USP <1223> Revision and the Alternative Microbiological Methods Workshop Tony Cundell, Ph. D. Consulting Microbiologist, Scarsdale, New York, USA

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1 USP <1223> Revision and the Alternative Microbiological Methods Workshop Tony Cundell, Ph. D. Consulting Microbiologist, Scarsdale, New York, USA September, 2015 biomerieux Meeting 1

2 Presentation Outline Regulatory and compendial guidance documents Summary of the USP workshop on the revision to USP <1223> USP microbiology expert committee s position on advance microbiological methods Equivalence options for AMM validation USP Rapid Sterility Test initiative Take home message September, 2015 biomerieux Meeting 2

3 Alternative Microbial Method Validation The pioneering 2000 PDA Technical Report #33 The Evaluation, Validation and Implementation of New Microbiological Testing Methods was revised in November Other influential documents include USP <1223> Validation of Alternative Microbiological Methods, and Ph. Eur Alternative Methods for Control of Microbiological Quality. September, 2015 biomerieux Meeting 3

4 Workshop The USP Alternative Microbiological Methods Workshop, March 16-17, 2015 at the USP Headquarters attracted 66 registrants and invited speakers from the FDA, EDQM, JP, pharmaceutical industry and academia. The revisions to USP <1223> Validation of Alternative Microbiological Methods and plans for compendial rapid sterility test were discussed. September, 2015 biomerieux Meeting 4

5 USP <1223> Revisions The revisions included a discussion of the limitations of the CFU, the acceptable procedure concept, the performance, results and equivalence options for alternative method validation, and application of non-inferiority test as a statistical tool. The revised chapter was published online in the July-August Pharmacopeial Forum with an official date of December 1, September, 2015 biomerieux Meeting 5

6 FDA Position Erika Pfeiler (CDER, FDA) gave the Agency s position on alternative microbiology methods (AMMs). She reviewed FDA s policies and stated that CDER has approved AMMs for water testing, environmental monitoring, bioburden testing, microbial limits (for release and stability) and sterility testing (for release and stability). She stated that FDA welcomes submissions for the use of AMMs, they are routinely approving around 5 AMMs annually, different approaches to validation are acceptable and validation studies should depend on your product and process. September, 2015 biomerieux Meeting 6

7 EDQM Position Stephen Wicks (EDQM) reviewed the current revision to Ph. Eur. chapter This draft is currently available for public review (through Pharmeuropa) and the comment period closed March 31, RMM consultant Michael Miller was encouraged by Wick s statement that the revised chapter will be largely aligned with PDA s Technical Report No. 33 revised in November September, 2015 biomerieux Meeting 7

8 JP Position Nobuyasu Yamaguchi (Osaka University) provided an overview of the Japanese Pharmacopeia s (JP) new informational chapter on rapid microbiological methods (RMM). The chapter will be published in the 17th edition of the JP with an English version being provided in the northern hemisphere summer of September, 2015 biomerieux Meeting 8

9 Invited Statistician s Position Edwin van den Heuvel (Eindhoven University of Technology) presented a detailed review of how to use non-inferiority models when statistically comparing data sets arising from AMM validation studies. He concluded that this statistic approach, widely used in clinical trials, is well suited to method validation. Note: Verdonk and Van den Heuvel made a significant contribution in their 2010 paper using a MPN method to established a LOD of 1 CFU for the BacT/ALERT and AKUScreen systems using BioBall inocula. September, 2015 biomerieux Meeting 9

10 Industry Speaker David Roesti, an industry speaker from Novartis, presented his company s work on validating a rapid sterility test that was approved by more than 50 countries including the U.S. and EU. In general, he was supportive of the USP <1223> revisions September, 2015 biomerieux Meeting 10

11 USP Position As AMMs move further away from classical methods based on the colony-forming unit, the USP needs to respond to this RMM validation challenge. The current compendial methods are unsuitable for the emerging short-lived cell-derived drug products, sterile compounded preparations and radiopharmaceuticals as these methods are growth based requiring at least a 14-day incubation. We need a new paradigm. September, 2015 biomerieux Meeting 11

12 USP Position The USP believes that the widespread implementation of AMMs for both in-process and finished product testing will improve good manufacturing practices, maintain product quality and promote patient safety. Existing method validation approaches are limiting AMM implementation and future method development. September, 2015 biomerieux Meeting 12

13 USP Position The colony-forming unit (CFU) is an estimate of viable bacterial or fungal numbers in a water, air, soil, food or drug sample. Unlike direct microscopic counts where all cells, dead and living, may be counted, CFU estimates viable cells that are capable of dividing in the solid plate count medium under the incubation conditions employed. i.e. the great plate count anomaly. Staley and Konopka, 1985 Measurements of of in situ activities of non-photosynthetic microorganisms in aquatic and terrestrial habitats. Ann. Rev. Microbiol. 39: September, 2015 biomerieux Meeting 13

