In pharmaceutical manufacturing industry Validation is very important part of Quality assurance and in Good manufacturing Practice activities or guidelines .FDA gives special emphasis on validation , also it is one of the prime requirement of all regulatory authorities world wide. It is of great importance in Pharmaceutical manufacturing as well as medical devices manufacturing industry.
Validation is a process of collection of documentary evidence , it is a process of demonstration that any of the procedure, process, method, or activity is being adapted is capable of producing consistant and satisfactory result in terms of measurements or in terms of product quality.
To demonstrate this it is required that the systems it slef and equipment are properly designed and qualified. To demonstrate that a pharmaceutical product manufactured with any process in any pharmaceutical company it is required to validate many procedures, processes, methods activities associated with pharmaceutical manufacturing including machinery , skills and testing procedures , methods.
Validation In pharmaceutical is classified as follows
1.Cleaning Validation
2.Process Validation
3.Analytical Method Validation
4.Computer System Validation
And qualifying systems ,equipments are required to qualify for following Qualifications:
1.Design qualification (DQ)
2.Component qualification (CQ)
3.Installation qualification (IQ)
4.Operational qualification (OQ)
5.Process qualification (PQ)
Design Qualification (DQ)- It consists process of gathering documentary evidence of a particular instruments or machine’s fundamental operational and functional specification of an instrument , and its inherent program , or equipment and details about and its detailed design and its qualifications , why this instrument and is supplier chosen.
Installation Qualification (IQ) - It consists process of gathering documentary evidence and process of Demonstration that the process or equipment being installed complies with all of its qualifications of successful installation in a particular aria , so as to comply with intended requiremts of process , with respect to its specifications, is it installed correctly, are all necessary accessories and components installed correctly and its documentation required for continued utilization are installed properly.
Operational Qualification (OQ) - It consists process of gathering documentary evidence and of Demonstration of all aspects of a equipment , process are functioning properly and accurately so as to yield intended ,mesurments, results quality of a pharmaceutical being manufactured.
Performance Qualification (PQ) - It consists process of gathering documentary evidence and process of Demonstration of all aspects of a equipment , process are functioning properly and accurately so as to produce intended ,mesurments, results , intended quality of a pharmaceutical manufactured over a period of time. in a consistent manner
Validation Master Plan
It is a document which identifies and provides complete steps, guide or map or guidelines for caring out a particular validation procedure.
Where ever there is requirement of any validation , Validation procedure is first asiged a Validation Master Plan.
The Validation Process
It is a process of monitoring ,testing,and evaluation of all steps and process involved in a pharmaceutical manufacturing
.
Computer system Validation:
It requires that the software or programs which are utilized by pharmaceutical companies in manufacturing of pharmaceuticals should work without any error, it provides or leads to an accurate measures or activity .Example Dispensing of Raw Material using computarised system. Process control using a computarised system
In 21 CFR Part 11 this topic is covered in very detail and you can read it over here
Here screen shot prints are gathered to validate and document that the procedure adapted is leads to correct measures or activity
Sunday, March 21, 2010
Validation of Aseptic Process and Sterilisation
Media Fill Run to ensure the sterility Sterile dosage form evaluation of manufacturing process by Process Simulations /media fill run
Validation of sterile dosage form manufacturing is devided in to three parts
A. Process Simulations :
B. Filtration Efficacy.
C. Sterilization of Equipment, Containers, and Closures :
Filtration Efficacy and Sterilization of Equipment, Containers, and Closures are allready disscused.
In this article we will be focused on ( A. Process Simulations , ie.Media fill run)
We have answered following important regularly asked questions about media fill run.
1.Media Fill Study Design
2.Specific provisions in written procedures relating to aseptic processing
3. Duration of Media Fill Runs
5. Line Speed during media fill run
6. Environmental Conditions
7.Microbilogical Enrichment Media for Media Fill
8. Incubation and Examination of Media-Filled Units
9. Interpretation of Test Results in media fill run
10.Evaluation of state of aseptic line control
Apart from this article we have provided more information about media fill find it over here
http://whoguideline.blogspot.com/2009/07/media-fill-test-assurance-of-sterility.html
We have provided answere to your question , if media fill run fails , a case study
http://whoguideline.blogspot.com/2008/09/midia-fill-failed.html
-----------------------------------------------------------------------------------------------------------To ensure the sterility of products purporting to be sterile, sterilization, aseptic filling and closing operations must be adequately validated (CFR 211.113). The goal of even the most effective sterilization processes can be defeated if the sterilized elements of a product (the drug formulation, the container, and the closure) are brought together under conditions that contaminate any of those elements.
An aseptic processing operation should be validated using a microbiological growth medium in place of the product. This process simulation, also known as a media fill, normally includes exposing the microbiological growth medium to product contact surfaces of equipment, container closure systems, critical environments, and process manipulations to closely simulate the same exposure that the product itself will undergo. The sealed containers filled with the medium are then incubated to detect microbial contamination. Results are then interpreted to assess the potential for a unit of drug product to become contaminated during actual operations (e.g., start-up, sterile ingredient additions, aseptic connections, filling, closing). Environmental monitoring data from the process simulation can also provide useful information for the processing line evaluation.
1. Study Design
A media fill program should incorporate the contamination risk factors that occur on a production line, and accurately assesses the state of process control. Media fill studies should closely simulate aseptic manufacturing operations incorporating, as appropriate, worst-case activities and conditions that provide a challenge to aseptic operations.
