There are many traditional

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1 How to avoid CIP failures: part 1 In this two-part article Nigel Fletcher, principal consultant at Foster Wheeler Energy's pharmaceutical division, aims to take the pain out of CIP implementation for multi-purpose API plants. Here he considers the cleaning procedure and materials There are many traditional approaches to the protocols for Clean-In-Place (CIP) and, in the main they are very successful at cleaning API units. Failures tend to creep in where sites try to make one CIP fit all, make one 'solvent' the universal cleaning agent or try to take shortcuts for environmental, safety or economic reasons. These issues can be avoided but a systematic approach is needed, along with small changes to cleaning techniques. As many modern API facilities are multi-purpose this can seem a chal- A typical centralised CIP system lenge but the methods outlined here in the Foster Wheeler CIP roadmap, provide a technique that can take much of the pain out of the CIP process. The roadmap (see figure 1) is a plan with various nodes, which the cleaning protocol designer needs to visit and resolve to produce a successful result. In this way, the cleaning process can be built up systematically step by step. Ideally, this is addressed at the plant design stage; if not carried out then, problems are usually seen later on. The basic method of rinse/wash/ rinse/final rinse/(optional) dry is so well proven it is difficult to suggest major improvements to this formula. However, the key is to ensure that each step is carried out correctly and that there is a mechanism to deal with cleaning failures. Typically cleaning failures are blamed on: the operator for not carrying out a step correctly plant construction the process being cleaned just one of those things. While there may be an element of fault in any of the items listed it is rare that anyone asks the basic question: Is the cleaning method right for this process? It is always assumed that whoever wrote the protocol must have got it right. The real life case study described opposite illustrates what can and does happen. Before considering the steps in the roadmap, it must be realised that every material to be removed or cleaned away has to be taken through the roadmap. This may initially seem to be a massive task when handling hundreds of reagents or raw materials, but a few minutes of consideration will that it show it is not quite the insuperable task it seems. Firstly, most substances are soluble in some solvent or water and the few that are not, such as activated charcoal, are well known but can be dealt with in other ways. Secondly, the number of solvents commonly used in the pharmaceutical industry are few, probably fewer than 20, and most sites have 10 to 15 of these available in bulk form. It is more than likely that the material to be dissolved will be soluble in one of these. Thirdly, if conventional dissolution does not work then mechanical cleaning will; this is considered later. CIP roadmap Cleaning is all about three things dissolution, dislodgement and suspension. If you cannot dissolve the material then you must dislodge it or mechanically remove it from the surfaces to be cleaned. It is not always necessary to dissolve every speck of dirt, as simple rinsing can remove a lot of material and this is where suspension comes into play. If the dirt is dislodged or simply rinsed off the surface then it has to be carried out of the equipment and this can happen only if it is suspended in the cleaning fluid. If at least two of these three mechanisms do not occur then the equipment or surfaces will not be cleaned. So the starting point is to look at data about the product to find out: what will dissolve the product; its physical forms during the processing; and the intermediates that are its necessary precursors. The data will also tell you about reagents, their forms and their expected fate. In many reactions, one or more reagents are added in excess to drive the product reaction forward. The data and associated description of the process given by the research chemists will give information useful for cleaning. For example, there may be references to crusting or solids precipitation. This data must be analysed for information on the physical chemistry of the product and intermediates and the chemistry of the reactions. In the case of physical chemistry, 46 manufacturing chemist March 2008

2 START HSE Considerations Gaseous Wastes Liquid Wastes COST CIP Protocol Design Draft CIP Protocol Final Version Physical Chemistry Process Research Data CIP Agent Selection CIP Trials Reaction Data Cleaning Objectives Protocol Template Route selection GMP vs. Non-GMP Pattern Analysis Draining Calculations COP Plant Design Wet Chemistry Dry Processing Wet-IP this data will refer to what the product and intermediates will dissolve in, how fast they will dissolve, what the solubility is in g/litre and solid information on particle size and density. The chemical information gathered can be used to determine if there is a way of decomposing the product/intermediate chemically. For example turning a base into an acid salt by adding a solution of hydrochloric acid, or whether the material will break down if mixed with hypochlorite. This can be very valuable to reduce the toxicity or potency of the material or break it down into chemicals that are soluble in water or the common organic solvents. At this point it is important to define the terminology used in these situations. Cleaning refers to a process of removing all residues or materials from a surface so that the surface is essentially free of all foreign substances. Sometimes the word decontamination is used to mean cleaning. However, decontamination means removal of a contaminant