ASTM F2383 - 11

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Designation: F2383 −11
Standard Guide for
Assessment of Adventitious Agents in Tissue Engineered
Medical Products (TEMPs)
1
This standard is issued under the ﬁxed designation F2383; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope
1.1 This guide is intended as a resource for individuals and
organizations involved in the production, delivery, and regula-
tion of tissue engineered medical products (TEMPs). The
safety from contamination by potentially infectious adventi-
tious agents is important in the development of all TEMPs as
well as their components. This guide addresses how to assess
safety risks associated with adventitious agents and their
byproducts. These agents currently include bacteria, fungi,
mycoplasma, viruses, endotoxins, transmissible spongiform
encephalopathies (TSEs), and parasitic organisms. This guide
does not address TEMPs with live animal cells, tissues or
organs, or human cells, including stem cells, grown on any
animal feeder cells. Also excluded is patient follow-up testing.
1.2 This guide does not apply to any medical products of
human origin regulated by the U.S. Food and Drug Adminis-
tration under 21 CFR Parts 16 and 1270 and 21 CFR Parts 207,
807 and 1271. This guide does apply to cellular therapies
regulated under the PHS (Public Health Service) act.
1.3 The values stated in SI units are to be regarded as
standard. No other units of measurement are included in this
standard.
1.4 This standard does not purport to address all of the
safety concerns, if any, associated with its use. It is the
responsibility of the user of this standard to establish appro-
priate safety and health practices and to determine the
applicability of regulatory limitations prior to use.
2. Referenced Documents
2.1 ASTM Standards:
2
E1873 Guide for Detection of Nucleic Acid Sequences by
the Polymerase Chain Reaction Technique
F2210 Guide for Processing Cells, Tissues, and Organs for
Use in Tissue Engineered Medical Products
F2211 Classiﬁcation for Tissue Engineered Medical Prod-
ucts (TEMPs)
F2312 Terminology Relating to Tissue Engineered Medical
Products
F2386 Guide for Preservation of Tissue Engineered Medical
Products (TEMPs)
2.2 ANSI/AAMI Standard:
ST72 Bacterial Endotoxin—Test Methodologies, Routine
Monitoring and Alternatives to Batch Testing
3
2.3 Federal Regulations:
4
9 CFR Animals and Animal Products
21 CFR 210 Current Good Manufacturing Practice in
Manufacturing, Processing, Packing, or Holding of Drugs,
General
21 CFR 211 Current Good Manufacturing Practice for Fin-
ished Pharmaceuticals
21 CFR 610.12 General Biological Products Standards—
Sterility
21 CFR 610.13 (b) General Biological Products Standards—
Purity Test for Pyrogenic Substances
21 CFR 820 Quality System Regulation
21 CFR 1270 Human Tissue Intended for Transplantation
21 CFR 1271 Human Cells, Tissues, and Cellular and
Tissue-Based Products
2.4 MDA Standard:
Code of Practice for the Production of Human-Derived
Therapeutic Products
5
2.5 U. S. Pharmacopeia Document:
United States Pharmacopeia (USP), Edition XXIV (24)
6
3. Terminology
3.1 Deﬁnitions:
1
This guide is under the jurisdiction of ASTM Committee F04 on Medical and
Surgical Materials and Devices and is the direct responsibility of Subcommittee
F04.45 on Adventitious Agents Safety.
Current edition approved March 1, 2011. Published March 2011. Originally
approved in 2005. Last previous edition approved in 2005 as F2383 – 05. DOI:
10.1520/F2383-11.
2
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Standards volume information, refer to the standard’s Document Summary page on
the ASTM website.
3
Available from American National Standards Institute (ANSI), 25 W. 43rd St.,
4th Floor, New York, NY 10036, http://www.ansi.org.
4
Available from U.S. Government Printing Office Superintendent of Documents,
732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401, http://
www.access.gpo.gov.
5
Available from Medicines and Healthcare Products Regulatory Agency
(MHRA), Hannibal House, Elephant & Castle, London SE1 6TQ, U.K.
6
Available from U.S. Pharmacopeia (USP), 12601 Twinbrook Pkwy., Rockville,
MD 20852-1790, http://www.usp.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
1
 

3.1.1 adventitious agents, n—unintentionally introduced mi-

crobiological or other infectious contaminant. In the produc-

tion of TEMPs, these agents may be unintentionally introduced

into the manufacturing process or into the ﬁnal product or both.

