Somehow, nonspecific methods are viewed as less robust than specific methods. In fact, for cleaning validation, using a method such as TOC actually makes it more difficult for a manufacturer to meet its cleaning validation acceptance limits (again provided the limits are set correctly and the TOC data are converted appropriately into the target residue).4 If such methods were unacceptable, almost all biotechnology facilities would be shut down because TOC is used widely in the industry for measuring residues of the actives (in biotech, TOC is usually measuring degraded actives, but the measured TOC is expressed as if it were the undegraded active).
The use of TOC is further supported by a Human Drug Current Good Manufacturing Practice (cGMP) Note from FDA in which it states: "We think TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation."5 The cGMP note was replicated as a "Q&A for cGMP for Drugs" in 2002.6 FDA goes on to state the conditions that should be adhered to if TOC is used as the analytical method. However, the implication is that such methods are acceptable if used correctly.
Where did the myth come from? My speculation is that it came from using TOC as an analytical method, but only setting limits based on compendia water specifications (that is, 500 ppb TOC). It should be clear from the Myth 1 discussion that in this case TOC is an unacceptable method (correctly stated, it is the limit setting that is unacceptable, but it is easy to see how this became "TOC is unacceptable"). This is further complicated by a statement in the PIC/S guidance document that analytical methods for measuring residues "should be specific for the substance assayed".2 Could this be interpreted that only a "specific analytical method" be used? Again, such an interpretation would wreak havoc with the biotech industry. If a specific analytical method was required, the statement would be more explicit. This statement is probably akin to that in FDA's guidance that for rinse samples, "a direct measurement of the residue or contaminant" should be made.1 Is TOC a direct measure of an organic active? I would argue that it is. This conundrum of what is meant in the PIC/S guidance should be recognized, but it should not deter us from using TOC appropriately for cleaning validation purposes.
Some believe that FDA's guidance document requires specific methods. What it actually says is that you should "determine the specificity and sensitivity of the analytical method...."1 This is a far cry from requiring specific methods. A more reasonable interpretation is that you should understand the specificity of your analytical method, and take that into consideration as you utilize that method so that it is used correctly. This brings us to the issue of using nonspecific methods such as TOC correctly. For simplicity, I will discuss the correct use of TOC. One FDA requirement is that the TOC appropriately oxidize and measure the organic species in the target residue.6 Therefore, you will perform analytical method validation using the residue and TOC to confirm the method's applicability. Applicability indicates that the target residue is appropriately oxidized, and that it is appropriately water soluble such that it can be measured.
Another requirement is that any detected carbon be attributed to the target residue. The carbon in a sample may be partially from the active, excipients and cleaning agent. However, we are not allowed to apportion the measured carbon among these different sources. If we use TOC, we must consider (as a worst-case assumption) that all the carbon is because of the target residue (the active, if that is the target residue). FDA also states that you "should limit background... as much as possible." Why? Because it is just good practice to decrease the background (the TOC blank) to as low and as consistent a value as possible. This is why low TOC water, ultra-clean swabs and precleaned vials are typically used for swabbing with TOC. A final requirement is determining sample stability to confirm method applicability under expected holding conditions (post sampling, before analysis). Of course, this last requirement is relevant to any analytical method. There are other TOC requirements that are common to all analytical methods, including performing sampling recovery studies.1 The bottom line is you can use TOC, but use it correctly.
Summary
Recognition of these myths, and their lack both of scientific and written regulatory justification, can help companies avoid unnecessary work that adds little or no value to a cleaning validation programme.
References
1. http://www.fda.gov/ora/inspect_ref/igs/valid.html2. PIC/S Document PI 006-2 http://www.picscheme.org/
3. http://www.ich.org/
4. D. A. LeBlanc, "Why TOC is Acceptable", Cleaning Memos3, Cleaning Validation Technologies, 24–27 (2003).
5. FDA, Human Drug cGMP Notes, 1st Quarter 2002, PDA Letter 38(9), 9–13 (2002).
6. http://www.fda.gov/cder/guidance/cGMPs/equipment.htm
Destin A. LeBlanc is a consultant at Cleaning Validation Technologies, San Antonio, TX, USA.
