ISO/DIS 3826-4:2026(en)

ISO/TC 76/WG 1

Secretariat: DIN

Date: 2025-12-15

Plastics collapsible containers for human blood and blood components — Part 4: Aphaeresis blood bag systems with integrated features

Poches en plastique souple pour le sang et les composants du sang — Partie 4: Systèmes des poches d'aphérèse pour le sang avec accessoires intégrés

© ISO 2026

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Contents Page

Foreword 7

Introduction 9

1 Scope 1

2 Normative references 2

3 Terms and definitions 2

4 Dimensions 7

5 Design 12

5.1 Leucocyte filter 12

5.2 Pilot samples 13

5.3 Access line needle and return line needle 13

5.4 Needle stick protection device 13

5.5 Pre-collection sampling device 13

5.6 Red blood cell storage bag 14

5.7 Plasma storage bag 14

5.8 Platelet storage bag 14

5.9 Post-collection sampling device 14

5.10 Collection and transfer tube(s) 14

5.11 Outlet port(s) 15

5.12 Suspension 15

6 Requirements 16

6.1 General 16

6.2 Physical requirements 16

6.2.1 Conditions of manufacture 16

6.2.2 Sterilization 16

6.2.3 Transparency 16

6.2.4 Coloration 17

6.2.5 Thermal stability 17

6.2.6 Water vapour transmission for plastics containers intended to store RBC 17

6.2.7 Tensile resistance 18

6.2.8 Resistance to leakage 18

6.2.9 Suspension 19

6.2.10 Outlet Port(s) 19

6.2.11 Emptying under pressure 19

6.2.12 Blood-taking needle 19

6.2.13 Particulate contamination 19

6.3 Chemical requirements 20

6.3.1 Requirements for the raw container or sheeting 20

6.3.2 Requirements for the test fluid 20

6.4 Biological requirements 21

6.4.1 General 21

6.4.2 Microbial barrier properties 21

7 Packaging 21

7.1 General 21

7.2 Shelf-life 21

7.3 Over-package materials 21

7.4 Over-package sealing 22

7.5 Over-package resistance 22

7.6 Arrangement of components in the over-package 22

8 Labelling 22

8.1 General 22

8.2 Label on plastics containers 22

8.3 Label on over-package 23

8.4 Package insert or instructions for use 23

8.5 Label on shipping box 24

8.6 Label requirements 24

9 Anticoagulant and/or preservative solution 25

10 Application of tests 25

Annex A (normative) Chemical tests 26

A.1 General 26

A.2 Determination of residue on ignition 26

A.3 Preparation of the test fluid 26

A.4 Tests 27

A.4.1 Determination of oxidizable constituents 27

A.4.2 Determination of ammonia 27

A.4.3 Determination of chloride ions 27

A.4.4 Determination of metals 27

A.4.4.1 Heavy metals 27

A.4.4.2 Alternative methods for testing for heavy metals 27

A.4.5 Determination of acidity or alkalinity 28

A.4.6 Determination of the evaporation residue 28

A.4.7 Determination of turbidity and degree of opalescence 28

A.4.7.1 General 28

A.4.7.2 Reagents 28

A.4.7.2.1 Hydrazine sulfate solution 28

A.4.7.2.2 Hexamethylenetetramine solution 28

A.4.7.2.3 Primary opalescent suspension 28

A.4.7.2.4 Standard of opalescence 28

A.4.7.2.5 Reference suspensions 28

A.4.7.3 Expression of results 29

A.4.8 Determination of degree of coloration 29

A.4.8.1 General 29

A.4.8.2 Method 1 29

A.4.8.3 Method 2 29

A.4.8.4 Expression of results 29

A.4.9 Determination of the UV absorption 29

A.4.10 Determination of plasticizer as extractable di(2-ethylhexyl) phthalate (DEHP) 29

A.4.10.1 Reagents 30

A.4.10.2 Preparation of standard solutions 30

A.4.10.2.1 Solution 1 30

A.4.10.2.2 Solution 2 30

A.4.10.2.3 Standard solutions A to E 30

A.4.10.3 Calibration curves 30

A.4.10.4 Extraction procedure 30

A.4.10.5 Expression of results 30

Annex B (normative) Physical tests 32

B.1 Transparency test 32

B.2 Test for rate of collection 32

B.3 Test for permanence of labelling 32

B.4 Test for particulate contamination 32

B.5 Test for sterile connection of tubing 32

Annex C (normative) Biological tests 34

C.1 General 34

C.2 Preparation of the test solutions 34

C.2.1 Test fluid I (polar extractant) 34

C.2.2 Test fluid II (non-polar extractant) 34

C.3 Test for impermeability to microorganisms 35

C.4 Test for bacterial endotoxins 35

Annex D (informative) Rationale, guidance and history of the development of this document 36

D.1 General 36

D.2 Rationale applicable to the whole standard 36

D.3 Rationale for particular clauses and sub-clauses 36

D.3.1 Main body of ISO 3826-4 36

Annex E (informative) Sustainability 39

E.1 General 39

E.2 Areas for environmentally conscious design and manufacturing 39

Annex F (informative) Atrributive and variable testing 41

Annex ZA 42

Bibliography 56

Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of any patent rights identified during the development of the document will be in the Introduction and/or on the ISO list of patent declarations received (see www.iso.org/patents).

Any trade name used in this document is information given for the convenience of users and does not constitute an endorsement.

For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISO's adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www.iso.org/iso/foreword.html.

This document was prepared by Technical Committee ISO/TC 76, Transfusion, infusion and injection equipment for medical and pharmaceutical use, in collaboration with the European Committee for Standardization (CEN) Technical Committee CEN/TC 205, Non-active medical devices, in accordance with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).

This second edition cancels and replaces the first edition (ISO 3826-4:2015), which has been technically revised.

The main changes compared to the previous edition are as follows:

— the Scope has been extended and clarified to cover apheresis blood bag systems, with an updated list of integrated features;

— Clause 2 has been updated;

— Clause 3 has been revised and expanded to align with current ISO terminology;

— Clause 4 has been revised to update the schematic representations of apheresis blood bag systems and associated components, introduce new connection standards, and reorganize dimensional data in an updated Table 1;

— Clause 5 has been revised to include operation with hydraulic/peristaltic pumps for leucocyte filters; extend plasma storage bag shelf-life, clarify pilot sample tubing requirements, add reference to ISO 7864 for needles, revise outlet port septum dimensional requirement to align with ISO 3826‑1;

— Clause 6 has been revised to align with ISO 3826-1, clarify nominal capacity, add tensile and emptying/suspension tests, expand particulate and contamination requirements, allow pharmacopoeial methods, reinforce ISO 10993 biological evaluation, and replace previous compatibility clause with updated biocompatibility framework;

— Clause 7 “Packaging” has been revised to clarify applicability to sealed over-packages, align shelf-life with ICH/WHO guidance, update terminology, replace “strength” with “resistance,” and add clearer provisions for component arrangement and sterile pathways (with ISO 11607-1 reference);

— Clause 8 “Labelling” — revised to clarify applicability to apheresis sets, reference MDR and UDI requirements, restructure labelling provisions, and require tamper‑evident features;

— Addition of new Clause 10 “Application of tests” distinguishing between type testing and batch testing;

— Annex A “Chemical tests” and Annex B “Physical tests” received only editorial revisions, with notes allowing the use of equivalent or pharmacopoeial methods;

— Annex C “Biological tests” has been revised to align with ISO 10993 series and expand guidance on selecting and justifying biological evaluation strategies; delete former subclauses on cytotoxicity testing (C.5), haemolysis testing (C.6), and detailed biological test methods (C.7, including Table C.1);

— Annexes D, E and F (informative) were added to provide rationale and historical background of the standard, to introduce sustainability guidance for design, manufacturing, packaging and life-cycle, and to explain attributive and variable testing with the option to substitute variable data methods;

— Annex ZA (informative) — added to provide the relationship between this European Standard and the General Safety and Performance Requirements of Regulation (EU) 2017/745, including correlation table for relevant clauses;

— Bibliography — updated to reflect current references and applicable standards.

A list of all parts in the ISO 3826 series can be found on the ISO website.

Any feedback or questions on this document should be directed to the user’s national standards body. A complete listing of these bodies can be found at www.iso.org/members.html.

Introduction

The manufacturers of the plastics container or the suppliers are expected to disclose in confidence to the national control authority, if requested by them, full details of the plastics material(s) and the components of the materials and their methods of manufacture, details of manufacture of the plastics containers including the chemical names and quantities of any additives, whether incorporated by the manufacturer of the plastics containers or present in the raw material, as well as full details of any additives that have been used.

Universal leucocyte depletion is mandatory in various countries. This document is considered a basic document for other standards which include technical innovations.

The requirements in this document are intended to

a) ensure that the quality of blood and blood components is maintained as high as necessary,

b) make possible efficient and safe collection, identification, storage, separation, and transfusion of the contents with special attention to reducing or minimizing the risks resulting from

— contamination, in particular microbiological contamination,

— air embolism,

— errors in identification of plastics containers and any representative samples of contents, and

— interaction between the plastics container and its contents,

c) ensure functional compatibility when used in combination with transfusion sets as specified in ISO 1135‑4 and ISO 1135‑5, and when used in combination with

d) provide a package with appropriate resistance to breakage and deterioration.

Plastics collapsible containers for human blood and blood components — Part 4: Aphaeresis blood bag systems with integrated features

This document specifies requirements including performance requirements for aphaeresis blood bag systems with integrated features. Aphaeresis blood bag systems need not contain all of the integrated features identified in this document. This part of ISO 3826 does not cover the specific portion of the aphaeresis set that pumps or centrifuges whole blood as an integrated feature

The integrated features refer to:

— needle stick protection device;

— leucocyte filter;

— sterile barrier filter;

— pre-collection sampling device;

— red blood cell storage bag;

— plasma storage bag;

— platelet storage bag;

— polymorphonucleic (e.g. stem) cell storage bag;

— post-collection sampling devices;

— connections for storage solutions, anticoagulant, and replacement fluid;

— donor or patient access line(s);

— waste or removal bag;

— processing bag and collection bag.

This document specifies additional requirements for blood bag systems used to collect varying quantities of blood components or cells by aphaeresis. This document can be used on automated or semi-automated blood collection systems. This document does not specify additional requirements for integrated features that are intended for removal from the aphaeresis set post procedure/donation for storage and transfusion.

