APR January/February 2022 - 61

« MICROBIOLOGY
that " rFC intermediate precision is better than some claimed precision " ,
a value which was motivated through consideration of PDA TR 33 and
USP<1010>, Analytical Data - Interpretation and Treatment. Again, the
acceptance criterion for " non-inferiority " is derived from a confidence
interval, namely requiring that the upper limit of the one-sided 95%
confidence interval for the total rFC variability (blue horizontal line
Figure 2(b) is smaller than the claimed precision value (orange vertical
line Figure 2(b).
Conclusion
The use of statistical hypothesis testing to address the parameters
equivalency, accuracy and precision makes it possible to statistically
limit the risk to patient safety of falsely concluding non-inferiority of
the rFC method compared to the LAL method.
A risk assessment including literature reviews helped justify the
parameters specificity, linearity, range and limit of quantitation. The
risk assessment also helped to identify a few easy to address gaps (i.e.,
medium risks) for ensuring sufficient robustness.
This validation strategy offers new rFC users a simple approach
to address a full validation while minimizing the workload in the
laboratory through leveraged knowledge from literature. Different
from current published studies, this presented validation approach
uses statistical non-inferiority hypothesis testing based on pharma
water samples spiked with an endotoxin standard (as opposed to
water samples containing autochthonous endotoxins).
Acknowledgements
The authors would like to offer thanks to Dr Amela Wolf, Dr Boris
Zimmermann, Dr Sven Deutschmann, Genentech Analytical
Operations, and QC Kaiseraugst Operations for providing review and
their generation of the data.
References
1.
2.
3.
4.
5.
Tindall B, Demircioglu D, Uhlig T. (2021). Recombinant bacterial endotoxin testing: a
proven solution. BioTechniques, Vol. 70 (5).
Loverock B, Simon B, Burgenson A, Baines A. (2010). STIMULI TO THE REVISION PROCESS:
A Recombinant Factor C Procedure for the Detection of Gram-negative. Pharmacopeial
Forum, Vol. 36 (1).
Akers J, Guilfoyle D, Hussong D, McCullough K, Mello R, Singer D, et al. (2020). Functional
Challenges for Alternative Bacterial Endotoxins Tests Part 2: Comparability. American
Pharmaceutical Review.
Bolden J, Knutsen C, Levin J, et al. (2020). Currently available recombinant alternatives
to horseshoe crab blood lysates: Are they comparable for the detection of environmental
bacterial endotoxins? A Review. PDA Journal of Pharmaceutical Science and Technology,
Vol. 74 (5) pp 602-611.
6.
7.
Bolden, J, Knight M, Stockman S, Omokoko B. (2017). Results of a harmonized endotoxin
recovery study protocol evaluation by 14 BioPhorum Operations Group (BPOG) member
companies. Biologicals, Vol 48, pp 74 - 81.
Kikuchi Y, Haishima Y, Fukui C, Murai T, Nakagarwa Y, Ebisawa A, et al. (2017). Collaborative
Study on the Bacterial Endotoxins Test Using Recombinant Factor C-based Procedure for
Detection of Lipopolysaccharides. Pharmaceutical and Medical Device Regulatory Science,
Vol 48 (4), pp 252-260.
8.
Kikuchi Y, Haishima Y, Fukui C, Nakagawa Y, Ebisawa A, Morioka T, et al. (2018). Collaborative
Study on the Bacterial Endotoxins Test Using Recombinant Factor C-based Procedure for
Detection of Lipopolysaccharides, part 2. Pharmaceutical and Medical Device Regulatory
Science, Vol 49 (10), pp 708-719.
9.
10.
11.
12.
Piehler M, Roeder R, Blessing S, Reich J. (2020). Comparison of LAL and rFC Assays-
Participation in a Proficiency Test Program between 2014 and 2019. Microorganisms, Vol
8 (3), pp 418.
Marius M, Vacher F, Bonnevay T. (2020). Comparison of bacterial endotoxin testing
methods in purified pharmaceutical water matrices. Biologicals, Vol 67, pp 49-55.
Muroi M, Ogura N, Mizumura H, Aketagawa J, Oda T, Tanamoto K. (2019). Application of a
Recombinant Three-Factor Chromogenic Reagent, PyroSmart, for Bacterial Endotoxins Test
Filed in the Pharmacopeias. Biological and Pharmaceutical Bulletin, Vol. 42 (12).
Bolden J, Smith K. (2017). Application of Recombinant Factor C Reagent for the Detection
of Bacterial Endotoxins in Pharmaceutical Products. PDA Journal of Pharmaceutical Science
and Technology, Vol. 719 (5), pp 405-412.
13. Williams K. (2020). LAL and rFC Comparison Study Caveats. American Pharmaceutical
Review.
14. Abate W, Sattar A, Liu J, Conway, Jackson S. (2017). Evaluation of recombinant factor C
assay for the detection of divergent lipopolysaccharide structural species and comparison
with Limulus amebocyte lysate-based assays and a human monocyte activity assay.
Journal of Medical Microbiology, Vol 66 pp 888-897.
15.
16.
17.
Bolden J (2019). Recombinant Factor C. In K. Williams, Endotoxin Detection and Control in
Pharma, Limulus, and Mammalian Systems. (Chapter 13). Springer.
18.
Uhlig T, Williams K, Tindall B. (2021). rFC Validation - Simpler than you thought. PDA
Journal of Pharmaceutical Science and Technology
Eu Ph 5.1.10, Guidelines for Using the Test for Bacterial Endotoxins. 01/2021:50110
Manual of Policies and Procedures, Center for Drug Evaluation and Research. Acceptability
of Standards from Alternative Compendia (BP/EP/JP). MAPP 5310.7 Rev 1.
Parenteral Drug Association, Inc., Evaluation, Validation and Implementation of Alternative
and Rapid Microbiological Methods. Technical Report No. 33, Revised 2013
www.americanpharmaceuticalreview.com |
| 61
»
http://www.americanpharmaceuticalreview.com

