| Validation of processes for surface preparation is crucial to many industries, including pharmaceuticals, biomedical device and even food preparation. The effectiveness of the methods for surface preparation in these industries should be established, documented and monitored on an on-going basis. Validation helps ensure that the surface has been cleaned to an acceptable contamination level. This maximum tolerable contamination level may be termed the target level. Sampling and analysis techniques must have the specificity, sensitivity, reliability and robustness to assure that contamination does not exceed the target limit. The areas of surface where contamination is most adherent or where the negative consequences of contamination are greatest must receive special attention. The nature of potential contaminants must also be considered. While much attention is paid to biological debris, microbes, and pyrogens, other organic and inorganic contaminants can potentially impact product quality. As applied to processes for surface preparation, validation is a quantifiable, structured approach to demonstrate and document process effectiveness and process consistency. The following are suggestions for a comprehensive validation process. Process efficacy must be evaluated prior to implementing the procedure. The procedure should require re-validation after changes to the processes that may significantly affect the types and amount of contamination left on the surface, or when significant changes are made to the cleaning process and result of re-validation must be documented.Some general considerations in establishing target levels include the effect of different levels of contamination on the success of subsequent operations; the detection capability of the various analytical techniques available; the anticipated end-use and performance requirement of the product; and the economic and social cost of non-conformance or failure. |
Tuesday, April 20, 2010
In and Out Validating Processes For Surface Preparation
By: Barbara Kanegsberg and Mantosh Chawla
Single Use Products Dispose of Cleaning
Holly Haughney, Ph.D., Hazel Aranha, Ph.D., RAC
Faster processing, improved quality assurance, and simplified cleaning validation are critical factors fueling the impetus towards disposable systems for pharmaceuticals and biopharmaceuticals processing. While the concept of a completely disposable manufacturing process would have been considered utopian a few years ago, today it is just another shift in the manufacturing paradigm. New aseptic processing initiatives by FDA have spurred greater interest in disposable processing systems as a way to minimize opportunities for product cross-contamination and to aid in compliance.
Disposable Systems Eclipse Stainless Steel
The elimination of cleaning and cleaning validation is a significant benefit of disposable processing. Cleaning process equipment consumes time and valuable operator resources. Cleaning chemicals require suitable handling systems for the delivery and disposal of the fluids. Care must also be taken to use these chemicals in the appropriate concentrations to ensure that they perform their specified function. In addition, proper handling techniques are needed to ensure that the system is properly cleaned and that the operators are protected from contact with potentially hazardous cleaning fluids.
During the cleaning of stainless steel systems the filter housings are typically dismantled prior to cleaning. Following cleaning, stainless steel hard-piped systems must be rinsed with a suitable amount of water to ensure that the residual cleaning fluid is removed. For some applications, the cost of the cleaning operation increases when water for injection (WFI) is required for the system flush. Following each cleaning and flushing, the systems must be re-assembled and re-sterilized, which adds further time to the operation as well as increases labor costs.
Perhaps the most critical element of cleaning is validation of the process. Complicated cleaning processes are cumbersome to document, and it is even harder to prove that traces of the cleaning chemicals have been removed. Instead of having to prove that the cleaning has been effective, disposable systems are used one time and discarded. Gaps in cleaning validation documentation can cause regulatory scrutiny, and in the worst case, production of new or existing products is delayed. Failure to execute specified cleaning standard operating procedures (SOPs) are a non-compliance. For example, in the case of caustic solutions (often used for cleaning), if the concentration of the caustic is incorrect or if the temperature of the cleaning fluid used is not at the SOP-specified temperature, the validity of the cleaning process may be questioned.
Disposable systems also offer drug developers an alternative in terms of sterilization. While stainless steel systems are confined to steam sterilization processes, either autoclave or steam-in-place (SIP), disposable systems can be purchased pre-sterilized by gamma irradiation. Existing steam sterilization processes can also be used for the disposable capsule filters. Most capsule filters can be subjected to sterilization by autoclave, and some capsules (which have suitable materials of construction) can also be subjected to SIP.
Disposable products that are supplied pre-sterilized by gamma irradiation eliminate the need for sterilization and sterilization validation procedures and can reduce the maintenance of sterilization equipment. The user can essentially remove the product from its package and install it in the process. The disposable product supplier provides validation documentation. While the cost of sterilization by gamma irradiation is comparable to that of traditional steam sterilization methods, the gamma irradiation process reduces labor, and circumvents many of the potential issues associated with in-house steam sterilization. For example, if condensate has not been properly drained from a filter that has been steamed in place, the filter membrane could become wet out. The bubble point of the membrane must be exceeded to expel the fluid from the pores and allow steam penetration. This situation could lead to an extended steam cycle, or in the worst case, damage the filter due to excessive pressure in the forward direction, if an increased pressure is used to expel fluid at an elevated temperature.
A Myriad of Disposable Applications
Disposable products have a growing presence in filtration, purification and separation applications used to make a wide range of biopharmaceuticals, such as vaccines, monoclonal antibodies, and patient specific treatments. Small-scale tangential flow filters (TFF), direct flow filters (DFF) of all sizes, and membrane chromatography units are available for use in single-use systems. In addition, these capsules can be assembled with bioprocessing bags, tubing, valves or clamps, and connection devices to form fully integrated single-use filtration systems. Disposable filters can also be manifolded together to maximize processing capacity.
Disposable products are available in a range of sizes, making them ideal for use at every stage of drug development, from discovery to production. Single-use products that use the same materials of construction minimize re-validation requirements as a new process is scaled up.
The tubing used in these systems is usually clear and the capsule filters are typically designed with clear or translucent housings. This design feature allows operators to observe fluid levels and flow, as well as to detect fluid discoloration and air pockets, thereby enabling problems to be immediately identified and addressed.
Disposable Products in Different Manufacturing Scenarios
High-growth biotechnology companies, large pharmaceutical companies and contract manufacturers stand to gain significant speed, safety and cost saving benefits from using disposable systems.
A disposable processing approach is especially cost-effective and efficient for start-up biotech companies that do not have hard-piped processing systems already in place. As many biotech start-ups have not fully defined their operating parameters, single-use products can save them from making premature investments in capital equipment. In a market where funding can be scarce, single-use products provide an effective cost and labor saving strategy. In addition, the timeliness of making a batch for clinical trials can be crucial for the timeline of development, and disposable systems can be assembled much faster than a comparable hard piped system. For these reasons, the trend towards building a disposable infrastructure from the ground up is building momentum in this sector.
Large pharmaceutical companies have a slightly different motivation for incorporating disposable systems into their drug processes. Cost, capacity and compliance issues are the deciding factors in this sector. The time and labor spent to dismantle, clean, and re-sterilize stainless steel products is performed at considerable cost to large pharmaceutical companies. Time required to meet the FDA’s stringent requirement for documentation on cleaning and cleaning validation procedures is eliminated as the systems are intended for single use. Expansion of an existing process can be more cost-effective with a shorter timeline for the expansion if disposable system components are used. A further benefit for pharmaceutical companies is that it is possible to change an existing filtration process to a disposable process train thus eliminating cleaning and cleaning validation as well as system assembly requirements. This is a viable option since the filters used in stainless steel housings and the filter capsules use the same materials of construction, thus avoiding extensive re-validation.
Single-use products help contract manufacturers reduce cross-contamination risks, upfront equipment costs, space requirements, and complicated cleaning and cleaning validation procedures. This increases profit margin, enhances safety, and reduces compliance concerns, enabling pharmaceutical and biotech product manufacturers and contract manufacturing facilities to be more competitive in a growing market.
Disposability at the Point of Connection
With multiple connection points required in disposable processing operations, the connection method has considerable influence over the speed and safety of the whole process. Current methods include quick connectors, which require assembly under a laminar flow hood and tubing welders that mandate the use of a welding device.
The key to streamlining aseptic connections is to reduce the total number of steps needed to complete the process. Despite the name “quick connector,” it can take up to 18 minutes to make a connection with such a device. This is due to the fact that operations must be performed under a laminar flow hood, which generally requires 15 - 20 minutes to set up, or in a laminar flow environment, which may or may not be readily accessible, depending upon the layout of the facility. By contrast, a connection can be made anywhere in the facility in seconds with a new connector (Pall Kleenpak™ connector) (Table 1) because it does not require the use of a laminar flow environment, or any other capital equipment. Beyond the time required to set up and make the connection, laminar flow hoods are costly, require maintenance, and take up precious space in a cramped environment.
