Skip to main content
SpringerLink
Log in

A Guide to Total Quality Management System (TQMS) in Molecular Diagnostics from Experiences in Seeking Accreditation and Implementation

  • Medicine
  • Published:
SN Comprehensive Clinical Medicine Aims and scope Submit manuscript

Abstract

The molecular diagnostic laboratories in developing countries are progressively improving and attaining international accreditation. Hence, understanding and implementing the concept of quality are the needs of the hour. Total quality management system (TQMS) in a diagnostic laboratory is an integrated program involving all laboratory staff aiming for integration, consistency, and increase in efficiency. A comprehensive understanding of such a system is unfortunately only through practice. Our endeavors in establishment of TQMS for laboratory accreditation has helped us gain comprehensive understanding of the process and have compelled us to share the knowledge with the community engaged in such diagnostics. A number of accreditation bodies have put forth guidelines for laboratories seeking accreditation; however, such documents can be overwhelming at times leading to confusion and difficulty in implementation. We aim to present to the reader a lucid script of basic reasoning behind such accreditation guidelines in conjunction with thorough and practical generalized workflows for TQMS implementation. The goal of TQMS is to provide the best possible care for patients; and to achieve top-notch quality, there should be a continuous drive for improvement. The clinical vignettes presented in this paper illustrate the value of applying select ISO 15189:2012 recommendations in a molecular diagnostic laboratory to efficiently ensure quality through TQMS and a basic understanding of nuances for its practical implementation. Implementation of TQMS in a diagnostic setting enables seamless flow of laboratory results and instills confidence in clinicians regarding disease interpretation and treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. •• Elliott K, McQuaid S, Salto-Tellez M, Maxwell P. Immunohistochemistry should undergo robust validation equivalent to that of molecular diagnostics. J Clin Pathol. 2015;68(10):766–70. https://doi.org/10.1136/jclinpath-2015-203178 A study shows to establish the basis on which IHC laboratories can bring the same level of robust validation seen in the molecular diagnostic laboratories and the principles applied to all routine IHC tests.

    Article  CAS  PubMed  Google Scholar 

  2. • Berwouts S, Morris MA, Dequeker E. Approaches to quality management and accreditation in a genetic testing laboratory. Eur J Hum Genet. 2010;18(l1):S1–19. https://doi.org/10.1038/ejhg.2010.104 This study focus is on pragmatic approaches to attain the levels of quality management and quality assurance required for accreditation according to ISO 15189, within the context of genetic testing. Attention is also given to implementing efficient and effective quality improvement.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Guzel O, Guner EI. ISO 15189 accreditation: requirements for quality and competence of medical laboratories, experience of a laboratory I. Clin Biochem. 2009;42(4–5):274–8. https://doi.org/10.1016/j.clinbiochem.2008.09.011.

    Article  PubMed  Google Scholar 

  4. •• Newman H, Maritz J. Basic overview of method validation in the clinical virology laboratory. Rev Med Virol. 2017:e1940.1–7. https://doi.org/10.1002/rmv.1940 This review will provide a basic overview of method validation/verification, specific for clinical virology laboratories, and includes explanation of statistical analysis and acceptance/rejection criteria.

  5. Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices. Off J Eur Communities 1998 (Dec 7); L331:1–37. Available at http://www.gmp-compliance.org/guidemgr/files/IVD_DIRECTIVE.PDF. Accessed 20 July 2018.

  6. •• Kumar SA, Jayanna P, Prabhudesai S, Kumar A. Evaluation of quality indicators in a laboratory supporting tertiary cancer care facilities in India. Lab Med. 2014;45(3):272–7. https://doi.org/10.1309/LMP0E6DVC0OSLYIS This study followed the guidelines specified by International Organization for Standardization (ISO) 15189:2007 to identify noncompliant elements of processes.