FDA recommends that the media fill program address applicable issues such as:
1. Factors associated with the longest permitted run on the processing line that can pose contamination risk (e.g., operator fatigue)
3. Representative number, type, and complexity of normal interventions that occur with each run, as well as nonroutine interventions and events (e.g., maintenance, stoppages, equipment adjustments)
4. Lyophilization, when applicable
5. Aseptic assembly of equipment (e.g., at start-up, during processing)
6. Number of personnel and their activities
7. Representative number of aseptic additions (e.g., charging containers and closures as well as sterile ingredients) or transfers
8. Shift changes, breaks, and gown changes (when applicable)
9. Type of aseptic equipment disconnections/connections
10. Aseptic sample collections
11. Line speed and configuration
12.Weight checks
13. Container closure systems (e.g., sizes, type, compatibility with equipment)
2.Specific provisions in written procedures relating to aseptic processing (e.g., conditions permitted before line clearance is mandated)
A written batch record, documenting production conditions and simulated activities, should be prepared for each media fill run. The same vigilance should be observed in both media fill and routine production runs. The firm’s rationale for the conditions and activities simulated during the media fill should be clearly defined. Media fills should not be used to justify practices that pose unnecessary contamination risks.
A written batch record, documenting production conditions and simulated activities, should be prepared for each media fill run. The same vigilance should be observed in both media fill and routine production runs. The firm’s rationale for the conditions and activities simulated during the media fill should be clearly defined. Media fills should not be used to justify practices that pose unnecessary contamination risks.(One example might be the movement of personnel into and out of the aseptic processing and gowning change rooms during a shift change.)
All personnel who are authorized to enter the aseptic processing room during manufacturing, including technicians and maintenance personnel, should participate in a media fill at least once a year. Participation should be consistent with the nature of each operator’s duties during routine production.
Each change to a product or line change should be evaluated using a written change control system. Any changes or events that have the potential to affect the ability of the aseptic process to exclude contamination from the sterilized product should be assessed through additional media fills. For example, facility and equipment modifications, line configuration changes, significant changes in personnel, anomalies in environmental testing results, container closure system changes, extended shutdowns, or end product sterility testing showing contaminated products may be cause for revalidation of the system.
When data from a media fill indicate the process may not be in control, an investigation should be conducted to determine the origin of the contamination and the scope of the problem. Once corrections are instituted, process simulation run(s) should be performed to confirm that deficiencies have been corrected and the process has returned to a state of control. When an investigation fails to reach well-supported, substantive conclusions as to the cause of the media fill failure, three consecutive successful runs in tandem with increased scrutiny of the production process may be warranted.
3. Duration of Runs
The duration of aseptic processing operations is a major consideration in media fill design. Although the most accurate simulation model would be the full batch size and duration because it most closely simulates the actual production operations, other appropriate models can be justified. The duration of the media fill run should be determined by the time it takes to incorporate manipulations and interventions, as well as appropriate consideration of the duration of the actual aseptic processing operation. Interventions that commonly occur should be routinely simulated, while those occurring rarely can be simulated periodically.
While conventional manufacturing lines are usually automated, operated at relatively high speeds, and designed to limit operator intervention, some processes still include considerable operator involvement. When aseptic processing employs manual filling or closing, or extensive manual manipulations, the duration of the process simulation should generally be no less than the length of the actual manufacturing process to best simulate contamination risks posed by operators.
For lyophilization operations, FDA recommends that unsealed containers be exposed to partial evacuation of the chamber in a manner that simulates the process. Vials should not be frozen, and precautions should be taken that ensure that the medium remains in an aerobic state to avoid potentially inhibiting the growth of microorganisms.
4. Size of Runs
The simulation run sizes should be adequate to mimic commercial production conditions and accurately assess the potential for commercial batch contamination. The number of units filled during the process simulation should be based on contamination risk for a given process and sufficient to accurately simulate activities that are representative of the manufacturing process. A generally acceptable starting point for run size is in the range of 5,000 to 10,000 units. For operations with production sizes under 5,000, the number of media filled units should at least equal the maximum batch size made on the processing line.
When the possibility of contamination is higher based on the process design (e.g., manually intensive filling lines), a larger number of units, generally at or approaching the full production batch size, should be used. In contrast, a process conducted in an isolator can have a low risk of contamination because of the lack of direct human intervention and can be simulated with a lower number of units as a proportion of the overall operation.
Media fill size is an especially important consideration because some batches are produced over multiple shifts or yield an unusually large number of units. These factors should be carefully evaluated when designing the simulation to adequately encompass conditions and any potential risks associated with the larger operation.
5. Line Speed
The media fill program should adequately address the range of line speeds employed during production. Each media fill run should evaluate a single line speed, and the speed chosen should be justified. For example, use of high line speed is often most appropriate in the evaluation of manufacturing processes characterized by frequent interventions or a significant degree of manual manipulation. Use of slow line speed is generally appropriate for evaluating manufacturing processes with prolonged exposure of the sterile drug product and containers/closures in the aseptic area.
6. Environmental Conditions
Media fills should be adequately representative of the conditions under which actual manufacturing operations are conducted. An inaccurate assessment (making the process appear cleaner than it actually is) can result from conducting a media fill under extraordinary air particulate and microbial quality, or under production controls and precautions taken in preparation for the media fill. To the extent standard operating procedures permit stressful conditions (e.g., maximum number of personnel present and elevated activity level), it is important that media fills include analogous challenges to support the validity of these studies. Stressful conditions do not include artificially created environmental extremes, such as reconfiguration of HVAC systems to operate at worst-case limits.
7. Media
In general, a microbiological growth medium, such as soybean casein digest medium, should be used. Use of anaerobic growth media (e.g., fluid thioglycollate medium) should be considered in special circumstances. The media selected should be demonstrated to promote growth of gram-positive and gram-negative bacteria, and yeast and mold (e.g., USP indicator organisms). The QC laboratory should determine if USP indicator organisms sufficiently represent production-related isolates. Environmental monitoring and sterility test isolates can be substituted (as appropriate) or added to the growth promotion challenge. Growth promotion units should be inoculated with a <100>8. Incubation and Examination of Media-Filled Units
Media units should be incubated under conditions adequate to detect microorganisms that might otherwise be difficult to culture. Incubation conditions should be established in accord with the following general guidelines:
1. Incubation temperature should be suitable for recovery of bioburden and environmental isolates and should at no time be outside the range of 20-35oC. Incubation temperature should be maintained within +2.5oC of the target temperature.
