Revision of the “Guideline of the German Medical Association on Quality Assurance in Medical Laboratory Examinations – Rili-BAEK”

Measurement accuracy

The closeness of agreement between the mean of the measured values obtained within a control period and the target value. This is usually quantified numerically using the systematic deviation of measurement, which is inversely proportional to the accuracy.

Analyte

(see “Measurand”)

Audit

Systematic, documented process to determine the extent to which established audit criteria have been met.

Central laboratory

Central laboratory means that the medical laboratory examinations are usually performed for the entire institution (e.g., hospital) in one single organisational unit “medical laboratory” by appropriately qualified technical personnel. The central laboratory can also be an external laboratory managed by another legal entity/operator.

Control sample

Sample with target values provided.

Control strain

A reference culture or reference strain of microorganism, virus or cell-lines which is directly obtained from an approved culture collection or from a national reference laboratory or, where applicable, which is adequately characterised using suitable methods (e.g., characterisation of an isolate by an EQA, by sequencing or mass spectrometry). Normative procedures (e.g., sensitivity testing) require the use of corresponding normative control strains.

Deviation of measurement

The difference between a measurement result and the true value of the measurand. The difference between the measurement result of a control sample and the target value of this control sample is used to estimate the deviation of measurement as part of quality assurance of medical laboratory examinations.

The relative deviation of measurement is calculated by dividing the deviation of measurement by the target value.

Deviation of measurement, random (imprecision)

The difference of a measured value from the mean that would result from an infinite number of repeated measurements of the same measurand. The imprecision is estimated by calculating the difference between the value of the single measurement and the arithmetic mean of the measured values.

Deviation of measurement, root mean square of the

The root mean square of the deviation of measurement is a measure of the scatter of the measured values around the (conventional) true value of the measurand (here, the target value of the control sample). It is calculated using the formula

where

∆ represents the root mean square of the deviation of measurement.

x ₀ represents the true value of the measurand; here, the target value of the control sample.

x _i represents the value of the single measurement.

n is the number of individual values used for calculation.

The following mathematical relationship exists between the root mean square of the measurement deviation, the systematic measurement deviation and the empirical standard deviation of a sample.

where

s represents the empirical standard deviation of a random sample.

δ represents the systematic deviation of measurement.

The relative root mean square of the deviation of measurement is calculated by dividing ∆ by the target value x ₀.

Deviation of measurement, systematic (inaccuracy)

This is the arithmetic mean which would result from an infinite number of repeated measurements of the same measurand, minus the true value of the measurand. The systematic deviation of measurement δ of a measurement procedure is estimated by taking the difference between the arithmetic mean x ‾ calculated from an appropriate number of repeated measurements, and the target value x ₀, e.g.,

The relative systematic deviation of measurement is calculated by dividing δ by the target value x ₀.

Device

Technical object or technical apparatus used to process, analyse or manufacture something.

Documentation, documented information

This refers to linked information and its storage media (digital or analogue), for example, records, instructions (including quality regulations), flow charts, method descriptions, specifications, calibration tables, reference ranges, drawings, reports, findings, legal provisions or standards.

Documentation may also involve the use of process-oriented quality management programmes.

Equipment

Equipment includes, but is not limited to, devices, reagents, control samples, reference materials, consumables and analytical systems.

Error limits

The maximum permissible limits for measurement deviations as defined by this guideline. Should these limits be exceeded, the deviations are considered errors and require corrective measures.

Examination, medical laboratory

An in-vitro diagnostic procedure used for obtaining values from sample material.

Finding

Findings are laboratory examination results assessed by a physician.

Influencing factor

Influencing factors affect the patients being examined. They influence the composition of the specimen as a result of illness or defects or other biological phenomena. They reflect the patient’s status.

Instructions

Instructions are defined procedures for carrying out specific operations. Instructions include, for example, standard operating procedures, documents, videos and apps. Instructions must be clear and comprehensible for the medical laboratory staff.

Interfering factors

Interfering factors influence medical laboratory examinations. They interfere with the examination procedures and thus lead to a distortion of the results of the examination. They do not represent the patient’s status.

Laboratory, medical

Depending on the context, a medical laboratory as defined by this guideline as follows

• spatial definition: a room, a part of a room or multiple rooms in which medical laboratory examinations are performed,

• personnel definition: a person under whose responsibility medical laboratory examinations are performed,

• organisational definition: a functional or organisational unit in which medical laboratory examinations are performed.

Laboratory examinations, patient-near immediate

Patient-near immediate laboratory examinations are defined as medical laboratory examinations that are performed directly as single measurements without sample preparation.

