Medical devices utilizing animal tissues and their derivatives

ISO/TR 22442-4:2010 offers suggestions for designing and conducting validation assays to help determine if processes used in the manufacture of medical devices derived from non-viable animal tissues might serve to reduce the risk of iatrogenic transmission of transmissible spongiform encephalopathies (TSEs). The TSE-removal methods used to process animal tissues should also reduce the risk of transmitting TSE infections via non-viable tissues of human origin; this Technical Report does not address this issue. Some current information on human tissues and TSEs is presented which may be applied by analogy to other animal tissues. ISO/TR 22442-4:2010 does not intend to imply a need for validation of methods involving specific materials identified as having a "negligible risk" of contamination with TSE agents as listed in Annex C of ISO 22442-1:2007. It is intended to clarify final draft international standards included in the ISO 22442 series, as well as in ISO 14160. ISO/TR 22442-4:2010 builds upon the specific discussion in ISO 22442-3 relative to TSE agents and attempts to summarize the current state of the art in the arena of TSE agent elimination. As the understanding of inactivation and elimination of TSE agents evolves, this document will be revised when possible.

Dispositifs médicaux utilisant des tissus animaux et leurs dérivés

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Publication Date
15-Nov-2010
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6060 - International Standard published
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04-Nov-2010
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16-Nov-2010
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TECHNICAL ISO/TR
REPORT 22442-4
First edition
2010-12-01
Medical devices utilizing animal tissues
and their derivatives —
Part 4:
Principles for elimination and/or
inactivation of transmissible spongiform
encephalopathy (TSE) agents and
validation assays for those processes
Dispositifs médicaux utilisant des tissus animaux et leurs dérivés —
Partie 4: Principes d'inactivation et/ou d'élimination des agents
transmissibles de l'encéphalopathie spongiforme bovine (ESB) et
essais de validation de ces procédés
Reference number
ISO/TR 22442-4:2010(E)
ISO 2010
---------------------- Page: 1 ----------------------
ISO/TR 22442-4:2010(E)
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ii © ISO 2010 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/TR 22442-4:2010(E)
Contents Page

Foreword ............................................................................................................................................................iv

Introduction.........................................................................................................................................................v

1 Scope......................................................................................................................................................1

2 Normative references............................................................................................................................1

3 Terms and definitions ...........................................................................................................................2

4 Elimination of TSE agents: basic considerations..............................................................................2

4.1 General ...................................................................................................................................................2

4.1.1 TSEs of concern ....................................................................................................................................2

4.1.2 Animal tissues of concern....................................................................................................................2

4.1.3 Tissues infected with TSE agents .......................................................................................................2

5 Potential methods to eliminate TSE agents .......................................................................................3

5.1 Methods for inactivating infectivity.....................................................................................................3

5.1.1 General ...................................................................................................................................................3

5.1.2 Physical methods for inactivating TSE infectivity.............................................................................3

5.1.3 Chemical methods for inactivating TSE infectivity............................................................................4

5.2 Methods for removing TSE infectivity without inactivating infectivity............................................5

6 Experimental validation of methods for eliminating TSE agents from medical devices

utilizing non-viable animal tissues......................................................................................................6

6.1 General ...................................................................................................................................................6

6.2 Defining of product families for purposes of designing TSE process validation studies.............6

6.3 Selection and testing of product for establishing and verifying the infecting dose of TSE

agent .......................................................................................................................................................6

6.4 TSE agent spiking materials ................................................................................................................6

6.5 Availability of bioassay animals (conventional and transgenic mice, other rodents, farm

animals) ..................................................................................................................................................7

6.6 Potential development of cell culture assays for infectivity.............................................................7

TSE

6.7 Correlations between PrP and infectivity assays..........................................................................7

6.8 Reductions in infectivity compared with failure to detect at limits of detection ............................8

6.9 Determining numbers of replicate validations needed to support inferences of reduction

in infectivity rather than variations in assay performance ...............................................................8

TSE

6.10 Requirements for step-wise reductions in PrP and infectivity verses whole-process

validation................................................................................................................................................8

Bibliography........................................................................................................................................................9

© ISO 2010 – All rights reserved iii
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ISO/TR 22442-4:2010(E)
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.

International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.

The main task of technical committees is to prepare International Standards. Draft International Standards

adopted by the technical committees are circulated to the member bodies for voting. Publication as an

International Standard requires approval by at least 75 % of the member bodies casting a vote.

