Goals
When you have completed this unit, you should be able to:
a. Perform an audit of an aseptic/sterile processing area
b. Access and understand aseptic/sterile manufacturing requirements
c. Understand worldwide regulatory agency requirements for aseptic/sterile processing
d. Use a range of information tools, from the contents of this module to the Intranet in support of an aseptic/sterile processing audit
e. Recognize compliance or non-compliance of areas to regulations pertaining to aseptic/sterile processing requirements.
Definitions
Action levels: established microbial or particle levels that, when exceeded, should trigger an appropriate investigation and corrective action based on the investigation.
Air Lock: a small room with interlocked doors, constructed to maintain air pressure control between adjoining rooms (generally with different air cleanliness standards). The intent of an air lock is to preclude ingress of particulate matter and microorganism contamination from a lesser controlled area.
Alert levels: established static and operational microbial or particulate levels giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which require follow-up investigation.
Alert levels (environmental monitoring): established static and operational microbial or particulate levels giving early warning of potential drift from normal operating conditions which are not necessarily grounds for definitive corrective action but which require follow-up investigation.
Alert levels (media fill): an established number of media filled units which indicate the presence of microbial growth (e.g. positive units). The cause of the growth should be investigated, but is not necessarily a reason for definitive corrective action.
Aseptic filling: a process by which the drug or biological product, container, and closure are sterilized separately then assembled under strict environmental conditions.
Bioburden: the total number of microorganisms associated with a specific item prior to sterilization.
Cleanroom: a room designed, maintained, and controlled to prevent particle and microbiological contamination of drug products using high efficiency particulate air filters (HEPA). Air from the filters may either flow down (vertical) or across (horizontal) the surface to be kept clean.
Compounding: a process in which one bulk drug substance is combined with another bulk drug substance and/or one or more excipients to produce a drug product.
Controlled access areas: those facilities, or areas of facilities, which allow only authorized personnel to access. These may be also known as restricted access areas.
Endotoxins: toxic molecules consisting of lipopolysaccharide originating from the outer cell wall of Gram-negative bacteria. Endotoxins may cause fever reactions in humans.
Environmental monitoring program: a defined documented program which describes the routine particulate and microbiological monitoring of processing and manufacturing areas, and includes a corrective action plan when action levels are exceeded. This program provides meaningful information on the quality of the aseptic processing environment when a given batch is being manufactured as well as environmental trends of the manufacturing area. An adequate program identifies potential routes of contamination, allowing for implementation of corrections before contamination occurs.
Grade A: the normal air classification for an aseptic processing area. This classification means that there are not more than 3,500 particles measuring 0.5µm or larger in one cubic meter of air, when measure during activity. Grade A may be considered equivalent ISO class 5 and FDA class 100. Other grades/requirements can be found in the EU-GMP.
High efficiency particulate air (HEPA) filter: high efficiency particulate air filter with a minimum 0.3 micron particle retaining efficiency of 99. 97 percent.
HVAC: heating, ventilation and air conditioning system.
Integrity test: a test to determine the functional performance of a filter or filter system and detect the presence of individual leaks in the filter media, frame, and seal.
Laminar flow (LAF): an airflow moving in a single direction and in parallel layers at a constant velocity from the beginning to the end of a straight-line vector. However, true laminarity is not achievable in clean room applications. “Unidirectional flow” is the more accurate description fro clean room applications and is defined as; an airflow moving in a single direction, in a robust and uniform manner and at sufficient speed to reproducibly sweep particles away from the critical processing or testing areas.
Media fills: a method of evaluating an aseptic process using a microbial growth medium. (Media fills are understood to be synonymous to simulated product fills, broth trials, broth fills etc. The term “process simulation” is sometimes used interchangeably with media fill).
Media growth promotion test: a test performed to demonstrate that microbial growth media will support microbial growth.
Pyrogens: fever producing substances.
Sampling frequency: an established time interval for collecting samples, e.g. once per minute, once per week, once per month, etc.
Shift: scheduled periods of work or production, usually less than 12 hours in length, staffed by alternating groups of workers.
Sterile: free of any viable organisms. (In practice, no such absolute statement regarding the absence of microorganisms can be proven, see sterilization.)
