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Technical Guidance Series (TGS)
for WHO Prequalification – Diagnostic Assessment
Quality control for in vitro diagnostic medical
devices for WHO prequalification
TGS–8
Draft for comment 9 April 2019
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: TGS-8
Quality control for in vitro diagnostic medical devices for WHO prequlafication
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WHO/EMP/RHT/PQT/2019.05
© World Health Organization 2019. All rights reserved.
This is a draft intended for review by Member States and all interested parties for the purpose of consultation on the draft text. The content of this document is not final, and the text may be subject to revisions before publication. The document may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means without the permission of the World Health Organization.
WHO Prequalification – Diagnostic Assessment: Technical Guidance Series
The WHO Prequalification Programme is coordinated through the Department of Essential
Medicines and Health Products. The aim of WHO prequalification of in vitro diagnostic
medical devices (IVDs) is to promote and facilitate access to safe, appropriate and affordable
IVDs of good quality in an equitable manner. Focus is placed on IVDs for priority diseases and
their suitability for use in resource-limited settings. The WHO Prequalification Programme
undertakes a comprehensive assessment of individual IVDs through a standardized
procedure that is aligned with international best regulatory practice. It also undertakes post-
qualification activities for IVDs, to ensure their ongoing compliance with prequalification
requirements.
Products that are prequalified by WHO are eligible for procurement by United Nations
agencies. The products are then commonly purchased for use in low- and middle-income
countries.
WHO
Prequalification
– Diagnostic
assessment
Procurement of
prequalified IVDs
IVDs prequalified by WHO are expected to be accurate, reliable and able to perform as
intended for the lifetime of the IVD under conditions likely to be experienced by a typical
user in resource-limited settings. The countries where WHO-prequalified IVDs are procured
often have minimal regulatory requirements, and the use of IVDs in these countries presents
specific challenges. For instance, IVDs are often used by health-care workers who do not have
extensive training in laboratory techniques, in harsh environmental conditions, in the
absence of extensive pre-test and post-test quality assurance capacity, and for patients with
a disease profile that differs from the profiles encountered in high-income countries.
Therefore, the requirements of the WHO Prequalification Programme may differ from the
requirements of high-income countries, or from those of the regulatory authority in the
country of manufacture.
The Technical Guidance Series (TGS) was developed following a consultation held on 10–13 March
2015 in Geneva, Switzerland. The consultation was attended by experts from national regulatory
authorities, national reference laboratories and WHO prequalification dossier reviewers and
inspectors. The guidance series is a result of the efforts of this and other international
working groups.
This guidance is intended for manufacturers interested in WHO prequalification of their IVD.
It applies in principle to all IVDs that are eligible for WHO prequalification for use in WHO
Member States. This guidance should be read in conjunction with relevant international and
national standards and guidance.
The TGS documents are freely available on the WHO website.1
Prequalification
requirements
About the Technical
Guidance Series
Audience and
scope
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: TGS-8
Quality control for in vitro diagnostic medical devices for WHO prequlafication
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Contents
List of contributors .......................................................................... 5
1 Abbreviations and definitions ................................................... 6
1.1 Abbreviations ........................................................................... 6
1.2 Definitions ................................................................................ 6
2 Introduction…………………………………………………………………….….11
2.1 Key concepts………………………………………………………………………11
2.2 Rationale for quality control .................................................. 11
2.2.1 Quality control…………………………………….……………………………11
2.2.2 Quality Assurance…………………………………………………………….12
2.2.3 Quality Management System……………………………………………12
2.3 Purpose of this document...................................................... 13
2.4 Limitations of this guidance ................................................... 13
3 Preamble ................................................................................. 15
4 Quality management system requirement ............................. 17
5 Quality control process design ................................................ 19
5.1 Risk management and assessment ........................................ 19
5.2 QC – Monitoring and Measurement of Product .................... 20
5.3 Design change and risk analysis reviews ............................... 21
6 Standards and reference materials for QC activities utilising performance panels....................................................................... 22
6.1 Reference material characterization ..................................... 22
6.2 Reference methods ................................................................ 24
6.3 Rference material preparation and storage………………………..24
7 Quality Control Plan………………………………………………………………26
7.1 QC activities associated with monitoring performance………28
8 Sampling Process……………………………………………………………….….29
8.1 Sampling procedures……………………………………………………….…29
8.2 Risk analysis / performance evaluation ................................. 30
8.3 QC plan design considerations…………………………………………...30
8.4 Traceability………………………………………………………………………..31
8.5 Analytical sample preservation…………………………………………..32
9 QC methods………………………………………………………………………….33
9.1 QC specifications .................................................................... 33
9.2 Validation of QC methods ...................................................... 34
9.3 Interpretation of the results .................................................. 34
10 Conclusion…………………………………………………………………………..35
11 REFERENCES............................................................................. 37
12 Bibliography ............................................................................. 38
Acknowledgements
The document Quality Control of In Vitro Diagnostic (IVD) Devices for WHO Prequalification was developed with support from the Bill & Melinda Gates Foundation Umbrella Grant and the UNITAID grant for “Increased access to appropriate, quality-assured diagnostics, medical devices and medicines for prevention, initiation and treatment of HIV/AIDS, TB and malaria”. The first draft was prepared in collaboration with Dr Fatima Gruszka, Paris, France, and with input and expertise from Mr Don Boyer, Ottawa, Canada. This document was produced under the coordination and supervision of Ms Kim Richards and Dr Joey Gouws of the WHO Department Access to Medicines, Vaccines and Pharmaceuticals cluster (MVP), Geneva, Switzerland.
List of contributors
The draft technical specifications document was posted on the WHO website for public consultation on 29 March 2019. Various stakeholders – including manufacturers submitting to WHO prequalification of IVDs, IVD manufacturing industry associations, various national and international regulatory bodies, and IVD standards organizations – were informed of the consultation in order to solicit feedback. A 3-month response period was provided.
Comments were received from the following:
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1 Abbreviations and definitions
1.1 Abbreviations
HIV human immunodeficiency virus
IFU instructions for use
ISO International Organization for Standardization
IVD in vitro diagnostic medical device
QA quality assurance
QC quality control
QMS quality management system
NRA National Regulatory Authority
R&D research and development
UN United Nations
WHO World Health Organization
1.2 Definitions
The definitions below related to risk management of in vitro diagnostic medical
devices (IVDs), transcribed from EN ISO 14971:2012 Medical devices – application of
risk management to medical devices (4), are generally used in this guidance. Where
a source other than ISO 14971 is used, the source is indicated.