A connector that requires only a few simple hand movements reduces the risks of operator error. With operation of equipment, such as a laminar flow hood or tubing welder, comes increased opportunity for incorrect usage. For example, laminar flow hoods require the use of HEPA filters and these filters are changed-out on a schedule and tested. If a HEPA filter fails the post use test, then all connections between the change out period are at risk of contamination. The need to maintain and document maintenance for these types of equipment give drug developers further reason to take a simpler approach to aseptic connections. Both tubing welders and laminar flow hoods also require validation, adding to the number of steps involved in the connection process, and ultimately slowing down development.
Disposable Processing Benefits as They Relate to Filters
Available for direct flow filtration (DFF) and tangential flow filtration (TFF) applications, disposable filters demonstrate strong cost and time savings over their stainless steel counterparts by eliminating the need to assemble, clean and validate cleaning of the units (Table 2). Like single-use aseptic connectors, disposable filters can also be supplied pre-sterilized by gamma irradiation, avoiding the need for SIP or autoclave sterilization processes.
Ease of scalability provides long-term economic justification for the use of disposable filter systems. By using filters that are made of the same materials of construction, process volumes can be scaled from 100 ml at the bench stage, to thousands of liters at production scale with minimal re-validation. Single-use filters can also be manifolded together to increase processing volume without necessarily increasing the filter size as a further means of simplifying scale-up. A smaller footprint, which is characteristic of single-use systems, maximizes limited space in facilities to increase manufacturing capacity.
Assembled Single-Use Systems Maximize Benefits
The benefits of single-use system components increase when they are assembled together. A typical single-use filtration system combines multiple filter elements, bioprocessing bags, clamps, tubing and connection devices to form a fully integrated, pre-sterilized solution for filtration applications. The drug product manufacturer receives a fully assembled, pre-sterilized filtration system. This not only saves assembly, cleaning and sterilization time, but it also significantly reduces the chances for operator error.
The entire single-use filtration system can be gamma irradiated prior to delivery to the biopharmaceutical manufacturing site. These filtration systems are offered in a range of sizes, so that corresponding filters and bags are available for every stage of development. This ensures that the most appropriate and economical disposable filter scheme is used. By using the same materials of construction, these systems also ensure reproducible results during scale up. Together, thesefactors can streamline drug development to increase manufacturing capacity, while meeting validation requirements.
Factors Driving Change in the Drug Development Arena
Ongoing globalization, revolutionary technological breakthroughs, and government regulation and deregulation, have consistently impacted the pharmaceutical industry landscape in recent years. The overriding concerns of the biotechnology and pharmaceutical industries are regulatory and compliance issues, insufficient manufacturing capacity, and addressing the economic challenges of producing niche drugs and therapies.
Disposable systems reduce possibilities for non-compliance as related to system validation and cleaning issues. They improve the economic feasibility of producing niche drugs by enabling faster, more cost-effective product changeovers. Disposable systems ease the manufacturing capacity crunch by simplifying scale-up, eliminating process steps maximizing throughput, and speeding product changeovers. All this streamlines manufacturing and allows the manufacturers to respond nimbly to the dynamic marketplace.
Faster processing, improved quality assurance, and simplified cleaning validation are critical factors fueling the impetus towards disposable systems for pharmaceuticals and biopharmaceuticals processing. While the concept of a completely disposable manufacturing process would have been considered utopian a few years ago, today it is just another shift in the manufacturing paradigm. New aseptic processing initiatives by FDA have spurred greater interest in disposable processing systems as a way to minimize opportunities for product cross-contamination and to aid in compliance.
Disposable Systems Eclipse Stainless Steel
The elimination of cleaning and cleaning validation is a significant benefit of disposable processing. Cleaning process equipment consumes time and valuable operator resources. Cleaning chemicals require suitable handling systems for the delivery and disposal of the fluids. Care must also be taken to use these chemicals in the appropriate concentrations to ensure that they perform their specified function. In addition, proper handling techniques are needed to ensure that the system is properly cleaned and that the operators are protected from contact with potentially hazardous cleaning fluids.
During the cleaning of stainless steel systems the filter housings are typically dismantled prior to cleaning. Following cleaning, stainless steel hard-piped systems must be rinsed with a suitable amount of water to ensure that the residual cleaning fluid is removed. For some applications, the cost of the cleaning operation increases when water for injection (WFI) is required for the system flush. Following each cleaning and flushing, the systems must be re-assembled and re-sterilized, which adds further time to the operation as well as increases labor costs.
Perhaps the most critical element of cleaning is validation of the process. Complicated cleaning processes are cumbersome to document, and it is even harder to prove that traces of the cleaning chemicals have been removed. Instead of having to prove that the cleaning has been effective, disposable systems are used one time and discarded. Gaps in cleaning validation documentation can cause regulatory scrutiny, and in the worst case, production of new or existing products is delayed. Failure to execute specified cleaning standard operating procedures (SOPs) are a non-compliance. For example, in the case of caustic solutions (often used for cleaning), if the concentration of the caustic is incorrect or if the temperature of the cleaning fluid used is not at the SOP-specified temperature, the validity of the cleaning process may be questioned.
Disposable systems also offer drug developers an alternative in terms of sterilization. While stainless steel systems are confined to steam sterilization processes, either autoclave or steam-in-place (SIP), disposable systems can be purchased pre-sterilized by gamma irradiation. Existing steam sterilization processes can also be used for the disposable capsule filters. Most capsule filters can be subjected to sterilization by autoclave, and some capsules (which have suitable materials of construction) can also be subjected to SIP.
Disposable products that are supplied pre-sterilized by gamma irradiation eliminate the need for sterilization and sterilization validation procedures and can reduce the maintenance of sterilization equipment. The user can essentially remove the product from its package and install it in the process. The disposable product supplier provides validation documentation. While the cost of sterilization by gamma irradiation is comparable to that of traditional steam sterilization methods, the gamma irradiation process reduces labor, and circumvents many of the potential issues associated with in-house steam sterilization. For example, if condensate has not been properly drained from a filter that has been steamed in place, the filter membrane could become wet out. The bubble point of the membrane must be exceeded to expel the fluid from the pores and allow steam penetration. This situation could lead to an extended steam cycle, or in the worst case, damage the filter due to excessive pressure in the forward direction, if an increased pressure is used to expel fluid at an elevated temperature.
Disposable products have a growing presence in filtration, purification and separation applications used to make a wide range of biopharmaceuticals, such as vaccines, monoclonal antibodies, and patient specific treatments. Small-scale tangential flow filters (TFF), direct flow filters (DFF) of all sizes, and membrane chromatography units are available for use in single-use systems. In addition, these capsules can be assembled with bioprocessing bags, tubing, valves or clamps, and connection devices to form fully integrated single-use filtration systems. Disposable filters can also be manifolded together to maximize processing capacity.
Disposable products are available in a range of sizes, making them ideal for use at every stage of drug development, from discovery to production. Single-use products that use the same materials of construction minimize re-validation requirements as a new process is scaled up.
The tubing used in these systems is usually clear and the capsule filters are typically designed with clear or translucent housings. This design feature allows operators to observe fluid levels and flow, as well as to detect fluid discoloration and air pockets, thereby enabling problems to be immediately identified and addressed.
High-growth biotechnology companies, large pharmaceutical companies and contract manufacturers stand to gain significant speed, safety and cost saving benefits from using disposable systems.
A disposable processing approach is especially cost-effective and efficient for start-up biotech companies that do not have hard-piped processing systems already in place. As many biotech start-ups have not fully defined their operating parameters, single-use products can save them from making premature investments in capital equipment. In a market where funding can be scarce, single-use products provide an effective cost and labor saving strategy. In addition, the timeliness of making a batch for clinical trials can be crucial for the timeline of development, and disposable systems can be assembled much faster than a comparable hard piped system. For these reasons, the trend towards building a disposable infrastructure from the ground up is building momentum in this sector.
Large pharmaceutical companies have a slightly different motivation for incorporating disposable systems into their drug processes. Cost, capacity and compliance issues are the deciding factors in this sector. The time and labor spent to dismantle, clean, and re-sterilize stainless steel products is performed at considerable cost to large pharmaceutical companies. Time required to meet the FDA’s stringent requirement for documentation on cleaning and cleaning validation procedures is eliminated as the systems are intended for single use. Expansion of an existing process can be more cost-effective with a shorter timeline for the expansion if disposable system components are used. A further benefit for pharmaceutical companies is that it is possible to change an existing filtration process to a disposable process train thus eliminating cleaning and cleaning validation as well as system assembly requirements. This is a viable option since the filters used in stainless steel housings and the filter capsules use the same materials of construction, thus avoiding extensive re-validation.