Wednesday, August 18, 2010
Dispelling Cleaning Validation Myths: Part I B
By: Destin A. LeBlanc
Rinse sampling has also been misused by not performing recovery studies. A concern of FDA (expressed in its guidance document) is the dirty pot analogy.1 Do you determine the pot is clean by evaluating the pot or the rinse water? One obvious answer is to test the pot. However, another is to test the rinse water providing it can be established that any residue on the pot would be present in the rinse water. Just as recovery studies for swab sampling are done by spiking model surfaces with the target residue and then sampling by the swab procedure, rinse sampling recoveries should also be performed by spiking model surfaces with the target residue and performing rinse sampling on those surfaces to demonstrate quantitative recovery.
Lab rinse sampling recoveries cannot replicate production equipment rinsing. However, it is possible to simulate the rinsing conditions to demonstrate whether the rinsing process quantitatively removes surface residue. If it does demonstrate acceptable recovery, then the dirty pot analogy has been overcome. Where rinse sampling is used to demonstrate cleanliness of inaccessible surfaces (for example), rinse sampling recoveries should be performed to 'validate' that method. In this scenario, quantitative recovery is not 100% recovery. The acceptable recovery level is generally the same as that for swab sampling, which can vary from about 50–75%.
I believe the misuse of rinse sampling has lead to the myth that its use is unacceptable. Correct use of rinse sampling includes
Myth 2This is the idea that to use rinse sampling, you have to correlate it with swab sampling results. If what you mean is: "I need to make sure I get passing results by both swab and rinse samples," there may be an element of truth in this. However, if what is intended is that there should be a direct 1:1 (or similar) mathematical relationship between swab and rinse sampling values, then it is unreasonable to expect this to occur. Why? Swab sampling and rinse sampling measure two different things.
Swab sampling involves measuring the residue on a small area, which generally includes the worst-case locations (those most difficult to clean or likely to have unacceptable residue if cleaning is inadequate). However, rinse sampling covers a much larger surface area (perhaps the entire surface area of a manufacturing vessel), and, therefore, essentially averages the residue over all sampled surfaces. If failure occurs in swab sampling, it is reasonable to expect it to come from the worst-case locations and that, perhaps, other swabbed locations provide acceptable results.
If such is the case, it may be possible (if not probable) that a rinse sample will give acceptable results. But, if rinse sample results are unacceptable, you can expect that at least one swab sampling site should have failing results. The assumption in this is that you have calculated your limits appropriately (and did not do something such as set rinse limits based on compendia specifications for water).
I find it difficult to speculate on this myth's origins, except perhaps from an overzealous analytical group. Cleaning validation is hard enough in terms of ensuring necessary resources are available. Performing studies to mathematically 'correlate' swab and rinse sampling values does not add any value. What's more, do not expect them to mathematically correlate.
Myth 3
It is amazing how this one myth, that nonspecific methods are either unacceptable or less acceptable than specific methods, persists. Specific methods measure the target analyte (usually a given compound) in the presence of expected interferences.3 Specific methods include HPLC developed for a given compound.
Nonspecific methods measure a general property, but do not determine what compound that property is a result of. Methods include TOC and conductivity. TOC measures the organic carbon in a sample. In finished drug manufacture, the measured organic carbon in a cleaning validation swab sample may exist because of any combination of the active, excipient(s) and cleaning agent (as well as contributions for the blank, which could include the water, the swab and the vial).
Rinse sampling has also been misused by not performing recovery studies. A concern of FDA (expressed in its guidance document) is the dirty pot analogy.1 Do you determine the pot is clean by evaluating the pot or the rinse water? One obvious answer is to test the pot. However, another is to test the rinse water providing it can be established that any residue on the pot would be present in the rinse water. Just as recovery studies for swab sampling are done by spiking model surfaces with the target residue and then sampling by the swab procedure, rinse sampling recoveries should also be performed by spiking model surfaces with the target residue and performing rinse sampling on those surfaces to demonstrate quantitative recovery.
Lab rinse sampling recoveries cannot replicate production equipment rinsing. However, it is possible to simulate the rinsing conditions to demonstrate whether the rinsing process quantitatively removes surface residue. If it does demonstrate acceptable recovery, then the dirty pot analogy has been overcome. Where rinse sampling is used to demonstrate cleanliness of inaccessible surfaces (for example), rinse sampling recoveries should be performed to 'validate' that method. In this scenario, quantitative recovery is not 100% recovery. The acceptable recovery level is generally the same as that for swab sampling, which can vary from about 50–75%.
I believe the misuse of rinse sampling has lead to the myth that its use is unacceptable. Correct use of rinse sampling includes
- Carefully defining and controlling the rinse conditions.
- Performing a rinse recovery study.
- Making sure what you analyse is a direct measure of the target residue.
- Setting limits for that target residue (in the rinse solution) based on scientific principles.