by various techniques. At the end of decontamination, the surface may still have material on it. Arguably, the target should be to get the surface truly clean so there is no risk whatsoever to the next process. This is a choice that has to be made when designing the cleaning protocol. agent selection Armed with this information the selection of the cleaning agent can be undertaken. Remember the solvents used in the process itself have been chosen for one of two reasons; either the product is soluble in it or the product is not soluble in it but side products are, as in solvent exchanges. This means that the Figure 1: Foster Wheeler s CIP roadmap Case study: Selecting the correct cleaning agent The author was invited to review the cleaning process for a wellknown pharmaceutical product that regularly failed to meet the required final rinse analysis. Also, reports were coming from the operators that the equipment did not look clean despite their considerable efforts to improve the 'look' of the plant. The first impression was that the protocol was sound and followed a logical step-by-step approach to cleaning the plant sequentially. However, what was interesting was that the protocol required the plant to be washed with caustic soda solution. Normally this is not a problem and can provide an element of sanitisation for aqueous and/or final step processes. In this case, however, the suspicion was that this was the wrong choice of cleaning agent. The product being cleaned was a hydrochloric acid salt. A review of first review should consider these solvents and tabulate the information in a manner similar to that in table 1 (p48). What does this then tell us about the cleaning process? In the case study, for the final step of the process, any residual intermediate can be removed with water but final product and reagent residues will not be removed and will require an organic solvent. Methanol quite clearly would be the best choice as both reagent and product are soluble in it. It may be necessary to use two cleaning agents, one after the other. In the case study, hot methanol should be used first to remove the final product and the reagent and then, second, water can be used to remove the intermediate and to remove residual methanol. This method then has to be applied to all process steps and a selection of cleaning agents identified. This is not the end of the matter, however. For example, if we had selected dichloromethane for removal of the intermediate we would also know that we might have to use a large volume of it, as the intermediate is only slightly soluble. This would require the protocol writer to estimate the amount of material to be removed, thus ensuring sufficient solvent was charged as part of the cleaning process. This could influence the whole protocol if excessive volumes of waste have to be dealt with. It would also influence how this volume was introduced into the equipment. Continuing with the case study if it were estimated that 1-2kg of intermediate were crusted on the walls of the 3,000-litre equipment then we would have to introduce at least 2,000 litres of solvent to dissolve the residue. In fact, this would produce a saturated solution and is not a workable proposition for a cleaning protocol. Typically, achieving 50% saturation in the solution is more than enough but in our case study this would mean putting 4,000 litres into a 3,000 litre item of equipment. This is clearly difficult and so techniques to address the problem will have to be considered, the research data for the product showed that the base was completely insoluble in water. Thus the caustic soda was converting the salt back into the base, which in turn was not being washed out of the equipment, as it was insoluble. The solution: The author proposed that the caustic soda wash was replaced by a citric acid wash. This instantly improved the situation as the product was being left in a water-soluble state and so could be washed out. After the first test of the new washing solution the operators reported that the equipment actually looked clean. Final rinse checks showed a considerably reduced level of product. Other improvements in cleaning sequences and techniques were then incorporated and the rinse failures fell to zero. March 2008 manufacturing chemist 47

3 Table 1: Cleaning Agents Material/Solvent Methanol Dichloromethane Water Final Product (final step) Yes at 60 C Yes, ambient Not soluble Intermediate (penultimate step) Not soluble Partially, 1-2 g/l at 40 C Very soluble all temps Reagent NaX (penultimate step) Partially, 30 g/l at 50 C Not soluble Not soluble such as two 50% washes (dissolution) or high pressure jetting to achieve mechanical removal. There are many other techniques but each situation should be judged individually, taking into account the availability of the cleaning equipment, access, operator availability etc. In the case study, methanol does not present undue health problems, nor is it particularly dangerous to handle. It would also present only a modest environmental problem for disposal. Conversely, if dichloromethane had been selected, then the HSE considerations would be very different. While this is a simplistic example, this analysis must be carried out for all the cleaning agents selected; it might mean that the best cleaning agent needs to be replaced by a safer or more environmentally acceptable solvent. Also the cost of the (spent) cleaning agent has to be taken into account as well as its final disposal cost. CIP protocol The next step is the design of the protocol. Many manufacturers have templates for protocols for other purposes and it is important that the cleaning protocol follows the style of these so it can be lodged in the site's document system, will be familiar to the operators and can be copied