Jim Knows Best | Pharmaceutical Waters Industry Expert - METTLER TOLEDO
 
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Jim Knows Best | Pharmaceutical Waters Industry Expert

Jim Cannon

Regulations

Joao from Brazil asks:

Are there any regulatory determinations that do not allow a water system to: 1.) Recirculate the PW, in the return that passes through the pre-treated water deionized tank? 2.) Save the reject water from R.O, the return to the deionize tank? I am validating a PW system and my region is too dry and I want save more water if possible. All controls are done and the results are okay.

There are no Pharmacopeia regulations that prevent the recirculation of the Pure Water (PW) distribution loop to the pre-treated water tank and in fact that procedure is encouraged because the water is then flowing and not remaining stagnant in the piping.

In regards to reclaiming the reverse osmosis (RO) reject, it is not prohibited by the Pharmacopeia and many companies have this feature included on their water system. I would provide the following caution because I do not have the flow diagram for your PW system. Generally the RO reject is partially recovered and returned to the feed side of the RO. The reject will be more concentrated with salts and organics and feeding it straight to a deionized tank would significantly change the conductivity and organic levels in the tank. You may want to consider recycling the RO reject to the front of the RO, and shown below is a basic schematic of that process, though this shows a two-pass RO and I don't know if yours is a single-pass or two-pass RO system.

Salvador from Mexico asks:

We have a doubt about conductivity related with exclusion of nitrates and heavy metals analysis for China and India. I remember one of your presentations where you have some comparative parameters between them. Can you share with me that information please? We already have one of your systems working here and we are making a periodical inspection of our data system and also comparing it to the regulations in order to see if we can improve some analysis.

In regards to the Pharmacopeia requirements for testing of nitrates and heavy metals for Water for Injection (WFI) and Purified Water (PW), there are required tests for China and India. The European Pharmacopeia also still requires nitrate testing for WFI and PW. Since you are required to test for conductivity, if you are measuring the conductivity in-line and are under the limit of 1.3 µS/cm at 25˚ C, it would be improbable that you would fail the tests for nitrates or heavy metals. But if the requirement is to test for those parameters, your own SOPs would establish the testing schedule. Copied below are the current Pharmacopeia requirements for WFI and PW.

Ileana from Cuba asks:

As you know USP 645 is a compendial procedure, for this reason it must be verified according to USP 1226. I am looking for the specific parameters to be evaluated.

In the United States Pharmacopeia – National Formulary (USP-NF) there are three sections that apply to the regulations and/or recommendations for Pharmaceutical Waters. I have copied the current sections below, which are divided into three areas; Pharmaceutical Water Monographs, Test Chapters and General Information. If a section is not numbered it is part of the Pharmaceutical Water Monographs, if a section is numbered and the number is below 1,000 then it is a Test Chapter, and finally if a section is numbered at 1,000 or greater than it is a General Information section.



For Bulk Water for Injection and Bulk Purified Water, I have copied the current required tests (USP37-NF32) below. These are the established and harmonized test procedures for these waters.

In regards to your specific question and the need to verify according to USP 1226, I will clarify this issue. The most important point of USP 1226 is included in the first two sentences of the chapter; “The intent of this general information chapter is to provide general information on the verification of compendial procedures that are being performed for the first time to yield acceptable results utilizing the personnel, equipment, and reagents available. This chapter is not intended for retroactive application to already successfully established laboratory procedures.”

USP 1226 is only intended for use on procedures or tests that are being undertaken for the first time and have not been established as an accepted procedure. Because USP 645 (conductivity) and USP 643 (TOC) are the established compendial procedures, you are not required to verify under USP 1226. Therefore, you are only required to follow USP 645 and USP 643 for the test reporting and validation of your water for injection or purified waters.


Joao from Brazil asks:

Why do I have high conductivity measure, after R.O. treatment? What can I do to fix this?

The most common reason for higher conductivity, post RO treatment, is carbon dioxide in the processed water. This can occur when the feedwater to the RO is being adjusted with acid to protect the RO membrane. If the pH of the feedwater is lowered too much, you will produce CO2, which passes through the RO membrane raising the conductivity. Test the pH of the feedwater. RO membranes prefer a slightly acidic feedwater, but if you are below 5.6, raise the pH of the feedwater to the range of 6.0 to 6.3 and then test the conductivity of the product water from the RO.

Why are the results (in-line vs. a QC lab) so different? I believe they would be, but sometimes I detect a double...so weird.

Pure water will absorb CO2 from the atmosphere at a very fast rate, especially if the water is at ambient temperature. For example, if the conductivity of the water measured in-line is 0.06 μS and you then proceed to take the sample of the water for off-line testing, the conductivity will increase to 2.1 μS in less than 2 minutes. The best procedure is to measure your conductivity in-line and use that to validate your system. The Global Pharmacopeias are encouraging in-line versus off-line testing because of the variability of off-line testing. This same phenomenon also occurs with TOC testing. A purified water system with in-line testing for TOC may show a value of 20 ppb. That same water when tested off-line could easily have a value of 140 to 300 ppb, depending on sampling technique, sample container and atmospheric contamination. This is why in-line testing is being strongly encouraged by the Pharmacopeias.

What is the recommended method and material (glass/plastic) for collecting samples (for TOC or conductivity tests)? I am trying to validate a PW system and having many difficulties with these tests.