(See Terminology F2312.)

3.1.1.1 Discussion—In this guide, adventitious agents also

include microbiological or other infectious contaminants that

may be endogenous to the starting cells or tissue.

3.1.2 endotoxin, n—pyrogenic high molar mass lipopolysac-

charide (LPS) complex associated with the cell wall of

gram-negative bacteria.

3.1.2.1 Discussion—Though endotoxins are pyrogens, not

all pyrogens are endotoxins. Endotoxins are speciﬁcally de-

tected through a Limulus Amebocyte Lysate (LAL) test.

4. Signiﬁcance and Use

4.1 TEMPs may be composed of biological products (for

example, human cells, organs, tissues, derivatives, and pro-

cessed biologics), biomaterials (for example, substrates and

scaffolds composed of polymers or collagen), and biomol-

ecules (for example, recombinant proteins, alginates, and

hyaluronates) (see Terminology F2312). Those TEMPs that

contain human viable cells, organs, or tissues differ in terms of

adventitious agent safety from other TEMPs because of the

need to preserve viability of the organ, tissue, or cellular

components. The need for preservation of viability limits

processing options for the reduction or elimination of adven-

titious agents. Examples of TEMPs are listed in Classiﬁcation

F2211.

4.2 To ensure production and use of TEMPs with minimal

risks associated with microorganisms and other adventitious

agents, a multi-tiered approach is required. Donor testing, as

well as testing of components and raw materials by sufficiently

sensitive assays that are state of the art is usually necessary.

Compliance with good manufacturing practices (GMPs) and

good tissue practices (GTPs), where applicable, is required (21

CFR 210, 211, 820, 1270, and 1271). Although some of the

components of the TEMPs may be processed to remove

potential microbiological contaminants, viable tissues and

cellular components are generally unable to withstand rigorous

processing without losing functionality. For those TEMPs

containing tissues or cells for which banking is not possible,

even greater reliance on donor screening, component testing,

and manufacturing controls is required. When more upfront

testing is possible, there is generally greater conﬁdence in the

safety of the ﬁnal product. Process validation can enhance

conﬁdence in the ability of the TEMPs’ producer to minimize

risks from adventitious agents.

4.3 Throughout this guide, the reader is referred to other

documents that may provide speciﬁc information that can be

applied in the manufacture and testing of TEMPs. Although

many of these documents were not written with TEMPs in

mind, parts are often applicable. Most of the potentially

applicable position papers and guidance documents from many

regions of the world can be accessed via the internet. New

documents are continually produced. The MDCA (U.K. Medi-

cal Devices Agency, now part of MHRA, Medicines and

Healthcare Products Regulatory Agency) Code of Practice for

the Production of Human-Derived Therapeutic Products pro-

vides information on quality control, microbiological safety of

donations, production, and processing practices. Two Rijksin-

stituut voor Volksgezondheid en Milieu (RIVM) reports pro-

vide valuable information. One of these reports addresses

preclinical safety assessment of TEMPs, and the other provides

an approach to risk management for TEMPs (1,2).

4.4 References may be made to draft guidances and rules.

These should not be read as requirements.