The following definitions are used throughout this guide. 1
Accepted reference value: A value that serves as an agreed-upon reference for comparison. 2
Accuracy: Closeness of agreement between a test result and the true, or the accepted 3 reference value. 4
Analytical Sensitivity: Ratio between the variation of the information value of the analysis method 5 and the variation of the analyte quantity. The variation of the analyte quantity is 6 generally obtained by preparing various standard solutions, or by adding the 7 analyte to a matrix. 8
Analytical Specificity: Property of an analysis method to respond exclusively to the determination of 9 the quantity of the analyte considered, with the guarantee that the measured 10 signal comes only from the analyte. Response in reagent blank and blank control 11 samples. 12
Batch /Lot: Definite amount of material produced during a single manufacturing cycle, and 13 intended to have uniform character and quality. The uniform conditions of 14 manufacture or production of the batch or lot must be such as to ensure a 15 homogeneous product. 16
Bias: Difference between the expected test results and an accepted reference value. 17
Blank: Test carried out on a matrix or a reagent which does not contain the analyte 18 (matrix blank or reagent blank). 19
Calibrator: reference material used for calibration of equipment or a measurement 20 procedure. 21
Calibration: Series of operations establishing under specified conditions the relation between 22 the values of the quantity indicated by a measuring instrument or system, or the 23 values represented by a materialized measurement or a reference material, and 24 the corresponding values of the quantity measured by standards or reference 25 materials. 26
Certified reference material (CRM): Reference material, accompanied by a certificate, one or more 27 whose property values are certified by a procedure which establishes its 28 traceability to an accurate realization of the unit in which the property values are 29 expressed, and for which each certified value is accompanied by an uncertainty at 30 a stated level of confidence. 31
Commutability: property of a reference material (RM), demonstrated by the equivalence of the 32 mathematical relationships among the results of different measurement 33 procedures for an RM and for representative samples of the type intended to be 34 measured. 35
Evidence: Information that can be proved true based on facts obtained through observation, 36 measurement, test or other means. 37
Source: Modified from (1), definition 3.8.1 38
Homogeneity: uniformity of a specified property value throughout a defined portion of a 39 reference material (RM).Tests for homogeneity are described in ISO Guide 35. 40
Intended use: Use for which a product, process or service is intended according to the 41 specifications, instructions and information provided by the manufacturer. 42
Source: (4), definition 2.5 43
Note 1: The intended use is the clinical use for which the procedure was designed. 44
Note 2: The concept includes definition of the measurand, the target condition 45 and the clinical use of the measurement procedure, which may include screening, 46 diagnosis, prognosis or monitoring of patients.2 47
Note 3: The concept includes the physical, economic and resource limitations in 48 the environments of intended use. 49
IVD: Medical device intended by the manufacturer for the examination of specimens 50 derived from the human body, to provide information for diagnostic, monitoring 51 or compatibility purposes. 52
Note 1: IVDs include reagents, calibrators, control materials, specimen 53 receptacles, software and related instruments or apparatus, or other articles. 54 They are used, for example, for the following test purposes: diagnosis, aid to 55 diagnosis, screening, monitoring, predisposition, prognosis, prediction and 56
2 Notes 1 and 2 are from the website of the Clinical and Laboratory Standards Institute (CLSI); see http://htd.clsi.org
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determination of physiological status. 57 Note 2: In some jurisdictions, certain IVDs may be covered by other regulations. 58
Source: (4), definition 2.6 59
Life cycle: All phases in the life of a medical device, from its initial conception to final 60 decommissioning and disposal. 61
Source: (4), definition 2.7 62
Linearity: The ability of a method of analysis, within a certain range, to provide an 63 instrumental response or results proportional to the quality of analyte to be 64 determined in the laboratory sample. This proportionality is expressed by an a 65 priori defined mathematical expression. 66
Lower Limit of Quantification (LLOQ): the lowest standard curve point that can still be used for 67 quantification. It is the value above which quantitative results may be obtained 68 with a specified degree of confidence, or the lowest concentration of an analyte 69 that can be accurately measured. 70
Manufacturer: Natural or legal person with responsibility for the design, manufacture, packaging 71 or labelling of a medical device, assembling a system, or adapting a medical device before 72 it is placed on the market or put into service, regardless of whether these operations are 73 carried out by that person or on that person’s behalf by a third party. 74
Note 1: The provisions of natural or regulations can apply to the definition of 75 manufacturer. 76
Note 2: For the definition of labelling, see (6), definition 3.8. 77
Source: (4), definition 2.8 78
Medical device: Any instrument, apparatus, implement, machine, appliance, implant, in vitro 79 reagent or calibrator, software, material or other similar or related article that is 80 intended by the manufacturer to be used, alone or in combination, for human 81 beings for one or more of the following specific purposes: 82
- diagnosis, prevention, monitoring, treatment or alleviation of disease; 83
- diagnosis, monitoring, treatment, alleviation of or compensation for an 84 injury; 85
- investigation, replacement, modification, or support of the anatomy or 86 of a physiological process; 87
- supporting or sustaining life; 88
- control of conception; 89
- disinfection of medical devices; and 90
- providing information for medical purposes by means of in vitro 91 examination of specimens derived from the human body; 92
and that does not achieve its primary intended action in or on the human body by 93 pharmacological, immunological or metabolic means, but may be assisted in its 94 function by such means. 95
Note 1: This definition has been developed by the Global Harmonization Task Force 96 (GHTF). 97
Note 2: Products that could be considered to be medical devices in some jurisdictions but 98 for which there is not yet a harmonized approach are: 99
⎯ aids for people with a physical disability; 100
⎯ devices for the treatment or diagnosis of diseases and injuries in animals; 101
⎯ accessories for medical devices (see Note 3); 102
⎯ disinfection substances; and 103
⎯ devices incorporating animal and human tissues that can meet the requirements 104 of the above definition but are subject to different controls. 105
Note 3: Accessories intended specifically by manufacturers to be used together with a 106 “parent” medical device to enable that medical device to achieve its intended purpose 107 should be subject to this international standard. 108
Source: (4), definition 2.9 109
Precision: Closeness of agreement between independent test results obtained under 110 prescribed conditions. Precision depends on the distribution of random errors and 111 does not have any relationship with the true or specified value. The 112 measurement of precision is expressed on the basis of the standard deviation of 113 the test results. The expression "independent test results" refers to results 114 obtained such that they are not influenced by a previous result on the same or a 115 similar test. 116
Process: Set of interrelated or interacting activities that transforms inputs into outputs. 117
Note 1: Inputs to a process are generally outputs of other processes. 118
Note 2: Processes in an organization are generally planned and carried out under 119 controlled conditions to add value. 120
Source: (4), definition 2.13 121
Quantification limit: Lowest amount of an analyte to be examined in a test material that can be 122 quantitatively determined under the experimental conditions described in the 123 method with a defined variability (given coefficient of variation). 124
Reference material: Material or substance one or more of whose property values are sufficiently 125 homogeneous and well established to be used for the calibration of an apparatus, 126 the assessment of a measurement method, or for assigning values to materials. 127
Reference method: measurement method, that has been shown to have the appropriate trueness 128 and precision for its intended use and has been officially defined as reference 129 method by a competent body. 130
