1 5 equipment-qualification
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This document discusses the qualification of equipment used in the production of artemisinin-based combined medicines. It covers the objectives, principles, and stages of equipment qualification, including design qualification, installation qualification, operational qualification, and performance qualification. The stages of qualification ensure that equipment is suitable for its intended uses and capable of consistently meeting specifications. Qualification applies to all production and quality control equipment and must demonstrate acceptable performance under worst-case conditions. Periodic requalification is necessary to confirm continued suitability of equipment for its uses.
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1 5 equipment-qualification
- 1. EQUIPMENT AND ITS QUALIFICATION Rutendo Kuwana Technical Officer, WHO, Geneva Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-. 27, 2009, Kampala, Uganda
- 2. Basic Principles of GMP Artemisinin based combined medicines February 2 | 23-27, 2009, Kampala, Uganda Equipment 13
- 3. Artemisinin based combined medicines February 3 | 23-27, 2009, Kampala, Uganda Equipment Objectives To review the requirements for equipment – selection – design – use – Maintenance
- 4. Artemisinin based combined medicines February 4 | 23-27, 2009, Kampala, Uganda Validation Objectives (2) To discuss the principles of qualification of equipment, with specific focus on: The different stages of qualification Requalification and Qualification of “in use” equipment
- 5. Artemisinin based combined medicines February 5 | 23-27, 2009, Kampala, Uganda Equipment Principle Equipment must be – located – designed – constructed – adapted – maintained to suit the operations to be carried out 13.1
- 6. Artemisinin based combined medicines February 6 | 23-27, 2009, Kampala, Uganda Equipment Principles Equipment layout and design must aim: – to minimize risks of error – to permit effective cleaning and maintenance To avoid: – cross-contamination, dust and dirt build-up – any adverse effect on the quality of products Equipment must be installed to: – minimize risks of error – minimize risks of contamination 13.1, 13.2
- 7. Artemisinin based combined medicines February 7 | 23-27, 2009, Kampala, Uganda 13.5 Equipment Balances and Measuring Equipment Appropriate range and precision available In production and quality control Calibrated – scheduled basis – checks – records maintained
- 8. Equipment Production equipment Appropriate design – easily and thoroughly cleaned on a scheduled basis – procedures and records No hazard to the products – contact parts of suitable non-reactive materials – non additive and – not absorptive Defective equipment – removed, or – labelled to prevent use 13.9, 13.10 Artemisinin based combined medicines February 8 | 23-27, 2009, Kampala, Uganda
- 9. Artemisinin based combined medicines February 9 | 23-27, 2009, Kampala, Uganda 13.11 – 13.13 Equipment Production equipment Closed equipment used when possible Open equipment, or when equipment opened, precautions taken to prevent contamination Non-dedicated equipment cleaned according to validated cleaning procedures between different products Current drawings of critical equipment and support systems maintained
- 10. Equipment Control laboratory equipment Equipment and instruments – suitable for the tests to be performed Defective equipment – removed – labelled Artemisinin based combined medicines February 10 | 23-27, 2009, Kampala, Uganda 13.7, 13.10
- 11. Artemisinin based combined medicines February 11 | 23-27, 2009, Kampala, Uganda 13.6, 13.8 Equipment Washing, cleaning and drying Equipment used for washing and drying – not the source of contamination Equipment design should promote easy cleaning Cleaning on scheduled basis, procedures and records Washing and cleaning – manual – automated (Clean in place (CIP), Steam in place (SIP))
- 12. Basic Principles of GMP Artemisinin based combined medicines February 12 | 23-27, 2009, Kampala, Uganda
- 13. Artemisinin based combined medicines February 13 | 23-27, 2009, Kampala, Uganda Equipment Possible Issues Poor design Lack of safety Poor quality finishes Lack of cleaning Lack of maintenance No usage log or record Use of inappropriate weighing equipment Open-plan location of compressing machines
- 14. Basic Principles of GMP Remember to look at punches and dies Are there specifications for these? How are they cleaned, stored, issued for use and returned to storage? Are they in a good condition and checked at regular intervals? Artemisinin based combined medicines February 14 | 23-27, 2009, Kampala, Uganda
- 15. Artemisinin based combined medicines February 15 | 23-27, 2009, Kampala, Uganda Validation General Qualification policy for systems and equipment To include instruments used in production and quality control New systems and equipment: All stages of qualification applicable (DQ, IQ, OQ and PQ) In some cases: Not all stages of qualification may be required – e.g. electrical supply systems 3.1 – 3.4
- 16. Artemisinin based combined medicines February 16 | 23-27, 2009, Kampala, Uganda Validation General Qualification policy for systems and equipment To include instruments used in production and quality control New systems and equipment: All stages of qualification applicable (DQ, IQ, OQ and PQ) In some cases: Not all stages of qualification may be required – e.g. electrical supply systems 3.1 – 3.4
- 17. Artemisinin based combined medicines February 17 | 23-27, 2009, Kampala, Uganda Validation General (continued) Qualification should be done in accordance with predetermined and approved qualification protocols The results of the qualification should be recorded and reflected in qualification reports The extent of the qualification should be based on the criticality of a system or equipment, e.g. – Blenders, autoclaves or computerized systems 3.10 – 3.11