NOTE 1 Annex D provides explanations about the history of the development of the standard and summarises the different arguments discussed within ISO/TC 76 during the elaboration of the document.

NOTE 2 Annex E provides recommendations regarding sustainability.

NOTE 3 Annex F provides information on attributive and variable testing.

The following documents are referred to in the text in such a way that some or all of their content constitutes requirements of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies.

ISO 1135‑4, Transfusion equipment for medical use — Part 4: Transfusion sets for single use, gravity feed

ISO 1135‑5, Transfusion equipment for medical use — Part 5: Transfusion sets for single use with pressure infusion apparatus

ISO 18250‑8, Medical devices — Connectors for reservoir delivery systems for healthcare applications — Part 8: Citrate-based anticoagulant solution for apheresis applications

ISO 8536‑4, Infusion equipment for medical use — Part 4: Infusion sets for single use, gravity feed

ISO 80369‑7, Small-bore connectors for liquids and gases in healthcare applications — Part 7: Connectors for intravascular or hypodermic applications

ISO 23908, Sharps injury protection — Sharps protection mechanisms for single-use needles, introducers for catheters and needles used for blood testing, monitoring, sampling and medical substance administration — Requirements and test methods

ISO 3696, Water for analytical laboratory use — Specification and test methods

ISO 10993‑1, Biological evaluation of medical devices — Part 1: Requirements and general principles for the evaluation of biological safety within a risk management process

ISO 14971, Medical devices — Application of risk management to medical devices

ISO 10993‑12, Biological evaluation of medical devices — Part 12: Sample preparation and reference materials

ICH Q1A (R2). Stability Testing of New Drug Substances and Products. International Council for Harmonisation (ICH), 2003

WHO Technical Report Series No. 953, Appendix 1 – Annex 2 (2018, updated March 2021)

For the purposes of this document, the following terms and definitions apply.

ISO and IEC maintain terminology databases for use in standardization at the following addresses:

— ISO Online browsing platform: available at https://www.iso.org/obp

— IEC Electropedia: available at https://www.electropedia.org/

3.1

aphaeresis

process by which blood being removed from a subject is immediately separated into component parts, usually to allow a desired component or components to be retained while the remainder is returned to the subject

3.2

aphaeresis set

whole aphaeresis blood bag system with integrated features

Note 1 to entry: Can also be called an aphaeresis kit or harness.

3.3

centrifugation

process in which circular motion is applied to a chamber about a central axis such that the fluid contents of the chamber are separated according to density where the most dense is towards the outer circumference of motion and the least dense is towards the inner circumference of motion

3.4

connector

mechanical device, consisting of one of two mating halves and designed to join a conduit to convey liquids or gases

[SOURCE: ISO 80369-1:2018, 3.4]

Note 1 to entry: In apheresis blood bag systems, connectors may include Luer connectors, break-away couplings, and spike-and-port assemblies that allow the connection of the fluid pathway between bags, tubing, or external devices.

3.5

citrate anticoagulant

citrate, in the form of sodium citrate or acid-citrate-dextrose, is added to the blood as it is drawn from the subject’s circulation and binds or chelates ionised calcium within the blood, thereby, impeding those steps of the coagulation pathway that are dependent on the presence of ionised calcium

3.6

clamp

device that prevents the flow of fluid through the tubing

Note 1 to entry: These can be locking (permanent) or non-locking (temporary).

3.7

extracorporeal circuit

path followed by whole blood or blood components when they are outside the subject’s circulation

3.8

fluid pathway

route along which fluids (whole blood, blood components, ancillary intravenous solutions) pass composed of tubing, chambers, connectors (3.4) and pressure sensors, and needles

Note 1 to entry: The fluid pathway is typically designed to maintain sterility of the fluid and to minimize the risk of restrictions or obstructions that could lead to cellular damage or trigger the coagulation cascade.

3.9

gauge pressure

pressure zero-referenced against local atmospheric pressure

Note 1 to entry: Container internal gauge pressure is:

— positive when the container is pressurized above the surrounding atmospheric pressure, and is

— negative when the container is subjected to suction.

[SOURCE: ISO 15747:2018, 3.4]

3.10

nominal capacity

customary volume of blood or blood component that the container is intended to collect under normal conditions of use

3.11

leucocyte filter

filter used to reduce the content of leucocytes in blood or blood components

3.12

pilot sample

sample of unmistakable identity to be used for testing

3.13

plasma

liquid component of blood

Note 1 to entry: It makes up of about 55 % of total blood volume.

3.14

plastics container

bag of plastic material, complete with any collecting tube and needle, port(s), anticoagulant and/or preservative solutions, and transfer tube(s) and associated container(s) or connection(s), where applicable, that are intended to or can be removed from the aphaeresis set for storage, transfer, or disposal of collected blood components

3.15

platelets

thrombocytes

small, irregularly shaped, clear cells with no nucleus involved in haemostasis leading to the formation of blood clots

3.16

platelet additive solution

PAS

solution in which platelets (3.15) are suspended

3.17

red blood cell additive solution

RAS

solution added to packed red cells to increase the storage life of red blood cells and prevent haemolysis

3.18

platelet storage bag

PSB

bag suitable for appropriate storage of a therapeutic dose of platelet concentrates obtained from a single donation

3.19

raw container

empty container that has not yet been sterilized and has no identification other than eventual embossing

[SOURCE: ISO/DIS 15747:2025, 3.11]

3.20

red blood cell storage bag

bag suitable for storage of a therapeutic dose of red cells obtained from a single donation

3.21

pre-collection sampling device

device integrated in the collect line of blood collection systems or aphaeresis disposable sets designed to allow blood samples to be obtained at the beginning of a collection procedure without breaching the sterility of the collected components

Note 1 to entry: Usually incorporates a small reservoir from which the required blood samples are withdrawn. If a skin plug is obtained at the point of venepuncture, it is likely to be trapped in the reservoir rather than being drawn into the collected component(s), thereby, reducing the risk of bacterial contamination of the collected component(s).

Note 2 to entry: Also called PDS (pre-donation sampling device).

3.22

post-collection sampling device

device that can be integrated to allow a blood component sample to be taken, for example, for sterility testing or bacterial screening

Note 1 to entry: Also called PDS (post-donation sampling device).

3.23

needlestick protection device

NPD

device integrated in the donor line of blood bag systems containing the donor needle and designed to prevent undesirable needle sticks after use of the donor needle

Note 1 to entry: See ISO 23908.

3.24

empty container

raw container with identification, which is suitable for the acceptance and storage of fluids where applicable and to be used for testing purposes

[SOURCE: ISO 15747:2018, 3.3, modified — "and administration of the injection solution" has been replaced by "of fluids where applicable and to be used for testing purposes"]

3.25

replacement fluid

fluid used during an aphaeresis procedure to replace some or all of the blood volume associated with the collected components

3.26

anticoagulant safety connector

connector (3.4) specifically intended for use with citrate anticoagulant (3.5) to prevent accidental misconnection of anticoagulant with replacement fluid (3.25)

Note 1 to entry: For requirements, see ISO 18250-8.

3.27

sheeting

plastics material intended for the production of raw containers

[SOURCE: ISO 15747:2018, 3.12, modified – “empty” has been replaced by “raw”]

3.28

shelf-life

defined period of time during which a medical device, when stored in its original packaging and under specified storage conditions, maintains its intended performance, safety, and functional characteristics within established acceptance criteria, as demonstrated by validated stability studies

3.29

sterile barrier filter

filter intended to prevent microorganisms or bacteria from entering a sterile fluid pathway (3.8)

3.30

plasma storage bag

bag suitable for storage of a therapeutic dose of plasma obtained from a single donation

3.31

waste or removal bag

bag suitable for use to remove waste blood product during aphaeresis procedures

3.32

cell collection bag

Bag suitable for collection of cells during a single aphaeresis procedure that may or may not be stored

3.33

processing bag

Bag used during aphaeresis procedure to process cellular products for separation

3.34

collection tube

tubing used to connect to the donor/patient to collect and return whole blood for the aphaeresis procedure

3.35

transfer tube

tubing used to transfer fluids from centrifugation or additive solutions to different plastic containers or to transfer replacement fluid to the fluid processing section of the aphaeresis set to return to the donor/patient through the collection tubing

3.36

type testing

conformity testing on the basis of one or more specimens of a product representative of the production

Note 1 to entry: type tests are carried out to demonstrate conformity with the requirements of this document and/or when a significant change is made in the product design, materials and/or method of manufacture, the effects of which cannot be predicted based on previous experience (see Clause 10).

3.37

batch testing

conformity testing performed on a defined production batch, typically conducted to confirm that each batch meets the specified requirements before release for use

3.38

storage capacity

maximum volume of fluid that the container can hold safely under specified conditions, without leakage, rupture, or loss of function

Note 1 to entry: the storage capacity usually exceeds the nominal capacity and is determined by the physical design and material properties of the container.

Figure 1, Figure 2, Figure 3, and Figure 4 illustrate the components of an aphaeresis blood bag system with integrated features. The general drawings and the drawing of each feature are for guidance only.

Figure 5 illustrates the components of a plastics container. The values of the dimensions shown in Figure 5 are binding and form part of the requirements of this document; the dimensions and storage capacities given in Table 1 are for guidance only.

Key

1 pre-collection sampling device

2 pre-collection sampling container

3 multiple sampling device

4 access and return line needle (or connection device)

5 needle stick protection device (NPD)

6 access line to aphaeresis extracorporeal circuit from donor or patient

7 return line from aphaeresis extracorporeal circuit to donor or patient

8 leucocyte filter for red blood cells (LCF)

9 inlet port

10 red blood cell storage bag

11 plasma storage bag

12 leucocyte filter for platelets (LCF)

13 platelet storage bag (PSB)

14 anticoagulant safety connector for citrate anticoagulant as defined in ISO 18250-8

15 sterile barrier filter

16 replacement fluid line if applicable to the set shall be provided with spike in accordance with ISO 8536‑4 or a needle for fluid containers with narrow septums

17 red cell additive solution (RAS) connection to the extracorporeal circuit - male luer in accordance with ISO 80369-7

18 platelet additive solution (PAS) connection to the extracorporeal circuit - female luer in accordance with ISO 80369-7

19 bacterial sampling port

20 post-collection sample container

21 aphaeresis extracorporeal circuit (not covered by this document)

22 hanger eyelet

23 outlet port

24 anticoagulant metering pump

^a Means of closure. The means can be positioned at other sites.