Sterilization: a validated process used to render a product free of viable organisms. Note: In a sterilization process, the nature of microbiological death of reduction is described by an exponential function. Therefore, the number of microorganisms that survive a sterilization process can be expressed in terms of probability. While the probability may be reduced to a very low number, it can never be reduced to zero.
Sterility assurance level (SAL): The SAL of a sterilizing process is the degree of assurance with which the process in question renders a population of items sterile. The SAL for a given process is expressed as the probability of a non-sterile item in that population. An SAL of 10-6 for example, denotes a probability of not more than one viable micro-organism in 1 × 106 sterilized items of the final product. The SAL of a process for a given product is established by appropriate validation studies.
Sterility test: a test performed on a sample of the product lot to determine if viable microorganisms are present.
Unidirectional Air Flow: an airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed, to reproducibly sweep particles away from the critical processing or testing area.
Vent filter: a non-shedding porous material capable of removing viable and non-viable particles from gases passing in and out of a closed vessel.
Explanation of Topic
Sterile products
A number of dosage forms are required to be sterile e.g.to be without viable microorganisms.
Examples of dosage forms required to be sterile are eye-drops, injectables and large volume parenteral. They are required to be sterile to ensure the safety of patients, which includes aspects as route of administration and risks for infections. Sterility cannot however be guaranteed through testing; rather, it is assured through the application of a validated production process.
Medical devices are often required to be sterile and they are put through a terminal sterilization process. It is not the intention of this training module to explicitly cover the manufacture and sterilization of medical devices.
In the manufacture and control of sterile products special attention needs to be paid to eliminate the risks of microbial and particulate contamination. Sterile products, intended for
direct injection into the bloodstream, will bypass the normal body defense mechanisms. Onset of action is rapid and therefore reversal of undesired effects is difficult, or even impossible, to achieve. It is of utmost importance that everyone involved in the manufacture and control of such products keeps focus on the key quality factors and potential hazards to the patient.
Key requirements for sterile products are sterility, apyrogenicy, low particulate counts (Note! Cotton fibers may be more dangerous than glass particles as they can clog capillaries and serve as vectors for microorganisms), chemical and biological purity and container integrity. Patient risks are generally greater for large volume products used for infusion, as the patient will be exposed to very large volumes intravenously.
The best way to assure sterility is to sterilize the product in its final packaging. Such products are often referred to as “terminally sterilized” products. Sterilization is commonly achieved by steam sterilization (autoclaving), dry heat, gamma or electron beam irradiation or ethylene oxide fumigation.
For terminally sterilized as well as aseptically prepared products the same basic principles apply. Challenge to the sterilization step as well as the potential for recontamination of the product once it has been sterilized should be minimized.
In auditing you need to know the product (liquid or powder), whether it is aseptically prepared or terminally sterilized, what the container type is, whether the product is for single/multi-use and preserved/unpreserved. How it will be used must also be considered. Is the product administered as an injectable or infusion directly to the bloodstream, intrathecal (to the spine) or subcutanally? Is it for ophthalmic, topical or inhalation use? What are the indications and the health status of the patients?
Sterile products manufacture
General principles
Common steps in the manufacture of sterile products are preparation of solution, filtration, filling, closure, sterilization if the product is not filled aseptically, container closure integrity testing, visual inspection and labelling. For some products aseptic filling may be followed by freeze drying. Another technique used is blow-fill and seal, where the container is formed, filled and sealed in a sequence in a blow-fill and-seal machine.
Terminally sterilized products
The bulk product is usually formulated by dissolving ingredients in water for injection. The solution is then filtered in order to remove particles and to lower the bioburden (number of microorgansims in the solution). The holding time for the solution must be validated to ensure control of bioburden. The filtered solution is filled into pre-washed containers and sealed to prevent recontamination. Filling and sealing is performed in a clean environment in order to minimize risks for particulate and microbiological contamination. Microbiological contamination levels should be kept to a minimum level of challenge to the sterilization step.
The filled containers are sterilized using a process demonstrated via validations to deliver a
SAL of 10 – 6 or better.
Figure 1: Stainless steel tanks for preparation of solutions
Aseptically produced products
The same formulation principles as for terminally sterilized products apply except that a cleaner environment is utilized. The bulk solution is then filtered both to remove particles and to remove all microorganisms to render the product sterile. The sterile bulk solution is filled into washed, sterilized containers under conditions that minimize the potential for microbial contamination of the product. The environment standards of cleanliness are required to be higher for aseptic manufacturing than for products to be terminally sterilized.