- 18. Artemisinin based combined medicines February 18 | 23-27, 2009, Kampala, Uganda Validation General (continued) Qualification should be done in accordance with predetermined and approved qualification protocols The results of the qualification should be recorded and reflected in qualification reports The extent of the qualification should be based on the criticality of a system or equipment, e.g. – Blenders, autoclaves or computerized systems 3.10 – 3.11
- 19. Qualification and Validation Artemisinin based combined medicines February 19 | 23-27, 2009, Kampala, Uganda Definitions Validation Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results It is a process using documented evidence that provides a high degree of assurance that a specific process will consistently produce the predetermined outcome. Glossary
- 20. Qualification and Validation Artemisinin based combined medicines February 20 | 23-27, 2009, Kampala, Uganda Definition Qualification Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results (Validation usually incorporates the concept of qualification) A process of establishing confidence that the equipment is capable of consistently operating within established limits and tolerances. Studies therefore done prior to use
- 21. Qualification Vs. Validation Qualification - confirm compliance with specified requirements or criteria (Do you have the right tool for the job?) - Performed on one element or component of the process to be validated - Conduct tests to establish if the component of a process has the attributes to produce a specified outcome. Validation - Proof. Document that the process will consistently produce a predetermined outcome. Artemisinin based combined medicines February 21 | 23-27, 2009, Kampala, Uganda
- 22. Artemisinin based combined medicines February 22 | 23-27, 2009, Kampala, Uganda Validation Stages of qualification 3.11 Design qualification Installation qualification Operational qualification Performance qualification
- 23. Artemisinin based combined medicines February 23 | 23-27, 2009, Kampala, Uganda Validation Stages of qualification 3.11. Design qualification Installation qualification Operational qualification Performance qualification Change control
- 24. Artemisinin based combined medicines February 24 | 23-27, 2009, Kampala, Uganda Validation General Systems: Qualified before equipment Equipment: Qualified before routine use Systems and equipment: Periodic requalification, as well as requalification after change Certain stages done by the supplier or a third party Maintain the relevant documentation, e.g. – standard operating procedures (SOPs), specifications and acceptance criteria, certificates and manuals 3.5 – 3.9
- 25. Validation Design qualification User requirements should be considered when deciding on the specific design of a system or equipment A suitable supplier should be selected for the appropriate system or equipment (approved vendor) Artemisinin based combined medicines February 25 | 23-27, 2009, Kampala, Uganda 4.1 – 4.2
- 26. Artemisinin based combined medicines February 26 | 23-27, 2009, Kampala, Uganda Validation Installation qualification Verifies that the correct equipment has been received and installed as per plan and protocol. Also that it is complete and undamaged (parts, services, controls, gauges and other components) - Normally advised to prepare requirements for calibration, maintenance and cleaning at this stage Verifies that equipment has been properly installed and calibrated including connections to utilities. Calibrate the measuring, control and indicating devices – against appropriate, traceable national or international standards 5.1 – 5.4
- 27. Artemisinin based combined medicines February 27 | 23-27, 2009, Kampala, Uganda Validation Installation qualification (2) Documented records for the installation – installation qualification report Indicate satisfactory installation Include details, e.g. – The supplier and manufacturer – System or equipment name, model and serial number – Date of installation – Spare parts, relevant procedures and certificates 5.5
- 28. Artemisinin based combined medicines February 28 | 23-27, 2009, Kampala, Uganda Validation Operational qualification Systems and equipment should operate correctly – operation verified as in the qualification protocol Verifies that the equipment operates consistently within established limits and tolerances over the defined operating ranges. Studies on critical variable to include conditions encompassing upper and lower operating limits and circumstances (i.e. “worst case conditions”) Challenges equipment functionally to verify compliance with manufacturer’s specifications and end – user defined requirements. To include verification of operation of all system elements, parts, services, controls, gauges and other components 6.1 – 6.3
- 29. Artemisinin based combined medicines February 29 | 23-27, 2009, Kampala, Uganda Validation Operational qualification (2) Documented records (Operational qualification report) Finalize and approve SOP (operation) Training of operators provided – training records Systems and equipment released for routine use after completion of operational qualification, provided that: – All calibration, cleaning, maintenance, training and related tests and results were found to be acceptable 6.4 – 6.7