2.Incubation time should not be less than 14 days. If two temperatures are used for the incubation of the media filled units, the units should be incubated for at least 7 days at each temperature (starting with the lower temperature).
Each media-filled unit should be examined for contamination by personnel with appropriate education, training, and experience in inspecting media fill units for microbiological contamination. If QC personnel do not perform the inspection, there should be QC unit oversight throughout any such examination. All suspect units identified during the examination should be brought to the immediate attention of the QC microbiologist. To allow for visual detection of microbial growth, we recommend substituting clear containers (with otherwise identical physical properties) for amber or other opaque containers. If appropriate, other methods can also be considered to ensure visual detection.
When a firm performs a final product inspection of units immediately following the media fill run, all integral units should proceed to incubation. Units found to have defects not related to integrity (e.g., cosmetic defect) should be incubated; units that lack integrity should be rejected. Erroneously rejected units should be returned promptly for incubation with the media fill lot.
After incubation is underway, any unit found to be damaged should be included in the data for the media fill run, because the units can be representative of drug product released to the market. Any decision to exclude such incubated units (i.e., non-integral) from the final run tally should be fully justified and the deviation explained in the media fill report. If a correlation emerges between difficult to detect damage and microbial contamination, a thorough investigation should be conducted to determine its cause
Written procedures regarding aseptic interventions should be clear and specific (e.g., intervention type; quantity of units removed), providing for consistent production practices and assessment of these practices during media fills. If written procedures and batch documentation are adequate to describe an associated clearance, the intervention units removed during media fills do not need to be incubated.(To assess contamination risks during initial aseptic setup (before fill), valuable information can be obtained by incubating all such units that may be normally removed. These units are typically incubated separately, and would not necessarily be included in the acceptance criteria for the media fill.
Where procedures lack specificity, there would be insufficient justification for exclusion of units removed during an intervention from incubation. For example, if a production procedure requires removal of 10 units after an intervention at the stoppering station infeed, batch records (i.e., for production and media fills) should clearly document conformance with this procedure. In no case should more units be removed during a media fill intervention than would be cleared during a production run.
The ability of a media fill run to detect potential contamination from a given simulated activity should not be compromised by a large-scale line clearance. We recommend incorporating appropriate study provisions to avoid and address a large line clearance that results in the removal of a unit possibly contaminated during an unrelated event or intervention.
Appropriate criteria should be established for yield (Total units incubated/total number of units filled.) and accountability (reconciliation of filled units). Media fill record reconciliation documentation should include a full accounting and description of units rejected from a batch.
9. Interpretation of Test Results
The process simulation run should be observed by the QC Unit, and contaminated units should be reconcilable with the approximate time and the activity being simulated during the media fill. Video recording of a media fill may serve as a useful aide in identifying personnel practices that could negatively affect the aseptic process.
Any contaminated unit should be considered objectionable and investigated. The microorganisms should be identified to species level. The investigation should survey the possible causes of contamination. In addition, any failure investigation should assess the impact on commercial drugs produced on the line since the last media fill.
Whenever contamination exists in a media fill run, it should be considered indicative of a potential sterility assurance problem, regardless of run size. The number of contaminated units should not be expected to increase in a directly proportional manner with the number of vials in the media fill run. Test results should reliably and reproducibly show that the units produced by an aseptic processing operation are sterile. Modern aseptic processing operations in suitably designed facilities have demonstrated a capability of meeting contamination levels approaching zero and should normally yield no media fill contamination.
10.
Recommended criteria for assessing state of aseptic line control are as follows:1. When filling fewer than 5000 units, no contaminated units should be detected. -- One (1) contaminated unit is considered cause for revalidation, following an investigation.
2. When filling from 5,000 to 10,000 units: -- One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill. -- Two (2) contaminated units are considered cause for revalidation, following investigation.
3.When filling more than 10,000 units: -- One (1) contaminated unit should result in an investigation. -- Two (2) contaminated units are considered cause for revalidation, following investigation.
For any run size, intermittent incidents of microbial contamination in media filled runs can be indicative of a persistent low-level contamination problem that should be investigated.
Accordingly, recurring incidents of contaminated units in media fills for an individual line, regardless of acceptance criteria, would be a signal of an adverse trend on the aseptic processing line that should lead to problem identification, correction, and revalidation.
A firm's use of media fill acceptance criteria allowing infrequent contamination does not mean that a distributed lot of drug product purporting to be sterile may contain a nonsterile unit. The purpose of an aseptic process is to prevent any contamination. A manufacturer is fully liable for the shipment of any nonsterile unit, an act that is prohibited under the FD&C Act (Section 301(a) 21 U.S.C. 331(a)). US FDA also recognizes that there might be some scientific and technical limitations on how precisely and accurately process simulations can characterize a system of controls intended to exclude contamination.
As with any process validation run, it is important to note that invalidation of a media fill run should be a rare occurrence. A media fill run should be aborted only under circumstances in which written procedures require commercial lots to be equally handled. Supporting documentation and justification should be provided in such cases.
Validation of sterile dosage form manufacturing is devided in to three parts
A. Process Simulations :
B. Filtration Efficacy.
C. Sterilization of Equipment, Containers, and Closures :
Filtration Efficacy and Sterilization of Equipment, Containers, and Closures are allready disscused.
In this article we will be focused on ( A. Process Simulations , ie.Media fill run)
We have answered following important regularly asked questions about media fill run.
