commensurate with the risk to product quality associated with the utility. The impact should be determined using a risk assessment and documented as part of the CCS.

In general, higher-risk utilities are those that:

• contact the product directly (for example, water for washing and rinsing, gases and steam for sterilization)
• contact materials that will ultimately become part of the product
• contact surfaces that come into contact with the product
• directly impact the product in other ways

Utilities should be designed, installed, qualified, operated, maintained and monitored to ensure that the utility system functions as expected.

Results for critical parameters and critical quality attributes of high-risk utilities should be subject to regular trend analysis to ensure that system capabilities remain appropriate.

Records of utility system installation should be maintained throughout the system's lifecycle. Such records should include current drawings and schematic diagrams, construction material lists and system specifications. Typically, important information includes attributes such as:

• pipeline flow direction, slopes, diameter and length
• tank and vessel details
• valves, filters, drains, sampling and user points

Pipes, ducts and other utilities should not be present in cleanrooms. If this is unavoidable, they should be installed so that they do not create recesses, unsealed openings and surfaces that are difficult to clean. Installation should allow the outer surface of the pipes to be cleaned and disinfected.

Water systems

Water treatment plant and distribution systems should be designed, constructed, installed, commissioned, qualified, monitored and maintained to prevent microbiological contamination and ensure a reliable source of water of an appropriate quality.

Measures should be taken to minimize the risk of presence of particulates, microbial contamination/proliferation and endotoxin/pyrogen (for example, sloping of piping to provide complete drainage and avoid dead legs). Filters that are included in the system should be monitored and maintained. Water produced should comply with the current monograph of the relevant Pharmacopeia.

Water systems should be qualified and validated to maintain the appropriate levels of physical, chemical and microbial control, taking into consideration the effect of seasonal variation.

In water distribution systems, water flow should remain turbulent through the pipes to minimize the risk of microbial adhesion and subsequent biofilm formation. The flow rate should be established during qualification and be routinely monitored.

Water for injections (WFI) should be produced from water meeting specifications that have been defined during the qualification process. The WFI should be stored and distributed in such a manner as to minimize the risk of microbial growth (for example, by constant circulation at a temperature above 70°C). WFI should be produced by distillation or a purification process that is equivalent to distillation. This may include reverse osmosis coupled with other appropriate techniques such as electrodeionization (EDI), ultrafiltration or nanofiltration.

Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters, the filters should not be a source of contamination and the integrity of the filter should be tested before installation and after use. Controls should be in place to prevent condensation from forming on the filter (for example, by heating).

To minimize the risk of biofilm formation, sterilization, disinfection or regeneration of water systems should be carried out according to a predetermined schedule and as a remedial action following out-of-limit or specification results. Disinfection of a water system with chemicals should be followed by a validated rinsing/flushing procedure. Water should be tested after disinfection/regeneration. Chemical testing results should be approved before the water system is in use again. Microbiological/endotoxin results should be within specification and approved before batches manufactured using water from the system are certified/released.

Regular ongoing chemical and microbial monitoring of water systems should be performed to ensure that the water continues to meet compendial expectations. Alert levels should be based on the initial qualification data. These should be reassessed periodically on data obtained during subsequent re-qualifications, routine monitoring and investigations. Ongoing monitoring data should be reviewed to identify an adverse trend in system performance.

Sampling programs should reflect the CCS requirements. They should also include all outlets and points of use, at a specified interval, to ensure that representative water samples are obtained for regular analysis. Sample plans should:

• be based on the qualification data
• consider the potential worst case sampling locations
• ensure at least 1 representative sample is included for each day the water is used for manufacturing processes

Alert level excursions should be documented and reviewed. An investigation to determine whether the excursion is a single (isolated) event or if results point to an adverse trend or deterioration of the system should be conducted. Each action limit excursion should be investigated to determine the probable root causes and any potential impact on the quality of products and manufacturing processes as a result of the use of the water.

WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, as these may give a better indication of overall system performance than discrete sampling. Sensor locations should be based on risk.

Steam used as a direct sterilizing agent

Feed water to a pure steam (clean steam) generator should be appropriately purified. Pure steam generators should be designed, qualified and operated to ensure that the quality of steam produced meets defined chemical and endotoxin levels.

Steam used as a direct sterilizing agent should be of suitable quality. It should not contain additives at a level that could contaminate the product or equipment. For a generator supplying pure steam used for the direct sterilization of materials or product-contact surfaces (for example, porous hard-good autoclave loads), steam condensate should meet the current monograph for WFI of the relevant Pharmacopeia (microbial testing is not mandatory for steam condensate). A suitable sampling schedule should be in place to ensure that representative pure steam is analyzed regularly. Other aspects of the quality of pure steam used for sterilization should be assessed periodically against validated parameters. These parameters should include the following (unless otherwise justified): non-condensable gases, dryness value (dryness fraction) and superheat.

