Supplementary Training Modules on Good Manufacturing Practice Water for Pharmaceutical Use Part 3: Inspection of water systems Presented by Dr. Errol Allcoc 30 June 2005, Pretoria, South Africa Errol.Allcock@microsep.co.za 083-459 6267 This is Part 3 of Module 2, covers the topic of inspection of water systems. The suggested time for Part 3 is 60 minutes. At the conclusion of this part there is an optional group session (45 minutes) and test paper (45 - 60 minutes). (Note for the trainer: the times noted are very approximate.)

Objectives To understand: The specific requirements for inspecting water systems, including the need for a Water Quality Manual validation of water treatment systems Water system inspection techniques The objectives of Part 3 are to acquire an understanding of: The specific requirements for inspecting water systems. Now that you have a basic understanding of how and why water must be purified for pharmaceutical use, you must be able to put theory into practice during your GMP inspections. You need not be an engineer to inspect water systems but you should be able to “read” a schematic drawing of a water system, and be able to relate it to the direction of flow in the actual plant. You should understand basic requirements for inert materials of construction for equipment, and the essentials of basic water microbiology. The need for a Water Quality Manual: It is an advisory inclusion of all GMP guidelines to suggest that the manufacturer has a quality manual especially prepared for the water treatment system. This pays dividends because it is easier for the manufacturer to co-ordinate the running, maintenance, sampling and testing of pharmaceutical water systems if it can be consolidated and controlled in one document set. Validation of pharmaceutical water systems: This part also explains what to look for in the validation of a high purity water system – such as those used to prepare purified water and WFI. Inspection techniques: Explains how to get started, what questions to ask and what to look for when you conduct your water system inspections.

Review What is the water to be used for? sterile products non-sterile products liquid products solid dose products washing and rinsing Check specifications and trends When commencing an inspection, start with the use of water – the inspection approach will be different according to the products being made. Options may include: Sterile products: Production of WFI is the most challenging. Check pyrogen and endotoxin requirements for the water. Non-sterile products: Check if there are any special requirements for the pharmaceutical products, such as aluminium limit test for dialysis products. Liquid products: These are more susceptible to microbiological contamination so more stringent bacterial limits may be appropriate. Solid dose products: e.g. tablets and capsules may use water as part of the granulation step. Water is also used for washing and rinsing equipment. It is necessary to have specifications for these types of water. Check specifications and trends, especially the requirements for pyrogen or endotoxins for sterile manufacturing, and microbial limits. Microbial limits are always a problem. Only a few of the pharmacopoeia recommend microbial limits but the pharmaceutical manufacturer should be setting its own limits and frequency of monitoring. A suggested table of sampling points and target, alert and action limits is given in Part 2.

WHO water treatment guidance (1) All water-treatment systems should be subject to: planned maintenance validation monitoring Maintenance work should be documented “All water-treatment systems, including stills, should be subject to planned maintenance, validation and monitoring.” “Maintenance should be documented. Following maintenance work, the approval process should be documented.” (WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report, Geneva, World Health Organization, 1992 (WHO Technical Report Series, No. 823) Annex 1, 17.32. Annex 1, 17.32

WHO water treatment guidance (2) For reliable production, water treatment plants should be: Designed Constructed Maintained Operated within design limits Controlled to prevent microbial growth Annex 1 requires that water-treatment plants be designed, constructed and maintained so as to ensure the reliable production of water of an appropriate quality. They should operated within their design limits. Water should be produced, stored and distributed so as to prevent microbial growth. This can be achieved, for example, by constant circulation at 70°C or at not more than 4°C. Annex 1, 17.33

Prepare a checklist or an aide-memoire and review: Water Quality Manual Water system drawing Validation Sampling procedures, locations and plan Records of testing Sanitation and maintenance Schedules of maintenance The inspector should prepare a check list or aide-memoire with special emphasis on: Water Quality Manual – the recommendations are explained on the following slides. Water system drawing – this is often called a Piping and Instrumentation Diagram or P&ID. Ideally this should be made available to the inspector before the visit. Validation – the system must be under control and shown to be able to produce water of the required quality consistently and reliably. There are slides after those on the Water Quality Manual which will help you understand the special validation requirements for systems producing water of high purity. Sampling procedures, sampling locations, and sampling plan. Records of testing – evaluate trends to see if the system is under control. High contamination results may indicate a lack of sanitation and maintenance. Sanitation and maintenance procedures – also check the records to see that practice reflects the SOP requirements. Schedules of maintenance - check periodic and preventative maintenance and check to see what happens if alert and action limits are exceeded. Review the check list as you conduct the inspection and be prepared to amend it if necessary.

