Goals
When you have completed this module, you should be able to:
Ø Understand what the GMP requirements are for microbiological and sterility testing laboratories
Ø Identify which GMP regulations govern microbiological and sterility testing laboratories
Ø Use a range of information tools, from the contents of this training module to the Intranet, in support of microbiological and sterility testing
Ø Recognize compliance or non-compliance of a microbiological and sterility testing laboratories
Definitions
Bioburden: The normal microbes found in raw materials, on drug product components, and other materials prior to sterilization or other forms of processing.
Endotoxins: Toxic molecules consisting of lipopolysaccharide originating from the outer cell wall of Gram-negative bacteria. Endotoxins may cause fever reactions in humans.
Inoculum: A small quantity of a microbiological organism transferred into a large volume of culture media to grow large quantities of the microbiological organism.
Objectionable organism: A microorganism that has been shown to cause harm to humans. Depending on the route of administration and the type of drug product, these organisms will be different for different products.
Microbial limits testing: A test used to determine the quantity of organisms in a pharmaceutical raw material, in process sample, or finished sample and indicator organisms for a particular drug product.
Media: A substrate for growing microorganisms. If the tests are compendial tests, the type of growth media (e.g. trypticase soybean casein digest, blood, etc.) will be suggested. Different media are used to characterize different microorganisms based on nutritional requirements/preferences.
Microbial cultures: The growing of microorganisms, tissue cells, or other living matter in a specially prepared nutrient media.
Out of specification (OOS) result: A laboratory test that is outside its regulatory or compendial limits. In some cases, there may be additional tests and/or limits that are used to assess the quality of a material, but are not included in registrations or compendia. In these cases, the general principles described here are useful, but more latitude is allowable in the disposition of the material as long as it meets its legal requirements.
Out of trend (OOT) result: A test result that lies outside of a current trend analysis for a particular product. The test result itself may be within the acceptance criteria for the test. Pyrogens: Fever producing substances.
Rapid Microbial Identity Test: A commercially prepared test that is able to identify microorganisms through interactions with chemicals within a matter of hours instead of days.
Stock cultures: Pure microbial cultures that are kept for use in the lab. Sources of these cultures may be the American Type Tissue Collection or microorganisms isolated from the production environment.
Explanation of Topic
Introduction
The purpose of this training module is to provide information on what to include in a microbiological and sterility testing laboratory audit. Microbiological testing is used to release products, determine if production environments are satisfactory and determine if results of in- process testing are satisfactory.
Laboratory Administration, Organization and Personnel
It is important to understand how the microbiological laboratory functions. When auditing the lab, review the current organization chart. Determine what tests the lab performs. Determine the distribution of personnel across shifts. Discuss with the lab manager or responsible person any corrective actions from previous audits. Determine the status of these corrective actions and if they were corrected within the agreed time period.
Personnel
Personnel working in a microbiological laboratory should follow general laboratory rules such as that lunches or other non-microbiological items should not be stored in the same refrigerator used for storage of laboratory cultures or tests.
There should also be an approved SOP regarding dress code, covering the need for physical and dress discipline segregation from other laboratories and production.
These rules apply to employees and visitors/contractors to the lab. All personnel working in the laboratory should be trained in both GMP and the technical skills required for their job function.
GMP training should be given at intervals specified in a site SOP. Personnel should also be formally trained and qualified, according to site procedure on the operation of specific instruments, and the use of specific methods and techniques.
Personnel working in the microbiological laboratories should be trained in contamination control including aseptic techniques.
This competency and all training should be documented. Personnel should have an extensive understanding of sources of contamination. The site should have an SOP on training to include qualification practices/programs in the microbiology laboratory.
Laboratory facilities for microbiological testing
Because of the varied types of testing performed in a microbiological laboratory, the laboratory may be divided into designated areas for particular types of tests and preparation of reagents and media. These areas may include bench tops, semi controlled environments, contained environments and fully controlled environments.