Myth 2This is the idea that to use rinse sampling, you have to correlate it with swab sampling results. If what you mean is: "I need to make sure I get passing results by both swab and rinse samples," there may be an element of truth in this. However, if what is intended is that there should be a direct 1:1 (or similar) mathematical relationship between swab and rinse sampling values, then it is unreasonable to expect this to occur. Why? Swab sampling and rinse sampling measure two different things.
Swab sampling involves measuring the residue on a small area, which generally includes the worst-case locations (those most difficult to clean or likely to have unacceptable residue if cleaning is inadequate). However, rinse sampling covers a much larger surface area (perhaps the entire surface area of a manufacturing vessel), and, therefore, essentially averages the residue over all sampled surfaces. If failure occurs in swab sampling, it is reasonable to expect it to come from the worst-case locations and that, perhaps, other swabbed locations provide acceptable results.
If such is the case, it may be possible (if not probable) that a rinse sample will give acceptable results. But, if rinse sample results are unacceptable, you can expect that at least one swab sampling site should have failing results. The assumption in this is that you have calculated your limits appropriately (and did not do something such as set rinse limits based on compendia specifications for water).
I find it difficult to speculate on this myth's origins, except perhaps from an overzealous analytical group. Cleaning validation is hard enough in terms of ensuring necessary resources are available. Performing studies to mathematically 'correlate' swab and rinse sampling values does not add any value. What's more, do not expect them to mathematically correlate.
Myth 3
It is amazing how this one myth, that nonspecific methods are either unacceptable or less acceptable than specific methods, persists. Specific methods measure the target analyte (usually a given compound) in the presence of expected interferences.3 Specific methods include HPLC developed for a given compound.
Nonspecific methods measure a general property, but do not determine what compound that property is a result of. Methods include TOC and conductivity. TOC measures the organic carbon in a sample. In finished drug manufacture, the measured organic carbon in a cleaning validation swab sample may exist because of any combination of the active, excipient(s) and cleaning agent (as well as contributions for the blank, which could include the water, the swab and the vial).
Dispelling Cleaning Validation Myths: Part I A
By: Destin A. LeBlanc
Every regulated technology seems to come up with a list of what regulatory authorities supposedly say you should and should not do. Cleaning validation for pharmaceutical process manufacturing equipment is no different. Unfortunately, while many of these 'thou shalts' and 'thou shalt nots' have a partial basis in fact, they are actually distortions of the truth that come to have a life of their own. Hence I call them myths even though cleaning validation is only about 15 years old.
This article will explore eight of these myths and attempt to explain the origin of each (although in many cases the explanation of the origin is just speculation on my part). In addition, I will try to explain why the myth is wrong, how something seemingly prohibited can be properly used, and how those things apparently required may be unnecessary.
My list of myths is not intended to be exhaustive. The first three are examined in Part I of this article. Myths 4–8 will be covered in Part II to be published in a forthcoming issue.
1. Regulatory authorities do not like rinse sampling.
2. You must correlate rinse sampling results with swab sampling results.
3. You cannot use nonspecific analytical methods.
4. If you use total organic carbon (TOC), you must correlate it with a specific method, such as HPLC.
5. Any measured residue is unacceptable.
6. Dose-based calculations are unacceptable.
7. Recovery percentages of different spiked levels should be linear.
8. You cannot validate manual cleaning. Myth 1
The notion that regulatory authorities do not like or allow rinse sampling is false. FDA's cleaning validation guidance says: "There are two general types of sampling that have been found to be acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions."1 Some may want to emphasize that because direct sampling (i.e., swab sampling) is more desirable, it must follow that rinse sampling is less desirable. Although there may be certain logic to this, it overlooks the clear statement that both methods are acceptable. The Pharmaceutical Inspection Cooperation Scheme (PIC/S) guidance document says: "There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions)."2 Again, this is a clear statement that rinse sampling is acceptable. I should point out that the PIC/S document goes on to say that a "combination of the two methods is generally the most desirable."
Why, therefore, has the myth arisen that rinse sampling is unacceptable? In the early days of cleaning validation, rinse sampling was used inappropriately. For example, some companies using rinse sampling set limits such that the rinse sample was acceptable if it met compendia specifications. In other words, they worked by the maxim: "water-for-injection [WFI] in, WFI out, therefore, my equipment is clean." This use of rinse sampling is inappropriate, but still survives despite the fact that FDA's guidance document clearly states that "...it is not acceptable to simply test the rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates [sic]."1 I should make it clear here that you can use TOC to measure a contaminant in the rinse water. However, the acceptance limit of TOC is not automatically 500 ppb: it must be justified based on traditional limit calculations, and may be higher or lower than 500 ppb.