^b The position of the lines can be different than depicted.

^c Spike design is defined in ISO 8536‑4.

^d Additive (preservative) solution lines are optional and can be different than depicted.

Figure 1 — Schematic representation of components of a single needle donor aphaeresis blood bag system with integrated features — red cell blood bag with in-line leucocyte filter, platelet storage bag with in-line leucocyte filter, and pre-/post-donation sampling

Key

1 pre-collection sampling device

2 pre-collection sampling container

3 multiple sampling device

4 access line needle (or connection device)

5 needle stick protection device (NPD)

6 collect line to aphaeresis extracorporeal circuit from donor or patient

7 return line from aphaeresis extracorporeal circuit to donor or patient

8 leucocyte filter for red blood cells (LCF)

9 inlet port

10 red blood cell storage bag

11 plasma storage bag

12 leucocyte filter for platelets (LCF)

13 platelet storage bag (PSB)

14 anticoagulant safety connector for citrate anticoagulant as defined in ISO 18250-8

15 sterile barrier filter

16 replacement fluid line if applicable to the set shall be provided with spike in accordance with ISO 8536‑4 or a needle for fluid containers with narrow septums

17 red cell additive solution (RAS) connection to the extracorporeal circuit - male luer in accordance with ISO 80369-7

18 platelet additive solution (PAS) connection to the extracorporeal circuit - female luer in accordance with ISO 80369-7

19 bacterial sampling port

20 post-collection sample container

21 aphaeresis extracorporeal circuit (not covered by this document)

22 return line needle (or connection device)

23 hanger eyelet

24 outlet port

25 anticoagulant metering pump

^a Means of closure. The means can be positioned at other sites.

^b The position of the lines can be different than depicted.

^c Spike design is defined in ISO 8536‑4.

^d Additive (preservative) solution lines are optional and can be different than depicted.

Figure 2 — Schematic representation of components of a dual needle donor aphaeresis blood bag system with integrated features — red cell blood bag with in-line leucocyte filter, platelet storage bag with in-line leucocyte filter, and pre-/post-donation sampling devices

Key

1 pre-collection sampling device

2 pre-collection sampling container

3 multiple sampling device

4 access and return line needle

5 needle stick protection device (NPD)

6 collect line to aphaeresis extracorporeal circuit from donor or patient

7 return line from aphaeresis extracorporeal circuit to donor or patient

8 inlet port

9 waste bag

10 cell collection bag (may be multiples)

11 saline fluid lines with spike in accordance with ISO 8536‑4

12 replacement fluid line with spike in accordance with ISO 8536‑4 or a needle for fluid containers with narrow septums

13 sterile barrier filter

14 anticoagulant safety connector for citrate anticoagulant as defined in ISO 18250-8

15 sample bulb

16 hanger eyelet

17 outlet port

18 aphaeresis extracorporeal circuit (not covered by this document)

19 anticoagulant metering pump

^a Means of closure. The means can be positioned at other sites.

^b The position of the lines can be different than depicted.

^c Spike design is defined in ISO 8536‑4.

Figure 3 — Schematic representation of components of a single needle therapeutic aphaeresis blood bag system with integrated features — cell collection bag, waste bag, and pre-/post-collection sampling

Key

1 pre-collection sampling device

2 pre-collection sampling container

3 multiple sampling device

4 access line needle

5 needle stick protection device (NPD)

6 collect line to aphaeresis extracorporeal circuit from donor or patient

7 return line from aphaeresis extracorporeal circuit to donor or patient

8 inlet port

9 waste bag

10 cell collection bag (may be multiples)

11 saline fluid lines with spike in accordance with ISO 8536‑4

12 replacement fluid line with spike in accordance with ISO 8536‑4 or a needle for fluid containers with narrow septums

13 sterile barrier filter

14 anticoagulant safety connector for citrate anticoagulant as defined in ISO 18250-8

15 sterile barrier filter

16 sample bulb

17 aphaeresis extracorporeal circuit (not covered by this document)

18 hanger eyelet

19 outlet port

20 return line needle

21 anticoagulant metering pump

^a Means of closure. The means can be positioned at other sites.

^b The position of the lines can be different than depicted.

^c Spike design is defined in ISO 8536‑4.

Figure 4 — Schematic representation of components of a dual needle therapeutic aphaeresis blood bag system with integrated features — cell collection bag, waste bag, and pre-/post-collection sampling

Key

1 tamper evident protector(s)

2 fill tube

3 inlet port

4 outlet port(s)

5 tear line of protector

6 label area

7 eyelets (optional)

8 puncturable non-resealable closure(s) (optional)

9 side slits (optional)

10 hanger eyelet

^a Internal diameter ≥ 2,7 mm, wall thickness ≥ 0,5 mm.

^b External view.

^c Cross-sectional view.

^d Means of closure can be located elsewhere (optional).

NOTE See Table 1 for explanation of dimensions.

Figure 5 — Schematic representation of plastics container

Table 1 — Dimensions for plastic containers, label areas and storage capacity

Dimensions in millimetres

Dimensions in millimetres

Figure 6 — Dimensions of the closure-piercing device (extracted from ISO 1135‑4)

5.1.1 When provided as an integrated feature, the leucocyte filter is integrated in plastic container(s) as a blood component filter. It is designed to reduce the leucocyte content of one blood component unit. The filters can be designed to work by gravity or gauge pressure filtration at 4 °C or ambient temperature, depending on manufacturer’s specifications. Further, the filters can be designed to work by hydraulic or peristaltic pumps, depending on manufacturer’s specifications.

NOTE Leucocyte filters can be subjected to national requirements and/or standards.

5.1.2 Where provided as part of the integrated features, manufacturers shall give recommendations for the intended use of the leucocyte filters considering parameters including

— capacity of the leucocyte filter,

— leucoreduction efficiency,

— blood component filtration temperature,

— filtration height, and

— use of gauge pressure.

For donor aphaeresis blood bag systems with an integrated red blood cell storage bag, the plastics container can be designed so that pilot samples of unmistakable identity can be collected for the performance of compatibility tests without the closed system of the plastics container being penetrated. This can be accomplished, for example, by using an unmistakable numbering system on the tubing.

The tubing shall be designed so that stripping of the tubing up to 5 times with a tube stripper is possible and if applicable will not remove the existing numbering system when following the plastics containers instruction for use concerning tube stripping.

NOTE The number of segments for pilot samples can be defined in national regulations.

5.3.1 Where provided, the access and return line needle shall be fitted with a protective cover. The protective cover shall maintain the sterility of the fluid path and shall be readily removable.

5.3.2 For therapeutic aphaeresis, the access or return line needle can be removable or interchangeable to allow connection to other means of venous access (e.g. to a femoral vein catheter or jugular/subclavian vein catheter, central line, etc.) or to allow other gauges of needle to be fitted to allow for differences in vein sizes and to allow better comfort for the patient.

5.3.3 Additional guidance on needles is provided in ISO 7864^[3].

5.4.1 Needles shall contain a needle-stick protection device, e.g. one that conforms to the requirements of ISO 23908.

5.4.2 Manufacturers shall give recommendations for the optimal use of the needle stick protection device.

NOTE Needle stick protection devices can be subjected to national requirements and/or standards.

5.5.1 The pre-collection sampling device shall permit the collection, under aseptic conditions, of a range of donor samples.

5.5.2 If the pre-collection sampling device includes a pre-collection sampling bag, then its capacity shall be at least 25 ml.

5.5.3 The pre-collection sampling device shall be designed to be filled with a mean flow rate of at least 50 ml/min when tested in accordance with B.2.

5.5.4 Means shall be provided which prevent the return of blood and/or air from the sampling site towards the donor and donation after the filling of the pre-collection sampling device. The means may or may not be integrated. If the means is not integrated, the accompanying documents shall identify suitable means.

NOTE In the collection of specific samples, the presence of anticoagulant and haemolysis in the pre-collection sample is to be avoided.

5.5.5 Manufacturers shall give recommendations for the optimal use of the pre-collection sampling device.

5.6.1 Red blood cell storage bags shall allow the storage of packed red cells in a preservative red cell storage media (RAS) for up to 42 days when refrigerated between 2 °C and 6 °C or in accordance with national standards.

5.6.2 The manufacturer shall provide information regarding the suitability of the container for freezing (cryopreservation) of red cells in cryopreservation solution.

5.7.1 Plasma storage bags shall allow the storage of plasma for 3 years when refrigerated at below -25 °C.

5.7.2 The manufacturer shall provide information regarding the suitability of the container for freezing plasma.

5.8.1 Platelet storage bags shall have good gas permeability for both oxygen and carbon dioxide and shall allow storage of platelet concentrates under temperature-controlled conditions between 4 and 7 days (under continuous agitation).

5.8.2 Platelet storability is also influenced by the number of platelets, volume of platelet concentrate, size of the container and agitation, and is usually assessed by observation of swirling and by measurement of pH, hypotonic shock response, and aggregation.

5.9.1 Post-collection sampling device shall permit the collection, under aseptic conditions, of blood component samples into evacuated sample tubes.

5.9.2 If the post-collection sampling device includes a post collection sample container, the capacity of the container shall be at least 10 ml for bacterial control.

5.10.1 The aphaeresis set and the plastics container(s) can be provided with one or more collection or transfer tube(s) to allow the collection of blood components and addition of red cell additive solution or platelet additive solution or transfer to another container, e.g. via a leucocyte filter.

5.10.2 If a transfer tube is present and if necessary to avoid unexpected flow between containers, it shall be fitted with a device which when loosened or opened, permits the free flow of blood components in either direction. Examples include clamping devices and frangible couplers.

5.10.3 The tubes shall be such that they can be sealed hermetically and tubing subject to vacuum does not collapse under normal fluid transfer.

5.10.4 There shall be no leakage at the tubing-component/tubing-connectors junctions within the aphaeresis set, and the plastics container shall also conform to the requirements specified in 6.2.7 and 6.2.8.

5.10.5 Requirements for sterile connection of transfer tubing: Tubing design shall allow the efficient transfer of blood components between containers. Design should also allow the joining of tubes supplied by a single manufacturer or from different manufacturers using a sterile tube welding device. Typically, this is to enable the connection of leukocyte filters (LCF) or other required devices when these are not included in the set. Sterile tube welding devices join the two opposing ends of the tube while maintaining a sterile fluid pathway.

