by Dr. Ray Nims
United States Pharmacopeia (USP) general chapter <1050> Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin originally appeared in supplement 10 to USP23-NF18 in May 1999 and was at that time essentially a verbatim adoption of the International Conference of Harmonization (ICH) Guideline Q5A (R1) having the same title.
The chapter describes the methods of evaluating the viral safety of biotechnology pharmaceutical products that are manufactured using cell lines of human or animal origin.
In 2006, an ad hoc advisory panel was assembled by the USP and tasked with revision of this chapter. The goals were to update the chapter and, more specifically, to add greater detail in the viral clearance validation section. The hope was that a user following the recommendations set forth in the general chapter would have greater confidence that viral clearance validation data generated would prove acceptable to the regulatory agencies.
The organization of the revised chapter <1050> was not changed. It comprised the following main sections: 1) Introduction; 2)Potential sources of viral contamination; 3) Cell line qualification: testing for viruses; 4) Testing for viruses in unprocessed bulk; 5) Rationale and action plan for viral clearance studies and viruses tests on purified bulk; and 6) Evaluation and characterization of viral clearance procedures. The changes proposed for the initial 5 sections were minor and primarily reflected attempts to update the chapter and to align the chapter more closely with FDA guidance documents. The most extensive changes were to section 6, in keeping with the goals described above.
The revised chapter was published for public comment in Pharmacopeial Forum 36(3) in the fall of 2010. Comments received as a result of the public review apparently suggested that a more extensive update of the chapter was warranted. At any rate, the revised chapter was not made effective during the USP’s 2005-2010 revision cycle. A new ad hoc advisory panel now being assembled as part of USP's 2010-2015 revision cycle will take over the responsibility for moving the revision of this chapter forward.
Showing posts with label USP. Show all posts
Showing posts with label USP. Show all posts
Wednesday, February 16, 2011
Wednesday, June 23, 2010
Assessing rapid microbial detection systems
by Dr. Ray Nims
With each passing year, it seems that there are more options available for rapid microbial detection. These rapid systems come in a variety of “flavors”, that is - they differ with respect to a set of key attributes. For instance, how rapid is rapid? What is the sensitivity? What is the maximum sample volume that may be tested? Is it quantitative or qualitative? What units are the results given in? Is it destructive or non-destructive (i.e., can the organism, once detected, be identified)? When one considers the variety of applications for which rapid methods may potentially replace existing culture methods, it rapidly becomes clear that there may not be “one shoe that fits all”.
In order to select an appropriate rapid method for use in one of the many microbial detection applications, one must first assess the available rapid systems for the key attributes mentioned above. This then provides the opportunity to rule out systems which for one reason or the other will not suit the application. There may be some applications for which no rapid system currently meets all requirements. Those rapid systems which do appear to possess the attributes required may be further evaluated for cost and for performance capabilities using specific sample matrices.
In the table below, we have listed some of the currently available rapid microbial detection systems. These include only systems which are 48 hours in duration or less, and therefore some of the sterility replacement assays involving reduced incubation durations (e.g., BacT/ALERT®, Growth Direct™) are not listed.
The key attributes of these rapid systems are displayed in the table below. The systems are arranged by principle of detection, as in the table above. For certain methods (e.g., Micro Pro™) increased sensitivity can be gained through increasing the duration of the incubation time. For non-destructive methods, the ability to identify the organism(s) detected is facilitated by an additional incubation post-detection.
What is the regulatory position on rapid microbial detection methods? The U.S. FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing states that other suitable microbiological tests (e.g., rapid methods) may be considered for environmental monitoring, in-process control testing, and finished product release testing after it has been demonstrated that these new methods are equivalent or better than conventional (e.g., USP) methods. Additionally, the FDA Process Analytical Technology (PAT) initiative encourages the voluntary development and implementation of innovative approaches in pharmaceutical development, manufacturing, and quality assurance (from MJ Miller, PDA Journal 45: 1-5, 2002).
Are rapid methods being used in the pharmaceutical industry? ScanRDI was approved by the FDA for water testing at GSK and for sterility testing at Alcon; Pallchek has been approved by the FDA for bioburden testing at GSK; and Wyeth received approval for use of Celsis for microbial limits testing.
Like all methods proposed to replace existing “gold standards”, these rapid microbial detection systems must be demonstrated through comparability protocols to be equivalent to or better than the existing methods. The effort required should pay dividends in terms of shortened turnaround times and reduced costs.
