Technical Guidance Series (TGS) - WHO

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



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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

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


Life cycle: All phases in the life of a medical device, from its initial conception to final 60 decommissioning and disposal. 61


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


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


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


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


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


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



Page | 24

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



Page | 26

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



Page | 28

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



Page | 30

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



Page | 32

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



Page | 34

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



Page | 36

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

11 REFERENCES

1. ISO 9000:2015 Quality management systems – fundamentals and vocabulary. Geneva: International Organization for Standardization (ISO); 2015

2. ISO 13485:2016, Medical devices — Quality management systems — Requirements for regulatory purposes

3. GHTF/SG1/N071:2012 -FINAL DOCUMENT -Global Harmonization Task Force -(revision of GHTF/SG1/N29:2005)

4. EN ISO 14971:2012 Medical devices – application of risk management to medical devices. Geneva: International Organization for Standardization (ISO)ISO 14971 2007. Medical devices — Application of risk management to medical devices

5. WHO. Technical Guidance Series (TGS) 7 for WHO Prequalifidaction – Diagnostic Assessment: Risk Management for manufacturers of in vitro diagnostic medical devices. Geneva: World Health Organization (WHO); 2018 (http://www.who.int/diagnostics_laboratory/guidance/technical_guidance_series/en/).

6. CLSI. Risk management techniques to identify and control laboratory error sources; approved guideline. Second edition CLSI document EP18-A2 (ISBN 1-56238-712-X). Wayne, PA, Clinical and Laboratory Standards Institute (CLSI). 2009.

7. ISO 5725-1:1994. Accuracy (trueness and precision) of measurement methods and results -- Part 1: General principles and definitions (and Corrigendum 1:1998). (www.iso.org)

8. WHO manual for the preparation of secondary reference materials for in vitro diagnostic assays designed for infectious disease nucleic acid or antigen detection: calibration to WHO International Standards (Annex 6) (http://apps.who.int/medicinedocs/documents/s23325en/s23325en.pdf)

9. WHO guidance TGS 3 Principles of Performance Studies (http://apps.who.int/iris/bitstream/handle/10665/258985/WHO-EMP-RHT-PQT-TGS3-2017.03-eng.pdf?sequence=1)

10. WHO guidance TGS 4 Guidance on test method validation for in vitro diagnostic medical devices (http://apps.who.int/iris/bitstream/handle/10665/258971/WHO-EMP-RHT-PQT-TGS4-2017.04-eng.pdf?sequence=1)

11. General guidelines for the establishment, maintenance and distribution of chemical reference substances. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007, Annex 3 (WHO Technical Report Series, No. 943).

12. ISO 73:2009 Risk management – vocabulary. Geneva: International Organization for Standardization (ISO); 2009.

http://www.who.int/diagnostics_laboratory/guidance/technical_guidance_series/en/

http://apps.who.int/iris/bitstream/handle/10665/258985/WHO-EMP-RHT-PQT-TGS3-2017.03-eng.pdf?sequence=1






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12 Bibliography

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3. BS 5309-1:1993, Sampling Chemical Products — Part 1: Introduction and General Principles 4. CORDEIRO RAPOSO, F., ROBOUCH, P., DE LA CALLE, M. B., EMTEBORG, H., CHAROUD-GOT J.

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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

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Effects” for further guidelines, especially if your QC material is intended for a specific test system.

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