Microbiological testing should be performed in a suitably clean environment that meets the appropriate regulatory requirements, i.e., the sterility test area for sterile products should meet the same criteria as the production area.
The physical area should be in good repair with walls and ceiling tiles intact. The laboratory should be orderly. Clean work should be separated from non-clean work e.g. work with microorganisms should be done separately including use of separate refrigerators.
The laboratory should be kept clean and sanitary. An appropriate disinfection program for the microbiological testing area should be approved and the associated methods and procedures in place. Personnel should follow the site dress code as indicated in an approved SOP.
Microbiological laboratories should be separated from production facilities. Personnel should not go from the laboratory to the production, or vice versa, without a change of garment.
Bench tops
Bench tops may be used for routine microbial procedures such as streaking cultures, pouring agar (media), preparing reagents, and other routine functions performed in a microbiology lab. Bench tops should be kept clean and disinfected on a routine basis. There should be an approved procedure describing the cleaning and disinfection process, the cleaning and disinfectant agents to be used and frequency.
Equipment
Most microbiological laboratory equipment will have the same requirements. All equipment requiring calibration should be calibrated and maintained in good working order.
If equipment is out of calibration or under repair, it should be appropriately labeled. The calibration program/procedure should be documented and include directions on how to manage a routine calibration failure.
If the equipment is considered critical it should be alarmed. Appropriate preventative maintenance procedures and programs for critical equipment and systems should be approved and in place. All maintenance work performed on the equipment should be documented.
Routine microbial laboratory equipment may include:
Ø Incubators
Ø Water baths
Ø Hoods, both fume and HEPA
Ø Autoclaves for sterilizing media
Ø Ovens for sterilizing glassware
Ø Isolators
Ø Equipment used for identification (e.g. Biolog, Vitec)
Ø Equipment used for preparing and dispensing media
Ø Equipment use should be monitored and documented.
SOPs and equipment manuals should be available for all instrumentation. If equipment maintenance logbooks are used, they should be up-to-date with complete entries and controlled.
SOPs for laboratory equipment should include:
Ø Maintenance frequency and maintenance activities
Ø Calibration (if appropriate)
Ø Cleaning, and operation
Ø Method of cleaning/disinfection, cleaning agents, and frequency of cleaning
Ø Operation of equipment including monitoring frequency and documentation
Ø Emergency procedures in the case of a power outage or temperature deviation
Qualification of Equipment
Critical instruments and equipment should be qualified and calibrated and included in a routine calibration program. Equipment used to provide a controlled temperature should be set at the appropriate temperature for its intended use.
Qualification should include temperature mapping where appropriate as for walk-in incubators and ovens. Autoclave load patterns should be established, assigned to cycles, and tested.
Tests should include heat penetration studies and biological challenge tests. If media is sterilized in house it should take into account the heat sensitivity of some media and the risk of ‘oversterilising’ the media. Autoclave re-qualification should occur periodically, according to established change control procedures and with associated test protocols to verify that the autoclave has remained in a validated state.
Stock cultures
Microbial cultures are pure strains of one particular microorganism. Stock cultures are used as inoculum for testing or reference samples. The cultures can be either isolated from an environmental sample or purchased commercially as a pure strain.
Microbial cultures may be kept almost indefinitely if care is taken during the transfer process. Microbial cultures should only be transferred or “passed” five successive times if they will be used as positive controls or in assays.
The passages and dates of transfer should be documented. Stability and maintenance of cultures should be documented. Once an agar slant containing a culture is removed from storage, it should not be used again. Storage conditions for cultures should be monitored and documented.
Cultures may be frozen onto sterile glass beads and stored at -20 C. They may also be stored under ° nitrogen in a mixture of glycerol, to prevent cell breakage upon thawing. Cultures may also be lyophilized (freeze dried) and kept in a powder state. The laboratory should have an SOP that includes storage conditions for microbial cultures used in the laboratory.
