Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119): Environmental and process monitoring
On this page
- General
- Environmental and process monitoring - overview
- Environmental monitoring – total particle
- Environmental and personnel monitoring – viable particle
- Aseptic process simulation (APS) (also known as media fill)
General
The site's environmental and process monitoring program forms part of the overall contamination control strategy (CCS) and is used to monitor the controls designed to minimize the risk of microbial and particle contamination. Note: When taken in isolation, the reliability of each element of the monitoring system (viable, non-viable and APS) is limited and should not be considered an indicator of asepsis. When considered together, the results help confirm the reliability of the design, validation and operation of the system being monitored.
In general, this program consists of the following elements:
- environmental monitoring – total particle
- environmental and personnel monitoring – viable particle
- temperature, relative humidity and other specific characteristics
- APS (aseptically manufactured product only)
The information from these systems should be used for routine batch certification/release and for periodic assessment during process review or investigation. This applies to both terminal sterilization and aseptic processes. However, the criticality of the impact may differ depending upon the product and process type.
Environmental and process monitoring - overview
An environmental monitoring program should be established and documented. The purpose of the environmental monitoring program is to:
- give assurance that cleanrooms and clean air equipment continue to provide an environment of appropriate air cleanliness, in accordance with design and regulatory requirements
- effectively detect excursions from environmental limits that trigger an investigation and assessment of risk to product quality
Risk assessments should be used to establish the comprehensive environmental monitoring program. They should cover sampling locations, frequency of monitoring, monitoring methods and incubation conditions (such as time, temperature(s), aerobic and/or anaerobic conditions).
Risk assessments should be based on detailed knowledge of the following:
- the process inputs and final product
- the facility and equipment
- criticality of specific processes and steps
- the operations involved
- routine monitoring data
- monitoring data obtained during qualification
- typical microbial flora isolated from the environment
Risk assessments should:
- determine critical monitoring locations
- determine locations where the presence of microorganisms during processing may have an impact upon product quality (for example, grade A areas, aseptic processing areas and grade B areas that directly interface with a grade A area
- include other information such as air visualization studies
- confirm the effectiveness of the site's environmental monitoring program through regular reviews
- The monitoring program should be considered in the overall context of the trend analysis and the CCS for the site.
Cleanrooms, clean air equipment and personnel should be routinely monitored throughout all critical stages of processing, including equipment set-up and when in operation.
Other characteristics such as temperature and relative humidity should be controlled within ranges that align with product/processing/personnel requirements and support the maintenance of defined cleanliness standards (for example, grades A or B).
The monitoring of grade A areas should demonstrate that aseptic processing conditions are maintained during critical operations. Locations that pose the highest risk of contamination to the sterile equipment surfaces, containers, closures and product should be monitored. Monitoring locations and the orientation and positioning of sampling devices should be justified and appropriate for obtaining reliable data from the critical zones.
Sampling methods should not pose a risk of contamination to the manufacturing operations.
Appropriate alert levels and action limits should be set for viable and total particle monitoring. The maximum total particle action limits are described in Table 5 and the maximum viable particle action limits are described in Table 6. However, more stringent action limits may be applied based on data trending, the nature of the process or as determined within the CCS. Both viable and total particle alert levels should be established based on cleanroom qualification test results and periodically reviewed based on ongoing trend data.
Alert levels for grade A (total particle only), grade B, grade C and grade D areas should be set in order to detect, and address, adverse trends (such as number of or individual events that indicate a deterioration of environmental control).
Monitoring procedures should define the trending approach. Trends should include:
- increasing numbers of excursions from action limits or alert levels
- consecutive excursions from alert levels
- regular but isolated excursion from action limits that may have a common cause (for example, single excursions that always follow planned preventative maintenance)
- changes in microbial flora type and numbers and predominance of specific organisms
- Particular attention should be given to organisms recovered that may indicate a loss of control, deterioration in cleanliness or that may be difficult to control such as spore-forming microorganisms and molds
Grades C and D cleanrooms should be monitored in operation based on data collected during qualification and routine data to allow effective trend analysis. The requirements of alert levels and action limits will depend on the nature of the operations being carried out. Action limits may be more stringent than those listed in tables 5 and 6.