and reused where possible. Next, the cleaning objectives have to be set to identify what is an acceptable level of cleanliness. A lot has been written about acceptable residual levels and whether the dose-based method, contamination level or dilution method in the next batch is used. Selection is entirely dependent on companies preferred QA/QC practices. Whatever method is used, residual levels have to be calculated so that a precise statement can be put in the protocol regarding the permitted level in the final rinse sample or swab test. This number is the final goal of the cleaning operation. Set this value too low and there will be many cleaning failures, or, conversely, too high and there would be an unacceptable risk to the patient a realistic level has to be set. 1,2 The second point to make about the target for the cleaning is that this is the intended end result. That is to say, at the beginning of the cleaning the equipment will contain far more material than is acceptable. Let us say it contains 20 times too much material and the cleaning protocol has to reduce it by at least a factor of 20. This means that during the cleaning it will drop from 20 times too much to, say, 15 times too much and then 8 times and so on until the target is achieved. This also means that the progress of the cleaning can be monitored and the protocol designed to take this into account. For example, if we were to sample the end of the first rinse and analyse it we might find that the residue level was down to 15 times too much. contact Foster Wheeler Energy Ltd Shinfield Park Reading Berkshire RG2 9FW UK T F fw_pharma@fwc.com Suppose we were to do this when carrying out an approved protocol but discovered that the residue level was still 18 times too much, we could simply have a statement in the protocol that said if the residue level was above 15 times too much then repeat the rinse and sample again. A second failure would have to be addressed by a supervisor but if this second rinse achieved the correct level then the protocol could proceed. benchmarks What is being proposed is that a series of test points are placed at suitable points in the protocol to stop it if the test point values for residual levels are not met and allow a choice to be made. If this is not done, the whole cleaning procedure would be carried out before the problem was identified and the cleaning failure would require a complete repeat of the whole procedure extremely wasteful of time and resource. These test points would have to be validated with the protocol but would at least allow the manufacturer to be confident that the cleaning process progressed smoothly along a predictable track to a successful conclusion. We now have two elements of the protocol: the cleaning agents and the cleaning target, together with a set of cleaning test points to be achieved during the procedure. In the next part, we will consider route selection; the order in which the cleaning will be carried out. bibliography 1. J Agalloco, Journal of Parenteral Science and Technology, September-October A G Zeller, Pharmaceutical Technology Europe, November manufacturing chemist March 2008

4 How to avoid CIP failures: part 2 In this second part of his article, Nigel Fletcher, principal consultant at Foster Wheeler Energy s pharmaceutical division, looks at the plant design process when implementing CIP into API plants In the first article (Manufacturing Chemist, March 2008), the two elements of the protocol the cleaning agents and the cleaning target were discussed, together with a set of cleaning test points to be achieved during the procedure. This article will consider route selection: the order in which cleaning will be carried out. Typically, starting cleaning at the top and working downwards is reasonable after all, fluids flow down under the action of gravity. But this is where some care is needed and knowledge of the plant s physical design is required. If we are dealing with a simple train or set of vessels then this may dictate passing the cleaning fluids from one to the next and so on until the last, lowest one is reached. This may work if the cleaning fluid is suitable for all the materials dirtying the plant on the way down. But problems occur when one of the materials is not soluble in the fluid flowing into the START HSE Considerations Gaseous Wastes Liquid Wastes COST CIP Protocol Design Draft CIP Protocol Final Version Physical Chemistry Process Research Data CIP Agent Selection CIP Trials Reaction Data Cleaning Objectives Protocol Template Route selection GMP vs. Non-GMP Pattern Analysis Draining Calculations Figure 1: The Foster Wheeler CIP roadmap COP Plant Design Wet Chemistry Dry Processing Wet-IP equipment. So it is necessary to identify exactly where to stop this flow and divert it out of the process train and introduce a new solvent at this point to clean the equipment downstream. There are a couple of points to make here relating to this route selection. First, the solvent does not have to simply flow once through the equipment. If the cleaning agents table (in part 1) told you that the solubility is low or dissolution is slow, then this indicates that the solvent needs to be recycled or re-contacted with the dirt until the solvent reaches the chosen exhaustion point. The second point is that with slowly dissolving materials, there can be some merit in using a pulsed or burst washing technique. In this technique the solvent is sprayed into the equipment in a burst lasting maybe 15 to 20 seconds and then allowed to drain for a short period, say, 30 seconds, before the burst is repeated. This technique can help reduce the amount of solvent used and can make the washing more effective as saturated solution drains away from the residual dirt, allowing better access to the next