- 30. How may runs are to be performed during Operational Qualification (OQ) testing? Guidelines stress the importance of equipment qualification simulating actual production conditions, including 'worst case' situations and that "tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results." "three consecutive batches" is recommended for process validation rather than for equipment qualification. No specific number of "runs" for equipment qualification, but multiple tests to simulate actual operating ranges and to establish consistency are expected Artemisinin based combined medicines February 30 | 23-27, 2009, Kampala, Uganda
- 31. Qualification of Equipment IF ONE TYPE AND MODEL OF EQUIPMENT IS QUALIFIED, CAN IT BE USED IN A DIFFERENT PROCESS WITHOUT ADDITIONAL Artemisinin based combined medicines February 31 | 23-27, 2009, Kampala, Uganda QUALIFICATION? For IQ document whether each equipment is installed correctly and operates consistently according to established limits and tolerances. OQ should also be performed for each different use of the equipment or system to document the suitability for that use Not be required for additional pieces of the same type/model of equipment when used in the same process or for each piece of the same type/model of equipment used in the same process, provided installation qualification has been performed
- 32. Artemisinin based combined medicines February 32 | 23-27, 2009, Kampala, Uganda Validation Performance qualification Verifies that the equipment performs according to design specifications and user defined requirements in a reliable and reproducible manner under normal production conditions. Verified in accordance with a performance qualification protocol Documented records – performance qualification report Show satisfactory performance over a period of time i,e. carried out long enough to prove that the equipment is under control and turns out product of specified quality consistently. Manufacturers to justify the selected period 7.1 – 7.2
- 33. Qualification Plan To ensure that requirements are met and confirm by examination and collection of objective evidence - Challenges to equipment to be designed - Re-create intended use - Test, Test, Test Artemisinin based combined medicines February 33 | 23-27, 2009, Kampala, Uganda
- 34. Qualification Plan 1. Purpose 2. Scope 3. Equipment Description 4. Operational Specifications 5. Acceptance Criteria 6. Testing Results 7. Discrepancies/Corrective Actions 8. Conclusions/Final Report Artemisinin based combined medicines February 34 | 23-27, 2009, Kampala, Uganda
- 35. Artemisinin based combined medicines February 35 | 23-27, 2009, Kampala, Uganda Validation The next slide shows a typical format for: "A qualification protocol / report" It reflects the minimum information that should be included This is an example – and should be used as such Specific formats need to be designed for a specific system or piece of equipment 7.2
- 36. Qualification Plan Artemisinin based combined medicines February 36 | 23-27, 2009, Kampala, Uganda
- 37. Worst Case Scenarios Conditions that include upper and lower processing limits Circumstances that present the highest chance of process or product failure relative to ideal situations Identify those conditions that are likely to be experienced during routine manufacture/process Artemisinin based combined medicines February 37 | 23-27, 2009, Kampala, Uganda
- 38. More Examples The following case illustrates the importance of performing adequate equipment qualification on each piece of processing equipment A pharmaceutical firm used two blenders to produce a tablet. Both blenders from same equipment manufacturer, same model number and same design. Supplier told the drug manufacturer that the units were "identical." though one was older. Manufacturer did not include the older blender as part of its process validation. Company marketed about 100 batches of tablets using the old blender. Retention samples showed some batches failed content uniformity investigation showed out of specification batches were from one of the two "identical" blenders – the old one. The older blender had a slightly smaller capacity and different operational characteristics (RPMs) when run at the same settings as the newer blender. Subsequently, the firm recalled its total production of the product it made using the older blender. The firm decided to qualify the old blender using production size lots. Artemisinin based combined medicines February 38 | 23-27, 2009, Kampala, Uganda
- 39. Qualification of “Old” Equipment What about "old manufacturers" who have not performed DQ, or IQ for existing, in-use systems and/or equipment? It is not always possible to have all details for IQ or OQ for established equipment. The manufacturer should however have data that verifies the operating parameters and limits for the critical variables of the equipment. In addition, calibration, cleaning, preventative maintenance, operating procedures and operator training procedures for the use of the equipment should be documented and used as SOPs ……. PIC/S Artemisinin based combined medicines February 39 | 23-27, 2009, Kampala, Uganda
- 40. Artemisinin based combined medicines February 40 | 23-27, 2009, Kampala, Uganda Validation Qualification of “in-use” systems and equipment Data to support and verify the suitable operation and performance of systems and equipment Should include operating parameters and limits for critical variables, calibration, maintenance and preventive maintenance, standard operating procedures (SOPs) and records 9.1 – 9.2
- 41. Risk assessment of operations or Artemisinin based combined medicines February 41 | 23-27, 2009, Kampala, Uganda functions If any question is answered “Yes”, the operation/function should be considered as GMP relevant. During risk assessment, the probability of occurrence and detectability should be considered and measures to reduce the risk identified.