With each passing year, it seems that there are more options available for rapid microbial detection. These rapid systems come in a variety of “flavors”, that is - they differ with respect to a set of key attributes. For instance, how rapid is rapid? What is the sensitivity? What is the maximum sample volume that may be tested? Is it quantitative or qualitative? What units are the results given in? Is it destructive or non-destructive (i.e., can the organism, once detected, be identified)? When one considers the variety of applications for which rapid methods may potentially replace existing culture methods, it rapidly becomes clear that there may not be “one shoe that fits all”.
In order to select an appropriate rapid method for use in one of the many microbial detection applications, one must first assess the available rapid systems for the key attributes mentioned above. This then provides the opportunity to rule out systems which for one reason or the other will not suit the application. There may be some applications for which no rapid system currently meets all requirements. Those rapid systems which do appear to possess the attributes required may be further evaluated for cost and for performance capabilities using specific sample matrices.
In the table below, we have listed some of the currently available rapid microbial detection systems. These include only systems which are 48 hours in duration or less, and therefore some of the sterility replacement assays involving reduced incubation durations (e.g., BacT/ALERT®, Growth Direct™) are not listed.
The key attributes of these rapid systems are displayed in the table below. The systems are arranged by principle of detection, as in the table above. For certain methods (e.g., Micro Pro™) increased sensitivity can be gained through increasing the duration of the incubation time. For non-destructive methods, the ability to identify the organism(s) detected is facilitated by an additional incubation post-detection.
What is the regulatory position on rapid microbial detection methods? The U.S. FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing states that other suitable microbiological tests (e.g., rapid methods) may be considered for environmental monitoring, in-process control testing, and finished product release testing after it has been demonstrated that these new methods are equivalent or better than conventional (e.g., USP) methods. Additionally, the FDA Process Analytical Technology (PAT) initiative encourages the voluntary development and implementation of innovative approaches in pharmaceutical development, manufacturing, and quality assurance (from MJ Miller, PDA Journal 45: 1-5, 2002).
Are rapid methods being used in the pharmaceutical industry? ScanRDI was approved by the FDA for water testing at GSK and for sterility testing at Alcon; Pallchek has been approved by the FDA for bioburden testing at GSK; and Wyeth received approval for use of Celsis for microbial limits testing.
Like all methods proposed to replace existing “gold standards”, these rapid microbial detection systems must be demonstrated through comparability protocols to be equivalent to or better than the existing methods. The effort required should pay dividends in terms of shortened turnaround times and reduced costs.
Wednesday, February 10, 2010
USP 63 Mycoplasma Update
By Dr. Ray Nims
The United States Pharmacopeia’s (USP) new chapter <63> Mycoplasma Tests was planned to become effective on May 1, 2010 as part of USP 33. This new chapter was intended to fill a void in the USP for mycoplasma testing, which had been addressed previously within the FDA’s 1993 Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals and the European Pharmacopoeia (EP) chapter 2.6.7 Mycoplasmas (a separate document applying only to mycoplasma testing of live and inactivated viral vaccines, 21 CFR 610.30 will not be considered here). Since there were some methodological differences between the FDA guidance and the EP chapter, it was hoped by the industry that the USP guidance would serve to harmonize mycoplasma testing as much as practically possible.
Indeed, a quick look at the new USP chapter <63> indicates that the chapter was based in large part on EP chapter 2.6.7. A comparison of the three documents (USP, FDA, and EP) reveals methodological differences in only a few areas. These include the assessment of nutritive properties of the solid growth media (agar) used for mycoplasma testing, the assessment of inhibitory substances in the test material, the incubation temperature ranges to be used, and the number of positive controls to be used.
The EP chapter 2.6.7 states that “The solid medium complies with the test if adequate growth is found for each test micro-organism (growth obtained does not differ by a factor greater than 5 from the value calculated with respect to the inoculum)”. There is a different requirement within USP chapter <63>: “The solid medium complies with the test if a count within a 0.5-log unit range of the inoculate amount is found for each test microorganism”. Assuming an inoculate of 100 colony forming units (CFU), the acceptable ranges for the recovered organisms would be 32-316 CFU for the USP version vs 20-500 CFU for the EP version. The USP version is therefore more stringent in this respect.
Similarly, for the assessment of inhibitory substances, EP chapter 2.6.7 states that “…if plates directly inoculated with the product to be examined have fewer than 1/5 of the number of colonies of those inoculated without the product to be examined” there are inhibitory substances in the test material. The USP version indicates that there are inhibitory substances “…if plates directly inoculated with the test article/material are not within a 0.5-log unit range of the number of colonies of those inoculated without the test article/material.” So the USP version is again more stringent in this respect.
