ASTM F2383-05

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Designation:F2383–05
Standard Guide for
Assessment of Adventitious Agents in Tissue Engineered
Medical Products (TEMPs)
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 F2312 Terminology Relating to Tissue Engineered Medical
Products
1.1 This guide is intended as a resource for individuals and
F2386 Guide for Preservation of Tissue Engineered Medi-
organizations involved in the production, delivery, and regula-
cal Products (TEMPs)
tion of tissue engineered medical products (TEMPs). The
2.2 ANSI/AAMI Standard:
safety from contamination by potentially infectious adventi-
ST72 Bacterial Endotoxin—Test Methodologies, Routine
tious agents is important in the development of all TEMPs as
Monitoring and Alternatives to Batch Testing
well as their components. This guide addresses how to assess
2.3 Federal Regulations:
safety risks associated with adventitious agents and their
9 CFR Animals and Animal Products
byproducts. These agents currently include bacteria, fungi,
21 CFR 210 Current Good Manufacturing Practice in
mycoplasma, viruses, endotoxins, transmissible spongiform
Manufacturing,Processing,Packing,orHoldingofDrugs,
encephalopathies (TSEs), and parasitic organisms. This guide
General
does not address TEMPs with live animal cells, tissues or
21 CFR 211 Current Good Manufacturing Practice for
organs, or human cells, including stem cells, grown on any
Finished Pharmaceuticals
animal feeder cells.Also excluded is patient follow-up testing.
21 CFR 610.12 General Biological Products Standards—
1.2 This guide does not apply to any medical products of
Sterility
human origin regulated by the U.S. Food and Drug Adminis-
21 CFR 610.13 (b) General Biological Products
trationunder21CFRParts16and1270and21CFRParts207,
Standards—Purity Test for Pyrogenic Substances
807 and 1271. This guide does apply to cellular therapies
21 CFR 820 Quality System Regulation
regulated under the PHS (Public Health Service) act.
21 CFR 1270 Human Tissue Intended for Transplantation
1.3 This standard does not purport to address all of the
21 CFR 1271 Human Cells, Tissues, and Cellular and
safety concerns, if any, associated with its use. It is the
Tissue-Based Products
responsibility of the user of this standard to establish appro-
2.4 MDA Standard:
priate safety and health practices and to determine the
Code of Practice for the Production of Human-Derived
applicability of regulatory limitations prior to use.
Therapeutic Products
2. Referenced Documents
2.5 U. S. Pharmacopeia Document:
United States Pharmacopeia (USP), Edition XXIV (24)
2.1 ASTM Standards:
E1873 Guide for Detection of Nucleic Acid Sequences by
3. Terminology
the Polymerase Chain Reaction Technique
3.1 Definitions:
F2210 Guide for Processing Cells, Tissues, and Organs for
3.1.1 adventitious agents, n—unintentionally introduced
Use in Tissue Engineered Medical Products
microbiologicalorotherinfectiouscontaminant.Intheproduc-
F2211 Classification for Tissue Engineered Medical Prod-
tionofTEMPs,theseagentsmaybeunintentionallyintroduced
ucts (TEMPs)
This guide is under the jurisdiction of ASTM Committee F04 on Medical and
Surgical Materials and Devices and is the direct responsibility of Subcommittee Available fromAmerican National Standards Institute (ANSI), 25 W. 43rd St.,
F04.45 on Adventitious Agents Safety. 4th Floor, New York, NY 10036.
Current edition approved April 1, 2005. Published April 2005. DOI: 10.1520/ AvailablefromU.S.GovernmentPrintingOfficeSuperintendentofDocuments,
F2383-05. 732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401.
2 5
For referenced ASTM standards, visit the ASTM website, www.astm.org, or Available from Medicines and Healthcare Products Regulatory Agency
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM (MHRA), Hannibal House, Elephant & Castle, London SE1 6TQ, U.K.
Standards volume information, refer to the standard’s Document Summary page on Available from U.S. Pharmacopeia (USP), 12601Twinbrook Pkwy., Rockville,
the ASTM website. MD 20852.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.
F2383–05
intothemanufacturingprocessorintothefinalproductorboth. preclinicalsafetyassessmentofTEMPs,andtheotherprovides
(See Terminology F2312.) an approach to risk management for TEMPs (1,2).
