Basic Principles of GMP

Basic Principles of GMP
World Health Organization Basic Principles of GMP 9 June, 2018 Equipment 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: Presentation minutes Group session (2 activities) 60 minutes Plenary session 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). 13

World Health Organization
Equipment World Health Organization 9 June, 2018 Objectives To review the requirements for equipment selection design use maintenance To discuss problems related to issues around selected items 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.

Equipment 9 June, 2018 Principle Equipment must be located designed constructed adapted maintained to suit the operations to be carried out 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. 13.1

World Health Organization 9 June, 2018 What does location design construction adaptation maintenance cleaning calibration … mean in practice? What does it mean in practice? Discuss what to inspect for each of these.

Equipment 9 June, 2018 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 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. 13.1, 13.2

Equipment 9 June, 2018 Pipes Fixed pipework clearly labelled indicate contents and direction of flow Service pipings and devices adequately marked non-interchangeable connections or adaptors for dangerous gases and liquids Another important aspect to inspect is that of transfer of product and materials through pipelines, and services supplied to the factory. It is important that all pipelines are clearly labelled, indicating the contents and the direction of flow. This is important, whether it be pipelines transferring product from storage tanks to the filling line, or whether it be service pipings containing water, compressed air or other materials. Pipe connections should be of the right standard and specification for the material and pipeline to prevent any wrong connections and mix-ups. Some services, particularly compressed gases, have statutory standards of connection. The connectors are thus designed to prevent any connection other than to a pipe containing the same gas. The use of adaptors is not recommended. The quality and quantity of material delivered through pipelines are normally monitored and tested at regular intervals, e.g. the supply of distilled or purified water . Pressure regulators are also often required to meet standards legislated elsewhere. Many processes and items of equipment these days are reliant on the quality of services. If incorrect pressures or incorrect quality standards are available, the factory and equipment may not perform to the validated standard. Product produced in this way could be borderline in quality or, periodically, substandard. The problem is that, in large-volume production, quality control may not identify a problem with parts of the batch because the sample required to be taken is too small. This is particularly true of sterile production. 13.3, 13.4

World Health Organization Basic Principles of GMP 9 June, 2018 Contents and direction of flow indicated e.g. water lines, equipment components, air-handling systems

Equipment 9 June, 2018 Balances and Measuring Equipment Appropriate range and precision available In production and quality control Calibrated scheduled basis checks records maintained 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. 13.5

Equipment 9 June, 2018 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 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. 13.9, 13.10

Equipment 9 June, 2018 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 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. 13.11 – 13.13

World Health Organization 9 June, 2018 Current drawings of critical equipment Verify against qualification protocol and report, as well as supplier's manual Check if in accordance with drawing, or changes (change control) Verify critical components installed, e.g. filters, control and monitoring devices Current drawings of critical equipment Verify against qualification protocol and report, as well as supplier's manual Check if in accordance with drawing, or changes (change control) Verify critical components installed e.g. filters, control and monitoring devices

World Health Organization 9 June, 2018 What are the questions you can ask about this piece of equipment? Discuss points such as qualification, maintenance and cleaning of the high speed mixer/granulator. SOPs and records for operation, preventative maintenance

World Health Organization 9 June, 2018 And for this one? Discuss the aspects of the fluid bed dryer such as: Procedures and records for qualification, Quality of inlet air and air out to the atmosphere, filtration levels, Controllers and recorders e.g. temperature (inlet and outlet), Calibration, PLC, FBD bag (dedicated or not, Cleaning of the FBD and the bag, including drying after cleaning, FBD bowl and integrity checks, Air volume, pressure .

World Health Organization 9 June, 2018 What do these labels indicate for this piece of equipment? Do you notice any GMP non-compliance? Discuss the need for: Calibration of components and control devices such as timers, temperature controllers etc. Traceability to the standards used, Date of calibration and calibration intervals, Verification between calibration intervals, Due date for the next calibration

World Health Organization 9 June, 2018 Components and parts of equipment that are used in the production of different products, should be inspected carefully. Care they in a good condition? How are they cleaned and is the cleaning procedure validated? How does the company prevent cross-contamination between products when the same parts are used in the production of different products? Inspect the integrity and cleanliness of sieves and screens - and look for traces of rust, product residue after cleaning, and intactness or damage.

World Health Organization 9 June, 2018 What are some of the key questions you can ask about the blender? Discuss aspects such as: Cleaning and cleaning validation, sample locations, calibration and verification of time, rpm, Transfer of materials Process validation (capacity of the blender versus batch size, sub lots, times etc)

World Health Organization 9 June, 2018 Transfer of material to the compression machine through a closed system is preferred to prevent possible contamination Discuss the advantages of closed systems to prevent possible contamination of materials and products

World Health Organization Basic Principles of GMP 9 June, 2018 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?

World Health Organization 9 June, 2018 What measures can a company take to ensure that products are not contaminated with metal particles? Is there a need for metal detection? Discuss the value of this. What about the checks for integrity of equipment and equipment parts such as sieves, before and after use?

World Health Organization 9 June, 2018 Coating of tablets Is qualification of a coating machine necessary? If so, what has to be done? What about maintenance? And cleaning validation? Trainer to discuss the points

World Health Organization 9 June, 2018 Don't forget the packaging lines! Trainer to discuss the packaging line equipment such as blister packaging machines, strip packaging machines, bulk packaging. Explain the aspects relating to the equipment to ensure proper operation, consistency, forming and sealing (blister), primary packaging of product and the protection of the product during this process. Maintenance, qualification and cleaning of the machines SOPs and records

Equipment 9 June, 2018 Control laboratory equipment Equipment and instruments suitable for the tests to be performed Defective equipment removed labelled 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. 13.7, 13.10

Equipment 9 June, 2018 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)) 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. 13.6, 13.8

Equipment World Health Organization 9 June, 2018 Group Session For the given type of equipment What would your concerns be in relation to the manufacture of products, when inspecting this particular piece of equipment? What are the signs of poor practice in cleaning, operation and maintenance? For this group session we have given each group a specific piece of equipment to consider. The equipment has been selected from the list you provided earlier. Your first task is to identify the concerns that you might have about this equipment during an inspection. What we are trying to get from you is a list of the critical points that you think must be considered when inspecting this piece of equipment. The second task is to identify (and list) the signs of poor use, cleaning and maintenance of the piece of equipment. You should finish with 2 flip-charts — one, a list of concerns, the other, a list of signs.

World Health Organization 9 June, 2018 This is one example – please select different equipment for the groups

Equipment World Health Organization 9 June, 2018 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 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.

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