Manufacturers of sterile tube welding devices typically specify acceptable tube dimensions (external and/or internal diameter and wall thickness) for use on their equipment. Aphaeresis blood bag system manufacturers shall specify in their product documentation, the material, internal and external diameter, and wall thickness of all their tubing to allow blood transfusion services to assess the suitability for tube welding.

When a blood transfusion service wishes to weld tubing of different specifications, they should carry out a validation before proceeding. A protocol is provided in Annex B.5 as a minimum standard for such validations. See also [4].

5.10.6 Transfer tubes that end in connectors for additive solutions shall maintain the sterility of the fluid path.

5.11.1 The plastics container (except for any waste bag) shall be provided with one or more outlet ports for the administration of blood and blood components through a transfusion set. The port(s) which shall have a puncturable, non-resealable closure port septum placed (14 + 1 / - 2) mm from the top of the port shall allow connection of a transfusion set having a closure-piercing device in accordance with ISO 1135‑4 without leakage on insertion or during conditions of use including emptying under gauge pressure (see 6.2.10.3 and 6.2.11). Before the closure is pierced by the point of the closure-piercing device, the outlet port(s) shall be tightly occluded by the closure-piercing device. When used in accordance with manufacturer's instructions, the piercing device shall not damage the plastic film of the plastics container on insertion.

NOTE For the dimensions of the closure-piercing device, see ISO 1135‑4.

When designing the outlet port to ensure good compatibility with closure-piercing devices, manufacturers should avoid the use of tubing that is highly inflexible. Thin-walled outlet ports (tubing) less than 1 mm should also be avoided as this tends to twist and collapse on insertion.

5.11.2 Each outlet port shall be fitted with a hermetically sealed, tamper-evident protector to maintain the sterility of the internal surface.

5.11.3 When tested in accordance with 6.2.10.3, the connection between the closure-piercing device and the blood component bag port shall show no evidence of leakage.

The plastics containers, except waste bag, provided on the set shall have adequate means of suspension or positioning (see, for example, eyelets in Figure 5) which do not interfere with the use of the plastics container during collection, storage, processing, transport, or administration. The means of suspending or positioning the container shall meet the requirements of 6.2.9.

The plastics container shall be transparent, virtually colourless (see 6.2.4), flexible, sterile, non-pyrogenic, biologically safe (see 6.4), and non-breakable under conditions of use (see 6.2.5). It shall be compatible with the contents under normal conditions of storage. The plastics container shall meet the requirements for terminal sterilization and shall not become tacky during sterilization and storage for its shelf-life at temperatures not exceeding 40 °C.

The plastics container shall be stable biologically, chemically, and physically with respect to its contents during its shelf-life and shall not permit penetration of microorganisms. Any substances leached from the plastics container by the contained anticoagulant and/or preservative solution, blood, and blood components by either chemical interaction or physical dissolution, shall be evaluated on a case-by-case basis from manufacturers.

In many countries, national pharmacopoeias specify formulations of different plastics materials such as flexible PVC with different plasticizers and other plastics materials while government regulations or standards can detail suitable tests for assessing chemical or physical interactions.

All processes involved in the manufacture, assembly, and storage of the plastics container shall be carried out under clean and hygienic conditions in compliance with the appropriate national regulations and in accordance with relevant legislation and international agreements such as current GMP requirements.^[5] Every practicable precaution shall be taken at all stages to reduce the risk of adventitious contamination by microorganisms or foreign matter.

6.2.2.1 The aphaeresis set shall have been sterilized by a validated method.

6.2.2.2 The method of sterilization used shall not adversely affect the materials or contents, nor cause any loosening of joints and deterioration of welds in the plastics material.

6.2.2.3 The manufacturer shall be able to produce evidence acceptable to the national control authority of the effectiveness of the sterilization process actually used. If required by the national control authority, positive controls to check the effectiveness of sterilization shall be included in each sterilization lot.

When tested as specified in B.1, the opalescence of the suspension shall be perceptible when viewed through the plastics container as compared with a similar plastics container filled with water.

NOTE Limits and test procedures given in pharmacopoeias, for example, those specified in the European Pharmacopoeia for plastics containers for blood and blood components, can be applied for the aphaeresis blood bag system.

The material of the sterilized plastics container shall not be coloured to such an extent that assessment of the colour of the blood is adversely affected.

General

The instructions for use shall indicate if the plastics container is intended for freezing and/or irradiation applications.

The user shall be aware of particular requirements from any other regulatory authority (e.g. EDQM Guide to the preparation, use and quality assurance of blood components)^[6].

Freezing

This requirement refers to bags intended for freezing.

The plastics container filled to its nominal capacity with water as specified in ISO 3696, shall withstand a slow freezing to and storage at −80 °C for 24 h, subsequent immersion in water at (37 ± 2) °C for 60 min, and returning to (23 ± 2) °C. The plastics container shall meet the requirements of 5.10.3, 6.2.7, 6.2.8, 6.2.9 and 6.2.13.

Plastics containers intended to be shock-frozen (blast frozen) shall be validated for this application.

If a refrigerant solution is used, the plastics container may be enclosed in a protective bag to avoid direct contact between the refrigerant solution and the plastics container.

NOTE Limits and test procedures given in pharmacopoeias, for example, those specified in the European Pharmacopoeia for plastics containers for blood and blood components, can be applied for the aphaeresis blood bag system.

Ionizing Irradiation

This requirement refers primarily to containers intended to store irradiated blood components.

The plastics container, filled to nominal capacity with water as specified in ISO 3696 (for containers with a nominal capacity of greater 350 ml the maximum filling volume shall not exceed 350 ml), shall withstand a maximum irradiation dose of 50 m² x s⁻² (Gy) using validated irradiation equipment.

The plastics container following irradiation shall meet the requirements of 5.10.3, 6.2.4, 6.2.7, 6.2.8, 6.2.9 and 6.2.13.

The integrity of plastics containers intended to be irradiated shall be validated for this specific application.

The plastics container, without an over-package, shall be filled to its nominal capacity with water as specified in ISO 3696, sealed and labelled ready for use. The plastics container shall then be capable of being stored for 42 days at a temperature of (4 ± 2) °C without loss of a mass fraction of more than 2 % of water from the solution.

NOTE 1 The storage of certain blood components, such as platelet concentrates, can require specific gas exchange rates for oxygen and carbon dioxide.

NOTE 2 Limits and test procedures given in pharmacopoeias, for example, those specified in the European Pharmacopoeia for plastics containers for blood and blood components, can be applied for the aphaeresis blood bag system.

Any connection between the components of the aphaeresis set, excluding protective caps, shall withstand a static tensile force of not less than 15 N for 15 s.

Further, tubes connected to the plastics container shall withstand, without leakage occurring (see 6.2.8), a tensile force of 20 N applied to the tubing for 15 s. The tensile force shall be applied at right angles to the edge of the joint and along the longitudinal axis of the plane of the plastics container at a temperature of (23 ± 2) °C.

The instructions for use shall indicate if the plastics container is intended for centrifugation or not intended for centrifugation.

Bags intended for centrifugation

Where the manufacturer specifies that the plastics container is suitable for centrifugation, the tests of this subclause are applicable.

When filled to nominal capacity for storage with water as specified in ISO 3696 and sealed, the plastics container shall not develop leaks under conditions of centrifugation at 5 000 g at (37 ± 2) °C for 10 min. The plastics container is then squeezed between two plates to an internal pressure equivalent to 50 kPa above atmospheric pressure at a temperature of (23 ± 2) °C for 10 min. No leakage is allowed on visual inspection.

For containers of flexible polyvinyl chloride (PVC), both tests should be repeated at (4 ± 2) °C. Plastics containers that are normally centrifuged without solution shall be subjected to the same centrifugation conditions as noted above without solution. Following this, the plastics container shall withstand an internal pressure equivalent to 50 kPa above atmospheric pressure after filling to nominal capacity.

Bags not intended for centrifugation

Where the manufacturer specifies that the plastics containers are not intended to be centrifuged, the tests of this subclause are applicable.

When filled to nominal capacity for storage with water as specified in ISO 3696 and sealed, the plastics container is then squeezed between two plates to an internal pressure equivalent to 50 kPa above atmospheric pressure at a temperature of (23 ± 2) °C for 10 min. No leakage is allowed on visual inspection.

NOTE 1 This test is used to verify that the seals of the bag are robust.

NOTE 2 When the plastics container is filled with anticoagulant solution, such as an ACD solution or other solutions with similar pH, leakage can be detected by pressing the plastics container against sheets of blue litmus paper and observing the development of pink spots on the paper. For solutions of other pH, the same method with an appropriate indicator can be used. Alternative methods affording at least the same degree of sensitivity can be used.

NOTE 3 Limits and test procedures given in pharmacopoeias, for example, those specified in the European Pharmacopoeia for plastics containers for blood and blood components, can be applied for the aphaeresis blood bag system.

The plastic container shall be capable of withstanding a tensile force of 20 N applied along the longitudinal axis of the outlet port(s) for 60 min at a temperature of (23 ± 2) °C without breaking.

Insertion force

It shall be possible to puncture the output port septum of the blood component bag with a closure piercing device that meets the requirements of ISO 1135‑4.

Published work indicates that insertion forces under specified conditions should be considered, see [7].

Pull force

When a closure-piercing device conforming to ISO 1135‑4 is inserted into the blood component bag port, this shall resist a pull force of 15 N for 15 s and shall remain in place.

Leakage after closure piercing

Fill the plastics container with a volume of water at a temperature of (23 ± 2) °C equal to its specified nominal capacity for storage. After puncturing the septum of the containers as described in 6.2.10.1, each test closure-piercing device shall remain in the septum point for 5 h. Then, place the plastics containers between two plane parallel plates loaded with an internal pressure of 20 kPa for 15 s and inspect for any leakage.

The plastics container, when filled with a volume of water at a temperature of (23 ± 5) °C equal to its nominal capacity for storage and connected to a transfusion set as specified in ISO 1135‑4 or ISO 1135‑5 inserted in an outlet port (see 5.11), shall empty without visual leakage (see 6.2.8) when gradually squeezed between two plates to a gauge pressure of 50 kPa. The plastic container shall empty within 2 minutes when tested above if intended for transfusion.

NOTE Limits and test procedures given in pharmacopoeias, for example, those specified in the European Pharmacopoeia for plastic containers for blood and blood components, can be applied for the aphaeresis blood bag system.

6.2.12.1 The joint between the blood-taking needle and the needle hub shall withstand a static tensile (pull) force and compressive (push) force of 20 N for 15 s along the longitudinal axis.