If action limits are exceeded, operating procedures should prescribe a root cause investigation. This type of investigation is an assessment of the potential impact to the product (including batches produced between monitoring and reporting) and the requirements for taking corrective and preventive actions. If alert levels are exceeded, operating procedures should prescribe assessment and follow-up, including an investigation and/or the corrective actions that should be taken to avoid further deterioration of the environment.
Environmental monitoring - total particle
A total particle monitoring program should be established to obtain data for assessing potential contamination risks and ensure the environment for sterile operations in a qualified state is maintained.
The limits for environmental monitoring of airborne particle concentrations for each graded area are given in Table 5.
| 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 | 29 | 29 |
| B | 3,520 | 352,000 | 29 | 2,930 |
| C | 352,000 | 3,520,000 | 2,930 | 29,300 |
| D | 3,520,000 | Not predeterminedFootnote a | 29,300 | Not predeterminedFootnote a |
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Notes:
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For grade A, particles should be monitored for the full duration of critical processing, including equipment assembly.
The grade A area should be monitored continuously (for particles ≥0.5 and ≥5 µm) and with a suitable sample flow rate (at least 28 litres (1 ft3) per minute) in order to capture all interventions, transient events and any system deterioration. The system should frequently correlate individual sample results with alert levels and action limits at the frequency that would make it possible to identify, and respond to any potential excursion in a timely manner. Alarms should be triggered if alert levels are exceeded, and procedures should outline the actions that should be taken in response to alarms, such as additional microbial monitoring.
A similar system can be used for the grade B area, although the sample frequency may be decreased. The grade B area should be monitored at such a frequency and with suitable sample size so that any increase in contamination levels and system deterioration is captured by the program. If alert levels are exceeded, alarms should be triggered.
The monitoring system selection should consider any risk presented by materials used in the manufacturing operation (for example, those involving live organisms, powdery products or radiopharmaceuticals) that may give rise to biological, chemical or radiation hazards.
Where contaminants are present due to the processes involved that would potentially damage the particle counter or present a hazard (for example, live organisms, powdery products and radiation hazards), the frequency and strategy used should be such as to assure the environmental classification both before and after being exposed to the risk. Increased viable particle monitoring should be considered to ensure comprehensive monitoring of the process. Simulated operations should also be monitored and performed at appropriate intervals. The approach should be defined in the CCS.
The size of monitoring samples taken using automated systems is usually a function of the system's sampling rate. It's not necessary for the sample volume to be the same as that used for formal classification of cleanrooms and clean air equipment. Monitoring sample volumes should be justified.
Environmental and personnel monitoring - viable particle
Where aseptic operations are performed, microbial monitoring should be done frequently using a combination of methods such as settle plates, volumetric air sampling, glove, gown and surface sampling (for example, swabs and contact plates). The CCS should justify the method of sampling that is chosen and demonstrate that the method does not have a detrimental impact on grades A and B airflow patterns. Cleanroom and equipment surfaces should be monitored at the end of an operation.
Viable particles in the cleanrooms should also be monitored when normal manufacturing operations (such as post-disinfection, before manufacturing starts, after the batch is completed and after a shutdown period) are not taking place. Associated rooms that have not been used should also be monitored for viable particles.
Viable particles monitoring is done to detect potential incidents of contamination that may affect the controls in the cleanrooms. In case of an incident, additional sample locations may be used to verify the effectiveness of a corrective action (for example, cleaning and disinfection).
Continuous viable air monitoring in the grade A area (for example, air sampling or settle plates) should be undertaken for the full duration of critical processing, including equipment (aseptic set-up) assembly. A similar approach should be considered for grade B cleanrooms based on the risk of impact on the aseptic processing. The monitoring should capture all interventions, transient events and system deterioration and avoid any risk caused by monitoring operations.
A risk assessment should evaluate the locations, type and frequency of personnel monitoring based on the activities performed and the proximity of personnel to critical zones. Monitoring should involve personnel at periodic intervals during the process, but not to compromise the process. In particular, personnel should be monitored after they have been involved in critical interventions. At a minimum, gloves should be monitored, but areas of gown as applicable to the process may also be monitored. Where monitoring of gloves is performed after critical interventions, the outer gloves should be replaced before the activity resumes. Where monitoring of gowns is required after critical interventions, the gown should be replaced before further activity takes place in the cleanroom. In addition, the personnel should be monitored each time they exit the grade B cleanroom (gloves and gown).