5. Sources of Risk

5.1 Donor—In some cases, donors with potential previous

exposure to certain infectious agents must be excluded. Guid-

ance on donor selection is available from the American

Association of Tissue Banks (AATB) and the U.K. Department

of Health (3,4). The U.S. Food and Drug Administration

(FDA) has produced many documents that provide useful

information on donor testing (5-11). There may be speciﬁc

requirements for different regions of the world. For TEMPs

with autologous cells, donor testing is also recommended

because of the potential for expansion of adventitious agents

during manufacturing (12), and the potential for cross-

contamination of other products manufactured concurrently in

the same facility.

5.2 Nonviable Animal Material—The sponsor (product

owner) has the responsibility to substantially reduce risks from

adventitious agents, including TSEs, in nonviable animal

materials. Mitigation of such risks can include scrutiny over

donor sourcing or proven, rigorous processing, or both.

5.3 Cell Banks—Many TEMPs include cells that can be

banked. Master Cell Banks (MCB) and Working Cell Banks

(WCB) can be prepared and extensively tested for the presence

of adventitious agents. Although TEMPs are not included in

the scope of International Conference on Harmonization (ICH)

guidelines, the ICH guideline on cell substrate characterization

does provide useful information on the production, testing, and

storage of cell banks (13). Further information may be found in

an FDA publication on cell line characterization and the ICH

guideline on viral safety (14,15).

5.4 Raw Materials:

5.4.1 The raw materials used in the manufacture of the

cellular components of TEMPs are controlled by a number of

requirements that describe the microbiological safety testing of

components of cell culture media and reagents used in the

manipulation of the cells during culture. Some of these

materials are manufactured synthetically, for example, amino

acid supplements of culture medium. Much more frequently,

however, materials are of animal origin such as bovine serum

(essential for many mammalian culture systems) or, in the case

of anchorage-dependent cell lines, trypsin.

5.4.2 Raw materials of human and animal origin are of

particular concern to the manufacturer and licensing

authorities, owing to their potential contamination with extra-

neous agents from the source animal. Most manufacturers of

The boldface numbers in parentheses refer to the list of references at the end of

this standard.

F2383 − 11

biotechnology-derived products do not themselves produce

raw materials, but depend on external suppliers. A certiﬁcate of

analysis indicating all tests performed, with results, and includ-

ing data on the adventitious agent testing should also be

obtained. A critical examination of the microbiological safety

testing carried out by the supplier is recommended. As this may

not be appropriate to satisfy the regulatory agencies, manufac-

turers may have to repeat and extend the adventitious agent

testing performed by the supplier to ensure that raw materials

meet the performance and safety requirements for the produc-

tion process. Alternatively, it may be appropriate for the

TEMPs manufacturer to demonstrate that their processing

methods reduce the risk to an acceptable level. Tissue culture

components are also discussed in Guide F2210.

5.4.3 Other raw materials should be tested to demonstrate

they are free of adventitious agents. In some cases, the testing

performed by the raw material supplier is sufficient. If a raw

material is available only as research grade, then the sponsor

should test that material for adventitious agents.

5.5 Transport—After packaging, the external surfaces of the

containers may need to be decontaminated or cleaned or both.

Container integrity and shipping validation are also important

elements for ensuring TEMPs with a minimized deﬁned risk

from adventitious agent contamination are delivered to the

handlers and users of the ﬁnal products.

5.6 Processing—Adventitious agents can be introduced into

the TEMPs during processing. The agents can be derived from

contaminated environments, personnel, raw materials, and

processing materials, including water, and cross-contamination

from previously or concurrently processed products. Process-

ing is addressed in detail later.

5.7 Storage—Adventitious agents can be introduced during

the storage of all materials. Storage of the starting tissues or

cells, raw materials, and ﬁnal product requires a standardized

procedure. The outer surface of the container may need to be

decontaminated again prior to use.

6. Processing and Process Validation

6.1 Compliance with GMPs or GTPs, or both, when in

effect, is essential for the production of TEMPs that have a

minimized deﬁned risk of transmitting adventitious agents.