A major criterion for patient-near immediate laboratory examinations is the ability to make instant decisions about further diagnosis or treatment based on the results of the laboratory examination.

Location

The geographical location (postal address) of a company or an institution where medical laboratory examinations are performed.

Mean, robust

Expected value for the population mean estimated using a robust method. A robust method is insensitive to outliers.

Measurand

Defined variable that is to be measured.

Measurement

Sum of all actions involved in determining a measurand.

Measurement method

General description of the logical sequence of actions for performing measurements.

Measurement procedure

Complete set of specifically described operations used to perform particular measurements according to a given method.

Minimal difference (MD)

The smallest distance between a measurement result and a cut-off at which they can be denoted as being different. The MD is calculated from the standard deviation (SD):

MD=1.65 × SD.

NAAT

Nucleic acid amplification technique, e.g., polymerase chain reaction (PCR), including systems with isothermal amplification and sole signal amplification, e.g., branched DNA (bDNA).

NAAT systems, closed (e.g., for detection of pathogen-specific nucleic acid)

Systems (e.g., unit-use test cartridges) that already contain all the necessary reagents, including individual ready-to-use packs for sample preparation into which no further external reagents can be introduced or can enter the system after the sample material has been added. Furthermore, the system cannot be opened throughout the process chain so that the risk of contamination and/or the release of amplificates is eliminated.

Nominal value

Target value determined without using a reference measurement procedure.

Organisational unit

An organisational unit is any distinct section of a medical institution (e.g., the central laboratory or another subunit of the hospital) where medical laboratory examinations are performed. It is characterised by:

• a defined group of users (doctors, nurses),

• a pool of measuring stations and/or measuring devices assigned solely to this unit and

• measuring stations that can only be operated by designated personnel.

Peer review

Critical (self-)assessment of medical care in consultation with colleagues which uses a structured process to continuously improve the quality and safety of patient care.

Performance of a measurement method

The following criteria are used to describe the performance of a measurement method: analytical sensitivity, analytical specificity, measurement precision, accuracy expressed in terms of systematic deviation of measurement, reproducibility expressed as random deviation of measurement, repeatability, measuring interval, theoretical and practical limits of detection, and linearity.

Pre-analytical phase

The pre-analytical phase includes all steps prior to the actual measurement; in particular the

• collection of specimen

• transport and storage of the specimen or sample material,

• assessment of the specimen or sample material,

• sample preparation (e.g., separation of corpuscular components by centrifugation).

Precision

In the context of this guideline, precision refers to reproducibility. It expresses the extent of the reciprocal convergence of the results of repetitive measurements of the same measurand when performed under varying measurement conditions (e.g., laboratory personnel, test, time, reagent deterioration). The extent of precision is usually quantified by the statistical measures of the imprecision of measurements “standard deviation” and “relative standard deviation (coefficient of variation)” which are inversely related to precision.

Qualitative examination

A qualitative laboratory examination is used to determine a qualitative characteristic. A characteristic is qualitative when its values are assigned to a scale on which no intervals are defined (topological scale).

Nominal characteristics are qualitative characteristics whose values are not ordinally related (nominal scale): e.g., detectable, not detectable.

Ordinal characteristics are qualitative characteristics whose values are ordinally related (ordinal scale): e.g., titre level, + to +++, indication of a range of values, pH value on a test strip.

Medical laboratory examinations are assigned to Part B 1 or Part B 2 based on how the results are reported (scale level).

Quality assurance, risk-based

A quality assurance concept which ensures the laboratory runs a sufficient number of control samples for a given measurand/examination, taking into account e.g., the relevance of test results, testing frequency, the respective positive or negative rates and, where applicable, the performance of further test procedures. Risk-based quality assurance also includes suitable measures for detecting irregularities in the test system as well as preventive measures to minimise negative effects. The risk assessment of a specific examination must be documented.

Quality policy

The overall intentions and objectives of a medical laboratory with regard to quality, as formally expressed by the laboratory management.

Quantitative examination

A quantitative laboratory examination is used to determine a quantitative characteristic. A characteristic is quantitative when its values are assigned to a scale on which intervals are defined (metric or cardinal scale).

Medical laboratory examinations are assigned to Part B 1 or Part B 2 based on how the results are reported (scale level).

Reference measurement procedure

A thoroughly investigated measurement procedure whose results have an uncertainty of measurement commensurate with its intended use, such as in assessing the trueness of other measurement procedures used for the same measurand and for the characterisation of reference materials.

Reference method value

A target value obtained using a reference method.

