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Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119): Production and specific technologies

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Terminally sterilized products

Components and materials should be prepared in at least a grade D cleanroom to limit the risk of microbial, endotoxin/pyrogen and particle contamination, and render the product suitable for sterilization. A product that is at a high or unusual risk of microbial contamination (for example, actively supports microbial growth, must be held for long periods before filling, is not processed mostly in closed vessels,) should be prepared in at least a grade C environment. Ointments, creams, suspensions and emulsions should be prepared in at least a grade C environment before terminal sterilization.

For guidance on terminally sterilized drugs, please consult:

Primary packaging containers and components should be cleaned using validated processes to ensure that particle, endotoxin/pyrogen and bioburden contamination is appropriately controlled.

Products for terminal sterilization should be filled in at least a grade C environment.

The CCS may identify that the product is at an unusual risk of contamination from the environment. For example, if the filling operation is slow, or the containers have wide necks or are necessarily exposed for more than a few seconds before closing, the product should be filled in grade A with at least a grade C background.

Processing the bulk solution should include a filtration step with a microorganism-retaining filter, where possible, to reduce bioburden levels and particles before filling into the final product containers. There should be a maximum permissible time between preparation and filling.

Examples of operations to be carried out in the various grades are given in Table 3.

Table 3: Examples of operations and grades for terminally sterilized preparation and processing operations
Grade Examples of operations for terminally sterilized products
A filling products, when unusually at risk
C preparing solutions, when unusually at risk filling products
D preparing solutions and components for subsequent filling

Aseptic preparation and processing

The aseptic process should be clearly defined. The risks associated with the aseptic process, and any associated requirements, should be identified, assessed and appropriately controlled.

The site's contamination control strategy (CCS) should clearly define the:

Methods and procedures to control these risks should be described and implemented. Accepted residual risks should be formally documented.

Precautions to minimize microbial, endotoxin/pyrogenic and particle contamination should be taken, as per the site's CCS:

The presence of materials liable to generate particles and fibres should be minimized in cleanrooms.

Where possible, equipment such as restricted access barriers systems (RABS), isolators or other systems should be used to reduce the need for critical interventions into grade A and to minimize the risk of contamination. Robotics and automated processes (for example, dry heat tunnel, automated lyophilizer loading, sterilization in place) can also be considered to eliminate direct human critical interventions.

Examples of operations to be carried out in the various environmental grades are given in Table 4.

Table 4: Examples of operations and grades for aseptic preparation and processing operations
Grade Examples
A
  • aseptic assembly of filling equipment
  • connections made under aseptic conditions (where sterilized product contact surfaces are exposed) that are post the final sterilizing grade filter (these connections should be sterilized by steam-in-place whenever possible)
  • aseptic compounding and mixing
  • replenishing sterile bulk product, containers and closures
  • removing and cooling unprotected (for example, with no packaging) items from sterilizers
  • staging and conveying sterile primary packaging components in the aseptic filling line while not wrapped
  • aseptic filling, sealing containers such as ampoules, vial closure, transferring open or partially stoppered vials
  • loading of a lyophilizer
B
  • background support for grade A (when not in an isolator)
  • conveying or staging, while protected from the surrounding environment, of equipment, components and ancillary items for introduction into grade A
C
  • preparing solutions to be filtered, including sampling and dispensing
D
  • cleaning equipment
  • handling components, equipment and accessories after cleaning
  • assembling under HEPA-filtered airflow of cleaned components, equipment and accessories before sterilization
  • assembling closed and sterilized single-use systems (SUS) using intrinsic sterile connection devices

For sterile drugs where the final formulation cannot be filtered, the following should be considered:

Unwrapping, assembling and preparing sterilized equipment, components and ancillary items with direct or indirect product contact should be:

This also applies to the filling line set-up and filling of the sterile drug. Where an isolator is used, the background should be in accordance with the information on background environment in the section on Barrier technologies.

Preparing and filling sterile drugs such as ointments, creams, suspensions and emulsions should be performed in grade A with a grade B background when the:

Where an isolator or RABS is used, the background should be in accordance with the information on background environment in the section on Barrier technologies.

Aseptic connections should be performed in grade A with a grade B background unless subsequently sterilized in place or conducted with intrinsic sterile connection devices that minimize any potential contamination from the immediate environment. Intrinsic sterile connection devices should be designed to mitigate the risk of contamination.

Where an isolator is used, the background should be in accordance with the paragraph on background environment in the section on Barrier technologies. Aseptic connections should be appropriately assessed and their effectiveness verified. For requirements regarding intrinsic sterile connection devices, refer to the section on Closed systems.

Aseptic manipulations (including non-intrinsic sterile connection devices) should be minimized through the use of engineering design solutions such as preassembled and sterilized equipment. Whenever feasible, product contact piping and equipment should be pre-assembled and then sterilized in place.