Every regulated technology seems to come up with a list of what regulatory authorities supposedly say you should and should not do. Cleaning validation for pharmaceutical process manufacturing equipment is no different. Unfortunately, while many of these 'thou shalts' and 'thou shalt nots' have a partial basis in fact, they are actually distortions of the truth that come to have a life of their own. Hence I call them myths even though cleaning validation is only about 15 years old.
This article will explore eight of these myths and attempt to explain the origin of each (although in many cases the explanation of the origin is just speculation on my part). In addition, I will try to explain why the myth is wrong, how something seemingly prohibited can be properly used, and how those things apparently required may be unnecessary.
My list of myths is not intended to be exhaustive. The first three are examined in Part I of this article. Myths 4–8 will be covered in Part II to be published in a forthcoming issue.
1. Regulatory authorities do not like rinse sampling.
2. You must correlate rinse sampling results with swab sampling results.
3. You cannot use nonspecific analytical methods.
4. If you use total organic carbon (TOC), you must correlate it with a specific method, such as HPLC.
5. Any measured residue is unacceptable.
6. Dose-based calculations are unacceptable.
7. Recovery percentages of different spiked levels should be linear.
8. You cannot validate manual cleaning. Myth 1
 Key points |
Why, therefore, has the myth arisen that rinse sampling is unacceptable? In the early days of cleaning validation, rinse sampling was used inappropriately. For example, some companies using rinse sampling set limits such that the rinse sample was acceptable if it met compendia specifications. In other words, they worked by the maxim: "water-for-injection [WFI] in, WFI out, therefore, my equipment is clean." This use of rinse sampling is inappropriate, but still survives despite the fact that FDA's guidance document clearly states that "...it is not acceptable to simply test the rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates [sic]."1 I should make it clear here that you can use TOC to measure a contaminant in the rinse water. However, the acceptance limit of TOC is not automatically 500 ppb: it must be justified based on traditional limit calculations, and may be higher or lower than 500 ppb.
Sunday, August 15, 2010
Running a Marathon in Flip-Flops – Part 1: The Value of Incorporating Prerequisites into Process Validation3
Manufacturing and inspection instrument calibration verification. Another important factor that should be assessed during prerequisites verification efforts (i.e., prior to manufacturing runs) is verifying and documenting that each instrument used in the manufacturing and testing process and that requires periodic calibration is within the current calibration interval and that each will remain within that interval throughout the process validation activity. For example, a validation engineer managed a shipping validation project for a biopharmaceutical product using numerous rented temperature and humidity monitors. When the data was collected and reviewed, it was noted that several of the instruments had results just out of the specified ranges. Upon investigation, it was noted that numerous instruments used in the study went out of calibration during the process resulting in questionable results. All product shipped was then considered of questionable quality as was the study itself requiring a redo of the process and lost saleable product.
Raw material status verification. Just as the manufacturing equipment and utilities needed to produce a product must be able to perform within predetermined criteria, the raw materials that go into the product must also meet their predetermined specifications. As dictated by the good manufacturing practices (GMP) regulations, a raw material must be tested and approved prior to use. The acceptance of the raw materials called for in a process validation should be verified prior to use. While this may seem to be a redundant task, spot-checking this aspect of the materials management quality system prior to a critical effort such as process validation again makes good business sense versus being a specific regulatory requirement.
Consider the situation when a contract manufacturer received a purchase order to produce a liquid oral dosage pharmaceutical product for a new customer. Of course, this activity requires process validation for which the minimum of three consecutive batches for process validation was agreed to by both parties. The raw material lots were assigned for each of the raw materials to be used in the three process validation batches. As typically is the case with contract manufacturing, the time period for manufacturing each lot was dictated by the customer's order of the product. Due to an unanticipated lack in the customer's product sales, the third batch was manufactured more than a year after the first two validation batches were made. The shelf life of the active ingredient was only one year and it had therefore expired. However, no raw material status prerequisite check was performed prior to manufacture. Upon testing of the third lot, the quality control testing laboratory found the product samples to be subpotent.