Minor differences in incubation temperature for test cultures exist between the documents (36 ± 1°C for the USP and PTC documents vs 35-38°C for the EP chapter). The USP and PTC documents specify the number and types of positive controls to be used in the assays: at least two known Mycoplasma species or strains should be included as positive controls (one a dextrose fermenter and one an arginine hydrolyzer). The EP chapter specifies that at least one of the six Mycoplasma species listed in the chapter be used as a positive control.
The USP chapter <63> differs from EP chapter 2.6.7 also in that the former does not provide requirements for validation of a nucleic acid-based test for mycoplasma. The USP chapter mentions the possibility of replacing the culture method with an alternative (nucleic-acid or enzymatic) method, stating that the alternative method must be validated and shown to be comparable to the agar/broth and cell culture methods. The EP chapter laid the foundation for validation of a nucleic acid-based mycoplasma detection test for the first time in version 5.8 (effective July 2007). This provided the industry with expectations for implementation of a rapid alternative test to the approved culture test for mycoplasma, which is 28 days in duration. Similar guidance is not yet forthcoming from the FDA or USP.
The issues of nutritive properties and inhibitory substances are not addressed within the FDA’s 1993 Points to Consider guidance. In order to now be compliant with the FDA and EP requirements as well as the new USP chapter, testing labs will have to make adjustment within their protocols to account for the stricter USP criteria for assessing nutritive properties and inhibitory substances. Due to errors within some of the monographs to appear in the issuance of the USP to become effective May 1, 2010, this issuance of USP 33, including chapter <63>, was retracted in January of 2010. However, it will be re-issued in March 2010 with an official date six months after reissue, and the methodological differences may need to be accounted for in testing protocols used by quality control laboratories for which USP compliance is applicable.
Once this chapter becomes effective, the mycoplasma test methods described will be considered compendial, meaning that labs following the methods outlined in the chapter will not be required to perform method validation. The labs will only be required to perform method verification for each test sample type (matrix qualification) per USP <1226>.
The United States Pharmacopeia’s (USP) new chapter <63> Mycoplasma Tests was planned to become effective on May 1, 2010 as part of USP 33. This new chapter was intended to fill a void in the USP for mycoplasma testing, which had been addressed previously within the FDA’s 1993 Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals and the European Pharmacopoeia (EP) chapter 2.6.7 Mycoplasmas (a separate document applying only to mycoplasma testing of live and inactivated viral vaccines, 21 CFR 610.30 will not be considered here). Since there were some methodological differences between the FDA guidance and the EP chapter, it was hoped by the industry that the USP guidance would serve to harmonize mycoplasma testing as much as practically possible.
Indeed, a quick look at the new USP chapter <63> indicates that the chapter was based in large part on EP chapter 2.6.7. A comparison of the three documents (USP, FDA, and EP) reveals methodological differences in only a few areas. These include the assessment of nutritive properties of the solid growth media (agar) used for mycoplasma testing, the assessment of inhibitory substances in the test material, the incubation temperature ranges to be used, and the number of positive controls to be used.
The EP chapter 2.6.7 states that “The solid medium complies with the test if adequate growth is found for each test micro-organism (growth obtained does not differ by a factor greater than 5 from the value calculated with respect to the inoculum)”. There is a different requirement within USP chapter <63>: “The solid medium complies with the test if a count within a 0.5-log unit range of the inoculate amount is found for each test microorganism”. Assuming an inoculate of 100 colony forming units (CFU), the acceptable ranges for the recovered organisms would be 32-316 CFU for the USP version vs 20-500 CFU for the EP version. The USP version is therefore more stringent in this respect.
Similarly, for the assessment of inhibitory substances, EP chapter 2.6.7 states that “…if plates directly inoculated with the product to be examined have fewer than 1/5 of the number of colonies of those inoculated without the product to be examined” there are inhibitory substances in the test material. The USP version indicates that there are inhibitory substances “…if plates directly inoculated with the test article/material are not within a 0.5-log unit range of the number of colonies of those inoculated without the test article/material.” So the USP version is again more stringent in this respect.
Minor differences in incubation temperature for test cultures exist between the documents (36 ± 1°C for the USP and PTC documents vs 35-38°C for the EP chapter). The USP and PTC documents specify the number and types of positive controls to be used in the assays: at least two known Mycoplasma species or strains should be included as positive controls (one a dextrose fermenter and one an arginine hydrolyzer). The EP chapter specifies that at least one of the six Mycoplasma species listed in the chapter be used as a positive control.