There should be an authorized list of allowed and qualified interventions, both inherent and corrective, that may occur during production (refer to the general information in the Aseptic process simulation (APS) (also known as media fill section). Interventions should be carefully designed to effectively minimize the risk of contamination to the environment, process and product. When designing interventions, consider any impact on air-flows and critical surfaces and products. Engineering solutions should be used whenever possible to minimize incursion by operators during the intervention. Aseptic technique should be observed at all times, including the appropriate use of sterile tools for manipulations.

Procedures listing the types of inherent and corrective interventions, and how to perform them, should be first evaluated via risk management and APS and be kept up to date. Non-qualified interventions should only be used in exceptional circumstances, with consideration given to the risks associated with the intervention and with the quality unit's authorization. The details of the intervention conducted should be subject to risk assessment, recorded and fully investigated under the manufacturer's pharmaceutical quality system (PQS). Non-qualified interventions should be thoroughly assessed by the quality department and considered during batch disposition.

Interventions and stoppages should be recorded in the batch record. Each line stoppage or intervention should be sufficiently documented in batch records. The associated time, duration of the event and operators involved should be noted in batch records. Refer to the general information in the Aseptic process simulation (APS) (also known as media fill section).

The duration of each aspect of aseptic preparation and processing should be minimized, with a maximum time defined and validated. Include the following:

Personnel with specific expertise in aseptic processing should observe aseptic operations (including APS) on a regular basis. They should verify the correct performance of operations, including operator behaviour in the cleanroom, and address any inappropriate practices they may detect.

Finishing of sterile drugs

Open primary packaging containers should be maintained under grade A conditions with the appropriate background for the technology (refer to the information on background environment in the section on Barrier technologies). For partially stoppered vials or prefilled syringes, refer to the section on Lyophilization).

Final containers should be closed following appropriately validated methods.

Where final containers are closed by fusion (for example, Blow-Fill-Seal (BFS), Form-Fill-Seal (FFS), small- and large-volume parenteral (SVP and LVP) bags, glass or plastic ampoules), the critical parameters and variables that affect seal integrity should be evaluated, determined, effectively controlled and monitored during operations. Glass ampoules, BFS units and small volume containers (≤100 ml) closed by fusion should be subject to 100% integrity testing using validated methods. For large-volume containers (>100 ml) closed by fusion, reduced sampling may be acceptable if scientifically justified and should be based on data that demonstrates the consistency of the existing process and a high level of process control. Visual inspection is not an acceptable integrity test method.

Samples of products using systems other than fusion should be taken and checked for integrity using validated methods. The frequency of testing should be based on the knowledge and experience of the container and closure systems being used. A scientifically justified sampling plan should be used. Sample size should be based on information such as supplier management, packaging component specifications and process knowledge.

Containers sealed under vacuum should be tested to ensure the vacuum is maintained after an appropriate pre-determined period prior to certification/release and during shelf life.

When validating the integrity of the container closure, any transportation or shipping requirements that may negatively impact that integrity (for example, decompression or extreme temperatures) should be considered.

Where the equipment used to crimp vial caps can generate large quantities of non-viable particle, measures to prevent particle contamination should be taken. Measures could include locating the equipment at a separate station that is equipped with adequate air extraction.

Vial capping of aseptically filled products can be undertaken as an aseptic process using sterilized caps or as a clean process outside the aseptic processing area. If choosing the latter approach, vials should be protected by grade A conditions up to the point of leaving the aseptic processing area, and then stoppered vials should be protected with a grade A air supply until the cap has been crimped. The supporting background environment of grade A air supply should meet at least grade D requirements. Manual capping should be performed under grade A conditions either in an appropriately designed isolator or in grade A with a grade B background.

Where capping of an aseptically filled sterile drug is conducted as a clean process with grade A air supply protection, vials with missing or displaced stoppers should be rejected prior to capping. Appropriately qualified, automated methods for stopper height detection should be in place.

Where human intervention is required at the capping station, appropriate technological and organizational measures should be used to prevent direct contact with the vials and to minimize contamination. RABS and isolators may be beneficial in assuring the required conditions.

All filled containers of parenteral products should be inspected individually for extraneous contamination or other defects. Defect classification and criticality should be determined during qualification and based on risk and historical knowledge. Factors to consider include the potential impact of the defect to the patient and the route of administration.

Different defect types should be categorized and batch performance analyzed. Batches with unusual levels of defects, when compared with routine defect numbers for the process (based on routine and trend data), should be investigated. A defect library that captures all known classes of defects should be generated and maintained. The defect library should be used for training production and quality assurance personnel.

There should be no critical defects during subsequent sampling and inspection of acceptable containers. Any critical defect identified subsequently should trigger an investigation, as this would indicate a possible failure of the original inspection process.