APR January/February 2022

Table of Contents for the Digital Edition of APR January/February 2022

APR January/February 2022 - Cover1
APR January/February 2022 - Cover2
APR January/February 2022 - 1
APR January/February 2022 - 2
APR January/February 2022 - 3
APR January/February 2022 - 4
APR January/February 2022 - 5
APR January/February 2022 - 6
APR January/February 2022 - 7
APR January/February 2022 - 8
APR January/February 2022 - 9
APR January/February 2022 - 10
APR January/February 2022 - 11
APR January/February 2022 - 12
APR January/February 2022 - 13
APR January/February 2022 - 14
APR January/February 2022 - 15
APR January/February 2022 - 16
APR January/February 2022 - 17
APR January/February 2022 - 18
APR January/February 2022 - 19
APR January/February 2022 - 20
APR January/February 2022 - 21
APR January/February 2022 - 22
APR January/February 2022 - 23
APR January/February 2022 - 24
APR January/February 2022 - 25
APR January/February 2022 - 26
APR January/February 2022 - 27
APR January/February 2022 - 28
APR January/February 2022 - 29
APR January/February 2022 - 30
APR January/February 2022 - 31
APR January/February 2022 - 32
APR January/February 2022 - 33
APR January/February 2022 - 34
APR January/February 2022 - 35
APR January/February 2022 - 36
APR January/February 2022 - 37
APR January/February 2022 - 38
APR January/February 2022 - 39
APR January/February 2022 - 40
APR January/February 2022 - 41
APR January/February 2022 - 42
APR January/February 2022 - 43
APR January/February 2022 - 44
APR January/February 2022 - 45
APR January/February 2022 - 46
APR January/February 2022 - 47
APR January/February 2022 - 48
APR January/February 2022 - 49
APR January/February 2022 - 50
APR January/February 2022 - 51
APR January/February 2022 - 52
APR January/February 2022 - 53
APR January/February 2022 - 54
APR January/February 2022 - 55
APR January/February 2022 - 56
APR January/February 2022 - 57
APR January/February 2022 - 58
APR January/February 2022 - 59
APR January/February 2022 - 60
APR January/February 2022 - 61
APR January/February 2022 - 62
APR January/February 2022 - 63
APR January/February 2022 - 64
APR January/February 2022 - 65
APR January/February 2022 - 66
APR January/February 2022 - 67
APR January/February 2022 - 68
APR January/February 2022 - 69
APR January/February 2022 - 70
APR January/February 2022 - 71
APR January/February 2022 - 72
APR January/February 2022 - 73
APR January/February 2022 - 74
APR January/February 2022 - 75
APR January/February 2022 - 76
APR January/February 2022 - 77
APR January/February 2022 - 78
APR January/February 2022 - 79
APR January/February 2022 - 80
APR January/February 2022 - 81
APR January/February 2022 - 82
APR January/February 2022 - 83
APR January/February 2022 - 84
APR January/February 2022 - Cover3
APR January/February 2022 - Cover4
https://www.nxtbookmedia.com