SN Comprehensive Clinical Medicine

, Volume 1, Issue 2, pp 123–133 | Cite as

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

  • Seetha DayakarEmail author
  • Heera R. Pillai
  • Sanughosh Kalpathodi
  • Ganesan Jeya Chandran
  • Radhakrishnan R. NairEmail author
Part of the following topical collections:
  1. Topical Collection on Medicine


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.


Molecular diagnostics Total quality management system Next-generation sequencing Real-time PCR/PCR ISO15189:2012 Accreditation 


At present, globally, healthcare management relies on a battery of molecular diagnostic tests that help clinicians to take highly informed decisions for better prognosis of disease. It is a dynamic area leading to insights in research and treatment that are revolutionizing health care. Molecular diagnostics detect and measure the presence of genetic material or proteins associated with a specific health condition. It helps to uncover the underlying mechanisms of disease and also enables clinicians to individualize therapy, thus facilitating the practice of personalized medicine. These tests cover an array of diseases and contribute to early and precise diagnosis of the disease aiding in preventing disease progression [1••]. Molecular diagnostics gained wide acceptance and attention owing to its quick turnaround time and reliability [2•]. Though there has been a steep increase in the number of laboratories performing such tests on clinical samples for disease diagnosis, the documentation or guidelines for efficient functioning of such laboratories are often tabooed as complicated and incomprehensible for use in regular practice. Nonetheless, it does not diminish the fact that these labs must strictly abide by uniform guidelines globally so that the results generated are reproducible across centers [3]. Till recently, molecular testing was offered only by specialized reference laboratories possessing appropriate resources and technical expertise. The European conformity (CE) marking for in vitro diagnostic (IVD) devices and food and drug administration (FDA)–labeled commercial certified assays allow routine clinical laboratories to offer molecular analysis without large investments [4••, 5]. The approach to new molecular assays in a clinical laboratory requires expert selection of the appropriate biological specimen and suitable test by clinicians. It is necessary to evaluate performance of the pre-analytical and analytical phases of the test and to generate clinically useful patient reports [6••]. This requires proper training to laboratory personnel and clinicians to add value and robustness to the tests performed on precious clinical specimens [7••, 8••, 9••]. Thus, national and international accreditations help the laboratories to establish and maintain a total quality management system (TQMS). It improves the effectiveness in accordance with the requirements of the International Organization for Standardization (ISO) [10, 11]. In India, the National Accreditation Board for testing and calibration Laboratories (NABL) provides guidelines and accreditation to such laboratories in accordance with international standards [12••].

In this review, we focus on development and implementation of a quality management system which improves effectiveness of molecular diagnostic laboratories. We aim to go beyond the complexities of available quality manuals in presenting the concept of TQMS to laboratory personnel undertaking routine molecular tests. Our experience in implementing TQMS procedures in human genetic (somatic/familial) and infectious disease testing has been enlightening in the rigor of following these guidelines and also in its adaptability to most other testing’s with slight modifications. ISO 15189:2012 is a standard document that provides the specific requirements for quality and competence of medical laboratories performing molecular testing. This standard promotes global harmonization of medical practices and overall workflow of molecular diagnostic tests. It also protects the health and safety of both patients and healthcare providers. Thus, it supports efficient exchange of information and protection of data in improving the quality of patient care. Molecular diagnostic laboratories need to have a comprehensive quality manual (QM) and quality system procedure (QSP) to cover many critical areas of testing such as equipment selection, procurement, maintenance, and plan for breakdown. It also helps to check the competency of technical staff, internal quality control (IQC), proficiency testing (PT), external quality assurance service (EQAS), inter laboratory comparison (ILC), and the outlier management [13]. A properly designed quality manual, as per ISO15189:2012 and NABL 112, has to be developed in each facility for proper management of medical laboratories.

TQMS provides integration of all processes required to fulfill quality policy and objectives to meet the needs of the users. It ensures the best clinical care by using processes, methods, and technology that are consistent with the best practices [14, 15, 16]. A detailed description of manuals comprising the TQMS is given in the sections below.