1.Media Fill Study Design
2.Specific provisions in written procedures relating to aseptic processing
3. Duration of Media Fill Runs
5. Line Speed during media fill run
6. Environmental Conditions
7.Microbilogical Enrichment Media for Media Fill
8. Incubation and Examination of Media-Filled Units
9. Interpretation of Test Results in media fill run
10.Evaluation of state of aseptic line control
Apart from this article we have provided more information about media fill find it over here
http://whoguideline.blogspot.com/2009/07/media-fill-test-assurance-of-sterility.html
We have provided answere to your question , if media fill run fails , a case study
http://whoguideline.blogspot.com/2008/09/midia-fill-failed.html
-----------------------------------------------------------------------------------------------------------To ensure the sterility of products purporting to be sterile, sterilization, aseptic filling and closing operations must be adequately validated (CFR 211.113). The goal of even the most effective sterilization processes can be defeated if the sterilized elements of a product (the drug formulation, the container, and the closure) are brought together under conditions that contaminate any of those elements.
An aseptic processing operation should be validated using a microbiological growth medium in place of the product. This process simulation, also known as a media fill, normally includes exposing the microbiological growth medium to product contact surfaces of equipment, container closure systems, critical environments, and process manipulations to closely simulate the same exposure that the product itself will undergo. The sealed containers filled with the medium are then incubated to detect microbial contamination. Results are then interpreted to assess the potential for a unit of drug product to become contaminated during actual operations (e.g., start-up, sterile ingredient additions, aseptic connections, filling, closing). Environmental monitoring data from the process simulation can also provide useful information for the processing line evaluation.
1. Study Design
A media fill program should incorporate the contamination risk factors that occur on a production line, and accurately assesses the state of process control. Media fill studies should closely simulate aseptic manufacturing operations incorporating, as appropriate, worst-case activities and conditions that provide a challenge to aseptic operations.
FDA recommends that the media fill program address applicable issues such as:
1. Factors associated with the longest permitted run on the processing line that can pose contamination risk (e.g., operator fatigue)
3. Representative number, type, and complexity of normal interventions that occur with each run, as well as nonroutine interventions and events (e.g., maintenance, stoppages, equipment adjustments)
4. Lyophilization, when applicable
5. Aseptic assembly of equipment (e.g., at start-up, during processing)
6. Number of personnel and their activities
7. Representative number of aseptic additions (e.g., charging containers and closures as well as sterile ingredients) or transfers
8. Shift changes, breaks, and gown changes (when applicable)
9. Type of aseptic equipment disconnections/connections
10. Aseptic sample collections
11. Line speed and configuration
12.Weight checks
13. Container closure systems (e.g., sizes, type, compatibility with equipment)
2.Specific provisions in written procedures relating to aseptic processing (e.g., conditions permitted before line clearance is mandated)
A written batch record, documenting production conditions and simulated activities, should be prepared for each media fill run. The same vigilance should be observed in both media fill and routine production runs. The firm’s rationale for the conditions and activities simulated during the media fill should be clearly defined. Media fills should not be used to justify practices that pose unnecessary contamination risks.
A written batch record, documenting production conditions and simulated activities, should be prepared for each media fill run. The same vigilance should be observed in both media fill and routine production runs. The firm’s rationale for the conditions and activities simulated during the media fill should be clearly defined. Media fills should not be used to justify practices that pose unnecessary contamination risks.(One example might be the movement of personnel into and out of the aseptic processing and gowning change rooms during a shift change.)
All personnel who are authorized to enter the aseptic processing room during manufacturing, including technicians and maintenance personnel, should participate in a media fill at least once a year. Participation should be consistent with the nature of each operator’s duties during routine production.
Each change to a product or line change should be evaluated using a written change control system. Any changes or events that have the potential to affect the ability of the aseptic process to exclude contamination from the sterilized product should be assessed through additional media fills. For example, facility and equipment modifications, line configuration changes, significant changes in personnel, anomalies in environmental testing results, container closure system changes, extended shutdowns, or end product sterility testing showing contaminated products may be cause for revalidation of the system.
When data from a media fill indicate the process may not be in control, an investigation should be conducted to determine the origin of the contamination and the scope of the problem. Once corrections are instituted, process simulation run(s) should be performed to confirm that deficiencies have been corrected and the process has returned to a state of control. When an investigation fails to reach well-supported, substantive conclusions as to the cause of the media fill failure, three consecutive successful runs in tandem with increased scrutiny of the production process may be warranted.
3. Duration of Runs
The duration of aseptic processing operations is a major consideration in media fill design. Although the most accurate simulation model would be the full batch size and duration because it most closely simulates the actual production operations, other appropriate models can be justified. The duration of the media fill run should be determined by the time it takes to incorporate manipulations and interventions, as well as appropriate consideration of the duration of the actual aseptic processing operation. Interventions that commonly occur should be routinely simulated, while those occurring rarely can be simulated periodically.
While conventional manufacturing lines are usually automated, operated at relatively high speeds, and designed to limit operator intervention, some processes still include considerable operator involvement. When aseptic processing employs manual filling or closing, or extensive manual manipulations, the duration of the process simulation should generally be no less than the length of the actual manufacturing process to best simulate contamination risks posed by operators.
For lyophilization operations, FDA recommends that unsealed containers be exposed to partial evacuation of the chamber in a manner that simulates the process. Vials should not be frozen, and precautions should be taken that ensure that the medium remains in an aerobic state to avoid potentially inhibiting the growth of microorganisms.
4. Size of Runs
The simulation run sizes should be adequate to mimic commercial production conditions and accurately assess the potential for commercial batch contamination. The number of units filled during the process simulation should be based on contamination risk for a given process and sufficient to accurately simulate activities that are representative of the manufacturing process. A generally acceptable starting point for run size is in the range of 5,000 to 10,000 units. For operations with production sizes under 5,000, the number of media filled units should at least equal the maximum batch size made on the processing line.
When the possibility of contamination is higher based on the process design (e.g., manually intensive filling lines), a larger number of units, generally at or approaching the full production batch size, should be used. In contrast, a process conducted in an isolator can have a low risk of contamination because of the lack of direct human intervention and can be simulated with a lower number of units as a proportion of the overall operation.