    Article  PubMed  Google Scholar 

  7. •• Clinical & Laboratory Standards Institute. Quality management for molecular genetic testing; Approved guideline. Available at https://clsi.org/standards/products/molecular-methods/documents/mm20/. Accessed 20 July 2018 . This report provides guidance for implementing international quality management system standards in laboratories that perform human molecular genetic testing for inherited or acquired conditions.

  8. •• Clinical & Laboratory Standards Institute. Nucleic acid amplification assays for molecular haematopathology; approved guideline-second edition. 2012. Available at https://clsi.org/standards/products/molecular-methods/documents/mm05/. Accessed 20 July 2018. This report addresses the performance and application of assays for gene rearrangement and translocations by both polymerase chain reaction (PCR) and reverse-transcriptase PCR techniques, and includes information on specimen collection, sample preparation, test reporting, test validation, and quality assurance.

  9. •• Clinical & Laboratory Standards Institute. Molecular Diagnostic methods for infectious diseases. 3rd edition. 2015. Available at https://clsi.org/standards/products/molecular-methods/documents/mm03/. Accessed 20 July 2018. This report describes topics relating to clinical applications, amplified and nonamplified nucleic acid methods, selection and qualification of nucleic acid sequences, establishment and evaluation of test performance characteristics, inhibitors, and interfering substances, controlling false-positive reactions, reporting and interpretation of results, quality assurance, regulatory issues, and recommendations for manufacturers and clinical laboratories.

  10. ISO 15189:2012(en) Medical laboratories - Requirements for quality and competence. Available at https://www.iso.org/obp/ui/#iso:std:iso:15189:ed-3:v2:en. Accessed 20 July 2018.

  11. ISO/IEC 17025:2005. General requirements for the competence of testing and calibration laboratories. Available at https://www.iso.org/standard/39883.html. Accessed 20 July 2018.

  12. •• Long-Mira E, Washetine K, Hofman P. Sense and nonsense in the process of accreditation of a pathology laboratory. Virchows Arch. 2016;468(1):43–9. https://doi.org/10.1007/s00428-015-1837-1 A review is to elaborate why it is necessary to obtain accreditation but also why certain requirements for accreditation might be experienced as inappropriate.

    Article  PubMed  Google Scholar 

  13. Panteghini M. Traceability as a unique tool to improve standardization in laboratory medicine. Clin Biochem. 2009;42(4–5):236–40 https://doi.org/10.1016/j.clinbiochem.2008.09.098.

    Article  PubMed  Google Scholar 

  14. Handoo A, Sood SK. Clinical laboratory accreditation in India. Clin Lab Med. 2012;32(2):281–92. https://doi.org/10.1016/j.cll.2012.04.009 A study shows a test results from clinical laboratories must ensure accuracy, as these are crucial in several areas of health care. It is necessary that the laboratory implements quality assurance to achieve the total quality management and internationally acceptable standard for clinical laboratories is ISO15189, which is based on ISO/IEC standard 17025.

    Article  PubMed  Google Scholar 

  15. Tibbets MW, Gomez R, Kannangai R, Sridharan G. Total quality management in clinical virology laboratories. Indian J Med Microbiol. 2006;24(4):258–62 http://www.ijmm.org/text.asp?2006/24/4/258/29383. A review report shows the quality of results from the laboratory is significantly influenced by many pre-analytical and post-analytical factors which needed attention. The end goal of the TQM should be to provide the best care possible for the patient.

    Article  CAS  PubMed  Google Scholar 

  16. Wadhwa V, Rai S, Thukral T, Chopra M. Laboratory quality management system: road to accreditation and beyond. Indian J Med Microbiol. 2012;30(2):131–40 http://www.ijmm.org/text.asp?2012/30/2/131/96647.

    Article  CAS  PubMed  Google Scholar 

  17. •• Clinical & Laboratory Standards Institute. Hand book for a developing a laboratory quality manual. 1st edition. 2017. Available at https://clsi.org/standards/products/quality-management-systems/documents/qms25/. Accessed 20 July 2018. This handbook assists laboratories in developing a quality manual- a vital component of implementing and maintaining a complete laboratory quality management system.