Repeatability: Conditions where independent test results are obtained with the same method on 131 identical test items in the same laboratory by the same operator using the same 132 equipment within short intervals of time. 133
Reproducibility: Conditions where independent test results are obtained with the same method on 134 identical samples by the same or different operator(s) using different IVD on 135 different days. 136
Risk: Effect of uncertainty on objectives. 137
Note 1: An effect is a deviation from the expected, either positive or negative or both. 138
Note 2: Objectives can have different aspects (e.g. financial, health and safety, and 139 environmental goals) and can apply at different levels (e.g. strategic, organization-wide, 140 project, product and process). 141
Note 3: Risk is often characterized by reference to potential events and consequences, or 142 a combination of these. 143
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Note 4: Risk is often expressed in terms of a combination of the consequences of an event 144 (including changes in circumstances) and the associated likelihood of occurrence. 145
Note 5: Uncertainty is the state, even partial, of deficiency of information related to 146 understanding or knowledge of an event, and its consequence or likelihood. 147
Source: (12), definition 1.1 and (1), definition 3.7.9 148
Risk management: The systematic application of management policies, procedures and practices to 149 the tasks of analysing, evaluating, controlling and monitoring risk. 150
Source: [4] 151
Risk management plan: For the particular medical device being considered, the manufacturer shall 152 establish and document a risk management plan in accordance with the risk 153 management process. 154
Source: [4], para 3.4 155
Stability: characteristic of a reference material, when stored under specified conditions, to 156 maintain a specified property value within specified limits for a specified period of 157 time. 158
Target value: property value of an RM specified on the basis of its intended use. The target 159 value of an RM property is usually specified in the design phase of RM production. 160
Top management: Person or group of people who direct(s) and control(s) a manufacturer at the 161 highest level. 162
Source: (4), definition 2.26 163
Trueness: the measure of trueness is normally expressed as “bias”. The closeness of 164 agreement between the average value obtained from a series of test results (i.e. 165 the mean recovery) an accepted reference or true value. 166
Uncertainty: The list of uncertainty sources and their associated standard uncertainties, 167 established in order to assess the compound standard uncertainty associated with 168 a measurement. 169
Verification: Confirmation, through the provision of objective evidence, that specified 170 requirements have been fulfilled. 171
Note 1: The term “verified” is used to designate the corresponding status. 172
Note 2: Confirmation can comprise activities such as: 173
- performing alternative calculations; 174
- comparing a new design specification with a similar proven design specification; 175
- undertaking tests and demonstrations; and 176
- reviewing documents before issues occur. 177
Source: (4), definition 2.28 178
179
180
181
2 Introduction 182
2.1 Key concepts 183
Quality control is an activity or a set of activities intended to ensure that a manufactured 184
product adheres to a defined set of quality criteria, including meeting customer and 185
regulatory requirements. The activity(ies) focus on identifying whether or not quality 186
requirements for the product are being met, and specifically to identify defects in the 187
products that are produced. It is part of quality management which is focused on fulfilling 188
the quality requirements of the product (ISO 9000:2015) (1). 189
2.2 Rationale for quality control 190
2.2.1 Quality control 191
The testing of product to determine whether or not specifications have been met is referred 192
to as quality control (QC). Since the quality of each and every IVD cannot be tested after it 193
has been manufactured, effective QC activities can be implemented at each step of the 194
manufacturing process, from raw material inputs, throughout the manufacturing process 195
and final products to provide confidence in the quality, safety and performance of the 196
finished product. Testing at the various stages of manufacturing helps identify where a 197
production problem is occurring and the corrective actions that need to be undertaken in 198
the manufacturing process to meet product specifications and product quality objectives. 199
Various QC techniques and activities are available to fulfill requirements for quality. Options 200
include observation, inspection or testing of products to uncover defects or to determine if 201
products adhere to established quality requirements. Standards against which products will 202
be assessed need to be established. Sampling plans, including the number of production 203
units to be assessed, collecting data and reporting results to management, especially where 204
corrective action is required, are all elements of QC focusing on fulfilling quality 205
requirements. For IVDs, some QC activities can be addressed through performance 206
evaluation which is the assessment and analysis of data to establish or verify the ability of an 207
in vitro diagnostic device to achieve its intend use (ISO 13485:2016)(2). 208
209
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2.2.2 Quality Assurance 210
Quality assurance (QA) is all the planned and systematic activities implemented within the 211
quality system that can be demonstrated to provide confidence that a product or service will 212
fulfill requirements for quality. QA aims to improve and stabilize production and processes 213
to avoid or minimize issues that lead to product defects. QA is part of quality management 214
focused on providing confidence that quality requirements will be fulfilled (ISO 9000:2015) 215
(1). 216
217
2.2.3 Quality Management System 218
A Quality Management System (QMS) includes establishing quality policies, responsibilities 219
and processes to achieve quality objectives through quality planning, quality assurance, 220
quality control and quality improvement (ISO 9000:2015) (1). Quality objectives in the IVD 221
sector include both customer and regulatory requirements. 222
Many National Regulatory Authorities (NRAs) require that manufacturers design, develop, 223
implement and monitor a QMS, combined with the other conformity assessment elements, 224
to provide a level of assurance that IVDs will be safe and perform as intended by the 225
manufacturer. Compliance with the international QMS standard ISO 13485 has become the 226
norme upon which NRAs and manufacturers rely to provide this assurance. Proper use of 227
this standard provides evidence that IVDs will consistently meet both customer and 228
regulatory requirements. 229
The scope and complexity of the quality management system that a manufacturer 230
needs to establish is influenced by varying needs, objectives, the products provided, 231
processes employed, the size and structure of the organisation, and the specific regulatory 232
requirements that need to be met (GHTF/SG1/N071:2012)(3). 233
234
235
2.3 Purpose of this document 236
The purpose of this document is to provide IVD manufacturers with guidance on ISO 13485 237
requirements related to the implementation of QC activities, including processes and 238
procedures, to ensure that the results obtained through the use of an IVD are consistent, 239
comparable, accurate and within specified limits of precision. 240
2.4 Limitations of this guidance 241
This guidance document should not be taken as a prescriptive checklist of what quality 242
control activities should be performed on product. It is intended to guide manufacturers to 243
consider and implement quality control measures that are applicable to their particular 244
product(s), taking into consideration QC standards, procedures, sampling plans, testing, 245
inspection and any other applicable activity in order to generate evidence that products 246
meet quality requirements. 247
It is possible that, depending on the type or classification of the product and on the 248
particular regulatory jurisdiction that additional quality control activities may be required. 249
Manufacturers must be aware that regulatory and legal issues are specific for each 250
regulatory authority and are beyond the scope of this document. 251
Given the diversity of IVDs, this guidance document is not intended to cover specific aspects 252
of all manufactured IVDs and the various configurations of product, their design and 253
manufacturing processes. QC plans should be risk-based, established on individual products 254
Quality Management