14 USP Position Signals other than CFUs that may be used for microbial enumeration and detection include: Autofluorescent cells detected by flow cytometry Vital stained cells detected by solid-phase and fluid fluorescent microscopy PCR amplified nucleic acid targeted sequences Number or weight of genomic units ATP levels measured by bioluminescence September, 2015 biomerieux Meeting 14

15 USP Position Typically these signals will be numerically higher than CFU and may not be directly statistically related to the CFU result. However, they should move directionally with CFU so as to rapidly detect adverse bioburden trends. Materials with an established fitness for use using CFU will retain their quality level despite the measurement of an alternate signal. To take advantages of emerging technologies we may need cut the ties to the CFU as a so-called gold standard. September, 2015 biomerieux Meeting 15

16 USP Position Four options available in USP <1223> to establish the equivalence of an alternative method are: 1) acceptable procedures, i.e. merely meeting a minimum performance requirement without demonstrating equivalence to the compendial method, 2) performance equivalence to the compendial method, 3) results equivalent to the compendial method, 4) decision equivalence to the compendial method. September, 2015 biomerieux Meeting 16

17 Option 1: Acceptable Procedure This is not strictly an equivalence option that requires direct comparison to an official compendial method but is based on the scientific literature. For example, with a nucleic acid-based technology, a highly purified bacterial genome could be used expressed as copies/ml in place of CFUs. The Limit of Detection would be the lowest concentration where 95% of the diluted samples would be positive, i.e. that could be copies per ml. The dynamic range of a qpcr method may be 10 to 10,000 copies/ml September, 2015 biomerieux Meeting 17

18 Option 1: Acceptable Procedure With a nucleic acid-based technology (cont.): The linearity of the PCR reaction will have a regression coefficient greater than 0.95 At the limit of quantification, i.e. 100 to 200 copies/ml the Relative Standard Deviation (RSD) will be less than 10% September, 2015 biomerieux Meeting 18

19 Option 2: Performance Equivalence In general, performance equivalence requires the demonstration of equivalence or better with respect to classical validation criteria, e.g. accuracy, precision, specificity, limit of detection, limit of quantification, robustness and ruggedness, appropriate for the type of test. Note: This is the current approach used in our industry. However, it is possible that the alternative method may be worse for one or more of the validation criteria and still be acceptable in terms of the USP General Notices. September, 2015 biomerieux Meeting 19

20 Option 3: Results Equivalence For results equivalence, the alternative and compendial test methods should give equivalent numerical results. Because the same sample cannot be tested in microbiology, typically a tolerance interval is established when comparing the two methods, with the alternative method determined to numerically superior or non-inferior. September, 2015 biomerieux Meeting 20

21 Option 4: Decision Equivalence A decision equivalence is similar to a results equivalence but differs in that a numerical result is not generated; instead a pass/fail result is obtained. With this approach, the frequency of positive results generated should be no worse than with the compendial method. Examples where this option could be applied are sterility testing and absence of a specified microorganism. September, 2015 biomerieux Meeting 21

22 Compendial Rapid Sterility Test As a follow-up to the Open Conference, the USP Microbiology Expert Committee called for volunteers to serve on an expert advisory panel to develop users requirements and candidate technologies for multi-sourced, non-proprietary rapid sterility tests for short-lived products. Based on the panel s recommendation collaborative proof of concept studies will be conducted, methods selected and a compendial test chapter written. September, 2015 biomerieux Meeting 22

23 Compendial Rapid Sterility Test The advantages of having a compendial rapid testing test are that the technology, unlike an alternate test method, would not be validated by the end user and who be acceptable after method suitability testing as per USP <71>. Short-lived products like cell therapies, radiopharmaceutical and compounded sterile products would be tested prior to infusion into patients. September, 2015 biomerieux Meeting 23

24 Is a Rapid Sterility Test Achievable? Ambition leads me not only farther than any man has been before me, but as far as I think it possible to go. James Cook, R.N. of the H.M.S. Endeavour September, 2015 biomerieux Meeting 24 24

25 Conclusions Stakeholders should bear in mind that patient safety based on risk analysis, good manufacturing practices and superior quality system management will be maintained, irrespective whether you change to an alternative microbiological method using a different signal than colony-forming units. The opportunities afforded through the application of AMMs to process analytical technology, failure investigations and timely results and improved overall quality are within our reach. Let s do it! September, 2015 biomerieux Meeting 25

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