The USP chapter <63> differs from EP chapter 2.6.7 also in that the former does not provide requirements for validation of a nucleic acid-based test for mycoplasma. The USP chapter mentions the possibility of replacing the culture method with an alternative (nucleic-acid or enzymatic) method, stating that the alternative method must be validated and shown to be comparable to the agar/broth and cell culture methods. The EP chapter laid the foundation for validation of a nucleic acid-based mycoplasma detection test for the first time in version 5.8 (effective July 2007). This provided the industry with expectations for implementation of a rapid alternative test to the approved culture test for mycoplasma, which is 28 days in duration. Similar guidance is not yet forthcoming from the FDA or USP.
The issues of nutritive properties and inhibitory substances are not addressed within the FDA’s 1993 Points to Consider guidance. In order to now be compliant with the FDA and EP requirements as well as the new USP chapter, testing labs will have to make adjustment within their protocols to account for the stricter USP criteria for assessing nutritive properties and inhibitory substances. Due to errors within some of the monographs to appear in the issuance of the USP to become effective May 1, 2010, this issuance of USP 33, including chapter <63>, was retracted in January of 2010. However, it will be re-issued in March 2010 with an official date six months after reissue, and the methodological differences may need to be accounted for in testing protocols used by quality control laboratories for which USP compliance is applicable.
Once this chapter becomes effective, the mycoplasma test methods described will be considered compendial, meaning that labs following the methods outlined in the chapter will not be required to perform method validation. The labs will only be required to perform method verification for each test sample type (matrix qualification) per USP <1226>.
Monday, December 14, 2009
Advantages of Compendial Methods
By Dr. Lori Nixon
When you are developing a new product specification, it is usually recommended to rely on the appropriate compendial method for applicable “generic” quality characteristics such as pH, residual solvents, trace metals, bioburden, etc. By compendial method, we mean methods that are described as chapters in the United States Pharmacopeia (USP) or others that may be applicable for a specific regulatory region. The three main compendia include the USP, European Pharmacopoeia, Japanese Pharmacopeia (USP, PhEur, JP); these are the “tripartite” bodies that are involved in the International Conference on Harmonization (ICH).
Why rely on compendial methods rather than just using your own? It is generally recommended to refer to compendial methods where applicable. The advantage to the drug sponsor is a reduced requirement for validation supporting such methods (the methods themselves are considered validated, and may only require product-specific verification in the particular testing lab). Compendial methods are “familiar” to regulatory reviewers; they are also generally expected. If you propose your own method as an alternate method, you will need to justify why your own method is equivalent or better. For the testing lab, there is some advantage in having methods that can be applied to multiple products (avoiding a multiplicity of similar methods) and where the change process is relatively well-defined and publically communicated. You may also find it simpler to transfer testing between different labs.
To reference the compendial method in your specification, you may refer simply to the test by attribute and chapter, along with the associated limit for your product. For example, your specification may include a limit of 10 EU/mL for bacterial endotoxin as measured by USP<85>. The general expectation here is that at the time of testing, the current version of USP is used. Clearly, this will require that your testing lab is aware of any potential changes to the USP and can prepare for such changes accordingly. As with any other change to an analytical method, changes to compendial methods can impact training, internal procedures, product-specific re-validation/verification, etc.
In practice, labs often rely on additional internal descriptive procedures in order to execute the compendial methods (i.e., rather than just directing analysts to follow the chapter directly). This is usually a good idea, for several reasons. It can be easier to train analysts according to a standard documentation format, and it is often necessary to describe details that may be specific to the particular lab, equipment, instrumentation, reagents, reporting requirements, etc. Again, even if there is a lab-specific procedure, it is usually best to refer directly to the compendial method (USP<85>, e.g.) in the sponsor’s product specification.
Be aware of compliance with compendial testing requirements when you are outsourcing testing. For example, almost any chemical testing lab with have a method for pH, but that doesn’t necessarily mean that it will comply with USP<791>. For example, in this case the USP method describes measuring the sample temperature within a certain range; often “generic” lab methods for pH do not specify control of the sample temperature. There are additional requirements such as the calibration standards chosen, etc that must also be considered. When reviewing vendor methods, check the following:
- Does the method purport to comply with any compendia? (should be clearly stated in the vendor’s procedure if so)
- Which compendia?
- Check details of the method to ensure that it does indeed comply with the current compendial procedure(s) in question
- Does the lab have a mechanism to stay current with upcoming compendial changes?