6.2.12.2 The joint between the needle hub and the connected tubing shall withstand a static tensile (pull) force of 20 N for 15 s along the longitudinal axis.

Plastics containers shall be manufactured so that contamination with particles is minimised.

When tested as described in B.4, the fluid path within the plastics container should be free from visible and sub-visible particles.

NOTE Limits and test procedures given in pharmacopoeias, for example, those specified in the European Pharmacopoeia for parenteral solutions, can be applied for the aphaeresis blood bag system. Similar devices with the same intended use can be another source of consideration for particle size ranges and particle count limits.

The raw container or the sheeting shall fulfil the requirements given in Table 2. Alternatively, it may be tested as described in the relevant pharmacopoeias.

Table 2 — Ignition residues for polyolefins and PVC

The limits specified in Table 3 shall not be exceeded when the appropriate tests are carried out on the extract obtained in accordance with Annex A. Alternatively, it may be tested as described in the relevant pharmacopoeias (such as Eur. Ph., 3.3.5^[8]).

Table 3 — Chemical limits on extracts from plastics container

Materials used in the manufacture of plastics containers for human blood and blood components shall be carefully chosen so as to minimize the risks arising from leaching of chemical constituents into the product. Particular attention shall be given to the toxicity of the materials used and the biological compatibility of the plastics container with the product.

NOTE National pharmacopoeias have monographs on plastic materials which specify the composition and limit of different constituents, as well as limits of metals such as Ba, Pb, Cd, Sn, Cr, and, for example, vinyl chloride monomers, where applicable.

The biological safety of the plastic container and its materials shall be assessed by the manufacturer in accordance with the requirements of ISO 10993-1, within the framework of the risk management process defined by ISO 14971.

The biological tests shall be carried out according to Annex C.

The impermeability to microorganisms of the plastics container(s), except the waste bag, shall be determined when tested in accordance with C.3.

NOTE For further requirements on microbial barrier, see ISO 11607-1^[9].

The requirements in 7.2 to 7.6 are related to the aphaeresis set in its sealed protective over-package.

The shelf-life of the aphaeresis set shall be established by the manufacturer based on validated stability data.

If the aphaeresis set contains anticoagulant and/or preservative solution, the shelf-life shall not exceed the period within which water loss from the container reaches a mass fraction of 5 % when stored under specified temperature and humidity conditions. Such conditions shall be in accordance with ICH Q1A(R2) and/or WHO Technical Report Series No. 953, considering the relevant climatic zone.

For the determination of the applicable climatic zone, reference shall be made to Appendix 1 – Annex 2 of WHO Technical Report Series No. 953 (2018, updated March 2021)

The materials of the over-package or any treatment to its interior surface should neither interact with the aphaeresis set or its contents nor support mould growth. If chemical fungicides are used, evidence shall be provided to show there has been no harmful penetration of or effect on the aphaeresis set and its contents.

Where the over-package forms a sterile barrier, the over-package shall be sealed in such a manner as to be tamper-evident and to prevent opening or reclosing without displaying signs that the seal has been destroyed.

The over-package shall be resistant enough to protect the product under conditions of normal handling and use.

The aphaeresis set and components shall be arranged in the over-package in a manner which will minimise the access and return lines or other tubing essential for performance and safety from kinking and acquiring a permanent set. If the aphaeresis set is a sterile fluid pathway, then the set shall be arranged to maintain the sterile fluid pathway.

NOTE For further requirements on sterile barrier packaging systems, see ISO 11607-1^[9].

The labelling of a plastics container is recommended to include the requirements as specified in 8.2 to 8.5. If graphical symbols are used, refer to ISO 3826‑2^[10]and ISO 15223‑1^[11].

NOTE 1 The label content requirements can be defined in national regulations.

NOTE 2 Labelling of medical devices containing phthalates is subject to applicable legislation, including Regulation (EU) 2017/745 (MDR),^[12] which replaced the former Medical Device Directive 93/42/EEC. See also EN 15986^[13].

NOTE 3 Unique Device Identification (UDI) requirements are defined Regulation (EU) 2017/745 and in relevant international guidance (e.g. IMDRF UDI framework^[14]).

With the exception of sample containers, the following information shall be at least included on the container label:

a) the name and address of the manufacturer;

b) nature, and volume (in millilitres) or mass (in grams) and formulation of anticoagulant and/or preservative solution incorporated in the container (if applicable);

c) catalogue number;

d) lot designation;

e) expiry date, if required.

NOTE All items can be included additionally in a bar code conforming to a 128 code^[15].

The over-package label shall contain at least:

a) the name and address of the manufacturer;

b) description of the contents;

c) catalogue number;

d) lot designation;

e) expiry date;

f) instruction or symbol that the aphaeresis set is for single use only;

g) statement or symbol defining the conditions of sterility and non-pyrogenicity;

h) any special conditions for storage of the package;

i) reference to the package insert or instructions for use for the aphaeresis set;

j) applicable special environmental and storage conditions (particularly for sets with incorporated solutions); and

k) instruction or symbol indicating not to use the aphaeresis set if there is any visible sign of deterioration.

If a transparent over-package is used, all the information required under 8.2 and 8.3 should appear on the label of the plastics container or the package insert or instructions for use.

NOTE Items a) through e) can be included additionally in a bar code conforming to a 128 code^[15].

The package insert shall contain at least:

a) the name and address of the manufacturer;

b) description of the contents;

c) formulation of any solutions incorporated in the set;

d) catalogue number;

e) definition of the storage conditions for the sets;

f) statement whether the container can be centrifuged;

g) intended purpose

h) explanation of all symbols used on the shipping box, over-package, and bag labels if required;

NOTE Symbol definitions are not required when using symbols defined in ISO 15223-1.

i) necessary instructions for proper use of the set (if applicable) and if applicable also information about any residual risks; and

j) instruction indicating that the aphaeresis set shall not be used more than n^[1] days after removal from the over-package.

NOTE It is permissible to provide the instructions for use on the over-package label rather than on a package insert.

The label, which should be visible when paletted, shall contain:

a) the name and address of the manufacturer;

b) description of the contents;

c) model or catalogue number;

d) lot designation;

e) expiry date;

f) applicable special environmental and storage conditions (particularly for sets with incorporated solutions); and

g) if the transit container functions as an over-package, an instruction indicating that the aphaeresis set shall not be used more than n^[2] days after removal from the over-package.

NOTE Items c) through e) can be included additionally in a bar code conforming to a 128 code^[15].

The label on the plastics container shall be such that:

a) an appropriate label area is reserved for information related to the plastics container manufacturer and user;

NOTE Usually, 30 % of the label area is intended for entries of the manufacturer and 70 % of the label area is intended for entries or over-labelling of those who fill the plastics container with blood or blood components.

b) by leaving a portion of the plastics container visible and free of markings, the contents can be adequately inspected visually;

c) there is no diffusion of the print from the label into the material of the plastics container;

d) the printing on the label remains legible at the time of use;

e) any adhesive used on the label shall not support mould growth or migration of mould or chemicals from the adhesive through the bag into the contents of the bag. Evidence shall be provided to show there has been no harmful effect on the plastics container and its contents;

f) labelling shall include tamper-evident features to help indicate the existence of tampering (e.g. permanently deformed label, torn label or inability to re-attach).

g) when tested in accordance with B.3, the label(s) shall not separate from the plastics containers after removal from water. Printing on the label or on the plastics container shall remain legible.

The quality of the anticoagulant and/or preservative solution, if any, shall satisfy the requirements of the national pharmacopoeia and national regulations.

A distinction is made between type testing and batch testing. All tests specified in Annexes A to C are type testing. They shall be repeated if one or more of the following conditions is changed significantly so that the requirements as specified in Clause 6 might be affected:

— the design;

— the plastic composition;

— the process of manufacturing the aphaeresis set;

— the sterilization process.

1. 
   (normative)
   
   Chemical tests
   1. General

Take materials for testing from the blood and blood derivatives contact materials of the finished, sterilized, and if necessary, emptied plastics containers, i.e. in the state in which they would be used for transfusion, collection, separation, and administration procedures including the plastic sheet used for the collecting bag and the plastic tubing used for the collection tube, transfer tube, and any parts that come into contact with blood and blood components.

NOTE For points from A.2 to A.4 equivalent or more accurate methods as described in pharmacopeias can be used.

• 1. Determination of residue on ignition

Weigh 1,00 g to 2,00 g of the material (in small pieces) into a suitable crucible that has been previously ignited, cooled, and weighed. Heat at 100 °C to 105 °C for 1 h, then ignite to (550 ± 25) °C. Allow to cool in a desiccator and weigh. Repeat ignition until constant mass is attained. Calculate mass of residue on ignition per gram of starting material.

• 1. Preparation of the test fluid

Fill the empty container twice to the nominal capacity with water for injection, shake for approximately 1 min, and then empty. After the rinse water has drained off, fill the empty container to the nominal volume with water for injection, then compress the container so that the remaining air escapes from the container, and subsequently close it. Extract the container for at least 30 min in pressurized, saturated steam at (121 ± 2) °C. Use 250 ml water for injection as a comparative fluid (blank sample). Heating and cooling times are not included in the 30 min cycle time requirement.

If appropriate, the extraction can be performed on pieces of sheeting or raw container. Use pieces with a total surface area of 1 500 cm² which includes both sides of the plastic sheet. Wash this material twice with 100 ml water for injection and discard the water after use. Drain the pieces, cover them with 250 ml water for injection, and extract for 30 min in pressurized, saturated steam at (121 ± 2) °C. As a comparison fluid (blank sample), treat water for injection in the same manner.

Test on pieces of sheeting are only possible if the plastics material is homogeneous. Laminated sheeting must be transformed into an equivalent container first to selectively test the inner surface.

If the container is not intended for sterilization at temperatures of at least 121 °C, then the extraction can alternatively be performed at (100 ± 2) °C for a duration of 2 h or at (70 ± 2) °C for a duration of (24 ± 2) h, in which case, the selected temperature should not be lower than that at which the container is being sterilized.

In the event that the solution resulting from extraction of a single container or single sample of sheeting has insufficient volume to allow for all of the required testing, the solutions from two or more extractions can be combined to produce a composite test solution. If alternative sterilization methods other than thermal sterilization are to be applied to the container, e.g. γ-irradiation, ethylene oxide, or e-beam, use sterilized containers for preparation of the test fluid.