Media fill size is an especially important consideration because some batches are produced over multiple shifts or yield an unusually large number of units. These factors should be carefully evaluated when designing the simulation to adequately encompass conditions and any potential risks associated with the larger operation.
5. Line Speed
The media fill program should adequately address the range of line speeds employed during production. Each media fill run should evaluate a single line speed, and the speed chosen should be justified. For example, use of high line speed is often most appropriate in the evaluation of manufacturing processes characterized by frequent interventions or a significant degree of manual manipulation. Use of slow line speed is generally appropriate for evaluating manufacturing processes with prolonged exposure of the sterile drug product and containers/closures in the aseptic area.
6. Environmental Conditions
Media fills should be adequately representative of the conditions under which actual manufacturing operations are conducted. An inaccurate assessment (making the process appear cleaner than it actually is) can result from conducting a media fill under extraordinary air particulate and microbial quality, or under production controls and precautions taken in preparation for the media fill. To the extent standard operating procedures permit stressful conditions (e.g., maximum number of personnel present and elevated activity level), it is important that media fills include analogous challenges to support the validity of these studies. Stressful conditions do not include artificially created environmental extremes, such as reconfiguration of HVAC systems to operate at worst-case limits.
7. Media
In general, a microbiological growth medium, such as soybean casein digest medium, should be used. Use of anaerobic growth media (e.g., fluid thioglycollate medium) should be considered in special circumstances. The media selected should be demonstrated to promote growth of gram-positive and gram-negative bacteria, and yeast and mold (e.g., USP indicator organisms). The QC laboratory should determine if USP indicator organisms sufficiently represent production-related isolates. Environmental monitoring and sterility test isolates can be substituted (as appropriate) or added to the growth promotion challenge. Growth promotion units should be inoculated with a <100>8. Incubation and Examination of Media-Filled Units
Media units should be incubated under conditions adequate to detect microorganisms that might otherwise be difficult to culture. Incubation conditions should be established in accord with the following general guidelines:
1. Incubation temperature should be suitable for recovery of bioburden and environmental isolates and should at no time be outside the range of 20-35oC. Incubation temperature should be maintained within +2.5oC of the target temperature.
2.Incubation time should not be less than 14 days. If two temperatures are used for the incubation of the media filled units, the units should be incubated for at least 7 days at each temperature (starting with the lower temperature).
Each media-filled unit should be examined for contamination by personnel with appropriate education, training, and experience in inspecting media fill units for microbiological contamination. If QC personnel do not perform the inspection, there should be QC unit oversight throughout any such examination. All suspect units identified during the examination should be brought to the immediate attention of the QC microbiologist. To allow for visual detection of microbial growth, we recommend substituting clear containers (with otherwise identical physical properties) for amber or other opaque containers. If appropriate, other methods can also be considered to ensure visual detection.
When a firm performs a final product inspection of units immediately following the media fill run, all integral units should proceed to incubation. Units found to have defects not related to integrity (e.g., cosmetic defect) should be incubated; units that lack integrity should be rejected. Erroneously rejected units should be returned promptly for incubation with the media fill lot.
After incubation is underway, any unit found to be damaged should be included in the data for the media fill run, because the units can be representative of drug product released to the market. Any decision to exclude such incubated units (i.e., non-integral) from the final run tally should be fully justified and the deviation explained in the media fill report. If a correlation emerges between difficult to detect damage and microbial contamination, a thorough investigation should be conducted to determine its cause
Written procedures regarding aseptic interventions should be clear and specific (e.g., intervention type; quantity of units removed), providing for consistent production practices and assessment of these practices during media fills. If written procedures and batch documentation are adequate to describe an associated clearance, the intervention units removed during media fills do not need to be incubated.(To assess contamination risks during initial aseptic setup (before fill), valuable information can be obtained by incubating all such units that may be normally removed. These units are typically incubated separately, and would not necessarily be included in the acceptance criteria for the media fill.
Where procedures lack specificity, there would be insufficient justification for exclusion of units removed during an intervention from incubation. For example, if a production procedure requires removal of 10 units after an intervention at the stoppering station infeed, batch records (i.e., for production and media fills) should clearly document conformance with this procedure. In no case should more units be removed during a media fill intervention than would be cleared during a production run.
The ability of a media fill run to detect potential contamination from a given simulated activity should not be compromised by a large-scale line clearance. We recommend incorporating appropriate study provisions to avoid and address a large line clearance that results in the removal of a unit possibly contaminated during an unrelated event or intervention.
Appropriate criteria should be established for yield (Total units incubated/total number of units filled.) and accountability (reconciliation of filled units). Media fill record reconciliation documentation should include a full accounting and description of units rejected from a batch.
9. Interpretation of Test Results
The process simulation run should be observed by the QC Unit, and contaminated units should be reconcilable with the approximate time and the activity being simulated during the media fill. Video recording of a media fill may serve as a useful aide in identifying personnel practices that could negatively affect the aseptic process.
Any contaminated unit should be considered objectionable and investigated. The microorganisms should be identified to species level. The investigation should survey the possible causes of contamination. In addition, any failure investigation should assess the impact on commercial drugs produced on the line since the last media fill.
Whenever contamination exists in a media fill run, it should be considered indicative of a potential sterility assurance problem, regardless of run size. The number of contaminated units should not be expected to increase in a directly proportional manner with the number of vials in the media fill run. Test results should reliably and reproducibly show that the units produced by an aseptic processing operation are sterile. Modern aseptic processing operations in suitably designed facilities have demonstrated a capability of meeting contamination levels approaching zero and should normally yield no media fill contamination.
10.
Recommended criteria for assessing state of aseptic line control are as follows:1. When filling fewer than 5000 units, no contaminated units should be detected. -- One (1) contaminated unit is considered cause for revalidation, following an investigation.
2. When filling from 5,000 to 10,000 units: -- One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill. -- Two (2) contaminated units are considered cause for revalidation, following investigation.