Manual inspections should be conducted under suitable and controlled conditions of illumination and background. Inspection rates should be appropriately controlled and qualified. Operators performing the inspection should undergo visual inspection qualification (and wear corrective lenses if these are normally worn) at least once a year. The qualification should be undertaken using appropriate samples from the manufacturer's defect library sets. Qualification should also take into consideration worst-case scenarios (for example, inspection time, line speed where the product is transferred to the operator by a conveyor system, container size or fatigue) as well as eyesight checks. Operator distractions should be minimized and there should be frequent breaks, of an appropriate duration.

Automated inspection process should be validated for its ability to detect known defects (which may impact product quality or safety) and be as good as or better than manual inspection methods. The performance of the equipment should be challenged using representative defects before start-up and at regular intervals throughout the batch.

Inspection results should be recorded and trends noted for defect types and numbers. Reject levels for the various defect types should also be trended based on statistical principles. The impact to the product on the market should be assessed as part of the investigation when adverse trends are observed.

Sterilization

Where possible, the finished product should be terminally sterilized, using a validated and controlled sterilization process. This provides a greater assurance of sterility than a validated and controlled sterile filtration process and/or aseptic processing. Where it's not possible for a product to undergo terminal sterilization, consideration should be given to using post-aseptic processing terminal heat treatment, combined with aseptic process to give improved sterility assurance.

The selection, design and location of the equipment and cycle/program used for sterilization should be based on scientific principles and data that demonstrate repeatability and reliability of the sterilization process. All parameters should be defined and, where critical, should be controlled, monitored and recorded.

All sterilization processes should be validated. Validation studies should consider the product composition, storage conditions and maximum time between when a product or material is being prepared to be sterilized and the start of sterilization.

The sterilization process should be validated for its suitability for the product and equipment, and its efficacy in consistently achieving the desired sterilizing conditions in all parts of each type of load to be processed. Validation should be done using physical measurements and biological indicators (BI) where appropriate. For effective sterilization, the entire product and the surfaces of equipment and components should be subject to the required treatment and the process should be designed to ensure that this is achieved.

Particular attention should be given when the adopted product sterilization method is not described in the current edition of the Pharmacopoeia or is used for a product that is not a simple aqueous solution. Where possible, heat sterilization is the method of choice.

Validated loading patterns should be established for all sterilization processes and load patterns should be re-validated periodically. Maximum and minimum loads should also be considered as part of the overall load validation strategy.

The validity of the sterilizing process should be reviewed and verified at scheduled intervals based on risk. Heat sterilization cycles should be re-validated at least once a year for load patterns that are considered worst-case. Other load patterns should be validated at a frequency justified in the CCS.

Routine operating parameters should be established and adhered to for all sterilization processes (for example, physical parameters and loading patterns).

Mechanisms should be in place to detect a sterilization cycle that does not conform to the validated parameters. Any failed sterilization or one that deviated from the validated process (longer or shorter phases such as heating cycles, for example) should be investigated.

Suitable BIs placed at appropriate locations should be considered as an additional method to support the validation of the sterilization process. BIs should be stored and used according to the manufacturer's instructions. Where BIs are used to support validation and/or to monitor a sterilization process (for example, with ethylene oxide), positive controls should be tested for each sterilization cycle. If BIs are used, strict precautions should be taken to avoid transferring microbial contamination to the manufacturing or other testing processes. BI results in isolation should not be used to override other critical parameters and process design elements.

The reliability of BIs is important. Suppliers should be qualified and transportation and storage conditions should be controlled in order that BI quality is not compromised. Before using a new batch/lot of BIs, the population, purity and identity of the indicator organism of the batch/lot should be verified. For other critical parameters, such as D-value or Z-value, the batch certificate provided by the qualified supplier can normally be used.

There should be a clear means of differentiating products, equipment and components that have not been subjected to the sterilization process from those that have. Equipment such as baskets or trays used to carry products and other items of equipment and/or components should be clearly labelled (or electronically tracked) with the product name, batch number and an indication of whether or not it has been sterilized. Indicators such as autoclave tape or irradiation indicators may be used, where appropriate, to indicate whether a batch (or sub-batch material, component, equipment) has passed through a sterilization process. However, these indicators show only that the sterilization process has occurred. They do not indicate product sterility or where the required sterility assurance level was achieved.

Sterilization records should be available for each sterilization run. Each cycle should have a unique identifier. Their conformity should be reviewed and approved as part of the batch certification/release procedure.

Where required, materials, equipment and components should be sterilized using validated methods appropriate for the specific material. Suitable protection after sterilization should be provided to prevent recontamination. Sterilized items that are not used immediately after sterilization should be stored using appropriately sealed packaging and a maximum hold time should be established.