System
Quality Assurance
Quality Control
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and it is the manufacturer’s responsibility to describe and establish the appropriate plan for 255
each product placed on the market. Incorporating risk management will require the 256
manufacturer to identify the hazards associated with the IVD, to estimate and evaluate the 257
associated risks, to control these risks, and to monitor the effectiveness of the controls (ISO 258
14971:2012) (4). 259
Certain generic standards provide the framework for quality management system. These 260
generic standards belong to the ISO 9000 series and stand alone standards such as ISO 261
13485 (2) that is based on ISO 9001. The guidance from GHTF (3) is also primarily concerned 262
with quality management systems. 263
264
3 Preamble 265
IVDs are intended for use in the collection, preparation and examination of samples taken 266
from the human body. These devices include reagents, instruments, software, sample 267
collection devices and receptacles, calibrators, control materials and related accessories. 268
These devices can be used alone or in combination as a system (ISO 14971:2007 – H1 – 269
General) (5). They are intended by the manufacturer for the examination of specimens 270
derived from the human body to provide information for diagnostic, monitoring or 271
compatibility purposes (ISO 14971:2007) (5). IVDs are used on biological specimens or on 272
constituents obtained from biological specimens. They provide for qualitative or quantitative 273
measurement methods for one biomarker or combinations of biomarkers. 274
In ISO 13485: 2016 (Clause 8.2.6) (2) it states that “The organization shall monitor and 275
measure the characteristics of the product to verify that product requirements have been 276
met. This shall be carried out at applicable stages of the product realization process in 277
accordance with the planned arrangements and documented procedures. 278
Evidence of conformity with the acceptance criteria shall be maintained. The identity of the 279
person authorizing release of product shall be recorded (see 4.2.5). As appropriate, records 280
shall identify the test equipment used to perform measurement activities. 281
Product release and service delivery shall not proceed until the planned and documented 282
arrangements have been satisfactorily completed.” 283
The organization shall apply suitable methods for the monitoring, and where applicable, the 284
measurement of the product. 285
QC is intended to provide assurance that the IVD will perform within specifications for safety 286
and performance. IVDs need to be suitable for user requirements and for their intended 287
clinical use. As an output of risk analysis process, QC offers a means of risk mitigation by 288
providing evidence of the performances of the devices, or the process under investigation 289
(ISO 14971:2007 - A.2.4.2 Intended use and identification of characteristics related to the 290
safety of the medical device) (5). 291
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QC enables the monitoring and measurement of the product or the process by identifying 292
nonconformities or bias that require corrective or preventive actions in the devices or in 293
modification to the QMS. Validated statistical QC procedures are a key tool to maintain risk 294
at an acceptable level. 295
296
4 Quality management system requirement 297
ISO 13485:2016 sets out requirements for a QMS that can be used by an organization 298
involved in one or more stages of the life-cycle of a medical device, including design and 299
development, production, storage and distribution, installation, servicing and final 300
decommissioning and disposal of medical devices, and design and development, or provision 301
of associated activities (e.g. technical support). (2) The scope of a manufacturer’s QMS can 302
also extend to suppliers or to activities sub-contracted to an external organization. 303
A QMS is intended to assist organizations in improving quality and enhancing customer 304
satisfaction. Customers require products with characteristics that satisify their needs and 305
expectations. An effective and well implemented QMS requires organizations to analyse 306
customer requirements, define the processes that contribute to the achievement of a 307
product which is of acceptable quality to the customer and to keep the processes for 308
achieving quality under control. A QMS provides confidence to the organization and its 309
customers that it is able to provide products that consistently fulfil requirements. 310
An effective QMS requires top management commitment to the development and 311
implementation of the QMS and maintenance of its effectiveness. Evidence of this 312
commitment is in the form of communication to the organization of the importance of 313
meeting customer and applicable regulatory requirements; a documented quality policy and 314
objectives; undertaking management reviews; and the availability of resources (ISO 315
13485:2016 5.1) (2). 316
QC activities reside within an effective QMS and should be carried out by qualified and 317
independent staff, under controlled and established delegations (ISO 13485:2016 5.5.1) (2). 318
Quality control authorities, processes, activities and approvals should be independent from 319
manufacturing activities. The outputs of design and development shall be in a form suitable 320
for verification against the design and development inputs and shall be approved prior to 321
release of product. (ISO 13485:2016 7.3.4) (2). 322
QC also applies to all purchased product used in the manufacture of an IVD (e.g.: 323
components) to determine if specified purchasing requirements have been met. An 324
organization will determine the extent of its verification activities based on evaulations 325
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undertaken and provided by the supplier. Consideration shall also be given to the risks 326
associated to product that is being purchased. If incoming product deviates from 327
requirments a determination is required as to whether the changes will affect the product 328
realization process or the IVD (ISO 13485:2016 7.4.3) (2). 329
330
5 Quality control process design 331
5.1 Risk management and assessment 332
IVDs are designed to have performance characteristics that determine the accuracy of 333
diagnostic results. Failure to meet the performance characteristics required for the intended 334
use of an IVD could result in a hazardous situation that should be evaluated as a risk to 335
patients. These hazards or hazardous situations can occur prior, during or after use. The 336
importance and likelihood of these failures can vary depending upon the IVD, the sample, 337
the user, the environment, and the skill and knowledge level among end users. 338
For this reason, it is imperative for a manufacturer to establish, document and maintain an 339
ongoing process for identifying hazards and managing risks associated with an IVD, 340
estimating and evaluting the associated risks, controlling the risks and monitoring the 341
effectiveness of the controls. (6) An effective process shall include risk analysis; risk 342
evalution; risk control; and collecting production and post-production information. Risk 343
management activities need to be planned. The plan shall include what risk activities will be 344
undertaken and when during the IVDs life cycle; who will be responsible for administering 345
the plan and their authorities; the review of risk management activities; establishing criteria 346
for risk acceptability; verification activities; and activities to collect and review production 347
and post prodution information (ISO 14971:2007) (4). 348
Quality control is a means to verify that risks occuring during the design or manufacturing 349
processes are identified, eliminated or reduced to an acceptable level. (EP18-A2 Risk 350
Management Techniques to Identify and Control Laboratory Error Sources; Approved 351
Guideline – Second Edition) (7). 352
Further information on how to apply a risk management plan for IVDs can be found in Annex 353
H – Guidance on risk management for in vitro diagnostic medical devices in ISO 14971:2007. 354
(5) Annex H sets out considerations for undertaking risk analysis, risk evalution, production 355
and post-monitoring in the risk management of IVDs. 356
357
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5.2 QC – Monitoring and Measurement of Product 358
ISO 13485:2016 sets out requirements for an organization to monitor and measure the 359
characteristics of product or processes to verify that requirements have been met. It is the 360
responsibility of the manufacturer to determine at which stages of the product realization 361
process that planned QC activities, in accordance with documented arrangements and 362