Microbial cultures and test plates with growth should be inactivated before being sent for disposal. The procedures for inactivation should be in compliance with the site’s waste disposal policy and procedure.
Culture media
Culture media may be prepared by the individual laboratory or may be purchased from an outside vendor. Media should be subject to growth promotion testing to verify that the media supports growth of the particular target organism.
Organisms that should be used for growth promotion testing are listed in the pharmacopoeias. There should be approved procedures for preparing and testing media. Water used in media preparation should be distilled or deionized.
Also review the sterilization process, as some media may be sensitive to ‘over sterilisation’. Media lots should be tested for sterility by incubating representative modules under appropriate conditions, e.g. time and temperature.
Once the sterility is demonstrated, the culture media should be stored under recommended conditions stated in the site SOP or manufacturer’s directions. If media is purchased from an external vendor as ready to use, it should be accompanied with documentation/Certificate of Analysis that the media support growth when stored under recommended storage conditions.
There should also be an assigned lot number and expiration date associated with the media. If the media is expected to be sterile, there should be test results or information from the vendor confirming its sterility. If the supplier is certified reduced testing will be acceptable.
Preparation of Reagents, Solutions, and Glassware
Reagents should be clearly marked with contents, expiration date, and storage conditions. If the laboratory prepares solutions and standards for testing, these should be documented.
Types of microbiological tests
There are a number of microbial tests that pharmaceutical microbiology laboratories will perform. Many of them are pharmacopoeial tests. Some of these are very specific to certain products. Others are considered routine and performed by most microbiological laboratories. These include:
Ø Pharmacopoeial Microbial Limits testing
Ø Pyrogen/Bacterial Endotoxin Test
Ø Water Testing using Standard Methods
Ø Antimicrobial Effectiveness Test
Ø Growth Promotion
Ø Identity Testing
Ø Bioburden Testing
Ø Environmental Monitoring
A brief discussion of these tests is included. Most of the tests are compendial tests found in the USP/NF and European Pharmacopoeia and are performed according to the test methods described there.
However the site must demonstrate that the method works under the actual conditions that it will be used, in order to use the test. Raw materials and drug products should be assessed for the need to perform microbiological testing. Compendial or registration commitments may drive the need for and extent of such testing.
In addition, a risk assessment that reviews the manufacturing and processing conditions for the material, whether the material is organic, data on the ability of the material to support microbiological growth, water activity of the material, etc. can be useful in determining the need or extent of microbiological testing.
No one system can detect all potential contaminants. The methods that are selected should be capable of reliably isolating the numbers and types of organisms considered significant regarding system control and potential impact on product.
Consideration should be given to timely results to initiate corrective action vs. slower recovery methods that give higher counts.
Microbial Limit testing
This test is performed to determine the quantity of microorganisms in pharmaceutical ingredients and non-sterile medicinal products. The microbial limits test includes a standard plate count for total aerobic bacteria and molds and yeasts as well as several designated microbial species such as Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella species and Escherichia coli.
Microbial Limit testing is performed on API materials, raw materials, other pharmaceutical ingredients and non-sterile medicinal products.
Bioburden Testing
Components, raw materials, and equipment are tested to determine the quantity and type of microorganisms they contain. The same techniques as for microbial limit testing are applied. This testing is usually performed on materials undergoing sterilization, e.g., components and solutions, as part of aseptic processing. The results of the bioburden testing can be used to set sterilization parameters.
Pyrogen/Bacterial Endotoxin Test
Sterile products and their components are usually tested for pyrogens and endotoxins. The current accepted test is the Bacterial Endotoxin Testing, also known as the Limulus Amoebocyte Lysate (LAL) test. This pharmacopoeial test is performed to determine if there is any endotoxin in the product or component.
Methods used are the gel clot method, turbidimetric and chromatogenic methods. The gel clot method is sensitive to vibrations and equipment needs to be placed in a stable position. The site should have an SOP that defines what should be tested and how it should be tested.