The Total Quality Management System Essentials

The TQMS process and interactions in the molecular diagnostics lab are detailed in Fig. 1a. And the model starts with the collection of the most appropriate samples from patients or public health institutions for each diagnostic test and ends with the release of results according to ISO 15189:2012. The TQMS should present clear guidelines to address general problems; especially in case of nonconformance with laboratories’ own policies and procedures, quality program guidelines should encourage scientific and laboratory staff to regularly discuss quality issues.
Fig. 1

a Total quality management system process and interactions in molecular diagnostics. b Overview of next-generation sequencing. c unidirectional workflow of PCR and quality checkpoints

The Quality Manual

According to the ISO notion, quality is the ability to satisfy customer’s expectations. Quality manual is a document based on description, assignment of responsibilities, and documentation of all processes related to quality management. In India, NABL requires establishment of a Quality manual (QM), which should describe the TQMS to be followed by the organization/laboratory looking for accreditation [17••]. QM documents for NABL accreditation following ISO guidance 15189 should comply with documents NABL 160 and 112, and a detailed workflow should be embedded in the manual.

Quality System Procedure

Quality system procedure addresses all the quality system essentials consistent with overall policy of an organization to ensure accurate, reliable, and timely laboratory results, and to have quality throughout the laboratory operations. Strictly complying with QSP yields results with high quality and helps in detecting errors and prevents them from recurring. To satisfy the ISO guidelines, each laboratory is expected to develop QSPs based on their needs (Fig. 1a).

Molecular diagnostic laboratories following such QSPs should show evidence of monitoring of their reagents, primers, sequencing chemistries, and platforms for regular quality check.

This documentation can be organized at four levels for convenience. The apex document or level A document is the manual which includes quality policy and objectives to be followed for implementation of various elements of ISO 15189. Level B documents are QSPS, which describe detailed procedures of the activities of individual functional units needed to implement management system. All procedures are cross-referred in the quality manual. Management system procedures are further supplemented with detailed work instructions—standard operating procedures (SOPs) termed as level C1 documents and brief work desk instructions termed as level C2 documents. Forms and formats constitute level D1 documents. The reports comprised of registers (a), filed reports (b), and data in data base (c) that are grouped as level D2 documents.

Internal Audit and Management Review

Management and internal reviews of TQMS at planned intervals help to address continued adequacy and effectiveness of a diagnostic laboratory. Internal audits have to be completed once in 12 months with trained unbiased auditors, when systems are in place and should include pre- and post-examination and can then be extended to all elements of the TQMS (Fig. 1a). The laboratory shall take necessary action for nonconformities raised by auditors. Corrective actions should be taken without delay to resolve raised nonconformities.

Laboratory director is expected to inform well in advance and accommodate the management and technical team (including instrumentation and information technology divisions) for the management review conducted yearly. The management review includes periodic review of requests for sample requirements, assessment of user feedback, staff suggestions, internal audits, risk management, use of quality indicators, and review by external referral laboratories. It also helps in assessing the results of proficiency testing, monitoring of complaint resolutions, performance of suppliers, and identification and control of nonconformities.

Competence of Personnel and Training

The laboratory should be headed by the laboratory director/authorized signatory with a M.D. or Ph.D. degree in the respective discipline and have accomplished a post-doctoral training in this field and subsequently has at least 4 years of experience. The laboratory team has to be comprised of trained and dedicated research technologists.

Due to technical nature of many molecular methods, the training requirements are often extensive and highly complex. All technical and laboratory staff is expected to be well versed with technical and management requirements of the laboratory. The competence assessment must be carried out by allowing them to participate in mock testing of laboratory procedures including waste management and personal safety procedures.

Equipment Calibration and Testing/Maintenance

The laboratory needs to be spacious enough to carry out molecular biology procedures. All instruments have to be calibrated by appropriate accredited service agencies. Information of manufacturer’s name, model, serial number, and contact information of the supplier; date of manufacturing/receiving; and the schedule for preventive maintenance should be on display on the instrument.

