Abstract
From the beginning of the twenty-first century onwards, laboratories that offer human ART treatment or are involved in the handling of human gametes and/or tissue became subject to increasing demands and precepts set down by regulatory and legislative authorities. The regulations differ from country to country, and some directives (e.g., the EuropeanTissue Directive 2004/23/EC-2006/86/EC) are subject to interpretation according to legislation or guidelines set down by national authorities in individual countries. In many countries, it has become necessary to obtain accreditation and/or certification by a national or international body that will carry out in-depth assessments and inspections to ensure that all aspects of facilities and treatment meet a required standard.
There is no doubt that success in ART is crucially dependent on carefully controlled conditions in every aspect of the IVF laboratory routine (Figure 9.1).
Figure 9.1 Critical elements of an ART treatment cycle.
From the beginning of the twenty-first century onwards, laboratories that offer human ART treatment or are involved in the handling of human gametes and/or tissue became subject to increasing demands and precepts set down by regulatory and legislative authorities. The regulations differ from country to country, and some directives (e.g., the EuropeanTissue Directive 2004/23/EC-2006/86/EC) are subject to interpretation according to legislation or guidelines set down by national authorities in individual countries. In many countries, it has become necessary to obtain accreditation and/or certification by a national or international body that will carry out in-depth assessments and inspections to ensure that all aspects of facilities and treatment meet a required standard.
Certification and Accreditation
Certification: a neutral independent third party confirms (certifies) that a system complies with an internationally accepted standard, such as an ‘ISO Norm.’ In practice, this means that laboratories can search for a company that will assess whether or not their quality system has the structure required by the ISO Norm. A wide and varied choice of companies offers this service, and their fees may differ considerably. Certification provides testimony that a correctly structured QMS is in place, according to an internationally accepted standard. Certification is often presented to patients as reassurance and guarantee of the clinic’s high quality, but this is not the case. These certificates merely confirm that there is a quality management whose structure corresponds to an internationally recognized ISO standard: the appropriate structure is in place, but there is no guarantee of the content. For example, an IVF laboratory with very poor results can be certified, but will never be accredited because poor treatment outcomes usually indicate a lack of competence.
Accreditation requires evidence that your laboratory has the appropriate competencies for the service provided, including adequate facilities/space, equipment/instruments, personnel who are adequately and continuously trained and able to demonstrate the competence to fulfill their tasks. Accreditation can only be granted by a ‘National Accreditation Office,’ and there is no elective choice in selecting the third party who will audit the clinic/laboratory. If the laboratory seeks accreditation in a very specific field, e.g., ‘comparative genome hybridization,’ a local/national expert might not be available, and the national accreditation office might appeal for an expert from a neighboring country. The national/federal accreditation office is likely to be a member of the International Association for Laboratory Accreditation ILAC (International Laboratory Accreditation Cooperation, https://ilac.org) or EA (European Co-operation for Accreditation, www.european-accreditation.org).
It is important to note that certification and accreditation are valid only for limited time periods of between 2 and 5 years, and re-certification and surveillance are required in order to maintain validity of the acquired certification/accreditation. Nicely framed certificates on display at the clinic entrance are completely meaningless if the date is beyond its period of validity.
Benefits of Certification/Accreditation
From Elder et al. (2015), Chapter 2.
1. Improvement in quality of care provided
2. Recognition of individual training and competencies by providing education
3. Improved management structure
4. Cost reduction via quality improvement policies such as ‘Gemba Kaizen,’ a Japanese concept of continuous improvement designed to enhance processes and reduce waste (Imai, 1997)
5. Patient satisfaction
6. Third-party recognition for reimbursement of treatments
7. Better market position
8. ‘Firewall’ in cases of litigation
ISO9001:2015
The International Organisation for Standardization (ISO) (www.iso.org) is a network of the national standards institutes of 162 countries, consisting of one member per country; a Central Secretariat in Geneva, Switzerland, coordinates the system. The ISO is an independent body, not associated with the government of any particular country. Some of the 162 member institutes (www.iso.org/members.html) may be a part of their country’s government structure, but others have been set up by national partnerships of industry associations, and therefore are in the private business domain. The ISO therefore tries to reach a consensus on issues that concern both business requirements and the broader needs of society. Their standard for quality management is published as ISO9001:2015.
In order to obtain ISO certification, a unit with an established quality management system (QMS) is inspected and assessed by an external auditor. If all the requirements of the ISO standard are met, a certificate is issued stating that the QMS conforms to the standards laid down in ISO9001:2015. Many countries now require that IVF clinics and laboratories show evidence such as this, that an effective QMS is in place. ART laboratories in the USA should conform to the American Society for Reproductive Medicine guidelines (ASRM, 2014) and must undergo certification and accreditation by an appropriate agency, such as the College of American Pathologists (CAP) or Joint Commission International (JCI). In the UK, all IVF clinics must apply for a license from the Human Fertilisation and Embryology Authority (HFEA) and ensure that all of their procedures are compliant with the HFEA Code of Practice. The HFEA monitors all UK data and carries out annual audits and inspections.
