ASTM E2656-10
(Practice)Standard Practice for Real-time Release Testing of Pharmaceutical Water for the Total Organic Carbon Attribute
Standard Practice for Real-time Release Testing of Pharmaceutical Water for the Total Organic Carbon Attribute
SIGNIFICANCE AND USE
Pharmaceutical water is the most common component or ingredient used in pharmaceutical and biopharmaceutical manufacturing. Acceptable purity of the water is important to the quality of the final pharmaceutical product. TOC concentration is a key indicator and attribute of the purity of this water and also an important monitor of the overall performance of the water purification system. TOC analysis is the measurement of all the covalently bound carbon present in the water, not including carbon in the form of carbon dioxide (CO2), bicarbonate icon (HCO3–), or carbonate ion (CO32–), and is reported as the mass of organic carbon per volume.
Application of this practice provides pertinent information to make informed decisions on the release of water meeting pharmaceutical TOC concentration specifications.
SCOPE
1.1 This practice establishes an approach to the real-time release testing (RTRT) of pharmaceutical water based on the total organic carbon (TOC) attribute using on-line total organic carbon (OLTOC) instrumentation that is in agreement with current regulatory thinking.
1.2 This practice is harmonized with or supports the concepts of relevant ASTM International Committee E55 on Manufacture of Pharmaceutical Products standards, ICH Harmonized Tripartite Guidelines, the US FDA PAT Guidance, and US FDA Pharmaceutical cGMPs.
1.3 This practice does not provide general guidance information for pharmaceutical procedures that are considered standard practice in the pharmaceutical industry. This practice provides specific guidance for non-standardized procedures.
1.4 This practice does not address the user’s various internal procedures for risk, change, or quality management systems. The overall project effort associated with this practice shall be proportional to the overall risk of failing the pharmaceutical water’s TOC concentration specification.
1.5 This practice does not purport to establish how to comply with pharmacopeias. The RTRT methodology selected must assure compliance with the user’s current required pharmacopeias. However, compliance with pharmacopeia TOC methods is not necessarily sufficient to meet current regulatory expectations for RTRT.
1.6 This practice does not purport to substitute for or replace compendial bioburden testing requirements. It is strictly applicable to the TOC attribute of water quality.
1.7 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: E2656 − 10
StandardPractice for
Real-time Release Testing of Pharmaceutical Water for the
Total Organic Carbon Attribute
This standard is issued under the fixed designation E2656; 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 2. Referenced Documents
2.1 ASTM Standards:
1.1 This practice establishes an approach to the real-time
release testing (RTRT) of pharmaceutical water based on the E2281 Practice for Process Capability and Performance
Measurement
total organic carbon (TOC) attribute using on-line total organic
carbon (OLTOC) instrumentation that is in agreement with E2363 Terminology Relating to ProcessAnalytical Technol-
current regulatory thinking. ogy in the Pharmaceutical Industry
E2500 Guide for Specification, Design, and Verification of
1.2 This practice is harmonized with or supports the con-
Pharmaceutical and Biopharmaceutical Manufacturing
cepts of relevant ASTM International Committee E55 on
Systems and Equipment
Manufacture of Pharmaceutical Products standards, ICH Har-
E2537 Guide for Application of Continuous Quality Verifi-
monizedTripartiteGuidelines,theUSFDAPATGuidance,and
cation to Pharmaceutical and Biopharmaceutical Manu-
US FDA Pharmaceutical cGMPs.
facturing
1.3 This practice does not provide general guidance infor-
D4839 Test Method forTotal Carbon and Organic Carbon in
mation for pharmaceutical procedures that are considered
WaterbyUltraviolet,orPersulfateOxidation,orBoth,and
standard practice in the pharmaceutical industry. This practice
Infrared Detection
provides specific guidance for non-standardized procedures.