3.1.1.1 Discussion—In this guide, adventitious agents also 4.4 References may be made to draft guidances and rules.
include microbiological or other infectious contaminants that These should not be read as requirements.
may be endogenous to the starting cells or tissue.
5. Sources of Risk
3.1.2 endotoxin, n—high molecular weight lipopolysaccha-
5.1 Donor—In some cases, donors with potential previous
ride (LPS) complex associated with the cell wall of gram-
exposure to certain infectious agents must be excluded. Guid-
negative bacteria that is pyrogenic in humans. Though endot-
ance on donor selection is available from the American
oxins are pyrogens, not all pyrogens are endotoxins. (See
Association ofTissue Banks (AATB) and the U.K. Department
Terminology F2312.)
ofHealth(3,4).TheU.S.FoodandDrugAdministration(FDA)
4. Significance and Use
has produced many documents that provide useful information
4.1 TEMPs may be composed of biological products (for ondonortesting(5-11).Theremaybespecificrequirementsfor
example, human cells, organs, tissues, derivatives, and pro- different regions of the world. For TEMPs with autologous
cessed biologics), biomaterials (for example, substrates and cells, donor testing is also recommended because of the
potential for expansion of adventitious agents during manufac-
scaffolds composed of polymers or collagen), and biomol-
ecules (for example, recombinant proteins, alginates, and turing (12), and the potential for cross-contamination of other
products manufactured concurrently in the same facility.
hyaluronates) (see Terminology F2312). Those TEMPs that
contain human viable cells, organs, or tissues differ in terms of 5.2 Nonviable Animal Material—The sponsor (product
owner) has the responsibility to substantially reduce risks from
adventitious agent safety from other TEMPs because of the
need to preserve viability of the organ, tissue, or cellular adventitious agents, including TSEs, in nonviable animal
materials. Mitigation of such risks can include scrutiny over
components. The need for preservation of viability limits
processing options for the reduction or elimination of adven- donor sourcing or proven, rigorous processing, or both.
5.3 Cell Banks—Many TEMPs include cells that can be
titious agents. Examples of TEMPs are listed in Classification
F2211. banked. Master Cell Banks (MCB) and Working Cell Banks
(WCB) can be prepared and extensively tested for the presence
4.2 To ensure production and use of TEMPs with minimal
risks associated with microorganisms and other adventitious of adventitious agents. Although TEMPs are not included in
agents, a multi-tiered approach is required. Donor testing, as the scope of International Conference on Harmonization (ICH)
well as testing of components and raw materials by sufficiently guidelines, the ICH guideline on cell substrate characterization
sensitive assays that are state of the art is usually necessary. does provide useful information on the production, testing, and
Compliance with good manufacturing practices (GMPs) and storageofcellbanks(13).Furtherinformationmaybefoundin
good tissue practices (GTPs), where applicable, is required (21 an FDA publication on cell line characterization and the ICH
CFR 210, 211, 820, 1270, and 1271). Although some of the guideline on viral safety (14,15).
components of the TEMPs may be processed to remove 5.4 Raw Materials:
5.4.1 The raw materials used in the manufacture of the
potential microbiological contaminants, viable tissues and
cellular components are generally unable to withstand rigorous cellular components of TEMPs are controlled by a number of
requirementsthatdescribethemicrobiologicalsafetytestingof
processing without losing functionality. For those TEMPs
containing tissues or cells for which banking is not possible, components of cell culture media and reagents used in the
manipulation of the cells during culture. Some of these
even greater reliance on donor screening, component testing,
and manufacturing controls is required. When more upfront materials are manufactured synthetically, for example, amino
acid supplements of culture medium. Much more frequently,
testing is possible, there is generally greater confidence in the
safety of the final product. Process validation can enhance however, materials are of animal origin such as bovine serum
(essential for many mammalian culture systems) or, in the case
confidence in the ability of the TEMPs’ producer to minimize
risks from adventitious agents. of anchorage-dependent cell lines, trypsin.