Referral laboratory

A medical laboratory under the control of another legal entity and/or economic operator, to which the specimen or sample material is submitted for examination.

Report

Reports are summarized presentations of laboratory examination results.

Responsibility of the central laboratory

Responsibility in this case refers to guidance and supervision. In the context of patient-near immediate laboratory examinations, “under the responsibility of the central laboratory” means that the central laboratory monitors whether the individual organisational units of an institution adhere to the guideline with respect to internal quality assurance.

Responsibility does not mean that the control samples are measured and evaluated by employees of the central laboratory.

Risk management

Risk management is used to handle potential risks and to avoid and prevent errors and adverse events.

Sample material

The specimen used for the medical laboratory examination, with or without prior sample preparation.

Sample preparation

Sample preparation includes all changes made to the material to be examined prior to loading it into the measuring device or instrument by the person collecting the sample or by the person carrying out the measurement. Pipetting/volume dosing is not considered sample preparation in the sense of this definition. If the collection system contains additives included by the manufacturer, this also does not constitute sample preparation.

Specimen

The body fluid/material (e.g., venous blood, cerebrospinal fluid, aspirate, tissue, urine, stool) taken from or excreted by a person for examination purposes, including any additives, which is stored in an appropriate container.

Standard deviation, empirical

The empirical standard deviation of a random sample is a measure of the distribution of the results around the mean. It is calculated by taking the square root of the mean of the (estimated) random measurement deviations, i.e.,

The coefficient of variation (CV) is obtained by dividing s by the mean x ‾ .

Target value

The target value of a control sample as determined and declared by the manufacturer or as determined by a reference institution.

Trueness of measurement

The closeness of agreement between the mean of the measured values obtained in a control period and the target value. This is usually quantified numerically using the systematic deviation of measurement, which is inversely correlated with trueness of measurement.

Unit-use reagents

These are reagents which are portioned for single measurements and are fully consumed after one examination.

Validation of a measurement procedure

This is the objective proof that the determined requirements are met by a measurement procedure. Objective proof can be obtained through observation, measurement, testing or other methods.

Validation of an examination result

This consists of the technical validation (assessment of the analytical quality) and medical validation (plausibility), including, where applicable, an analysis of conformity with an orientation diagnosis made by the requestor (including a constellation check of the results).

4.1 Identification

Institutions in which medical laboratory examinations are conducted must be legally identifiable.

4.2 Organisation

The responsibility, duties and competence of the staff performing medical laboratory examinations must be clearly defined and documented.

5.1 Management

The medical laboratory must be managed by a professionally qualified person.

Management responsibilities encompass technical, organisational, administrative activities, training and continuing education as well as consultation. Quality management also falls under the responsibility of management.

5.2 Personnel

Medical laboratory examinations may only be performed by personnel who are professionally qualified in accordance with legal regulations, and who are authorised to do so by management.

A sufficient number of staff must be available to carry out the medical laboratory examinations as well as to conduct quality management and, if necessary, to provide reserve capacities in the context of emergency care.

Staff members are required to participate in regular meetings, specialised training and continuing education. Participation in training and continuing education programmes must be documented.

The training of new staff and the familiarisation of staff with new analytical systems and laboratory medical examination procedures must be regulated and documented.

5.3 Rooms and environmental conditions

1. Rooms are to be available for medical laboratory examinations where the intended work can be performed without an adverse effect on the quality of the medical laboratory examinations and on the health and safety of the staff and the patients.

2. Environmental conditions that affect the quality of the examination results are to be identified, monitored, regulated and documented.

3. Access to and use of rooms and areas whose condition can impact medical laboratory examinations must be established and monitored.

4. Adequate space for storage and appropriate room conditions are to be ensured in order to maintain the integrity of specimens, stored microorganisms, cells, devices, reagents, laboratory materials, records, reports and other documents. Measures are to be taken to safeguard against unauthorised access.

5. Provisions are to be made which guarantee the prompt availability of data. In order to ensure information security and data protection, data integrity is to be maintained and the data must be protected against unauthorised access.

5.4 Equipment

1. The medical laboratory must have the equipment necessary to perform its tasks. The requirements of the guideline also apply to equipment that is used by the medical laboratory but not under its responsibility.

2. The medical laboratory must have a procedure in place to regularly monitor the proper functioning of its devices, reagents and analysis systems and this procedure must be implemented. Maintenance is to be performed and documented based on defined specifications.