As the actual sterilization step is the filtration step the bioburden must be kept to an absolute minimum and there must be a good understanding of the types of microorganisms present.
Solutions should be protected from contamination and holding times kept to a minimum. The choice of filter must be carefully considered to be compatible with the product and process conditions. Filter validation conditions should be equivalent to ordinary process use. Effective filtration depends on the integrity of the whole system not only on the filter itself.
Regular media fills are performed in order to verify the consistent manufacture of sterile products using the process of choice. The overall microbiological vulnerability of the aseptic manufacturing process is assessed. A nutrient media shown to promote microbial growth replaces product. Media fills should be performed in the same way as ordinary filling, however there may be practical limitations (e.g. powder filling). Filled and sealed containers are incubated to microbial growth (bacterial and fungi over a range of temperatures).
Contaminants, which may have penetrated the integrity of the process and entered into the containers, will then be visible. Incubated containers are inspected for turbidity and the level of contamination is compared with published standards. Media fills are performed as part of the initial validation and thereafter on a regular basis. Each filling line as well as all operators involved needs to be qualified by media fills.
Figure 2: Dry heat sterilizer with the door open.
Equipment used may be sterilized by dry heat. Product containers will be sterilized by dry heat. In large scale production sterilization tunnels attached to the washing machine are often used.
Container Integrity
The consequences of a problem in the quality of sterile products are so significant that 100% inspection is necessary. The EU GMP guide requires 100% leak testing of containers closed by fusion and 100% inspection of parenteral products for particulate contamination. Leak testing is usually performed by methods of dye batch testing and/or electrostatic testing, the later is preferred. Such a non-destructive high voltage inspection method allows defects as pinholes and cracks to be detected.
Figure 3: This is a schematic showing the point at which an ampoule may leak.
The high-voltage leak detector relies on the ampoule contents being conductive.
For vials and bottles the fit between vial and stopper is of great importance and should be challenged by microbial intrusion tests as part of the validation. Commonly a suspension of Br. Diminuta is used. The products used in such challenge tests should have been exposed to worst-case handling and storage conditions. Vials, bottles and stoppers at extremes of dimension specifications should be used.
Lyophilization
Products with limited stability in solutions may be lyophilised (freeze dried), which once the containers have been closed constitute a hostile environment for microbial survival. The process itself includes freezing of a wet substance (which have been sterilized by filtration) causing the ice to sublime directly to vapor at low pressure whilst suppling heat.
Lyophilization renders the product being chemically and/or biologically stable as well as making moisture levels too low to permit microbial growth.
Blow Fill Seal (BFS)
Generally BFS gives the potential for greater levels of sterility assurance during the filling process, as product exposure to the environment is minimal. The BFS process combines a solution filling system with extrusion blow molding; typically pharmaceutical grade polymers (e.g. polyethylene or polypropylene) are used. The equipment used will sterilize the polymer granules, form the container to be filled, fill the solution into the container and finally seal the container. The process requires minimal operator intervention as it is highly automated.
Therefore there is a reduction of the potential for microbial contamination.
Figure 4: A blow-fill-seal technician in front of the machine.
Isolator Technology
Isolator technology separates the aseptic process from human intervention, and thus greatly reduces the risk of microbial contamination during processing. Designs vary, but the “glove box” style may be most common. Whatever the design, the isolator must only be used after a thorough validation process. Transfer systems, gloves, gaskets and seals must be thoroughly inspected and maintained, especially when one considers that the decontamination agents used may be chemically aggressive.
Again, FDA’s Guidance for Industry – Sterile Drug Products. Produced by Aseptic Processing – Current Good Manufacturing Practices contains much useful information and background.
Sterilization
The European Pharmacopeia requires that wherever possible, the production process be one in which the product is sterilized in its final container. This is known as terminal sterilization. If a product is to be terminally sterilized, filling should be done in at least a C grade environment.
Methods of Terminal Sterilization
The most common method, and the one that is preferred for aqueous preparations, is the application of saturated steam under pressure using an autoclave. Reference conditions for terminal sterilization of aqueous preparations are heating at a minimum of 1210 C for 15 minutes.