Single-use products help contract manufacturers reduce cross-contamination risks, upfront equipment costs, space requirements, and complicated cleaning and cleaning validation procedures. This increases profit margin, enhances safety, and reduces compliance concerns, enabling pharmaceutical and biotech product manufacturers and contract manufacturing facilities to be more competitive in a growing market.
With multiple connection points required in disposable processing operations, the connection method has considerable influence over the speed and safety of the whole process. Current methods include quick connectors, which require assembly under a laminar flow hood and tubing welders that mandate the use of a welding device.
The key to streamlining aseptic connections is to reduce the total number of steps needed to complete the process. Despite the name “quick connector,” it can take up to 18 minutes to make a connection with such a device. This is due to the fact that operations must be performed under a laminar flow hood, which generally requires 15 - 20 minutes to set up, or in a laminar flow environment, which may or may not be readily accessible, depending upon the layout of the facility. By contrast, a connection can be made anywhere in the facility in seconds with a new connector (Pall Kleenpak™ connector) (Table 1) because it does not require the use of a laminar flow environment, or any other capital equipment. Beyond the time required to set up and make the connection, laminar flow hoods are costly, require maintenance, and take up precious space in a cramped environment.
A connector that requires only a few simple hand movements reduces the risks of operator error. With operation of equipment, such as a laminar flow hood or tubing welder, comes increased opportunity for incorrect usage. For example, laminar flow hoods require the use of HEPA filters and these filters are changed-out on a schedule and tested. If a HEPA filter fails the post use test, then all connections between the change out period are at risk of contamination. The need to maintain and document maintenance for these types of equipment give drug developers further reason to take a simpler approach to aseptic connections. Both tubing welders and laminar flow hoods also require validation, adding to the number of steps involved in the connection process, and ultimately slowing down development.
Disposable Processing Benefits as They Relate to Filters
Available for direct flow filtration (DFF) and tangential flow filtration (TFF) applications, disposable filters demonstrate strong cost and time savings over their stainless steel counterparts by eliminating the need to assemble, clean and validate cleaning of the units (Table 2). Like single-use aseptic connectors, disposable filters can also be supplied pre-sterilized by gamma irradiation, avoiding the need for SIP or autoclave sterilization processes.
Ease of scalability provides long-term economic justification for the use of disposable filter systems. By using filters that are made of the same materials of construction, process volumes can be scaled from 100 ml at the bench stage, to thousands of liters at production scale with minimal re-validation. Single-use filters can also be manifolded together to increase processing volume without necessarily increasing the filter size as a further means of simplifying scale-up. A smaller footprint, which is characteristic of single-use systems, maximizes limited space in facilities to increase manufacturing capacity.
Assembled Single-Use Systems Maximize Benefits
The benefits of single-use system components increase when they are assembled together. A typical single-use filtration system combines multiple filter elements, bioprocessing bags, clamps, tubing and connection devices to form a fully integrated, pre-sterilized solution for filtration applications. The drug product manufacturer receives a fully assembled, pre-sterilized filtration system. This not only saves assembly, cleaning and sterilization time, but it also significantly reduces the chances for operator error.
The entire single-use filtration system can be gamma irradiated prior to delivery to the biopharmaceutical manufacturing site. These filtration systems are offered in a range of sizes, so that corresponding filters and bags are available for every stage of development. This ensures that the most appropriate and economical disposable filter scheme is used. By using the same materials of construction, these systems also ensure reproducible results during scale up. Together, thesefactors can streamline drug development to increase manufacturing capacity, while meeting validation requirements.
Factors Driving Change in the Drug Development Arena
Ongoing globalization, revolutionary technological breakthroughs, and government regulation and deregulation, have consistently impacted the pharmaceutical industry landscape in recent years. The overriding concerns of the biotechnology and pharmaceutical industries are regulatory and compliance issues, insufficient manufacturing capacity, and addressing the economic challenges of producing niche drugs and therapies.
Disposable systems reduce possibilities for non-compliance as related to system validation and cleaning issues. They improve the economic feasibility of producing niche drugs by enabling faster, more cost-effective product changeovers. Disposable systems ease the manufacturing capacity crunch by simplifying scale-up, eliminating process steps maximizing throughput, and speeding product changeovers. All this streamlines manufacturing and allows the manufacturers to respond nimbly to the dynamic marketplace.
How To Succeed In The Search For Nothing: Effective Swabbing Techniques For Cleaning Validation
By: Howard Siegerman, Wendy Hollands, and Michael Strauss
Searching for nothing would seem to be an absolute waste of time — unless you are responsible for cleaning validation. In that case, success is deliciously ironic since you can say, “I found nothing and that’s good news.”
But perhaps we should start at the beginning.
Those involved in the manufacture and quality control of pharmaceuticals and biotechnology products are aware of the need to prove that the production equipment and the manufacturing environment are sufficiently clean such that the next lot of product will not be contaminated by materials from the previous lot (i.e., cross contamination will not be an issue). The procedures and documentation for that proof constitute what is known as cleaning validation. Essentially, one wants to prove with a high degree of certainty that any residues of drug product from a manufacturing lot and any residues of cleaning agents used to remove those drug residues, are below acceptable limits. To put a fine point on it, we’re not exactly searching for nothing (as in a zero value), but for extremely low values of residues — both drug product residues and cleaning agent residues.
CLEANING VALIDATION
Cleaning validation can be considered a three step process, involving 1) the cleaning and rinsing of the requisite surfaces, 2) sampling any drug or cleaning agent residues that might still remain on those surfaces and, 3) analyzing the sampled materials with the appropriate instrumentation. Steps 1 and 2 are manual, sometimes tedious procedures, but only if they are done properly do they permit accurate results to be reported in Step 3. The cleaning of surfaces (what cleaning agents to use, how to do the cleaning, etc.) and the analysis of the sampled materials (calibration curves, limits of detection) are themselves fascinating topics (at least to some people), but they are not our focus here. For this discussion, we will look only at Step 2 — the procedures that enable one to sample a cleaned surface with a high degree of reproducibility, to ensure that what is reported in Step 3 truly represents the condition of the sampled surface.
It may seem intuitively obvious, but one does not begin the cleaning validation process until there is an absence of visible residue on the surface. Residues are visible at surface concentrations of between 1 and 4 ug/cm2. The simple rule is that if you can still see residues on the surface, forget about any sampling activities, you haven’t finished Step 1 — the cleaning activities.
Figure 1: A polyester knit swab used for surface samplingSAMPLING SURFACES WITH SWABS
Assuming the surface is free of visible residue (i.e., that the cleaning stage is done), the challenge is now to sample that surface in a reproducible manner so that any (invisible) residues, present in extremely small amounts, are collected and delivered to the instrument for measurement. The best type of swab for sampling is one with a head made of laundered polyester knit fabric (Figure 1), since that material provides the lowest levels of releasable particles, the highest recovery, and the lowest background when total organic carbon (TOC) measurements are employed as the analytical technique. To sample the surface, the swab is moistened then drawn across the surface in a thorough and reproducible manner to collect any residue into the interstices of the polyester knit fabric. The swab is then deposited into a suitable collection vial, then the residues extracted from the swab head for subsequent anaysis.
It is worth devoting a moment to the technique for moistening a swab, since errors in technique here will lead to inconsistent results. There might be a temptation to simply saturate the swab head with high-quality (e.g., TOC-grade) water to do the residue collection. This will cause problems, since the excess liquid on the swab head will simply spread the residue over the surface to be sampled and will not allow the residue to be picked up reproducibly into the swab fabric. For best results, the swab should be damp, but not saturated. This is best accomplished by immersing the head into a container of high-quality water, and pressing both sides of the swab head against the side of the container a few times to expel any air trapped in the fabric and allow the water to fully penetrate the fabric. Then the swab head is raised out of the water and the flat sides of the swab are drawn across the rim of the container to expel excess water and leave the swab head moist. The degree of moistness of the swab head (otherwise known as the percent wetting level) need not be identical from run to run, since residues will be picked up over a fairly wide range of swab head moistness.
Ideally, to maximize reproducibility in swab head moistness, one would like to be able to dispense the optimum amount of water onto the swab head from a micropipette to produce, say, a 50% wetting level, but unfortunately this is impractical. The swab head material is not totally hydrophilic and water dispensed in such a manner will simply bead up on the swab head and will not be absorbed by the fabric.