The final impact of legislative, regulatory, accreditation and certification requirements is that every ART laboratory should have an effective total quality management (TQM) system. TQM is a system that can monitor all procedures and components of the laboratory; this must include not only pregnancy and implantation rates, but also a systematic check and survey of all laboratory materials, supplies, equipment and instruments, procedures, protocols, risk management and staff training/education (continued professional development, CPD).
Quality: fitness for purpose.
Quality management system: a system that encompasses quality control, quality assurance and quality improvement by providing defined sets of procedures for the management of each component.
Quality policy: a statement defining the purpose of the organization and its commitment to a defined quality objective.
Quality control: inspection of a system to ensure that a product or service is delivered under optimal conditions.
Quality assurance: monitoring the effectiveness of quality control and indicating preventive and corrective action taken when errors are detected.
Quality audit: review and checking of the quality management system to ensure its correct operation.
External quality assurance: testing a product or service against an external standard.
Irrespective of the numerous fine details involved in TQM, the first, and ultimate, test of quality control must rest with pregnancy and live birth rates per treatment cycle. An ongoing record of the results of fertilization, cleavage and embryo development provide the best short-term evidence of good quality control (QC). Daily records in the form of a laboratory logbook or electronic database are essential, summarizing details of patients and outcome of laboratory procedures: age, cause of infertility, stimulation protocol, number of oocytes retrieved, semen analysis, sperm preparation details, insemination time, fertilization, cleavage, embryo transfer and cryopreservation. Details of media and oil batches and all consumables that come into contact with gametes and embryos must also be recorded for reference, and the introduction of any new methods or materials must be documented. It is essential that all records are reviewed on a regular basis.
A QMS in the IVF laboratory aims to achieve specific goals:
1. Identify all of the processes to be included in the QMS:
provision and management of resources
ART processes
evaluation and continual improvement
monitoring of key performance indicators (KPIs).
2. Make available the resources and information necessary to operate and support these processes.
3. Implement any actions necessary to ensure that the processes are effective and subject to continual improvement.
4. Document control management (80% of nonconformities concern missing documents).
A QMS ensures continuous assessment and improvement of all component parts of the patient treatment cycle. KPIs to be monitored include rates of fertilization, cleavage, survival of injected oocytes, pregnancy, implantation and live births; satisfaction of patients and referring clinicians with the quality of the service should also be monitored, and suppliers of media, disposables, etc. also monitored and evaluated. Graphic analysis of these parameters can reveal problems early so that corrective action can be taken promptly to minimize the extent of any problem that might arise (Kastrop, 2003).
Basic Elements of a Quality Management System
A formal QMS should include:
Scope: a list of all treatments provided and links to the forms and documents used
Normative reference values, with levels of uncertainty: definition of a successful outcome
Terms and definitions: those used in IVF
Management responsibility: organization chart showing lines of responsibility and accountability of all staff
Resource management: provision of sufficient resources, including staff, to deliver the service
Provision of sufficient and appropriate facilities, with regular survey of all environmental parameters
Product realization: treatment plans, procedures, purchasing, traceability, witnessing
Measurement, analysis, improvement: monitoring of KPIs, risk management with frequency and grade of impact, reporting of adverse incidents, corrective and preventive action to improve service.
Implementing QMS in the IVF Laboratory
The first key requirement for implementing a formal QMS is appropriately educated and trained personnel, with training records that are regularly updated. Other key requirements include:
1. Complete list/index of standard operating procedures (SOPs)
2. Housekeeping procedures: cleaning and decontamination, with a calendar clearly indicating schedules
3. Correct operation, calibration and maintenance of all instruments with manual and logbook records
4. Proper procedure, policy and safety manuals
5. Consistent and correct execution of appropriate techniques and methods
6. Comprehensive documentation, record keeping, validation and reporting of results
7. System for specimen collection and handling
8. Safety procedures including personnel vaccination and appropriate handling and storage of materials
9. Infection control measures
10. Documentation of suppliers and dates of receipt and expiry of consumables
11. System of performance appraisal, correction of deficiencies and implementation of advances and improvements
12. Quality materials, tested with bioassays when appropriate
13. Quality assurance program
Laboratory Equipment
Equipment failure or suboptimal operation in an IVF laboratory can seriously jeopardize the prognosis for patients undergoing treatment, and therefore service contracts should be set up with reliable companies. As part of the service, the companies should train all staff regarding routine maintenance and emergency procedures, and provide calibration certificates for the tools that they use in servicing and calibrating the equipment. Alarms should be fitted to all vital equipment, and provision made for emergency call-out. Any defect requiring correction must be documented, with description, date and details of repair. Back-up equipment should be held in reserve.