fresh burst wash. If possible, the chosen routes should be washed in parallel to save as much time in the overall turnaround time so that while the reactor train is being progressively washed, then the centrifuge or isolation train is also being washed. Part of the route selection is also to choose the correct wash techniques to go with the route. Cascade washing, as described above, is a very simple and effective method but it is not the only technique that must be considered. If we have a vessel with a problem crust or ring of material to be removed, then the main washing cascade or route may have to bypass this vessel. This is because simple flushing may not be appropriate and another technique, such as refluxing or high-pressure washing, may be needed. In fact, flushing may be counter-productive and cause glazing of the crust, which could give rise to a cleaning failure from this vessel. In the case of a crust, there has to be specific information from the research data to warn of this phenomenon. Usually the crust consists of the reaction product and some of the unreacted raw materials but usually in a glazed form. This is more difficult to remove than more common or ordinary deposits and the selection of the correct technique is critical. Typically the main techniques are: Prolonged flushing often not very successful due to glazing; Immersion (filling the equipment with solvent until the crust is covered and then stirring, hot or cold, until the crust is dissolved). This is reasonably successful when the correct solvent is chosen and the crust is a simple ring around the body of the vessel, but often fails due to poor solvent selection; Refluxing (also known as boiling out) gives similar results to immersion, and is more appropriate where the crusting is distributed across the whole of the internal surface of the equipment; High-pressure washing a less common technique as it requires the equipment to be opened for the HP washer to be inserted, but an extremely successful technique; Focused washing rarely used. This technique requires the equipment to be opened and a low pressure spray head is inserted into the equipment which directs jets at the crusted areas. Solvent is recycled. The washing uses both dissolution and dislodgement techniques and can be successful; Manual cleaning is a last resort method nowadays, but requires a special cleaning sequence following the 46 manufacturing chemist April 2008

5 manual intervention to bring the equipment back to a GMP state. In respect of this last point, it is important to know the GMP boundary of the plant where cleaning validation can stop. This is not where cleaning stops but where the validation of the results will stop. It is also useful to know so that equipment outside the boundary can be used to receive spent cleaning solutions. It is important to know this because no samples for analysis should come from this area of the plant as they are not validated. What this tells us is that sample points should be inside the GMP boundary of the plant and that these need cleaning just as much as the main process equipment. In other words, the sample points are part of the route selection and these routes end only in the sample bottle. The case study (see page 48) illustrates what can happen when this point is not understood. spraying and draining Up until this point, only passing reference has been made to methods by which equipment is cleaned. Two techniques can be adopted here: pattern analysis and draining calculations. Pattern analysis uses the spray device or cleaning solvent injection point as a point source. Most sprayball manufacturers make balls that have a defined spray pattern usually described as 360, 180 upwards or downwards, 270 upwards or downwards, conical, elliptical, hollow cone etc. As well as this, the 'throw', or distance the jets travel needs to be known to carry out the pattern analysis. pattern analysis This information is combined and used by the CIP consultant to either diagnose where a problem lies or for the CIP designer to attempt to get the CIP fluid to the right point in the equipment. The methods of pattern analysis are simple and can be used to identify exactly where the jets/sprays will contact the surface, provided the analysis is carried out in plan and elevation. This particular method is often not carried out and the operator is disappointed by the apparent poor performance of the spray device. Figure 2 shows a simple analysis where spray devices with throws between 1.0m and 1.5m will contact the vessel surfaces. The red areas show poor contact, yellow areas may have contact but should be investigated and the white areas are those where spray contact will be satisfactory. The one small area of blue is an area where it is unlikely there will be any satisfactory contact and where uncleaned deposits may be found. Repeating this analysis in elevation will show which nozzles will not be cleaned properly and which inserts, such as dip-pipes, will interfere with the cleaning. This information is critical to determine if any other techniques should be adopted or where to look for 'dirt' so decisions can be made as to whether they need cleaning or can be Figure 2: Spray pattern analysis for spray devices with throws between 1-1.5m. Blue is no contact, red is poor contact, yellow has some contact and white has satisfactory contact accepted. This may be important if the total amount of a product held up in the process train is critical an area that causes many disputes in the pharmaceutical industry. Once the pattern analysis has been carried out, then there has to be a consideration of how the cleaning fluid sprayed into the equipment will drain out. There are two distinct considerations with respect to fluid draining. The first is how it drains out of the