procedures, need to occur. 363
Documenting QC responsibilities, such as delegation of authorities, decision making charts 364
and product status charts shall be developed during the product design and development 365
phase in order to clarify the process. Those responsible for authorizing release of product at 366
various stages of product realization need to be identified and documented (ISO 13485:2016 367
– 4.2.5) (2). As appropriate, records shall identify the test equipment used to perform 368
measurement activities. No product can be released or service delivered until the planned 369
and documented QC arrangements have been satisfactorily completed. 370
The means of verifying that the product realization processes achieve specified level of 371
quality requirements (homogeneity, reproducibility, repeatability, etc.) must be developed. 372
The analytical performance characteristics of products, such as analytical sensitivity, 373
analytical specificity, accuracy, repeatability, reproducibility, range and limitations need to 374
be verified through QC steps with appropriate sampling processes and procedures. 375
The design and documentation of the QC processes should describe the nature of the 376
controls, the description and specification of the reference materials, the origin of the 377
materials, the metrological traceability, calibrators and trueness-controls. 378
All materials required for the manufacturing of an IVD, including reference materials and 379
reference measurement procedures, as well as equipment to be used, must be defined. The 380
accepted reference values assigned for reference materials should be determined and 381
maintained. Acceptability limits are to be determined during the design and development 382
phase of the product. The manufacturer shall have documented procedures and records 383
that define appropriate statistical techniques appropriate for the function that are used to 384
monitor or detect trends in the process. 385
The preparation, calibration and maintenance of a metrologically-traceable calibrator should 386
be designed and documented for each QC procedure. 387
Analysis methods shall be described in documented procedures specifying all the means and 388
actions required to carry out the analysis of the analyte, notably the scope, principle, 389
definitions, reagents, apparatus, procedures, expression of results, precision and test report. 390
The calculations and interpretation of results shall be detailed for each QC procedure. 391
Where relevant, clinical QC performance, such as diagnostic sensitivity and diagnostic 392
specificity, quantification limits, linearity, etc. on specified and characterized clinical samples 393
and acceptance intervals, must be documented in the design outputs. 394
Calculation of means for the determination and control of the values, such as cut-off values, 395
calibrator values or standard materials values shall be considered. 396
Specifications should detail acceptance and rejection criteria, that should be extensively 397
assessed during QC validation processes. 398
5.3 Design change and risk analysis reviews 399
The QC process should be reviewed periodicaly and also during design change of the 400
products or the processes. The design of the QC proccess shall also be updated in 401
accordance with periodical risk analysis reviews. If the outputs of the risk analysis is 402
determine that a change to the detection activity (i.e. QC processes) is required then further 403
analysis of the process is required. (6) 404
405
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6 Standards and reference materials for QC activities utilising 406
performance panels 407
408
QC activities associated with monitoring the performance of an IVD are used to validate that 409
product quality requirements (as defined by both the customer and the NRA, as applicable) 410
have been met. 411
6.1 Reference material characterization 412
Reference materials shall be characterized and tested to ensure that they are fit for use in a 413
measurement process. To become a characterized reference material, materials need to be 414
investigated to determine if they are sufficiently homogeneous and stable with respect to 415
one or more specified properties, and they are fit for their intended use in the development 416
of measurement and test methods that target those properties. 417
The trueness of reference materials and QC methods used in routine procedures must be 418
established through higher order reference material or by using a reference method. 419
Metrological treacability must be assessed and documented in order to establish the 420
pertinent characteristics of the analyte into the reference materials. 421
The trueness of measurement of a value assigned to a defined quantity of a calibrator or 422
trueness control material, depends on the metrological traceability of the value established 423
through a chain of comparison of measurement procedures and measurement standards 424
(calibrators), usually having successively decreasing uncertainties of measurement. The 425
uncertainty of the value assigned to a given calibrator or trueness control material depends 426
on the chain of stated metrological traceability and the combined uncertainties. (8) 427
A metrological traceability chain or calibrators used in routine testing should be defined with 428
the relevant International System of Units if there is an existing international primary 429
standard or a high order level standard. 430
Nevertheless, even when there is existing reference material, different procedures may lead 431
to different measured results, particularly when using proteins with several epitopes and 432
immulogical methods or for catalytic concentration measures of some conjugated enzymes 433
due to biomolecules interactions. The metrological traceability of the assigned value for a 434
product calibrator would require other measured procedures and new calibrations in order 435
to assign specific internal values. 436
Some reference materials with no assigned value can be used for precision, repeatability or 437
reproducibility control procedures (precision control materials). 438
For the internal calibrated reference materials the preparation is sometimes carried out 439
using concentrated analytes spiked in a biological matrix. The origin of the analyte used to 440
prepare spiked samples and the nature of the matrix will affect the measured value and 441
stability of the resulting calibrated reference materials. The metrological traceability of the 442
internal calibrated reference materials and their relations to a medical discrimination limit 443
shall be established. 444
For spiked matrix-based calibration standards, samples should be prepared based on the 445
theoretical concentration of analytes, for specific criteria set up in advance, to achieved 446
accuracy and precision over the range of the standards. 447
It is often usefull to have a reference defined as non specific or interfering material with 448
determined values which could be used to control the calibration and accuracy of the test. 449
Dilution above and below the lower limit of detection of relevent non-specific analytes or 450
samples are generally essential to verify the specificity of the test. 451
The values assignment and the intervals of acceptable values, for each calibrated reference 452
material, should be established through validated statistical methods in accordance with a 453
specified measurement procedure. 454
The number of reference panel members validated for routine controls should be 455
maintained. Procedures for the preparation, validation and release of new panel members 456
should be documented. 457
The procedure to determine the value of each reference material should specify the 458
required testing material for the calculation of the coefficient variation, standard deviations 459
and confidence intervals that are statistically based to determine the values or range and 460
acceptation criteria. 461
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The assessment of the stability of the samples should be based on a real time basis and if no 462
data is available, accelarated studies can provide an intial base that will be complemented 463
with real time data. 464
6.2 Reference methods 465
If calibrators with treacable values to an international standard are not available, then 466
international conventional reference measurement procedures or reference methods could 467
be refered to as known gold standard tests. Calibration materials with no international 468
values assigned (eg. some antibodies, tumour markers or commercialy available 469
seroconversion characterized panels) can also be used. 470
However, for many biomarkers, there is neither high level standards nor reference 471
measurement procedures. The manufacturer will have to design documented measurement 472