Gases and vacuum systems

Gases that come in direct contact with the product/primary container surfaces should be of appropriate chemical, particulate and microbial quality. All relevant parameters, including oil and water content, should be specified, considering the use and type of the gas and the design of the gas generation system. Where applicable, gases should comply with the current monograph of the relevant Pharmacopoeia or the product quality requirement.

Gases used in aseptic processes should be filtered through a sterilizing grade filter (with a nominal pore size of a maximum of 0.22 µm) at the point of use. When the filter is used on a batch basis (for example, to filter gas used for overlay of aseptically filled products) or as a product vessel vent filter, the filter should be tested for integrity and the results reviewed as part of the batch certification/release process. Transfer pipework or tubing that is located after the final sterilizing grade filter should be sterilized. When gases are used in the process, microbial monitoring of the gas should be performed periodically at the point of use.

Where backflow from vacuum or pressure systems poses a potential risk to the product, there should be mechanism(s) to prevent backflow when the vacuum or pressure system is shut off.

Heating and cooling and hydraulic systems

Major items of equipment associated with hydraulic, heating and cooling systems should, where possible, be located outside the filling room. There should be appropriate controls to contain any spillage and/or cross-contamination associated with the system fluids.

Any leaks from these systems that would present a risk to the product should be detectable (for instance, an indication system for leakage).

Personnel

There should be sufficient appropriate personnel, suitably qualified, trained and experienced in the manufacture and testing of sterile drugs, and any of the specific manufacturing technologies used in the site's manufacturing operations. This requirement ensures compliance with GMP applicable to the manufacture and handling of sterile drugs.

Only the minimum number of personnel required should be present in cleanrooms. The maximum number of operators in cleanrooms should be determined, documented and considered during activities such as initial qualification and APS, so as not to compromise sterility assurance.

All personnel, including cleaning, maintenance and monitoring staff and those who access cleanrooms, should receive regular training, gowning qualification and assessment in disciplines relevant to the correct manufacture of sterile drugs. Training should include the basic elements of microbiology and hygiene. There should be a specific focus on:

• cleanroom practices
• contamination control
• aseptic techniques
• protection of sterile drugs (for those operators entering the grade B cleanrooms and/or intervening into grade A)
• potential safety implications to the patient if the product is not sterile

The level of training should be based on how critical the function is and on the area in which the personnel are working.

The personnel accessing grade A and B areas should be trained for aseptic gowning and aseptic behaviours. Compliance with aseptic gowning procedures should be confirmed by assessment and periodic reassessment at least annually. Assessment should involve both visual and microbial assessment (using monitoring locations such as gloved fingers, forearms, chest and hood (facemask/forehead). Refer to the Environmental and personnel monitoring - viable particle section for the expected limits (Table 6). The unsupervised access to the grade A and B areas where aseptic operations are or will be conducted should be restricted to appropriately qualified personnel who have passed the gowning assessment and have participated in a successful APS.

Unqualified personnel should not enter grade B cleanrooms or grade A areas in operation. In exceptional cases, manufacturers should establish written procedures outlining the process by which unqualified personnel are brought into the grade B and A areas. An authorized person from the manufacturer should supervise the unqualified personnel during their activities and assess the impact of those activities on the cleanliness of the area. Access by these persons should be assessed and recorded in accordance with the pharmaceutical quality system (PQS).

There should be systems in place to prevent disqualified personnel from working in or accessing cleanrooms without supervision. The systems that are put in place should be based on ongoing assessment and/or identification of an adverse trend from the personnel monitoring program and/or after a failed APS. Once disqualified, retraining and requalification should be completed before permitting the operator to have any further involvement in aseptic practices. Requalification for operators entering grade B cleanrooms or performing intervention in grade A areas should include participation in a successful APS.

High standards of personal hygiene and cleanliness are essential to prevent excessive shedding or increased risk of introducing microbial contamination. Personnel should be instructed to report any specific health conditions or ailments that may cause the shedding of abnormal numbers or types of contaminants and be prevented from accessing cleanrooms. Health conditions and actions to be taken should be provided by the designated competent person and described in procedures.