In exceptional circumstances, when a technical committee has collected data of a different kind from that

which is normally published as an International Standard (“state of the art”, for example), it may decide by a

simple majority vote of its participating members to publish a Technical Report. A Technical Report is entirely

informative in nature and does not have to be reviewed until the data it provides are considered to be no

longer valid or useful.

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.

ISO/TR 22442-4 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices,

Subcommittee SC 1, Tissue product safety.

ISO 22442 consists of the following parts, under the general title Medical devices utilizing animal tissues and

their derivatives:
⎯ Part 1: Application of risk management
⎯ Part 2: Controls on sourcing, collection and handling

⎯ Part 3: Validation of the elimination and/or inactivation of viruses and transmissible spongiform

encephalopathy (TSE) agents

⎯ Part 4: Principles for elimination and/or inactivation of transmissible spongiform encephalopathy (TSE)

agents and validation assays for those processes [Technical Report]
iv © ISO 2010 – All rights reserved
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ISO/TR 22442-4:2010(E)
Introduction
Certain medical devices utilize materials of animal origin.

Animal tissues and their derivatives are used in the design and manufacture of medical devices to provide

performance characteristics that were chosen for advantages over non-animal based materials. The range

and quantities of materials of animal origin in medical devices vary. These materials can comprise a major

part of the device (e.g. bovine/porcine heart valves, bone substitutes for use in dental or orthopaedic

applications, haemostatic devices), can be a product coating or impregnation (e.g. collagen, gelatine,

heparin), or can be used in the device manufacturing process (e.g. tallow derivatives such as oleates and

stearates, fetal calf serum, enzymes, culture media).

This document is a Technical Report (TR) to offer suggestions for designing and conducting validation assays

to help determine if processes used in the manufacture of medical devices derived from non-viable animal

tissues might serve to reduce the risk of iatrogenic transmission of transmissible spongiform encephalopathies

(TSEs). This document will refer to the infective vector as “TSE agent” rather than prion to remain consistent

with the other Parts of ISO 22442. Some current information on human tissues and TSEs is also presented

which may be applied by analogy to other animal tissues.

Iatrogenic transmission of the human TSE Creutzfeldt-Jakob disease (CJD) has been convincingly attributed

to exposure to the human dura mater allograft (Hannah, E. L., E. D. Belay, et al. 2001) used in surgery as a

patching material and to hormones extracted from human pituitary glands (Mills, J. L., L. B. Schonberger, et

al. 2004)—both non-viable tissues; recently, sub-clinical infection with the vCJD agent was detected at

autopsy in a patient with hemophilia and plausibly attributed to his treatment with processed human plasma-

derived coagulation factor (UK Health Protection Agency 2009 at:

http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1234859690542?p=1231252394302

and

http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_100357).

In addition, corneal grafts have transmitted CJD (Kennedy, Hogan et al, 2001) and several transfused red

blood cell concentrates have transmitted variant CJD (vCJD) (Llewelyn, Hewitt et al 2004; Peden, Head et al

2004; Peden, Ritchie and Ironside 2005).

Exposure to the agent of bovine spongiform encephalopathy (BSE) has been responsible for more than 210

cases of vCJD worldwide, most of them thought to have resulted from dietary exposure to infected beef

products. Although, except for the iatrogenic vCJD infections just described, no transmissions of a BSE-

derived agent via medical or veterinary products have been recognized, there is no reason to doubt that a

medical device contaminated with BSE agent of ruminant origin could transmit infection to a susceptible

subject. Indeed, two veterinary vaccines derived from non-viable ovine tissues transmitted the ovine/caprine

TSE scrapie to sheep (World Health Organization 2006). Humans are not known to have been infected with

the scrapie agent.

This Technical Report generally uses terminology suggested by the World Health Organization (WHO

Guidelines on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies, 2006 (World

Health Organization 2006)), while recognizing that there is no international consensus regarding either

preferred terminology, the probable molecular nature of the transmissible agents (the all-protein or “prion”

theory (Prusiner 1982) currently most widely held) or the precise role of various forms of the host-coded prion

protein in the replication of the infectious agents or pathogenesis of disease. The sole intent of the TR is to

suggest strategies to validate the effectiveness of methods that might reduce the risk of accidentally

transmitting TSEs by medical devices prepared using non-viable animal tissues.
© ISO 2010 – All rights reserved v
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ISO/TR 22442-4:2010(E)

The following referenced documents are standards helpful for the proper interpretation of this document:

⎯ ISO 22442-1, Medical devices utilizing animal tissues and their derivatives — Part 1: Application of risk

management

⎯ ISO 22442-2, Medical devices utilizing animal tissues and their derivatives — Part 2: Controls on

sourcing, collection and handling

⎯ ISO 22442-3, Medical devices utilizing animal tissues and their derivatives — Part 3: Validation of the

elimination and/or inactivation of viruses and transmissible spongiform encephalopathy (TSE) agents

⎯ ISO 14160, Sterilization of health care products — Liquid chemical sterilizing agents for single-use

medical devices utilizing animal tissues and their derivatives — Requirements for characterization,

development, validation and routine control of a sterilization process for medical devices

These documents include both normative and informative annexes also directly relevant to the topic of this

ISO TR. All terms defined in those documents are used verbatim in this report.