Other combinations of time and temperature may be used, but the effectiveness must be demonstrated via validations and deliver a SAL of 10-6or better.
Autoclave conditions must be monitored and recorded via probes that are to be inserted into the coolest part of the load. Polypropylene containers may be autoclaved, but not polyethylene.
Dry heat may also be used; reference conditions for this method are a minimum of 1600 C for at least 2 hours. Other combinations of time and temperature may be used, but the effectiveness must be demonstrated via validations and deliver a SAL of 10-6 or better. As with autoclaves, probes must be used to record conditions within the coolest part of the oven.
Sterilization via ionizing radiation can be achieved using a source of gamma radiation.
The reference dose for this method to achieve sterilization is an absorbed dose of 25 kGy. Other doses may be used, provided that the effectiveness must be demonstrated via validations and deliver a SAL of 10-6 or better.
Gas sterilization through the use of ethylene oxide is the method of last resort.
Wherever possible, gas concentration, relative humidity, temperature and duration of exposure must be measured & recorded. The effectiveness of the process must be checked via the use of a suitable biological indicator (see European Pharmacopeia 5.1.2
Biological Indicators of Sterilizations) and a representative sample of the batch must be tested for sterility prior to release.
Aseptic Processing
Where terminal sterilization is not possible for example when a product is heat sensitive, aseptic processing is used. It is a manufacturing process designed to prevent the introduction of viable organisms and particulate contamination into the drug product. The material is rendered sterile by a filtration process that removes microorganisms. The filter must be challenged before and after filling to demonstrate its integrity has not been compromised. Primary packaging components are to be sterilised before use. Aseptic processing is not limited to filling of product; it may also include aseptic blending followed by filling.
Properties of the perfect filter:
– Compatibility with products and non-extractables.
– Can cope with unlimited flow rates,
– Is inert to all chemicals,
– Is a total sink for microorganisms
– Is physically & thermally stable.
Both terminal sterilization and aseptic processing are applicable to liquid products, although care must be taken to ensure that product quality is not affected by the chosen method if terminal sterilization is used.
Clean Rooms
There are special requirements for premises used for the manufacturing of sterile products. The environment needs to be controlled with respect to microbial and particulate contamination as well as temperature and humidity.
Different means of protecting the room from contamination is put in place, e.g. special HVAC systems to provide highly filtrated air, the room is kept an overpressure to the exterior at all times (including when doors are opened), sterilization/sanitation of material/equipment entered into the clean room, separation of premises into different areas/rooms in which different activities are performed. The air in the room is changed (different rates for different grades) frequently (e.g. at least 20 times/hour for grade B rooms) in order to keep particulate levels low.
The correct pressure differential between different areas and grades of cleanliness are monitored as well as microbial and particulate contamination levels, air flows are visualized to confirm the correct movement of air (i.e. smoke studies), and recovery tests are performed in order to confirm how quickly a room meet the accepted criteria after contamination.
Qualification of rooms includes: air supply capacity, air velocity/uniformity, air change rate, air flow patterns, HEPA filter integrity, pressurization, unidirectional flows (LAFs), particle count, recovery rate, microbial counts (air and surface), temperature and humidity. The correct performance of a room is also addressed during process simulation tests (media fills) performed regularly for aseptic processes.
Clean Room Gowning
The greatest risk for contamination in a modern, well designed clean room is people.
Introduction of people into a pharmaceutical clean room may seriously compromise the integrity of the facility with regards to particulate and microbial contamination. Despite efforts made in personal hygiene and correct wearing of special, non-shedding, gowning, people account for over 80% of all particulate contamination in the clean room and virtually all the microbiological contamination.
The garment should be comfortable to wear and made using antistatic fabric of minimum pore size (prevent passage from the person to the environment but allow passage of moisture). There should be tight seals around neck, wrists and ankles. Additionally it should be possible to wash and sterilize them (if used in grade A/B). Separate laundry is desirable.
In grade A/B areas sterilized full suits and hoods are used as well as special boots/footwear (sterilized or disinfected), sterile gloves and face masks (goggles). Gowning is changed every work session or at least daily. Two-piece suits should not be used in grade A/B areas.
In grade C areas non-shedding full suits, gloves and shoes as well as complete hair and beard cover are used.