Where justified, components that are packaged with multiple sterile packaging layers do not need to be stored in a cleanroom if the integrity and configuration of the sterile pack allows the items to be readily disinfected when being transferred by operators into grade A areas (for example, multiple sterile coverings that can be removed at each transfer from lower to higher grade). Where protection is achieved by containment in sealed packaging, this packaging process should be undertaken prior to sterilization.

The transfer of materials, equipment, components and ancillary items that are sterilized in sealed packaging into grade A areas should be done using appropriate validated methods (for example, airlocks or pass-through hatches). The exterior of the sealed packaging should be disinfected as well. The use of rapid transfer port technology should also be considered.

The effectiveness of these methods to control the potential risk of contamination of the grade A and B areas should be demonstrated. Likewise, the effectiveness of the disinfection procedure used to reduce any contamination on the packaging to acceptable levels for entry of the item into the grade A and B areas should be demonstrated.

Where materials, equipment, components and ancillary items are sterilized in sealed packaging or containers, the packaging should be qualified for minimizing the risk of particulate, microbial, endotoxin/pyrogen or chemical contamination, and for compatibility with the selected sterilization method. The packaging sealing process should be validated. The validation should consider the integrity of the sterile protective barrier system, the maximum hold time before sterilization and the maximum shelf life assigned to the sterilized items. The integrity of the sterile protective barrier system for each of the sterilized items should be checked prior to use.

An effective and validated disinfection and transfer process should be in place for materials, equipment, components and ancillary items that are not a direct or indirect product contact part and are necessary for aseptic processing but cannot be sterilized. Once disinfected, these items should be protected to prevent recontamination. These items and others representing potential routes of contamination should be included in the environmental monitoring program.

Sterilization by heat

Each heat sterilization cycle should be recorded using equipment with suitable accuracy and precision (electronical or manual methods). The system should have safeguards and/or redundancy in its control and monitoring instrumentation to detect a cycle that does not meet the validated cycle parameter requirements and thus abort or fail the cycle. An example of a safeguard would be to use duplex/double probes connected to independent control and monitoring systems.

The position of the temperature probes used to control and/or record should be determined during validation. The position should be selected based on system design and to correctly record and represent routine cycle conditions. Validation studies should be designed to demonstrate the suitability of system control and recording probe locations and to verify the function and location of these probes, by using an independent monitoring probe located at the same position used during validation.

The entire load should reach the required temperature before measurement of the sterilizing time-period starts. For sterilization cycles controlled by using a reference probe within the load, specific consideration should be given to ensuring the load probe temperature is controlled within a defined temperature range before the cycle starts.

After the high temperature phase of a heat sterilization cycle is complete, precautions should be taken against contamination of a sterilized load during cooling. Any cooling liquid or gas that comes into contact with the product or sterilized material should be sterilized.

In cases where parametric release has been authorized, a robust system should be applied to the product lifecycle validation and the routine monitoring of the manufacturing process. This system should be periodically reviewed.

For further guidance on parametric release, please consult:

Moist heat sterilization

Moist heat sterilization can be achieved using steam (direct or indirect contact). Other systems such as superheated water systems (cascade or immersion cycles) could be used for containers that may be damaged by other cycle designs (for example, Blow-Fill-Seal containers, plastic bags).

Other than products in sealed containers, items to be sterilized should be dry and packaged in a protective barrier system that allows air to be removed, steam to penetrate and prevents recontamination after sterilization. All loaded items should be dry when they are removed from the sterilizer. Load dryness should be confirmed by visual inspection as a part of the sterilization process acceptance.

For cycles, time, temperature and pressure should be used to monitor the process and be recorded. Each sterilized item that is removed from the autoclave should be inspected for damage, packaging material integrity and moisture. Any item found not to be fit for purpose should be removed from the manufacturing area and an investigation performed.

For autoclaves capable of performing pre-vacuum sterilization cycles, the temperature should be recorded at the chamber drain throughout the sterilization period. Load probes may also be used where appropriate but the controlling system should remain related to the load validation. For steam-in-place systems, the temperature should be recorded at appropriate condensate drain locations throughout the sterilization period.

Validation of cycles should include a calculation of equilibration time, exposure time, correlation of pressure and temperature, and minimum/maximum temperature range during exposure. Validation of fluid cycles should include temperature, time and/or F0. Critical processing parameters should be subject to defined limits (including appropriate tolerances) and be confirmed as part of the sterilization validation and routine cycle acceptance criteria.

Leak tests on the sterilizer should be carried out periodically (normally weekly) when a vacuum phase is part of the cycle or the system is returned, post-sterilization, to a pressure lower than the environment surrounding the sterilizer.

There should be adequate assurance of air removal before and during sterilization when the sterilization process includes air purging (for example, autoclave loads, lyophilizer chambers). For autoclaves, this involves an air removal test cycle (normally performed daily) or use of an air detector system. Loads to be sterilized should be designed to support effective air removal and be free draining to prevent condensation from building up.

