TOC in Pharmaceutical

Applications
USP & Cleaning Validation

By Debora Polinengtyas
PT. Ditek Jaya
Applications of TOC Analyzers in
Pharma Industries

 Measurement of TOC in Purified Water/

Water For Injectibles As Per USPXXIII & in
Water For Injectibles As Per EP.
 Measurement of TOC in Raw/Feed Water for
Monitoring Performance Of Water Purification
System.
 Cleaning Validation.
Summary

 TOC can also be used as a Process Control attribute

to monitor the performance of unit operations
comprising the purification and distribution system.
 TOC determination can also be used to monitor the
performance of various operations in the preparation
of drugs.
Acceptable Methods/ Guidelines of
Analytical Technologies

 Analytical Technologies utilized to measure TOC

share the objective of completely oxidizing the
organic molecules in an aliquot of sample water to
CO2, measuring resultant CO2 levels and expressing
this response as Carbon concentration.
 All technologies must discriminate between the
inorganic carbon, which may be present in water
from sources such as dissolved CO2 and bicarbonate
and the CO2 generated from the oxidation of organic
molecules in the sample.
Approaches of Measurement

 Two General approaches are used to

measure TOC.
 Approach I
One approach determines TOC by subtracting the
measured Inorganic Carbon (IC) from the
measured total carbon (TC), which is the sum of
organic carbon and inorganic carbon.
TOC = TC - IC
Approaches of Measurement

 Approach II
This approach first purges the IC from the
sample before any Carbon measurement is
performed. However, this IC purging step also
purges some of the organic molecules.
Remaining organic matter in the sample is also
oxidized to CO2 and quantified as Non Purgeable
Organic carbon (NPOC).
TOC = POC + NPOC
In Pharmaceutical water, amount of POC is negligible
and can be discounted. Therefore for the purpose of
this methodology, NPOC is equivalent to TOC.
Apparatus Required

This test method is performed either as an on

line test as an off line laboratory test using
a calibrated instrument. The suitability of the
apparatus must be periodically demonstrated
as described in this chapter. In addition it
must have a manufacturer’s specified
detection limit of 0.05 mg of carbon per liter
(50 ppb or 0.05 ppm) or lower.
Standards Required & Glassware
Preparation

Standards Required
i) USP 1,4 Benzoquinone RS.
ii) USP Sucrose RS.
iii) Reagent Water: Water having TOC level of not
more than 0.10 mg (100 ppb or 0.10 ppm) of
carbon/liter as per USP XXIII and not more
than 0.10 mg (100 ppb or 0.10 ppm) of
Carbon/ liter as per EP.
Glassware Preparation: Use glassware & sample
containers that have been cleaned of organic
residues. Use reagent water for final rinse.
Sample Collection and Handling

Collection of Samples & Standards

Use extreme caution when obtaining
samples for TOC analysis. Collect test
solution in a tight container with minimal
head space and test in a timely manner to
minimize the impact of organic
contamination from the closure &
container.
Standard & System Suitability
Solution
Preparation
(Standard Solution: Dissolve in the reagent water
an accurately weighed quantity of USP Sucrose
RS previously dried at 105 C for 2 hours, to
obtain a solution having conc. of 1.19 mg of
sucrose per liter (0.50mg of Carbon/liter)
System Suitability Solution: Dissolve in Reagent
Water an accurately weighed quantity of USP 1,4
Benzoquinone to obtain a solution having conc. of
0.75 mg per liter (0.50 mg of carbon per liter).
Other Control Solutions

Prepare appropriate reagent blank solutions or

other specified solutions needed for establishing
the apparatus base line or for calibration
adjustments following the manufacture’s
instructions, and run the appropriate blank to
zero the instrument.
System Suitability Test

 Measure reagent water area and record the response

Rw.
 Measure Sucrose Solution Area and record the
response Rs.
 Calculate the corrected Standard Solution Response
by subtracting the reagent water response from the
response of Standard Solution (Rs- Rw).
System Suitability Test