The manner in which the swab is used to sample the surface (i.e., the swabbing pattern) is critical to ensure accurate and reproducible collection of residues. For easily accessible surfaces, a template with a 5 cm 5 cm opening can be used to sample the same surface area each time (Figure 2). As with wiping, linear overlapping strokes over the surface to be sampled will ensure that the residue is collected into the moist swab head. Figure 3 shows a typical sampling pattern employing two swabs. The first side of the first swab is swiped horizontally ten times over the template opening, then the swab is flipped over and the second side is swiped vertically ten times over the same surface. This swab is deposited into the collection vial (Figure 4). The first side of the second swab is swiped diagonally upwards ten times, then flipped over and the second side swiped diagonally downward ten times. The second swab is deposited into the same collection vial. In this manner, the surface has been swabbed a total of 40 times, and there is a reasonable expectation that any residue on the surface has been transferred into the two swab heads. It is not required to use two swabs; often one will do.
Figure 2: A template for surface sampling
Figure 3. Swabbing patterns
Figure 4. A notched swab handle simplifies separating the swab head from the handle.
Only the head needs to be extracted for TOC measurement.Operators can verify that their technique for dampening the swab heads and swabbing surfaces is appropriate through replicate recovery experiments of known challenges dispensed onto sample surfaces. Ideally, one would like to recover 100% of the challenge, but recoveries may be limited to 75% – 80%, depending on the sampling conditions and the residue. It must be recognized that the swab head may not get everything off the surface and that the extraction liquid may not get all of the residue out of the swab head. Indeed, a 90% efficiency at each stage produces an overall recovery of only 81% (i.e. 0.9 0.9).
Pre-cleaned vials and swabs are available commercially that provide TOC background levels of less than 10 ppb and less than 50 ppb TOC, respectively. This may be important if very low levels of residues are sought, since one never wants to report an analytical value obtained by subtracting two large numbers to produce a small difference.
CONCLUSIONS
The search for nothing really involves:
Howard Siegerman is the Director of Technology, Wendy Hollands is the Product Manager,and Michael Strauss is the Business Development Manager at ITW Texwipe,300B Route 17 South,Mahwah,NJ 07430.They can be reached at 201-684-1800;www.texwipe.com.
Searching for nothing would seem to be an absolute waste of time — unless you are responsible for cleaning validation. In that case, success is deliciously ironic since you can say, “I found nothing and that’s good news.”
But perhaps we should start at the beginning.
Those involved in the manufacture and quality control of pharmaceuticals and biotechnology products are aware of the need to prove that the production equipment and the manufacturing environment are sufficiently clean such that the next lot of product will not be contaminated by materials from the previous lot (i.e., cross contamination will not be an issue). The procedures and documentation for that proof constitute what is known as cleaning validation. Essentially, one wants to prove with a high degree of certainty that any residues of drug product from a manufacturing lot and any residues of cleaning agents used to remove those drug residues, are below acceptable limits. To put a fine point on it, we’re not exactly searching for nothing (as in a zero value), but for extremely low values of residues — both drug product residues and cleaning agent residues.
CLEANING VALIDATION
Cleaning validation can be considered a three step process, involving 1) the cleaning and rinsing of the requisite surfaces, 2) sampling any drug or cleaning agent residues that might still remain on those surfaces and, 3) analyzing the sampled materials with the appropriate instrumentation. Steps 1 and 2 are manual, sometimes tedious procedures, but only if they are done properly do they permit accurate results to be reported in Step 3. The cleaning of surfaces (what cleaning agents to use, how to do the cleaning, etc.) and the analysis of the sampled materials (calibration curves, limits of detection) are themselves fascinating topics (at least to some people), but they are not our focus here. For this discussion, we will look only at Step 2 — the procedures that enable one to sample a cleaned surface with a high degree of reproducibility, to ensure that what is reported in Step 3 truly represents the condition of the sampled surface.
It may seem intuitively obvious, but one does not begin the cleaning validation process until there is an absence of visible residue on the surface. Residues are visible at surface concentrations of between 1 and 4 ug/cm2. The simple rule is that if you can still see residues on the surface, forget about any sampling activities, you haven’t finished Step 1 — the cleaning activities.
Figure 1: A polyester knit swab used for surface sampling
Assuming the surface is free of visible residue (i.e., that the cleaning stage is done), the challenge is now to sample that surface in a reproducible manner so that any (invisible) residues, present in extremely small amounts, are collected and delivered to the instrument for measurement. The best type of swab for sampling is one with a head made of laundered polyester knit fabric (Figure 1), since that material provides the lowest levels of releasable particles, the highest recovery, and the lowest background when total organic carbon (TOC) measurements are employed as the analytical technique. To sample the surface, the swab is moistened then drawn across the surface in a thorough and reproducible manner to collect any residue into the interstices of the polyester knit fabric. The swab is then deposited into a suitable collection vial, then the residues extracted from the swab head for subsequent anaysis.
It is worth devoting a moment to the technique for moistening a swab, since errors in technique here will lead to inconsistent results. There might be a temptation to simply saturate the swab head with high-quality (e.g., TOC-grade) water to do the residue collection. This will cause problems, since the excess liquid on the swab head will simply spread the residue over the surface to be sampled and will not allow the residue to be picked up reproducibly into the swab fabric. For best results, the swab should be damp, but not saturated. This is best accomplished by immersing the head into a container of high-quality water, and pressing both sides of the swab head against the side of the container a few times to expel any air trapped in the fabric and allow the water to fully penetrate the fabric. Then the swab head is raised out of the water and the flat sides of the swab are drawn across the rim of the container to expel excess water and leave the swab head moist. The degree of moistness of the swab head (otherwise known as the percent wetting level) need not be identical from run to run, since residues will be picked up over a fairly wide range of swab head moistness.
Ideally, to maximize reproducibility in swab head moistness, one would like to be able to dispense the optimum amount of water onto the swab head from a micropipette to produce, say, a 50% wetting level, but unfortunately this is impractical. The swab head material is not totally hydrophilic and water dispensed in such a manner will simply bead up on the swab head and will not be absorbed by the fabric.
The manner in which the swab is used to sample the surface (i.e., the swabbing pattern) is critical to ensure accurate and reproducible collection of residues. For easily accessible surfaces, a template with a 5 cm 5 cm opening can be used to sample the same surface area each time (Figure 2). As with wiping, linear overlapping strokes over the surface to be sampled will ensure that the residue is collected into the moist swab head. Figure 3 shows a typical sampling pattern employing two swabs. The first side of the first swab is swiped horizontally ten times over the template opening, then the swab is flipped over and the second side is swiped vertically ten times over the same surface. This swab is deposited into the collection vial (Figure 4). The first side of the second swab is swiped diagonally upwards ten times, then flipped over and the second side swiped diagonally downward ten times. The second swab is deposited into the same collection vial. In this manner, the surface has been swabbed a total of 40 times, and there is a reasonable expectation that any residue on the surface has been transferred into the two swab heads. It is not required to use two swabs; often one will do.
Figure 2: A template for surface sampling
Figure 3. Swabbing patterns
Figure 4. A notched swab handle simplifies separating the swab head from the handle.
Only the head needs to be extracted for TOC measurement.
Pre-cleaned vials and swabs are available commercially that provide TOC background levels of less than 10 ppb and less than 50 ppb TOC, respectively. This may be important if very low levels of residues are sought, since one never wants to report an analytical value obtained by subtracting two large numbers to produce a small difference.
CONCLUSIONS
The search for nothing really involves:
- good cleaning and rinsing protocols,
- proper swabbing techniques to ensure that any residues left on the surface are collected into the swab, and
- pre-cleaned vials and swabs for minimum background levels. Rigorous attention to detail and technique will enable success in finding nothing.
Howard Siegerman is the Director of Technology, Wendy Hollands is the Product Manager,and Michael Strauss is the Business Development Manager at ITW Texwipe,300B Route 17 South,Mahwah,NJ 07430.They can be reached at 201-684-1800;www.texwipe.com.
