Advertisement
Rapid Communication| Volume 19, ISSUE 12, P1529-1536, December 2017

Download started.

Ok

Strategy for an abbreviated in-house qualification of a commercially available Rapid Microbiology Method (RMM) for canadian regulatory approval

  • Jolene Chisholm
    Affiliations
    The Arthritis Program, Krembil Research Institute, University Health Network, Toronto, Canada

    Cell Therapy Program, University Health Network, Toronto, Canada
    Search for articles by this author
  • Shashank Bhatt
    Affiliations
    The Arthritis Program, Krembil Research Institute, University Health Network, Toronto, Canada

    Cell Therapy Program, University Health Network, Toronto, Canada
    Search for articles by this author
  • Amélie Chaboureau
    Affiliations
    The Arthritis Program, Krembil Research Institute, University Health Network, Toronto, Canada

    Cell Therapy Program, University Health Network, Toronto, Canada
    Search for articles by this author
  • Sowmya Viswanathan
    Correspondence
    Correspondence: Sowmya Viswanathan, PhD, The Arthritis Program, Krembil Research Institute, University Health Network, 60 Leonard Avenue, Room 3 KD479, Toronto, Ontario, Canada, M5T 2S8.
    Affiliations
    The Arthritis Program, Krembil Research Institute, University Health Network, Toronto, Canada

    Cell Therapy Program, University Health Network, Toronto, Canada

    Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada
    Search for articles by this author
Published:October 20, 2017DOI:https://doi.org/10.1016/j.jcyt.2017.09.004

      Abstract

      Background aims

      Cell therapy products (CTP) typically require full sterility, endotoxin and Mycoplasma testing before product release. Often this is not feasible with fresh cells, and sponsors may rely on rapid microbiological methods (RMM). RMM must be qualified in-house using the sponsor's facilities, equipment, consumables, cells and matrices to meet regulatory approval. Herein, we present a cost-effective strategy to conduct an in-house abbreviated qualification of a commercially available RMM kit to meet Health Canada regulatory requirements.

      Methods

      We performed an abbreviated qualification using a polymerase chain reaction (PCR)-based Mycoplasma testing method involving assay sensitivity and ruggedness, based on an experimental plan that was pre-approved by Health Canada. Briefly, investigational CTPs were tested in-house using a PCR-based Mycoplasma detection kit. Assay sensitivity was determined using a 10-fold dilution series of genomic DNA of only two Mycoplasma species, Mycoplasma arginini and Mycoplasma hominis in the absence of CTP-matrix as the kit had been previously validated against nine species. Matrix interference was measured by testing independent CTP samples. Testing by different operators on different days measured ruggedness.

      Results

      The RMM Mycoplasma qualification exceeded sensitivity (4 genome copies per reaction for M. arginini and 0.12 genome copies per reaction for M. hominis) and met ruggedness requirements without matrix interference, as required by the Pharmacopoeial guidelines (Ph. Eur. 2.6.7 and USP <1223>).