Molecular methods using PCR may require the use of bio safety cabinets in a diagnostic laboratory for protecting integrity of clinical samples to avoid errors and for personal safety. These cabinets consist of a high efficiency particulate air (HEPA) combination of heating, ventilation, and air-conditioning (HVAC) control system to prevent sustained positive pressurization of the laboratory. The PCR workstation is a UV sterilization cabinet to decontaminate reagents and equipment prior to carrying out PCR reactions. These cabinets have to be serviced and calibrated as recommended by the supplier. Wipe tests and culture using blood agar plates have to be performed regularly to check for background cross contamination. Typically, cabinets are cleaned before and after each use. A detailed cleaning protocol must be attached to the QSP.

Pipettes used for molecular methods require sophisticated calibration and generally tend to use much smaller volumes than those used in other areas. Internal calibration schemes do not suffice for such minute volume calibrations accurately. A six-point (decimal place) weighing balance is required for accurate gravimetric calibration of such small volumes. In common practice, laboratories prefer sending pipettes to external agencies for calibration, which may significantly increase the cost of calibration compared to in-house methods. However, choice of in-house or external calibration must comply with the acceptable precision and accuracy tolerances required in the laboratory as per ISO 8655 guidelines. Thorough retrospective analysis of all laboratory results should be carried out if pipettes are found to have performed poorly during calibration checks.

Centrifuge maintenance and speed verification are assessed across a range of speeds using a calibrated tachometer or stroboscope. Platinum resistance thermometer (PRT) with digital indicator and timing devices in high-speed centrifuges is use to calibrate temperature. It is recommended to have annual maintenance contracts inclusive of checking the condition of centrifuges twice a year.

Temperature-controlled equipment such as water baths, incubators, ovens, refrigerators, and deep freezers must be verified for accuracy and performance (with calibrated temperature-recording devices) for the intended temperature required. Refrigerators and deep freezers requiring critical and continuous temperature control must be fitted with 24 × 7 temperature recorders/data loggers. Daily temperature logs should be maintained for storage freezers to account for temperature fluctuations due to mechanical or other faults that can lead to damage of sensitive reagents and may eventually affect the test results. Temperature must be monitored with calibrated recording devices at multiple points with the doors shut. All records must be documented and filed for future reference.

Purchasing and Inventory

The laboratory needs to identify critical support services it requires to operate user-defined criteria for each critical supply and service. It is imperative for the laboratory’s management to collaborate with the organization purchasing unit to ensure a continuous supply of materials and proper logistics. All processes, from raising a purchasing order to receipt and storage of purchased items, should be documented. Selection criteria of vendors shall be decided by a logical scoring system taking in account their current turn over, reliability, cost, communication, and support capabilities.

Quality Assurance, Proficiency Testing, and Measuring Uncertainty

ISO/IEC (International Electrotechnical Commission) 170 Guide 43:2010 has guidelines for development, selection, and use of proficiency testing by laboratory accreditation bodies [18••, 19]. All laboratories operating under such accreditation should follow these guidelines which encompass most testing parameters performed in such molecular diagnostic setups.

However, a number of laboratories using next-generation sequencing (NGS) face a major obstacle due to absence of established proficiency testing (PT) system for NGS, which causes lack of error identification, missing indications of QC problems as well as verification of test performance in laboratories. Therefore, there is a scope for the development of national-level Next-Generation Sequencing - Standardization of Clinical Testing (NGS-SCT) workgroups to provide recommendations for NGS-PT program. Such NGS-SCT groups should propose PT opportunities for both wet and dry laboratory pipelines covering the entire NGS workflow [20].

Internal quality assurance (IQA) is necessary to ensure high assay reproducibility, performance, and enable detection of errors in daily practice. Assays can be performed according to standard operating procedures (SOP) with appropriate positive, negative, and internal quality controls [21, 22]. Implementation of new tests requires a verification and validation procedure using predefined parameters [23, 24].

External quality assurance (EQA) involves use of results of many laboratories analyzing same specimen of known composition and value, supplied by the external agencies for quality control purposes [25•, 26••, 27, 28••].

Quality control procedures need to be designed to detect errors in a manner that does not generate false alarms and periodic review of it is essential. The use of the Westgard rules is a useful approach to identify QC violations as shown in Table 1 [29•, 30••].
Table 1

Westgard rules is an interpretation and action of QC violation




1 2s

One control observation exceeding the mean ± 2s.

It is used only as a “warning” rule that initiates testing of the control data by other control rules.