Due to the lack of consistent process steps that can reliably eliminate TSEs, it is important that one must use

low-risk source animals and tissues.

Although not directly applicable to validating methods purported to reduce the TSE risk from medical devices

manufactured from non-viable animal tissues, UK and US competent authorities have solicited expert advice

on desirable features of validation studies for devices intended to remove TSE infectivity from human blood

potentially contaminated with TSE agents, and this advice may be helpful in evaluating methods for animal-

derived tissues as well. These features included preliminary evaluation using TSE-spiked material with high

titers of infectivity, selecting experimental agents relevant to the infection of concern, and accepting studies

TSE

using assays for PrP as a preliminary screening strategy to dismiss unpromising methods. These methods

were required to indicate significant reduction in infectivity demonstrated by bioassays in known susceptible

experimental animals. To qualify a method as potentially useful, the assay needed to demonstrate similar

results for the same candidate method with two TSE agent-bioassay combinations, whenever possible. These

criteria should be met before concluding that the method offers sufficient promise to consider in practice.

Demonstration that a method reduces TSE infectivity for tissues endogenously infected, and that the complete

manufacturing process eliminates all detectable infectivity, while desirable, are not currently feasible. Very low

titers of infectivity in most tissues outside the nervous system and limited animals known to be susceptible to

naturally occurring TSE agents without adaptation to a new species are limiting factors. The lack of standard

reference infected materials of known titer and biological properties from humans and animals with TSEs is

thought to be an additional impediment to developing validation studies (World Health Organization (2006),

Annex 2). Considering the extremely limited attempted validation efforts for methods for improving TSE safety

of human blood-derived and other human tissue-derived medical products — products with demonstrated

iatrogenic transmissions — care must be taken not to discourage new efforts to validate methods that might

improve the TSE safety of medical devices derived from animal tissues.

It should be noted again that, as summarized above, animal tissues have not been directly implicated in

causing any iatrogenic TSE infections of humans (Minor, Newham et al. 2004). However, experience with

food-borne BSE and field transmissions of scrapie to sheep by ovine tissue-derived veterinary vaccines

suggests that the risk of iatrogenic transmissions of TSEs (other than BSE) from animals to humans, while

theoretical, remains worthy of continued attention.
vi © ISO 2010 – All rights reserved
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TECHNICAL REPORT ISO/TR 22442-4:2010(E)
Medical devices utilizing animal tissues and their derivatives —
Part 4:
Principles for elimination and/or inactivation of transmissible
spongiform encephalopathy (TSE) agents and validation assays
for those processes
1 Scope

This Technical Report offers suggestions for designing and conducting validation assays to help determine if

processes used in the manufacture of medical devices derived from non-viable animal tissues might serve to

reduce the risk of iatrogenic transmission of transmissible spongiform encephalopathies (TSEs).

The TSE-removal methods used to process animal tissues should also reduce the risk of transmitting TSE

infections via non-viable tissues of human origin; this Technical Report does not address this issue. Some

current information on human tissues and TSEs is presented which may be applied by analogy to other animal

tissues.

This Technical Report does not intend to imply a need for validation of methods involving specific materials

identified as having a “negligible risk” of contamination with TSE agents as listed in Annex C of

ISO 22442-1:2007.

This Technical Report is intended to clarify final draft international standards included in the ISO 22442 series,

as well as in ISO 14160.

This Technical Report builds upon the specific discussion in ISO 22442-3 relative to TSE agents and attempts

to summarize the current state of the art in the arena of TSE agent elimination. As the understanding of

inactivation and elimination of TSE agents evolves, this document will be revised when possible.