procedures to support internal value assignment to its calibrators. The trueness of the 473
calibrators should then be assigned through a hierarchy of comparisons with internal high 474
level, and lower level, calibrators in agreement with available objective data (clinical data, 475
comparators, bibliography, prevalence data, etc.). 476
6.3 Reference material preparation and storage 477
Documented procedures shall describe all necessary activities and tasks leading to the 478
release and maintenance of a reference material (certified or non-certified, primary or 479
secondary reference material, stock or working solutions of reference material). 480
Reference standards shall be well characterized, during and after their preparation, and their 481
specifications and qualification shall be documented. 482
Each standard shall be uniquely identified and the dates of reception, preparation, 483
dispensing and labeling recorded. Traceability of each aliquot shall be established. Their 484
storage conditions shall be specified (temperature, light, humidiy, etc.), expiry dates based 485
on the suppliers information or allocated dates, according to internal studies shall be 486
specified. 487
Criterion to develop a sufficient amount of reference material (stock and working samples) 488
for each QC step, the need of positive and negative controls and their nature, the need for 489
blank controls and interference controls shall be documented. 490
The method to prepare, validate and qualify new reference material shall be established and 491
documented. Stock reference material and working reference material preparation and 492
handling procedures shall be developed and recorded. 493
Their preparation shall specifiy the size of the aliquots in order to be suitable for single use if 494
applicable, and freeze / thawing cycles. 495
The source and lot number, expiration date, certificates of internal or external analyses, 496
characteristics and specifications shall be documented for each reference material. 497
The recovery of an analyte can vary depending on the matrix. To compensate for such 498
effects, calibration standards and reference materials shall be prepared in the same 499
biological matrix as the samples defined in the intended use of the product with sufficient 500
range to ensure upper and lower detection levels are covered. Selectivity, accuracy and 501
precision of the reference materials have to be determined and documented. 502
The commutability of the prepared reference materials shall be assessed. The design of the 503
internal reference material shall be documented and its preparation recorded to ensure the 504
traceability of the matrix and spiked material characterization, origins, clinical data, labelling 505
and treatment. 506
Procedures to avoid discrepancies between old and new reference material, or stock 507
solution and routine samples shall be implemented. All reference substances prepared in the 508
laboratory or externally supplied shall be retested at regular intervals to ensure that 509
deterioration has not occurred. It is recommended that the WHO guidance document, WHO 510
Manual for the establishment of Secondary Standards (9) is consulted for detailed guidance 511
on establishment and maintenance of reference materials. 512
The interval for retesting depends on a number of factors including stability of the 513
substance, storage conditions employed, type of container and extent of use (how often the 514
container is opened and closed). 515
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Detailed information on the handling, storage and retesting of reference substances is given 516
in the WHO General guidelines for the establishment, maintenance and distribution of 517
chemical reference substances (9). 518
The results of these tests shall be recorded and signed by the authorized person. 519
In the event of noncompliant reference substance retesting results, a retrospective check of 520
tests performed using this reference substance since its previous examination shall be 521
carried out. Risk analysis shall be applied in evaluating outcomes, retrospective checks and 522
consideration of possible corrective actions. 523
In addition to reference materials, preparation of original patient specimens, compliant with 524
the test intended use, should be introduced in the control panel. Their characteristics shall 525
complement panels and permit control of the tests behaviour done under real conditions. 526
For further information on the development of performance panels, refer to WHO guidance 527
TGS 3– Principles of Performance Studies. (10) 528
7 Quality Control Plan 529
Manufacturers of IVDs are required to plan, develop and document the processes needed 530
for product realization. Processes for risk management must also be included as part of the 531
product realization process and shall be maintained. One of the elements that a 532
manufacturer needs to consider for incorporation into its product realization process are 533
requirements for verification, validation, monitoring, measurement, inspection and test, 534
handling, storage, distribution and traceability activities specific to the product together with 535
the crieteria for product acceptance (2). 536
As a result, QC processes and plans need to be developed and documented. These should 537
include: 538
- Quality control process flowchart 539
- Responsibilities and delegations 540
- Quality controls steps 541
- Quality control methods, equipment and reference materials 542
- Decision points which have an impact on product status 543
544
Product realization plans, and specifically QC plans, should specify the acceptance and 545
rejection criteria for each control. The procedures planned shall ensure objectivity of 546
inspections and of test results. 547
The QC plan must be developed in accordance with the intended use of the product (nature 548
and type of sample, population, range of measurement, limits) and shall be established and 549
defined for each type of control and assay. The standard reference material values used for 550
QC shall be established during the design phase using documented processes. 551
All data relating to QC checkpoints and sampling processes, inspection and test methods, 552
reference material, test panels and specifications, statistical methods and interpretation, 553
acceptance criteria and decisions shall be documented and detailed in the product 554
realization plans. All outsourced QC shall go through the same level of control. 555
The QC plan and checkpoints should take into consideration all the steps of the 556
manufacturing process. This includes raw materials, (including water quality, chemicals, 557
biologicals, components, consumables, labels, printed goods), sub-assembly controls, in 558
process controls, semi-finished goods controls, references materials controls, finished goods 559
controls, subcontracted QC and certificate of analysis controls including the Instructions for 560
Use (IFU). QC of retention samples of the products, or when applicable, returned goods and 561
control and qualification of reference materials is also required. 562
The analytical procedures and tests methods for each control point shall specify the required 563
equipment, materials, instructions, records and decision matrices of the QC. 564
QC inspection, testing and / or measurement must be performed using qualified and 565
calibrated equipment, or based on instruments linked to international standards or 566
referenced panels. Methods to qualify internal reference material and international 567
reference standards shall be determined during the design phase. 568
The sampling process developed for each step of the QC should provide evidence of 569
statistical analysis and supporting data. 570
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571
The specifications for reference material used for QC procedure shall be documented in the 572
QC plan in order to ensure the availability of reference material calibrated or compared to 573
international standards. 574
7.1 QC activities associated with monitoring performance 575
The methods used for QC shall be planned to identify the specification of conformity of the 576
assay’s or subcomponent performance. 577
For IVDs that produce a result expressed quantitatively, where there are two specified limits 578
for the results, QC activities to verify trueness, precision, limits of detection and cut off 579
verification shall be planned. 580
For semi-quantitative IVDs, where the results can have any value between two specified 581
limits, QC activities to verify the accuracy, trueness, precision, limits of detection and cut off 582
of the test should be considered. 583
For qualitative IVDs, where the true quantitative signal can only have a specified value 584
between the lower and upper confidence bounds, QC activites to verify the sensitivity, 585