Review water quality manual (1) A water quality manual is advisable A brief description of water systems is required Include drawings of the purification, storage distribution system (P&ID) Review water quality manual: A water quality manual is advisable. Remember, it is not a regulation. Refer to clause 3.5 in Part One of the WHO GMP guidelines. However, a good water quality manual helps both the pharmaceutical manufacturer and the inspector, so its preparation should be actively encouraged. The water quality manual should contain a brief description of the water systems. It should list all equipment in the system, the source of the raw water and the storage systems. The water quality manual should include a drawing (schematic drawings are desirable) of the purification, storage, and distribution system.

Review of water quality manual (2) The water quality manual should show: pipelines non-return (or check) valves breather points couplings pipe slopes velocities  valves  sampling points  drain points  instrumentation  flow rates s Review water quality manual: (Contd.) The water quality manual should show: Pipelines Valves Non-return (or check) valves Sampling points Breather points Drain points Couplings Instrumentation – check calibration requirements Pipe slopes Flow rates Velocities

Review water quality manual (3) The manual should contain: Specification for each system element Standard procedures for use System changes Routine and non-routine maintenance Investigations and corrective action Validation studies Review water quality manual: (Contd.) The water quality manual should contain: Specification for each element in the system including the manufacturer’s recommended flow rates. Make sure that there are suppliers’ manuals for the make and model of the equipment, with a note of any changes or modifications. The water system should be operated in accordance with the manufacturer’s specifications. Standard procedures for use including: - startup - shutdown - back-washing - regeneration - sanitizing - maintenance and testing Log of system changes with validation studies, if required. Note: filter replacement (like for like) is not a “change” but is part of maintenance. Substituting a heat exchanger for a UV light is an example of a critical change that must be validated. Routine and non-routine maintenance procedures – records can be maintained separately. Investigations and corrective action procedures. Validation studies – the required nature of these is explained in later slides.

Review water quality manual (4) The manual should contain Chemical and microbiological specifications Sampling instructions Test procedures Responsible persons Training requirements Review water quality manual: (Contd.) The water quality manual should contain: Chemical and microbiological specifications including re-sampling, action and shutdown limits. Sampling instructions and testing procedures. Note that the test procedures must be validated. Test procedures. (Results of tests need not be kept in the Manual but may be stored elsewhere. Test results should ideally include graphical presentations.) Persons responsible for operation/ maintenance and deputies. These are usually the responsible engineer or technician, and the responsible or authorized person, together with the operators who run and maintain the equipment or test the water. Training requirements. Personnel should be trained in all aspects of the theory, care and maintenance of their equipment. The records for personnel training need not be kept in the Manual, but may be stored elsewhere.

Review validation (1) Validation for water systems consists of three phases Phase 1: 2 – 4 weeks Phase 2: 4 weeks Phase 3: 1 year Review validation: There is some good reference material available for water system validation including: The US FDA “Guide to inspections of High Purity Water Systems”, FDA, July 1993. Validating water systems is sometimes difficult because of the time involved. The water is needed for manufacturing so the validation is often concurrent. The schedule given in these slides is recommended for very high purity water systems, such as those producing WFI. A less demanding schedule can be negotiated for water for lower risk products. Validation for water systems consists of three phases. The time lines for the phases are: Phase 1: 2 – 4 weeks Phase 2: 4 weeks Phase 3: 1 year At least a year of running the system under control is needed to be assured that the system is properly validated. This is to ensure that seasonal variations are taken into account.

Review validation (2) Phase 1 – Investigational Phase (2 – 4 weeks) DQ, IQ and OQ Develop operational parameters cleaning and sanitization procedures and frequencies Sample daily at each point of use End of Phase I, develop SOPs for the water system Review validation: (Contd.) Phase 1 Phase 1 of the water system validation is conducted over a period of a few weeks. Design Qualification for the system, and Installation Qualification and Operational Qualification for all elements of the system, should follow normal validation procedures, explained in Module 4 in the WHO series on Basic GMP Training (2001). During OQ, the operational parameters, cleaning and sanitization procedures and frequencies are developed. The system is operated to produce water and it is sampled daily at each point of use. At the end of this time period SOP’s for operation of the water system should be developed.