• 1. Tests
     1. Determination of oxidizable constituents

Combine 20,0 ml of the test fluid with 20,0 ml potassium permanganate solution [c(KMnO₄) = 0,002 mol/l] and 1,0 ml sulfuric acid [c(H₂SO₄) = 1 mol/l] and boil for 3 min. Add 1,0 g of potassium iodide and titrate the solution with sodium thiosulphate solution [c(Na₂S₂O₃) = 0,01 mol/l] until light brown. Then add 5 drops of starch solution and titrate until colourless.

Calculate the consumption of potassium permanganate solution [c(KMnO₄) = 0,002 mol/l] for the test fluid and comparator fluid. The difference between the two values shall not be greater than 1,5 ml.

NOTE Potassium permanganate concentration [c(KMnO₄) = 0,002 mol/l] equals sodium thiosulphate solution concentration [c(Na₂S₂O₃) = 0,01 mol/l].

• • 1. Determination of ammonia

Make alkaline 10 ml of the test fluid by the addition of 2 ml of caustic soda [c(NaOH) = 1 mol/l], dilute with distilled water to 15 ml, and then add 0,3 ml Nessler's reagent^[3].

Prepare the comparison solution simultaneously by making alkaline 8 ml of ammonium standard solution [ρ(N) = 1 mg/l] by the addition of 2 ml caustic soda [c(NaOH) = 1 mol/l], diluting with distilled water to 15 ml and then adding 0,3 ml Nessler's reagent.

After 30 s, examine the solution which shall not be more strongly yellow-coloured than the comparison solution.

• • 1. Determination of chloride ions

Add 0,3 ml of silver nitrate solution [c(AgNO₃) = 0,1 mol/l] to 0,15 ml of diluted nitric acid. Add the resultant solution to 15 ml of the extract.

Prepare a reference solution in the same way using 12 ml of chloride standard solution (5 mg Cl^– per litre) and 3 ml of water.

Shake the mixtures. After 2 min, the solution prepared by using the extract shall not be more turbid than the reference solution. Avoid exposure of the solution to direct daylight.

• • 1. Determination of metals
       1. Heavy metals

The metals Ba, Cd, Cr, Cu, Pb, Sn, and Al are determined by atomic spectrometric analysis. The detection limit using Atomic Absorption Spectrometry (AAS) can be raised by concentrating the test fluid by evaporation in accordance with A.3, in which case, 2,5 ml hydrochloric acid solution [ρ(HCl) = 10 g/l] is added to 250 ml test fluid.

• • • 1. Alternative methods for testing for heavy metals

Chemical determination of the total of heavy metals can be used instead of the atomic spectrometric determination of metals in the test fluid according to A.3.

1,2 ml thioacetamide reagent is added to 12 ml of the test fluid and 2 ml ammonium acetate buffer solution (pH = 3,5) and immediately mixed.

Prepare the comparison solution in the same manner using 10 ml lead solution [ρ(Pb²⁺) = 2 mg/l] and adding 2 ml of the test fluid. After 2 min, examine the solution. It shall not be a deeper shade of brown than the comparison solution.

• • 1. Determination of acidity or alkalinity

After the addition of 2 drops of phenolphthalein solution, 10 ml of the test fluid shall not be coloured red. However, on the addition of less than 0,4 ml caustic soda [c(NaOH) = 0,01 mol/l], red coloration shall occur. After the addition of 0,8 ml hydrochloric acid [c(HCl) = 0,01 mol/l], this coloration shall disappear again. On the addition of 5 drops methyl red solution, the solution shall have an orange-red coloration.

• • 1. Determination of the evaporation residue

Evaporate 100 ml of the test fluid on a water bath and dry at 105 °C to constant mass.

• • 1. Determination of turbidity and degree of opalescence
       1. General

Using identical test tubes of colourless, transparent, neutral glass with a flat base and an internal diameter of 15 mm to 25 mm, compare the liquid to be examined with a reference suspension freshly prepared as described below, the depth of the layer being 40 mm. Compare the solutions in diffused daylight 5 min after preparation of the reference suspension viewing them vertically against a black background. The diffusion of light shall be such that reference suspension 1 can readily be distinguished from water and that reference suspension 2 can readily be distinguished from reference suspension 1.

• • • 1. Reagents
         1. Hydrazine sulfate solution

Dissolve 1 g of hydrazine sulfate in water and dilute to 100 ml. Allow to stand for 4 h to 6 h.

• • • • 1. Hexamethylenetetramine solution

Dissolve 2,5 g of hexamethylenetetramine in 25 ml of water in a 100 ml glass-stoppered flask.

• • • • 1. Primary opalescent suspension

Add to the solution of hexamethylenetetramine (A.4.7.2.2) 25 ml of the hydrazine sulfate solution (A.4.7.2.1). Mix and allow to stand for 24 h.

This suspension is stable for two months provided that it is stored in a glass container free from surface defects. The suspension shall not adhere to the glass and shall be well-mixed before use.

• • • • 1. Standard of opalescence

Dilute 15 ml of the primary opalescent suspension (A.4.7.2.3) to 1 000 ml with water.

This suspension shall be freshly prepared and can be stored for at most 24 h.

• • • • 1. Reference suspensions

Prepare the reference suspensions in accordance with Table A.1. Mix and shake before use.

Table A.1 — Reference suspensions

Volumes in millilitres

• • • 1. Expression of results

A.4.7.3.1 A liquid is deemed to be clear if its clarity is the same as that of water or of the solvent used when examined under the conditions described above or if its opalescence is not more pronounced than that of reference suspension 1.

A.4.7.3.2 A liquid is deemed to be slightly opalescent if its opalescence is more pronounced than as described in A.4.7.3.1, but not more pronounced than that of reference suspension 2.

A.4.7.3.3 A liquid is deemed to be opalescent if its opalescence is more pronounced than as described in A.4.7.3.2, but not more pronounced than that of reference suspension 3.

A.4.7.3.4 A liquid is highly opalescent if its opalescence is more pronounced than as described in A.4.7.3.3, but not more pronounced than that of reference suspension 4.

• • 1. Determination of degree of coloration
       1. General

The examination of the degree of coloration of liquids in the range brown-yellow-red shall be carried out by one of the two methods specified in A.4.8.2 and A.4.8.3.

• • • 1. Method 1

Using matched tubes of colourless, transparent, neutral glass having an internal diameter of 12 mm, compare 2 ml of the liquid to be examined with 2 ml of water. Compare the colours in diffused daylight viewing them horizontally against a white background.

• • • 1. Method 2

Using matched tubes of colourless, transparent, neutral glass having an internal diameter of 16 mm, compare 10 ml of the liquid to be examined with 10 ml of water. Examine the column of liquid down the vertical axis of the tube in diffused daylight against a white background.

• • • 1. Expression of results

A liquid is deemed to be colourless if it has the appearance of water when examined under the conditions as specified for method 1 or 2.

• • 1. Determination of the UV absorption

Determine the UV absorbance of the extract in a cuvette with an internal light path of 1 cm against the blank. The absorbance is determined in the range from 230 nm to 360 nm.

• • 1. Determination of plasticizer as extractable di(2-ethylhexyl) phthalate (DEHP)

NOTE This determination applies only to flexible PVC containing DEHP.

• • • 1. Reagents

A.4.10.1.1 Ethanol, volume fraction, φ, in the range from 95,1 % to 96,6 %, density, ρ, in the range from 0,805 0 g/ml to 0,812 3 g/ml.

A.4.10.1.2 Extraction solvent, ethanol: water mixture of density, ρ, ranging from 0,937 3 g/ml to 0,937 8 g/ml as determined with a pycnometer.

A.4.10.1.3 Di(2-ethylhexyl)phthalate (C₂₄H₃₈O₄), a colourless, oily liquid insoluble in water, soluble in organic solvents; ρ, in the range from 0,982 g/ml to 0,986 g/ml, refractive index at 20 °C n in the range from 1,486 to 1,487.

• • • 1. Preparation of standard solutions
         1. Solution 1

Dissolve 1 g of DEHP (A.4.10.1.3) in ethanol (A.4.10.1.1) and dilute to 100 ml with ethanol.

• • • • 1. Solution 2

Dilute 10 ml of solution 1 (A.4.10.2.1) to 100 ml with ethanol.

• • • • 1. Standard solutions A to E

a) Solution A: Dilute 20 ml of solution 2 (A.4.10.2.2) to 100 ml with extraction solvent (A.4.10.1.2) (DEHP content: 20 mg/100 ml).

b) Solution B: Dilute 10 ml of solution 2 to 100 ml with extraction solvent (DEHP content: 10 mg/100 ml).

c) Solution C: Dilute 5 ml of solution 2 to 100 ml with extraction solvent (DEHP content: 5 mg/100 ml).

d) Solution D: Dilute 2 ml of solution 2 to 100 ml with extraction solvent (DEHP content: 2 mg/100 ml).

e) Solution E: Dilute 1 ml of solution 2 to 100 ml with extraction solvent (DEHP content: 1 mg/100 ml).

• • • 1. Calibration curves

Measure the maximum absorbance of the standard solutions (A.4.10.2.3) at 272 nm using the extraction solvent as the reference solution and plot a curve of absorbance against DEHP concentrations.

• • • 1. Extraction procedure

Fill the empty plastics container to half of the nominal capacity through the collecting tube with a volume of extraction solvent heated to 37 °C. Expel the air completely from the plastics container and seal the collecting tube. Immerse the filled plastics container in a horizontal position in a water-bath maintained at (37 ± 1) °C for (60 ± 1) min without shaking. Remove the plastics container from the water-bath, invert it gently 10 times, and transfer the contents to a glass flask.

Measure the maximum absorbance at 272 nm using the extraction solvent as the reference solution.

• • • 1. Expression of results

Determine the quantity of extractable DEHP by comparing the result obtained for the plastics container (see A.4.10.4) with the calibration curve of absorbance for the standard solutions (see A.4.10.3).

1. 
   (normative)
   
   Physical tests
   1. Transparency test

Fill the empty plastics container to its nominal capacity with a volume of the primary opalescent suspension (A.4.7.2.3) diluted to an absorbance of 0,37 to 0,43 at 640 nm (dilution factor about 1:16) as measured in a cuvette with an internal light path of 1 cm.

• 1. Test for rate of collection

From a reservoir containing sufficient liquid at (37 ± 2) °C, having a viscosity of 3,4 × 10⁻⁶ m²/s at 37 °C, and under gauge pressure of 9,3 kPa, allow the plastics container to fill at a temperature of (23 ± 2) °C through a blood-taking needle as specified in 5.3 in the same hydrostatic plane as the top of the bag.