How are cleanroom garments validated
The validation protocol is specified in the ANSI/AAMI/ISO 11137-1:2006 document entitled “Sterilization of health care products – Radiation – Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices” and ANSI/AAMI/ISO 11137-2:2006 “Sterilization of health care products – Radiation –Part 2: Establishing the sterilization dose. Aventis dodges 483 despite validation protocol, Part 11 issues. (Human drugs).: An article from: Validation Times
These documents address both Method 1 and VDmax (Verification Dose Maximum) methods to determine the device bioburden and perform a verification dose experiment. Specifically, the VDmax methods described in 11137-2:2006 are for selected sterilization doses of 25 kGy and 15 kGy. The method for 25 kGy is applicable to products having an average bioburden less than or equal to 1,000 CFUs (colony forming units) per device. The method for 15 kGy is applicable to products having an average bioburden less than or equal to 1.5 CFUs per device.
Under a new AAMI document for VDmax (AAMI TIR 33:2006), sterilization doses can be validated from 15 kGy to 35 kGy in 2.5 kGy increments. The VDmax method is based on the same concept as Method 1 and is now more commonly used than Method 1 in the United States. It can be applied to any type of product that can use Method 1 and is widely accepted by the FDA.
Both gamma irradiation sterilization validation protocols begin with determining the bioburden on the sample item proportion (SIP). The SIP is generally 10% of a medium cleanroom coverall because the product is too large for the precise performance of the required tests of sterility. This would also be the justification for the gamma sterilization validation of other cleanroom items that are too large for accurate performance of the required tests.
In the VDmax25 method described in Worked Example Table 31, a minimum of 40 samples are required. Ten devices from three separate production lots are washed with other contaminated garments, dried and packaged with these garments, and are submitted for bioburden determination. It is recommended that 20 samples be prepared from each lot in the event that the variance in bioburden between lots requires subsequent dose verification of a specific lot.
The 30 samples are sent to a contract laboratory to undergo exhaustive extractions for both the bioburden and bioburden validation testing. If the bioburden per SIP is less than 30–50 CFUs per sample, another validation bioburden validation approach may be necessary. These two tests are often performed simultaneously. Each sample is extracted multiple times (usually four) and the extracts or rinsates are filtered. The filter from each extraction is placed on an agar culture medium such as tryptic soy agar and incubated allowing the total aerobic bacteria and fungi CFUs to be counted. No validation protocol trips Rhone-Poulenc audit.(Rhone-Poulenc Chimie)(Brief Article): An article from: Validation Times
In the validation stage, the counts from the first extract for each sample are divided by the total from all extractions to determine the percentage or efficiency of recovery in the first extraction. A bioburden recovery factor is then calculated as the inverse of the percentage of recovery. This value is used to calculate the bioburden for each of the thirty samples and an average for each of the three lots is obtained. These numbers are later multiplied by 10, if the SIP is 10%, to determine the number of CFUs for the total device (coverall).
As long as no single lot has an average more than twice, the overall average then the verification dose experiment can use 10 samples from any of the three lots. A chart in the “ANSI/AAMI/ ISO 11137-2-2006 Sterilization of health care products – Radiation – Establishing the sterilization dose” then indicates an SIP dose reduction factor that should produce a biological reduction equal to that of the Method 1 sterilization dose. Firms can give FDA validation protocol to avoid 3-lot hassles. (Process validation).: An article from: Validation Times
The ten additional samples previously prepared along with the thirty samples tested for bioburden are then sent to the contract sterilizer with an instruction to irradiate at the calculated verification dose for the SIP samples. The samples are then subjected to a test of sterility and cultured in tryptic soy broth. If there are one or zero positive samples per the ten sample lot, then it can be accepted and substantiate 25 kGy as the sterilization dose. If two positives are obtained then a confirmatory verification dose test is performed. In this test, ten additional samples are irradiated and tested exactly as performed previously.
If there are zero positives in this confirmatory test, the validation passes and 25 kGy is substantiated. If any positives are obtained in the confirmatory test and no errors in testing or dosing can be confirmed, then 25 kGy is not substantiated and a higher dose must be validated (i.e., 27.5 kGy in AAMI TIR 33-2006). Additionally, at the time of validation, a one-time bacteriostasis/ fungistasis test is performed with product to assure an appropriate sterility test method was used.
The Periodic "Lecture" About Validation
The Point of this Column is to remind you of what you already know. If you read A2C2 Magazine (soon to be Controlled Environments), technology is important to you. If you follow this column, the quality of cleaning that you produce using that technology must be of value to your enterprise. If your business is pharmaceuticals, you assume validation as a part of critical cleaning. So then, are you using a validation strategy? Do you validate the performance of your cleaning system? Do you do an independent check of the cleanliness data that you normally generate?
One Reason To Do Validation
This exercise is an insurance policy. Users conduct validation to prove that their normal cleaning test is currently valid (hasn't been “fooled”). But, because validation represents additional work, it isn't justified for every operation. Usually, when a cleaning test is “fooled”, unexpected types of contamination are involved. Table 1 lists some examples.
A Second Reason To Do Validation
A frustrating situation, in which validation is essential, occurs when there is no flaw in the cleaning test. Yet performance in the next step of use fails due to a cause unrelated to the cleanliness of the parts. Often, the defect is incorrectly attributed to the cleaning process. Effort is wasted in troubleshooting a process which is performing flawlessly while the true cause of failure remains undetected.
What is Not Validation
A quotation attributed to philosopher George Santayana is “fanaticism is the practice of redoubling your efforts when you have forgotten your aim.” Validation does not mean that the normal test should be rerun many times under increased scrutiny.
More, of similar data, adds no new insight. More eyes looking in the wrong direction won't see approaching disaster. More thought with the same point of view won't produce inspiration. One validates a result by examining it from another point of view. This means something different must be done.
An Overall Approach Toward Validation
I often recommend a “total cleanliness” approach to validation of cleanliness tests.
Others call this approach “brute force.” Instead of measuring NVR, TOC, using an OSEE instrument, or counting particles, do all of the following:
A Specific Approach Toward Validation
Consider an approach toward validation focused on the nature of the cleaning test under scrutiny. Measure the parameter being measured in the normal cleaning test using another approach sensitive to the same parameter.
An excellent way to do this is to use ASTM standards as validation tests. Good ones are: (1) ASTM E21.05, “Standard Method for Measurement of Nonvolatile Residue (NVR) on Surfaces,” (2) D903-98(2004) Standard Test Method for Peel or Stripping Strength of Adhesive Bonds for particulates and surface films.
Timing
Validation by another cleaning test should substitute for the normal cleaning test.
Depending upon results and required certainty, the validation test might replace the normal test every 5% to 20% of cleanliness tests.
Summary
While validation of cleanliness testing is not justified for every cleaning operation, considering use of it for every operation is justified.
John Durkee is an independent consultant specializing in critical cleaning for contamination control. Contact him at PO Box 847, Hunt, TX 78024 or 122 Ridge Rd. West, Hunt, TX 78024; 830-238-7610; Fax 612-677-3170; or jdurkee@precisioncleaning.com
One Reason To Do Validation
This exercise is an insurance policy. Users conduct validation to prove that their normal cleaning test is currently valid (hasn't been “fooled”). But, because validation represents additional work, it isn't justified for every operation. Usually, when a cleaning test is “fooled”, unexpected types of contamination are involved. Table 1 lists some examples.
A Second Reason To Do Validation
A frustrating situation, in which validation is essential, occurs when there is no flaw in the cleaning test. Yet performance in the next step of use fails due to a cause unrelated to the cleanliness of the parts. Often, the defect is incorrectly attributed to the cleaning process. Effort is wasted in troubleshooting a process which is performing flawlessly while the true cause of failure remains undetected.
What is Not Validation
A quotation attributed to philosopher George Santayana is “fanaticism is the practice of redoubling your efforts when you have forgotten your aim.” Validation does not mean that the normal test should be rerun many times under increased scrutiny.
More, of similar data, adds no new insight. More eyes looking in the wrong direction won't see approaching disaster. More thought with the same point of view won't produce inspiration. One validates a result by examining it from another point of view. This means something different must be done.
I often recommend a “total cleanliness” approach to validation of cleanliness tests.
Others call this approach “brute force.” Instead of measuring NVR, TOC, using an OSEE instrument, or counting particles, do all of the following:
- Boil a part in a suitable solvent(s) to extract everything which contaminates its surface
- Heat another part to a suitable temperature to vaporize everything which contaminates its surface.
- Clean another part in the normal manner, and weigh it again.
A Specific Approach Toward Validation
Consider an approach toward validation focused on the nature of the cleaning test under scrutiny. Measure the parameter being measured in the normal cleaning test using another approach sensitive to the same parameter.