D5173 Guide for On-Line Monitoring of Total Organic
1.4 Thispracticedoesnotaddresstheuser’svariousinternal Carbon in Water by Oxidation and Detection of Resulting
Carbon Dioxide
procedures for risk, change, or quality management systems.
The overall project effort associated with this practice shall be D5904 Test Method forTotal Carbon, Inorganic Carbon, and
Organic Carbon in Water by Ultraviolet, Persulfate
proportional to the overall risk of failing the pharmaceutical
Oxidation, and Membrane Conductivity Detection
water’s TOC concentration specification.
D5997 Test Method for On-Line Monitoring of Total
1.5 This practice does not purport to establish how to
Carbon, Inorganic Carbon in Water by Ultraviolet, Persul-
comply with pharmacopeias. The RTRT methodology selected
fate Oxidation, and Membrane Conductivity Detection
must assure compliance with the user’s current required
D6317 Test Method for Low Level Determination of Total
pharmacopeias.However,compliancewithpharmacopeiaTOC
Carbon, Inorganic Carbon and Organic Carbon in Water
methods is not necessarily sufficient to meet current regulatory
by Ultraviolet, Persulfate Oxidation, and Membrane Con-
expectations for RTRT.
ductivity Detection
1.6 Thispracticedoesnotpurporttosubstitutefororreplace
2.2 Pharmacopoeia Documents:
compendial bioburden testing requirements. It is strictly appli-
ICH Q2 (R1) Validation of Analytical Procedures: Text and
cable to the TOC attribute of water quality. 3
Methodology
1.7 This standard does not purport to address all of the
ICH Q7 Good Manufacturing Practice Guide for Active
safety concerns, if any, associated with its use. It is the
Pharmaceutical Ingredients
responsibility of the user of this standard to establish appro-
ICH Q8 (R1) Pharmaceutical Development
priate safety and health practices and determine the applica-
bility of regulatory limitations prior to use.
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
This practice is under the jurisdiction of ASTM Committee E55 on Manufac- the ASTM website.
ture of Pharmaceutical and Biopharmaceutical Products and is the direct responsi- Available from International Conference on Harmonisation of Technical
bility of Subcommittee E55.03 on General Pharmaceutical Standards. Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH
Current edition approved Aug. 1, 2010. Published October 2010. DOI: 10.1520/ Secretariat, c/o IFPMA, 15 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20,
E2656-10. Switzerland, http://www.ich.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E2656 − 10
ICH Q9 Quality Risk Management 4.1.2 Risk Assessment—Perform quality risk analysis on the
ICH Q10 Pharmaceutical Quality System prospective RTRT system designs to establish the sampling
ISO 15839 Water Quality — On-line Sensors/Analyzing locations representative of the point-of-use.
Equipment for Water: Specifications and Performance 4.1.3 Data Quality—Ensure the quality of the data from the
Tests TOC measurement system is suitable for the intended use in
JP Chapter <2.59> Test for Total Organic Carbon the water RTRT system. Ensure equivalency/consistency to
Ph. Eur. Chapter <2.2.44> Total Organic Carbon in Water data from existing TOC measurement systems used to release
for Pharmaceutical Use water to the TOC attribute, if they exist.
US FDA PAT Guidance Guidance for Industry: PAT — A 4.1.4 Implementation Strategies—Develop process to as-
Framework for Innovative Pharmaceutical Development, sure successful implementation of RTRT.
Manufacturing, and Quality Assurance 4.1.5 Continuous Verification Procedures—Develop quality
US FDAPharmaceutical cGMPs Pharmaceutical cGMPs for control strategies to ensure consistent system performance.
the 21st Century — A Risk-Based Approach 4.1.6 Continuous Process Improvement—Assess and imple-
US FDA Procedures and Methods Validation Guidance for ment process improvement practices.