An extensive investigation was conducted which resulted in the batch failing and all three consecutive batches for process validation having to be redone at the manufacturer's cost. This situation could have been avoided with a simple verification of raw material status prior to manufacture of each process validation batch. Analytical test method status verification. This verification is one of the more controversial prerequisite verifications to incorporate into the process validation program due to the perception that the laboratory is seen as independent of the production process. Nonetheless, as stated previously, the results obtained by the laboratory for a specific process are a critical piece in the overall process of manufacturing and releasing a quality product as the laboratory produces results on which many of the validation conclusions rely. Therefore, it is of paramount importance to verify and document that all the test methods have been validated (nonpharmacopeial methods) or shown to be suitable (pharmacopeial methods).
The purpose of performing this prerequisite verification is not to check the adequacy of the test method validation or suitability effort. Rather, it is a spot check to verify and document that method validation (if necessary) has been completed and closed out prior to moving forward with the costly and time consuming effort associated with process validation. As a recent example, a sterile pharmaceutical manufacturer undergoing a preapproval inspection was recently given a 483 observation when the agency investigator discovered that the finished product potency test for the drug product had not been validated prior to beginning the validation activity. The entire validation was called into question by the investigator and ultimately had to be repeated.
Specified process parameters verification. If a product has been thoroughly developed, all of the critical manufacturing process parameters (i.e., processing ranges) that are specified in the MBR are based upon results obtained during the process development effort and verified during the confirmation run or technology transfer phase.
However, many times one or more ranges specified in a MBR are not associated with any justification at all (i.e., where the range came from in the first place). While it may seem to be a worthy risk to simply run the process validation with specified yet unsubstantiated ranges (versus generating a development report retrospectively), it truly presents a significant risk.
While never recommended, ranges that have not been challenged or assessed prior to process validation must be challenged during the process validation effort. This "dry run" approach during process validation has a significant cost factor if a "failure" occurs during execution of the runs. This is true even if the process is well-characterized and well-established. Without some sort of documentation supporting the range specified (e.g., a development report), a processing failure associated with a specified process parameter can only be assigned a defendable corrective and preventive action (CAPA) if it involves a thorough retrospective analysis of a statistically significant number of historical batches for which the specified process parameter data is obtainable. Of course, this would lead a savvy auditor to question the development of other parameters for other products as well. As you can see, this can be very costly on many fronts. The only way to avoid this situation prior to digging up the proverbial can of worms is to verify and document the origin of each specified process parameter present in the MBR prior to the execution of the process validation runs.
Product quality attributes verification.The purpose of this final process validation prerequisite is to verify and document that the in-process and finished product quality attributes match those in product development reports or are the most currently approved specifications reported in the product regulatory submission.
When a product has been approved in both the United States and countries outside the US this verification becomes even more important because product specifications for the same product can differ from country to country. For example, a solid dosage form manufacturer was undergoing a process (re)validation effort after making some process improvements. The product was approved for distribution in both the US and Canada. Prior to commencing the process validation runs, this prerequisite verification of the product quality attributes was conducted, at which time it was recognized that the impurity specification differed between the two countries for the same product. The Canadian specifications were tighter than the US specifications. However, only the U.S. values were listed in the validation protocol. If this prerequisite had not been verified prior to performing the production runs, the process validation effort may have resulted in problems meeting the more strict Canadian requirements.
ConclusionIn order to compete in the Boston Marathon, runners must demonstrate to the race organizers that they are ready to compete, so the unqualified entrants are weeded out of this prestigious event. In addition, the qualified runners check their own gear before the event as they want to maximize their chances to succeed.
The same concept applies to process validation. By using the process validation prerequisite approach, many of the potential pitfalls and hazards along the process validation route can be avoided before the costly production runs and laboratory testing.
Not only does this approach make good economical sense, but using this approach can also demonstrate, during government and customer audits, that quality is built into the process, and the quality systems approach to regulated product manufacturing is alive and well in your facility.
Nancy Cafmeyer, a consultant at Advanced Biomedical Consulting (ABC), LLC, with over 28 years industry experience has consulted at numerous pharmaceutical, nutritional supplement, and medical device manufacturers and prior to working for ABC has held both hand-on and management positions at companies such as King Pharmaceutical, Geopharma, and Daniels Pharmaceuticals.
Jonathan M. Lewis, a principal at Advanced Biomedical Consulting (ABC), LLC, has consulted at over 50 different biopharmaceutical, pharmaceutical, and medical device manufacturers and prior to starting ABC has held both hand-on and management positions at companies such as Cardinal Health, KMI, and PAREXEL International.