Distortion and damage of non-rigid containers that are terminally sterilized, such as containers produced by BFS or FFS technologies, should be prevented through appropriate cycle design and control (for instance, setting correct pressure, heating and cooling rates, and loading patterns).

Steam-in-place systems that are used for sterilization (for example, for fixed pipework, vessels and lyophilizer chambers) should be appropriately designed and validated to assure all parts of the system are subjected to the required treatment. The system should be monitored for temperature, pressure and time at appropriate locations during routine use, to ensure all areas are effectively and reproducibly sterilized. These locations should be demonstrated as being representative of, and correlate with, the slowest-to-heat locations during initial and routine validation. Once a system has been sterilized by steam-in-place, it should remain integral and, where operations require, maintained under positive pressure or otherwise equipped with a sterilizing vent filter prior to use.

For fluids load cycles where superheated water is used to transfer the heat, the heated water should consistently reach all of the required contact points. Initial qualification studies should include temperature mapping of the entire load. The equipment should be checked routinely to ensure that nozzles (where the water is introduced) are not blocked and drains are free of debris.

Validation of the sterilization of fluids loads in a superheated water autoclave should include temperature mapping of the entire load and heat penetration and reproducibility studies. All parts of the load should heat up uniformly and achieve the desired temperature for the specified time. Routine temperature monitoring probes should correlate to the worst-case positions identified during the qualification process.

Dry heat sterilization

Dry heat sterilization uses high temperatures of air or gas to sterilize a product or article. Dry heat sterilization is of particular use in the thermal removal of difficult-to-eliminate thermally robust contaminants such as endotoxin/pyrogen. It is often used in the preparation of components for aseptic filling.

The combination of time and temperature to which product, components or equipment are exposed should produce an adequate and reproducible level of lethality and/or endotoxin/pyrogen inactivation/removal when operated routinely within established limits. The process may be operated in an oven or in a continuous tunnel process (for example, for sterilization and depyrogenation of glass containers).

Dry heat sterilization/depyrogenation tunnels should be configured to ensure that airflow protects the integrity and performance of the grade A sterilizing zone by maintaining appropriate pressure differentials and airflow through the tunnel. Air pressure difference profiles should be assessed. The impact of any airflow change should be assessed to ensure the heating profile is maintained.

All air supplied to the tunnel should pass through at least a HEPA filter. Tests (at least twice a year) should be performed periodically to demonstrate air filter integrity. Any tunnel parts that come into contact with sterilized components should be appropriately sterilized or disinfected.

Critical process parameters that should be considered during validation and/or routine processing should include:

For a thermal process used as part of the depyrogenation process for any component or product contact equipment/material, validation studies should demonstrate that the process provides a suitable Fh value and results in a minimum 3 log10 reduction in endotoxin concentration. When this is attained, there is no additional requirement to demonstrate sterilization in these cases.

Containers spiked with endotoxin should be used during validation and be carefully managed with a full reconciliation performed. Containers should represent the materials normally processed (in terms of the composition of the packaging materials, porosity, dimensions, nominal volume). Endotoxin quantification and recovery efficiency should also be demonstrated.

Dry heat ovens are typically used to sterilize or depyrogenate primary packaging components, starting materials or active substances. They may also be used for other processes. They should be maintained at a positive pressure relative to lower-grade clean areas throughout the sterilization and post-sterilization hold process, unless the integrity of the packaging is maintained. All air entering the oven should pass through a HEPA filter. Critical process parameters that should be considered in qualification and/or routine processing should include:

Sterilization by radiation

Sterilization by radiation is used mainly to sterilize heat-sensitive materials and products. Ultraviolet irradiation is not an acceptable method of sterilization.

For guidance on ionizing radiation sterilization, please consult:

Validation procedures should consider the effects of variation in the density of the product and packages.

Sterilization with ethylene oxide

This method should only be used when no other method is practicable. Process validation should show that:

Direct contact between gas and microbial cells is essential. Precautions should be taken to avoid the presence of organisms, such as crystals or dried protein, in material. The nature, porosity and quantity of packaging materials can significantly affect the process.

Before exposure to the gas, materials should be brought into equilibrium with the humidity and temperature required by the process. Steam used to condition the load for sterilization should be of an appropriate quality. The time required for this should be balanced against the need to minimize the time before sterilization.

Each sterilization cycle should be monitored with suitable BIs, using the appropriate number of test units throughout the load at defined locations that have been shown to be worst-case locations during validation.

Critical process parameters that could be considered as part of the sterilization process validation and routine monitoring include:

After sterilization, the load should be aerated to allow EO gas and/or its reaction products to desorb from the packaged product to predetermined levels. Aeration can occur within a sterilizer chamber, and/or in a separate aeration chamber or aeration room. The aeration phase should be part of the overall EO sterilization process validation.