2 Normative references

The following referenced documents are indispensable for the application 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 22442-1, Medical devices utilizing animal tissues and their derivatives — Part 1: Application of risk

management

ISO 22442-2, Medical devices utilizing animal tissues and their derivatives — Part 2: Controls on sourcing,

collection and handling

ISO 22442-3, Medical devices utilizing animal tissues and their derivatives — Part 3: Validation of the

elimination and/or inactivation of viruses and transmissible spongiform encephalopathy (TSE) agents

ISO 14160, Sterilization of single-use medical devices incorporating materials of animal origin — Validation

and routine control of sterilization by liquid chemical sterilants
© ISO 2010 – All rights reserved 1
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ISO/TR 22442-4:2010(E)
3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 22442-1, ISO 22442-2,

ISO 22442-3, and ISO 14160 apply.
4 Elimination of TSE agents: basic considerations
4.1 General
4.1.1 TSEs of concern

BSE of cattle is the only TSE of animal origin known so far to have transmitted disease to humans (i.e, a

zoonosis). Scrapie, while of theoretical concern, has not been recognized as a zoonosis in spite of hundreds

of years of experience. Nonetheless, some competent regulatory authorities have adopted precautionary

policies that discourage the sourcing of ovine-derived and caprine-derived injectable materials from herds with

a history of scrapie (e.g. transcripts of the FDA TSE Advisory Committee meeting 03 June 1999, accessed 16

July 2009 at http://www.fda.gov/ohrms/dockets/ac/cber99.htm#Transmissible%20Spongiform, European

Union Directive from 2003 [OJ L 105, 26.4.2003 p. 18, http://eur-

lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2003:105:0018:0023:EN:PDF ], and Japanese notification

177 http://www.nihs.go.jp/cgtp/cgtp/guidline/03052001.pdf). The susceptibility of sheep and goats to infection

with the BSE agent has posed another more recent concern (World Health Organization 2006). Although pigs

have been experimentally infected with the BSE agent (Wells, Hawkins et al. 2003; Castilla, Gutierrez-Adan et

al. 2004), they were not infected when exposed by the oral route and no naturally transmitted porcine TSE has

been recognized, and most authorities remain generally satisfied that porcine tissues are an unlikely source of

human exposure to any TSE agent. The same thing is true for tissues of other animals less commonly used in

the manufacture of medical devices, such as horses. (Animals not susceptible to infection with TSE agents by

the oral route have not been considered “TSE-relevant animal species” by EMEA; tissues of such species

were not considered to be of concern regarding TSE risk in the manufacture of medicinal products for human

or veterinary use in a 2004 note for guidance of the EMEA at
http://www.emea.europa.eu/pdfs/human/bwp/TSE%20NFG%20410-rev2.pdf.)
4.1.2 Animal tissues of concern

Examples of animal tissues currently used in their non-viable form to manufacture medical devices include

porcine heart valves, bovine pericardium, and bovine collagen. While none of these tissues has been

demonstrated to contain a TSE agent (World Health Organization 2006), experiments with animal tissues

have been very limited in number, and the assays used vary in sensitivity of detection. Furthermore, it is

conceivable that almost any animal tissue collected as part of routine slaughter might be accidentally

contaminated with higher-risk tissues. Regulations and procedures requiring removal, segregation and safe

disposal of “specified-risk” materials from animal carcasses — especially from carcasses of older animals —

should reduce but not completely eliminate this risk. The European Commission has recently proposed “risk-

proportionate rules for animal by-products” to clarify and facilitate risk management in selection of source

materials of animal origin (see EU regulation 1069/2009).
4.1.3 Tissues infected with TSE agents

Agents might contaminate tissues in two ways: (1) a tissue infected during the TSE disease process, or (2)

infectivity introduced into the tissue from infected tissue (for example, due to contact with tissues of the

nervous system, lymphoreticular cells or from blood in the tissues). This second or “exogenous” source of

contamination with a TSE agent might occur during harvesting of the tissue from an infected source or from

instruments or surfaces contaminated with TSE agent from a previously handled source. These distinctions

are important for several reasons: Endogenously infected tissues (except for tissues of the CNS, which have

been found to contain the great majority of total infectivity in the body of an infected animal) generally contain

very small amounts of agent, so suitable models to validate methods for eliminating endogenous infectivity are

logistically difficult to develop. Exogenous contamination is more easily modeled by intentionally spiking

tissues with TSE agents of known provenance, biological characteristics and content of infectivity as defined

by titrations in susceptible animals. Several strains of scrapie agent and one strain of BSE-derived agent

2 © ISO 2010 – All rights reserved
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ISO/TR 22442-4:2010(E)