- 42. Qualification flow Scheme (extracted from CEFIC Guidance) Artemisinin based combined medicines February 42 | 23-27, 2009, Kampala, Uganda
- 43. Example of Document Matrix Artemisinin based combined medicines February 43 | 23-27, 2009, Kampala, Uganda
- 44. Requalification Required for: - significant change in batch size - change in operating parameters - component specifications have changed - new accessories or components are added to previously qualified equipment - process changes that potentially impact product effectiveness or quality Artemisinin based combined medicines February 44 | 23-27, 2009, Kampala, Uganda
- 45. Some Experiences What if the results are not good? Study report destroyed and manufacturer pretends it never happened So what should be done? Document the study, but don’t approve it Identify and describe any corrective actions needed or any noteworthy observations or deviations Start another study using the findings and conclusions from the failed study Artemisinin based combined medicines February 45 | 23-27, 2009, Kampala, Uganda
- 46. More experiences – poor qualification Artemisinin based combined medicines February 46 | 23-27, 2009, Kampala, Uganda reports Specifications not approved Failure to provide clear, complete instructions in the protocol Instrument calibration records or status not included Full range of intended operating parameters not challenged Inadequate sample sizes Atypical data points Unexplained deviations from protocol Inconsistencies between final report and data collection/recording forms
- 47. Qualification and Validation Artemisinin based combined medicines February 47 | 23-27, 2009, Kampala, Uganda Annex 6 WHO References Good manufacturing practices (GMP): guidelines on the validation of manufacturing processes Validation of analytical procedures used in the examination of pharmaceutical materials
Editor's Notes
- During this session we shall be examining the issues around equipment selection, design, installation, use and maintenance. The session is divided up roughly as follows: Presentation30 minutes Group session (2 activities)60 minutes Plenary session30 minutes Test and discussion:20 – 30 minutes The session will last one half-day. (Preparation for the group session for this module is important. During the introduction module, you will have asked the trainees to indicate the equipment that causes them concern during an inspection. During the lead up to this session, your team should have reviewed the resulting lists and selected the most common causes for concern. You should have prepared a list indicating which group is going to deal with which piece of equipment).
- Our objectives for the session are: Firstly to look at the general requirements concerning equipment. What is important in a general sense? What are the reasons for selecting a certain type of equipment? Are there any important problems relating to certain types of equipment? The second objective is to prepare in group session a list of the concerns that you have when inspecting factories. For example, you might include your own lack of knowledge of the operations of a particular type of machine or process. After that you will finalize your presentation by looking at specific problems relating to some of the items of equipment you selected before starting our programme. The purpose of this is to provide you with examples of the sort of questions that you may wish to ask during an inspection.
- Qualification of systems and equipment 1. Principle 2. Scope 3. General 4. Design qualification 5. Installation qualification 6. Operational qualification 7. Performance qualification 8. Requalification 9. Qualification of “in use” systems and equipment
- In this section we will deal with equipment used in the manufacture and testing of pharmaceutical products. Because of the wide range of processes and equipment used, we shall only deal with GMP requirements in general terms during this session. All the requirements mentioned in this presentation are relevant to both production and quality control equipment. These apply to the design of the equipment, its use and its maintenance. The equipment used should be located in areas of production or testing in such a way as to support the operators in ensuring that the manufacturing process or testing procedure is followed correctly. The location can prevent omission of steps in the process and avoid possible cross-contamination and mix-ups of products and materials. The design can also assist in easy cleaning and maintenance of equipment. Proper design can prevent operation errors. An example of this is the way in which batch numbers can be changed in the machine. If the labelling machine has a solid block which has to be removed to enable a new batch number to be set up - then physical checks can be done. However, new devices are available that permit changes of batch numbers using a keyboard. In this case there needs to be some form of safeguard to prevent inadvertent batch number changes. Equipment should be constructed of materials that suit the operation and use of the equipment for the range of products manufactured and tested on site. The construction materials should not corrode or deteriorate and thus influence the manufacturing or testing procedure. In cases where manufacturers adapt existing equipment to serve intended needs, inspectors should evaluate that the adaptation will not result in a negative or adverse effect in respect of the quality of the product. Suitable materials should be used when equipment is adapted.