The SOP should also include established endotoxin limits and maximum valid dilution for each test item.
Standard Test Methods-Water
Water used in pharmaceutical production and the test area should be tested for the number of organisms and type of microorganisms. Depending on the type of water used in the manufacturing process there will be different pharmacopoeial requirements. Examples are shown below.
| Type of water | Total aerobic count | Microbiological characteristics |
| Drinking water | < 500 cfu/ml | No coliform organisms present |
| Purified water | < 100 cfu/ml | Absence of objectionable organisms |
| Water for Injection (WFI) | < 0.1 cfu/ml | Essentially sterile |
Purified water is typically used in the final steps of active pharmaceutical ingredients (API) processing and in the manufacturing of solid dosage forms, e.g., formulation and cleaning. WFI is used for sterile injectables. Total aerobic counts should be tracked and trended. Care should be taken when collecting a water sample.
The port should be sanitized, flushed for a specified number of minutes or volume equal to normal use, and the sample collected aseptically (i.e., hose not touching the container) in sterile container. Samples should be refrigerated and tested within 24 hours.
Antimicrobial Effectiveness Test
The Antimicrobial Effectiveness Test, a test described in the pharmacopoeias, demonstrates the effectiveness of the preservative system in a product. A product is tested against a controlled quantity of different types of microorganisms.
The test then compares the level of microorganisms found in a control sample versus the test sample over a period of 28 days.
This testing is performed as part of a stability study. It is necessary to determine if a preservative system will continue to be effective over the product’s shelf life and if the preservative system is compatible with the formulation of the product.
If a formulation changes or a significant product or packaging change occurs, it is necessary to retest the effectiveness of the preservative system.
Growth Promotion Testing
This test is performed to indicate that the selected test media is capable of supporting microbial growth. Environmental isolates may be used in addition to indicator organisms to test growth promotion. Organisms should be incubated at their optimum temperature so that erratic results are not generated.
Identity Testing of Microorganisms
Microbial organisms found through testing may need to be identified. The degree of identification needed and when should be specified in an SOP.
The site should have an approved SOP that contains the test method in use. Identification may be performed through a series of testing with selected growth media or through a rapid microbial identification system.
Rapid microbial systems use electronic instruments designed specifically for microbial ID. The equipment should be validated and there should be validated written procedures for operation and maintenance.
Cultures of known microorganisms should be used as positive controls to verify that the test is working properly. There should be an SOP in place describing the test parameters and the operating conditions.
Environmental Monitoring
This testing may include personnel, surface, water, air and other specialized testing. Agar test samples from the air, personnel, and surfaces are incubated appropriately to grow both fungal and bacterial contaminants.
The temperature ranges used for incubation may be based upon the relevant compendia, regulatory guidance or validated conditions. If growth appears, the laboratory should isolate the particular organisms, and characterize them as appropriate. When to characterize and to what level should be described in SOP. All isolates and characterizations should be documented as to date, and type of sample.
Media fills
Filled items will be incubated and inspected for growth (turbidity). If growth appears, the laboratory should isolate the particular organisms, and characterize them as appropriate.
Sterility testing
Since sterility testing is a test for release of sterile product, it should be conducted under the same conditions as production. The cleanliness level of the testing facility should be equivalent to the product facility. Analysts should be qualified and highly trained in aseptic techniques.
The material flow and handling of test samples should be similar to how product is handled. Microbial environmental monitoring should be conducted. Sterility testing is a pharmacopoeial test. Testing should be performed using known to be sterile negative controls.
Material should be handled in the same way as material is handled in production and the facility should be part of the site’s environmental monitoring program.
Sterility testing may be carried out in a LAF unit placed in an environment suitable for aseptic work or in an isolator. Isolators are freestanding and sealed from the outside environment. The analyst tests samples by either using glove ports or donning a half- body suit built into the isolator.
If the sample is tested within an isolator, the isolator should have controlled HEPA filters. The isolators are decontaminated typically with hydrogen peroxide (H2 O2 ), though there are other agents used. Materials usually enter through a port that is connected to an autoclave.