(301V) adapted to propagate to high titers in rodents have been especially useful to model exogenously

infected materials (see C.1 of ISO 22442-3:2007 and Annex D of ISO 22442-03:2007. The selection of model

agents for validation studies is constrained by several considerations:

a) although the actual unpassaged TSE agent likely to be present in the tissue of concern might be

considered most “relevant” for purposes of validating inactivation/removal studies, the infectivity titers in

such agents are usually both unknown and lower than those of rodent-adapted agents (Wells 2007); and

b) or handling of the BSE agent and rodent-adapted strains derived from BSE agent, regulatory authorities

may require high-containment research facilities not widely available. In general, studies with rodent-

adapted scrapie agent have been considered acceptable, keeping in mind that reported resistance of

various strains of TSE to inactivation procedures has not been uniform (Peretz, Supattapone et al. 2006)

5 Potential methods to eliminate TSE agents
5.1 Methods for inactivating infectivity
5.1.1 General

Most authorities recommend that, whenever possible, TSE agents potentially contaminating source materials

be inactivated rather than simply separated from the raw materials. The presence of residual active agent

might pose a continuing danger of later accidental contamination of a tissue-derived product as well as

contaminating manufacturing facilities and non-disposable equipment. However, unfortunately, most of the

physical and chemical methods known to be effective for inactivating TSE agents are relatively harsh and

often impair the functional properties of tissues. For sanitizing the facilities and processing equipment that

cannot be destroyed after single use or protected from direct contact with potentially contaminated materials,

decontamination methods that reliably inactivate TSE agents are preferred to those that simply remove the

agents.
5.1.2 Physical methods for inactivating TSE infectivity
5.1.2.1 Heat

When suspensions of tissue from scrapie-infected rodents were rapidly heated with continuous stirring,

relatively rapid loss of infectivity occurred within a few minutes (Rohwer 1984; Rohwer 1984), reaching the

assay limit of detection. However, macerates and dried preparations of TSE agents retained some infectivity

even after long exposures to heat (Asher, Pomeroy et al. 1986; Asher, Pomeroy et al. 1987; Taylor, Fraser et

al. 1994). Dry heat appears to be less effective than moist heat for inactivating TSE agents (Taylor 2001).

(Indeed, two reports suggesting surgical transmissions of iatrogenic CJD involved instruments that had been

sterilized by exposure to dry heat (Nevin, McMenemy et al. 1960; Foncin, Gaches et al. 1980).) One series of

studies even found small amounts of infectivity in ash from scrapie agent incinerated in an oven at

temperatures up to 600 C (Brown, Liberski, et al. 1990), though not at a higher temperature (Brown, Rau et al.

2004). Tissue devices are unlikely to tolerate heat treatments adequate to inactivate TSE agents without loss

of function.

There have been suggestions that for adequate decontamination of TSE agents one should specify exposure

to steam in a porous-load autoclave for at least 18 minutes at 20-bar pressure. This has been shown to be

ineffective (Taylor and McBride 1987). A WHO Consultation (World Health Organization 1999) warned that

such treatment was unlikely to decontaminate a surface soiled with dried-on tissue from a TSE-contaminated

source. A consultant to the US CDC cautioned that many pathogens survive heat and chemical treatments

when contaminated surfaces have not been thoroughly cleaned and that thorough cleaning of critical surfaces

must be employed for safe reuse of all medical devices (Rutala W, FDA TSE Advisory Committee, 17 July

2003 accessed 16 July 2009 at http://www.fda.gov/ohrms/dockets/ac/03/slides/3969s1.htm); the same

consultant (Rutala 2010) noted, however, that the extreme rarity of iatrogenic transmissions of CJD attributed

to surgical instruments (none documented in medical literature since 1980) suggests that current standard

methods for sanitization and terminal sterilization of surgical instruments are probably effective in removing

sufficient CJD agent to reduce the risk to undetectable levels.
© ISO 2010 – All rights reserved 3
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ISO/TR 22442-4:2010(E)

This observed efficacy is likely a combined effect of cleaning and moist heat and the potential efficacy of

either method individually has been shown in the laboratory to be insufficient. (Bundesgesundheitsbl-

Gesundheitsforsch-Gesundheitsschutz 2001, UK Department of Health 2009)
5.1.2.2 Radiation

The TSE agents have resisted inactivation by both ultraviolet and ionizing radiations (Alper, Haig et al. 1966;

Latarjet, Muel et al. 1970; Latarjet 1979).
5.1.3 Chemical methods for inactivating TSE infectivity
5.1.3.1 Alkaline hydrolysis treatments

Exposure to sodium hydroxide (≥ 1N, especially at elevated temperatures) has been found effective in

removing
...

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