1 3s

One control data observation exceeding the mean ± 3s.

Rejection. Method is primarily sensitive to random error.

2 2s

Two consecutive control observations exceeding the same mean + 2s or mean – 2s limit.

Rejection. Method is sensitive to systematic error.

R 4s

One control observation exceeding the mean + 2s and another exceeding the mean – 2s in one run with two level control

Rejection. Method is sensitive to random error.

4 1s

Four consecutive observations exceeding the mean + 1s or mean – 1s

Rejection. Sensitive to systematic error


10 consecutive control observations falling on one side of the mean (above or below, with no other requirement on size of deviations)

Rejection. Sensitive to systematic error. This rule may not be used.

Measurement uncertainty (MU) estimation is critical for overall quality assurance of diagnostic setups and should be performed as recommended in ISO 15189. MU reporting should be evaluated with respect to different test purposes like comparison with reference intervals and thresholds for clinical decision limits [31••].

Environmental Conditions

The laboratory ambient temperature must be maintained at 22–26 °C. Work surfaces should be made of inert materials that can be thoroughly decontaminated after every use. Molecular diagnosis laboratories have to be conscious of directional movement of samples and nucleic acids. Unidirectional workflows in molecular diagnostic labs prevent amplicon contamination of unprocessed samples and laboratory reagents (Fig. 1c). It is also recommended that monthly check for monitoring any such contamination be conducted by wipe test and sterility check using blood agar for the entire laboratory. Waste should be properly segregated and disposed by following standard local pollution control board recommendations or WHO guidelines [32].

Standard Operating Procedure Manual

The Standard Operating Procedure Manual (SOPM) is a tool that laboratory technologist’s use for safe and efficient guidance through a specific procedure. A poorly designed SOP can result in misdiagnosis. This can also result in QA failures and regulatory lapses. Laboratory personnel have to be trained in all aspects of SOPs. The SOP has to be reviewed periodically and revised as needed and should be supervised by two qualified personnel and signed by the laboratory director. Methods, reagents, instruments, instrument software, and versions used have to be documented. Development of SOP for NGS assays and target-enrichment protocols, regarding captured regions, must be documented.

Next-Generation Sequencing and Real-Time PCR/Conventional PCR

NGS techniques are increasingly impacting research and diagnostics, especially for complex genetic/infectious diseases. NGS in diagnostics allows for unbiased screening of samples with a higher throughput and eventually will result in obtaining results faster and make diagnostics much more cost effective by eliminating multiple testing on samples [33••, 34•]. The general NGS workflow is elaborated in Fig. 1b [35••]. NGS produces enormous amounts of data and can unravel findings that can be pivotal for disease diagnostics. However, these results must be interpreted with caution, and further evaluation must be carried out using other gold-standard techniques in case of discrepancies.

The concept of use of NGS techniques in diagnostics is apparently new in developing countries and thus prevalent TQMS procedures do not suffice for its complete QM. In order to change this, the standardization and simplification of NGS workflows are a central requirement, involving QMA methods.

The American College for Medical Genetics and Genomics has published detailed NGS diagnostic lab standards for patient care [36•]. Furthermore, the College of American Pathologists has developed an NGS checklist for accreditation of molecular laboratories [37••]. Currently, no clinical NGS-based infectious disease testing (laboratory-developed tests) is yet approved by the US Food and Drug Administration (FDA). Nevertheless, the FDA has published detailed clinical application and validation approaches for regulatory clearances of NGS diagnostic for clinical microbiology [38••].

Molecular diagnostic laboratories currently heavily rely upon the use of methods like real-time PCR for quick turnaround times from sample to pathogen detection with high reliability. Real-time PCR functions by measuring the fluorescence of DNA/RNA intercalating dyes and fluorescent probes added to the PCR mixture prior to amplification [39••]. Using mixtures of compounds that emit fluorescence at different wavelengths, real-time PCR has evolved to quantify multiple targets simultaneously from a single sample. Compared to conventional PCR’s, real-time assays provide a more sensitive limit of detection (LOD) and faster results [40••]. Also, chances of sample cross contamination are minimal for real-time PCR. Also, an overall cost reduction strongly supports the routine use of real-time PCR assays and other rapid molecular assays in clinical diagnostics [41•].