Advanced Biomedical Consulting (ABC), LLC, PO Box 76405, St. Petersburg, FL 33734, tel. 888.671.4292, fax 727.897.9522, info@advancedbiomedicalconsulting.com
http://www.abcforfda.com/
References
1. I.R. Gerry and R.A. Nash, Eds. Pharmaceutical Process Validation, (Marcel Decker, Inc., New York, 2nd ed., 1993), pp. xiii-24.
2. Code of Federal Regulations, Title 21, Food and Drugs, Part 211, (FDA, Department of Health and Human Services, Rockville, MD, April 1, 2006).
3. Guideline on General Principles of Process Validation, (FDA, Rockville, MD, May 1987).
4. Compliance Policy Guide Manual, Chapter 4, Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval, Document 7132c.08, (FDA, Rockville, MD, 2006).
5. Guidance for Industry, Q7A, Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, (FDA, Rockville, MD, August 2001).
Raw material status verification. Just as the manufacturing equipment and utilities needed to produce a product must be able to perform within predetermined criteria, the raw materials that go into the product must also meet their predetermined specifications. As dictated by the good manufacturing practices (GMP) regulations, a raw material must be tested and approved prior to use. The acceptance of the raw materials called for in a process validation should be verified prior to use. While this may seem to be a redundant task, spot-checking this aspect of the materials management quality system prior to a critical effort such as process validation again makes good business sense versus being a specific regulatory requirement.
Consider the situation when a contract manufacturer received a purchase order to produce a liquid oral dosage pharmaceutical product for a new customer. Of course, this activity requires process validation for which the minimum of three consecutive batches for process validation was agreed to by both parties. The raw material lots were assigned for each of the raw materials to be used in the three process validation batches. As typically is the case with contract manufacturing, the time period for manufacturing each lot was dictated by the customer's order of the product. Due to an unanticipated lack in the customer's product sales, the third batch was manufactured more than a year after the first two validation batches were made. The shelf life of the active ingredient was only one year and it had therefore expired. However, no raw material status prerequisite check was performed prior to manufacture. Upon testing of the third lot, the quality control testing laboratory found the product samples to be subpotent.
An extensive investigation was conducted which resulted in the batch failing and all three consecutive batches for process validation having to be redone at the manufacturer's cost. This situation could have been avoided with a simple verification of raw material status prior to manufacture of each process validation batch. Analytical test method status verification. This verification is one of the more controversial prerequisite verifications to incorporate into the process validation program due to the perception that the laboratory is seen as independent of the production process. Nonetheless, as stated previously, the results obtained by the laboratory for a specific process are a critical piece in the overall process of manufacturing and releasing a quality product as the laboratory produces results on which many of the validation conclusions rely. Therefore, it is of paramount importance to verify and document that all the test methods have been validated (nonpharmacopeial methods) or shown to be suitable (pharmacopeial methods).
The purpose of performing this prerequisite verification is not to check the adequacy of the test method validation or suitability effort. Rather, it is a spot check to verify and document that method validation (if necessary) has been completed and closed out prior to moving forward with the costly and time consuming effort associated with process validation. As a recent example, a sterile pharmaceutical manufacturer undergoing a preapproval inspection was recently given a 483 observation when the agency investigator discovered that the finished product potency test for the drug product had not been validated prior to beginning the validation activity. The entire validation was called into question by the investigator and ultimately had to be repeated.
Specified process parameters verification. If a product has been thoroughly developed, all of the critical manufacturing process parameters (i.e., processing ranges) that are specified in the MBR are based upon results obtained during the process development effort and verified during the confirmation run or technology transfer phase.
However, many times one or more ranges specified in a MBR are not associated with any justification at all (i.e., where the range came from in the first place). While it may seem to be a worthy risk to simply run the process validation with specified yet unsubstantiated ranges (versus generating a development report retrospectively), it truly presents a significant risk.
While never recommended, ranges that have not been challenged or assessed prior to process validation must be challenged during the process validation effort. This "dry run" approach during process validation has a significant cost factor if a "failure" occurs during execution of the runs. This is true even if the process is well-characterized and well-established. Without some sort of documentation supporting the range specified (e.g., a development report), a processing failure associated with a specified process parameter can only be assigned a defendable corrective and preventive action (CAPA) if it involves a thorough retrospective analysis of a statistically significant number of historical batches for which the specified process parameter data is obtainable. Of course, this would lead a savvy auditor to question the development of other parameters for other products as well. As you can see, this can be very costly on many fronts. The only way to avoid this situation prior to digging up the proverbial can of worms is to verify and document the origin of each specified process parameter present in the MBR prior to the execution of the process validation runs.