Personnel in grade A and B areas should be monitored for microbial contamination. Where operations are manual in nature (for example, aseptic compounding or filling), there should be increased emphasis on microbial monitoring gowns due to increased risk. This should be justified within the CCS.
Routine monitoring by manufacturing personnel should be subject to regular oversight by the quality unit. Refer to the information on observing aseptic operations.
Manufacturers should consider adopting suitable alternative monitoring systems such as rapid methods in order to expedite the detection of microbiological contamination issues and reduce the risk to product. Rapid and automated microbial monitoring methods may be adopted after validation has demonstrated they are equal or superior to established methods.
Sampling methods and equipment used should be fully understood. There should be procedures for operating the equipment correctly and for interpreting the sampling results. There should also be data available to support the recovery efficiency of the sampling methods chosen.
Action limits for viable particle contamination are shown in Table 6.
| Grade | Air sample cfu/m³ | Settle plates (diam. 90 mm), cfu/4 hoursFootnote a | Contact plates (diam. 55 mm), cfu/plateFootnote b | Glove print, including 5 fingers on both hands, cfu/glove |
|---|---|---|---|---|
| A | No growthFootnote c | |||
| B | 10 | 5 | 5 | 5 |
| C | 100 | 50 | 25 | |
| D | 200 | 100 | 50 | |
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| Notes: The types of monitoring methods listed in Table 6 are examples. Other methods may be used if they provide information throughout the entire critical process where the product may be contaminated (for example, aseptic line set-up, aseptic processing, filling and lyophilizer loading). 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 correlate them to cfu. | ||||
Microorganisms detected in grade A and B areas should be identified to species level. The potential impact of such microorganisms on product quality (for each batch implicated) and overall state of control should be evaluated. Microorganisms detected in grade C and D areas should also be identified, for example:
- where action limits or alert levels are exceeded
- following the isolation of organisms that may:
- indicate a loss of control, deterioration in cleanliness
- be difficult to control such as spore-forming microorganisms and molds
- be at a sufficient frequency to maintain a current understanding of the typical flora of these areas
Aseptic process simulation (APS) (also known as media fill)
Periodic verification of the effectiveness of the controls in place for aseptic processing should include an APS using a sterile nutrient media and/or surrogate in place of the product. The APS should not be the primary means to validate the aseptic process or aspects of the aseptic process. The effectiveness of the aseptic process should be determined through process design, adherence to pharmaceutical quality system and process controls, training and evaluation of monitoring data. Selection of an appropriate nutrient media and/or surrogate should be made based on the ability of the media and/or surrogate to imitate physical product characteristics that pose a risk to product sterility during the aseptic process.
Where processing stages may indirectly impact the viability of any introduced microbial contamination (for example, aseptically produced semi-solids, powders, solid materials, microspheres, liposomes and other formulations where product is cooled or heated or lyophilized), alternative procedures that represent the operations as closely as possible should be developed. Where surrogate materials, such as buffers, are used in parts of the APS, the surrogate material should not inhibit the growth of any potential contamination.
The APS should imitate as closely as possible the routine aseptic manufacturing process and include all the critical manufacturing steps.
- The APS should assess all aseptic operations performed subsequent to the sterilization and decontamination cycles of materials used in the process to the point where the container is sealed.
- For non-filterable formulations, any additional aseptic steps should be assessed.
- Where aseptic manufacturing is performed under an inert atmosphere, the inert gas should be substituted with air in the process simulation unless anaerobic simulation is intended.
- Processes requiring the addition of sterile powders should use an acceptable surrogate material in the same containers as those used in the process under evaluation.
- Separate simulations of individual unit operations (for example, processes involving drying, blending, milling and subdividing a sterile powder) should be avoided. Any use of individual simulations should be supported by a documented justification, and ensure that the individual simulations combined continue to fully cover the whole process.
- The process simulation procedure for lyophilized products should represent the entire aseptic processing chain, including filling, transport, loading, a representative duration of the chamber dwell, unloading and sealing. The lyophilization process simulation should be conducted under specified, documented and justified conditions representing worst-case operating parameters.
