Understanding past & proposed changes to USP Chapter on Total Organic Carbon

The implementation of a total organic carbon (TOC) method into the United States Pharmacopeia (USP) has its origins in the early 1990s, when the Water Quality Committee (WQC) of the Pharmaceutical Manufacturers Association (PMA, later renamed PhRMA) debated improvements in the testing of purified water (PW) and water-for-injection (WFI). The resulting inclusion of modern analytical techniques replaced much older methods — some of which had been listed in the USP for more than 150 years. Finally, two new regulations were put in place: Chapter <645> for conductivity, which replaced a series of individual ion tests; and Chapter <643> which replaced the oxidizable substances test with a TOC method.

TOC testing as a substitute method for oxidizable substances was first proposed in an article by Godfrey Crane in the Pharmacopeial Forum in 1990. The USP held an open conference in Colorado Springs (Colorado, USA) in July 1993 to discuss changes to the entire testing menu for PW and WFI. The WQC had focussed on conventional laboratory, wet persulfate and combustion methods for determining organic contamination in high-purity water instead of online testing for TOC.

After the open conference, there was a series of refinements to the Chapter <643> method, most of which focussed on the System Suitability requirement and the compounds that were to be used to confirm that the system or instrument really was suitable for the task at hand: namely to oxidize and measure any organic compounds that were likely to be found in compendial waters. At least seven different compounds were considered until a WQC-sponsored study determined that sucrose and 1,4-benzoquinone were most appropriate as compounds for preparing the standard solution and system suitability solution, respectively.

During this process, the WQC specified an acceptable TOC detection limit and range of appropriate technologies. The wide range of allowed technologies provided a competitive environment for instrument companies while offering a fair and open selection of instrumentation for the pharmaceutical industry. The Chapter <643> method was enacted in the USP 23 Fifth Supplement in May 1997 and the oxidizable substances test was deleted from the 8th Supplement in May 1998.

Changes since May 1997

TOC and conductivity requirements of reagent blank water.

After implementation and use in the industry, many workers identified areas of possible improvement to the Chapter <643> method. The European Pharmacopoeia (EP) adopted the <643> method and rapidly implemented it as its chapter 2.2.44 in July 1999 — with two minor but important differences. Chapter <643> allowed the reagent water blank (the water used to prepare the standard and system suitability solutions) to contain as much as 250 ppb background TOC and required that it met a conductivity specification as described in USP Chapter <661>. The EP 2.2.44 reduced the TOC allowed in the reagent water to 100 ppb and specified a conductivity for the water of not more than 1.0 μScm

^-1

. The USP, understanding that the 250 ppb limit was too high, particularly considering that the maximum allowed in the sample water was a nominal 500 ppb, reduced the level to 100 ppb in the 4th Supplement (June 2001) noting that: "... a conductivity requirement may be necessary...."

Proposed changes

The USP July-August 2002

In-Process Revision

represents a review of Chapter <643> and provides guidance for TOC measurement methodology in PW and WFI. There are four important proposed changes to the USP <643> method:

1. Modify the system suitability response efficiency calculation to reflect a more realistic standard preparation.

2. Make the allowed TOC limit a specific value rather than a pass/fail compared with the standard solution response. This approach more easily allows any future changes to the limit.

3. Clarify the frequency with which the user should perform the system suitability procedure.

4. Calculate the carbon concentration (C_c) of the unknown sample (r_u) using a normalization factor that minimizes the effects of minor calibration and instrumental errors.

The proposed updated method retains the <643> necessity that "Analytical technologies utilized to measure TOC share the objective of completely oxidizing the organic molecules in an aliquot of sample water...." A possible interpretation of this requirement implies that the instrument of choice should isolate a fixed volume of water (as compared with a continually moving stream) and confirm complete oxidation.

The system suitability and subsequent response efficiency calculation has been the focus of Chapter <643> since its inception. The current method requires the measurement of the following:

• standard solution (500 ppb C by sucrose RS) = r_s

• reagent control water = r_w

• system suitability solution (500 ppb C by 1,4-benzoquinone RS) = r_ss

• the subsequent calculation of the response efficiency= [(r_ss-r_w )/(r_s-r_w)] × 100.

The July 1998 <643> method and the EP 2.2.44 method specified that the sucrose and 1,4-benzoquinone should be weighed to provide carbon concentrations of 1.19 and 0.75 mg/L, respectively, to produce the specified carbon concentrations. Practically, this is difficult if not impossible, and some type of correction should be applied to adjust for the inability to weigh theoretically exact amounts and the resulting deviation from the exact 500 ppb concentration. The new proposed calculation for the response efficiency is an effort to "correct" for the inability to weigh and prepare exactly the sucrose standard solution and 1,4-benzoquinone system suitability solution to a 500 ppb carbon concentration.