Product quality attributes verification.The purpose of this final process validation prerequisite is to verify and document that the in-process and finished product quality attributes match those in product development reports or are the most currently approved specifications reported in the product regulatory submission.
When a product has been approved in both the United States and countries outside the US this verification becomes even more important because product specifications for the same product can differ from country to country. For example, a solid dosage form manufacturer was undergoing a process (re)validation effort after making some process improvements. The product was approved for distribution in both the US and Canada. Prior to commencing the process validation runs, this prerequisite verification of the product quality attributes was conducted, at which time it was recognized that the impurity specification differed between the two countries for the same product. The Canadian specifications were tighter than the US specifications. However, only the U.S. values were listed in the validation protocol. If this prerequisite had not been verified prior to performing the production runs, the process validation effort may have resulted in problems meeting the more strict Canadian requirements.
ConclusionIn order to compete in the Boston Marathon, runners must demonstrate to the race organizers that they are ready to compete, so the unqualified entrants are weeded out of this prestigious event. In addition, the qualified runners check their own gear before the event as they want to maximize their chances to succeed.
The same concept applies to process validation. By using the process validation prerequisite approach, many of the potential pitfalls and hazards along the process validation route can be avoided before the costly production runs and laboratory testing.
Not only does this approach make good economical sense, but using this approach can also demonstrate, during government and customer audits, that quality is built into the process, and the quality systems approach to regulated product manufacturing is alive and well in your facility.
Nancy Cafmeyer, a consultant at Advanced Biomedical Consulting (ABC), LLC, with over 28 years industry experience has consulted at numerous pharmaceutical, nutritional supplement, and medical device manufacturers and prior to working for ABC has held both hand-on and management positions at companies such as King Pharmaceutical, Geopharma, and Daniels Pharmaceuticals.
Jonathan M. Lewis, a principal at Advanced Biomedical Consulting (ABC), LLC, has consulted at over 50 different biopharmaceutical, pharmaceutical, and medical device manufacturers and prior to starting ABC has held both hand-on and management positions at companies such as Cardinal Health, KMI, and PAREXEL International.
Advanced Biomedical Consulting (ABC), LLC, PO Box 76405, St. Petersburg, FL 33734, tel. 888.671.4292, fax 727.897.9522, info@advancedbiomedicalconsulting.com
http://www.abcforfda.com/
References
1. I.R. Gerry and R.A. Nash, Eds. Pharmaceutical Process Validation, (Marcel Decker, Inc., New York, 2nd ed., 1993), pp. xiii-24.
2. Code of Federal Regulations, Title 21, Food and Drugs, Part 211, (FDA, Department of Health and Human Services, Rockville, MD, April 1, 2006).
3. Guideline on General Principles of Process Validation, (FDA, Rockville, MD, May 1987).
4. Compliance Policy Guide Manual, Chapter 4, Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval, Document 7132c.08, (FDA, Rockville, MD, 2006).
5. Guidance for Industry, Q7A, Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, (FDA, Rockville, MD, August 2001).
Running a Marathon in Flip-Flops – Part 1: The Value of Incorporating Prerequisites into Process Validation 2
If the effective version generated during protocol generation is the same as what is being used on the production floor, then it is safe to initiate the process validation production runs. If not, there is a high probability that the protocol may be inaccurate (possibly resulting in numerous "failures") or that the process itself is not ready for process validation or even worse, commercial production.
For example, during a recent process validation activity at a liquid dosage pharmaceutical plant, modifications were made to the MBR less than a day before the already approved protocol was to be executed. Certain processes were modified without the knowledge and consent of the validation team. As a result, there were numerous deviations (i.e., investigations) that needed to be documented and addressed during the execution of the process validation production runs. This was due to the approved protocol not stating the correct directions to follow, which resulted in a big waste of time and money-let alone questioning compliance (i.e., the ability of the quality system to catch issues prior to and during production). If the MBR status was verified as a prerequisite, this issue would have been caught prior to executing the runs.
Operator and test personnel training verification. In manufacturing as well as in the analytical laboratory, many standard operating procedures (SOPs) and analytical test procedures are used. As the purpose of process validation is to provide assurance of the repeatability of a process, operators and analysts must be trained on all procedures that may affect the manufacturing and testing of the process. This prerequisite checks the training records of the operators and laboratory testing analysts to ensure that they have documented training on the procedures that they will be performing during the process validation activity. Again, not only is this a compliance risk, but it is also good business practice as failures due purely to untrained operator or analyst errors result in additional consecutive process validation production runs (i.e., avoidable wastes of time and money).