An excellent way to do this is to use ASTM standards as validation tests. Good ones are: (1) ASTM E21.05, “Standard Method for Measurement of Nonvolatile Residue (NVR) on Surfaces,” (2) D903-98(2004) Standard Test Method for Peel or Stripping Strength of Adhesive Bonds for particulates and surface films.
Timing
Validation by another cleaning test should substitute for the normal cleaning test.
Depending upon results and required certainty, the validation test might replace the normal test every 5% to 20% of cleanliness tests.
Summary
While validation of cleanliness testing is not justified for every cleaning operation, considering use of it for every operation is justified.
John Durkee is an independent consultant specializing in critical cleaning for contamination control. Contact him at PO Box 847, Hunt, TX 78024 or 122 Ridge Rd. West, Hunt, TX 78024; 830-238-7610; Fax 612-677-3170; or jdurkee@precisioncleaning.com
How are cleanroom garments validated
In Understanding Cleanroom Apparel Sterilization - Part 1, I discussed the Method 1 validation protocol. The validation protocol is specified in the ANSI/AAMI/ISO 11137-1:2006 document entitled “Sterilization of health care products – Radiation – Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices” and ANSI/AAMI/ISO 11137-2:2006 “Sterilization of health care products – Radiation –Part 2: Establishing the sterilization dose. These documents address both Method 1 and VDmax (Verification Dose Maximum) methods to determine the device bioburden and perform a verification dose experiment. Specifically, the VDmax methods described in 11137-2:2006 are for selected sterilization doses of 25 kGy and 15 kGy. The method for 25 kGy is applicable to products having an average bioburden less than or equal to 1,000 CFUs (colony forming units) per device. The method for 15 kGy is applicable to products having an average bioburden less than or equal to 1.5 CFUs per device. Under a new AAMI document for VDmax (AAMI TIR 33:2006), sterilization doses can be validated from 15 kGy to 35 kGy in 2.5 kGy increments. The VDmax method is based on the same concept as Method 1 and is now more commonly used than Method 1 in the United States. It can be applied to any type of product that can use Method 1 and is widely accepted by the FDA. For comparison purposes, I will discuss the procedure for Method VDmax25 for multiple production batches.
Both gamma irradiation sterilization validation protocols begin with determining the bioburden on the sample item proportion (SIP). The SIP is generally 10% of a medium cleanroom coverall because the product is too large for the precise performance of the required tests of sterility. This would also be the justification for the gamma sterilization validation of other cleanroom items that are too large for accurate performance of the required tests. In the VDmax25 method described in Worked Example Table 31, a minimum of 40 samples are required. Ten devices from three separate production lots are washed with other contaminated garments, dried and packaged with these garments, and are submitted for bioburden determination. It is recommended that 20 samples be prepared from each lot in the event that the variance in bioburden between lots requires subsequent dose verification of a specific lot.
The 30 samples are sent to a contract laboratory to undergo exhaustive extractions for both the bioburden and bioburden validation testing. If the bioburden per SIP is less than 30–50 CFUs per sample, another validation bioburden validation approach may be necessary. These two tests are often performed simultaneously. Each sample is extracted multiple times (usually four) and the extracts or rinsates are filtered. The filter from each extraction is placed on an agar culture medium such as tryptic soy agar and incubated allowing the total aerobic bacteria and fungi CFUs to be counted. In the validation stage, the counts from the first extract for each sample are divided by the total from all extractions to determine the percentage or efficiency of recovery in the first extraction. A bioburden recovery factor is then calculated as the inverse of the percentage of recovery. This value is used to calculate the bioburden for each of the thirty samples and an average for each of the three lots is obtained. These numbers are later multiplied by 10, if the SIP is 10%, to determine the number of CFUs for the total device (coverall). As long as no single lot has an average more than twice, the overall average then the verification dose experiment can use 10 samples from any of the three lots. A chart (Table 9 for average bioburdens up to 1,000) in the “ANSI/AAMI/ ISO 11137-2-2006 Sterilization of health care products – Radiation – Establishing the sterilization dose” then indicates an SIP dose reduction factor that should produce a biological reduction equal to that of the Method 1 sterilization dose.
The ten additional samples previously prepared along with the thirty samples tested for bioburden are then sent to the contract sterilizer with an instruction to irradiate at the calculated verification dose for the SIP samples. The samples are then subjected to a test of sterility and cultured in tryptic soy broth. If there are one or zero positive samples per the ten sample lot, then it can be accepted and substantiate 25 kGy as the sterilization dose. If two positives are obtained then a confirmatory verification dose test is performed. In this test, ten additional samples are irradiated and tested exactly as performed previously. If there are zero positives in this confirmatory test, the validation passes and 25 kGy is substantiated. If any positives are obtained in the confirmatory test and no errors in testing or dosing can be confirmed, then 25 kGy is not substantiated and a higher dose must be validated (i.e., 27.5 kGy in AAMI TIR 33-2006). Additionally, at the time of validation, a one-time bacteriostasis/ fungistasis test is performed with product to assure an appropriate sterility test method was used.
NOTE: The VDmax method calculates the verification dose for 10 samples rather than 100 samples as used in Method 1. This difference in sample size is allowed because the VDmax method targets a verification dose of
10-1while the Method 1 method targets a verification dose of 10-2. This reduction in sample size can result in large savings due to the smaller sample size.
The validated sterilization dose continues to be used as long as the quarterly dose audits continue to pass, the process stays in control and no specifics of the process changes. Any change in the process requires an evaluation of the potential impact that the change may have on the product bioburden and may require a complete re-validation.
The calculated sterilization dose whether determined by Method 1 validation or Method VDmax validation becomes one component of the customer specifications for gamma radiation of the product. Other factors are the density of the product, product dimensions, and the weight of the product in the transport container used. The contract sterilizer performs a dose mapping of each product. This assures that the correct radiation dose is delivered to every product in the box every time. Dosimeters are placed on the product during the gamma radiation process. After radiation the dosimeters are removed and read using a calibrated spectrophotometer. The product is released by Quality Assurance based on the dosime-try readings’ compliance with the customer’s specified minimum and maximum gamma dose for the product.
It is incumbent for the supplier of either reusable or disposable cleanroom garments to validate its sterile garment program for gamma radiation per ANSI/AAMI/ISO 11137-1:2006, “Sterilization of Health Care Products -Radiation – Part 1: Requirements for Development, Validation and Routine Control of a Sterilization process for medical devices” and ANSI/AAMI/ISO 11137-2:2006, “Sterilization of health care products – Radiation – Part 2: Establishing the Sterilization Dose” and to assure its promise to deliver garments sterilized to the contracted SAL by performing dose audits every three months.
ANSI/AAMI/ISO 11137-1:2006, “Frequency of sterilization dose audits” states the frequency of dose audits may be reduced to every six months if there has not been a change in the validated system and all quarterly dose audits have passed in the previous year. If there is a failure, dose audits must be performed every three months. Even if there has not been a change in the validated system, dose audits must be performed at least once a year.
I thank Martell Winters, Nelson Laboratories, and Gregg Mosley, Biotest Laboratories for their technical assistance in writing and reviewing this column.
Jan Eudy is IEST Past-President.She is also Corporate Q.A.Manager for Cintas Cleanroom Resources.
Both gamma irradiation sterilization validation protocols begin with determining the bioburden on the sample item proportion (SIP). The SIP is generally 10% of a medium cleanroom coverall because the product is too large for the precise performance of the required tests of sterility. This would also be the justification for the gamma sterilization validation of other cleanroom items that are too large for accurate performance of the required tests. In the VDmax25 method described in Worked Example Table 31, a minimum of 40 samples are required. Ten devices from three separate production lots are washed with other contaminated garments, dried and packaged with these garments, and are submitted for bioburden determination. It is recommended that 20 samples be prepared from each lot in the event that the variance in bioburden between lots requires subsequent dose verification of a specific lot.
The 30 samples are sent to a contract laboratory to undergo exhaustive extractions for both the bioburden and bioburden validation testing. If the bioburden per SIP is less than 30–50 CFUs per sample, another validation bioburden validation approach may be necessary. These two tests are often performed simultaneously. Each sample is extracted multiple times (usually four) and the extracts or rinsates are filtered. The filter from each extraction is placed on an agar culture medium such as tryptic soy agar and incubated allowing the total aerobic bacteria and fungi CFUs to be counted. In the validation stage, the counts from the first extract for each sample are divided by the total from all extractions to determine the percentage or efficiency of recovery in the first extraction. A bioburden recovery factor is then calculated as the inverse of the percentage of recovery. This value is used to calculate the bioburden for each of the thirty samples and an average for each of the three lots is obtained. These numbers are later multiplied by 10, if the SIP is 10%, to determine the number of CFUs for the total device (coverall). As long as no single lot has an average more than twice, the overall average then the verification dose experiment can use 10 samples from any of the three lots. A chart (Table 9 for average bioburdens up to 1,000) in the “ANSI/AAMI/ ISO 11137-2-2006 Sterilization of health care products – Radiation – Establishing the sterilization dose” then indicates an SIP dose reduction factor that should produce a biological reduction equal to that of the Method 1 sterilization dose.