Documentation must be available to confirm:
1. The equipment is installed in an appropriate location and is correctly connected.
2. The equipment has been checked for correct function and has been calibrated.
3. All personnel who will work with the equipment have been trained by the company.
Electrical appliances must be tested for safety before first use (e.g., by portable appliance testing) and then regularly tested by a trained operator. They should be designated as a potential source of fire, and must not be used if faulty; any faults must be reported and repaired immediately. Contracts for service and calibration should be held for:
Incubators
Incubator alarms
Flow cabinets
Microscopes
Micromanipulator stations
Heated surfaces/microscope stages
Centrifuges
Refrigerators and freezers
Embryo/oocyte freezing machines
Liquid nitrogen storage dewars
Low-level nitrogen alarms in the dewars
Air filtration equipment
Electronic witnessing system.
Key items of equipment in daily use must have systems of continuous monitoring to ensure optimal performance. Numerous systems for computer-controlled data acquisition, including verification of patient identity and chain of custody and monitoring, are available, with continuous monitoring and logging software systems that support multiple instrument inputs (Figure 9.2). A system such as this can continuously check and record airborne particle counts, as well as data from key equipment such as incubators, freezers, refrigerators and liquid nitrogen storage vessels. The data are monitored in real-time, and the computerized system can display historical data acquisition and analysis, trend-lines, correlation studies and various levels of alarm notification. Variation outside set parameters is covered by an alarm system that is monitored 24 hours a day.
Figure 9.2 Data from a facilities monitoring system in the IVF laboratory at Bourn Hall Clinic. The background shows the different monitoring modules that can be viewed: CO2 sensors, HEPA sensors, incubator temperature, refrigerators, freezers. Insets: 24-hour records from a single incubator showing (a) CO2 concentration and (b) temperature. Note dips during peak laboratory activity times, 8–10.30 am.
Temperature and pH are known to be critical parameters that must be carefully controlled, and their measurement in an IVF culture system requires special attention:
Temperature
The temperature of incubators, water baths, heating blocks, heated surfaces and microscope stages should not rely on a digital display from the equipment, but must be independently recorded and controlled, with individual fine tuning for each. Always note that the temperature of the incubator, bath or surface will differ from that in the culture media within a drop, tube or dish; 37°C should be the temperature to aim for within the media, not for the incubator or heating device. As with monitoring of all parameters that can have an impact on results, (pH, temperature, VOC levels, etc.), setpoints and tolerance intervals must be defined for each dish on each separate device, using a calibrated thermometer with type K thermocouple (PT100 or PT1000). Laboratory equipment is affected by environmental temperatures, and therefore regular adjustment according to seasonal variations is to be expected (Butler et al., 2013).
pH
An ‘optimal’ pH for in-vitro culture has not been precisely defined or characterized, and according to the manufacturers’ information, the range of acceptable pH differs with media type, since the hydrogen ion concentration is determined by the overall composition, including concentrations of amino acids and protein supplement (Swain, 2012). Different media companies advise that incubators are run at different CO2 concentrations in order to optimize the pH for their media.
pH is a number that reflects dynamic culture conditions; it changes rapidly if acid/base concentrations change. Although it is a critical parameter, in practice it is not easy to monitor effectively, especially in microdrop culture under oil. A standard glass probe pH meter is fragile, requires a volume of at least 1 mL that needs to be equilibrated (cannot be used for microdrops) and is not standardized, and therefore readings taken do not represent actual culture conditions. A number of alternative devices are available for use in IVF culture systems, but none provide an ideal solution to the problem of pH monitoring, and the different devices can yield different results when used to test a variety of different media and solutions. Therefore, whatever device is used, careful validation and calibration is essential; it may be unwise to rely on only one method. Although pH measurement is important, and is useful in monitoring manipulation and handling procedures, a change in pH reflecting CO2 concentration takes time, and depends upon the volume and the culture system being used. Please refer to Elder et al. (2015) and Pool (2004) for a comprehensive review of the science behind culture media pH and its importance in human IVF.
1. ISFET (ion-sensitive field effect transistor) probes:
Can be used in small volumes outside the incubator, are simple and fast.
Require frequent calibration and cleaning (sensitive to protein deposits), expensive.
2. RI pH meter:
Can be used for measurements inside the incubator, but not for microdrop culture.
Slow, drifts over time, and calibration is difficult/time consuming.
3. pH Online™, ‘fluorescent decay time’ pH meter:
Allows continuous pH measurement inside the incubator; can be used to monitor pH in up to 10 incubators simultaneously.
Requires disposable four-well Nunc dish, with one well fitted with a pH reactive fluorochrome spot.
Simple to use, but expensive and slow.
4. Blood gas analyzer:
Accurate, but not suitable for microdrops.
Method of choice for initial media pH testing.
Sampling errors can be a problem.
5. Beckmann pH meter:
Can be used to measure pH in 5-mL aliquots of media after overnight incubation in test-tubes with loose-fitting caps (see Pool, 2004).
Electrode selection, cleaning and regular replacement are important.
Must be correctly calibrated before each use.
6. SAFE Sens (Sterile Automated Fluoroscopic Evaluation):
Noninvasive continuous pH monitoring, based on emission of characteristic wavelength spectra at different pH by fluorescent dyes.
Uses small disposable cuvettes with a fluorescent membrane that are placed inside the incubator.
Provides accurate real-time pH reading every 30 minutes.
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