NOTE A suitable liquid for use in this test is a solution of glucose in water (400 g/l).

• 1. Test for permanence of labelling

Store the plastics container filled to nominal capacity and sealed for 24 h at a temperature of (4 ± 2) °C. Follow this initial storage period by a period of 24 h at a temperature of (−30 ± 5) °C, then submerge the plastics container in tap water maintained at a temperature of (37 ± 2) °C for 1 h.

• 1. Test for particulate contamination

B.4.1 Inspect plastics containers containing anticoagulant and/or preservative solutions as described in B.4.3.

B.4.2 Fill, under controlled conditions, the empty container with purified water which has been filtered previously through a membrane filter of pore diameter ≤ 0,2 μm. Use a volume of water corresponding to the nominal capacity of the container.

NOTE There is no standard liquid particulate test for medical devices. Methods for collection and analysis of particulate matter vary depending on the purpose of the evaluation and the location of the particulate matter. For example, pharmacopoeias specify limits for particle sizes, but for sets with integrated filters, fibres can be considered too.

B.4.3 Inspect the fluid in the plastics container by an appropriate method that will readily detect visible particles.

• 1. Test for sterile connection of tubing

This test is applicable to tubing that is suitable for use with a Sterile Welding Device (SWD).

lnstall and calibrate the SWD and train users before commencing.

Check that tubing dimensions are within the SWD manufacturer’s specified tolerances.

Make sterile connections between 12 cm segments for each combination of tubing shown in Table B.1 in strict accordance with SWD manufacturer’s instructions. Identify each weld individually.

Upon completion, visually inspect all welds for evidence of defects.

Gauge pressure test all welds for leaks by hermetically sealing one end of the tube, then applying a gauge pressure of 1,5 bar (50 kPa above atmospheric) for 10 s to the open end of the tube with the weld submerged below water. Check for emergence of air bubbles from the weld. Defects are not allowed.

Measure the breaking strain of each weld by stretching the tube segment at a speed of 500 mm/min with a universal tensile tester. Each weld must withstand a minimum of 40 N at (23 ± 2) °C (see also [4]).

Table B.1 — Matrix of required sterile connections and tests

Wet condition can be achieved with either biological fluids (e.g. plasma) or anticoagulant/preservative solutions.

NOTE Alternatively, points from B.1 to B.4 can be tested as described in the relevant pharmacopoeias (such as Eur. Ph., 3.3.4^[16]).

1. 
   (normative)
   
   Biological tests
   1. General

Biological testing shall be performed using in vitro or in vivo methods appropriate to the intended clinical use of the device, taking into account the category and duration of body contact, including contact with anticoagulant/preservative solutions and/or blood or blood components. The evaluation strategy shall ensure that testing is scientifically justified, proportionate to the identified risks, and appropriate for the material in its final finished form. Biological testing shall be conducted in accordance with ISO 10993-1 and the relevant parts of the ISO 10993 series^[17].

Manufacturers shall document the rationale for the chosen biological evaluation approach in the technical documentation, including any decisions to waive testing based on material characterization, already available biological data and/or pre-clinical and clinical data.

The use of animal testing shall be considered only as a last resort. In accordance with ISO 10993-2, all available alternatives — such as the use of existing data, chemical and physical characterization, in vitro methods, or other mitigation strategies — shall be thoroughly evaluated and exhausted before initiating in vivo studies.

• 1. Preparation of the test solutions

ISO 10993-12 defines sample preparation and reference materials. Manufacturers shall conduct adequate testing to demonstrate biocompatibility.

The extraction procedure described below is derived from ISO 10993-12 and is provided as a guidance example. Other extraction methods may be used, provided they are scientifically justified and appropriate to the intended use.

• • 1. Test fluid I (polar extractant)

Fill the empty plastics container twice to nominal capacity with water for injection, shake for approximately 1 min, and then empty. After the rinse water has drained off, fill the empty container with enough sterile endotoxin-free sodium chloride solution^[4] [ρ(NaCl) = 9 g/l] so that the ratio of the inner surface of the empty container, expressed in square centimetres, to the volume of sodium chloride solution, expressed in millilitres, is at least 6:1. Then compress the container so that the remaining air escapes from the container and close it. If the container is packed in an outer bag, extract it for at least (60 ± 12) min in pressurized, saturated steam at (121 ± 2) °C. Perform the extraction on a sufficient number of containers so that at least approximately 250 ml of extract is available. Mix the extracts from the individual containers after they have cooled. Treat in a flask in the same manner 250 ml of the sterile, endotoxin-free isotonic sodium chloride solution as comparison fluid (blank sample).

• • 1. Test fluid II (non-polar extractant)

Prepare the test fluid II in the same manner as the test fluid I according to C.2.1, but

— dry the empty containers after being rinsed with water for injection at (50 ± 2) °C for 1 h or until moisture can no longer be determined by visual inspection,

— using sesame oil for parenteral^[5] use or cottonseed oil^[6] as extraction agent,

— using sesame oil for parenteral⁵⁾ use or cottonseed oil⁶⁾ as comparison fluid according to the extraction agents used, and

— using the non-polar extractant mentioned in the specific biological test.

• 1. Test for impermeability to microorganisms

Fill empty containers to their nominal capacity under sterile conditions with a culture medium capable of supporting microbial growth, e.g. casein peptone-soybean flour peptone bouillon (CaSo), and seal. Ensure contamination did not occur during the addition of the growth media to the containers prior to executing further steps by holding the filled containers at a temperature of (32,5 ± 2,5) °C for 7 to 14 days.

Prepare a suspension of small challenge motile bacteria (e.g. Brevundimonas diminuta) at a high concentration (approximately 10⁶ CFU/ml). The final suspension shall be large enough to immerse the containers for at least 1 h. Remove the containers from the challenge suspension and disinfect the outside.

Incubate the containers for at least 7 days at a temperature of (32,5 ± 2,5) °C. There should be no growth of the challenge organism.

Positive controls should be used with the study using a container inoculated with 1 ml of a culture of the challenge organism. The positive control should demonstrate growth of the challenge organism.

NOTE Alternative validated test methods for testing impermeability to microorganisms can be used, provided they are at least equivalent to the one reported in C.3.

• 1. Test for bacterial endotoxins

Perform tests for bacterial endotoxins according to the relevant pharmacopoeia.

1. 
   (informative)
   
   Rationale, guidance and history of the development of this document

D.1 General

This Annex provides insights into the thinking process which led to establishment or modification of parts of this document. In that respect, it intends to give information about the history of the development of this document and to summarize the different arguments discussed within ISO/TC 76 during the elaboration of the document. It should help better understand the intention of the various requirements.

This Annex is intended for those who are familiar with the subject of this document but who have not participated in its development. An understanding of the rationale underlying the requirements is considered to be essential for their proper use.

Furthermore, as clinical practice and technology change, it is believed that a rationale will facilitate any further revision of this document necessitated by those developments.

The clauses and subclauses in this Annex have been numbered to correspond to the numbering of the clauses and subclauses of this document to which they refer. The numbering is, therefore, not consecutive.

D.2 Rationale applicable to the whole standard

Not applicable.

D.3 Rationale for particular clauses and sub-clauses

D.3.1 Main body of ISO 3826-4

Sub-clause 3.10 — Definition of “nominal capacity”

During the development of this second revision of ISO 3826-4, it was noted that a definition of “nominal capacity” was missing in the ISO 3826 series, although many test methods in this document (e.g. freezing, ionizing irradiation, centrifugation, leakage tests and emptying under pressure) require the plastics container to be filled to its nominal capacity. In the absence of a formal definition, different interpretations existed in practice regarding the volume to be used for testing, such as the maximum filling volume of the container, or other volumes not necessarily related to the intended use.

Such different interpretations resulted in inconsistencies in the outcome of several test methods. For example, for the test “emptying under pressure” (6.2.11), larger containers (e.g. 1 300 mL) filled to their maximum possible volume could not logically meet the emptying time of 2 min, while smaller containers (e.g. 600 mL) could, although the performance of both products was acceptable when filled for their intended clinical use. Similar considerations apply to tests for freezing, irradiation resistance and centrifugation, in which the behavior of the plastics container depends on the volume of liquid it is filled with.

To improve consistency and ensure that the tests better reflect the intended use of the plastics containers for blood and blood components, a definition of “nominal capacity” has therefore been introduced. The definition reflects the terminology used in pharmacopoeias and refers to the customary volume of blood or blood component that the container is intended to collect under normal conditions of use.

This clarification ensures that all performance tests requiring filling to nominal capacity are conducted using the same meaningful and clinically relevant volume. As a result, the reproducibility of the tests is improved, and the outcomes are aligned with the actual intended use of the plastics containers

Sub-clause 6.3 Chemical requirements, in particular regarding heavy metals

Since the publication of ICH guideline Q3D (R2) on elemental impurities^[22] (adopted 26 April 2022), which applies to finished products, the tests and limits for heavy metals are progressively removed from the individual Ph. Eur. monograph, and reference to ICH Q3D is introduced. ICH Q3D describes a new risk assessment procedure which addresses each heavy metal, depending on its individual toxicity, and no longer on a collective level as stated in Table 3 of this document. Manufacturers are encouraged to follow up on the latest advancement of the various pharmacopoeias and regulations, and to apply the most suitable risk assessment procedure.

ISO 3826-4 requirements for metals and heavy metals are based on the former approach. However, it is also stated that alternative methods, such as those described in pharmacopoeias, can be used. In particular, the different metals collectively regrouped in the term “heavy metals” are, since ICH Q3D (R2), classified in different categories (Class 1, 2A, 2B and 3) for which different limits are stated. Furthermore, the colorimetric method is old and does not allow for specific and accurate determination of the concentration.

As “alternatively, it may be tested as described in the relevant pharmacopoeias” is already stated in 6.3.2, ISO/TC 76 agreed during the development of the second revision of ISO 3826-4 not to modify the requirements for heavy metals, but to provide guidance as to which pharmacopoeias could be considered, with references pointing to the bibliography. More important modifications could eventually be implemented in a later revision, depending on the advancement of the on-going pharmacopoeias harmonisation and improvements.