The ten additional samples previously prepared along with the thirty samples tested for bioburden are then sent to the contract sterilizer with an instruction to irradiate at the calculated verification dose for the SIP samples. The samples are then subjected to a test of sterility and cultured in tryptic soy broth. If there are one or zero positive samples per the ten sample lot, then it can be accepted and substantiate 25 kGy as the sterilization dose. If two positives are obtained then a confirmatory verification dose test is performed. In this test, ten additional samples are irradiated and tested exactly as performed previously. If there are zero positives in this confirmatory test, the validation passes and 25 kGy is substantiated. If any positives are obtained in the confirmatory test and no errors in testing or dosing can be confirmed, then 25 kGy is not substantiated and a higher dose must be validated (i.e., 27.5 kGy in AAMI TIR 33-2006). Additionally, at the time of validation, a one-time bacteriostasis/ fungistasis test is performed with product to assure an appropriate sterility test method was used.
NOTE: The VDmax method calculates the verification dose for 10 samples rather than 100 samples as used in Method 1. This difference in sample size is allowed because the VDmax method targets a verification dose of
10-1while the Method 1 method targets a verification dose of 10-2. This reduction in sample size can result in large savings due to the smaller sample size.
The validated sterilization dose continues to be used as long as the quarterly dose audits continue to pass, the process stays in control and no specifics of the process changes. Any change in the process requires an evaluation of the potential impact that the change may have on the product bioburden and may require a complete re-validation.
The calculated sterilization dose whether determined by Method 1 validation or Method VDmax validation becomes one component of the customer specifications for gamma radiation of the product. Other factors are the density of the product, product dimensions, and the weight of the product in the transport container used. The contract sterilizer performs a dose mapping of each product. This assures that the correct radiation dose is delivered to every product in the box every time. Dosimeters are placed on the product during the gamma radiation process. After radiation the dosimeters are removed and read using a calibrated spectrophotometer. The product is released by Quality Assurance based on the dosime-try readings’ compliance with the customer’s specified minimum and maximum gamma dose for the product.
It is incumbent for the supplier of either reusable or disposable cleanroom garments to validate its sterile garment program for gamma radiation per ANSI/AAMI/ISO 11137-1:2006, “Sterilization of Health Care Products -Radiation – Part 1: Requirements for Development, Validation and Routine Control of a Sterilization process for medical devices” and ANSI/AAMI/ISO 11137-2:2006, “Sterilization of health care products – Radiation – Part 2: Establishing the Sterilization Dose” and to assure its promise to deliver garments sterilized to the contracted SAL by performing dose audits every three months.
ANSI/AAMI/ISO 11137-1:2006, “Frequency of sterilization dose audits” states the frequency of dose audits may be reduced to every six months if there has not been a change in the validated system and all quarterly dose audits have passed in the previous year. If there is a failure, dose audits must be performed every three months. Even if there has not been a change in the validated system, dose audits must be performed at least once a year.
I thank Martell Winters, Nelson Laboratories, and Gregg Mosley, Biotest Laboratories for their technical assistance in writing and reviewing this column.
Jan Eudy is IEST Past-President.She is also Corporate Q.A.Manager for Cintas Cleanroom Resources.
Understanding Contamination Control for Process Validation
David E. Gronostajski
Unwanted and potentially dangerous chemical or biological contaminants in pharmaceutical manufacturing have long been an area of concern. These contaminants can lead to unpredictable pharmacological effects or super- or sub-potency of the active drug substance. Worse, they may be toxic.
Because of the potentially dangerous implications of contaminants on patient safety, the FDA, through its Current Good Manufacturing Practices (cGMP) regulations, requires manufacturers to employ a number of technical and scientific techniques in the manufacturing cycle. These techniques share a common goal: to provide a high level of assurance that finished drug products meet their intended and defined specifications. The FDA calls this goal validation.
To understand how these techniques provide this assurance, it is important to understand how the specifications for active drug substances and excipient compounds originate. Specifications for active drug substances and the inactive chemicals with which they are compounded (“excipients”) that are approved by the FDA to be sold in the United States are found in the United States Pharmacopeia (USP) and National Formulary (NF). The compendia not only identify the types of compounds, but also the analysis mgthods, and reagents, and acceptance levels that are required to be used to test and release products.
The USP/NF section on General Notices, Foreign Substances and Impurities, however, states:
...it is manifestly impossible to include in each monograph a test for every impurity, contaminate or adulterant that might be present, including microbial contamination. These may arise from a change in the source of material or from a change in the proceýsing, or may be introduced from extraneous sources. Tests suitable for detecting such occurrences, the presence of which is inconsistent with applicable manufacturing practice or good pharmaceutical practice, should be employed in addition to the tests provided in the individual monographs.
This is one of the key reasons the FDA is taking a new look at how it applies cGMPs in the pharmaceutical industry. In September 2002, the FDA announced this initiative as “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach.” In part, this initiative will focus the validation efforts of manufacturers on materials and manufacturing systems that they have determined could lead to potential or actual patient risk due to contamination.
The Lifecycle Approach
The FDA has indicated that a Lifecycle Approach is a critical element of effective validations. When viewed in light of the USP/NF General Notice and the FDA initiative, contamination control and assurance in the pharmaceutical manufacturing process becoýes a sequence of activities that is part of the product Lifecycle. As such, the assurance methods and activities to control contamination are dynamic, and must constantly be refreshed when material or process changes occur, or when new information or technology becomes available.
First, the company must determine all the sources and types of biological and chemical contaminant introduction in the process and their impact on the final product through technically and scientifically sound risk-based methods. After determining the probability of occurrence, severity, or impact should it occur, and the existing levels of detection for each source, a risk of occurrence can be derived. When these risks are reviewed against accepted patient or human safety standards, key contaminant sources and the methods of assuring their control can be identified for subsequent validation.
Many technically sound risk-based techniques such as Failure Mode Effects and Analysis (FMEA) can be used for these evaluations. However, a technique that originated with the FDA in food safety, Hazard Assessment and Critical Control Points (HACCP), is growing in popularity for pharmaceuticals and medical devices. This technique provides companies with the ability to succinctly identify the critical sources and types of contamination as well as the mechanisms for controlling them in material and manufacturing processes.
Once the potential contamination sources are identified, the second activity in the Lifecycle approach is to conduct scientifically and technically sound qualification studies that provide evidence that contaminants can be controlled to the defined levels desired. These qualifications are required to not only demonstrate control under nominal process conditions, but also under conditions where the material or process is under stress. For FDA purposes, these prospective studies are defined as Protocols, and take the form of Installation Qualifications, Operational Qualifications, and Performance Qualifications. At a minimum, pharmaceutical contaminant process validations should consider the qualification of any:
* Active and excipient materials and their suppliers
* Microbiological bioburden of materials, processes, and environment
* Cleaning, disinfecting, and residue control of process equipment
* Air handling and purification
* Employee health, hygiene, and sanitation
* Production of water used in the process or for cleaning
* Manufacturing process and activity degradation
* Lubricants or process aids used in manufacturing
* Pesticides used in the manufacturing processing areas
* Computers and software that control any manufacturing or associated processes
The Impact of Change
Bnce these studies have been concluded, the materials, processes, and quality systems that support them have demonstrated themselves as valid. However, since change is inevitable, this validation must be reviewed for ongoing applicability when changes are made to any key factors contained in the original study. This becomes the Lifecycle aspect of validation. Changes that can impact the original state-of-validation can occur in many ways; any change in components or materials, suppliers, a supplier’s process, or in a supplier’s supplier may impact current contamination controls. Seemingly innocuous changes in cleaning and disinfection may become a source of change in the ability to provide assurance contaminants are being controlled. Because ‹any processes today are computer controlled, changes to process control soft ware may have significant impact on contaminant assurance.