5.4.2 Raw materials of human and animal origin are of
4.3 Throughout this guide, the reader is referred to other
documents that may provide specific information that can be particular concern to the manufacturer and licensing authori-
applied in the manufacture and testing of TEMPs. Although ties, owing to their potential contamination with extraneous
many of these documents were not written with TEMPs in agents from the source animal. Most manufacturers of
mind, parts are often applicable. Most of the potentially biotechnology-derived products do not themselves produce
applicablepositionpapersandguidancedocumentsfrommany rawmaterials,butdependonexternalsuppliers.Acertificateof
regions of the world can be accessed via the internet. New analysisindicatingalltestsperformed,withresults,andinclud-
documents are continually produced. The MDCA(U.K. Medi- ing data on the adventitious agent testing should also be
cal Devices Agency, now part of MHRA, Medicines and obtained. A critical examination of the microbiological safety
Healthcare Products Regulatory Agency) Code of Practice for testingcarriedoutbythesupplierisrecommended.Asthismay
the Production of Human-Derived Therapeutic Products pro- not be appropriate to satisfy the regulatory agencies, manufac-
turers may have to repeat and extend the adventitious agent
vides information on quality control, microbiological safety of
donations, production, and processing practices. Two Rijksin-
stituut voor Volksgezondheid en Milieu (RIVM) reports pro-
The boldface numbers in parentheses refer to the list of references at the end of
vide valuable information. One of these reports addresses this standard.
F2383–05
testing performed by the supplier to ensure that raw materials 6.2.2 When multiple processing steps are used, storage
meet the performance and safety requirements for the produc- conditions that protect the product intermediates from adven-
tion process. Alternatively, it may be appropriate for the titious agents must be incorporated into the process scheme.
TEMPs manufacturer to demonstrate that their processing When multiple products are being processed in the same
methods reduce the risk to an acceptable level. Tissue culture environment, even more stringent environmental controls may
components are also discussed in Guide F2210. need to be implemented.The use of disposable equipment may
be advantageous for ensuring microbiological safety of the
5.4.3 Other raw materials should be tested to demonstrate
TEMPs, but that equipment must be suitably disposed of so
they are free of adventitious agents. In some cases, the testing
that no other facilities or individuals are put at risk (19).
performed by the raw material supplier is sufficient. If a raw
material is available only as research grade, then the sponsor 6.3 Equipment Design and Qualification—Where dispos-
should test that material for adventitious agents.
able equipment is not appropriate, equipment design should be
5.5 Transport—After packaging, the external surfaces of considered to prevent contamination by adventitious agents.
the containers may need to be decontaminated or cleaned or Dead legs, crevices, and threaded fittings are likely sites to
both. Container integrity and shipping validation are also harboradventitiousagents.Contactsurfacesmustbeaccessible
important elements for ensuring TEMPs with a minimized and compatible with decontamination and cleaning agents.
defined risk from adventitious agent contamination are deliv- Equipmentisqualifiedbyperformingadesignqualification,an
ered to the handlers and users of the final products. installation qualification, and an operational qualification.
These qualification operations are defined in an ICH document
5.6 Processing—Adventitiousagentscanbeintroducedinto
on good manufacturing practices for active pharmaceutical
the TEMPs during processing. The agents can be derived from
ingredients (20).
contaminated environments, personnel, raw materials, and
processing materials, including water, and cross-contamination 6.4 Use of Suitable, Validated Analytical Test Methods—
from previously or concurrently processed products. Process- Processes cannot be validated without the use of validated
ing is addressed in detail later.
assays.Duringdevelopment,thoseassaysthatprovidethemost
relevant information should be established and validated. In
5.7 Storage—Adventitious agents can be introduced during
the storage of all materials. Storage of the starting tissues or some cases, the data from traditionally used assays for adven-
titious agents will not be available in time to release TEMPs
cells, raw materials, and final product requires a standardized
procedure. The outer surface of the container may need to be containingviablecellsforpatientuse.Other,morerapidassays
may have to be validated against the traditional assays. Data
decontaminated again prior to use.
from in-process testing are particularly useful for the manu-
facture of products containing viable cells since final product
6. Processing and Process Validation
testing results may not all be available prior to product use.
6.1 Compliance with GMPs or GTPs, or both, when in
Appropriate in-process testing is strongly recommended for
effect, is essential for the production of TEMPs that have a
such products. For further guidance, see Reference (21).
minimized defined risk of transmitting adventitious agents.
6.5 Process Validation Issues Relevant to Adventitious
One of the major considerations is aseptic processing. Asepti
...