3. Documentation is to be retained for every analysis system and device that is needed to perform medical laboratory examinations and which can impact the quality of these medical laboratory examinations. This documentation must contain, but is not limited to:

4. name of system or device,

5. name of the manufacturer, model and serial number or other form of identification,

6. date of commissioning,

7. instructions for use, operating instructions and other information from the manufacturer, or justification, if these are not available,

8. functional tests,

9. maintenance requirements including date, time and type of inspection that has been carried out,

10. the nature, date and time of equipment outages, malfunctions, structural modifications and repairs.

    These records must be retained for two years beyond the working life of the equipment and must be promptly accessible.

11. Only authorised and trained members of staff may operate devices and analysis systems. Instructions for operating and servicing the equipment must be kept up-to-date and accessible to members of staff in their workplace.

6.1 Pre-analytical phase

1. A complete list of the relevant laboratory examinations offered by the medical laboratory must be accessible to the submitter.

2. The medical laboratory must provide professionally competent advice regarding the examinations it offers, especially with regard to the selection of medical laboratory examination, the type of specimen, and the evaluation of the examination results.

3. The examination request form submitted by the submitter must contain the following information:

4. identity of the patient – including sex and date of birth in the case of age-specific and sex-specific measurands,

5. identity of the submitter of the material and the recipient of the report if not the same,

6. type of specimen and, if relevant, the anatomical site of collection and time of collection,

7. the examinations that have been ordered and

8. clinically relevant patient information.

9. Instructions outlining the correct method for collection, handling and transporting specimens must be available to the persons responsible for this.

   The instructions for collecting the specimen must contain, at minimum, the following:

10. the list of the medical laboratory examinations offered, or reference to this,

11. instructions on:

    1. preparing the patient,

    2. ordering the examination,

    3. the information required about the patient,

    4. the type and quantity of the specimen to be collected,

    5. collecting the specimen, with a description of the specimen containers and all required additives,

    6. special conditions for collecting, handling, storing and transporting the specimen, if applicable,

    7. unequivocal labelling the specimen and

    8. the actions to be taken between the time the specimen is collected and its arrival at the medical laboratory,

12. criteria for requesting additional medical laboratory examinations,

13. information and instructions to be provided to the patients regarding instructions for collecting the specimen and, if necessary, patient consent forms for collecting the specimen and for performing the medical laboratory examinations,

14. information for the patient regarding the self-collection of the specimen as well as for handling, storing and transporting it.

15. The medical laboratory must have instructions for receiving, labelling and processing the specimen for laboratory medical examinations.

16. Criteria are to be defined for rejecting medical laboratory examinations. Rejections are to be documented.

17. The submitted specimen and portions thereof must be clearly assigned to one patient. If this is not possible, the specimen may not be processed. The submitter of the material is to be notified accordingly. The procedure is to be documented.

    If the specimen cannot be assigned beyond a doubt to one patient and a specimen of the same quality cannot be collected or was collected when the patient was in a critical condition, the medical laboratory has to decide, after consulting with the sender of the specimen, whether the requested medical laboratory examinations should nevertheless be performed. The result of the consultation is to be documented.

18. On specimen arrival the medical laboratory must check whether there is any indication that:

19. the conditions defined in the instructions for obtaining the specimen have not been complied with, or

20. delivery was untimely for the requested medical laboratory examinations, or

21. the requested examination cannot be carried out.

    If such indications exist, the medical laboratory must decide, on the basis of established criteria, whether the examination should nevertheless be performed, or whether a new specimen should be requested.

    The procedure is to be documented.

22. Special processes may need to be defined for time-critical medical laboratory examinations.

23. Specifications for minimising influencing and interfering factors – in accordance with the state of the art in science and technology – can be found in Part B of this guideline.

6.2 Procedures for conducting medical laboratory examinations

1. The medical laboratory may only use examination procedures that meet medical requirements.

2. The medical laboratory may only use validated examination procedures. It must document the procedure used for validation and the results that were obtained.

3. All medical laboratory examination procedures must be documented and be available at the workstations at all times.

   This documentation is to include the manufacturer’s instructions for use and, where necessary, additional remarks.

   The documentation is to contain the following, where applicable:

4. identification of the examination procedure,

5. aim of the medical laboratory examination (medical indication),

6. principle of the examination procedure (method),

7. individual steps of the procedure (process),

8. calibration procedure,

9. procedure used to calculate the result,

10. required specimen taking into account the pre-analytical phase (including container and the necessary additives),

11. required instruments, reagents, culture media and test systems,

12. specification of the performance of the examination procedure,

13. information on possible interference factors, interference and cross-reactivity,

14. reference ranges for healthy subjects, therapeutic ranges, decision limits or other indications for interpreting the examination results,

15. process to be taken in the case of abnormal results,

16. safety precautions and

17. references.