Filter sterilization of products that cannot be sterilized in their final container

If the product cannot be sterilized in its final container, solutions or liquids should be sterilized by filtration using a sterile sterilizing grade filter (with a nominal pore size of a maximum of 0.22 µm that has been appropriately validated to obtain a sterile filtrate). The product should then be aseptically filled into a previously sterilized container. The filter that is selected/used should be compatible with the product and as described in the marketing authorization.

Suitable bioburden reduction prefilters and/or sterilizing grade filters may be used at multiple points during the manufacturing process to ensure a low and controlled bioburden of the liquid prior to the final sterilizing filter. Due to the potential additional risks of a sterile filtration process, as compared with other sterilization processes, an additional filtration through a sterile sterilizing grade filter, as close to the point of fill as possible, should be considered as part of an overall CCS.

The selection of components for the filtration system and their interconnection and arrangement within the filtration system, including pre-filters, should be based on the critical quality attributes of the product, justified and documented. The filtration system should minimize the generation of fibres and particles, not cause or contribute to unacceptable levels of impurities or otherwise not alter the product's quality and efficacy. Similarly, the filter characteristics should be compatible with the fluid and not be adversely affected by the product being filtered. Adsorption of product components and extraction/leaching of filter components should be evaluated.

The filtration system should be designed to:

Sterile filtration of liquids should be validated in accordance with relevant Pharmacopeia requirements. Validation can be grouped by different strengths or variations of a product but should be done under worst-case conditions. The rationale for grouping should be justified and documented.

During filter validation, the product to be filtered should be used for bacterial retention testing of the sterilizing grade filter, wherever possible. Where the product to be filtered is not suitable for use in bacterial retention testing, a suitable surrogate product should be justified for use in the test. The challenge organism used in the bacterial retention test should be justified.

Filtration parameters that should be considered and established during validation should include:

Routine process controls should be implemented to ensure adherence to validated filtration parameters. Results of critical process parameters should be included in the batch record, including the minimum time taken to filter a known volume of bulk solution and pressure difference across the filter. Any significant difference from critical parameters during manufacturing should be documented and investigated.

The integrity of the sterilized filter assembly should be verified by integrity testing before use (pre-use post sterilization integrity test or PUPSIT), to check for damage and loss of integrity caused by the filter preparation prior to use. A sterilizing grade filter that is used to sterilize a fluid should undergo a non-destructive integrity test post-use before the filter is removed from its housing.

The integrity test process should be validated and test results should correlate to the microbial retention capability of the filter established during validation. Examples of tests include bubble point, diffusive flow, water intrusion and pressure hold.

PUPSIT may not always be possible after sterilization due to process constraints (for example, the filtration of very small volumes of solution). In these cases, an alternative approach may be taken providing that there has been a thorough risk assessment performed and compliance has been achieved by implementing appropriate controls to mitigate any risk of a non-integral filtration system.

Points to consider in such a risk assessment should include:

The integrity of critical sterile gas and air vent filters (that are directly linked to the sterility of the product) should be verified by testing after use, with the filter remaining in the filter assembly or housing.

The integrity of non-critical air or gas vent filters should be confirmed and recorded at appropriate intervals. Where gas filters are in place for extended periods, integrity testing should be carried out at installation and before replacement. The maximum duration of use should be specified and monitored based on risk (for example, considering the maximum number of uses and heat treatment/sterilization cycles permitted, as applicable).

For gas filtration, unintended moistening or wetting of the filter or filter equipment should be avoided.

If the sterilizing filtration process has been validated as a system consisting of multiple filters to achieve the sterility for a given fluid, the filtration system is considered to be a single sterilizing unit. All filters within the system should satisfactorily pass integrity testing after use.

In a redundant filtration system (where a second redundant sterilizing grade filter is present as a backup but the sterilizing process is validated as only requiring 1 filter), a post-use integrity test of the primary sterilizing grade filter should be performed. If the filter is demonstrated to be integral, then a post-use integrity test of the redundant (backup) filter is not necessary. However, in the primary filter has failed, a post-use integrity test on the secondary (redundant) filter should be performed. This should be performed, along with an investigation and risk assessment to determine the reason for the primary filter test failure.

Bioburden samples should be taken from the bulk product and immediately before the final sterile filtration. If a redundant filtration set-up is used, the samples should be taken before the first filter. Systems for taking samples should be designed so as not to introduce contamination.

Liquid sterilizing grade filters should be discarded after the processing of a single batch. The same filter should not be used continuously for more than 1 working day unless such use has been validated.