3.When filling more than 10,000 units: -- One (1) contaminated unit should result in an investigation. -- Two (2) contaminated units are considered cause for revalidation, following investigation.
For any run size, intermittent incidents of microbial contamination in media filled runs can be indicative of a persistent low-level contamination problem that should be investigated.
Accordingly, recurring incidents of contaminated units in media fills for an individual line, regardless of acceptance criteria, would be a signal of an adverse trend on the aseptic processing line that should lead to problem identification, correction, and revalidation.
A firm's use of media fill acceptance criteria allowing infrequent contamination does not mean that a distributed lot of drug product purporting to be sterile may contain a nonsterile unit. The purpose of an aseptic process is to prevent any contamination. A manufacturer is fully liable for the shipment of any nonsterile unit, an act that is prohibited under the FD&C Act (Section 301(a) 21 U.S.C. 331(a)). US FDA also recognizes that there might be some scientific and technical limitations on how precisely and accurately process simulations can characterize a system of controls intended to exclude contamination.
As with any process validation run, it is important to note that invalidation of a media fill run should be a rare occurrence. A media fill run should be aborted only under circumstances in which written procedures require commercial lots to be equally handled. Supporting documentation and justification should be provided in such cases.
BATCH MANUFACTURING RECORD REVIEW: PROCESS CONTROL DOCUMENTATION
BATCH MANUFACTURING RECORD REVIEW: STERILE PHARMACEUTICAL MANUFACTURING PROCESS CONTROL DOCUMENTATION
Manufacturers should build process and environmental control activities into their aseptic processing operation. It is critical that these activities be maintained and strictly implemented on a daily basis. The requirement for review of all batch records and data for conformance with written procedures, operating parameters, and product specifications prior to arriving at the final release decision for an aseptically processed product calls for an overall review of process and system performance for that given cycle of manufacture. All in-process and laboratory control results must be included with the batch record documentation in accordance with section 211.188. Review of environmental and personnel monitoring data, as well as other data relating to acceptability of output from support systems (e.g., HEPA / HVAC, WFI, steam generator) and proper functioning of equipment (e.g., batch alarms report; integrity of various filters) are considered essential elements of the batch release decision.
While interventions and/or stoppages are normally recorded in the batch record, the manner of documenting these occurrences varies. In particular, line stoppages and any unplanned interventions should be sufficiently documented in batch records with the associated time and duration of the event. In addition to lengthened dwell time of sterile product elements in the critical area, an extensive intervention can increase contamination risk. Sterility failures have often been attributed to atypical or extensive interventions that have occurred as a response to an undesirable event during the aseptic process. Written procedures describing the need for line clearances in the event of certain interventions, such as machine adjustments and any repairs, should be established. Such interventions should be documented with more detail than minor events. Interventions that result in substantial activity near exposed product or container closures or that last beyond a reasonable exposure time should, where appropriate, result in a local or full line clearance.
Any disruption in power supply, however momentary, that could affect product quality is a manufacturing deviation and must be included in batch records (CFR 211.100, 211.192).
Regulations pertaining to sterile pharmaceutical manufacturing , batch reveiw records
21 CFR 211.100(a) states that “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.”
21 CFR 211.100(b) states that “Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.”
21 CFR 211.186 and 211.188 address, respectively, "Master production and control records" and "Batch production and control records."
21 CFR 211.192 states that “All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup.”
Manufacturers should build process and environmental control activities into their aseptic processing operation. It is critical that these activities be maintained and strictly implemented on a daily basis. The requirement for review of all batch records and data for conformance with written procedures, operating parameters, and product specifications prior to arriving at the final release decision for an aseptically processed product calls for an overall review of process and system performance for that given cycle of manufacture. All in-process and laboratory control results must be included with the batch record documentation in accordance with section 211.188. Review of environmental and personnel monitoring data, as well as other data relating to acceptability of output from support systems (e.g., HEPA / HVAC, WFI, steam generator) and proper functioning of equipment (e.g., batch alarms report; integrity of various filters) are considered essential elements of the batch release decision.
While interventions and/or stoppages are normally recorded in the batch record, the manner of documenting these occurrences varies. In particular, line stoppages and any unplanned interventions should be sufficiently documented in batch records with the associated time and duration of the event. In addition to lengthened dwell time of sterile product elements in the critical area, an extensive intervention can increase contamination risk. Sterility failures have often been attributed to atypical or extensive interventions that have occurred as a response to an undesirable event during the aseptic process. Written procedures describing the need for line clearances in the event of certain interventions, such as machine adjustments and any repairs, should be established. Such interventions should be documented with more detail than minor events. Interventions that result in substantial activity near exposed product or container closures or that last beyond a reasonable exposure time should, where appropriate, result in a local or full line clearance.
Any disruption in power supply, however momentary, that could affect product quality is a manufacturing deviation and must be included in batch records (CFR 211.100, 211.192).
Regulations pertaining to sterile pharmaceutical manufacturing , batch reveiw records
21 CFR 211.100(a) states that “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.”
21 CFR 211.100(b) states that “Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.”
21 CFR 211.186 and 211.188 address, respectively, "Master production and control records" and "Batch production and control records."
21 CFR 211.192 states that “All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup.”
Wednesday, February 24, 2010
Dry Vapour Disinfection Validation
Validation is achieved through the incubation of spore strips that have been exposed to the hydrogen peroxide vapour during the disinfection process. It is normal practice to place the spore strips in areas of the facility thought to be most inaccessible to the vapour (the strips must be retrievable without being compromised).
Hydrogen Peroxide Vapour
Validation spore strips & recovery media
The spore strips are stainless steel, oblong discs inoculated with Geobacillus stearothermophilius and are specifically for use in hydrogen peroxide vapour. Each strip or disc contains a standard spore population of 106. Geobacillus stearothermophilius is a commonly used indicator organism to verify the efficacy of sterilisation and disinfection procedures and is not harmful to humans.