One of the major considerations is aseptic processing. Aseptic

processing must be validated and then periodically revalidated

to prevent contamination by microbial contamination. Refs

(16-18)should be evaluated and applied to TEMPs, where

feasible. Relevant elements are raw materials testing; suitable

control of the processing environment and routine environmen-

tal monitoring; operator training; implemented documentation

systems; use of suitable, validated analytical test methods;

process design; equipment qualiﬁcation and process validation;

and container-closure system validation. Guide F2210, GMPs,

and GTPs address many of these issues. Process design,

equipment qualiﬁcation, and process validation are discussed

in the following sections.

6.2 Process Design:

6.2.1 Each step in the process should be evaluated for

potential exposure to environmental contamination, including

introduction of contamination by personnel. Processing

materials, such as water and buffers, should be free from

adventitious agents. Water quality should be evaluated. De-

pending on the intended use, either water for injection (WFI) or

sterile puriﬁed water may be appropriate. To ensure further

conﬁdence in the process, where feasible, inactivation steps

that are suitable for adventitious agents should be incorporated

into the process, and decontamination and cleaning protocols

established for any contact surfaces.

6.2.2 When multiple processing steps are used, storage

conditions that protect the product intermediates from adven-

titious agents must be incorporated into the process scheme.

When multiple products are being processed in the same

environment, even more stringent environmental controls may

need to be implemented. The use of disposable equipment may

be advantageous for ensuring microbiological safety of the

TEMPs, but that equipment must be suitably disposed of so

that no other facilities or individuals are put at risk (19).

6.3 Equipment Design and Qualiﬁcation—Where dispos-

able equipment is not appropriate, equipment design should be

considered to prevent contamination by adventitious agents.

Dead legs, crevices, and threaded ﬁttings are likely sites to

harbor adventitious agents. Contact surfaces must be accessible

and compatible with decontamination and cleaning agents.

Equipment is qualiﬁed by performing a design qualiﬁcation, an

installation qualiﬁcation, and an operational qualiﬁcation.

These qualiﬁcation operations are deﬁned in an ICH document

on good manufacturing practices for active pharmaceutical

ingredients (20).

6.4 Use of Suitable, Validated Analytical Test Methods—

Processes cannot be validated without the use of validated

assays. During development, those assays that provide the most

relevant information should be established and validated. In

some cases, the data from traditionally used assays for adven-

titious agents will not be available in time to release TEMPs

containing viable cells for patient use. Other, more rapid assays

may have to be validated against the traditional assays. Data

from in-process testing are particularly useful for the manu-

facture of products containing viable cells since ﬁnal product

testing results may not all be available prior to product use.

Appropriate in-process testing is strongly recommended for

such products. For further guidance, see Reference (21).

6.5 Process Validation Issues Relevant to Adventitious

Agent and Contamination Control:

6.5.1 In the case of cellular- and tissue-based TEMPs, it

may be necessary to perform many more runs than the

traditional three to ﬁve consecutive runs to ensure the process

controls and outputs are sufficient to minimize the risks from

adventitious agents and their byproducts. For TEMPs, the use

of medium or a product reference standard may be the most

logical approach to maintaining a validated state. Medium or

the standard can be periodically run through the process to

provide documented evidence that the process provides a

product meeting speciﬁcations that are related to adventitious

agent control.

6.5.2 Information on process validation can be found in

several documents. FDA has published guides on general

F2383 − 11

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ASTM F2383 - 11 是美国材料与试验协会发布的一项标准规范，专门针对卫生级及高纯度应用中使用的奥氏体不锈钢无缝管与焊接管的尺寸、公差及材料要求。该标准适用于食品、乳制品、饮料、制药及生物技术等行业中需要高度清洁和防腐蚀性能的管道系统。ASTM F2383 - 11 确保了管道与接头之间的互换性与密封性，同时规定了严格的表面光洁度和清洗处理要求，以最大程度降低污染风险。该标准推荐采用 304L 和 316L 等低碳不锈钢材质，并提供了从 DN 10 到 DN 200 的标准尺寸规格，以

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