- Do they have appropriate change control system to ensure that they can prepare for method changes and associated re-validation, etc?
- Consider what verification/validation is required to ensure that the vendor method provides reliable results for your particular product/sample type.
Of course, the downside of compendial methods is that they are region-specific, and one region may not recognize the compendia of another region. There have been efforts in recent years towards harmonizing methods (ICHQ4B for bioburden testing, for example), but this process is slow and far from complete.
If you intend to market or perform clinical trials in more than one region, you may need to ensure compliance with multiple compendia. In this case, consider the following:
• Has method been harmonized through the ICH process?
• Is it possible to create an internal “harmonized” method that meets the requirements of all relevant compendia?
• Is it possible to meet the requirements of all by following the “most stringent” compendial procedure?
• Will you need to test by multiple procedures to generate results acceptable to each region?
When you are developing a new product specification, it is usually recommended to rely on the appropriate compendial method for applicable “generic” quality characteristics such as pH, residual solvents, trace metals, bioburden, etc. By compendial method, we mean methods that are described as chapters in the United States Pharmacopeia (USP) or others that may be applicable for a specific regulatory region. The three main compendia include the USP, European Pharmacopoeia, Japanese Pharmacopeia (USP, PhEur, JP); these are the “tripartite” bodies that are involved in the International Conference on Harmonization (ICH).
photo of USP laboratories from DPR Construction Inc.
Why rely on compendial methods rather than just using your own? It is generally recommended to refer to compendial methods where applicable. The advantage to the drug sponsor is a reduced requirement for validation supporting such methods (the methods themselves are considered validated, and may only require product-specific verification in the particular testing lab). Compendial methods are “familiar” to regulatory reviewers; they are also generally expected. If you propose your own method as an alternate method, you will need to justify why your own method is equivalent or better. For the testing lab, there is some advantage in having methods that can be applied to multiple products (avoiding a multiplicity of similar methods) and where the change process is relatively well-defined and publically communicated. You may also find it simpler to transfer testing between different labs.
To reference the compendial method in your specification, you may refer simply to the test by attribute and chapter, along with the associated limit for your product. For example, your specification may include a limit of 10 EU/mL for bacterial endotoxin as measured by USP<85>. The general expectation here is that at the time of testing, the current version of USP is used. Clearly, this will require that your testing lab is aware of any potential changes to the USP and can prepare for such changes accordingly. As with any other change to an analytical method, changes to compendial methods can impact training, internal procedures, product-specific re-validation/verification, etc.
In practice, labs often rely on additional internal descriptive procedures in order to execute the compendial methods (i.e., rather than just directing analysts to follow the chapter directly). This is usually a good idea, for several reasons. It can be easier to train analysts according to a standard documentation format, and it is often necessary to describe details that may be specific to the particular lab, equipment, instrumentation, reagents, reporting requirements, etc. Again, even if there is a lab-specific procedure, it is usually best to refer directly to the compendial method (USP<85>, e.g.) in the sponsor’s product specification.
Be aware of compliance with compendial testing requirements when you are outsourcing testing. For example, almost any chemical testing lab with have a method for pH, but that doesn’t necessarily mean that it will comply with USP<791>. For example, in this case the USP method describes measuring the sample temperature within a certain range; often “generic” lab methods for pH do not specify control of the sample temperature. There are additional requirements such as the calibration standards chosen, etc that must also be considered. When reviewing vendor methods, check the following:
- Does the method purport to comply with any compendia? (should be clearly stated in the vendor’s procedure if so)
- Which compendia?
- Check details of the method to ensure that it does indeed comply with the current compendial procedure(s) in question
- Does the lab have a mechanism to stay current with upcoming compendial changes?
- Do they have appropriate change control system to ensure that they can prepare for method changes and associated re-validation, etc?
- Consider what verification/validation is required to ensure that the vendor method provides reliable results for your particular product/sample type.
Of course, the downside of compendial methods is that they are region-specific, and one region may not recognize the compendia of another region. There have been efforts in recent years towards harmonizing methods (ICHQ4B for bioburden testing, for example), but this process is slow and far from complete.
If you intend to market or perform clinical trials in more than one region, you may need to ensure compliance with multiple compendia. In this case, consider the following:
• Has method been harmonized through the ICH process?
• Is it possible to create an internal “harmonized” method that meets the requirements of all relevant compendia?
• Is it possible to meet the requirements of all by following the “most stringent” compendial procedure?
• Will you need to test by multiple procedures to generate results acceptable to each region?
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