The proposed revision adds the word "about" immediately before the weighed amounts as "... about 1.2 mg/L ..." and "... about 0.75 mg/L...." This statement minimizes the need for perfect weighing while requiring a compensation or correction factor for the final response efficiency. This correction factor is shown below:

If the C_s and C_ss were prepared perfectly, the ratio "factor" (63)C_ss/C_s) would equal 1 and the original response efficiency formula would apply. However, as perfect preparation is most unlikely, the ratio of the actual weighed values is calculated and used as a "correction factor."

Frequency of system suitability

No question about Chapter <643> is asked more frequently than: "How often should I do the system suitability test?" The original intent was that the frequency be based on instrument performance. However, the original <643> wording, that the system suitability should be periodically demonstrated, offered little guidance for establishing an acceptable frequency.

The new proposal includes the statement: "... at appropriate intervals based upon established instrument performance." This provides more guidance for establishing the system suitability frequency; however, each individual organization must decide what is most appropriate for their systems.

Calculating the TOC concentration of an unknown PW or WFI sample

Currently, chapter <643> requires the instrument to measure the unknown sample as r

_u

. If r

_u

is less than the limit response, calculated by r

_s

-r

_w

, then the water passes (The Test Solution meets the requirements if r

_u

is not more than the limit response r

_s

-r

_w

.). The new proposal, in an effort to make the test quantitative rather than pass/fail, and to normalize the test solution response to the sucrose standard solution response uses the following formula:

If the sucrose standard solution (r_s) is prepared perfectly and its TOC and the TOC in the reagent water are measured exactly, then 0.42C_sr_u/(r_s-r_w) = 1 and r_u would be measured as in the current method.

The 0.42C_sr_u/(r_s-r_w) formula is an attempt to normalize the unknown result to the response of the sucrose standard solution and therefore corrects for slight errors in instrument calibration, noise and drift.

Finally, the proposed method states: "Calculate the carbon concentration of the Test Solution ... not more than 0.50 mg per litre of carbon is present." This calculation then becomes a direct measure of the TOC present and not a relative or pass/fail test compared with a calculated limit response. This allowed limit of 0.50 mg/L (500 ppb) could also be more easily changed (reduced) in the future to reflect better water system performance for minimizing TOC.

In-process revision

Although the proposed method addresses most of the outstanding issues of <643> that had become apparent since its implementation into the USP and widespread use in the industry, it became obvious that these proposed changes would be difficult to realize. Since the inauguration of the TOC method, many thousands of instruments have been purchased to ensure that PW and WFI systems can comply with chapter <643>. Most of these instruments automatically calculate and report the response efficiency, limit response and the test solution TOC value. To meet the proposed changes, each of these instruments would need to be replaced, upgraded or refitted with new firmware or software that could make the new calculations. And this could only happen at a significant expense!

An alternative method

To implement the advantages of the proposed calculations, a further refinement to the proposed <643> method was published as an In-Process Revision in a recent

Pharmacopeial Forum

(Nov/Dec 2003). This revision allows pharmaceutical companies to satisfy USP <643> requirements using either one of two methods:

Method 1 follows the current calculations for the limit response (r_s-r_w). It requires the response efficiency to be between 85-115%, and states that the unknown water (r_u) must be less than the limit response to pass. Method 1 is "a limit test that is designed as a test for the TOC attribute specifically for PW and WFI."⁷

Method 2 is a "more general test ... for many types of pharmaceutical waters, including PW and WFI."⁷ It incorporates the response efficiency calculation (63[C_s(r_ss-r_w)/C_ss(r_s-r_w)]) and the TOC calculation for the unknown water sample as C_c = 0.42C_sr_u/(r_s-r_w), where C_c is the carbon concentration (TOC).

Both of these calculations represent a best effort at taking into account the variables of standard preparation and the appropriate response of the existing measurement system/instruments to the TOC present in the water, as discussed in the sections above.

Conclusion

There are additional changes in Chapter <643> that define better the method specifications and parameters. Both of the proposed <643> methods represent a best effort to ensure that the analytical technology chosen for TOC measurement is adequately qualified for use to measure PW and WFI.

Bibliography

1.

United Sates Pharmacopeia, 23rd Edition

(12601 Twinbrook Parkway, Rockville, Maryland 20852, USA, 1995)

2. United Sates Pharmacopeia, 23rd Edition,5th Supplement (12601 Twinbrook Parkway, Rockville, Maryland 20852, USA, May 1997).

3. European Pharmacopoeia (EDQM, 226, avenue de Colmar BP 907, F-67029 Strasbourg, France, September 1998).

4. United Sates Pharmacopeia, 24th Edition,4th Supplement (12601 Twinbrook Parkway, Rockville, Maryland 20852, USA, June 2001).

5. "In-Process Revision," Pharmacopeial Forum (July/August 2002).

6. "<643> TOC Official Revision," United Sates Pharmacopeia, 26th Edition,2nd Supplement (12601 Twinbrook Parkway, Rockville, Maryland 20852, USA, August 2003).

7. "<643> In-Process Revision," Pharmacopeial Forum (November/December 2003).