18. If the medical laboratory modifies an examination procedure so that the results, and thus the interpretation, change in a clinically significant way, this procedure must be validated and the sender of the material is to be informed as soon as possible.

6.3 Post-analytical phase

1. Results must be technically validated and, using the available clinical data, medically validated.

   Instructions on releasing the examination results must be available. These must include information about who may authorise the release of reports and how and to whom these reports may be issued. The instructions must also contain requirements for the direct issuance of reports to patients.

   Which person carried out the technical and medical validation is to be documented.

2. Reports must be easy to read and contain, at minimum, the following information:

3. date, and – if required – time the report was issued,

4. identity of the patient,

5. name or other means of identifying the submitter of the specimen and, if required, the address; the address of the recipient of the report if not the same as that of the submitter,

6. name of the medical laboratory,

7. date and time when the specimen arrived at the medical laboratory,

8. date and time specimen collection if this information is available and relevant for interpreting the results,

9. type of specimen

10. name of the laboratory examinations and the methods used if the latter is relevant for interpreting the examination results,

11. examination results and corresponding units as necessary,

12. reference intervals or other remarks for interpreting the examination results and

13. identity of the person responsible for releasing the report.

14. If there is a possibility that the examination result was affected by the condition of the specimen, this must be stated in the report. Where necessary, the report shall state that the results are conditional.

15. The medical laboratory must have instructions in place for subsequent amendments to reports. The changes are to be marked with the date, time and name of the person responsible for the changes. The original results are to remain accessible.

16. The medical laboratory must have procedures in place for immediately notifying a physician (or other clinical personnel responsible for patient care) if examination results exceed “alarming” or “critical” limits. This includes reports from referral laboratories.

17. When evaluating quantitative analysis results, the medical laboratory is to retain data on measurement uncertainty and makes this available on request. The minimum difference (MD) is a useful tool for describing measurement uncertainty.

18. Specimens and sample materials are to be stored in such a way that enables repeat or additional medical laboratory examinations to be performed over a period of time as established by the medical laboratory.

7.1 Documenting quality management

1. Quality management documentation must describe every relevant process. All employees must be instructed in how to use and implement the quality management documentation. This documentation must be continuously kept up to date.

   It must contain the following information, if applicable:

2. description of the medical laboratory, its legal status and its main tasks,

3. objectives and strategies: Description of the quality assurance policy, risk management and measures to enhance the laboratory and improve quality,

4. management: description of the responsibilities and qualifications,

5. staff:

   1. qualifications, familiarisations, training, continuing education and meetings

   2. health and safety procedures,

6. resources:

   1. rooms,

   2. facilities and equipment,

   3. environmental conditions,

7. partnerships (referral laboratories, external service providers and suppliers),

8. environmental issues,

9. processes: instructions for

   1. collecting the specimen,

   2. examination procedures, handling equipment, reagents and other relevant consumables, validation of the examination procedures,

   3. ensuring the analytical quality of the examination procedures through internal and external quality assurance as well as regular discussions about the results of the quality assurance,

   4. post-analytical procedures and generating and transmitting reports,

   5. technical and medical validation of the examination results,

   6. document control

   7. generating, storing and archiving records,

   8. resolving complaints,

   9. determining errors and corrective actions,

   10. preventive actions,

   11. communication and co-operation with patients, medical personnel and partners,

   12. internal audits or peer reviews,

   13. information security and data protection.

10. If the medical laboratory is a part of an organisation that has a quality management system in place, reference can be made to the corresponding documents of this organisation.

    The same applies to 7.2 and 7.3 below.

7.2 Document control

The medical laboratory is to define, document and maintain procedures for the control of all quality assurance documentation (internal and external). Each version of this documentation must be stored for future reference. Management must establish the retention period, taking legal requirements into consideration.

It must be ensured that only the current version of the documentation is accessible at the place where it is being used.

7.3 Complaint management

The medical laboratory is to establish and implement a procedure for documenting and handling complaints. Records of the complaints as well as the investigative, preventive and corrective actions taken by the medical laboratory, are to be drawn up and retained.

7.4 Examinations in referral laboratories

1. The medical laboratory must keep a list of all referral laboratories it commissioned by it. All medical laboratory examinations sent to a referral laboratory must be documented.

2. The commissioning medical laboratory is responsible for ensuring that the original submitter receives the examination results and findings from the referral laboratory.

3. When commissioning referral laboratories outside the scope of this guideline, the commissioning medical laboratory must ensure that the referral laboratory possesses the required competencies and that an equivalent quality management system is in place.

7.5 Error management

The medical laboratory is to define and apply procedures for corrective and preventative measures for defective processes.

