Biomaterials, Biomedical Technology & Quality System Published by IIPC, SCTIMST –
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Water Quality Management in Medical Device Manufacture C. V. Muraleedharan Division of Artificial Organs, Biomedical Technology Wing Sree Chitra Tirunal Institute for Medical Sciences & Technology Thiruvananthapuram 695 012, INDIA
Quality of water used for the preparation and processing of medical devices plays a very significant role in meeting the quality norms of the product. Most often the cost of the water used, whether for preparing the formulation or for processing the product, may be significant contributor to the cost of the product. The selection, design and operation of the water treatment method need to be based on these conflicting requirements of cost and quality. Selection of water quality: One of the basic considerations in the selection of water quality is the type of device and its processing route. It should be identified that there is no specific guideline available for the selection and qualification of water to be used in the processing of medical devices. Few guidelines are available in the case of water used in dialysis and reuse of dialysers. Most often medical device industry may have to adopt the guidelines from the pharmaceutical industry and modify to suit the specific requirements. There are many classification schemes available for the specifying the quality of water used in pharmaceutical industry. The most common one employed is set forth by various pharmacopeias. Though there are minor variations between different documents, the basic types of interest include the ones listed in table 1. Another water classification scheme, which could be adopted for water requirements of medical device industry, is based on the American Society for Testing Materials standards for reagent quality water. This standard specifies four types of water grades as Type I, II, III and IV based on the purity levels. The bacterial contamination level is further classified as Type A, B and C based on the extend of bacterial contamination. Table 2 provides the different types of water and their primary specifications.
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Table 1: Classification of water quality based on pharmacopoeia specifications Type
Details
Purified water
Purified water is intended to be used as an ingredient in the preparation of compendia dosage forms. It may be obtained by distillation, ionexchange treatment, reverse osmosis or other suitable means. Purified water is normally prepared from potable water. The pH levels are expected to be within 5 to 7 and there are specific quality checks related to the ionic and heavy metal contamination levels; but the bacteriological contamination levels are not specified other than indicating that it should meet the requirements of potable water.
Water for
Water for Injection (WI) is intended for use as a solvent for the
Injection
preparation of parenteral solutions. It needs to meet all requirements of purified water. In addition, the bacterial endotoxin levels are specified (0.25 USP EU/ml). Water for Injection is first rendered sterile by the process and there after protect it from microbial contamination.
Sterile water for
Sterile Water for Injection (WI) is Water for Injection sterilized and
injection
suitable packaged. In addition to the requirements for WI, it needs to meet the sterility requirements.
The choice of quality of water for a specific operation will have to depend on the many factors like nature of the product, nature and sequence of the process, whether terminal sterilization is possible etc. For all parenteral products, water for injection shall be used for preparation. Some of the products like ophthalmic irrigation solution, inhalation solutions used in humidifiers etc, Sterile Water for Injection could be the best choice. Topical and oral products, which do not have requirements for endotoxin, could be prepared in purified water. Cleaning of most of the medical devices shall be carried out using purified water in the earlier stages and water for injection in the terminal stages. But there are many products, which have large surface area like blood-contacting filters, medical textile products or which have regions where bacteria could trap during processing. In such cases water for injection shall be used in all stages of processing.
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Table 2: Specifications for Regent Water, ASTM Parameter
Type I
Type II
Type III
Type IV
Total matter (max), mg/l
0.1
0.1
1.0
2.0
Electrical conductivity (max),
0.06
1.0
1.0
5.0
__
__
6.2 – 7.5
5–8
Maximum soluble silica
Not detectable
Not detectable
10 mg/l
No limit
Maximum total bacteria
Type A
Type A
Type B
Type C
0 / ml
0 / ml
10 / ml
100 / ml
µmho/cm at 25°C pH, at 25°C
count
** The measurement of pH in Type I and Type II reagent waters is meaningless as the measurement process itself could change the pH levels Even though ASTM reagent grade water types does not have one to one matching in quality specifications with respect to the pharmaceutical grades, wherever purified water is used it could be replaced with ASTM Type III water with Type C bacteriological specifications. The Water for Injection could be replaced with ASTM Type II with Type B bacteriological specification. Sterile Water for Injection could be replaced with ASTM Type II with Type C bacteriological specification. Selection of water treatment technique: Many techniques are available for treatment of water to attain the specific quality requirements. In medical device industry it always preferable to have potable water as starting point in all water treatment operations to ensure consistent quality of treated water as well as to minimize the burden on the treatment plants. Distillation: Water distillation is one of the earliest techniques used for improving the quality of water. The quality of water in terms of the ionic content and bacterial endotoxin levels is controlled significantly by the feed water quality. Distillation process normally provides a 2.5 log to 3 log reduction in the endotoxin level and 2 log to 2.5 log reduction in dissolved salt levels.
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Ion Exchange: Contaminant cations and anions present in the feed water could be reduced using ion exchange or adsorption into activated media. The most significant use of ion exchange devices are in water softening and hence is used as primary or secondary stage in the water treatment system. Most of the ion exchange media could be regenerated by suitably removing the adsorbed ions using chemical methods. Membrane Based Processes: Different types of membrane based water treatment include Reverse Osmosis (RO), Electro Dialysis (ED), Ultra Filtration (UF) and Nano Filtration (NF) techniques. RO is a pressure driven process that retains virtually all ions and passes water. The pressure applied exceeds the osmotic pressure of the ionic salt solutions against a semi permeable membrane, there by forcing pure water through the membrane leaving salts behind. ED is a process in which ions are transferred through the membranes from less concentrated to a more concentrated solution as a result of passage of direct electric current. The flow of water is tangential to the membrane while the flow of ions is perpendicular to it. UF is a pressure driven filtration process, which retains non-ionic matter and generally passes ionic matter across the membrane depending on the molecular weight cut off of the membrane. Nano filtration is similar to ultra filtration in technique, but differs in the size of particulates that could be filtered. NF normally operates in the range of nanometric scales, which passes particles less than nanometer in size.