Dry Vapour Disinfection Validation
Incubation & validation process
A control strip which has not been subjected to the dry vapour is placed in to recovery media and incubated, with the exposed strips from the facility, at 56°C. The tubes of media are checked for signs of growth, indicated by a change in colour, at the pre determined intervals for a period of 7 days. No colour change indicates that the disinfection process was sufficient to achieve the expected parameters and kill the test microorganisms.
The result of each spore strip used is recorded and a detailed report is provided after the 7 day period, however, no change after 1 – 2 days is usually indicative of a successful disinfection process.
Hydrogen peroxide vapour has been shown to bio-deactivate a wide range of micro-organisms including:
- Endospore-forming bacteria
- Vegetative bacteria
- Atypical bacteria
- Viruses
- Fungi
During the delivery of the disinfection process Bio decontamination Ltd perform “real time humidity reporting” that produces an immediate indication of the success of the process. The data forms part of a comprehensive report provided to our clients.
Aspects of Validation of Aseptic Process and Sterilisation , (Process Simulations "Media Fill " , Filtration Efficacy , Sterilization of Equipment, Co
VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION
In this series of articles we are going to disscus aspects of Validation of Aseptic Process and Sterilisation routine qualifications and validation study recommendations .
Change control procedures are an important part of the quality systems established by any firm.
A change in facility, equipment, process, or test method should be evaluated through the written change control program, triggering an evaluation of the need for revalidation or requalification.
We have divided topic "Aspects of Validation of Aseptic Process and Sterilisation" in to three parts .
A. Process Simulations :
B. Filtration Efficacy. ( Filtration Efficacy will be discusses in this article )
C. Sterilization of Equipment, Containers, and Closures ,
( In next article we will be writing about this aspect "Sterilization of Equipment, Containers, and Closures ".
B. Filtration Efficacy.
Filtration is a common method of sterilizing drug product solutions. A sterilizing grade filter should be validated to reproducibly remove viable microorganisms from the process stream, producing a sterile effluent ( This article does not address virus removal ).
Currently, such filters usually have a rated pore size of 0.2 μm or smaller (0.22μ and 0.2μ are considered interchangeable nominal pore size ratings ).
Use of redundant sterilizing filters should be considered in many cases. Whatever filter or combination of filters is used, validation should include microbiological challenges to simulate worst-case production conditions for the material to be filtered and integrity test results of the filters used for the study. Product bioburden should be evaluated when selecting a suitable challenge microorganism to assess which microorganism represents the worst-case challenge to the filter. The microorganism Brevundimonas diminuta (ATCC 19146) when properly grown, harvested and used, is a common challenge microorganism for 0.2 μm rated filters because of its small size (0.3 μm mean diameter). The manufacturing process controls should be designed to minimize the bioburden of the unfiltered product. Bioburden of unsterilized bulk solutions should be determined to trend the characteristics of potentially contaminating organisms.
In certain cases, when justified as equivalent or better than use of B. diminuta, it may be appropriate to conduct bacterial retention studies with a bioburden isolate. The number of microorganisms in the challenge is important because a filter can contain a number of pores larger than the nominal rating, which has the potential to allow passage of microorganisms. The probability of such passage is considered to increase as the number of organisms (bioburden) in the material to be filtered increases. A challenge concentration of at least 107 organisms per cm2 of effective filtration area should generally be used, resulting in no passage of the challenge microorganism. The challenge concentration used for validation is intended to provide a margin of safety well beyond what would be expected in production.
Direct inoculation into the drug formulation is the preferred method because it provides an assessment of the effect of drug product on the filter matrix and on the challenge organism. However, directly inoculating B. diminuta into products with inherent bactericidal activity against this microbe, or into oil-based formulations, can lead to erroneous conclusions. When sufficiently justified, the effects of the product formulation on the membrane's integrity can be assessed using an appropriate alternate method. For example, a drug product could be filtered in a manner in which the worst-case combination of process specifications and conditions are simulated. This step could be followed by filtration of the challenge organism for a significant period of time, under the same conditions, using an appropriately modified product (e.g., lacking an antimicrobial preservative or other antimicrobial component) as the vehicle. Any divergence from a simulation using the actual product and conditions of processing should be justified.
Factors that can affect filter performance generally include (1) viscosity and surface tension of the material to be filtered, (2) pH, (3) compatibility of the material or formulation components with the filter itself, (4) pressures, (5) flow rates, (6) maximum use time, (7) temperature, (8) osmolality, (9) and the effects of hydraulic shock. When designing the validation protocol, it is important to address the effect of the extremes of processing factors on the filter capability to produce sterile effluent. Filter validation should be conducted using the worst-case conditions, such as maximum filter use time and pressure (Ref. 12). Filter validation experiments, including microbial challenges, need not be conducted in the actual manufacturing areas. However, it is essential that laboratory experiments simulate actual production conditions. The specific type of filter membrane used in commercial production should be evaluated in filter validation studies. There are advantages to using production filters in these bacterial retention validation studies. When the more complex filter validation tests go beyond the capabilities of the filter user, tests are often conducted by outside laboratories or by filter manufacturers. However, it is the responsibility of the filter user to review the validation data on the efficacy of the filter in producing a sterile effluent. The data should be applicable to the user's products and conditions of use because filter performance may differ significantly for various conditions and products.
After a filtration process is properly validated for a given product, process, and filter, it is important to ensure that identical filters (e.g., of identical polymer construction and pore size rating) are used in production runs. Sterilizing filters should be routinely discarded after processing of a single lot. However, in those instances when repeated use can be justified, the sterile filter validation should incorporate the maximum number of lots to be processed. Integrity testing of the filter(s) can be performed prior to processing, and should be routinely performed post-use. It is important that integrity testing be conducted after filtration to detect any filter leaks or perforations that might have occurred during the filtration. Forward flow and bubble point tests, when appropriately employed, are two integrity tests that can be used. A production filter’s integrity test specification should be consistent with data generated during bacterial retention validation studies.