In the case of erroneous examination results, management must specifically ensure that:

1. persons are designated as responsible for resolving issues,

2. the medical significance of the erroneous result is considered and, if necessary, the sender is informed thereof,

3. examinations are halted and reports are withheld as necessary,

4. corrective actions are taken immediately,

5. examination results that have been already released are recalled or the recipient is appropriately informed of the error,

6. the party responsible for the recalling of the examination results is established,

7. causes and corrective actions are documented and

8. the success of any corrective action is verified to ensure that all identified non-conformities have been eliminated.

The records documenting the identified non-conformities and the corrective actions are to be retained for two years.

1 Principles of quality assurance

1. Part B1 specifies minimum requirements for the quality assurance of results of quantitative medical laboratory examinations. These minimum requirements include internal and external quality assurance.

2. All examinations performed by the medical laboratory in accordance with (1) are subject to internal quality assurance. If several devices or measuring stations are used to perform a medical laboratory examination, internal quality assurance is to be performed on each of these devices or measuring systems.

3. In addition, the measurands listed in Tables B 1-2 a–d of this Part are subject to external quality assurance unless exempted.

4. The measurands in Tables B 1-2 a–d are listed alphabetically and according type of specimen. The criteria used for including a measurand in the table are, specifically, the frequency of the examination procedure and its medical relevance according to the current state of science. The deviations of measurements listed in the table are determined based on medical requirements and the current state of analytical technology. This Table is updated on a continuous basis.

5. Table B 1-1 contains the specifications and explanations for the pre-analytical phase of the specimens to be used – in order to minimise influencing and interference factors – as well as the specific transport conditions.

6. This Part of the guideline does not apply to the chamber counting of corpuscular components in body fluids, the determination of erythrocyte sedimentation rate, or the use of pH test strips.

2 Quality assurance procedure

Explanations for Table B 1-2 a below

Columns 2–4 list the requirements for use in the medical laboratories. Columns 2 and 4–6 list the requirements for the evaluation of the results by reference institutions.

The Rili-BAEK applicable concentration range is the concentration interval in which the specifications for the target values of control samples stated in Columns 3 and 5 shall apply.

If the target value of the control sample lies outside this interval, the regulations for measurands not listed in Table B 1-2 a shall apply. If control samples with target values under the Rili-BAEK-applicable concentration ranges are used, the error limits for this ranges can also be used to evaluate the measurements of these control samples.

RMV=reference method value.

NV=nominal value specific to the measurement method.

1 Principles of quality assurance

1. Part B 2 specifies minimum requirements for the quality assurance of the results of qualitative medical laboratory examinations. These minimum requirements include internal and external quality assurance.

2. All examinations performed by the medical laboratory in accordance with (1) are subject to internal quality assurance. If several devices or measuring stations are used to perform a medical laboratory examination, internal quality assurance is to be performed on each of these devices or measuring stations.

3. In addition, the measurands and nominal characteristics listed in Table B 2-2 of this Part are subject to external quality assurance.

4. The measurands in Tables B 2-1 and B 2-2 are listed alphabetically. The criteria used for including a measurand in the tables are, specifically, the frequency of the examination procedure and its medical relevance according to the current state of science. The tables are updated on a continuous basis.

5. This Part of the guideline does not apply to qualitative tissue examinations and to examinations whose internal and external quality assurance requirements are stated in other sections of Part B.

2 Quality assurance procedure

1 Principles of quality assurance

1. Part B 3 specifies the minimum requirements for the quality assurance of the results of medical laboratory examinations used to directly detect of medically relevant infectious agents. These minimum requirements can include subsequent examinations for the characterisation of pathogens (e.g., differentiation, identification, and typing) and their properties relevant for the treatment of infections (e.g., susceptibility testing to anti-infective agents). These minimum requirements apply to internal and external quality assurance.

2. All examinations performed by the medical laboratory in accordance with (1) are subject to internal quality assurance. If multiple instruments or measuring stations are used for an examination, internal quality assurance is to be performed on each of these devices or measuring stations.

3. In addition, the examinations listed in Tables B 3-2 and B 3-2 a are subject to external quality assurance.

4. The examinations in Tables B 3-1, B 3-1 a, B 3-2 and B 3-2 a are listed separately according to the type of pathogen or testing method(s) used. The criteria used for including an examination in the tables are, specifically, the frequency of the examination and its medical relevance according to the current state of science. The respective tables are updated on a continuous basis.

2 Quality assurance procedure

1 Principles of quality assurance

1. Part B 4 specifies minimum requirements for quality assurance for the results of ejaculate examinations. These minimum requirements include internal and external quality assurance.