All changes that could impact the original risk assessment assumptions must be reviewed for impact to the current validation. In some cases, this may involve revisiting the original risk assessment to determine if the risk factors need to be recalculated due to the change. If it is determined that the change could impact the current validated assurance levels, the change must be studied through a re-validation activity prior to implementation. But the validation dynamic is not only limited to changes made by the pharmaceutical firm or its suppliers. Companies are also expected to be aware, and act on, information from outside sources that may have a bearing on their original risk assessment. Items such as revisions to safe levels of contaminants, new toxic compounds, and mutated strains of microbiological contaminants can be reported in the literature and press. Companies may also become aware of a contaminant issue that occurred either internally or at a competitor for a process or material similar to the item in question. Likewise, information gathered from adverse reports of the drug use in patients may lead to information that requires the company to challenge its original risk assessment assumption and testing.
The above review process is useful on an individual change basis: a “micro” scale, if you will. Even if no intentional changes were made or have occurred, and all processes have operated normally and within limits, pharmaceutical companies are still required to annually review an amalgamation of all information and data sources of Validation of Pharmaceutical Processes, 3rd Edition
nonconformance to the quality system. This is done in an effort to determine if there are any negative trends and shifts in assurance levels that may be occurring on a “macro” scale and be observable only when a year’s worth of information is compiled. This is a requirement of the drug cGMPs under 21 CFR 211.180(e).
Conclusion
Contamination in finished pharmaceutical products is an area that is focused on by the FDA since it can lead to major regulatory or patient safety issues for companies unless they are controlled through proven, effective mitigation techniques and control. Because each and every tablet or capsule produced cannot be analyzed, companies must have technically and scientifically sound methods in place to demonstrate assurance that the type and levels of contaminants that could be in each of those products are under control.Process validation for business success
Validation for Medical Device and Diagnostic Manufacturers
Validation of Pharmaceutical Processes: Sterile Products, Second Edition
Cleaning and Cleaning Validation (Volume 1)
Classic Cosmetics cited for lack of process and cleaning validation in 4-item 483.(HUMAN DRUGS): An article from: Inspection Monitor
Unwanted and potentially dangerous chemical or biological contaminants in pharmaceutical manufacturing have long been an area of concern. These contaminants can lead to unpredictable pharmacological effects or super- or sub-potency of the active drug substance. Worse, they may be toxic.
Because of the potentially dangerous implications of contaminants on patient safety, the FDA, through its Current Good Manufacturing Practices (cGMP) regulations, requires manufacturers to employ a number of technical and scientific techniques in the manufacturing cycle. These techniques share a common goal: to provide a high level of assurance that finished drug products meet their intended and defined specifications. The FDA calls this goal validation.
To understand how these techniques provide this assurance, it is important to understand how the specifications for active drug substances and excipient compounds originate. Specifications for active drug substances and the inactive chemicals with which they are compounded (“excipients”) that are approved by the FDA to be sold in the United States are found in the United States Pharmacopeia (USP) and National Formulary (NF). The compendia not only identify the types of compounds, but also the analysis mgthods, and reagents, and acceptance levels that are required to be used to test and release products.
...it is manifestly impossible to include in each monograph a test for every impurity, contaminate or adulterant that might be present, including microbial contamination. These may arise from a change in the source of material or from a change in the proceýsing, or may be introduced from extraneous sources. Tests suitable for detecting such occurrences, the presence of which is inconsistent with applicable manufacturing practice or good pharmaceutical practice, should be employed in addition to the tests provided in the individual monographs.
This is one of the key reasons the FDA is taking a new look at how it applies cGMPs in the pharmaceutical industry. In September 2002, the FDA announced this initiative as “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach.” In part, this initiative will focus the validation efforts of manufacturers on materials and manufacturing systems that they have determined could lead to potential or actual patient risk due to contamination.
The Lifecycle Approach
The FDA has indicated that a Lifecycle Approach is a critical element of effective validations. When viewed in light of the USP/NF General Notice and the FDA initiative, contamination control and assurance in the pharmaceutical manufacturing process becoýes a sequence of activities that is part of the product Lifecycle. As such, the assurance methods and activities to control contamination are dynamic, and must constantly be refreshed when material or process changes occur, or when new information or technology becomes available.
First, the company must determine all the sources and types of biological and chemical contaminant introduction in the process and their impact on the final product through technically and scientifically sound risk-based methods. After determining the probability of occurrence, severity, or impact should it occur, and the existing levels of detection for each source, a risk of occurrence can be derived. When these risks are reviewed against accepted patient or human safety standards, key contaminant sources and the methods of assuring their control can be identified for subsequent validation.
Many technically sound risk-based techniques such as Failure Mode Effects and Analysis (FMEA) can be used for these evaluations. However, a technique that originated with the FDA in food safety, Hazard Assessment and Critical Control Points (HACCP), is growing in popularity for pharmaceuticals and medical devices. This technique provides companies with the ability to succinctly identify the critical sources and types of contamination as well as the mechanisms for controlling them in material and manufacturing processes.
Once the potential contamination sources are identified, the second activity in the Lifecycle approach is to conduct scientifically and technically sound qualification studies that provide evidence that contaminants can be controlled to the defined levels desired. These qualifications are required to not only demonstrate control under nominal process conditions, but also under conditions where the material or process is under stress. For FDA purposes, these prospective studies are defined as Protocols, and take the form of Installation Qualifications, Operational Qualifications, and Performance Qualifications. At a minimum, pharmaceutical contaminant process validations should consider the qualification of any:
* Active and excipient materials and their suppliers
* Microbiological bioburden of materials, processes, and environment
* Cleaning, disinfecting, and residue control of process equipment
* Air handling and purification
* Employee health, hygiene, and sanitation
* Production of water used in the process or for cleaning
* Manufacturing process and activity degradation
* Lubricants or process aids used in manufacturing
* Pesticides used in the manufacturing processing areas
* Computers and software that control any manufacturing or associated processes
The Impact of Change
Bnce these studies have been concluded, the materials, processes, and quality systems that support them have demonstrated themselves as valid. However, since change is inevitable, this validation must be reviewed for ongoing applicability when changes are made to any key factors contained in the original study. This becomes the Lifecycle aspect of validation. Changes that can impact the original state-of-validation can occur in many ways; any change in components or materials, suppliers, a supplier’s process, or in a supplier’s supplier may impact current contamination controls. Seemingly innocuous changes in cleaning and disinfection may become a source of change in the ability to provide assurance contaminants are being controlled. Because ‹any processes today are computer controlled, changes to process control soft ware may have significant impact on contaminant assurance.
All changes that could impact the original risk assessment assumptions must be reviewed for impact to the current validation. In some cases, this may involve revisiting the original risk assessment to determine if the risk factors need to be recalculated due to the change. If it is determined that the change could impact the current validated assurance levels, the change must be studied through a re-validation activity prior to implementation. But the validation dynamic is not only limited to changes made by the pharmaceutical firm or its suppliers. Companies are also expected to be aware, and act on, information from outside sources that may have a bearing on their original risk assessment. Items such as revisions to safe levels of contaminants, new toxic compounds, and mutated strains of microbiological contaminants can be reported in the literature and press. Companies may also become aware of a contaminant issue that occurred either internally or at a competitor for a process or material similar to the item in question. Likewise, information gathered from adverse reports of the drug use in patients may lead to information that requires the company to challenge its original risk assessment assumption and testing.
The above review process is useful on an individual change basis: a “micro” scale, if you will. Even if no intentional changes were made or have occurred, and all processes have operated normally and within limits, pharmaceutical companies are still required to annually review an amalgamation of all information and data sources of Validation of Pharmaceutical Processes, 3rd Edition
nonconformance to the quality system. This is done in an effort to determine if there are any negative trends and shifts in assurance levels that may be occurring on a “macro” scale and be observable only when a year’s worth of information is compiled. This is a requirement of the drug cGMPs under 21 CFR 211.180(e).Conclusion
Contamination in finished pharmaceutical products is an area that is focused on by the FDA since it can lead to major regulatory or patient safety issues for companies unless they are controlled through proven, effective mitigation techniques and control. Because each and every tablet or capsule produced cannot be analyzed, companies must have technically and scientifically sound methods in place to demonstrate assurance that the type and levels of contaminants that could be in each of those products are under control.Process validation for business success
Validation for Medical Device and Diagnostic Manufacturers Validation of Pharmaceutical Processes: Sterile Products, Second Edition
Cleaning and Cleaning Validation (Volume 1)Classic Cosmetics cited for lack of process and cleaning validation in 4-item 483.(HUMAN DRUGS): An article from: Inspection Monitor
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