ASTM E1298-89(2000)
(Guide)Standard Guide for Determination of Purity, Impurities, and Contaminants in Biological Drug Products
Standard Guide for Determination of Purity, Impurities, and Contaminants in Biological Drug Products
SCOPE
1.1 This guide covers the concepts of purity, impurity, and contamination in biological drug products.
1.2 This guide suggests methods for determination of impurities and contaminants in such products.
1.3 This guide is arranged as follows:SectionTerminology 2Significance and Use3Purity4 General Considerations4.1Estimation of Purity4.2Impurities5 General Considerations5.1Major and Minor5.2Nature and Consequences of5.3Contaminants6 General Considerations6.1Effects of contaminants6.2Methods for Determining Impurities and Contaminants7
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 appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.
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Designation:E1298–89(Reapproved 2000)
Standard Guide for
Determination of Purity, Impurities, and Contaminants in
Biological Drug Products
This standard is issued under the fixed designation E 1298; 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 (e) indicates an editorial change since the last revision or reapproval.
INTRODUCTION
The purity of biological drug products historically has been significantly lower than that of other
pharmaceutical drug products. This is a consequence of the structural complexity of biological drug
products as well as the fact that, until recently, these products were obtained only with great difficulty
and at high cost from natural sources such as human or animal serum or tissue. Although many of
these products were of low purity, long-term use in humans proved their safety and efficacy. The
development of recombinant DNA(rDNA) technology and the parallel development of sophisticated
preparatory,analytical,andimmunologicalmethods,haveresultedintheabilitytoproducehighpurity
biological drug products. It should be recognized that the standards for purity of rDNA-derived drugs
are comparable to those established for United States Pharmacopeia (USP)-quality drug substances.
For example, the purity of an rDNA-derived drug substance may exceed 97 % and impurities, (see
Section 4) such as host cell proteins are separately quantitated in the parts per million range (via
immunoassay).
1. Scope 2. Terminology
1.1 This guide covers the concepts of purity, impurity, and 2.1 Definitions:
contamination in biological drug products. 2.1.1 contaminants—all adventitious substances or micro-
1.2 This guide suggests methods for determination of im- organisms present in raw materials, bulk drugs, or final
purities and contaminants in such products. products.
1.3 This guide is arranged as follows: 2.1.2 deleterious impurities—impurities that might be a
health or safety concern, particularly with respect to toxicity,
Section
Terminology 2
carcinogenicity, or immunogenicity. Deleterious impurities
Significance and Use 3
must be controlled and their levels determined using suitable
Purity 4
General Considerations 4.1 analytical methods.
Estimation of Purity 4.2
2.1.3 impurities, of a biological drug product—all process-
Impurities 5
related (nonadventitious) substances present in the raw mate-
General Considerations 5.1
rials, bulk drug, or final drug product that are not considered to
Major and Minor 5.2
Nature and Consequences of 5.3
be the active material, additives, or excipients.
Contaminants 6
2.1.4 innocuous impurities—impurities that are not a health
General Considerations 6.1
or safety concern in the product.The route of administration of
Effects of contaminants 5.2
Methods for Determining Impurities and Contaminants 7
the drug may be a significant criterion in the determination of
whether an impurity is innocuous.
1.4 This standard does not purport to address all of the
2.1.5 purity, of a biological drug product—the measure of
safety concerns, if any, associated with its use. It is the
the biologically active drug in relation to the total substances
responsibility of the user of this standard to establish appro-
(not including additives) present in the drug product, usually
priate safety and health practices and determine the applica-
expressed on a percentage basis.
bility of regulatory limitations prior to use.
3. Significance and Use
ThisguideisunderthejurisdictionofASTMCommitteeE48onBiotechnology
3.1 This guide suggests analytical methods generally ap-
and is the direct responsibility of Subcommittee E48.02 on Characterization and
plied within the pharmaceutical industry to identify and quan-
Identification of Biological Systems.
titate the level of impurities and contaminants present in the
Current edition approved May 26, 1989. Published July 1989.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.
E1298
TABLE 1 Methods for Determination of Impurities and
preparation of a biological drug product. These methods are
Contaminants
not intended to be all-inclusive. The methods used by an
Common Impurities or Contaminants Detection Method
individual manufacturer must be specific to the product and
A
Endotoxin LAL, rabbit pyrogen
process of production.
B
Host Cell Proteins SDS-PAGE, immunoassays
C
Other Protein Impurities SDS-PAGE, HPLC, immunoassays
4. Purity
DNA DNA hybridization, UV
spectrophotom-
4.1 General Considerations—Numerous considerations are
etry
Mutants HPLC-tryptic mapping
involved in determining purity acceptability criteria, and these
Formyl methionine HPLC-tryptic mapping
criteria are ultimately determined on a case-by-case basis. In
Oxidized methionines Amino acid analysis, HPLC-tryptic
each individual case, the risk-to-benefit ratio must be evaluated
mapping, Edman degradation anal-
ysis
in determining an acceptable level of purity and the acceptable
D
Proteolytic clips IEF, SDS-PAGE (reduced), HPLC
types of impurities of any new drug product. For example, the
Deamidation IEF (standard comparison), HPLC
same purity requirements are not necessarily applied to a Microbial (bacteria, yeast, and fungi) Microbiological Testing (sterility, bio-
burden)
vaccine, which may be administered in one or two injections,
E F
Mycoplasmas Modified 21CFR Method, DNAF
as to a chronic care product, which may be administered G H
Viruses (endogenous and adventitious) CPE, Had, electron microscopy, re-
verse transcriptase activity
several times per week for many years. It is not difficult with
A
currentlyavailabletechnologytoachieveapuritylevelof97 % Limulus amebocyte lysate.
B
Sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
(w/w). At this level of purity, drug doses of 0.01, 0.1, and 1
C
High performance liquid chromatography.
mg/kgina70-kgpatientcorrespondtoimpuritiesof21µg,210 D
Isoelectric focusing.
E
µg,and2.1mg/dose,respectively.Atapurityof99.99 %,these Draft guidelines.
F
DNA binding fluorochrome.
figuresdecreaseto0.07µg,0.7µg,and7µg,respectively.Even
G
Cytopathic effect.
H
these latter levels of impurities may be significant if they are
Hemadsorption.
repeatedly administered for prolonged periods.Although regu-
latory guidance on acceptable purity levels has been difficult to
obtain, the lack of a database for rDNA-derived products has 5.2.1 Some distinctions have been made between major and
minor impurities. Although these distinctions were generated
given rise to a generally more conservative approach than that
to address more conventional drugs, they are likely to form the
which has been used previously for human biologics or
basisforconsiderationofbiologicaldrugs,whosenumberswill
blood-derived products. Also, the purity of a biological drug
increase as rDNA products begin to reach the marketplace in
substance cannot be defined without specifying the assay
larger numbers.
method used. Various levels of purity may be obtained by a
5.2.1.1 Amajor or significant impurity is one present at 0.5
variety of analytical methods. It is, therefore, extremely im-
to 1 % or greater. Levels of such an impurity should be kept as
portant to use analytically valid methods for the estimation of
low as technically possible. The manufacturer may consider
purity.
obtaining toxicologic, pharmacologic, and immunologic data
4.2 Estimation of Purity—Purity may be estimated by two
on major impurities.
basic methods: weight percentage correlations or relative
5.2.
...
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