specificity, accuracy, trueness, precision and cut off of the test should be considered. 586
587
Nature of the assay
/ testing
Sen
siti
vity
Spec
ific
ity
Acc
ura
cy
Tru
enes
s
Pre
cisi
on
Cu
t o
ff
valu
e
Lim
its
of
det
ect
ion
Stab
ility
Quantitative assay
QC ✓ ✓ ✓ ✓ ✓
Semi-quantitative
assay QC ✓ ✓ ✓ ✓ ✓ ✓
Qualitative assay
QC ✓ ✓ ✓ ✓ ✓ ✓
✓
588
Table 1 – Nature of the Controls 589
The QC plan must also integrate the need for planning QC procedure validation. Method 590
validation should be performed to provide evidence that the QC methods are fit for purpose 591
and achieve specified accuracy, precision, selectivity, sensitivity and reproducibility. Refer to 592
WHO guidance TGS 4 Guidance on test method validation for in vitro diagnostic medical 593
devices. (11) 594
QC method validation is a requirement to establish testing validity and shall be supported 595
and extended by planned method performance verification during routine analysis 596
(analytical QC and on-going method validation). 597
A decision matrix for results obtained and QC flowchart for approved, rejected or 598
reprocessed product should be considered in the product realization planning including 599
responsibilities for out-of-specification results, re-testing (criteria and limitations), rejection, 600
rework or release under concession. 601
8 Sampling Process 602
8.1 Sampling procedures 603
Procurement of samples for QC activities should be done and recorded in accordance with 604
approved written procedures and the sampling plan used should be appropriately justified. 605
Samples should be representative, in terms of characteristics and performance, of the batch 606
of materials or products from which they are taken. The analytical sample shall consist in 607
parts, units or subparts, or subunits of the batch from which it has been taken and should 608
include sampling from throughout the production batch or run (e.g. beginning, middle and 609
end). 610
The lot defines a quantity of material or product processed in one process or series of 611
processes, expected to be homogeneous. 612
613
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614
8.2 Risk analysis / performance evaluation 615
The sampling procedures, for each specific product, shall be established according to 616
statistical principles. The minimum analytical sample size of the product to obtain significant 617
results will be established according to determined criteria for acceptable risk and 618
confidence level. 619
The type and nature of all materials used in the manufacturing process should be 620
considered. All of the components, subcomponents and materials involved in the process 621
should go through an approval procedure with specified QC processes to ensure they meet 622
the specified requirements. 623
For the calculation of the acceptable confidence interval of the statistical method, the 624
manufacturer shall consider the risk analysis output and the risk resulting from the 625
probabilities of not detecting shifts or descripencies in the production quality and their 626
implication on the patient or user health. 627
628
8.3 QC plan design considerations 629
The sampling procedure should detail the operations, authorities and chronology of the 630
sampling process (points, location, operators etc.) for the collection of the specified size or 631
number of specimens from the ongoing production process to determine the characteristics 632
and the variability in those samples and compare their closeness to specified target values. 633
Validation of the sampling process methods should be established and documented to 634
demonstrate the homogeneity inside a batch and support the representativity of the 635
samples collected during the processes (formulation, lyophilization, oven drying, 636
sterilization, incubations, stripping , spaying or coating processes, etc.) or according to 637
specified criteria (per operator, per critical raw material, per run, per sequences, etc.) 638
All interpretation and equations needed for the calculation of the result should be specified 639
or under validated computerised calculations. All tables used for the calculation and 640
calibration curve used in analysing samples shall be traceable and recorded. 641
QC specifications and QC control records, at each level of the process shall reference 642
approval, rejection, retesting or reprocessing decision chart criteria according to the design 643
outputs and the validation of the process outputs. Acceptance criteria for derogation or 644
reprocessing shall be described. 645
8.4 Traceability 646
The specifications of the sampling protocol must provide all information to unambiguously 647
identify the analytical sample, subject matter of the QC procedure (activities, equipment or 648
goods), and ensure traceability of the data. 649
Traceability of all the characteristics of the product (name, reference or catalogue number, 650
batch or lot number, serial number, version reference, material, processing cycle or 651
flowchart of production, the list of components and formula, production site, rooms, 652
equipment, area, list of reference materials, etc., and the specification of the controls 653
(sampling process for each type of control, references and specifications, etc.)) shall be 654
detailed to allow the assessment and the verification of the product and the operations to 655
those detailed specifications. 656
In order to ensure an adequate sampling process, the status of the products during their 657
progress in the process of manufacturing shall be unambiguously identified to the user, the 658
operator or reviewer. 659
660
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The status of the product prior to QC release, such as quarantined (when awaiting for 661
reception, during investigation / sampling, labelling, returned goods under investigation, 662
etc.), product under reprocessing, rejected products, or approved products shall be clearly 663
recorded / displayed on the goods. 664
Samples must be identified clearly and indelibly, in a way to ensure traceability. Each 665
laboratory analytical sample of the products shall be allocated a unique code specific to the 666
quality control laboratory. 667
8.5 Analytical sample preservation 668
Before QC testing, samples must be stored separately from other products or other sources 669
of potential contamination and stored under specified storage conditions (temperature, 670
humidity etc.). When samples are transferred to the quality control laboratory for QC 671
assessment, they are to be maintained at specified conditions during transit and storage to 672
preserve their representative characteristics consistent with the remainder of the batch 673
from which they were sampled. 674
The sampling process for the collection of retention samples of products under QC must be 675
specified for stability (accelerated and real time stabilities) and regulatory purposes. The 676
sampling process of critical raw materials, intermediates or fully packed finished products, 677
with their packaging and labelling, shall be described. 678
Batch manufacturing records and QC records shall provide all information for traceability of 679
the procedures, specifications, resources required and resources involved, status and 680
identification of materials and equipment, records of operations, their conformity and check 681
of verification and the decision of approval or rejection. All specifications, operations and 682
results must be recorded and approved. 683
684
685
9 QC methods 686
9.1 QC specifications 687
QC specifications define the characteristics, descriptions, values, and storage intervals that 688
the product should meet to conform to requirements. This can include specifications for raw 689
materials, including water, semi-finished or finished goods, and reference materials that 690
impact the final product. The specifications for the QC steps and the QC methods should be 691
established according to the criticality of each product or criticality of the processes. All 692
through production, criteria must be established to monitor the extent to which these 693
products meet target specifications and control deviations. 694
All information required for the QC process should be included in the procedures and 695
decision matrices. This information could include required infrastructure, equipment, 696
instruments or other devices needed to perform the QC process, methodology, and required 697
control samples and their distribution. All QC procedures used shall specify the authority and 698
qualification of the operators needed for the test performance. 699
QC procedures shall be perfomed on maintained and qualified equipment which is usually 700
identified in the production (batch) records. (12). The calibration of the instruments needed 701
to perform tests shall be described and documented. Specific procedures should be 702