  18. •• Clinical & Laboratory Standards Institute. Using proficiency testing and alternative assessment to improve the clinical laboratory, approved guideline 3rd edition.2016. Available at https://clsi.org/standards/products/quality-management-systems/documents/qms24/. Accessed 20 July 2018.This report describes a complete proficiency testing (PT) process to assist laboratories in using PT as a quality improvement tool.

  19. Peterson J Hill R Black R Winkelman J et al. Review of proficiency testing services for clinical laboratories in the United States-final report of a technical working group. CDC 2008. Available at https://www.futurelabmedicine.org/pdfs/Proficiency%20Testing%20report%202007%20.pdf. Accessed 20 July 2018.

  20. Gargis AS, Kalman L, BerryMW BDP, Dimmock DP, et al. Assuring the quality of next-generation sequencing in clinical laboratory practice. Nat Biotechnol. 2012;30:1033–6. https://doi.org/10.1038/nbt.2403 A study recommends The US Centers for Disease Control and Prevention (CDC) convened this national workgroup, which collaborated to define platform-independent approaches for establishing technical process elements of a quality management system (QMS) to assure the analytical validity and compliance of NGS tests with existing regulatory and professional quality standards.

    Article  CAS  PubMed  Google Scholar 

  21. Niesters HG. Clinical virology in real time. J Clin Virol. 2002;25(Suppl. 3):S3–12. https://doi.org/10.1016/S1386-6532(02)00197-X.

    Article  CAS  PubMed  Google Scholar 

  22. College of American Pathologists. Accreditation checklists. Available at http://www.cap.org/web/oracle/webcenter/portalapp/pagehierarchy/accreditation_checklists.jspx?adf.ctrl-state=&_afrLoop=93351439383550#!%40%40%3F_afrLoop%3D93351439383550%26_adf.ctrl-state%3Dtie1wry1n_51. Accessed 20 July 2018.

  23. Clinical & Laboratory Standards Institute. User protocol for evaluation of qualitative test performance: approved guideline, 2nd edition. 2008. Available at. https://clsi.org/standards/products/method-evaluation/documents/ep12/. Accessed 20 July 2018. This document provides a consistent approach for protocol design and data analysis when evaluating qualitative diagnostic tests. Guidance is provided for both precision and method-comparison studies.

  24. Lewis SM. The WHO International external quality assessment scheme for haematology. Bulletin of WHO.1988;66: 283–90. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491126/.

  25. • Bhat V, Chavan P, Naresh C, Poladia P. The external quality assessment scheme (EQAS): experiences of a medium sized accredited laboratory. Clin ChimActa. 2015;446:61–3. https://doi.org/10.1016/j.cca.2015.04.007 This paper reveals that EQAS along with IQC is a very important tool for maintaining optimal quality of services.

    Article  CAS  Google Scholar 

  26. •• Ceriotti F. The role of external quality assessment schemes in monitoring and improving the standardization process. Clin Chim Acta. 2014;432:77–81. https://doi.org/10.1016/j.cca.2013.12.032 A study shows the evolution of External Quality Assessment Schemes (EQAS), focusing on the need for target values based on reference methods and control material commutability. Although the key role of EQAS in the standardization process has been clear from the start, it has never been totally implemented, mainly due to the lack of commutable materials.

    Article  CAS  PubMed  Google Scholar 

  27. Westgard JO, Burnett RW, Bowers GN. Quality management science in clinical chemistry: a dynamic framework for continuous improvement of quality. Clin Chem. 1990;36(10):1712–6 https://www.ncbi.nlm.nih.gov/pubmed/2208645.