Because of the nature of the closures and the barriers, the cleaning and disinfection process should be validated. The validation should also include the effectiveness of the disinfection against the organisms that will be used in the isolator.
There should be an SOP that includes when the isolator should be disinfected, the frequency, and the duration of contact with the chemical. The interface with the autoclave and the isolator needs also to be validated.
When sterility tests are performed in a clean room environment, the following must be taken into consideration:
Ø Certification of pre-sterilized materials
Ø Media preparation, storage and certification
Ø Maintenance of control cultures
Ø Bacteriostasis and fungistatis testing
Ø Laboratory operations
Ø Environmental conditions
The site should have an approved procedure in place to manage positive sterility tests e.g. growth detected. If there is a positive sterility test, an investigation needs to be conducted. The organism needs to be identified. Laboratory test failures over time need to be reviewed.
The organism isolated from the positive test should be compared to any organism isolated from environmental monitoring tests to determine if the environment is the source. Environmental monitoring results for production should be reviewed.
The isolated organism from the positive sterility test should also be compared with any organisms isolated from product pre-sterilization bioburden. Production records should be reviewed for events or conditions that would affect product sterility.
The pharmacopoeia only allows retesting if certain criteria are met. Retesting should be rare. Sterility retest results should also be compared to initial test results. The result of the investigation should be reported immediately to management and Quality to make the final determination about the product.
Documentation
For each type of testing there should be an SOP. Each SOP should contain specific instructions or reference a compendial test. It is the laboratory’s responsibility to prove that the test method works correctly under the specific laboratory conditions. The laboratory should follow good documentation practices.
All laboratory data should be captured in an authorized data system (e.g. LIMS, laboratory notebooks, etc.). The data should be complete and reviewed by a second person. If logbooks are used, they should be controlled. There should be some system of control evident to assure that only current versions of SOPs are in use. The SOPs should be part of the sites’ SOP review and revision system.
There should be a record retention program in place that is being followed. SOPs for the laboratory should include general instructions for culture medium, preparation, pH adjustment, sterilization, methods for performing tests, and storage. There should also be documentation requirements and SOPs for equipment operations and monitoring.
Records stating conditions and dates for batches of media prepared in the lab should be kept.
Test Method Validation
All test methods should be validated. Records should be in place to show what was done during the validation testing. Methods can be validated in a number of ways. If a site uses a method that appears in a pharmacopoeia it is considered validated, but the method must be shown to work under the actual conditions that it will be used (method qualification). A site can also conduct a validation study on their own method.
Sampling
There should be an SOP that defines microbial sampling procedures. Samples should be representative of the batch of material being assessed. Sampling should be conducted to prevent contamination from the sampling method. The laboratory should also have a procedure and system in place to manage samples.
When receiving samples, the laboratory should record the name or identification of the sample as indicated in the site’s SOP, type of sample, date received, type of storage needed (i.e. refrigeration, protected from light, etc.), and signature of person who received it. The sample may be entered into a logbook if it is controlled. If a sample leaves the storage area or the laboratory, the signature of the person who took the sample, as well as the date and time the sample was taken should be recorded.
The laboratory should account for all samples coming into the laboratory (i.e. each sample that is received in the laboratory should undergo testing). Since the sample may contain viable microorganisms which can quickly die over time, the laboratory should have a system in place for speedy processing of the sample.
If the sample is unable to be processed, it should be held under temperatures and conditions that will slow any deterioration of the sample.
Out of Specification or Out of Trend Investigations
Specifications should be based on sound scientific reasoning and established during product development.
They should also be specific for the drug product or sample being tested. Sometimes the laboratory results will not be within specifications e.g. they are considered out of specification. Some results may also be considered out of trend. This is determined through monitoring and comparing data for a specific test.