Review validation (3) Phase 2 – verifying control (4 - 5 weeks) Demonstrate the system is in control Same sampling as in phase 1 Phase 3 – verifying long-term control (1 year) PQ Demonstrate the system in control over a long period of time Weekly sampling Review validation: (Contd.) Phase 2 Phase 2 takes about one month. In this period the manufacturer must demonstrate by providing documented evidence that the system will consistently produce the desired water quality when operated in conformance with the SOP’s. This involves the same sampling as in phase 1. Phase 3 Over a longer period of time - usually one year - the manufacturer must demonstrate that the system is operating in accordance with SOP’s, and consistently producing the desired quality. This is needed to ensure that seasonal variations are picked up. Sampling is conducted weekly.

Conducting the inspection (1) Take the drawing and walk around the entire system Check: dead legs filter pipes and fittings DI storage tanks by-pass lines  pumps  UV lights  sample points  RO  non return valves  heat exchangers The inspection: After the desk top review, it is important to go into the factory and walk around the entire system. Check equipment against the drawings. Equipment such as valves and pumps should be tagged with unique numbers, linking to the numbers on the drawings. Check dead legs, pumps, filter, UV lights, pipes and fittings, sample points, DI & RO units, storage tanks, non-return valves, by-pass lines and heat exchangers. Note that these are examples only; there may also be other points to check, for example, burst discs or rupture discs and venting filters on water storage tanks, which prevent the tank collapsing if a vacuum is formed. Identify equipment numbers and ask to see individual installation and operational qualification, and maintenance records.

Conducting the inspection (2) Check: Stainless steel - PVC and most plastics not recommended Weld quality Hygienic couplings Passivation Air breaks or “Tundish” Inspection: (Contd.) Check the construction. Is the system made of stainless steel? What is the grade of stainless steel? PVC and most plastics are not recommended because bacteria are easily able to colonise. Polypropylene PTFE (eg Teflon®) can also be used for purified water and systems if specifically designed for this use. Check for: Electropolished internal welds. Electropolishing is basically the opposite of electroplating, thereby smoothing the surface. The smooth surfaces help reduce bacterial colonization. Hygienic couplings - no threaded fittings in the water flow which can become contaminated. Example on next slide. "Passivation" records. Whenever equipment in contact with water is repaired or changed, passivation should be considered, especially for systems producing water of very high purity. Passivation is the removal of free iron from the surface of the steel. This is performed by immersing the steel in an oxidant, such as nitric acid or citric acid solution. Since the top layer of iron is removed, passivation diminishes surface discoloration. While passivation does not affect the thickness or effectiveness of the passive layer, it is useful in producing a clean surface for a further treatment. WFI systems may need to be periodically re-passivated. No direct connections to drains or sewers, and that non-return valves and back-flow preventers are working or have been properly checked. Tundish is the engineering term for an air break to a fixed funnel, to prevent bacteria from a drain or sewer growing into the water treatment plant.

Conducting the inspection (3) Check pipes and pumps hygienic couplings welded pipes hygienic pumps hygienic sampling points acceptable floor no leaks Inspection: (Contd.) Check pipes and pumps. The photograph shows a good example of a neatly laid-out water treatment room with good equipment and pipes. There are hygienic couplings (Ladish® or Tri-Clover ® clamps), welded pipes and hygienic pumps. Note also hygienic sampling points.

Conducting the inspection (4) Check condition of equipment Staining on water storage tanks Inspection: (Contd.) Assess physical condition of equipment. Look for stains and leaks that could indicate problems. Check to make sure heat exchangers are double tube or double shell. If not, there should be continuous pressure monitoring to ensure the heating or cooling liquid does not contaminate the pure water through any pinholes. For single plate heat exchangers, the pressure of the heating or cooling liquid must be LOWER than the purified water at all times. An exception may be where the liquid is of a higher purity than the water being produced. Note from the heat exchanger example above that even high grade stainless steel, such as 318SS, can be subject to pit corrosion! Corrosion on plates of heat exchangers indicates possible contamination

Conducting the inspection (5) Check maintenance records Check maintenance of pump seals and O rings Inspection: (Contd.) Check maintenance of the entire system by examining the maintenance procedure and records. For example, check the “O” rings of connections and the maintenance of the pump seals. The pump on the left shows good connections and a good standard of engineering. The one on the right shows a threaded coupling, called a milk coupling or sanitary coupling. Threaded couplings and couplings in general should be avoided whenever possible. Where welding is impossible, hygienic couplings should be used or milk (sanitary) coupling, which are acceptable since the threaded fitting is not part of the fluid pathway, and so should not contaminate the water. The inspector must be satisfied that hidden seals and “O” rings have actually been removed, examined and/or replaced during maintenance.