- Prevention of cross-contamination and error is of great importance to the factory's operations. There must be no possibility of cross-contamination. The layout, design and location of equipment can result in possible cross-contamination of products. Cross-contamination in tablet compression and packaging machines is a common problem area. Most inspectors can give examples of tablets being found in a packaging machine after cleaning. If the design of a tablet inspection belt is such that it is difficult to clean the belt,the risk of tablets remaining in the equipment becomes greater. Inspectors should ask the company questions about the way in which equipment is cleaned to remove all of the materials from the previous batch. Another problem for cross-contamination is a tablet that rolls freely along the floor. Another source of cross-contamination is dust. What happens to the dust created at critical points, such as hopper loading for compressing machines or tablet-counting machines? Are there signs of dust on top of cupboards in the area? Complex-designed equipment could also result in maintenance not being performed as recommended by the supplier of the equipment. Equipment must be maintained to ensure that it performs in the way that it is supposed to. The company should be able to show to you that it has maintenance schedules for major pieces of equipment and that it has people who are capable of maintaining the equipment. Alternatively, it should be able to show that it uses contract maintenance people who understand the equipment, and the use to which it is to be put. You should thus verify whether the company has logbooks in which it records the use of the equipment and when planned preventative maintenance and regular maintenance had been performed. Assess whether there is a programme for maintenance, and whether this programme is followed. The operation of the equipment must not lead to adverse quality problems developing unnoticed. Again, old tablet presses are a common source of problems particularly at start up and shut down. The problem is that as the tablet machine starts to speed up or slow down - the tablet weight changes. It can easily produce out-of-specification tablets during start-up or shut-down. Inspectors can evaluate the company’s action in relation to this problem. Does the company reject first and last tablets from a machine session? What does the company do if tablets are found to be out-of-specification during a periodic check? Does it reject all the tablets made since the last good check? What does the company do if the compressing machine hopper gets low on granules.
- Often balances and other measuring equipment are the simplest and also sadly the most neglected of equipment. If the appropriate balance or measuring equipment is not used then a good quality product will not be produced. This is so fundamental to a successful operation, but how many times have we seen operators struggling with inappropriate or non-functioning measuring equipment? All balances and measuring equipment must be capable of weighing or measuring the materials over the desired range required for production and testing. You should verify what the range of weights are to be weighed in production, and assess whether the balance can in fact weigh the required range of weights. The balances and measuring equipment must further be precise. Proof of the range and accuracy of balances can be evaluated by the inspector as part of the validation report results for balances, which should indicate the results for accuracy, precision, range and linearity. It is important that the appropriate weighing and measuring equipment is available in the relevant areas, including production and quality control laboratories. If equipment is not readily available, the temptation will be for operators to use something that is not suitable - but more convenient. Balances and measuring equipment must be calibrated regularly for its ability to work within the specification. Proper records of calibration, check weighing and use must be maintained. Although calibration is done at regular intervals, check weighing has to be done on a daily basis. The inspector has to check the SOPs and records showing compliance with the procedure. The records should show that the check was done, by whom, and the actual results obtained. Such checks are of crucial importance in the laboratory, in tablet check weighing, and dispensing. They are also critical in any area where materials are weighed. Weighing and measuring equipment must only be used within the limits set for it. These limits may be set within the pharmacopoeia or by the supplier. The company should have SOPs to describe the ranges of acceptability of different weigh scales.