Over the course of time a trend may be noted that the assay is approaching the limit of its acceptance criteria. The site should also be monitoring laboratory results of test samples to determine if there is an out of trend result. Trends may indicate a process drift and should be investigated and the cause determined.
An approved SOP for defining what constitutes a trend and how to manage out of trend results should be in place. Investigations should be conducted for those test results that are outside the acceptance criteria of the test performed.
The site should have an approved SOP or testing protocol that includes details of the out of specification and out of trend elements to be investigated. If there are automated systems for documenting tracking and trending they should be validated.
Change Control Program
All laboratory equipment, methods and procedures should be part of a site change control program. This program should be outlined in an approved SOP. All changes to both equipment, including software and hardware changes, and analytical methods, need to be:
– Documented with a description of the work performed
– Evaluated for impact on qualification,
– Approved prior to implementation.
Computer equipment changes, including software and hardware changes need to be documented, evaluated for impact on qualification, and approved prior to implementation.
Changes to analytical methods need to be properly documented, evaluated for impact on method validation and approved prior to implementation. Change control procedures should also include directions for incorporating changes based on pharmacopoeia requirements and require that the incorporation is timely.
Summary
Microbial testing is necessary for product testing. Microbiological testing can prevent microbially contaminated product from reaching the market. It also, through in-process testing, ensures that our process is under control from a microbiological perspective.
This assurance is achieved through personnel highly trained in aseptic techniques, validated/qualified testing methods, qualified equipment, and extensive environmental monitoring.
Key Parameters in Auditing a Microbiological and Sterility Testing Quality Laboratory
Prior to the audit
Ø Find out which products are tested in the laboratory
Ø Find out which methods/specifications should be used
Ø Request a list of laboratory SOPs.
Ø Request a list of laboratory equipment.
Ø Request a list of laboratory deviations, out of specifications and/or out of trend investigations from the previous 12 months.
Ø Review previous audits to determine if there are pending actions.
During the audit
Conduct a walkthrough of the laboratory.
Ø Verify that there are designated areas for performing various testing functions.
Ø Verify that the laboratory is maintained in a clean and orderly fashion.
Ø Verify that the laboratory is in good repair, (i.e. no chipped paint on walls, no loose ceiling tiles, etc.).
Ø Verify that there is physical and dress discipline segregation from other laboratories.
Ø Verify that personnel are following the dress code for the area.
Ø Verify that all reagents and chemicals are labeled with expiration date and have not expired.
Ø Verify that equipment has been calibrated.
Ø Verify that incubators, freezers and refrigerators are temperature monitored.
Ø Verify that incubators have been subject to temperature mapping studies.
Ensure that documentation is in place and approved.
Ø Verify that the laboratory has approved SOPs on the following general topics:
– Cleaning of laboratory and equipment.
– Maintenance and disposal of laboratory cultures.
– Operation, maintenance, and cleaning of incubators, ovens, refrigerators/cold vaults, hoods, and water baths.
– Transfer methods, maintenance and storage of stock cultures.
– Operation, maintenance, and cleaning of autoclaves.
– Managing a microbiological laboratory out of specification result.
– Managing a laboratory spill.
– Preparation and storage of stock solutions, reagents and culture media.
Ø Verify that the laboratory has a system for collecting and maintaining data. If the system is computer based, it must be validated and comply with applicable ERES requirements. Review data and verify that the chosen product is tested as required.
Ø Ensure that the test method has been qualified for the product.
Ensure that a procedure is followed for sampling and handling samples.
Ø Verify that samples are labeled properly and uniquely identified.
Ø Verify that there is a system in place that assures samples are stored under correct conditions.
Ø Verify that the sample is signed in using a well documented and established procedure.
Ø Verify that there is a documented procedure for logging samples out of the lab.
Ø Verify that site requirements for sample handling and storage are included in a laboratory SOP.
Ø Verify that samples are handled and stored based on their storage and handling instructions.
Ensure that laboratory results and data are secure and accurate.
Ø Verify that data is checked by a second person.