2. Ejaculate examinations, as defined in this guideline, are examinations assessing sperm concentration, motility and morphology.

3. All ejaculate examinations performed by the medical laboratory are subject to internal and external quality assurance. If several devices or measuring stations are used to perform a medical laboratory examination, internal quality assurance is to be performed on each of these devices or at each of these measuring stations.

4. All examinations listed in (2) are also subject to external quality assurance.

2 Quality assurance procedure

1 Principles of quality assurance

1. Part B 5 specifies minimum requirements for the quality assurance of the results of molecular genetic and cytogenetic medical laboratory examinations. These minimum requirements include internal and external quality assurance as well as special requirements for carrying out certain measurement procedures.

   In general, molecular genetic and cytogenetic medical laboratory examinations are divided into postnatal, prenatal and tumour genetic diagnostics and have the following specimen requirements:

   1. A postnatal laboratory medical examination, as defined in this guideline, is the molecular genetic or cytogenetic examination of a blood sample, tissue sample, cell swab or cell culture from body tissue after birth.

   2. A prenatal laboratory medical examination, as defined in this guideline, is the molecular genetic or cytogenetic examination of fetal tissues such as amniotic cells, chorionic villi, fetal lymphocytes, isolated fetal cells or nucleic acids from maternal blood.

   3. A tumour genetic laboratory medical examination as defined in this guideline is the molecular genetic or cytogenetic examination of neoplastic tissue, bone marrow, circulating tumour cells and cell-free nucleic acids.

2. Molecular genetic and cytogenetic medical laboratory examinations, as defined in this Part of the guideline, are all examinations on the human genome and transcriptome whose purpose is to detect known sequence variants, identify unknown variants, investigate the structure or copy number of genomic segments or detect epigenetic modifications of genomic segments.

   Cytogenetic medical laboratory examinations, as defined in this Part of the guideline, include all examinations used for postnatal cytogenetic diagnostics, prenatal cytogenetic diagnostics and for the cytogenetic diagnosis of tumours. These methods include molecular cytogenetics (ISH, usually fluorescence in situ hybridisation [FISH]) and molecular karyotyping using array analysis.

3. All molecular genetic and cytogenetic examinations performed by the medical laboratory are subject to internal quality assurance. If an examination is performed on multiple instruments or at multiple measurement stations, internal quality assurance has to be performed on each of these instruments or measuring stations.

4. In addition, all examinations listed in the Tables in Part B 5 are subject to external quality assurance. Participation in an EQA programme is mandatory at every laboratory for each of the above-mentioned examinations in accordance with the frequency listed in the tables, provided that this examination is conducted at the location. If the laboratory only offers examinations whose methodology is not already verified by participation in an EQA programme in accordance with the tables in Part B 5, external quality assurance must take place by participating in an EQA programme that verifies the methodology used.

   An EQA programme as defined in this guideline is an interlaboratory test offered by reference institutions in accordance with Part E of this guideline.

5. The examinations and requirements on internal and external quality assurance are listed in the tables in Part B 5. Inclusion in the tables is based on the frequency of the examination and its medical significance in accordance with the current state of scientific knowledge. The tables are updated on a continuous basis.

2 Validation – special requirements for conducting certain examinations

1. Validation of molecular and cytogenetic measurement procedures in accordance with Part A 6.2.2 encompasses the entire measurement procedure including, if required, any subsequent bioinformatic analysis.

2. Measurement procedures used for circulating tumor DNA (ctDNA) from cell-free body fluids need to be able to detect a variant allele frequency (VAF) of at least 0.5 %. The method-specific limit of detection (LOD) for the result must be stated in the report. The quantitative reporting range must have a coefficient of variation of less than 25 %.

3. For molecular genetic examinations that obtain quantitative results, the performance of a measurement procedure must be determined and documented for each measurand and, in the case of high-throughput methods, for relevant measurands (at minimum for the markers listed in Tables B 5-2 and B 5-3). A limit of blank (LOB), limit of detection (LOD) and limit of quantification (LOQ) must be determined.

3 Quality assurance procedure

1 Obligations of the reference institutions

1. The reference institutions shall ensure that a sufficient number of external quality assurance programmes are offered for all of the measurands/examinations listed in the tables so that every medical laboratory can participate in at least one external quality assurance programme at the frequencies listed in the respective tables.

   They may only deviate from this if they can prove that there is an insufficient amount of suitable EQA samples/materials.