Where campaign manufacture of a product has been appropriately justified in the CCS and validated, the filter user should:

Form-Fill-Seal (FFS)

The conditions for FFS machines used for terminally sterilized products and in aseptic manufacture should comply with the environmental requirements of this annex as follows:

Contamination of the packaging films used in the FFS process should be minimized by appropriate controls during component fabrication, supply and handling. As packaging films are critical, procedures should be implemented to ensure the films that are supplied meet defined specifications and are of the appropriate quality, including material thickness and strength, microbial and particulate contamination, integrity and artwork, as relevant. The sampling frequency, the bioburden and, where applicable, endotoxin/pyrogen levels of packaging films and associated components should be defined and controlled within the PQS and considered in the CCS.

Particular attention should be given to understanding and assessing the operation of the equipment, including set-up, filling, sealing and cutting processes. It is important that critical process parameters are understood, validated, controlled and monitored appropriately.

Any product contact gases (for example, those used to inflate the container or used as a product overlay) must be appropriately filtered. This should be done close to when they will be used. The quality of the gases used and the effectiveness of gas filtration systems should be verified periodically in accordance with:

The controls identified during qualification of FFS should align with the CCS. Aspects to be considered include:

Critical process parameters for FFS should be determined during equipment qualification and include:

There should be appropriate procedures for verifying, monitoring and recording FFS critical process parameters and equipment operation during production.

Operational procedures should describe how forming and sealing issues are detected and rectified. Rejected units or sealing issues should be recorded and investigated.

Appropriate maintenance procedures should be established based on risk and include maintenance and inspection plans for tooling critical to the effectiveness of unit sealing. Any issues identified that indicate a potential product quality concern should be documented and investigated.

Blow-Fill-Seal

Blow-Fill-Seal equipment used for the manufacture of products that are terminally sterilized should be installed in at least a grade D environment. The conditions at the point of fill should comply with the following environmental requirements:

BFS used for aseptic processing:

Due to the generation of particles from polymer extrusion, cutting during operation and the restrictive size of critical filling zones of BFS equipment, in-operation monitoring of total particle for BFS equipment is not expected. However, data should be available to demonstrate that the design of the equipment ensures that critical zones of the filling process environment would meet grade A conditions in operation.

Viable environmental monitoring of BFS processes should be risk-based and designed in accordance with the requirements set out in the Environmental and process monitoring section. In-operation viable monitoring should be undertaken for the full duration of critical processing, including equipment assembly. For rotary-type BFS equipment, monitoring of the critical filling zone may not be possible.

The environmental control and monitoring program should consider the moving parts and complex airflow paths generated by the BFS process and the effect of the high heat outputs of the process (for example, through airflow visualization studies and/or other equivalent studies). Environmental monitoring programs should also consider factors such as the configuration and integrity of air filters, the integrity of cooling systems and equipment design and qualification. Refer to the heating and cooling and hydraulic systems section.

Air or other gases that come into contact with critical surfaces of the container during extrusion, formation or sealing of the moulded container should undergo appropriate filtration. The quality of gas used and the effectiveness of gas filtration systems should be verified periodically in accordance with:

Appropriate design, control and maintenance of the polymer granulate storage, sampling and distribution systems should prevent particulate and microbial contamination of the polymer granulate.

The capability of the extrusion system to provide appropriate sterility assurance for the moulded container should be understood and validated. The sampling frequency, the bioburden and, where applicable, the endotoxin/pyrogen levels of the raw polymer should be defined and controlled within the PQS and considered in the CCS.

Interventions requiring cessation of filling and/or extrusion, moulding and sealing and, where required, re-sterilization of the filling machine should be clearly defined. These interventions should also be described in the filling procedure and included in the APS as relevant. Refer to the information in the Aseptic process simulation (APS) (also known as media fill) section related to the following:

The controls identified during qualification of BFS should align with the site's CCS. Aspects to consider include:

Critical process parameters for BFS should be determined during equipment qualification and include:

Appropriate procedures for verifying, monitoring and recording BFS critical process parameters and equipment operation should be applied during production.

Operational procedures should describe how blowing, forming and sealing issues are detected and rectified. Rejected units or sealing issues should be recorded and investigated.

Where the BFS process includes adding components to moulded containers (for example, caps added to LVP bottles), the components should be appropriately decontaminated and added to the process using a clean, controlled process.

Appropriate maintenance procedures should be established based on risk and include maintenance and inspection plans for items critical to unit sealing, integrity and sterility.

The moulds used to form containers are considered critical equipment. Any changes or modification to moulds should result in an assessment of the integrity of the finished product container, and where assessment indicates, be validated. Any issues identified that indicate a potential product quality concern should be documented and investigated.

Lyophilization

Lyophilization is a critical process step. Activities that can affect the sterility of the product or material need to be regarded as extensions of the aseptic processing of the sterilized product. The lyophilization equipment and its processes should be designed to maintain product or material sterility during lyophilization. This is done by preventing microbial and particle contamination between when the products are filled for lyophilization and the lyophilization process is complete. All control measures in place should be determined by the site's CCS.