Ø Verify that there is an approved SOP on the topic of second person review.
Ø Verify that data is secure with only authorized personnel able to access it.
Ø Verify that raw data is recorded in a notebook or on controlled sheets of paper, not on loose paper.
Ø Verify that data is reported correctly according to approved procedure, i.e. each data point is recorded, as specified in the SOP, versus an average taken.
Ø Verify that any data reported includes its units of measurement.
Ø If loose sheets of paper or computer printouts are used to record additional data, verify that each page includes the number of the notebook and notebook page it should be attached to.
Ø Verify that requirements are the same for automatic raw data capture with computerized systems.
Ensure that out of specification and out of trend results are investigated.
Ø Verify that the site has an SOP in place.
Ø Verify that the site is following the SOP through review of out of specification and out of trend investigations.
Ø Verify that once an out of specification or out of trend is discovered, the rationale for the subsequent steps is based on sound scientific reasoning. Ensure that there is a change control program that includes the microbiological laboratory.
Ø Verify that methods, equipment, software, and instrumentation are part of the change control program.
Ø Verify that appropriate approvals and levels of approval are in place.
Ø Verify that testing after the modification or change is performed.
Ø Verify the results are within the acceptance criteria.
Ensure that personnel are trained and follow laboratory procedures.
Ø Verify that new employees, experienced employees and supervisors are fully trained/qualified.
Ø Verify that any contract employees (lab analysts and calibration and PM personnel) are fully trained and qualified to perform the assigned tasks.
– Ensure that training requirements are defined in an approved SOP.
– Ensure that lab personnel are receiving GMP and job skills training with an emphasis on aseptic technique and that it is documented.
Ø Verify that all laboratory personnel follow the dress code and general laboratory rules established by the site.
Ensure that laboratory equipment and instrumentation are maintained and operated according to approved SOPs.
Ø Verify that equipment and instrumentation (including software) are qualified.
Ø Verify that equipment and instrumentation (including software) is part of a preventive maintenance schedule.
Ø Verify that equipment is current with calibration and/or preventive maintenance.
Ø Verify, upon completion of repair work, that appropriate testing is performed as outlined in an approved change control program.
Ø Verify that the equipment list is accurate.
Ø Verify that all calibration procedures, whether internally or externally performed, have been approved by appropriate site personnel.
Ø Verify that calibration and maintenance is performed with sufficient frequency to assure optimal operating conditions of each piece or equipment or instrumentation.
Ø Verify that there are approved and followed SOPs for maintenance, calibration and change control.
Ø Verify that all repair and maintenance work has been documented.
Ø Confirm that if work is performed by external service contractors that:
– Internal requirements and expectations are followed.
– The work is pre-approved before beginning.
– Results are reported to the site in a timely manner and approved by the site.
Ø Verify that equipment use, cleaning and maintenance is documented. This is typically done in equipment logs, which are a specific requirement to meet US GMP regulations.
Ensure that test methods have been validated.
Ø Verify that there are SOPs directing the validation procedure/method.
Ø Verify that test methods have considered the characteristics of the product.
Ensure that there is an approved formal sterility testing program in place.
Ø Verify that the test conditions are equivalent to production conditions.
Ø Ensure that personnel are qualified for sterility testing.
Ø Verify that the method used is as required by the pharmacopoeia
Ø Verify that the test facility is part of the environmental monitoring program.
Ø Verify that isolators, if any are qualified and maintained
Ø Verify that media is prepared and tested appropriately
Ø Verify that there is an approved SOP for managing sterility test failures.
– Verify that the criteria for retesting is as required by the pharmacopoeia
– If there is a test failure, confirm that Quality is notified immediately.
– Determine the retest frequency
Review the Media Fill Procedure for the laboratory
Ø Verify that filled units are incubated at the correct temperature and time
Ø Verify that filled units are inspected for growth as appropriate
Ø Verify all filled units are accounted for
Ø If growth occur ensure microorganisms are identified