The molecular laboratory has to ensure high degree of quality which includes availability of a suitable biological starting material, best strategy to use to fit the purpose and choice of quality control programs [42] (Fig. 1c).

Safe Disposal of Infectious Laboratory Waste

Universal/local precautions applicable to clinical labs must be followed to minimize occupational hazards of personnel working in the laboratory. Safety measures like maintaining first aid facilities and general safety precautions of the laboratory (hand washing, eyewash, spill management, needle stick injury, and fire safety) should be meticulously observed (Table 2). Every individual performing laboratory procedure must undergo proper training in safe-handling and disposal of hazardous materials. They also must be vaccinated against all recommended pathogens for prevention of unwanted accidental infection, and antibody titers should be monitored regularly. Laboratory operations should be designed in a way that minimizes personnel risk [43••, 44•].
Table 2

Personnel protective equipment (PPE) used in molecular diagnostics

Type of PPE you would wear in an infectious disease (molecular biology) lab


Mask or respirator

Goggles or face shield

Wash hands


Sample preparation


Isolation of nucleic acids


Master mix preparation


Template room


Real-time PCR room




Post amplification





Autoclave room


Spill management (biological and chemical)

Sitting at desk and working with computers






✔ - compulsory; ✔* - optional; ✔** - UV protected; × - not needed

All wastes generated in the lab are segregated and disposed in bags which are color coded. Red bags are used for plastic tubes, plastic containers, infected gloves, and syringes (without needles). Green bags are used for general wastes like paper and stationery. Sharp containers are used for needles, blades, broken glass, and other sharps [45•, 46•].

Information System Management

The laboratory information system is used for collection, processing, recording, reporting, storage, and retrieval of information within the laboratory. It is the black box for the laboratory and enhances quality management through robust traceability. It is also used between the laboratory and external agencies to monitor test results and ensure quality. The clinical laboratory deals with private and confidential information; thus, the handling of information must be secure at all times and should be in compliance with the national or international requirements regarding data protection.

Difficulties and Bottlenecks in TQMS Implementation

Poor quality management due to improper staff training, lack of use of proper test controls, inefficient or lack of result verification process, non-implementation of regular quality control assessment, use of non-validated tests, understaffing, and inadequate attention to detail in ILC and EQAS lead to difficulty in implementing a robust quality management process.

EQAS and proficiency testing for PCR-based tests are not available in most molecular diagnostic laboratories leading to high cost of performing external agency testing. This results in most laboratories refraining from EQAS testing which can potentially lead to serious lapses in quality management. This can be effectively addressed by engaging more domestic laboratories for EQAS/PT/ILC testing through national policies on clinical diagnostics.

Preparation of clinical samples for downstream analysis and careful assessment of results while accounting for data from control reactions are few of the critical components that could derail the functioning of diagnostic laboratories if not implemented properly. Inhibition by chemicals found in clinical samples can be a major hurdle, but with the use of commercially available nucleic acid extraction kits, these issues can be efficiently managed.

Also, external and internal quality control assays must be performed simultaneously during sample processing. An effective example of this is the use of an internal amplification control (IAC) and external amplification control (EAC) during PCR-based testing of clinical specimens. This helps in accurate determination of specificity and sensitivity of each test performed and helps establish true negatives by estimating poor performance due to sample handling.

An IAC is a non-target nucleic acid sequence that is co-amplified simultaneously with the target sequence [47]. A negative response (no signal) in a molecular test can sometimes be due to inhibition of the whole reaction by some sample generated contaminants giving a false-negative result. Thus, the use of IAC along with the target-specific probes will always generate a control signal irrespective of the status of the target, ensuring completion of the reaction.

Similarly, EAC is a more specific amplification control that is mostly identical to the target nucleic acid sequence. Thus, two separate reactions are carried out for each test and control reaction under identical conditions to further ensure reliability of test results [48]. If the above strategy is carefully optimized, it represents a highly comprehensive and fail-safe approach in molecular testing.