 Test the System Suitability Solution & record

the response Rss.
 Test the reagent water in Instrument &
record the response Rw.
 Calculate the corrected System suitability
Solution Response by subtracting the reagent
water response from the response of
Standard Solution (Rss- Rw).
System Suitability Test

 Calculate the response efficiency by the formula:

100x (Rss-Rw)
(Rs- Rw)

 The System is suitable if the response efficiency is

not less than 85 % and not more than 115 %.
Sampling Handling &
Preservation
 Sampling: Collect representative sample in clean
glass containers with a tight fitting foil or Teflon lined
cap. Take care to avoid contamination of the sample
with organic substances. Sampling container must be
filled to the top(no head space).
 Sample Preservation: As far as possible, try to
analyze sample immediately. Storage should be
avoided. This is due to oxidation or bacterial activity.
However, if there is likelihood of storage, please take
foll. precautions:
Sampling Handling &
Preservation
* Sample should be protected from sunlight &
atmospheric oxygen.
*Sample should be kept at 4 C.
* In instances, where analysis can not be
performed within 2 hours from the time of
sampling, the sample is acidified to pH lower
than 2 by HCl.
MONITORING PERFORMANCE OF
WATER PURIFICATION PLANT

 TOC Measurement can help identifying problems in

Purification Systems and also identify the source of
the problem,
 TOC measurement at following points can help us in
identifying the problem source, extent of the problem
and also suggested remedial action:
- Raw water
- Storage Water
- Water after passing through ionized bed.
- Water after passing through activated charcoal
bed/ UV / Ionizer.
 CLEANING VALIDATION

 Target Residuals are organic materials.

 TOC can be index for total organic materials.
 Broad Spectrum: All organic residuals,
unexpected contaminants, in rinse water or
on surface water on instrument can be
detected.
 Single Component analysis is not suitable for
cleaning agent residue determination due to
selective adsorption of components of
cleaning agents.
 Cleaning Validation
 If TOC quantity is above threshold level,
please go for further analysis.
 In Bulk Plant, TOC can detect all organic
chemicals containing unidentified
intermediate reactants and by products
contrary to single component analysis.
 Major advantages of using TOC for cleaning
validation are as follows:
 Cleaning Validation
 Fast and Easy Measurement
contributing to Labour saving.
 Number of samples and frequency can
be increased due to fast measurement.
 Useful in tracking the cause of trouble.
 Lack of Interfering substances
 Inherent Sensitivity.
 Cleaning Validation
Methods of Measurement
Three methods of Cleaning
Validation
using TOC Analyzers
1. Rinse Water TOC monitoring.
2. Swab/ Water Extraction/ TOC.
3. Swab/ Direct Combustion/ TOC.
 Cleaning Validation
Rinse Water using TOC Analyzer
 Easier and Faster than other methods.
 Broad Spectrum Assay: detects all
carbon based residuals.
 Low Level Detection.
 Applied to Water soluble or dispersible
drugs.
 Cleaning Validation

Swab/ Water Extraction/ TOC Method

 Easier and Faster than Swab & HPLC Method.
 Broad Spectrum Assay: detects all carbon
based residuals.
 Low Level Detection.
 Applied to Water soluble or dispersible drugs.
 Application reports by Upjohn and Lilly etc.
 SWAB analysis by extraction
Area = 25cm2
Physical
sampling

SWAB Water TOC measurement

sampling extraction
(by FDA)
 Cleaning Validation

Swab/ Direct Combustion/ TOC Method

 Physical Sampling from the equipment or
facility surface with wetted swabs.
 “The most desirable is the direct method of
sampling the surface of the equipment” from
FDA “Guide to Inspection of Validation of
Cleaning Process”
 Possible to evaluate all kind of drugs
including insoluble.
SWAB analysis by direct
combustion

2”x2” (US)
4”x4” (Jpn)

Swab Sample TC measurement

sampling boat