- Production equipment must be suitably designed for the intended use of the equipment. Manufacturers will experience difficulty in obtaining the consistent results required, when they use equipment for purposes it had not been designed for. An example of this is where manufacturers use a small compressing machine to make tablets larger than the design specification. The machine will perhaps be unable to compress the tablets correctly or it will be unable to supply sufficient granules to each die. Using liquid-filling equipment to fill larger or smaller volumes than specified will lead to inaccurate volumes being dispensed. This applies to quality control equipment as much as it does to production equipment. Quality control equipment must be suitable for the tests to be carried out on it. The equipment must be designed to be cleaned easily even if it is dedicated to one product. This is even more important if the equipment is to be used on a number of different products. This means that the equipment should be easy to take apart. It should have all crevices designed out to enable easy cleaning and make visual inspection simple. If the equipment is used to produce a variety of products, a specific written cleaning procedure will be needed. Separate cleaning procedures may be needed for products requiring different cleaning processes. Inspectors should ensure that the manufacturer has an SOP for cleaning of each major piece of equipment. Verification of compliance with the SOP by reviewing the schedule for cleaning and records of cleaning is very important during the inspection. The manufacturer should have taken the design of the piece of equipment in consideration when the cleaning procedure was designed and validated. Production equipment should be placed or located in such a way that it can be used for the intended purpose. Think of the placement of granulators, ossilators and fluidized bed driers in the manufacture of orals solid dosage forms. Proper maintenance of equipment is important to ensure that the equipment will operate or perform in accordance with its specifications. Equipment must be made of materials that will not react with the product to be made. That often means very high quality stainless steel or other suitable material. The construction materials should not present any hazard to the product being manufactured, it should not react with the materials or product and should not absorb any substance in the product of material being processed. Some materials and products react or are absorbed by plastic, and some plastic contains plastisizers that may leach into products. Therefor, it also means that the product should not absorb anything from the equipment nor reacts with it. A frequent source of black spots in and on tablets is excessive lubrication of punches and dies on tablet compressing machines or insufficient lubrication. Grey contamination of creams or ointments can come from bearings or plastic scraper blades incorrectly adjusted. The equipment must be correctly labelled at all times. This is to show whether it is clean or dirty, and ready for use with the next batch or a new product. When a piece of equipment becomes defective for any reason, then it must be removed from the area or clearly labelled (status label). This is to prevent it from being used when it is no longer capable of producing a good quality product. Where a piece of equipment is installed in a line of equipment and it is defective, then its connection with other machines in the line should be interrupted. If this is not done, it may be possible that it could be operated inadvertently.
- Often balances and other measuring equipment are the simplest and also sadly the most neglected of equipment. If the appropriate balance or measuring equipment is not used then a good quality product will not be produced. This is so fundamental to a successful operation, but how many times have we seen operators struggling with inappropriate or non-functioning measuring equipment? All balances and measuring equipment must be capable of weighing or measuring the materials over the desired range required for production and testing. You should verify what the range of weights are to be weighed in production, and assess whether the balance can in fact weigh the required range of weights. The balances and measuring equipment must further be precise. Proof of the range and accuracy of balances can be evaluated by the inspector as part of the validation report results for balances, which should indicate the results for accuracy, precision, range and linearity. It is important that the appropriate weighing and measuring equipment is available in the relevant areas, including production and quality control laboratories. If equipment is not readily available, the temptation will be for operators to use something that is not suitable - but more convenient. Balances and measuring equipment must be calibrated regularly for its ability to work within the specification. Proper records of calibration, check weighing and use must be maintained. Although calibration is done at regular intervals, check weighing has to be done on a daily basis. The inspector has to check the SOPs and records showing compliance with the procedure. The records should show that the check was done, by whom, and the actual results obtained. Such checks are of crucial importance in the laboratory, in tablet check weighing, and dispensing. They are also critical in any area where materials are weighed. Weighing and measuring equipment must only be used within the limits set for it. These limits may be set within the pharmacopoeia or by the supplier. The company should have SOPs to describe the ranges of acceptability of different weigh scales.
- The general principles of GMP are applicable to production and QC equipment/apparatus. (For more details on QC, see the supplementary training material module on QC laboratories). Accurate results for materials and products tested are of vital importance in a quality control environment. To ensure this, all equipment and instruments used for quality control testing must be suitable for the tests to be performed. When a testing instrument or piece of equipment becomes defective in the laboratory, then the accuracy of results can not be guaranteed. Defective instruments and equipment should be removed from the area or clearly labelled (status label). This is to prevent analysts from using equipment for testing when the equipment should no longer be used.