For example, during a recent pre-approval inspection of a pharmaceutical manufacturer, an investigator was reviewing the executed process validation protocol for the product being assessed. The investigator asked to see the training records for two of the analysts who performed the release testing on the finished lot of product. When given those records, the company realized that the two analysts had not been trained on the test procedures. This situation called into question the validity of the test results and ended in the company repeating the costly and time consuming testing. This situation would have been easily avoided by verifying training prior to execution. Equipment and utility system qualification verification. Just as an individual marathon runner chooses a very specific pair of running shoes to compete in versus a pair of everyday flip flops, equipment and utility systems are two of the most critical areas affecting the outcome of a manufacturing process. It is important to verify that the commercial equipment and support utility systems have first been qualified and second have been qualified within the specified process ranges prior to executing the process validation manufacturing runs.
Not only is the lack of equipment or utility system qualification a common gap discovered during inspections, and for which entire process validation efforts been disregarded, but many unforeseen commercial production issues may arise when these activities have not been completed prior to process validation production runs. This situation was clearly demonstrated when a coating process for a solid oral dosage pharmaceutical was developed and optimized at a specific spray rate using a process development pan coater. The pan coater used during the process validation runs, although similar in function to the process development pan coater, was not challenged during equipment qualification at a spray rate that bracketed the intended use. When the process went into validation, the difference in the spray nozzles caused the commercial pan coater to be unable to consistently obtain the specified MBR specifications for spray rate.
In this case, the entire batch was lost because the problem was discovered after the coating process was already in progress. A prerequisite verification of equipment qualification would have avoided the loss of a potentially saleable batch as well as the requirement to run a new set of consecutive process validation batches.
For example, during a recent process validation activity at a liquid dosage pharmaceutical plant, modifications were made to the MBR less than a day before the already approved protocol was to be executed. Certain processes were modified without the knowledge and consent of the validation team. As a result, there were numerous deviations (i.e., investigations) that needed to be documented and addressed during the execution of the process validation production runs. This was due to the approved protocol not stating the correct directions to follow, which resulted in a big waste of time and money-let alone questioning compliance (i.e., the ability of the quality system to catch issues prior to and during production). If the MBR status was verified as a prerequisite, this issue would have been caught prior to executing the runs.
Operator and test personnel training verification. In manufacturing as well as in the analytical laboratory, many standard operating procedures (SOPs) and analytical test procedures are used. As the purpose of process validation is to provide assurance of the repeatability of a process, operators and analysts must be trained on all procedures that may affect the manufacturing and testing of the process. This prerequisite checks the training records of the operators and laboratory testing analysts to ensure that they have documented training on the procedures that they will be performing during the process validation activity. Again, not only is this a compliance risk, but it is also good business practice as failures due purely to untrained operator or analyst errors result in additional consecutive process validation production runs (i.e., avoidable wastes of time and money).
For example, during a recent pre-approval inspection of a pharmaceutical manufacturer, an investigator was reviewing the executed process validation protocol for the product being assessed. The investigator asked to see the training records for two of the analysts who performed the release testing on the finished lot of product. When given those records, the company realized that the two analysts had not been trained on the test procedures. This situation called into question the validity of the test results and ended in the company repeating the costly and time consuming testing. This situation would have been easily avoided by verifying training prior to execution. Equipment and utility system qualification verification. Just as an individual marathon runner chooses a very specific pair of running shoes to compete in versus a pair of everyday flip flops, equipment and utility systems are two of the most critical areas affecting the outcome of a manufacturing process. It is important to verify that the commercial equipment and support utility systems have first been qualified and second have been qualified within the specified process ranges prior to executing the process validation manufacturing runs.
Not only is the lack of equipment or utility system qualification a common gap discovered during inspections, and for which entire process validation efforts been disregarded, but many unforeseen commercial production issues may arise when these activities have not been completed prior to process validation production runs. This situation was clearly demonstrated when a coating process for a solid oral dosage pharmaceutical was developed and optimized at a specific spray rate using a process development pan coater. The pan coater used during the process validation runs, although similar in function to the process development pan coater, was not challenged during equipment qualification at a spray rate that bracketed the intended use. When the process went into validation, the difference in the spray nozzles caused the commercial pan coater to be unable to consistently obtain the specified MBR specifications for spray rate.
In this case, the entire batch was lost because the problem was discovered after the coating process was already in progress. A prerequisite verification of equipment qualification would have avoided the loss of a potentially saleable batch as well as the requirement to run a new set of consecutive process validation batches.
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