Real-time TOC analysis
Richard Godec is new product development manager, Jon Yourkin is pharmaceutical market manager, and Kevin Aumiller is product
manager, all with GE Analytical Instruments
In January 2011, FDA released Guidance for Industry: Process Validation: General Principles and Practices, which outlines the current regulatory thinking for process validation and control (1). It fully embodies the application
of quality by design (QbD) and process analytical technology (PAT) methodologies that pharmaceutical companies can use to
validate manufacturing processes. The new guidance also highlights the increased relevance of pharmaceutical manufacturing
standards developed with voluntary consensus organizations, such as ASTM International. Of the 15 references within the guidance
document, five refer to ASTM standards detailing best practices for process validation activities.
To understand why FDA is promoting ASTM standards in pharmaceutical manufacturing, one need only turn to federal law. The
National Technology Transfer & Advancement Act requires governmental bodies to, wherever possible, adopt volunteer consensus-based
standards to carry out policy. ASTM in collaboration with pharmaceutical companies, equipment vendors, process-design professionals,
professional societies, and FDA, created the ASTM Committee E55 on Manufacture of Pharmaceutical Products and dedicated it
to the development of new pharmaceutical manufacturing consensus standards in the spirit of this law. It is within this context
that a number of high-level guidance and lower-level technology practice standards were developed and released (2).
In October 2010, the ASTM E55 committee promulgated a new standard practice, E2656, "Real-time Release Testing of Pharmaceutical
Water for the Total Organic Carbon Attribute" (3). This real-time testing process is an example of QbD or PAT process that
can be implemented to improve quality and reduce costs associated with traditional laboratory sampling. The new E2656 standard
provides detailed suggestions and recommendations to use on-line total organic carbon (TOC) analysis for releasing water to
the TOC attribute into the manufacturing processes. To achieve improved product quality, minimize risk, and to reduce manufacturing
costs, many pharmaceutical companies are moving laboratory testing of TOC to real-time testing on line. This transition has
important aspects, including a greater process understanding, strict control of key process variables, and the establishment
of a process-capability specification to ensure the finished products meet quality requirements and regulatory guidelines.
The need for the standard was established based on prior problems encountered by pharmaceutical companies that had implemented
real-time water release based on TOC. Previous problems included false positives from inappropriate TOC instrument selection,
poor project implementation, insufficient understanding of the technologies, and insufficient knowledge to ensure the proposed
approach would meet regulatory expectations. Over 30 subject matter experts developed the standard to provide the critical
tools and solutions to these issues within a structured implementation process.
ASTM E2656 allows users to align with pharmacopoeia requirements for TOC analysis while also meeting the global regulatory
compliance expectations of greater process understanding and control that are called for in relevant federal regulations (1,
4, 5). The standard is divided into six sections to assist in implementation as outlined:
Technical evaluation: determine the appropriate TOC technology based on thewater-system characteristics and intended use of the device.
Risk assessment: determine the appropriate placement of on-line TOC instruments using risk-assessment tools.
Data quality: qualify all on-line TOC instruments, compare the on-line method to legacy laboratory methods, and validate the relationship
between the installation location and the relevant points of use.
Implementation strategies: develop processes to incorporate on-line TOC devices into quality, manufacturing, and maintenance systems.
Continuous-verification procedures: use statistical tools and ongoing verification strategies to assess process control.
Continuous-process improvement: Use the process knowledge gained from monitoring to make incremental improvements to the system.
Within each section of E2656, practical tools and best practices are identified to assist in the successful transition to
on-line release testing. Some key elements of the process are outlined in Table I.
Table I: Tools for on-line real-time release testing of pharmaceutical water using total organic carbon (TOC) analysis based
on ASTM E2656 (2).
In conclusion, the ASTM E2656 standard provides a structured process to efficiently implement on-line TOC analyzers for process
control and real-time release testing. The standard aligns with regulatory guidance and, as a consensus-based practice, is
supported by pharmaceutical manufacturers and other key players. ASTM E2656, provides a practical framework for improved water-system
1. FDA, Guidance for Industry: Process Validation: General Principles & Practices (Rockville, MD, Jan. 2011).
2. Public Law 104–113, "National Technology and Transfer Advancement Act of 1995" (Washington, DC, 1995).
3. ASTM International, ASTM Standard E2656, "Standard Practice for Real-time Release Testing of Pharmaceutical Water for
the Total Organic Carbon Attribute" (West Conshoken, PA, 2010), DOI:10.1520/E2656-10.
4. USP 34–NF 29 General Chapter <643>, "Total Organic Carbon," p. 251.
5. Eur.Ph (6th ed.), 2.2.44, "Total Organic Carbon in Water for Pharmaceutical Use," 01/2008:20244, p. 71.