- All equipment should be cleaned from time to time, even if it is dedicated to one product. The cleaning method should be validated so that it will routinely achieve the desired result. As discussed earlier, it should be designed to permit effective cleaning. During inspections, you should verify that cleaning is done as required in terms of the SOP for cleaning (especially the frequency of cleaning, between batches of the same product, between different products being manufactured on the same piece of equipment, as well as the records or logs maintained for the cleaning). The method chosen for cleaning must not be the source or cause of contamination. The location, layout and design of the wash area for equipment must be evaluated. In some companies, equipment is transported to a cleaning area equipped with all the services required for effective cleaning. In this case, inspectors should check the route that the equipment follows to get to the cleaning area. Assess what precautions are taken by the manufacturer to prevent cross-contamination on the way. In others, the equipment is cleaned where it is located. In this case, what precautions are taken to prevent cross-contamination during cleaning? Inspectors should also investigate where and how equipment is stored after cleaning to prevent contamination of clean equipment while other pieces are being cleaned. The manner of drying of equipment after cleaning, can also be a source of contamination. Another problem associated with cleaning, could be the use of compressed air and the use of brushes and brooms. The company’s attitude towards the use of compressed air and brushes for cleaning is a useful pointer. The use of compressed air is common for moving dust and dirt from inaccessible places on machines. Unfortunately it can then settle in an uncontrolled way on all the equipment and processes in the vicinity. The same is true of the use of brushes and brooms for cleaning. The methods chosen should be easy for all operators to use and should be designed for use with the particular piece of equipment concerned. They should be validated for effectiveness and described in written procedures. Validated and checked written cleaning procedures are essential. There may be considerable advantages in involving the operators in the preparations of these procedures. This is to ensure that, at all stages, they are practical and include all the steps required for ensuring that cleaning has been correctly completed. The procedures should be readily available, and the cleaning materials used must not damage the equipment. When vacuum cleaners are used, inspectors should check to ensure that they are working properly, and that the dust collection device is working effectively. Vacuum cleaners should not be the cause of cross-contamination.
- This is one example – please select different equipment for the groups
- Some of the problems that may be seen during inspection are: Equipment is of poor design and operated without appropriate safety guarding. While this is not a GMP issue the inspector should be very careful in the vicinity of such equipment for personal safety. Old equipment is operating with very poor quality paint finishes. The paint may be badly chipped or worn, or there may be evidence of rust. An assessment will have to be made as to whether this represents a hazard to the product. There are no written cleaning procedures available for the equipment. This must raise the question as to how the company knows that the cleaning procedure is effective. How does it ensure that the same cleaning procedure is used each time? It may be useful to ask each operator of the equipment to describe the cleaning procedure that he/she uses. There may be evidence of dust, residue or dirt on equipment. The company is unable to provide any maintenance procedures or records for the equipment. It may state that this is because a contractor maintains the equipment. In this case, they should be able to produce evidence of the maintenance done, including the checks for conformance to specification or calibration on completion of the maintenance. Unofficial maintenance is done by operators using inappropriate material such as sticky tape, elastic bands, cartons etc. The factory has no logbooks for the use of the equipment. Staff should be able to show some form of records of use and cleaning of the equipment. They may claim that the information is available in batch documentation. They will need to demonstrate that this is kept in a form that permits total use to be easily seen together with the range of batches that have been made on the equipment. A check needs to be made on the availability of appropriate weighing equipment. Is there an SOP describing the limitations of each weigh scale? If not, how does the company manage this? Do they understand the reasons why it is important? Some companies may have several different machines for the same process in one area. Claims may be made that there is no risk of cross-contamination. These will need to be checked carefully. This is not to say that total enclosure of all equipment is the only way to prevent cross-contamination and eliminate errors. However, any alternatives need very careful design, construction and validation to prove that the alternatives work. The company should be able to provide such evidence.
- General Qualification policy for systems and equipment. To include instruments used in production and quality control. New systems and equipment: All stages of qualification applicable (DQ, IQ, OQ and PQ). In some cases: Not all stages of qualification may be required. E.g. electrical supply systems.
- General Qualification policy for systems and equipment. To include instruments used in production and quality control. New systems and equipment: All stages of qualification applicable (DQ, IQ, OQ and PQ). In some cases: Not all stages of qualification may be required. E.g. electrical supply systems.
- 3.10 Qualification should be done in accordance with predetermined and approved qualification protocols. The results of the qualification should be recorded and reflected in qualification reports. 3.11 The extent of the qualification should be based on the criticality of a system or equipment (e.g. blenders, autoclaves or computerized systems).
- 3.10 Qualification should be done in accordance with predetermined and approved qualification protocols. The results of the qualification should be recorded and reflected in qualification reports. 3.11 The extent of the qualification should be based on the criticality of a system or equipment (e.g. blenders, autoclaves or computerized systems).