Laboratory Accreditation

Pre-assessment is the initial step for any laboratory seeking accreditation, and it is a comprehensive review carried out on-site by the accreditation body in accordance with ISO15189:2012. Reviews are carried out for legal identity of the laboratory, list of personnel working, their qualifications, the list of equipment, structure of laboratory organogram for efficient work management, availability of referral external documents, internal auditor training certificates of all laboratory personnel, and list of authorized signatories. It also includes assessment of documents pertaining to monitoring of laboratory EQAS/ILC and personnel technical skills and details of certificate of biomedical waste disposal from the local pollution control board and the agency that collects biological wastes from the lab. In case of referral laboratories, the memorandum of understanding (MoU) with clinical partners should also be assessed.

This is followed by a final assessment by the accreditation body where assessors, after verifying all documents, will raise any nonconformities according to the ISO15189:2012 checklist. The laboratory has to propose corrective action within a stipulated time following which the assessors will provide their final recommendation to the accreditation board for the final approval.

Once accreditation is granted, the laboratory accreditation enlists a set of specified fields for testing valid till the next evaluation period. It is mandatory for the accredited lab to comply with the requirements of the quality management as ascertained for the accreditation for all parameters throughout the entire accreditation period. The laboratories’ accreditation status will be dependent on surveillance and re-assessment process which mainly accounts for rigor in maintenance of quality parameters and deviations from laid-down laboratory SOPs during the course of the previous accredited time frame.


The major challenge for a molecular diagnostic laboratory is to select high-performing technological methodologies that enable reliable detection of all requests at a high sensitivity, with a limited amount of specimen and short turnaround time at low costs. Efficient molecular testing could bring reduction of inappropriate therapeutic prescriptions leading to better and faster prognosis and economical clinical care. Thus, a thorough quality management system is critical for the success and growth of molecular diagnostics taking into account the induction of new diagnostic tools and ensuring reliability of generated results.

Developing countries in the South American, African, and Indian sub-continents with a high burden of chronic and infectious diseases constantly battle a number of challenges to ensure quality standards in a molecular diagnostic laboratory. This includes but is not exclusive to high expenses for procurement of quality reagents, non-availability of reference standards, lack of awareness/training, minimalistic local guidelines, and difficulty in transportation of biological substances.

This review is a summary of anticipated pathways and hurdles during the accreditation process of a clinical molecular diagnostic laboratory in developing countries. Our review brings to light critical elements of the process in addition to overall guidelines. We believe this will be of help for laboratories seeking such accreditation in resource-limited settings. The experience we had undergone during this process could be of immense benefit to others.



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 Information


Compliance with Ethical Standards

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.


