Bioequivalence and Bioavailability Forum

Dear pmgjoshi!

❝ Dear sir,

       ^^ Not interested in opinions of madams in the forum?

❝ Specifically regarding the %RSD, is there any Statistical basis for the limits ?

No! Only the trivial observation that both inaccuracy and imprecision increase towards lower concentrations. The limits are arbitrary.

❝ Why 20% at LLOQ level? and why 15% at other than LLOQ level?

History and convenience. Shah’s paper (1987)^[1] was the basis of the first Arlington Conference in 1990. Two papers dealing with the topic^[2,3] were published before the conference report.^[4a-d] Arlington I (and Arlington II in 2000^[5]) lead to FDA’s guidance (2001).^[6] The most recent conference in the series (Arlington III) was held in 2006.^[7] For a historical overview see Shah (2007).^[8]

There was a lively discussion at Arlington I about the arbitrary cut-offs (20%/15%). Actually at the conference wider limits at LLOQ were proposed for bioassays only (I still have the conference notes somewhere); limits were widened for chromatographic methods by the editors of the report – contrary to the consensus reached at the conference. I know some of them personally – they exchanged arguments for quite a long time (before the age of the ’net – faxes going to and fro).
If you want to know where the numbers 20%/15% come from, please ask Vinod Shah – and share his answer with us.

Remember: 20%/15% are not carved in stone. In Ligand Binding Assays wider limits are not uncommon. Even for ‘conventional methods’ the guidance allows for wider limits, if justified. But to be honest, you have to have strong arguments from the method development phase to justify such a widening. First I would recommend replicate analyses (duplicates, triplicates) in order to bring variability down. I have seen only one case in almost 30 years where 30%/20% were used in an LC-method – but it was accepted.

References:

1. VP Shah
   Analytical methods used in bioavailabilty studies: A regulatory viewpoint
   Clin Res Pract Drug Re. Affairs 5, 51-60 (1987)
   
2. Karnes TH, Shiu G and VP Shah
   Validation of Bioanalytical Methods
   Pharm Res 8(4), 421-6 (1991)
   online resource
   
3. Karnes HT and C March
   Calibration and validation of linearity in chromatographic biopharmaceutical analysis
   J Pharm & Biomed Anal 9(10-12), 911-8 (1991)
   online abstract
   
4. Shah VP, Midha KK, Dighe S, McGilveray IJ, Skelly JP, Yacobi A, Layloff T, Viswanathan CT, Cook CE McDowall RD, Pittman KA and S Spector
   Analytical methods validation: Bioavailability, bioequivalence and pharmacokinetic studies
   1. Eur J Drug Metab Pharmacokinet 16(4), 249-55 (1991)
      online abstract
      
   2. J Pharm Sci 81(3), 309-12 (1992)
      online abstract
      
   3. Pharm Res 9(4), 588-92 (1992)
      online preview
      
   4. Int J Pharm 82, 1-7 (1992)
5. Shah VP, Midha KK, Findlay JWA, Hill HM, Hulse JD, McGilveray IJ, McKay G, Miller KJ, Patnaik RN, Powell ML, Tionelli A, Viswanathan CT and A Yacobi
   Bioanalytical Method Validation—A Revisit with a Decade of Progress
   Pharm Res 17(12), 1551-7 (2000)
   online resource
   
6. U.S. Department of Health and Human Services, Food and Drug Administration
   Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM)
   Guidance for Industry: Bioanalytical Method Validation
   Rockville, MD, USA (2001)
   online resource
   
7. Viswanathan CT, Bansal S, Booth B, DeStefano AJ, Rose MJ, Sailstad J, Shah VP, Skelly JP, Swann PG, and R Weiner
   Workshop/Conference Report—Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays
   The AAPS Journal 9(1), E30-E41 (2007)
   online resource
   
8. VP Shah
   The History of Bioanalytical Method Validation and Regulation: Evolution of a Guidance Document on Bioanalytical Methods Validation
   The AAPS Journal 9(1), E43-E47 (2007)
   online resource