- The lyophilization process simulation should mimic all aspects of the process, except those that may affect the viability or recovery of contaminants. For instance, boiling-over or actual freezing of the solution should be avoided. Factors to consider in determining APS design include, where applicable:
- using air to break vacuum instead of nitrogen or other process gases
- replicating the maximum interval between sterilization of the lyophilizer and its use
- replicating the maximum period of time between filtration and lyophilization
- considering quantitative aspects of worst-case situations (for example, loading the largest number of trays, replicating the longest duration of loading where the chamber is open to the environment)
The APS should consider various aseptic manipulations and interventions known to occur during normal production as well as worst-case situations.
- Inherent and corrective interventions representing the routine process should be performed in a manner and frequency similar to that during the routine aseptic process.
- The inclusion and frequency of interventions in the APS should be based on assessed risks posed to product sterility.
The APS should not be used to justify practices that pose unnecessary contamination risks.
In developing the APS plan, the manufacturer should consider:
- identifying worst-case conditions covering the relevant variables, such as container size and line speed, and their impact on the process
- the outcome of the assessment should justify the variables selected
- determining the representative sizes of container/closure combinations to be used for validation
- bracketing or matrix approach may be considered for validating the same container/closure configuration for different products where process equivalence is scientifically justified
- determining maximum permitted holding times for sterile product and equipment exposed during the aseptic process
- ensuring that the volume filled per container should be sufficient to ensure that the media contacts all equipment and component surfaces that may directly contaminate the sterile drug
- the volume used should provide sufficient headspace to support potential microbial growth and ensure that turbidity can be detected during inspection
- requiring that air substitute any inert gas used in the routine aseptic manufacturing process unless anaerobic simulation is intended
- consider including occasional anaerobic simulations as part of the overall validation strategy
- refer to the information on aseptic manufacturing performed under an inert atmosphere
- consider including occasional anaerobic simulations as part of the overall validation strategy
- ensuring that the selected nutrient media are capable of growing a designated group of reference microorganisms as described by the relevant pharmacopeia and suitably representative local isolates
- providing scientific justification for the method used to detect microbial contamination to ensure that contamination is reliably detected
- ensuring the process simulation is of sufficient duration to challenge the process, the operators that perform interventions, shift changes and the capability of the processing environment to provide appropriate conditions for the manufacture of a sterile drug
- ensuring that where the manufacturer operates different or extended shifts, the APS is designed to capture factors specific to those shifts that are assessed to pose a risk to product sterility
- for example, the maximum length of time an operator may be present in the cleanroom
- simulating normal aseptic manufacturing interruptions where the process is idle
- for example, shift changeovers, recharging dispensing vessels, introducing additional equipment
- ensuring that environmental monitoring is conducted as required for routine production and throughout the entire duration of the process simulation
- ensuring that where campaign manufacturing occurs, such as in the use of barrier technologies or manufacture of sterile active substances, consideration is given to designing and performing the process simulation so that it simulates the risks associated with the beginning and the end of the campaign
- demonstrating that the campaign duration does not pose any risk
- The performance of "end of production or campaign APS" may be used as additional assurance or investigative purposes. However, their use should be justified in the CCS and should not replace routine APS.
- If used, it should be demonstrated that any residual product does not negatively impact the recovery of any potential microbial contamination.
For sterile active substances, batch size should be large enough to represent routine operation, simulate intervention operation at the worst case and cover all surfaces that may come into contact with the sterile drug. All the simulated materials (surrogates or growth medium) should also be subjected to microbial evaluation. The simulation materials should be sufficient to satisfy the evaluation of the process being simulated and should not compromise the recovery of micro-organisms.
APS should be performed as part of the initial validation. There should be at least 3 consecutive satisfactory simulation tests that cover all working shifts that the aseptic process may occur in. These tests should also be performed right after operational practices, facilities, services or equipment that are assessed to have an impact on the sterility assurance of the product have been significantly modified. Examples include:
- modifications to the HVAC system or to equipment
- changes to process, number of shifts and personnel
- a major facility shut-down
Normally, APS (periodic revalidation) should be repeated twice a year (about every 6 months) for each aseptic process, each filling line and each shift. Each operator should participate in at least one successful APS annually. An APS should be performed after the last batch before shut-down, before long periods of inactivity or before a line is decommissioned or relocated.