In grade D areas general protective suits are worn as well as hair and beard cover and shoes/overshoes.
Visual inspection
Visual inspection of parenteral may be performed manually or automatically using camera vision systems. Pharmacopoeias provide information on how viewing units should be designed when performing manual inspections.
Personnel should undergo frequent eyesight checks and be trained in identification of defect types and the expected standards. Frequent breaks and rotation of tasks should be allowed. The premises used must be quiet and allow personnel to work separate from pass ways and noisy production areas. Appropriate lighting should be provided.
Walk through
During an aseptic/sterile processing audit, the auditor must observe the facility/area, process and personnel. The walk through is a critical part of any aseptic/sterile processing audit. In some of the cleanest areas you may not be allowed access due to the risk of contamination. It may however be possible to observe through a window. If you cannot observe work being carried out it may be very difficult to draw any conclusions. The issue has to be discussed/resolved. External personnel should not be breaching sterile area unless validated by site. If you cannot see into area in operation adequately you need to challenge how the company manage the area.
This must include examination of the appearance of the floors, walls, ceilings, housekeeping, operator activities during operations, movement of materials and people, manufacturing processes and the microbiology laboratory. You must take your time and if necessary observe these operations several times during your audit. If possible, the walk through must coincide with the shift changeover in order to observe two groups of operators. This allows the auditor to determine if behaviors and practices are consistent across both shifts. Inconsistent behaviors may suggest underlying training deficiencies. Prior to performing the walk through, obtain reference as-built diagrams of the following:
– Facility layout
– Personnel and material flow
– HVAC, room classifications, air pressure differentials; commissioning documents must be available to clearly demonstrate that the area as-built delivers the appropriate environment
– Production water systems
– Environmental sampling sites
We recommend that you verify that the various room classifications and air pressure differentials are compliant with the relevant regulations. During the walk through you must verify that the information you have received regarding the facility is accurate and assure that it is appropriate for the operations you observe. You may accomplish this through review of as- built diagrams and cleanroom certification reports and interviews with personnel. Also ensure that blackout procedures exists (that is procedures to return area to sterile to guarantee products).
Observe operator aseptic technique and gowning practices during the performance of the aseptic filling operation. Observe position and movement of the operator in relation to the exposed product and component areas. Breaches of the LAF air in these areas are unacceptable. Assure that the operators are properly gowned, with no exposed skin.
Observing the movement of personnel is of particular importance throughout the aseptic process area to assure that movements are appropriate, including hand sanitizing practices, vial and stopper jam corrective actions. Is equipment in the area sanitized and constructed of materials that will not cause contamination (i.e. non-porous, easily cleanable, non-reactive)? Is the facility/area constructed in a manner to assure that it can be sanitized, will not easily disintegrate or shed particles, and will not be a source of contamination? Also observe the sampling points for environmental monitoring and review the rational for choosing them.
As you perform your walk through, review available documentation where possible and identify equipment, batch records and personnel that you wish to gather more information about later in the audit. For example, identify staff to be included in your training record review and select equipment for IQ/OQ and PQ review.
Ensure that you include the Purified and Water for Injection (WFI) systems in the walk through and review all monitoring and trends for this system.
Key Parameters for Auditing an Aseptic Processing Facility
Prior to the audit
Ø Find out what sterile products are produced at the site.
Ø Find out if they are terminally sterilized or aseptically produced and the methods used.
Ø Review previous audit/inspection and actions taken.
Ø Review listed reference materials to assure that you are familiar with worldwide regulatory expectations.
Ø Ensure activities will be ongoing during your audit
Ø If processes in the cleanest rooms cannot be viewed from outside, find out what needs to be done to allow you access
During the audit
Inspect the facility for appearance and cleanliness.
Ø Surface finishes should be smooth, impervious, unbroken, minimize shedding, easily cleanable and resistant to cleaning agents.
Ø Windows should be non-opening and flush fitted.
Ø Door sealing should not prevent appropriate air movement (e.g. from clean rooms to support areas). Sliding doors should not be used. Where part of an air lock (e.g. changing room) doors should be interlocked or alarmed unless both are visible at once.
Ø Look for cracks in the ceilings (false ceilings should be sealed in place), walls, and floor (epoxy screed, terrazzo, sheet vinyl), dirt.
