Validation Overview Validation Documentation Validation Activities Validation Mistakes Validation Protocols Test Selection Common Verifications When to test Test Layout and Content Validation Protocol Execution Success Maintaining the Validated State 66
Validation The water that will be used in pharmaceutical or biotech manufacturing must be validated to prove that manufacturing is verified and traced back to regulations, standards, and the design it was engineered to. A special issue with water systems is that the incoming water can always be affected by changes such as the water source and additives in the drinking water (for instance chlorine). The water source will likely change with the seasons. In fact, seasonal changes are why one year of PQ is required for water purification treatment systems. Overview Before describing the different tests for a purified water treatment system, let's go through some general points regarding validation to achieve an efficient validation. Validation Documentation Validation by itself does not develop anything and can't test any equipment to be better (or worse). Validation can be quite a cost in the project so the goal is to optimize it. The way to improve validation is to make 67
it as clear and understandable as possible for all users of the validition documentation. The user include: The people reviewing and approving the protocol; The validation executers; The person writing the validation report; Quality Assurance, who may have to show and explain the validation protocol and report during an inspection a few years later. For these groups it is important that the test procedure, acceptance criteria, and the results are clear and that the documentation is assembled in a logical way. Evaluate how the usability of the documentation can be improved and incorporate feedback from others. Validation Activities The validation activities that normally are included for the system are: Design Verification (DV) or Design Review (DR), earlier Design Qualification (DQ); Factory Acceptance Testing (FAT); Site Acceptance Testing (SAT); Installation Qualification (IQ); Operational Qualification (OQ); Performance Qualification (PQ). What's important is having performed a risk assessment so you know 68
the process and the system that you are validating so you are testing the correct parts and process steps for the right acceptance criterias. Validation Mistakes to avoid Here are two examples of what not to do during validation: Example # You don't completely know the process of the system but must issue a validation protocol quickly so you use a protocol from another system as a starting point. What typically happens when this is done is the person executing the protocol becomes confused when realizing that parts of the software are not included, but the protocol requests material certificates for a concentrate (non-product wetted) line. This puts the whole validation in question and most likely demotivates the executer to perform validation. This sounds like an obvious mistake but, unfortunately, it has been done many times costing organizations time and money. You will avoid this by reviewing the drawings, reading the URS and the functional specification, joining the design review meeting if possible, and performing a risk assessment for product quality. Example #2 Without checking where screen prints are really making a point as 69
proof during the software testing, the requirement for including a screen print as confirmation of the test is included in the test procedure everywhere (because it is easy to copy and paste the same type of test procedure). In addition, the tester must write Attachment No, Test Protocol No and Name and amount of pages on each of them. This type of problem typically occurs when the issuer of the protocol is not closely involved in execution. The time saved in not optimizing the test procedure for each test is lost in efficiency during execution. Spend a little extra time when writing the protocol to make sure the colleagues executing the tests use their time efficiently and focus on what they really need to do. When specifying the test procedure the results also get more clear to review later on and the test will make sense. 70
Validation Protocols Test Selection Regardless of which format the URS is in (as described in chapter 3) and the design of the purified water treatment system, generally the same types of tests and verifications are performed. This is because the URS is based on the same standards and regulations as described in chapter 2 in this guide. In addition to tests and inspections performed to comply with standards and regulations, there may be tests and inspections for components, instruments, and valves if recommended in supplier manuals or because of safety functions that need to be checked. These types of tests most often fall under good engineering practice and would be included in FAT or SAT. You include tests for different reasons in your validation protocols such as: To comply with standards and regulations; For engineering reasons to verify process steps and parameters; To verify safety features (for users); To comply with a special user requirement; To verify the ergonomics of the system design (practical handling 7
for the user) regarding service, calibration of instruments, and water sampling; To inspect the actual outer measurements at FAT for shipping and bringing in the system into place on site. The following is a compilation of FDA, Pharmacopeia, and other tests most commonly included for a purified water treatment system. Guide: FDA Guide to inspections of High Purity Water Systems (7/93) The system shall have a complete and verified print. P&ID Verification 2 Equipment and piping shall be verified as installed correctly. Installation verifications of the PW System according to design specifications and manuals form sub-suppliers. 3 Piping, material. Material & Material Certificates verification Material & Material Certificates verification Sanitary fittings verification Piping usually consists of a high polished stainless steel. 4 Piping, dead-legs. Dead-legs defined as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use. The definition is developed for hot circulating systems. For cold systems any drops or unused portion of any length of piping has the potential for the formation of a biofilm and should be eliminated if possible or have special sanitizing procedures. 5 Piping, sanitary fittings. There should be no threaded fittings in a pharmaceutical water system. All pipe joints must utilize sanitary fittings or be butt welded. 72
6 Sanitary components, such as drainable pumps and shell and tube heat exchangers. Sanitary components verification 7 Equipment shall be verified to work as specified. Operational testing of components and process steps according to design specifications and operation manuals from the subsuppliers. FAT* if the PW System can be run with water at the supplier. OQ 8 Sampling daily after each step in the purification process and at each POU for two to four weeks. Operational parameters & sanitization procedures and frequencies will be developed. Water sampling, PQ Phase PQ, Phase 9 Demonstrate that the system will consistently produce the desired water quality when operated in conformance with the SOPs. Sampling as per. Water sampling, PQ Phase 2 PQ, Phase 2 0 Demonstrate that when the water is operated in accordance with the SOPs over a long period of time it will consistently produce water of the desired quality. Sampling is performed according to routine procedures and frequencies. The validation of the system is completed when the firm has a full year of data. Water sampling, PQ Phase 3 PQ, Phase 3 Material of Diaphragms for Pharma, Food & Biotech. Material & Material FDA CFR 2 Part 77 Certificates Verification FDA 2 CFR Part 77 Indirect Food Additives: Polymers. 77.2600 Rubber articles intended for repeated use. 77.550 Per fluorocarbon resins. 73
FDA CFR 2 Part Automation Validation See Software verification 2 Audit Trail Audit Trail 3 Record Retention, Reproducibility & Retrievability Record verification 4 Access Security Access levels Monograph, Water Purified Water Quality verification for Purified Water OQ and PQ Material of Gaskets Material & Material Certificates Verification Pharmacopeia: USP Pharmacopeia: USP USP Class VI, Section <88> Biological reactivity test, in vivo. FAT* = For commercial reasons, which means that it's a good idea for the buyer to verify that the system fulfils requirements before it leaves the supplier to avoid extra costs or schedule problems on site. Finally, quality critical tests and verifications must be done after installation and start-up on site with the potable water and environment it will continuously operate with. 74