established for each type of measuring equipment, considering the type of equipment, the 703
extent of use and supplier’s recommendations (e.g. checking pH meters before use or 704
checking of balances) or according to international standards. 705
All appropriate calibration procedures should be described in the specifications, to ensure 706
reliable qualitative or quantitative results. 707
As far as practicable, separate QC equipment can be dedicated to avoid cross-contamination 708
between the product samples or the tests. Control material must be protected and 709
preserved from any alteration or cross contamination from the samples themselves or from 710
other standards or QC procedures. 711
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9.2 Validation of QC methods 712
Validation shall be performed to provide evidence that the QC methods are fit for their 713
purposes and achieve specified accuracy, precision, selectivity, sensitivity and reproducibility 714
needed to verify the product that is being subjected to the QC process. 715
The method to determine the upper and lower QC limits, variability, interval confidence and 716
the characteristics of the normal distribution of the result should be determined according 717
to statistical principles. The ranges of acceptable variability of the process should be 718
specified according to the characteristic of interest of the product under QC, the risk analysis 719
output, the validation of the methods, statistical analysis of collected data and trends. 720
Potential interfering substances involving other manufaturing processes and other 721
exogenous substances that could bias the QC results should be considered during the 722
validation steps. 723
When there is a potential matrix effect, representative matrices may be used for a few steps 724
of the QC but the verification of the performances of the product shall include, as a 725
minimum, representative specified samples of each matrix to verify the performance of the 726
product according to the intended use. 727
For the control of the sensitivity, trueness, precision and LLOQ, replicates can be required to 728
verify the recovery and precision of the controlled samples at the targeted LLOQ or limit of 729
the method and at least one other higher level. 730
The precision of an analytical method should be documented and the closeness of individual 731
measures and the number of replicates defined. 732
9.3 Interpretation of the results 733
The interpretation of results and the final conclusions should be established under QC 734
authority, reviewed, approved and signed off by the authorized QA representative. 735
Justification on the methods used, specifications selected for the verification of the product 736
or the process, or any deviation from the prescribed procedure (eg. discussion about 737
discrepancies, false positive or false negative rate, calculations, slope, etc.), should be 738
recorded and approved. 739
740
All rejected results (non-conforming) should be documented including the assessment of the 741
failure. In case of failure, specifications for the retest should explain the reasons for 742
reanalysing, inconsistent replicates, instrument failure and operator errors. 743
In the case of retesting, QC panel members should be tested in replicates. The retest or 744
reintegration of results and their justification should be clearly documented. All units must 745
be specified and expressed in international units where appropriate. 746
The decision, if the results or variability falls inside or outside specified limits, should be 747
recorded as compliant or noncompliant and a decision matrix should define the further 748
actions to be taken to stop or move forward in the manufacturing process. Further actions 749
may require periodic review of cumulative results to ensure any changes, trending or drift 750
over time are detected. Trending should be reported as an input into the risk assessment 751
process and closely reviewed to determine if the problem is indicative of a more significant 752
problem. Trending analysis and review process shall be included in the Management review 753
process (2). 754
10 Conclusion 755
Quality control is an important and required process to detect whether or not performance 756
requirements and quality objectives for an IVD have been met. Additionally, QC results can 757
identify potential product risks and hazards and inform risk control measures to eliminate, 758
reduce or mitigate identified risks and hazards to an acceptable level. A well designed QC 759
plan (eg., flowchart, detailing responsibilities and delegations of authorities, decisions 760
making chart and product status) is an integral part of the quality planning and product 761
realization planning activity phases. 762
The values assignment and the intervals of acceptable values for each calibrated reference 763
material should be established through validated statistical methods in accordance to a 764
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specified measured procedure. The number of reference panel members validated for 765
routine control should be maintained. 766
The minimum analytical sample size of the product to obtain meaningful results will be 767
established according to determined criteria for acceptable risk and confidence level. The 768
calculations and interpretation of results shall be detailed for each QC procedure. Records of 769
QC processes shall describe the values, acceptance and rejection criteria as well as decision 770
matrices. 771
Manufacturers have a responsibility to design and implement QC activities throughout a 772
product’s realization and post-production phases to identify defects and sources of failures 773
in the products they produce. A manufacturer’s QC activities, QA processes and QMS, 774
collectively, are intended to eliminate or minimize sources of defects and failures as much as 775
possible. Where these cannot be eliminated and residual risk remains, strategies for 776
managing them must be addressed taking into consideration the nature of the impact, the 777
IVDs capabilities, operator requirements and continuous monitoring. Manufacturers must 778
also decide, especially for unacceptable risks, how best to disclose residual risk information 779
to the user through labelling or other documents accompanying the product. 780
781
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10. ILAC G19 Guidelines for forensic science laboratories. International Laboratory Accreditation Corporation. ILAC. Silverwater, 2002, pp. 15.
11. IUPAC, 2002 Ŕ Harmonized guidelines for single-laboratory validation of analysis methods; Pure Appl. Chem., Vol. 74; n°5, pp. 835-855.
12. Lamberty, H. Schimmel, J. Pauwels The study of the stability of reference materials by isochronous measurements. Fresenius J. Anal. Chem. 1998, 360 pp. 359–361
13. LAWN, R., ROPER, R., HOLCOMBE, G. STUART, B. Low-cost QC Laboratory Reference Materials – Investigation of Cost-effective Production Procedures. Laboratory of the Government Chemist (LGC), Teddington, 2001, LGC/VAM/2001/009
14. LINSINGER, T.P.J., PAUWELS, J., VAN DER VEEN, A.M.H., SCHIMMEL, H. and LAMBERTY, A. Homogeneity and stability of reference materials. Accreditation and Quality Assurance, 2001, Vol. 6, p. 20 to 25
15. THOMPSON, M., ELLISON, S.L.R. and WOOD, R. The International Harmonized Protocol for the Proficiency testing of Analytical Chemistry Laboratories. Pure and Appl. Chem, 2006, Vol. 78, p. 145 to 196
16. USP Stimuli article by the USP Council of Experts. Primary and Secondary Reference Materials for Procedures to Test the Quality of Medicines and Foods. USP Reference Standards Committee, 2011
17. ISO Guide 30, Terms and definitions used in connection with reference materials 18. Clinical and Laboratory Standards Institute (CLSI) guideline, EP-14-A2, “Evaluation of Matrix
Effects” for further guidelines, especially if your QC material is intended for a specific test system.
19. ISO 11843-5:2008. Capability of detection -- Part 5: Methodology in the linear and non-linear calibration cases. (www.iso.org)
20. ISO 13528, Statistical methods for use in proficiency testing by interlaboratory comparisons
21. ISO/CEI 17025 :2017 General requirements for the competence of testing and calibration laboratories.
22. ISO 3534-1:2013 Statistics — Vocabulary and symbols — Part 1: General statistical terms and terms used in probability
23. ISO 3534-1:2013, Statistics — Vocabulary and symbols — Part 3: Design of experiments 24. ISO/IEC Guide 98-3:2008, Uncertainty of measurement — Part 3: Guide to the expression of
uncertainty in measurement (GUM:1995)
25. ISO/TR 22971:2005. Accuracy (trueness and precision) of measurement methods and results -- Practical guidance for the use of ISO 5725-2:1994 in designing, implementing and statistically analysing interlaboratory repeatability and reproducibility results. (www