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

  1. 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. 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.CrossRefPubMedGoogle Scholar
  2. 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. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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. Scholar
  4. 4.
    •• Newman H, Maritz J. Basic overview of method validation in the clinical virology laboratory. Rev Med Virol. 2017:e1940.1–7. 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. 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 Accessed 20 July 2018.
  6. 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. This study followed the guidelines specified by International Organization for Standardization (ISO) 15189:2007 to identify noncompliant elements of processes.CrossRefPubMedGoogle Scholar
  7. 7.
    •• Clinical & Laboratory Standards Institute. Quality management for molecular genetic testing; Approved guideline. Available at 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. 8.
    •• Clinical & Laboratory Standards Institute. Nucleic acid amplification assays for molecular haematopathology; approved guideline-second edition. 2012. Available at 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. 9.
    •• Clinical & Laboratory Standards Institute. Molecular Diagnostic methods for infectious diseases. 3rd edition. 2015. Available at 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. 10.
    ISO 15189:2012(en) Medical laboratories - Requirements for quality and competence. Available at Accessed 20 July 2018.
  11. 11.
    ISO/IEC 17025:2005. General requirements for the competence of testing and calibration laboratories. Available at Accessed 20 July 2018.
  12. 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. A review is to elaborate why it is necessary to obtain accreditation but also why certain requirements for accreditation might be experienced as inappropriate.CrossRefPubMedGoogle Scholar
  13. 13.
    Panteghini M. Traceability as a unique tool to improve standardization in laboratory medicine. Clin Biochem. 2009;42(4–5):236–40 Scholar
  14. 14.
    Handoo A, Sood SK. Clinical laboratory accreditation in India. Clin Lab Med. 2012;32(2):281–92. 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.CrossRefPubMedGoogle Scholar
  15. 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 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.CrossRefGoogle Scholar
  16. 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 Scholar
  17. 17.
    •• Clinical & Laboratory Standards Institute. Hand book for a developing a laboratory quality manual. 1st edition. 2017. Available at 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. 18.
    •• Clinical & Laboratory Standards Institute. Using proficiency testing and alternative assessment to improve the clinical laboratory, approved guideline 3rd edition.2016. Available at 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. 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 Accessed 20 July 2018.
  20. 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. 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.CrossRefGoogle Scholar
  21. 21.
    Niesters HG. Clinical virology in real time. J Clin Virol. 2002;25(Suppl. 3):S3–12. Scholar
  22. 22.
  23. 23.
    Clinical & Laboratory Standards Institute. User protocol for evaluation of qualitative test performance: approved guideline, 2nd edition. 2008. Available at. 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. 24.
    Lewis SM. The WHO International external quality assessment scheme for haematology. Bulletin of WHO.1988;66: 283–90.
  25. 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. This paper reveals that EQAS along with IQC is a very important tool for maintaining optimal quality of services.CrossRefGoogle Scholar
  26. 26.
    •• Ceriotti F. The role of external quality assessment schemes in monitoring and improving the standardization process. Clin Chim Acta. 2014;432:77–81. 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.CrossRefPubMedGoogle Scholar
  27. 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 Scholar
  28. 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. 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.CrossRefPubMedGoogle Scholar
  29. 29.
    • Westgard JO. Internal quality control: planning and implementation strategies. Ann Clin Biochem. 2003;40(Pt 6):593–611 A review focuses on strategies for planning and implementing IQC procedures in order to improve the quality of the IQC.CrossRefGoogle Scholar
  30. 30.
    •• Bayat H. Selecting multi-rule quality control procedures based on patient risk. Clin Chem Lab Med. 2017;55(11):1702–8. 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.CrossRefPubMedGoogle Scholar
  31. 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. 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.CrossRefPubMedGoogle Scholar
  32. 32.
    Pruss A, Cirouit E, Rushbrook P. Safe management of wastes from health-care activities. Available at Accessed 20 July 2018.
  33. 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. 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.CrossRefPubMedGoogle Scholar
  34. 34.
    • Meldrum C, Doyle MA, Tothill RW. Next-generation sequencing for cancer diagnostics: a practical perspective. Clin Biochem Rev. 2011;32(4):177–95 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.PubMedPubMedCentralGoogle Scholar
  35. 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. 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.CrossRefGoogle Scholar
  36. 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. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    •• College of American Pathologists: molecular pathology checklist. next generation sequencing. Northfield, IL, College of American Pathologists, 2015, pp 8. Available at 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. 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 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. 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. 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.CrossRefPubMedGoogle Scholar
  40. 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. 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. 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. A study guideline will encourage better experimental practice, allowing more reliable and unequivocal interpretation of qPCR results.
  42. 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. Scholar
  43. 43.
    •• Laboratory safety guidance, occupational safety and health administration. Available at 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. 44.
    • Emmert E. Biosafety guidelines for handling microorganisms in the teaching laboratory: development and rationale. J Microbiol Biol Educ. 2013;14(1):78–83. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 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 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. 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 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. 47.
    Cone RW, Hobson AC, Huang ML. Coamplified positive control detects inhibition of polymerase chain reactions. J Clin Microbiol. 1992;30(12):3185–9 Scholar
  48. 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. Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Seetha Dayakar
    • 1
    Email author
  • Heera R. Pillai
    • 2
  • Sanughosh Kalpathodi
    • 2
  • Ganesan Jeya Chandran
    • 3
  • Radhakrishnan R. Nair
    • 1
    Email author
  1. 1.Laboratory Medicine and Molecular Diagnostics, Bio-Innovation CenterRajiv Gandhi Center for Biotechnology, KINFRA Film & Video ParkThiruvananthapuramIndia
  2. 2.Srinivasa Ramanujan Institute for Basic SciencesThiruvananthapuramIndia
  3. 3.Department of BiochemistryPSG Institute of Medical Sciences and ResearchCoimbatoreIndia

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