    CAS  PubMed  Google Scholar 

  28. •• Haselmann V, Geilenkeuser WJ, Helfert S, Eichner R, Hetjens S, Neumaier M, et al. Thirteen years of an international external quality assessment scheme for genotyping: results and recommendations. Clin Chem. 2016;62(8):1084–95. https://doi.org/10.1373/clinchem.2016.254482 A study shows significance on the evaluation of this long-term EQA scheme, various recommendations can be given to improve the quality of molecular genetic testing, such as the use of 2 different methods for genotyping.

    Article  CAS  PubMed  Google Scholar 

  29. • Westgard JO. Internal quality control: planning and implementation strategies. Ann Clin Biochem. 2003;40(Pt 6):593–611 https://www.ncbi.nlm.nih.gov/pubmed/14629798. A review focuses on strategies for planning and implementing IQC procedures in order to improve the quality of the IQC.

    Article  PubMed  Google Scholar 

  30. •• Bayat H. Selecting multi-rule quality control procedures based on patient risk. Clin Chem Lab Med. 2017;55(11):1702–8. https://doi.org/10.1515/cclm-2016-1077 A study shows a Multi-rule SQC procedures can be used for controlling intermediate and low sigma capability method to attain a low Max E (Nuf) so that the probability of patient harm is mitigated to acceptable levels.

    Article  CAS  PubMed  Google Scholar 

  31. •• Padoan A, Sciacovelli L, Aita A, Antonelli G, Plebani M. Measurement uncertainty in laboratory reports: a tool for improving the interpretation of test results. Clin Biochem. 2018;57:41–7. https://doi.org/10.1016/j.clinbiochem.2018.03.009 A study, which considers real Measuring Uncertainity data and hypothetical results obtained for a series of measurands, support the concept that MU may aid the physician's interpretation thus ensuring reliable clinical decision making.

    Article  PubMed  Google Scholar 

  32. Pruss A, Cirouit E, Rushbrook P. Safe management of wastes from health-care activities. Available at http://www.who.int/water_sanitation_health/publications/wastemanag/en/. Accessed 20 July 2018.

  33. •• Dietel M, Jöhrens K, Laffert MV, Hummel M, Bläker H, Pfitzner BM, et al. A 2015 update on predictive molecular pathology and its role in targeted cancer therapy: a review focussing on clinical relevance. Cancer Gene Ther. 2015;22(9):417–30. https://doi.org/10.1038/cgt.2015.39 A study shows the complex challenges on the level of drug design, molecular diagnostics, and clinical trials make necessary a close collaboration among academic institutions, regulatory authorities and pharmaceutical companies.

    Article  CAS  PubMed  Google Scholar 

  34. • Meldrum C, Doyle MA, Tothill RW. Next-generation sequencing for cancer diagnostics: a practical perspective. Clin Biochem Rev. 2011;32(4):177–95 https://www.ncbi.nlm.nih.gov/pubmed/22147957. A study reveals routine use of whole genome sequencing is likely to be a few years away, there are immediate opportunities to implement NGS for clinical use. Review the technology, methods and applications that can be immediately considered and some of the challenges that lie ahead.

    PubMed  PubMed Central  Google Scholar 

  35. •• Aziz N, Zhao Q, Bry L, Driscoll DK, Funke B, Gibson JS, et al. College of American Pathologists’ laboratory standards for next-generation sequencing clinical tests. Arch Pathol Lab Med. 2015;139:481–93. https://doi.org/10.5858/arpa.2014-0250-CP A study describes the important issues considered by the CAP committee during the development of the new checklist requirements, which address documentation, validation, quality assurance, confirmatory testing, exception logs, monitoring of upgrades, variant interpretation and reporting, incidental findings, data storage, version traceability, and data transfer confidentiality.