If you are going to perform off-line testing then the sample containers should be cleaned extensively and the material of the container is very important. Glass (borosilicate (Pyrex)) containers could be used but they should not be if they are new (unless they have been cleaned with ultrapure or purified water and also cleaned with dilute nitric or hydrochloric acid). The surface of the glass container, especially when new, will have ions that will leach into the water changing your test results. It would be best to use either polypropylene or PFDF container. These will also have to be cleaned with Ultrapure or Purified water. When you use the container to obtain a sample, you should fill it and empty it with the water you are going to be testing for a minimum of three times before taking the final sample. Once again, we would recommend that you perform the validation of conductivity and TOC with in-line instruments as your results will more accurately reflect the quality of the water and you will not experience the variability that can occur with off-line testing.


“Is it a requirement to perform on-line and off-line testing for conductivity of a pharmaceutical water system?”

To comply with USP <645>, EP or any other global pharmacopeia you only need to meet the conductivity limit at the testing point in your water system. If that point is measured with an on-line instrument and the value is below the limit then no further testing is required.

For more on USP regulations, download our PRO Insight on USP <643> and on-line TOC
 


"What does USP<645> mean by the 'Resistance Measurement Calibration'?"

A conductivity measuring system consists of two components: the electrodes that are placed in the water and the resistance measuring circuit that makes the measurement. Traditionally, the measuring circuit has been located in the transmitter. However, today's state-of-the-art technologies allow the resistance measuring circuit to be placed directly in the sensor—improving system accuracy and range. In either case, the measuring circuit must be calibrated or verified with NIST (or equivalent national authority)–traceable precision resistors.

Learn about high accuracy UniCond® conductivity sensors



“What is the calibration frequency required by the pharmacopeia regulations for conductivity sensors?”

There is no regulation for frequency of calibration; only that you must use calibrated instruments. The frequency in the Pharmaceutical industry is to calibrate the conductivity loop (sensor cell constant and resistance measuring circuit) on either an annual or semi-annual basis. Calibration periods longer than once a year could raise questions regarding the accuracy of on-line conductivity systems. More often than once every six months would just increase cost and workload.

Download our free guide to learn more about calibration requirements

 


Jon Browne asks:

Is it still a requirement to perform micro and endotoxin sampling on a hot WFI system? If so, why? Heat-resistant micro-organisms? If we are constantly recirculating WFI above sanitization temperatures, I don't see the need as to why we would need to sample micro or endo.

As a microbiologist, I understand questioning the test, because if you are above 67-68 °C, there should be no viable organisms.

The pharmacopeias (USP, EuP, JP, ChP, IP, MxP, BP) all have microbial and endotoxin testing listed as required compendial tests. The ability of microbial organisms to adapt is well documented, but more importantly, biofilm does communicate by quorum sensing and when sensing danger or death will secrete a metabolite layer to protect the community. I have seen examples of biofilm developing around the edge of a gasket on a pressure sensor in a hot WFI system, and the customer’s microbial plate count tests were almost always reporting 0 CFUs, but they were occasionally detecting endotoxins. The positive endotoxin test demonstrated that either biofilm or planktonic organisms were in the water loop even at high temperatures.

There is no discussion at the pharmacopeias' committee level to eliminate the microbial or endotoxin test, but there are discussions about the adoption of rapid microbial detection technology
 


Luis Poma Pagán asks:

We are a small pharmaceutical laboratory and we want to have a guaranteed TOC and conductivity meter to pass an audit with the Peruvian regulatory authority. What equipment do you recommend that is not very expensive and is practical for a plant that has a small production capacity?

Conductivity and TOC are compendial measurements for the validation of Purified Water (PW) or Water for Injection (WFI) systems, which will be measurements that an inspector will be verifying during an audit. While the pharmacopeias still permits off-line testing of these parameters, they strongly encourage on-line measurement of these parameters for real-time process control. The PAT (Process Analytical Technology) initiative of the FDA is driving the industry to incorporate on-line measurements. 

METTLER TOLEDO Thornton has been involved with pharmacopeia expert committees for over three decades and we were asked by the pharmacopeia to provide the scientific research to prove that conductivity and TOC could replace the older wet chemistry tests. Due to the scientific work we conducted, the pharmacopeias adopted conductivity and TOC in 1996 as the compendial tests. The TOC limit for PW and WFI is 5000 ppb, while the conductivity limits for on-line measurement changes with temperature. METTLER TOLEDO Thornton transmitters have the pharmacopeias' temperature set points in the software so you can set your alert and action limits in the transmitter and not have to use an external temperature device and look-up tables.

Regarding a conductivity loop and TOC system to meet your requirements and budget, for conductivity I would recommend the M300 Water transmitter (catalog number 30 280 776) and a sanitary conductivity sensor (catalog number 58 031 416). For the TOC system I would recommend the 4000TOCe (catalog number 30 415 866) with the M300TOC transmitter (30 414 214). These systems have all the pharmacopeias' set point tables and will provide you the accuracy and traceability for any audit
 


Thiện Trần asks:

Is an RO water loop that supplies pure water in pharmaceutical production required to be continuously maintained at <25 °C, or can it be interrupted for 1 hour at 26 °C?

The requirement to maintain an RO water loop at <25 °C is not a requirement of the major global pharmacopeia. The only 'recommendation' that they have in this regard, is to not maintain the temperature at 33 to 35 °C, because that is the growth temperature for biofilm.

If you state in your internal SOP that the water loop is maintained <25 °C except for a one hour period when it is circulated at 26 °C, the alternative is to just state in your SOP that the RO water loop is continuously kept at a temperature of 26 °C or below. This would then encompass the variation from below 25 °C to it being raised to 26 °C.

Conductivity measurement
Conductivity measurement

Applications

“Why should you make a temperature compensated conductivity measurement?”

Calibration of TOC analyzers and conductivity sensors without removing them from the water system
Calibration of TOC analyzers and conductivity sensors without removing them from the water system

Calibration

“Can you perform calibration of TOC analyzers and conductivity sensors without removing them from the water system?"

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