vessel, and the second is how the fluid is introduced into the equipment. A common approach to cleaning is to use the spray devices as a means of getting as much cleaning fluid into the equipment as possible. This is wrong. It is vitally important to ensure that the cleaning fluid drains out of the equipment as fast as it is introduced into it. If this does not happen then there will be 'puddling' or the collection of fluid in the bottom of the equipment. This gives rise to two possibilities. First, the possibility of re-deposition of the 'dirt' just removed or the settling out of suspended material in the base; and second, there is a possibility of starving the CIP system if the fluid is in recycle. This is because the fluid is being held up the system. This, in turn, means slowing down the cleaning process, which is clearly not desirable. If the calculations show that the fluid cannot leave fast enough, then adopting the burst spraying technique, described earlier, may be useful to limit or eliminate the hold-up of fluid in the equipment. 1,2 Burst spraying can also be useful where glazing appears to be a problem and here the second aspect of determining draining can become important. There is a calculation that may be undertaken that determines the time taken for the film formed on top of the 'dirt' or any surface to drain away. This can be used to determine the burst wash duration and subsequent draining time prior to the next burst wash. 3 The calculated draining time can also be used to decide when to step forward in the cleaning protocol as once this time has elapsed, then the equipment can be declared fluid free. These calculations are not perfect, but should be considered indicative and a first estimate for commissioning purposes. CIP protocol The information is now available to create the first draft of the CIP protocol. This information will include the best cleaning agent with acceptable cost and environmental properties, GMP considerations, cleaning objectives, route selection and pattern analysis (with drainage calculations if necessary). Once the draft protocol is pre- April 2008 manufacturing chemist 47

6 Case study: The location of sample points One plant visited had a large number of cleaning failures reported. On inspection, the sample points were valves on branches off the main process lines with short small bore tailpipes about mm long, terminating in an extracted box. These boxes were covered in product residues and splashes of unidentifiable materials. The operators had to take samples from these tail-pipes straight into sample bottles for analysis. Several points became clear after seeing samples being taken: 1. The extracted sample boxes were not cleaned producing a risk that when the operator opened them he could contaminate the sample. 2. The sample valve had been mounted with a relatively large dead-leg from the main process pared, it must be tested in a full plant trial using riboflavin on a new plant or, possibly, the real process on an existing plant. The results of the trials then must be fed back into the draft protocol and, if necessary, these results taken through the roadmap process and a second draft and trial undertaken. At the end of this second trial, it should be possible to 'finalise' the protocol and submit it for validation and approval by the QA department. It may be that there are difficulties in one or two areas not anticipated during the design process. These will have to line (more than 6 diameters) so the branch was not being cleaned during the main cleaning sequence. 3. The branch, valve and tail-pipe were not part of the cleaning sequence so there was no obvious way in which the sample point could reach the same level of cleanliness as the main process piping. 4. There was no strict timed period for flushing the sample point when taking a sample. So although the operators did flush the sample point, the flushing time was variable and shorter than required. Once proper cleaning and flushing had been instigated on the sample points the rinse analysis cleaning failures significantly declined. be addressed and specific solutions designed for them. This should not be seen as a failing of the CIP designer, providing the number of the problem areas is small. It is important to analyse these problems scientifically, methodically and then spend adequate time working out solutions. plant design So far, the left hand side of the Foster Wheeler CIP roadmap has been considered but not the physical design of the plant. The design of piping that drains, correct valve selection, equipment contact Foster Wheeler Energy Ltd Shinfield Park Reading Berkshire RG2 9FW UK T F fw_pharma@fwc.com design details, layout considerations and many other aspects of the plant design have to be taken into account when looking at the cleaning protocol. Ideally, plant design and cleaning protocol design happen simultaneously with the designer of the cleaning protocol being directly involved with the design of the plant itself. Sadly, this rarely happens and the cleaning protocol designer or consultant is left to make the best of the situation. Fortunately, more attention is now paid to cleaning and more effort is put into the 'cleanability' of the plant at the design stage. The above techniques can be used to assist either with the analysis of cleaning problems or to design cleaning protocols to avoid CIP failures. Once the problems have been identified and analysed, then the information is available to start the process of identifying a solution. Here the old adage of 'keep it simple' should never be forgotten. bibliography 1. T C Foster, Chemical Engineering, May 4, Nick J Loiacono, Chemical Engineering, May 4, J A Tallmadge and C Gutfinger, Industrial and Engineering Chemistry, Nov manufacturing chemist April 2008