    Article  PubMed  Google Scholar 

  36. • Rehm HL, Bale SJ, Bayrak-Toydemir P, Berg JS, Brown KK, Deignan JL, et al. Working Group of the American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee: ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013;15:733–47. https://doi.org/10.1038/gim.2013.92 A study guideline will assist clinical laboratories with the validation of next-generation sequencing methods and platforms, the ongoing monitoring of next-generation sequencing testing to ensure quality results, and the interpretation and reporting of variants.

    Article  PubMed  PubMed Central  Google Scholar 

  37. •• College of American Pathologists: molecular pathology checklist. next generation sequencing. Northfield, IL, College of American Pathologists, 2015, pp 8. Available at http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribution%20Folders/DctmContent/education/OnlineCourseContent/2016/LAP-TLTM/resources/AC-molecular-pathology.pdf. Accessed 20 July 2018. The Molecular Pathology and Microbiology Checklists covers clinical molecular testing in the areas of oncology, infectious disease (both for FDA-cleared/approved tests, and non-FDA-cleared/approved tests), hematology, inherited disease, HLA typing, forensics and parentage applications. It will be significantly useful for molecular scientists familiar with the checklist and possessing the technical and interpretive skills necessary to evaluate the quality of a laboratory's performance.

  38. •• Food and Drug Administration. Infectious disease next generation sequencing based diagnostic devices: Microbial Identification and Detection of Antimicrobial Resistance and Virulence Markers 2016. Available at https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm500441.pdf. Accessed 20 July 2018. This guidelines FDA is issuing this draft guidance to provide industry and Agency staff with recommendations for studies to establish the analytical and clinical performance characteristics of Infectious Disease Next Generation Sequencing Based Diagnostic Devices for Microbial Identification and Detection of Antimicrobial Resistance and Virulence Markers.

  39. •• Johnson G, Nour AA, Nolan T, Huggett J, Bustin S. Minimum information necessary for quantitative real-time PCR experiments. Methods Mol Biol. 2014;1160:5–17. https://doi.org/10.1007/978-1-4939-0733-5_2 A study aims to make nucleic acid analysis not just easy but reliable and allow qPCR to exploit its wide range of applications that today range from the quantifi cation of RNA to epigenetics and protein detection, using variations on essentially the same theme.

    Article  CAS  PubMed  Google Scholar 

  40. •• Dijkstra JR, van Kempen LC, Nagtegaal ID, Bustin SA. Critical appraisal of quantitative PCR results in colorectal cancer research: can we rely on published qPCR results? Mol Oncol. 2014;8(4):813–8. https://doi.org/10.1016/j.molonc.2013.12.016 A study describes common errors, and conclude that the current state of reporting on qPCR in colorectal cancer research is disquieting. The study suggests that the scientific community should examine its responsibility and be aware of the implications of these findings for current and future research.

  41. • Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55(4):611–22. https://doi.org/10.1373/clinchem.2008 A study guideline will encourage better experimental practice, allowing more reliable and unequivocal interpretation of qPCR results.

  42. Bustin SA, Beaulieu JF, Huggett J, Jaggi R, Kibenge FS, Olsvik PA, et al. MIQE précis: practical implementation of minimum standard guidelines for fluorescence-based quantitative real-time PCR experiments. BMC Mol Biol. 2010;21:11–74. https://doi.org/10.1186/1471-2199-11-74.

    Article  Google Scholar 

  43. •• Laboratory safety guidance, occupational safety and health administration. Available at https://www.osha.gov/pls/publications/publication.athruz?pType=Industry&pID=117. Accessed 20 July 2018. This report recommendations descriptions of mandatory safety and health standards, are advisory in nature, informational in content, and are intended to assist employers in providing a safe and healthful workplace. employers to comply with safety and health standards and regulations.

  44. • Emmert E. Biosafety guidelines for handling microorganisms in the teaching laboratory: development and rationale. J Microbiol Biol Educ. 2013;14(1):78–83. https://doi.org/10.1128/jmbe.v14i1.531 The guidelines are ease of use and are accompanied by an extensive appendix containing explanatory notes, sample documents, and additional resources. It provides educators with a clear and consistent way to safely work with microorganisms in the teaching laboratory.

