CHEMICAL QUALITY CONTROL ON WATER PRODUCED FROM WFI SYSTEM AT MEDICAL

TECHNOLOGY DIVISION

Abstract

Water for Injection (WFI) used in production of Technetium-99m (Tc-99m) bound to stringent specifications in
order to comply with Good Manufacturing Practice (GMP) requirements. The WFI should meet British
Pharmacopoeia (BP) and United States Pharmacopoeia (USP) grade specifications. The goal of the study is to
test the WFI system whether it is running optimally and operating normally after undergo some repairs and
maintenances. Physical appearance, pH, total organic carbon and conductivity test is done in order to evaluate
the water quality which consequently implies indirectly the condition of the water system. Results have shown that
purified water from sampling point 4 and WFI from sampling point 20 indirectly indicate possible problems in the
water system. Overall the WFI system running normally and optimally except for sampling point 4 and 20 which
need further investigation.

INTRODUCTION

Production of Technetium-99m (Tc99m) as well as production of radiopharmaceutical kits in Medical Technology

Division (BTP) require sterile Water for Injection (WFI). Tc99m is the most common radioisotope use in diagnostic
medical procedures and it is estimated that about 85% of diagnostic imaging use this radioisotope as radioactive
tracer. In BTP the commercial 99Mo/99mTc generator is the source for the production of Tc 99m. 99Mo as a parent
nuclide spontaneously undergo beta decay to Tc99m. Tc99m that forms through 99Mo decay will be chemically
extracted from the generator. The technetiums exit the generator in the form of pertechnetate ion (TcO 4-).

Technetium is a well known radioisotope in diagnostic medical applications. Its ability to dissolve in nitric acid,
concentrated sulphuric acid as well as in aqueous solution such as in WFI show the Tc99m suitable to use in broad
range of medical applications. TcO4- has an oxidation state of +7 which is suitable for medical application in bone
scans and in some thyroid scan. Other types of scans relying on Tc99m need a reducing agent to reduce the oxidation
state of the technetium down to +3 or +4 and ligand is added to form the coordination complex. The selection of
ligands determine the affinity of the complex to the targeted organ. For example when the Tc 99m tagged with
exametazime (HMPAQ), Tc99m could allow cerebral blood-flow imaging and when bound to diethylene triamine
pentaacetic acid (DTPA) it can allow renal imaging to be done.

Water is the critical elements among the others in radiopharmaceutical kits preparation. It is used in almost all
process namely in product formulating stage, cleaning, rinsing and in sterilization process (International Atomic
Energy Agency, 2008). In consideration regarding the importance of the need for clean and safe water, there are
regulations need to be fulfill in the production of WFI and purified water in the production of radiopharmaceutical
kits to ensure the kits produced are safe. Standard regulations have been set up in managing the production of
water for pharmaceutical use, especially water for injection (WFI) as well as purified water. Standard regulations
including regulatory standards set by the United States Pharmacopeia (USP), British Pharmacopoeia (BP) or
European Pharmacopoeia (EP) have been imposed thru enforcement of Good Manufacturing Practice (GMP). At
BTP, references from USP and BP have been used extensively in managing the quality control of the production
of WFI.

According to USP, WFI is allowed to be made from tap water by a distillation process or by purification system
that is equivalent or superior to distillation for the removal of chemicals and microorganisms. WFI need to be
clear, colorless and odorless liquid which is sterile, deionized and free from particulate matter and endotoxin. The
conductivity of the WFI and the total organic carbon (TOC) also need to be in the allowable recommended range
as shown in Table 1. The quality of the WFI is more reflective in the analyses of conductivity and TOC of the
water.
Based on specifications that have been adapted from Pharmaceutical Inspection Co-operation Scheme (PIC/S) in
order to compliant with the GMP requirements for releasing medicinal product, BTP have impose specifications
for WFI system as shown in Table 2.0

Table 2: BTP Specification for Water for Injection

Test Specifications
Physical Appearance Clear and colorless
pH 5.0-7.0
Total organic carbon 500 ppbC @ ≤ 0.5mg/ml
Conductivity < 1.3 µS/cm, 25°C

Result which is not in the range is considered as out of specification and report will be sent to Quality Assurance
(QA) unit for further action in order to rectify the problem arises.

MATERIALS AND METHODS Sampling of water

The water was collected from 17 sampling points designated as below:

Sampling points Type of water

4, 21 Purified water (pw)
5, 6, 7,8 ,9, 10 11, 12,13, 14, 20 Water for injection (WFI)
22, 23, 24, 25 Raw water (rw)

Physical appearance

The appearance of the samples was examined and it should be clear and colorless.

pH

0.3ml of saturated potassium chloride was added to 100ml of sample. The pH reading was taken by pH meter.
pH between 5.0-7.0 considered within specification.

Total organic carbon

Total organic carbon was determined by laboratory TOC analyzer. The complete instruction followed the
operational manual for laboratory TOC analyzer. Reading less than ≤ 0.5mg/l @ 500 ppbC considered within the
specification.

Conductivity

Conductivity was determined by using conductivity meter. The instruction should follow the operation manual for
conductivity meter. Briefly the conductivity meter will be calibrated in standard solution and consequently the
probe will be immersed in the samples. Result/reading not more than < 1.3 µS/cm at 25oC considered within the
specification.

CONCLUSION
Sampling point 4 (purified water) and sampling point 20 (WFI) which exhibit the most repeated out of
specifications compared to other sampling points could suggest that the BTP WFI system need further
investigation especially regarding the elements/system components which have relationship with conductivity and
pH. The monitoring results also suggesting that the softener system need to be checked as the water conductivity
have strong relation with the water hardness. Overall, the BTP WFI system has been running normally and
optimally as most of the sampling points pass the rigid specifications which have been specified throughout the
monitoring duration.

References

British Pharmacopoeia. (2005). (Vol. 1).

International Atomic Energy Agency. (2008). TECHNETIUM-99m RADIOPHARMACEUTICALS:

MANUFACTURE OF KITS (Vol. 466). Vienna.

Schwochau, K. (2008). Technetium: Chemistry and Radiopharmaceutical Applications.

Wikipedia. (2015). Total organic carbon, from [Link]