Ø Conveyors should not pass from “dirty” to “clean areas” unless part of a sterilizing tunnel.
Ø Flush mounted and easily cleanable intercoms or window mounted speech panels are preferable to conventional telephones.
Ø Ensure that cleanable traps with adequate air breaks are fitted. Sinks and drains should be prohibited in grade A/B premises.
Ø Pipes and ducts and other utilities should be installed so that they do not create recesses, unsealed openings and surfaces, which are difficult to clean.
Ø Flush fitting fixtures should be in place for lightning
Ø Look for rust, clutter within the aseptic and processing areas and pass-through areas.
Ø Look for dust on ledges.
Ø Review housekeeping logs for frequency of cleaning, cleaning agents used. How are cleaning agents and cleaning materials controlled? Inspect training records for personnel performing cleaning operations.
Ø Review the cleaning frequency for rooms of different classifications and determine if the frequencies are appropriate. Different classifications require different cleaning schedules and procedures.
Ø Inspect classified areas for particulate sources such as wooden pallets, cardboard and excessive paper. Materials that may be a source of particulate or microbial contaminants must not be present.
Ø Inspect disinfectants used and justification for shelf life and review rotation schedule if used.
Determine if the building design supports aseptic/sterile processing
Ø Ensure that there is adequate separation between zones of different classifications.
Ø Ensure that entry between zones of different classifications is logical and stepwise
Ø Ensure room classifications are as required
Ø Ensure flow of material and personnel is logical
Ø Ensure there is no mix-up risk for sterilized and non-sterilized material
Ø Ensure that airlocks are in place to facilitate transfer of materials and personnel.
Are interlocked doors in place? Can the doors be manually overridden? How is this monitored?
Ø Ensure that the area has controlled access.
Ø The use of barrier technology should be utilized where appropriate.
Inspect the facility utilities (compressed gases, water systems, steam and HVAC systems).
Ø Determine if all utility systems, which contact product or aseptic processing components, have been qualified.
Ø Determine what routine testing is conducted and how often.
Ø Determine what the microbial action and alert levels are for compressed gases, HVAC systems, water and steam.
Ø Determine what the particulate action and alert levels are for compressed gases and HVAC.
Ø Review action and alert levels; review what the site procedure is for a system exceeding these levels and confirm procedures are followed.
Ø Determine if redundant filtration and filter integrity testing is conducted for point of use filters.
Ø Determine if the utilities are alarmed. What actions occur after an alarm is triggered?
Inspect the HVAC system for the following additional items:
Ø Ensure that air pressure differentials within controlled areas are continuously monitored and alarmed to indicate when the air pressure is out of range. Ensure monitoring devices have been appropriately calibrated.
Ø Review the alarm printouts for trends.
Ø Determine what procedures are followed in response to these types of alarms. Ensure appropriate and timely actions are taken.
Ø Ensure the pressure differential between rooms of different classifications is at least .05” water or 10 – 15 pascals.
Ø Check that a maintenance program is in place for HVAC-systems and LAF-units
Ø Blackout procedures
Ensure that airflow directions are appropriate.
Ø Review air pressure differentials.
Ø Review flow pattern data.
Ø Review smoke studies.
Determine if personnel flow and material flow are designed to minimize the potential for contamination.
Ensure that all material entering the processing area is disinfected with an appropriate disinfectant.
Inspect the processing area while production is in progress.
Note: in some of the cleanest areas you may not be allowed access due to the risk of contamination. It may however be possible to observe through a window. If you cannot observe work being carried out it may be very difficult to draw any conclusions. The issue has to be discussed/resolved.
Ø Observe personnel and determine if they are using proper aseptic technique.
Ø Ensure that all personnel, including mechanics and QC inspectors, working in the area have had adequate training including participation in media fills.
Ø Ensure that all personnel working in the area are gowned properly.
Ø Observe personnel performance, including but not limited to: set-ups and adjustments of machines, correction of vial jams, stopper jams and selection of production samples (if required).
Ø Observe if environmental monitoring sampling equipment is placed properly.
Ø Ensure sampling points are representative
Ø Determine if there is adequate control, while production is in progress, to prevent cross-contamination.
Ø Determine if sterile components are used within their expiration dating.