    Article  PubMed  PubMed Central  Google Scholar 

  45. • Boyce JM, Pittet D, Healthcare Infection Control Practices Advisory Committee, HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Guideline for hand hygiene in health-care settings. Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Society for Healthcare Epidemiology of America/Association for Professionals in Infection Control/Infectious Diseases Society of America. MMWR Recomm Rep. 2002;25;51(RR-16):1–45 https://www.cdc.gov/mmwr/PDF/rr/rr5116.pdf. Accessed 20 July 2018. This report reviews studies published since the 1985 CDC guideline (Garner JS, Favero MS. CDC guideline for handwashing and hospital environmental control, 1985. Infect Control 1986; 7:231–43) and the 1995 APIC guideline (Larson EL, APIC Guidelines Committee. APIC guideline for handwashing and hand antisepsis in health care settings. Am J Infect Control 1995; 23:251–69) were issued and provides an in-depth review of hand-hygiene practices of Health Care Workers.

    Google Scholar 

  46. • National Research Council (US) Committee on Hazardous Biological Substances in the Laboratory. Biosafety in the laboratory: prudent practices for the handling and disposal of infectious materials. Washington (DC): National Academies Press (US); 1989. 4, Safe Disposal of Infectious Laboratory Waste. Available at https://www.ncbi.nlm.nih.gov/books/NBK218626/ Accessed 20 July 2018. This document will help for identifying hazards and establishing conditions for any operation involving hazardous biological materials, waste disposal, including incinerating. This report emphasizes all aspects of an effective safety program including medical surveillance, compliance with regulations, and a plan for obtaining consensus on and implementation of the guidelines.

  47. Cone RW, Hobson AC, Huang ML. Coamplified positive control detects inhibition of polymerase chain reactions. J Clin Microbiol. 1992;30(12):3185–9 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC270618/.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Costafreda MI, Bosch A, Pinto RM. Development, evaluation, and standardization of a real-time TaqMan reverse transcription-PCR assay for quantification of hepatitis A virus in clinical and shellfish samples. Appl Environ Microbiol. 2006;72:3846–55. https://doi.org/10.1128/AEM.02660-05.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge and thank the lab members Karthika, Jayalakshmi, Vineetha, Ashique, Sumaja, Rose, Sruthi, Vinod, Lekshmy and special thanks to Ms B Padmavathi Amma, Medical Laboratory Service her constant support to get accreditation.

Funding

Medical

Author information

Authors and Affiliations

  1. Laboratory Medicine and Molecular Diagnostics, Bio-Innovation Center, Rajiv Gandhi Center for Biotechnology, KINFRA Film & Video Park, Thiruvananthapuram, Kerala, 695585, India

    Seetha Dayakar & Radhakrishnan R. Nair

  2. Srinivasa Ramanujan Institute for Basic Sciences, Velloor, Pampady, Thiruvananthapuram, 686501, Kerala, India

    Heera R. Pillai & Sanughosh Kalpathodi

  3. Department of Biochemistry, PSG Institute of Medical Sciences and Research, Avanashi Road, Peelamedu, Coimbatore, Tamil Nadu, 641004, India

    Ganesan Jeya Chandran

Authors
  1. Seetha Dayakar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heera R. Pillai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sanughosh Kalpathodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ganesan Jeya Chandran
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Radhakrishnan R. Nair
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Seetha Dayakar or Radhakrishnan R. Nair.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Medicine

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dayakar, S., Pillai, H.R., Kalpathodi, S. et al. A Guide to Total Quality Management System (TQMS) in Molecular Diagnostics from Experiences in Seeking Accreditation and Implementation. SN Compr. Clin. Med. 1, 123–133 (2019). https://doi.org/10.1007/s42399-018-0018-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42399-018-0018-3

Keywords

Search

Navigation