The sterilization of the lyophilizer and associated equipment (for example, trays, vial support rings) should be validated and the holding time between the sterilization cycle and use should be appropriately challenged during APS. Refer to the information in the Aseptic process simulation section. The lyophilizer should be sterilized regularly, based on system design. Re-sterilization should be performed following maintenance or cleaning. Sterilized lyophilizers and associated equipment should be protected from contamination after sterilization.

Lyophilizers and associated product transfer and loading/unloading areas should be designed to minimize operator intervention as much as possible. The frequency of lyophilizer sterilization should be determined based on the design and risks related to system contamination during use. Lyophilizers that are manually loaded or unloaded with no barrier technology separation should be sterilized before each load. For lyophilizers loaded and unloaded by automated systems or protected by closed barrier systems, the frequency of sterilization should be justified and documented as part of the CCS.

The integrity of the lyophilizer should be maintained following sterilization and during lyophilization. The filter used to maintain lyophilizer integrity should be sterilized before each time the system is used and the results of integrity testing should be part of the batch certification/release. The frequency of vacuum/leak integrity testing of the chamber should be documented. The maximum permitted leakage of air into the lyophilizer should be specified and checked at the start of every cycle.

Lyophilization trays should be checked regularly to ensure that they are not misshapen or damaged.

Points to consider for the design of loading (and unloading, where the lyophilized material is still unsealed and exposed) include the following:

Closed systems

Closed systems can reduce the risk of microbial, particle and chemical contamination from the adjacent environment. Closed systems should always be designed to reduce the need for manual manipulations and associated risks.

It is critical to ensure the sterility of all product contact surfaces of closed systems used for aseptic processing. The design and selection of any closed system used for aseptic processing should ensure sterility is maintained. Connection of sterile equipment (for example, tubing/pipework) to the sterilized product pathway after the final sterilizing grade filter should be designed to be connected aseptically (for example, by intrinsic sterile connection devices).

Appropriate measures should be in place to ensure the integrity of components used in aseptic connections. The means by which this is achieved should be determined and captured in the CCS. Appropriate system integrity tests should be considered when there is a risk of compromising product sterility. Supplier assessment should include the collation of data in relation to potential failure modes that may lead to a loss of system sterility.

The background environment in which closed systems are located should be based on their design and the processes undertaken. For aseptic processing and where there are any risks that system integrity may be compromised, the system should be located in a grade A area. If it can be shown that the integrity of the system is maintained at every usage (for example, via pressure testing and/or monitoring), a lower classified area may be used. Any transfer between classified areas should be thoroughly assessed (refer to the section on Premises). If the closed system is opened (for example, for maintenance of a bulk manufacturing line), then this should be either:

Single-use systems (SUS)

Single-use systems (SUS) are used in the manufacture of sterile drugs as an alternative to reusable equipment. SUS can be individual components or made up of multiple components such as bags, filters, tubing, connectors, valves, storage bottles and sensors. Single-use systems should be designed to reduce the need for manipulations and complexity of manual interventions.

Specific risks associated with SUS should be assessed as part of the CCS. These risks include:

Sterilization processes for SUS should be validated and shown to have no adverse impact on system performance.

Assessment of suppliers of disposable systems including sterilization is critical to the selection and use of these systems. For sterile SUS, sterility assurance should be verified as part of the supplier qualification, and evidence of sterilization of each unit should be checked on receipt.

The adsorption and reactivity of the product with product contact surfaces should be evaluated under process conditions.

The extractable and leachable profiles of the SUS and any impact on the quality of the product, especially where the system is made from polymer-based materials, should be evaluated. Each component should be assessed to evaluate the applicability of the extractable profile data. For components considered to be at high risk from leachables, including those that may absorb processed materials or those with extended material contact times, an assessment of leachable profile studies, including safety concerns, should be considered. Simulated processing conditions should accurately reflect the actual processing conditions and be based on a scientific rationale.

SUS should be designed to maintain integrity throughout processing under the intended operational conditions. Attention to the structural integrity of the single use components is necessary where these may be exposed to more extreme conditions (such as freezing and thawing processes) either during routine processing or transportation. The integrity of intrinsic sterile connection devices (both heat-sealed and mechanically sealed) should be verified under these conditions.

Acceptance criteria should be established and implemented for SUS and correspond to the risks or criticality of a product and its processes. On receipt, each piece of SUS should be checked to ensure it has been manufactured, supplied and delivered in accordance with the approved specification. The outer packaging (exterior carton, product pouches) and label should be visually inspected and attached documents (for example, certificate of conformance and proof of sterilization) should be reviewed and documented before the product is used.

Critical manual handling operations of SUS such as assembly and connections should be subject to appropriate controls and verified during APS.

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2025-02-05