Method validation considerations for LC–MS/MS bioanalysis of protein drugs Perspective
or small molecule chromatographic methods. We clearly recognize that the proposed experimental designs and acceptance criteria are only recommendations at this point and that they will continue to evolve as our experi- ence with PrD-LCMS methods increases.
Future perspective The technique of protein bioanalysis by LC–MS/MS of a surrogate peptide after proteolytic digestion (PrD- LCMS) has been growing steadily over the past 6–7 years such that its use is now prevalent in the phar- maceutical industry. Since it offers the advantages of rapid method development, fewer critical reagents, good transferability and reliable performance most organizations see it as a very attractive compliment to conventional LBAs. The use of these methods is being further expanded via affinity- and immuno-purifica- tion techniques conducted either before digestion or after digestion (SISCAPA), techniques that can greatly improve method sensitivity and overall performance. The authors expect that such assays will be increasingly used in regulated bioanalytical studies in the coming years. The routine application of PrD-LCMS methods
References Papers of special note have been highlighted as: • of interest; •• of considerable interest
1
Li F, Fast D, Michael S. Absolute quantitation of protein therapeutics in biological matrices by enzymatic digestion and LC–MS. Bioanalysis 3(21), 2459–2480 (2011).
2 Ewles M, Goodwin L. Bioanalytical approaches to analyzing peptides and proteins by LC–MS/MS. Bioanalysis 3(12), 1379–1397 (2011).
3 Hustoft H, Malerod H, Wilson S, Reubsaet L, Lundanes E, Greibrokk T. A critical review of trypsin digestion for LC– MS Based proteomics In: Integrative Proteomics. Leung HC (Ed.) Tech Publishers, Shanghai, China. 73–92 (2012).
4 Becker J, Hoofnagle A. Replacing immunoassays with digestion-peptide immunoaffinity enrichment and LC–MS/ MS. Bioanalysis 4(3) 281–290 (2012).
• Reviews various affinity and immunoenrichment techniques that are currently being used to enhance the sensitivity and performance of proteolytic digestion (PrD)-LCMS methods.
5 Whiteaker J, Zhao L, Abbatiello S et al. Evaluation of large scale quantitative proteomic assay development using peptide affinity-based mass spectrometry. Mol. Cell. Proteomics 10(4), 1–10 (2011).
6 Vazvaei F, Duggan JX. Validation of LC–MS/MS bioanalytical methods for protein therapeutics. Bioanalysis 6(13), 1739–1742 (2014).
for regulated nonclinical and clinical studies has cre- ated the critical need for bioanalytical method valida- tion criteria that can be applied to such assays. This is the reason for the publication of the consortium White Paper referenced in this perspective. The validation recommendations and acceptance criteria highlighted here and more completely described in the White Paper are intended to provide a starting point for the routine validation of these methods. As more methods are validated and additional data are collected, the per- formance of these various method types will be more fully characterized, leading to the refinement of valida- tion strategies where appropriate.
Financial & competing interests disclosure The authors have no relevant affiliations or financial involve- ment with any organization or entity with a financial inter- est in or financial conflict with the subject matter or mate- rials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this
manuscript.
7 European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP).
www.ema.europa.eu
8 Guideline on Bioanalytical Method Validation. European Medicines Agency, London, UK (2011).
www.ema.europa.eu
9 Guidance for Industry: bioanalytical Method Validation. US FDA, Rockville, MD, USA (2001).
www.fda.gov
10 Bioanalytical Method Validation. Draft Guidance, US FDA, Rockville, MD, USA (2013).
www.fda.gov
11
Jenkins R, Duggan J, Aubry AF et al. Recommendations for validation of LC–MS/MS bioanalytical methods for protein biotherapeutics. AAPS J. 17(1), 1–16 (2015).
•• White Paper describing details of the recent industry experts ‘recommendations for the validation of PrD-LCMS methods’.
12 Knutsson M, Schmidt R, Timmerman P. LC–MS/MS of large molecules in a regulated bioanalytical environment – which acceptance criteria to apply? Bioanalysis 5(18), 2211–2214 (2013).
• Provides a very thoughtful perspective on PrD-LCMS from a number of European thought leaders on this subject.
13 King LE, Farley E, Imazato M et al. Ligand binding assay critical reagents and their stability: recommendations and best practices from the Global Bioanalysis Consortium Harmonization Team. AAPS J. 16(3), 504–515 (2014).
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