- There are a number of definitions of validation - all of which say the same thing in different ways. The definition on this slide is the one given in the WHO GMP texts. There is a more expanded version in the WHO text on the validation of manufacturing processes: The collection and evaluation of data, beginning at the process development stage and continuing through the production phase, which ensure that the manufacturing processes – including equipment, buildings, personnel and materials – are capable of achieving the intended results on a consistent and continuous basis. Validation is the establishment of documented evidence that a system does what it is supposed to do. There are three key points to take from these definitions: 1. The evidence must be documented. (The results of the validation must be recorded). 2. Validation applies to several aspects of manufacturing, including e.g. process development, materials, personnel and equipment). 3. It should demonstrate that the system does what is expected of it. Validation is carried out against a set of criteria that are defined in advance. These criteria are detailed in predefined protocol documents.
- Stages of qualification There are generally, four stages in qualification. Can you name them? Design qualification Installation qualification Operational qualification Performance qualification Change control We will look into more detail on these stages in the next slides.
- Stages of qualification There are generally, four stages in qualification. Can you name them? Design qualification Installation qualification Operational qualification Performance qualification Change control We will look into more detail on these stages in the next slides.
- Systems should be qualified before equipment. 3.6 Equipment should be qualified prior to being brought into routineuse to provide documented evidence that the equipment is fi t for its intended purpose. 3.7 Systems and equipment should undergo periodic requalification, as well as requalification after change. 3.8 Certain stages of the equipment qualification may be done by the supplier or a third party. 3.9 The relevant documentation associated with qualification including standard operating procedures (SOPs), specifications and acceptance criteria, certificates and manuals should be maintained. 3.10 Qualification should be done in accordance with predetermined and approved qualification protocols. The results of the qualification should be recorded and reflected in qualification reports. 3.11 The extent of the qualification should be based on the criticality of a system or equipment (e.g. blenders, autoclaves or computerized systems).S
- Design qualification User requirements should be considered when deciding on the specific design of a system or equipment. A suitable supplier should be selected for the appropriate system or equipment (approved vendor).
- Installation qualification 5.1 Systems and equipment should be correctly installed in accordance with an installation plan and installation qualification protocol. 5.2 Requirements for calibration, maintenance and cleaning should be drawn up during installation. 5.3 Installation qualification should include identification and verification of all system elements, parts, services, controls, gauges and other components. 5.4 Measuring, control and indicating devices should be calibrated against appropriate national or international standards, which are traceable.
- 5.5 There should be documented records for the installation (installation qualification report) to indicate the satisfactoriness of the installation, which should include the details of the supplier and manufacturer, system or equipment name, model and serial number, date of installation, spare parts, relevant procedures and certificates.
- Operational qualification Systems and equipment should operate correctly - operation verified as in the qualification protocol. Studies on critical variable to include conditions encompassing upper and lower operating limits and circumstances (that is “worst case conditions”). To include verification of operation of all system elements, parts, services, controls, gauges and other components.
- 6.4 There should be documented records for the verification of operation (operational qualification report) to indicate the satisfactory operation. 6.5 Standard operating procedures for the operation should be finalized and approved. 6.6 Training of operators for the systems and equipment should be provided, and training records maintained. 6.7 Systems and equipment should be released for routine use after completion of operational qualification, provided that all calibration, cleaning, maintenance, training and related tests and results were found to be acceptable.
- Performance qualification Systems and equipment should consistently perform in accordance with design specifications - verified in accordance with a performance qualification protocol. Documented records - performance qualification report. Show satisfactory performance over a period of time. Manufacturers to justify the selected period.
- Qualification of “in-use” systems and equipment The manufacturer should have data to support and verify the suitable operation and performance of systems and equipment. This should include operating parameters and limits for critical variables, calibration, maintenance and preventive maintenance, standard operating procedures (SOPs) and records. On the basis of this, OQ and PQ could be done (protocol and reports prepared). Remember – can still do requalification!
- The main reference text that the WHO has produced relating to validation is published as Annex 6 of the thirty-fourth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations, published in 1996 (WHO Technical Report Series NO. 863). The Annex is titled “Good Manufacturing Practices: Guidelines on the validation of manufacturing processes”. This document covers the subject in some detail. It provides a glossary of terms, discussions of the topic in general, types of validation, the different approaches that can be taken and recommendations on how to organize a validation program. It also presents an outline for a validation protocol and report. The focus is mainly on the validation of manufacturing processes, but many of the points also relate to other operations, such as cleaning. However, for guidance on the validation of analytical techniques, you should refer to Annex 5 of the WHO Expert Committee’s thirty-second report entitled “Validation of analytical procedures used in the examination of pharmaceutical materials” (WHO Technical Report Series No 863 and Quality assurance of pharmaceutical, A compendium of guidelines and related materials, volume I, pp 119-124. WHO, Geneva, 1997).