Water Release Testing for GMP Manufacturing

Industry Standards EP 2244 image

Pharmaceutical manufacturing requires many raw materials to produce drugs. Water is probably the largest raw material used by the bio/pharmaceutical manufacturing industry. The quality of the water used in manufacturing is defined by the global Pharmacopoeias who have harmonized the parameters and requirements for Purified Water (PW) and Water for Injection (WFI).

Pharmacopeias require PW and WFI water to pass 4 critical quality parameters:

Total organic carbon (TOC)

TOC is a measure of the organic material in the water which is food for microbes. Excess TOC levels allows microbes to thrive and proliferate. TOC usually comes from the remains of microbes that have passed through the filtration process
QbD1200 and PAT700

Conductivity
1. Conductivity measures residual inorganics that could remain in the water post-treatment, such as chlorine, which is added to drinking water to control microbial growth.
2. PAT700 from Beckman Coulter can measure both TOC and Conductivity on line in the water treatment plant
Microbial Contamination
1. It’s almost impossible to get rid of all microbes, so the goal is to prevent them proliferating in the water system. TOC measurement isn’t a measure of microbes, it’s a measurement of the organic material in the water that could be food for microbes. The goal is to keep the organic material down so microbes can’t proliferate.
2. Typical methods for sterilizing the water to reduce microbial growth are heat and ozone. The International Society for Pharmaceutical Engineering (ISPE) guide to Ozone Sanitization of Pharmaceutical Water Systems contains guidance on the use of ozone for microbial control in water systems.¹
Endotoxins in the water
1. Endotoxins are substances found in the cell walls of microbes. Microbes are in the drinking water used as the starting material for PW and WFI manufacturing. This water is sterilized by filtration. Microbes are shredded as they go through the filter, which kills them. However, parts of the cell wall of the microbes containing endotoxin material pass through into the water system.
2. It could be dangerous for a patient if endotoxins were injected as part of a medicinal product. Frequently these patients have compromised immune systems, so this could be detrimental to their health. These endotoxins need to be closely controlled for patient safety by ensuring they’re removed from purified water used in drug manufacturing.

Two water types are used in bio/pharmaceutical manufacturing

Purified water (PW)
1. Purified is derived from drinking water passed through various filtration and treatment steps. It’s used by both biopharmaceutical manufacturing and chemically-derived small molecule pharmaceutical companies working making injectables, powders or tablets. Purified water must meet the 4 critical quality parameters defined above to be used in manufacturing.
2. Pharmacopoeial requirements for PW production include:
  1. Must meet requirements for ionic and organic chemical purity, and be protected from microbial contamination
  2. Source water treatment steps can include deionization, distillation, reverse osmosis or other suitable purification process
  3. Purified water systems must be validated to ensure they reliably/consistently produce water of acceptable quality even with the seasonal variations of incoming drinking water quality
  4. Systems operated under ambient temperature conditions require monitoring and frequent sterilisation to control microbial levels
Water for Injection (WFI) –
1. Water for injection is purified water taken through additional treatment steps. It's used for injectable drugs, including all biologically derived pharmaceutical product as well small molecule chemically derived products that are delivered by injection. A biopharmaceutical product delivered by injection into the body requires an extra level of cleanliness because it bypasses the body's natural protection and goes straight into the bloodstream or tissue.
2. There should be no microbial contamination in the final product. When filling syringes for injection, the material is typically passed through a 0.2 micron filter to again shred any microbes coming through to ensure purity. Injectable drugs are manufactured in clean room environments to reduce potential contamination from the air and the production staff.
3. Pharmacopoeial requirements for WFI production include:
  1. WFI must meet all requirements for Purified Water—plus specifications for bacterial endotoxins prone to inhabit water
  2. Tests for total organic carbon (TOC) and water conductivity apply to WFI produced onsite for use in manufacturing
  3. Levels for WFI in USP <1231> (10 cfu/100 mL) are considered to represent a level above which the water is unfit for use
  4. On-line testing for conductivity and TOC can avoid contamination risks and provide immediate analysis and opportunities for real-time control/intervention

References

Good Practice Guide: Ozone Sanitization of Pharmaceutical Water Systems, ISPE. July, 2012. https://ispe.org/publications/guidance-documents/ozone-sanitization-pharmaceutical-water-systems

Water Release Testing Products

ANATEL PAT700

Use for on-line release testing for Conductivity and TOC Analysis

QbD1200

Use for point-of-use grab sample analysis for TOC analysis

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Water Release Testing Application Notes

Document Title	Description
Validation of online TOC for release testing using ICHQ2 {E588CF40-730C-4137-A5DC-8DDEAB7CF7D9}	Description does not have a content rendering
ICH Q2 Challenge Measuring TOC {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
Automating Biopharma Quality Control to Reduce Costs {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
QbD1200 USP System Suitability {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
QbD1200 Background Subtraction {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
QbD1200 Method Overview {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
Water Release Testing for GMP Manufacturing	Description does not have a content rendering
QbD1200 Detection Limit {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
QbD1200 Inorganic Carbon Removal {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
Importance of TOC measurement in WFI European Pharmacopoeia change {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
QbD1200 Calibration {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
QbD1200 Overload Recovery {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
QbD1200 JP SDBS Validation {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
Qbd1200 Preparing Reagent Solution {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
21 CFR Part 11 Data Integrity for On-line WFI Instruments {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
European Pharmacopoeia EP 2244 TOC {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
Quality Control Records 21 CFR Part 11 {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Description does not have a content rendering
USP 645	Description does not have a content rendering