Regulatory Aspects for This article .
21 CFR 211.63, 211.65, and 211.67 address, respectively, to the aspects of “Equipment design, size, and location,” “Equipment construction,” and “Equipment cleaning and maintenance.”
21 CFR 211.84(c) mentions, in part, that “Samples shall be collected in accordance with the following procedures: (3) Sterile equipment and aseptic sampling techniques shall be used when necessary.”
21 CFR 211.100(a) mentions , in part, that “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart.”
21 CFR 211.113(b) mentions that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.”
In this series of articles we are going to disscus aspects of Validation of Aseptic Process and Sterilisation routine qualifications and validation study recommendations .
Change control procedures are an important part of the quality systems established by any firm.
A change in facility, equipment, process, or test method should be evaluated through the written change control program, triggering an evaluation of the need for revalidation or requalification.
We have divided topic "Aspects of Validation of Aseptic Process and Sterilisation" in to three parts .
A. Process Simulations :
B. Filtration Efficacy. ( Filtration Efficacy will be discusses in this article )
C. Sterilization of Equipment, Containers, and Closures ,
( In next article we will be writing about this aspect "Sterilization of Equipment, Containers, and Closures ".
B. Filtration Efficacy.
Filtration is a common method of sterilizing drug product solutions. A sterilizing grade filter should be validated to reproducibly remove viable microorganisms from the process stream, producing a sterile effluent ( This article does not address virus removal ).
Currently, such filters usually have a rated pore size of 0.2 μm or smaller (0.22μ and 0.2μ are considered interchangeable nominal pore size ratings ).
Use of redundant sterilizing filters should be considered in many cases. Whatever filter or combination of filters is used, validation should include microbiological challenges to simulate worst-case production conditions for the material to be filtered and integrity test results of the filters used for the study. Product bioburden should be evaluated when selecting a suitable challenge microorganism to assess which microorganism represents the worst-case challenge to the filter. The microorganism Brevundimonas diminuta (ATCC 19146) when properly grown, harvested and used, is a common challenge microorganism for 0.2 μm rated filters because of its small size (0.3 μm mean diameter). The manufacturing process controls should be designed to minimize the bioburden of the unfiltered product. Bioburden of unsterilized bulk solutions should be determined to trend the characteristics of potentially contaminating organisms.
In certain cases, when justified as equivalent or better than use of B. diminuta, it may be appropriate to conduct bacterial retention studies with a bioburden isolate. The number of microorganisms in the challenge is important because a filter can contain a number of pores larger than the nominal rating, which has the potential to allow passage of microorganisms. The probability of such passage is considered to increase as the number of organisms (bioburden) in the material to be filtered increases. A challenge concentration of at least 107 organisms per cm2 of effective filtration area should generally be used, resulting in no passage of the challenge microorganism. The challenge concentration used for validation is intended to provide a margin of safety well beyond what would be expected in production.
Direct inoculation into the drug formulation is the preferred method because it provides an assessment of the effect of drug product on the filter matrix and on the challenge organism. However, directly inoculating B. diminuta into products with inherent bactericidal activity against this microbe, or into oil-based formulations, can lead to erroneous conclusions. When sufficiently justified, the effects of the product formulation on the membrane's integrity can be assessed using an appropriate alternate method. For example, a drug product could be filtered in a manner in which the worst-case combination of process specifications and conditions are simulated. This step could be followed by filtration of the challenge organism for a significant period of time, under the same conditions, using an appropriately modified product (e.g., lacking an antimicrobial preservative or other antimicrobial component) as the vehicle. Any divergence from a simulation using the actual product and conditions of processing should be justified.
Factors that can affect filter performance generally include (1) viscosity and surface tension of the material to be filtered, (2) pH, (3) compatibility of the material or formulation components with the filter itself, (4) pressures, (5) flow rates, (6) maximum use time, (7) temperature, (8) osmolality, (9) and the effects of hydraulic shock. When designing the validation protocol, it is important to address the effect of the extremes of processing factors on the filter capability to produce sterile effluent. Filter validation should be conducted using the worst-case conditions, such as maximum filter use time and pressure (Ref. 12). Filter validation experiments, including microbial challenges, need not be conducted in the actual manufacturing areas. However, it is essential that laboratory experiments simulate actual production conditions. The specific type of filter membrane used in commercial production should be evaluated in filter validation studies. There are advantages to using production filters in these bacterial retention validation studies. When the more complex filter validation tests go beyond the capabilities of the filter user, tests are often conducted by outside laboratories or by filter manufacturers. However, it is the responsibility of the filter user to review the validation data on the efficacy of the filter in producing a sterile effluent. The data should be applicable to the user's products and conditions of use because filter performance may differ significantly for various conditions and products.
After a filtration process is properly validated for a given product, process, and filter, it is important to ensure that identical filters (e.g., of identical polymer construction and pore size rating) are used in production runs. Sterilizing filters should be routinely discarded after processing of a single lot. However, in those instances when repeated use can be justified, the sterile filter validation should incorporate the maximum number of lots to be processed. Integrity testing of the filter(s) can be performed prior to processing, and should be routinely performed post-use. It is important that integrity testing be conducted after filtration to detect any filter leaks or perforations that might have occurred during the filtration. Forward flow and bubble point tests, when appropriately employed, are two integrity tests that can be used. A production filter’s integrity test specification should be consistent with data generated during bacterial retention validation studies.
Regulatory Aspects for This article .
21 CFR 211.63, 211.65, and 211.67 address, respectively, to the aspects of “Equipment design, size, and location,” “Equipment construction,” and “Equipment cleaning and maintenance.”
21 CFR 211.84(c) mentions, in part, that “Samples shall be collected in accordance with the following procedures: (3) Sterile equipment and aseptic sampling techniques shall be used when necessary.”
21 CFR 211.100(a) mentions , in part, that “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart.”
21 CFR 211.113(b) mentions that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.”
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