Ø Determine if there is adequate and clearly marked storage to prevent mix-ups of sterilized and unsterilized processing components/products.
Filling process
Ø Layout of filling line. Evaluate whether the design of the line is appropriate (filling level compared with level of protection walls, for aseptic filling design should be confirmed with smoke studies and possibilities for operator interference limited to what is necessary)
Ø Following filling integrity of products should be checked (container integrity validation and 100% integrity testing of ampoules closed by fusion, e.g. high voltage inspection methods)
Visual inspection
Ø Ensure visual inspection is preformed as required
Ø In manual operations check that the time operators perform visual inspection is regulated
Ø Check that personal is checked for eye-sight regularly Inspect the component preparation area.
Ø Ensure that sterilization equipment (autoclave, dry heat oven, sterilizing tunnel) has been validated and is properly maintained.
Ø Ensure that equipment used to wash/rinse containers and closures has been properly validated and maintained.
Ø Ensure the required water quality is used for washing/rinsing
Ø Ensure that there are approved procedures for departmental processes, operation of/and maintenance of equipment. Verify that operating procedures reflect those used during validation.
Ø Observe personnel to determine if they are appropriately gowned.
Ø Ensure that there is a documented training program in place for operators in this area.
Inspect the microbiology laboratory.
Ø Review sterility testing program, performance and test results.
Ø Review all investigations for completeness and lot disposition decisions.
Ø Determine if there are any trends regarding false positive test results and the root cause.
Review the Media Fill Procedure.
Ø Ensure there is a defined, approved program.
Ø Ensure that the media fill program is compliant with the applicable regulations and site Policy/Guideline requirements.
Ø Ensure that all operators have participated in a media fill within the year.
Ø Ensure that media fills are performed for every aseptic filling line for every shift semi-annually.
Ø Verify the number of units filled during a media fill and assure that the media fill is representative of the filling process. (For example: size and duration of fill; line speed; incubation (14 days and adequate temperature to detect organisms and examination of each filled unit)
Ø Ensure that all staff that might be involved in the aseptic filling process participates in the media fill.
Ø Review media fill performance documentation and all associated deviation reports.
Ø Ensure that the number of units filled during the media fill trial is equivalent to the number of units placed on incubation. Ensure that any variances in number are documented.
Review the Environmental Monitoring Program.
Ø Ensure that there is a defined, approved program.
Ø Review training records for staff performing program sampling and testing.
Ø Ensure that the program is compliant with all worldwide regulatory and site policy/guideline requirements.
Ø Ensure that there are established alert and action limits that are appropriate.
Ø Review test results and associated investigations.
Ø Ensure that the program requires review of test results prior to release of product batches.
Ø Ensure that data is tracked for trends and reviewed by QC unit on a regular basis.
Audit the manufacturing process and documentation.
Ø Choose a product and include the following in your data review:
Ø Review Process Validation reports and identify critical process parameters
Ø Review Manufacturing Process Description or batch records and assure the process is currently being performed according to the validated process.
Ø Review time limits for various process steps.
Ø Request data to support the sterilization process
Ø Ensure filters are checked before and verified after filtration. Filter testing should be validated for the products in scope.
Ø Review deviation documentation to assure that the validated process was followed.
Inspect the packaging and labeling area.
Ø Ensure that final units are inspected to remove damaged/defective units.
Ø Ensure that line clearances have been performed prior to and after the labeling and packaging of lots.
Review the release packet for a recently released lot.
Ø Ensure environmental monitoring data and investigations, including personnel data, were reviewed.
Ø Ensure that all investigations of deviations were properly performed and sound lot disposition decision was made.
Review all documentation associated with the following:
Ø Facilities and equipment
Ø State of repair and maintenance of facilities and equipment
Ø Personnel, material and process flow
Ø Compounding area
Ø Filtration processes
Ø Filling process
Ø Lyophilization process if applicable
Ø Inspection process
Ø Product testing
Ø Terminal sterilization if applicable
Ø Personnel (including observation of aseptic technique and gowning practice)
Ø Media fill program, practice and performance
Ø Ongoing environmental monitoring, including personnel monitoring
Ø Training and qualification of personnel, including gown qualification
Ø Sterility testing area and data
Ø Microbiology laboratory (see Laboratory Training unit)
Ø Water systems including Purified, Water for Injection, clean steam