      Discussion

      Our approach represents a minimal qualification that can be performed by an academic institution while ensuring regulatory compliance for implementing RMM testing for in-process and product-release testing of CTPs.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • MarketsandMarkets
        Stem cell therapy market by type (allogeneic, autologous), therapeutic application (musculoskeletal, wound, injury, CVD, surgery, and aGVHD), cell source (adipose tissue, bone marrow, neural, embryo/cord blood derived, iPSCs)—global forecasts to 2021.
        (Available from:)
        • Kielpinski G.
        • Prinzi S.
        • Duguid J.
        • du Moulin G.
        Roadmap to approval: use of an automated sterility test method as a lot release test for carticel, autologous cultured chondrocytes.
        Cytotherapy. 2005; 7 (T4748146451612M0 [pii]): 531-541
        • U.S. Code of Federal Regulations
        Title 21—Food and Drugs, Equivalent Methods and Procedures (21 CFR 610.9).
        2009
        • United States Pharmacopieal Convention
        Chapter 1223: validation of alternative microbiological methods.
        in: U.S. pharmacopoeial convention, 33rd. United States Pharmacopoeia, Rockville, MD2010
        • The Directorate for the Quality of medicines of the Council of Europe
        Chapter 5.1.6: Validation of Alternative Microbiological Methods.
        in: European Pharmacopoeia. 7th ed. Council of Europe, Strasbourg2012
        • The Directorate for the Quality of medicines of the Council of Europe
        Chapter 2.6.27: Microbiological Control of Cellular Products.
        in: European Pharmacopoeia. 7th ed. Council of Europe, Strasbourg2012
        • Parveen S.
        • Kaur S.
        • David S.A.
        • Kenney J.L.
        • McCormick W.M.
        • Gupta R.K.
        Evaluation of growth based rapid microbiological methods for sterility testing of vaccines and other biological products.
        Vaccine. 2011; 29: 8012-8023https://doi.org/10.1016/j.vaccine.2011.08.055
        • Montag T.
        • Nicol S.B.
        • Schurig U.
        • Heiden M.
        • Huber H.
        • Sanzenbacher R.
        • et al.
        Microbial safety of cell based medicinal products—what can we learn from cellular blood components?.
        Clin Chem Lab Med. 2008; 46: 963-965https://doi.org/10.1515/CCLM.2008.175
        • Stormer M.
        • Vollmer T.
        • Henrich B.
        • Kleesiek K.
        • Dreier J.
        Broad-range real-time PCR assay for the rapid identification of cell-line contaminants and clinically important mollicute species.
        Int J Med Microbiol. 2009; 299: 291-300https://doi.org/10.1016/j.ijmm.2008.08.002
        • Drexler H.G.
        • Uphoff C.C.
        Mycoplasma contamination of cell cultures: incidence, sources, effects, detection, elimination, prevention.
        Cytotechnology. 2002; 39: 75-90https://doi.org/10.1023/A:1022913015916
        • Razin S.
        • Yogev D.
        • Naot Y.
        Molecular biology and pathogenicity of mycoplasmas.
        Microbiol Mol Biol Rev. 1998; 62: 1094-1156
        • McGarrity G.J.
        • Kotaani H.
        • Butler G.H.
        Mycoplasmas and tissue culture cells.
        in: Maniloff J. McElaney R.H. Finch L.R. Baseman J.B. Mycoplasmas, molecular biology and pathogenesis. American Society for Microbiology, Washington (DC1992: 445-454
        • Government of Canada, Health Canada
        Guidance Document: Preparation of Clinical Trial Applications for use of Cell Therapy Products in Humans.
        2015
        • U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research
        Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene.
        (Therapy)1998
        • European Medicines Agency
        Committee for Medicinal Product for Human Use.
        (Guideline on Human Cell-Based Medicinal Products)2008
        • Ministry of Health, Labour and Welfare
        General notices.
        in: Japanese pharmacopoeia. 15th ed. 2006 (Tokyo)
        • Council of Europe
        Chapter 2.6.7: mycoplasmas.
        in: European pharmacopoeia. 7th ed. 2012 (Strasbourg)
        • Parenteral Drug Association
        Technical Report No. 33: Evaluation.
        (Validation and Implementation of Alternative and Rapid Microbiological Methods)2013
        • Read J.
        • Bhatt S.
        • Viswanathan S.
        Proposal for validation plan to assess [19F]-Cell Sense matrix interference testing for mycoplasma, sterility and endotoxin for the clinical trial application of “A Phase I Study Evaluating the Safety and Feasibility of Using [19F]-Cell Sense to Image Human Peripheral Blood Mononuclear Cells In Vivo”.
        (Control No. 186489)2016
        • Deutschmann S.M.
        • Kavermann H.
        • Knack Y.
        Validation of a NAT-based mycoplasma assay according European pharmacopoiea.
        Biologicals. 2010; 38: 238-248https://doi.org/10.1016/j.biologicals.2009.11.004
        • Le Blanc K.
        • Frassoni F.
        • Ball L.
        • Locatelli F.
        • Roelofs H.
        • Lewis I.
        • et al.
        Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study.
        Lancet. 2008; 371: 1579-1586https://doi.org/10.1016/S0140-6736(08)60690-X
        • Barile M.F.
        • Rottem S.
        Mycoplasmas in cell culture.
        in: Kahane I. Adoni A. Rapid diagnosis of mycoplasmas. Plenum Press, New York, NY1993: 155-193
        • Nikfarjam L.
        • Farzaneh P.
        Prevention and detection of mycoplasma contamination in cell culture.
        Cell J. 2012; 13: 203-212
        • United States Pharmacopoeial Convention
        Chapter 1225: validation of compendial procedures.
        in: United States pharmacopoeia. 33rd ed. 2010 (Rockville, MD)
        • Amikam D.
        • Glaser G.
        • Razin S.
        Mycoplasmas (mollicutes) have a low number of rRNA genes.
        J Bacteriol. 1984; 158: 376-378
        • Ueno T.
        • Niimi H.
        • Yoneda N.
        • Yoneda S.
        • Mori M.
        • Tabata H.
        • et al.
        Eukaryote-made thermostable DNA polymerase enables rapid PCR-based detection of mycoplasma, ureaplasma and other bacteria in the amniotic fluid of preterm labor cases.
        PLoS ONE. 2015; 10 (e0129032)https://doi.org/10.1371/journal.pone.0129032
        • Denoya C.
        • Colgan S.
        • du Moulin G.C.
        Alternative microbiological methods in the pharmaceutical industry: the need for a new microbiology curriculum.
        Am Pharm Rev. 2006; 9: 10-18
        • Duguid J.
        • Balkovic E.
        • du Moulin G.C.
        Rapid microbiological methods: where are they now?.
        Am Pharm Rev. 2011; 14: 7
        • U.S. Food and Drug Administration
        Division of Dockets Management. Comments to FDA on Draft Guidance for Validation of RMM for Sterility Testing of Cellular and Gene Therapy Products.
        (Available from:)
        • Dabrazhynetskaya A.
        • Volokhov D.V.
        • David S.W.
        • Ikonomi P.
        • Brewer A.
        • Chang A.
        • et al.
        Preparation of reference strains for validation and comparison of mycoplasma testing methods.
        J Appl Microbiol. 2011; 111: 904-914https://doi.org/10.1111/j.1365-2672.2011.05108.x
        • Dabrazhynetskaya A.
        • Volokhov D.V.
        • Lin T.L.
        • Beck B.
        • Gupta R.K.
        • Chizhikov V.
        Collaborative study report: evaluation of the ATCC experimental mycoplasma reference strains panel prepared for comparison of NAT-based and conventional mycoplasma detection methods.
        Biologicals. 2013; 41: 377-383https://doi.org/10.1016/j.biologicals.2013.07.002
        • Dabrazhynetskaya A.
        • Furtak V.
        • Volokhov D.
        • Beck B.
        • Chizhikov V.
        Preparation of reference stocks suitable for evaluation of alternative NAT-based mycoplasma detection methods.
        J Appl Microbiol. 2014; 116: 100-108https://doi.org/10.1111/jam.12352
        • Roche Custom Biotech
        MycoTOOL Mycoplasma Real Time PCR Kit.
        (Available from:)
        • Applied Biosystems
        MycoSEQ Mycoplasma Detection Kit.
        (Available from:)
        • Hussong D.
        • Mello R.
        Alternative microbiology methods and pharmaceutical quality control.
        Am Pharm Rev. 2006; 9: 62-69