eBook: TOC and Microbial Detection Monitoring - 12

Continuous TOC Monitoring for Real-time Release

Table 1 - Global requirements for TOC in bulk pharmaceutical waters

Pharmacopeia Reference

TOC Requirement

USP

Chapter <643>

0.5 mg/L

EP

2.2.44

0.5 mg/L

JP

JP 2.59 and G8 Quality Control of Water for 0.5 mg/L
Pharmaceutical Use
0.3 mg/L for control

Ch P

Ch P 2015 Chapter <0682>

1. General regulatory requirements
Begin by determining what fundamental requirements are
in place that regulate the product, material, or process in
question. It is also necessary to consider guidance from
each of the applicable regulatory bodies, based on the
requirements of the countries where the products are intended to be sold.
Regarding the production of bulk pharmaceutical waters,
all global pharmacopeias provide water monographs defining the fundamental regulations surrounding water production and monitoring. These monographs are official
documents that mandate the regulated compendial procedures with defined requirements that serve as the foundation for any program being established for monitoring
and control of water purification. Within these monographs
is the requirement to measure, monitor, and report on the
specified TOC, conductivity, and microbial limits defined
for bulk Purified Water (PW), and additionally endotoxins
for Water for Injection (WFI) and Pure Steam. These
requirements have been largely, but not completely,
harmonized by the major global pharmacopeias.
2. Parameter-specific regulatory requirements
Within each of the pharmacopeias, clear guidance is
given defining the process by which a TOC measurement
should be validated to be acceptable for use in qualifying
different classifications of water based upon the intended
use. A detailed description of the requirements for bulk PW

0.5 mg/L

and WFI can be found in USP Chapter <643>, while similar requirements exist for other pharmacopeias (Table 1).
In summary, the TOC measurement method must meet the
following requirements:
* Instrument Limit of Detection of 0.05 mg/L or lower of
carbon
* The instrument must be calibrated
* The instrument must distinguish between inorganic
carbon and organic carbon
* The instrument must pass a System Suitability Test
comparing two known solutions (USP 1,4-Benzoquinone RS, USP Sucrose RS)
3. Non-regulatory best practices
For pharmaceutical compendial compliance, it is
unnecessary to increase the effort to verify and validate a
measurement beyond the steps defined by relevant
regulating bodies. Therefore, the user should carefully
consider the recommendations provided in any nonregulatory references and how they apply to their specific
circumstance, to weigh the value of any additional effort
against the needs of their specific application.
Related to TOC, numerous test methods, guides, and
standard practices are available, covering a range of
specific uses of the measurement in a variety of water
purities and market applications. A user will need to
determine how or if these additional sources add value
to their specific needs.

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