Personnel who have been engaged in the following activities should not enter clean areas unless clearly defined and effective decontamination and entry procedures have been followed and documented:

• processing human or animal tissue materials
• cultures of micro-organisms, other than those used in the current manufacturing process
• any activities that may have a negative impact on quality (such as microbial contamination)

Wristwatches, make-up, jewellery, mobile phones and other non-essential items should not be allowed in clean areas. Electronic devices, such as mobile phones and tablets, that are supplied by the manufacturer solely for use in the cleanrooms may be acceptable if they can be cleaned and disinfected according to the grade in which they are used. The use and disinfection of such equipment should be included in the CCS.

Cleanroom gowning and hand washing should follow a written procedure and be designed to minimize contamination of cleanroom clothing and/or the transfer of contaminants to the clean areas.

The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. Clothing that protects the operator from the product should not compromise the protection of the product from contamination. Garments should be visually checked for cleanliness and integrity immediately before and after gowning. Gown integrity should also be checked upon exit. Particular attention should be paid to ensuring that sterilized garments and eye coverings have been subject to the sterilization process and are within their specified hold time. Their packaging should be visually inspected to ensure it has not been compromised. Reusable garments (including eye coverings) should be replaced if damaged or at a frequency that has been established during qualification studies. The qualification of garments should consider any necessary garment testing requirements, including damage to garments that may not be identified by visual inspection alone.

Clothing should be chosen to limit shedding due to operator's movement.

Clothing that is required for each cleanliness grade is described as follows.

For grade B (including access/interventions into grade A):

• garments that are dedicated for use under a sterilized suit should be worn before gowning
• refer to the following paragraph on cleanroom gowning
• sterilized, non-powdered, rubber or plastic gloves should be worn while donning the sterilized garments
• sterile headgear that encloses all hair (including facial) should be tucked into the neck of the sterile suit if separate from the gown
• sterile face mask and sterile eye coverings (such as goggles) should be worn to cover and enclose all facial skin and prevent the shedding of droplets and particles
• appropriate sterilized footwear (such as over-boots) should be worn
• trouser legs should be tucked inside footwear
• garment sleeves should be tucked into a second pair of sterile gloves worn over the pair worn while donning the gown
• protective clothing should minimize shedding of fibres or particles and retains particles shed by the body
  • Assess particle shedding and particle retention efficiencies of the garments during the garment qualification.
  • Pack and fold garments in such a way as to allow operators to don the gown without contacting the outer surface of the garment and to prevent the garment from touching the floor.

For grade C:

• hair, beards and moustaches should be covered
• single or 2-piece trouser suit gathered at the wrists and with high neck and appropriately disinfected shoes or overshoes should be worn
  • They should minimize the shedding of fibres and particles.

For grade D:

• hair, beards and moustaches should be covered
• a general protective suit and appropriately disinfected shoes or overshoes should be worn
• appropriate measures should be taken to avoid any ingress of contaminants from outside the clean area

Note: Additional gowning, including gloves and face mask, may be required in grade C and D areas when performing activities considered to be a contamination risk, as defined by the CCS.

Cleanroom gowning should be performed in change rooms of an appropriate cleanliness grade to maintain gown cleanliness. Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms that lead directly to grade B and C areas. Single or 2-piece facility trouser suits covering the full length of the arms and the legs and facility socks covering the feet should be worn before entering change rooms for grades B and C. Facility suits and socks should not present a risk of contamination to the gowning area or processes.

Every operator entering grade B or A areas should put on clean, sterilized protective garments (including eye coverings and masks) of an appropriate size at each entry. The maximum period for which the sterilized gown may be worn before replacement during a shift should be defined as part of the garment qualification.

Gloves should be regularly disinfected during operations. Garments and gloves should be changed immediately if they become damaged or present any risk of product contamination.

Reusable clothing for clean areas should be cleaned in a laundry facility that is adequately segregated from production operations. Cleaning should be conducted using a qualified process to ensure the clothing does not become damaged and/or contaminated by fibres or particles during repeated laundering. Laundry facilities should not introduce risk of contamination or cross-contamination. Inappropriate handling and use of clothing may damage fibres and increase the risk of shedding of particles. After washing and before packing, garments should be visually inspected for damage and visual cleanliness.

The garment management processes should be evaluated and determined as part of the garment qualification program and should include a maximum number of laundry and sterilization cycles.

Activities in clean areas that are not critical to production processes should be kept to a minimum, especially when aseptic operations are in progress. Movement of personnel should be slow, controlled and methodical to avoid excessive shedding of particles and organisms that could result from over-vigorous activity. Operators performing aseptic operations should adhere to aseptic technique at all times to prevent changes in air currents that may introduce lower-quality air into the critical zone. Movement next to the critical zone should be restricted. The path of the unidirectional (first air) airflow should not be obstructed.

A review of airflow visualization studies should be part of the training program.