2. The reference institutions shall announce one year in advance the external quality assurance programmes for the examinations pursuant to (1). This announcement shall include:

   1. The deadline for registering to participate in the external quality assurance programmes

   2. The respective date of sample/material shipment or provision, and the deadline for sending back the results

   3. The measurands/examinations included in the external quality assurance programme with details on the measurement/examination procedure, where applicable.

   4. The Type of sample material, the sample volumes of the liquid or reconstituted EQA samples, or type of material.

3. The reference institutions shall select the EQA samples/materials and check their suitability.

   The suitability of the selected EQA samples for those measurands/examinations whose evaluation is carried out on the basis of reference method values needs to be determined prior to their use in the external quality assurance programmes under routine conditions and using a routine measurement procedure.

4. Specific requirements for Part B 1

   The reference institutions shall operate their own calibration laboratories to determine the reference method values for the samples used in external quality assurance programmes if this is required by the tables in Part B 1. In exceptional cases, suitable calibration laboratories can be commissioned. The calibration laboratories are deemed suitable if they are accredited in accordance with DIN EN ISO/IEC 17025 and DIN EN ISO 15195 and if they are listed with the Joint Committee for Traceability in Laboratory Medicine (JCTLM) for at least 20 entries from the tables in Part B 1. Only accreditation bodies that are included in the Multilateral Agreement on the Mutual Acceptance of Calibration Certificates of the European Co-operation for Accreditation (EA) may be used.

5. For every external quality assurance programme, the reference institutions shall commission each participant to examine at least two EQA samples/materials. As a rule, the EQA samples/materials shall be dispatched with different target values.

6. The reference institutions shall provide or send the EQA samples/materials to each participant of the EQA accompanied by information on how to handle the samples/materials, including clinical information, where applicable, and how to submit the measurement/examination results.

7. Reference institutions shall only analyse measurement/examination results that were submitted by the participant of the EQA before the set deadline.

8. Every participant of the EQA is to be issued a certificate showing the submission date of the external quality assurance programme and stating which measurand/examination results correspond to the target values. In addition, every participant of an external quality assurance programme is to be issued a participation certificate for all measurands/examinations. The certificate and participation certificate are to be sent to the participants no later than eight weeks after the deadline to submit results of the external quality assurance programme.

   Participants of the EQA are also to be informed of:

   1. target values of the EQA samples/materials

   2. for quantitative target values, or where applicable, the position, distribution and measurement results for all participants and, if applicable, for the measurement/examination procedure used by the participant

   3. number of participants, where appropriate, listed according to measurement/examination procedure. Certificates are valid for six months or double the time interval listed in the tables.

9. If the reference institution finds that participants frequently are not being granted a certificate for measurements/examinations that use reagents or devices from a particular manufacturer and if the cause for this cannot be traced to the medical laboratories taking part in the external quality assurance programme or the reference institution, the appropriate federal authorities are to be notified if it can be defined as an “incident” according to Section 2 of Germany’s Medical Devices Safety Plan Ordinance.

10. Further details on conducting external quality assurance programmes and analysing the results of external quality assurance programmes are set forth in implementation regulations. These are published by the reference institutions.

2 Determining target values

1. After consulting with its competent committees and after formal consultation with the relevant parties concerned, the German Medical Association shall establish and announce which target value to use for the measurement/examinations and how target values are determined. Reference measurement procedures are to be used, where possible, when determining the target values in EQA samples.

2. The reference institutions shall establish the test plans for determining the target values of the EQA samples/materials, commission the reference laboratories and/or target value laboratories, analyse the measurement results and merge these into a target value.

3. The reference institutions must retain the documentation on determining the target values for a period of at least five years beginning from when they were used in the external quality assurance programmes.

Specific requirements for Part B 1

3 Assessing the results of external quality assurance programmes

1. Assessment is performed based on target values. The assessment criteria shall be communicated by the reference institutions to the participants if these criteria are not listed in the tables.

2. If the entire population or method-related sub-populations of the participants’ results show a considerable deviation to the target value, i.e., a deviation which influences the pass rate, the reference institutions must search for the cause and, if possible, rectify this in co-operation with the manufacturer of the EQA sample, the manufacturers of the respective test systems, or experts. They are to check whether, in such a case, increasing the pass limits or changing the target values would allow for a proper assessment.

They shall decide whether the results are to be analysed according to the target value or according to the modified pass limits, or whether the external quality assurance programme is to be repeated for this measurand/examination. The process is to be substantiated and documented. The participants of the external quality assurance programme and the Expert Group at the German Medical Association are to be informed in accordance with Parts B 1 to B 5. The reference institutions shall report annually to the German Medical Association on their activities in the previous calendar year.