Industry: Analytical Procedures and Methods Validation
5. Significance and Use
Chemistry, Manufacturing, and Controls Documentation
USP Chapter <643> Total Organic Carbon (TOC)
5.1 Pharmaceutical water is the most common component
USP Chapter <1225> Validation of Compendial Proce-
or ingredient used in pharmaceutical and biopharmaceutical
dures
manufacturing. Acceptable purity of the water is important to
USP Chapter <1226> Verification of Compendial Proce-
the quality of the final pharmaceutical product. TOC concen-
dures
trationisakeyindicatorandattributeofthepurityofthiswater
USP Chapter <1231> Water for Pharmaceutical Purposes
andalsoanimportantmonitoroftheoverallperformanceofthe
USP Guidance <1058> Analytical Instrument Qualifica-
water purification system. TOC analysis is the measurement of
tion
all the covalently bound carbon present in the water, not
including carbon in the form of carbon dioxide (CO ), bicar-
3. Terminology – 2–
bonate icon (HCO ), or carbonate ion (CO ), and is reported
3 3
3.1 For definitions of terms specific to this standard, refer to
as the mass of organic carbon per volume.
the Terminology sections of Practice E2281, Terminology
5.2 Application of this practice provides pertinent informa-
E2363, and Guide E2500. Refer to ICH Q2 (R1) for method
tion to make informed decisions on the release of water
validation terminology.
meeting pharmaceutical TOC concentration specifications.
4. Summary of Practice
6. Procedure
4.1 This practice provides the user with sufficient guidance
6.1 Technical Evaluation:
for developing the scientific and risk-based information nec-
6.1.1 The overall project scope shall be proportional to the
essary to make informed decisions on the implementation,
associated risk of exceeding the pharmaceutical water TOC
continuous verification, and continuous improvement of a
concentration specifications. Knowledge and understanding of
system to provide the real-time release testing of pharmaceu-
the TOC concentration in the water system, the OLTOC
tical water using on-line total organic carbon (RTRT-OLTOC)
measurement system technology performance, and the phar-
instrumentation that meets pharmaceutical water TOC specifi-
maceutical water system design shall be acquired to minimize
cations. This guidance is based on Practice E2281, Terminol-
risk, ensure correct quality decisions, and maximize return on
ogy E2363, and Guide E2500 standards as well as
investment (USP Chapter <1231> and (1-7) ). TOC measure-
ICH Q2 (R1), ICH Q7, ICH Q8 (R1), ICH Q9, and ICH Q10
ment technologies are referenced in Test Methods D4839,
guidelines. The following steps are required to meet the
D5173, D5904, D5997, and D6317.
objectives of this practice.
6.1.2 Technical assessments should be conducted to evalu-
4.1.1 Technical Evaluation—Evaluate and understand water
ate and develop a low-risk, science-based RTRT-OLTOC
systems, TOC measurement technologies, and the related
system design. Knowledge of related information from avail-
regulatory requirements.
able sources should be used to understand, interpret, and
implementtheresultsofthetechnicalassessments.Information
Available from International Organization for Standardization (ISO), 1, ch. de
on general and specific RTRT-OLTOC system design
la Voie-Creuse, Case postale 56, CH-1211, Geneva 20, Switzerland, http://
considerations, performance characteristics, and validation
www.iso.ch.
should be found in published documents and texts (8-15).
Available from Japanese Pharmacopoeia (JP), Standards Division, Office of
ComplianceandStandards,PharmaceuticalsandMedicalDevicesAgency(PMDA), 6.1.3 For existing water purification systems, the user
Shin-kasumigaseki Building, 3-3-2, Kasumigaseki, Chiyoda-ku, Tokyo 100-0013,
shouldassesshistorical,current,andpotentialorganiccontami-
Japan, http://www.std.pmda.go.jp.
nation. Evaluation of potential organic contamination should
Available from European Pharmacopoeia (Ph. Eur.), 7 allée Kastner, CS 30026,
be based on a realistic assessment of water system design and
F67081 Strasbourg, France, http://www.pheur.org.
Available from Food and Drug Administration (FDA), 5600 Fishers Ln.,
Rockville, MD 20857, http://www.fda.gov.