Sub-clause 6.4 and Annex C — Biological requirements and biological tests

During the development of this second revision of ISO 3826-4, ISO/TC 76 noted that the biological requirements and the list of test methods provided in the previous edition covered only a limited subset of the biological endpoints described in ISO 10993-1. Since ISO 10993-1 establishes a comprehensive, risk-based approach to biological evaluation, the partial list of tests previously included in Clause 6.4 and Annex C could have been misinterpreted as an exhaustive or prescriptive set of required tests, rather than as part of a broader evaluation strategy based on the intended clinical use, the nature and duration of body contact, and the available biological and clinical data.

In order to align the document with current regulatory expectations and with the principles of ISO 10993-1 and ISO 14971, Clause 6.4 has therefore been revised to clearly state that the biological safety of the plastics container and its materials shall be assessed within a risk-management framework in accordance with ISO 10993-1. Annex C has been restructured accordingly to emphasise this risk-based approach, to clarify the responsibilities of manufacturers in selecting and justifying appropriate biological tests, and to avoid duplicating or partially reproducing the content of the ISO 10993 series.

Annex C now retains only those test procedures that are particular to the performance requirements of ISO 3826-4 (e.g. the test for impermeability to microorganisms and the test for bacterial endotoxins), together with an extraction procedure derived from ISO 10993-12 provided as a guidance example. These procedures supplement—rather than replace—the biological evaluation required under ISO 10993-1. Alternative validated approaches may be used, provided that they are scientifically justified and appropriate for the intended use.

This revision ensures consistency with the ISO 10993 series, avoids potential misinterpretation regarding the scope of biological test requirements, and provides manufacturers with the necessary flexibility to design an appropriate biological evaluation programme based on a risk-management strategy.

1. 
   (informative)
   
   Sustainability

E.1 General

Upon implementing this document, readers are encouraged to consider measures beyond the explicitly stated requirements to actively reduce the use of natural resources and minimize the ecological footprint.

Thinking beyond the minimum requirements will help create a more sustainable and future-proof environment. Stakeholders are taking responsibility for their role in the process and offer improvements where possible, without compromising on quality, safety, or efficacy. Planned actions and shared responsibility in improving our business practices can shape a better and brighter future for generations to come.

E.2 Areas for environmentally conscious design and manufacturing

ISO/TC 76 has identified the following major areas for environmentally conscious design and manufacturing, to be considered during the development and/or testing of products according to the present document:

a) Material choice and consumption

— Minimize material consumption by considering component mass and volume, and the design of integrated features.

— Choose recycling-compatible materials to recycle the entire device, where possible, or choose materials that can be easily separated to increase their potential for recycling.

— Avoid mixing materials in one device where possible.

— Use production technologies that reduce material waste (e.g., hot runner systems in moulding).

— Select materials with a lower environmental impact.

b) Streamlining testing programs

— As quantitative testing often provides more meaningful results and statistical confidence, allowing for reduced sample sizes compared to attributive testing, set up quantitative test protocols to verify the requirements of this standard, where possible.

— Where practicable, simulations might replace certain physical tests.

c) Environmentally conscious selection and design of packaging materials and layers

— Consider packaging volumes to reduce material consumption and transportation volumes.

— Choose adequate layers of packaging materials, considering the use case and healthcare work environment, as well as product protection and logistics needs.

d) Consideration of device life cycle

— Provide needle-free connectors to reduce the need for needles and transfer devices.

— Plan and describe the disposal of devices.

— Consider hospital workflows, the number of uses per device, and device lifetime, balancing infection risks and patient safety with environmental consequences.

1. 
   (informative)
   
   Atrributive and variable testing

Some test methods incorporated into this document are written as attribute data test methods.

Manufacturers can substitute variable data test methods for the attribute data test methods provided in this document as long as they can provide evidence that the intention of the attribute data test method can be met.

a. Attribute data tests are more commonly known as pass/fail tests. Attribute data tests can only determine if the specification is met. They provide no indication of how the medical device fails and typically require a larger sample size to achieve the same statistical power as an equivalent variable data test.

b. Variable data tests are those tests that produce quantifiable results (e.g. the force required to separate components within a medical device or the actual leak rate). Variable data test results determine the value at which the medical device fails, provide a numerical result that can be statistically analysed, and typically require a smaller sample size to have the same statistical power as equivalent attribute data test results. Variable data provides a more holistic assessment of the device performance and safety margins.

Annex ZA
(informative)

Relationship between this European standard and the General Safety and Performance Requirements of Regulation (EU) 2017/745 aimed to be covered

This European standard has been prepared under M/575 to provide one voluntary means of conforming to the General Safety and Performance Requirements of Regulation (EU) 2017/745 of 5 April 2017 concerning medical devices [OJ L 117] and to system or process requirements including those relating to quality management systems, risk management, post-market surveillance systems, clinical investigations, clinical evaluation or post-market clinical follow-up.

Once this standard is cited in the Official Journal of the European Union under that Regulation, compliance with the normative clauses of this standard given in Table ZA.1 and application of the edition of the normatively referenced standards as given in Table ZA.2 confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding General Safety and Performance Requirements of that Regulation, and associated EFTA Regulations.

Where a definition in this standard differs from a definition of the same term set out in Regulation (EU) 2017/745, the differences shall be indicated in this Annex Z. For the purpose of using this standard in support of the requirements set out in Regulation (EU) 2017/745, the definitions set out in this Regulation prevail.

Where the European standard is an adoption of an International Standard, the scope of this standard can differ from the scope of the European Regulation that it supports. As the scope of the applicable regulatory requirements differ from nation to nation and region to region, the standard can only support European regulatory requirements to the extent of the scope of the European regulation for medical devices (EU) 2017/745).

NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk management process needs to be in compliance with Regulation (EU) 2017/745. This means that risks have to be ‘reduced as far as possible’, ‘reduced to the lowest possible level’, ‘reduced as far as possible and appropriate’, ‘removed or reduced as far as possible’, ‘eliminated or reduced as far as possible’, ’removed or minimized as far as possible’, or ‘minimized’, according to the wording of the corresponding General Safety and Performance Requirement.

NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with General Safety and Performance Requirements 1, 2, 3, 4, 5, 8, 9, 10, 11, 14, 16, 17, 18, 19, 20, 21 and 22 of the Regulation.

NOTE 3 When a General Safety and Performance Requirement does not appear in Table ZA.1, it means that it is not addressed by this European Standard.

Table ZA.1 — Correspondence between this European standard and Annex I of Regulation (EU) 2017/745 [OJ L 117] and to system or process requirements including those relating to quality management systems, risk management, post-market surveillance systems, clinical investigations, clinical evaluation or post-market clinical follow-up

Table ZA.2 — Applicable Standards to confer presumption of conformity as described in this Annex ZA

The documents listed in the Column 1 of Table ZA.2, in whole or in part, are normatively referenced in this document, i.e. are indispensable for its application. The achievement of the presumption of conformity is subject to the application of the edition of Standards as listed in Column 4 or, if no European Standard Edition exists, the International Standard Edition given in Column 2 of Table ZA.2.

WARNING 1: Presumption of conformity stays valid only as long as a reference to this European standard is maintained in the list published in the Official Journal of the European Union. Users of this standard should consult frequently the latest list published in the Official Journal of the European Union.

WARNING 2: Other Union legislation may be applicable to the product(s) falling within the scope of this standard.

Bibliography

[1] ISO 80369‑1:2018, Small-bore connectors for liquids and gases in healthcare applications – Part 1: General requirements

[2] ISO 15747:2018, Plastic containers for intravenous injections

[3] ISO 7864:2016, Sterile hypodermic needles for single use — Requirements and test methods

[4] NIGHTINGALE. M.J., LEES, B., BISET, R. and MERTENS, W., Use of a (proposed) standard protocol to validate Terumo TSCD-II connections between dissimilar blood bag tubing. Vox Sang. 2006, 91 pp. 264–269

[5] European Commission. EudraLex – Volume 4: EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, February 2022. Available at: https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en

[6] EDQM (European Directorate for the Quality of Medicines & HealthCare). Guide to the Preparation, Use and Quality Assurance of Blood Components, 21st ed., Council of Europe, Strasbourg, 2020

[7] NIGHTINGALE. M.J. and LEIMBACH, R., An evaluation of proposed changes to International Standards for blood bags and transfusion sets to improve their compatibility. Transfus. Med. 2008, 18 pp. 281–286

[8] European Pharmacopoeia 11th Ed. §3.3.5 (Empty sterile containers of plasticised poly(vinyl chloride) for human blood and blood components)

[9] ISO 11607‑1:2019, Packaging for terminally sterilized medical devices — Part 1: Requirements for materials, sterile barrier systems and packaging systems

[10] ISO 3826‑2:2008, Plastics collapsible containers for human blood and blood components — Part 2: Graphical symbols for use on labels and instruction leaflets

[11] ISO 15223‑1:2021, Medical devices — Symbols to be used with information to be supplied by the manufacturer — Part 1: General requirements

[12] Regulation (EU) 2017/745 of the European Parliament and of the Council on medical devices (MDR)

[13] EN 15986:2011, Symbol for use in the labelling of medical devices — Requirements for labelling of medical devices containing phthalates

[14] International Medical Device Regulators Forum (IMDRF). UDI Guidance: Unique Device Identification (UDI) of Medical Devices. IMDRF/UDI WG/N7 FINAL:2013

[15] International Council for Commonality in Blood Banking Automation, Inc. (ICCBBA). Available at: http://www.iccbba.org

[16] European Pharmacopoeia 11th Ed. §3.3.4 (Sterile plastic containers for human blood and blood components)

[17] ISO 10993 (all parts), — Biological evaluation of medical devices

[18] European Pharmacopoeia 11th Ed. Monograph 0193 (Sodium Chloride)

[19] European Pharmacopoeia 11th Ed. Monograph 0433 (Sesame Oil, Refined)

[20] United States Pharmacopeia (USP). Sesame Oil. USP-NF Monograph. Official as of January 1, 2018

[21] United States Pharmacopeia (USP). Cottonseed Oil. USP-NF Monograph. Official as of January 1, 2018

[22] ICH Q3D (R2). Guideline for Elemental Impurities. International Council for Harmonisation (ICH), 2022

1. If there are no applicable national regulations, n is determined by the manufacturer. ↑

2. If there are no applicable national regulations, n is determined by the manufacturer. ↑

3. See, for example, European Pharmacopoeia. ↑

4. See Reference [18]. ↑

5. See Reference [19] and Reference [20]. ↑

6. See Reference [21] ↑