Where manual operation (for example, aseptic compounding or filling) occurs, each type of container, container closure and equipment train should be initially validated, with each operator participating in at least 3 consecutive successful APS. They should be revalidated with 1 APS about every 6 months for each operator. The APS batch size should mimic that used in the routine aseptic manufacturing process.
The number of units processed (filled) for APS should be sufficient to effectively simulate all activities that represent the aseptic manufacturing process. The number of units to be filled should be justified in the CCS. Typically, a minimum of 5,000 to 10,000 units are filled. For small batches (those under 5,000 units), the number of containers for APS should at least equal the size of the production batch.
Filled APS units should be agitated, swirled or inverted before incubation to ensure contact of the media with all interior surfaces in the container. All integral units from the APS should be incubated and evaluated, including units with cosmetic defects or those that have gone through non-destructive in-process control checks. Units that are discarded during the process simulation and not incubated should be comparable to units discarded during a routine fill, and only if production SOPs clearly specify that units must be removed under the same circumstances (for example, type of intervention, line location, specific number of units removed).
In no case should more units be removed during a media fill intervention than would be cleared during a production run. Examples may include those that must be discarded during routine production after the set-up process or following a specific type of intervention. To fully understand the process and assess contamination risks during aseptic setup or mandatory line clearances, these units would usually be incubated separately. They would not necessarily be included in the acceptance criteria for the APS.
Where processes include materials that contact the product contact surfaces but are then discarded (for example, product flushes), the discarded material should be simulated with nutrient media and incubated as part of the APS, unless it can be shown that this waste process does not impact the sterility of the product.
Filled APS units should be incubated in a clear container to ensure visual detection of microbial growth. For product containers that are not clear (amber glass, opaque plastic), clear containers of identical configuration may be substituted to help detect contamination. If a clear container of identical configuration cannot be used as a substitute, a suitable method for detecting microbial growth should be developed and validated. Microorganisms isolated from contaminated units should be identified to the species level when practical, to help determine the likely source of the contaminant.
Filled APS units should be incubated without unnecessary delay to achieve the best possible recovery of potential contamination. The selection (and duration) of the incubation conditions should be scientifically justified and validated to provide an appropriate level of sensitivity for detecting microbial contamination.
When incubation is completed:
- Filled APS units should be inspected by personnel who have been appropriately trained and qualified to detect microbiological contamination. Inspection should be conducted under conditions that facilitate the identification of any microbial contamination.
- Samples of the filled units should undergo positive control by inoculation with a suitable range of reference organisms and suitably representative local isolates.
The target should be zero growth. Any contaminated unit should result in a failed APS and the following actions taken:
- an investigation to determine the most probable root cause(s)
- determination and implementation of appropriate corrective measures
- a sufficient number of successful, consecutive repeat APS (a minimum of 3) to demonstrate that the process has been returned to a state of control
- a prompt review of all appropriate records on aseptic production since the last successful APS:
- The outcome of the review should include a risk assessment of potential sterile breaches in batches manufactured since the last successful APS.
- All other batches not released to the market should be included in the scope of the investigation.
- Any decision on their release status should consider the investigation outcome.
- the quarantine of all products that have been manufactured on a line subsequent to a process simulation failure until the process simulation failure has been successfully resolved
- actions taken to limit the operator's activities, until the person has been retrained and requalified, where theroot cause investigation has determined that the failure was related to operator activity
- production to resume only after revalidation has been completed successfully
All APS runs should be fully documented and include a reconciliation of units processed (for example, units filled, incubated and not incubated). Justification for filled and non-incubated units should be included in the documentation. All interventions performed during the APS should be recorded, including the start and end time of each intervention and the person involved. All microbial monitoring data as well as other testing data should be recorded in the APS batch record.
An APS run should be aborted only when written procedures require commercial lots to be handled in the same way. In such cases, an investigation should be documented.
An aseptic process should have to undergo a repeat of the initial validation when:
- the specific aseptic process has not been in operation for an extended period of time
- a change to the process, equipment, procedures or environment that has the potential to affect the aseptic process
- new product containers or container-closure combinations have been added
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