8 9
Available from U.S. Pharmacopeia (USP), 12601 Twinbrook Pkwy., Rockville, The boldface numbers in parentheses refer to a list of references at the end of
MD 20852-1790, http://www.usp.org. this standard.
E2656 − 10
components to determine the probability of a specific or a surement of the TOC attribute in water shall be classified as an
broad spectrum of organic contaminants reaching the water impurity test. Under impurity tests are two additional
distribution system. The user should consult with TOC instru- classifications, quantitative and limit test. For each of these,
mentation vendors to determine if the TOC measurement there are recommended lists of validation tests to perform.All
system will meet the requirements of the intended application
pharmacopeia TOC test methods are limit tests. Limit testing
in light of any organic contamination assessment. produces only a pass or fail output as graphically represented
6.1.4 For new water purification systems, the presence of
byFig.1.Tocontrol,trend,andmonitoron-linesystemsandto
potential problematic compounds in the pharmaceutical water release water in real time using quantitative data, the analytical
system shall be addressed during the design and qualification
method requires the use of quantitative data, so the analytical
and validation activities and correction/mitigation/preventive
method shall be validated to the requirements of quantitative
actions shall be implemented accordingly.
tests (US FDA PAT Guidance). Quantitative data use is
6.1.5 TOC measurement system technology assessments
graphically represented in Fig. 2. Classifications and recom-
shallbeachievedbymeetingregulatoryguidancerequirements
mended tests are shown in Table 1. Additional helpful infor-
on analytical procedure verifications and validations
mation can be found in ISO 15839.
(ICH Q2 (R1), USP Chapter <1225>, and US FDAProcedures
6.1.5.3 The US FDA considers “real-time release to be
andMethodsValidation).Therequirementsshalldependonthe
comparable to Alternative Analytical Procedures” and the US
use of the data and the intended use of the instrumentation.
Regulation CFR 211.165 requires that the accuracy, sensitivity,
6.1.5.1 Legal USA Requirements and Verification of
specificity, and reproducibility of the alternative analytical test
USP Chapter <643>—The use of USP Chapter <643> TOC is
methods or procedures used for process control purposes be
legally recognized to meet the requirements for testing the
validated and documented appropriately (US FDA PAT Guid-
TOC attribute in pharmaceutical water. The users of
ance and US FDA Procedures and Methods Validation).
USP Chapter <643> TOC are not required to validate this
6.2 Risk Assessment:
method, but they shall verify it is suitable under actual
conditions of use. The user shall understand that Section 6.2.1 If the TOC concentration data is to be used in a
501(b) of the United States Food, Drug, and CosmeticAct (the quantitative way for trending, process control, or process
Act) legally recognizes the analytical procedures in the United statistical analysis, a statistical assessment of the process
States Pharmacopeia/National Formulary (USP/NF) for pur- performance should be done to estimate the risk of the process
poses of determining compliance with this Act (US FDA failing the specification requirement. This information should
Procedures and Methods Validation). The USAfederal regula- be used in the project implementation phase to understand and
tion CFR 211.194(a)(2) states: the suitability of a compendial improve, if necessary, the combined performance of the water
analytical procedure must be verified under actual conditions purification system and the TOC measurement system. These
of use. Users shall use USP Chapter <1226>, ICH Q2 (R1), or statistical assessments should be used for communicating the
equivalent to verify compendial procedures. level of process control for both regulatory inspection and to
6.1.5.2 The procedure for validation and verification of the ascertain the continued performance of the TOC impurity
TOC analytical method shall depend on the analytical proce-
removal and measurement system. See Fig. 3 and Fig. 4 for a
dure classification in ICH Q2 (R1), USP Chapter <1225>, or graphical presentation of a process with high and low prob-
the US FDA Procedures and Methods Validation. The mea- ability of failure.
FIG. 1 “Information Poor” Limit Test Output
...
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