Product Brochures

Title	Description
21 CFR Part 11 Data Integrity for On-line WFI Instruments	This whitepaper takes a look at how quality-critical on-line Total Organic Carbon (TOC) and conductivity instrumentation for WFI (water for injection) quality control can be configured to help companies comply with the FDA’s expectations on data integrity, including the use of Microsoft Active Directory and PDF data export.
ANATEL PAT700 Total Organic Carbon (TOC) and Conductivity Analyzer Product Brochure {A7DF4F56-8AF9-4BF1-88BE-766AB73FBC6B}	Product Brochure for the PAT700 TOC and Conductivity Analyzer
Quality Control Testing Instrumentation Solutions for GMP Manufacturing Brochure {A7DF4F56-8AF9-4BF1-88BE-766AB73FBC6B}	Brochure on instruments designed for Raw Materials QC, Production QC, and Final Product QC
Validation of On-line Total Organic Carbon Analysers for Release Testing Using ICH Q2 {E588CF40-730C-4137-A5DC-8DDEAB7CF7D9}	This paper discusses how characteristics for consideration during the validation of analytical procedures may be applied to on-line Total Organic Carbon (TOC) analysers to enable them to be used to provide release test data for Water for Injection (WFI) and Purified Water (PW).
ICH Q2 – the Challenge of Measuring Total Organic Carbon in Modern Pharmaceutical Water Systems {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	This page discusses some of the challenges when using TOC analysers to demonstrate pharmacopoeial TOC level compliance for modern water systems in the light of the ICH Q2 document2 from the International Conference on Harmonisation.
ICH Q2 – the Challenge of Measuring Total Organic Carbon in Modern Pharmaceutical Water Systems	This paper discusses some of the challenges when using TOC analysers to demonstrate pharmacopoeial TOC level compliance for modern water systems in the light of the ICH Q2 document2 from the International Conference on Harmonisation.
Brochure for QbD1200 TOC Analyzer {A7DF4F56-8AF9-4BF1-88BE-766AB73FBC6B}	The QbD1200 delivers the highest performance with unparalleled ease of operation and maintenance
Automating Biopharma Quality Control to Reduce Costs and Improve Data Integrity {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	This paper takes a look at four common quality control procedures and how automation can help improve data integrity by reducing opportunities for human error, whilst also saving time and reducing operating costs.
USP System Suitability {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	QbD1200 is designed so that System Suitability is very convenient and easy to perform.
Background Subtraction {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	When measuring a water sample to quantify TOC (Total Organic Carbon), most TOC analyzers add some combination of reagents and dilution water to the initial sample in order to complete the measurement.
Method Overview {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	The QbD1200 is unique in that it combines all required reagents (acid, oxidizer, and dilution water) into a single reagent instead of requiring multiple reagents.
Water Release Testing for GMP Manufacturing	The quality of the water used in manufacturing is defined by the global Pharmacopoeias who have harmonized the parameters and requirements for Purified Water (PW) and Water for Injection (WFI).
Detection Limit {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	For Detection Limit (DL), often referred to as Limit of Detection (LOD), both ICH and JP 16 offer clear direction.
Inorganic Carbon Removal {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	To quantify TOC, all analyzers must incorporate a strategy to account for the TIC. However, not all of these strategies are equally effective or reliable.
Importance of TOC measurement in WFI in light of European Pharmacopoeia change {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	This paper discusses the increased focus on Total Organic Carbon (TOC) and conductivity measurement, especially for companies seeking to use RO water treatment plants to create WFI, and provides best-practice advice for calibration.
Calibrating the QbD1200 TOC Analyzer {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	The calibration of a TOC Analyzer is a crucial part of ensuring a quality measurement.
Overload Recovery {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	Experienced operators can develop reasonable expectations about what the TOC values will be and the measurement values will tend to fall within an expected range most of the time.
JP SDBS Validation {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	The QbD1200 has a built in qualification routine, “SDBS”, which makes performing a JP 16 compliant validation convenient.
QbD1200 Preparing Reagent Solution {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	The QbD1200 TOC Analyzer uses a mixture of phosphoric acid (to aid in removal of CO2 from solution) and ammonium persulfate (to aid in oxidizing organic compounds).
21 CFR Part 11 Data Integrity for On-line WFI Instruments {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	This application note takes a look at how quality-critical on-line Total Organic Carbon (TOC) and conductivity instrumentation for WFI (water for injection) quality control can be configured to help companies comply with the FDA’s expectations on data integrity, including the use of Microsoft Active Directory and PDF data export.
European Pharmacopoeia EP 2.2.44 and Total Organic Carbon {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	This paper discusses the background behind the European Pharmacopoeia’s focus on complete oxidation of TOC in the light of the increased importance of on-line Total Organic Carbon (TOC) and conductivity measurement.
Quality Control Electronic Records for 21 CFR part 11 Compliance {442DF88C-CA7F-4B78-AF75-9D2B985534C0}	This paper describes how Quality Control instruments can be optimised for pharmaceutical use, helping to improve the integrity of the data in the final electronic record.
Automating Quality Control Testing for Improved 21 CFR Part 11 and ALCOA Data Integrity {A0D0EF0B-43F2-431C-BEB0-69F98765BDC4}	Infographic showing manual to automated - how our QC Suite instruments help you comply with 21CFR part 11 ALCOA
USP <645>	This standard applies to electrical conductivity, one of four critical water quality attributes defined by the United States Pharmacopeial Convention (USP) for purified water (PW) and water for injection (WFI).
Root cause investigation for pharmaceutical water systems	In this whitepaper we discuss some typical sources of contamination in water systems and how root-cause investigations can be supported using on-line Total Organic Carbon (TOC) analysers.