Water Treatment Systems: A Check List for specification / selection Reverse Osmosis 1. A diagram of the system, including the location of all valves, and all pressure, temperature, conductivity / total dissolved solids (TDS) and flow sensors. The conductivity / TDS meter should be temperature compensated for accuracy. 2. Identify all water contact materials, separating them into those that contact feed water and product water. Obtain the results of leach testing that identify and characterize the leachables using appropriate chemical analyses. 3. A complete description of the membranes utilized, including the physical design and materials of construction. 4. Nominal performance of each type of R.O. membrane, including the rejection of total dissolved solids (TDS), monovalent and polyvalent ions, bacteria and endotoxin; organic size cut-off; chlorine and pH tolerance; and temperature and pressure limits.
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5. Audible and visual alarms, including the recommended location, and the consequent action(s). 6. User manual shall include includes detailed instructions for installing, operating, monitoring, maintaining, troubleshooting, cleaning and disinfecting the device as well as any associated warnings or precautions. Recommended schedules for monitoring, maintaining, cleaning and disinfecting the device should be included, along with a monitoring log. The cleaning and disinfection instructions should include, at a minimum, the identity of appropriate cleaning agents and disinfectants, the recommended cleaning and disinfection frequency and the procedure for measuring residuals. Deioniser 1. A Device description that includes a generic diagram of the system and the identity of the resins (including the quality). 2. Describe all monitors and alarm systems. The D.I. should include a temperature-compensated audible and visual alarm to indicate when the bed is exhausted. Ultra filters or submicron filters be installed on the outlet line from the D.I. tanks to ensure removal of bacteria and endotoxin. 3. Identify all water contact materials, separating them into those that contact feed water and product water. For all product water contact materials, obtain results of leach testing that identify and characterize the leachables using appropriate chemical analyses. 4. The user manual should provide the expected life of the resin bed in terms of the quality and volume of water treated. The manual should identify the recommended quality of replacement tanks or resins. Ultra Filtration 1. A physical description of the device including the flow rates, expected pressure drop and the materials of construction. Describe any monitors or alarms that may be installed with this component. 2. Specifications for rejection of bacteria and pyrogens and data to demonstrate that the membrane meets the performance specifications. 3. List all water contact materials. For these materials, results of leach testing that identify and characterize the leachables using appropriate chemical analyses. 4. A user's manual that includes instructions for installing, operating, maintaining and troubleshooting the device. The manual should list any cleaning, disinfection or maintenance
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procedures that must be performed along with the recommended frequency. Recommended cleaning and disinfection agents and procedures for monitoring residuals should also be provided. The manual should specify the expected useful life of the device. Storage of treated water: Water in constant motion is less liable to have higher levels of contamination. Though continuously running true on line system is most appropriate for pure water applications, due to many practical considerations, treated water will have to be stored prior to end use. In such cases, it is always advisable to have heated storage tanks (65°C to 80°C) for storage of purified water. The holding tanks shall be provided with a venting port fitted with microbial filters. Validation of installations: Validation of the water processing installations in the medical device industry could be planned as a three-stage process. When all the equipment and piping has been installed and working as specified, the initial phase of validation can begin. During this phase, the operational parameters and the cleaning / sanitization procedures and frequencies will be developed. Sampling shall preferably be daily after each step in the purification process, during the first one month of run. The water sampling procedure should reflect how the water is being drawn at the point of use (E.g. if a hose is usually attached, the sample shall be taken at the outlet of the hose). If the process SOP calls for flushing of the line prior to collection, then the sampling shall also employ the same procedure. All parameters, which are specified for the quality of water, shall be checked during the first phase of validation. This phase will establish the variability in the quality of water over the period as well as its dependence on the feed water quality. The process SOPs shall get standardized during this phase. The second phase of system validation is to demonstrate that system will consistently work and maintain the desired water quality when operated in conformance with the SOPs. The sampling is taken as in the initial phase and for the same time period. The third phase of validation is designed to demonstrate that the system will maintain its quality even while moderately challenged. In this situation, it would be undesirable to introduce microorganisms into an on line system; therefore, reliance is placed on periodic testing for microbiological quality and installation of monitoring equipments at specific check points to ensure that the total system is operating properly and continuously fulfilling its intended function. The period of this phase shall be at least one year so that any seasonal variations in the quality of the feed water would be an automatic challenge to the system. Another case of automatic challenge would be the introduction of non-sterile air into the system during refilling after routine cleaning of the components and subsystems.
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References: 1. United States Pharmacopoeia, USP 29: NF 24, Section : Water for pharmaceutical purposes. 2. American Association for Medical Instrumentation- AAMI AAMI RD62 Water treatment equipment for hemodialysis (AAMI RD62: 2001) 3. American National standards Institute / American Association for Medical Instrumentation (ANSI/AAMI) Reuse of hemodialyzers (ANSI/AAMI RD47: 1993) 4. American National standards Institute / American Association for Medical Instrumentation (ANSI/AAMI), Dialysate for hemodialysis Water quality for dialysis, 3ed (AAMI WQD: 1998; AAMI Monograph) 5. ASTM International, ASTM D1193-06 Standard Specification for Reagent Water 6. American Water Works Association, Water Quality and Treatment, McGraw-Hill, NY, 1990 7. Guide to insection of High Purity Water Systems, FDA Guideline, 1993.
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