Conducting the inspection (6) Check air filters Check integrity testing, sterilization and replacement frequency Check burst discs Inspection: (Contd.) Check air filters which should be hydrophobic (otherwise, they can be blocked by a film of water condensate) and should be able to be sanitized. Those on WFI plants should be be able to be sterilized and integrity-tested. Check replacement frequency, which the pharmaceutical manufacturer should determine with assistance from the filter supplier. Check burst discs because if they have ruptured without being noted the storage system can become contaminated.

Zeolite water softener exchanges Ca and Mg for Na Conducting the inspection (7) Zeolite water softener exchanges Ca and Mg for Na Softened water out to deionizer By-pass valve By-pass lines Carefully check by-pass valves and lines These sometimes leak or are inadvertently left open A blanking piece is better during operation phase Inspection: (Contd.) By-pass valves and by-pass lines are often used for maintenance procedures. In critical situations there may be, for example, two pumps in parallel, in case one breaks down. Additionally, engineers like to be able to replace a pump or a filter without dismantling large sections of the system. However, valves in by-pass lines can leak, be left open, or be contaminated, and so they are undesirable. A “blanking” piece is often better during operation of the system, so that there is no physical connection.

Conducting the inspection (8) Further points to check: Activated carbon bed sanitization Temperature-compensated conductivity meters Influence of plastic pipe adhesive on TOC Non-condensable gases in pure steam Inspection: (Contd.) Further points to check: Activated carbon bed sanitization – these can become overgrown with bacteria quite quickly. Check sanitization frequency to ensure the AC remains uncontaminated. Calibration of temperature-compensated conductivity meters is often overlooked or not done properly. Influence of plastic pipe adhesive on Total Organic Carbon (TOC) compliance - some adhesives will leach into the water and these can be volatile. Non-condensable gases in pure steam – for example nitrogen and oxygen. They affect the apparent pressure of sterilization processes, lowering their effectiveness.

Conducting the inspection (9) Further points to check: (Contd.) Polypropylene welding inspection checking pin holes Retrospective validation of WFI system Rouging of WFI storage systems Spray ball efficacy Inspection: (Contd.) Further points to check: Polypropylene welding inspection. If polypropylene pipe is used and welded, has the manufacturer checked for pin holes? Retrospective validation of WFI system. Many water plants are 10 – 20 years old and may not have been properly validated. Can they be properly retrospectively validated? Rouging of WFI Systems. The high temperatures of these storage and distribution systems seem to lead to a build up of a deposit known as rouge. Check to see if the manufacturer carries out a periodic physical check for this effect, and what steps are taken to remove the rouge. Sometimes re-passivation is effective. Spray ball efficacy. This is not easy to determine and must be assessable. If the spray ball is jammed it will not work properly, but because it cannot be seen it is not easy to check. There are non-rotating or fixed spray balls or spray cones which may be better in small systems.

Conducting the inspection (10) Further points to check (Contd.) UV light – monitoring performance and lamp life and intensity Validating ozone dosage Specifications for acids, alkalis for DI and sodium chloride for water softener “Normally open” and “normally closed” valves Inspection: (Contd.) Further points to check: UV light – monitoring performance and lamp life. The lethal radiant energy from UV lights drops off quickly, so many have to be replaced approximately every 6 months. Does the manufacturer have an hour meter and is the lamp replaced according to the supplier’s recommendations? Can the intensity of the light be measured? Validating ozone dosage is difficult. It may be possible for the manufacturer to get the supplier’s validation studies showing worst case lethal effects. Water softener sodium chloride specifications. Like any ancillary material, the salt, acids and alkalis used as consumables in water treatment plant should have purchase specifications. Note: testing is not required unless for trouble shooting purposes. Check the drawings to see if valves are marked as “Normally Open” or “Normally Closed”, then physically check the valve position. It is surprising sometimes that valves are not returned to the correct operating position; for example, after de-ionizer regeneration.

Group Session You are given a schematic drawing of a water system to discuss List any problems and their solutions.  In this group session, you are given a schematic of a water system (See handout 2-3-24). Discuss the drawing and list any problems and their solutions. (Note to trainer: The following handout 2-3-25, giving correct answers, should not be distributed until after discussion.)

Group Session This slide indicates the modified water schematic. (See handout 2-3-25.)