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Single Pot Processing
Cleaning Validation Practices:
using a Single Pot Processor
This paper describes the results obtained on a Single Pot Processor related to cleaning and cleaning validation of two drug compounds: water-soluble theophylline and water-insoluble mebendazole. Both substances were produced using high-shear wet granulation and microwave drying, the Single Pot Processor was then cleaned using its Clean-In-Place system, without operator intervention. Swab samples were taken from areas considered critical during processing and analyzed for remains of the active ingredient. It was concluded from the results that the processor’s CIP system is capable of removing both substances to a level well within generally accepted regulations.
Concern regarding the cleanability of pharmaceutical processing equipment and operator exposure to active pharmaceutical ingredients (API) has been growing steadily recently, driven mainly by the increasingly strict regulations regarding operator safety and the occurrence of more potent active compounds. These concerns have led to most process equipment on the market these days being equipped with integrated Clean-In-Place (CIP) systems. This article examines the effectiveness of the CIP system in a Single Pot Processor and describes its ability to remove two different types of drug compound: water-soluble theophylline and water-insoluble mebendazole.
Figure 1: UltimaPro™ 75 Single Pot Processor
Methods and Materials
Theophylline (water soluble drug) • Materials
The formulation used to produce the theophylline is: - Lactose 200 Mesh - PVP K25 - Theophylline 65% 5% 30% DMV (The Netherlands) BASF (Germany) MEDEVA PHARMA (Belgium)
® The detergent used for the cleaning of the theophylline is P3-Cosa CIP-95 (Ecolab, Belgium) in a concentration of 2% (3,4).
P3-Cosa® CIP-95 is an alkaline detergent based on alkali and complexing agents with a pH between 12,3 and 12,7 of a 1% solution at 20°C in deionized water. It does not contain tensio-active ingredients (4).
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All raw materials were loaded into the bowl of the UltimaPro™ 75 (single pot Processor used during this study) using the Fill-OMatic (vacuum) loading system and dry mixed. Water (1.8 kg) was added using a pressure vessel for granulation of the material. The batches were dried using vacuum and microwaves, and the swinging bowl. The batch was discharged into a drum using a dust-free method. Total production time was 50 minutes. The processor was kept closed throughout to simulate actual production conditions when working with potent compounds. • Cleaning cycle
The cleaning cycle starts with a pre-wash of the product feed tube, the TRANSFLO™ system, the liquid addition system and the bowl with 35-L water of approximately 40°C. After discharging the pre-wash water, the product filter is cleaned using hot water and detergent for a time long enough to fill the bowl with the detergent solution. The bowl and lid are then cleaned by using the mixer and chopper at high speed. The cleaning solution is discharged and the discharge valve is cleaned afterwards with hot water and detergent. Consequently, the different machine parts are rinsed with cold water in the following order: TRANSFLO™ system, product filter, bowl and lid and discharge valve. This rinse with cold water is intended to remove any traces of the detergent. There is a final rinse with demineralized water and the supply lines for the cleaning media are blown dry with purified process air. Finally, the machine is dried using vacuum, TRANSFLO™ and the heated jacket. The total cleaning cycle takes about 90 minutes of which 30 minutes are spent drying and preparing the machine for the next batch (e.g. bringing the temperature of the jacket back down). For executing the cleaning cycle the following amounts of water were used: 80-L hot water (60°C), 60-L cold water (room temperature) and 50-L demineralized water (room temperature). To evaluate the reproducibility of the cleaning cycle four batches were produced, each followed by a cleaning cycle. Cleaning was always performed immediately after a production run, except for one batch that was held for one day between production and cleaning. • Sampling
Six main areas for sampling were chosen that are considered to be critical for cleaning: product filter, impeller, chopper, bowl and lid, TRANSFLO™ system and discharge valve. Both stainless steel surfaces and seals were included (see table). Sampling is done using the swab method by wetting a swab tissue with 2ml of ultra-pure water. The swab surfaces are predetermined and the exact size is known (8). The swab sample for the product filter was taken on a surface of 100 cm² in the lowest part of the filter, which is in closest contact with the product, especially during swinging. Although a rinse sample for a filter would give a better indication of the cleanliness, obstacles (too high rinse volume needed) made the swab sample more practical. The impeller wingnut is the part of the impeller that is located centrally at the bottom of the impeller. Because of its location, it is likely to be harder to clean by the impeller action. It has, therefore, been included in the study as a critical part. The impeller blade is one of the largest parts in direct contact with the product. To know exactly how much product remains on the impeller blades, both front surface and back surface, it was decided to swab the blade completely, although the surface is much larger than 100 cm².
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The lipseal of the impeller shaft was considered to be a critical part in the Single Pot Processor because it is not flush with the lid and no spray balls are available in the lid for this size of machine. The intention of including this part in the cleaning validation study was to see whether the movement of the water by using the mixer is enough to clean this centrally-located part as well. The reason for including a chopper knife and a 100 cm² surface of the bowl as critical locations is clear: these parts are in direct contact with the product and, if residues remain there, they will almost certainly contaminate a next batch. A similar reasoning was followed for the outlet valve: although the contact between the product and the outlet valve is short, there is a considerable risk that residues that remain in the outlet valve will contaminate the next batch. Although the bowl seal has no direct contact with the product due to the design of the equipment, it was included as critical area because of the possibility that water could infiltrate the small gap between the two metal surfaces of bowl rim and lid rim. Finally, the TRANSFLO™ opening was included to assess the possibility of water seeping through the TRANSFLO™ filter and being trapped. At the end of the cleaning cycle samples of the final rinse water were collected to determine whether the detergent had been removed. • Analysis of the swab samples
After transfer of the swab in a borosilicate tube (Corning Glass Works, Corning, NY, USA), 5 ml distilled water was added. The tube was vortex-mixed for 10 s, homogenised in an ultrasonic bath for 1 minute and 250μl of the solution was injected onto the column. The chromatographic system consisted of an isocratic pump (L-7110), a variable wavelength UV-detector (L-7400) and a PC-interface (D-7000). The integration of the peak area was performed using the HPLC System Manager V3.0 (Merck-Hitachi, Darmstadt, Germany). The analytical column (250 mm x 4 mm ID) was packed with 5 μm RP-C18 particles (Licrosphere, Merck, Darmstadt, Germany). Samples were manually injected using a syringe-loaded injector (Valco six-channel injector, Valco Instruments, Houston, TX, USA) and a loop of 250 µl. The mobile phase consisting of 50% (v/v) MeOH and 50% (v/v) distilled water was degassed before use; its flow rate was 1.0 ml/min. The UV-detector monitored the theophylline concentration at 280 nm. All experiments were run at ambient temperature. Stock solutions of theophylline at a concentration of 100 μg/ml were prepared in distilled water, stored at 8°C in stoppered flasks and were used to prepare a set of six calibration standards; their concentrations varied between 0.01-100 µg/ml. The method was linear over the entire concentration range (R²=0.9991). The within-day variability (n=5) was 0.28%, while the inter-day variability over the above-mentioned concentration range was determined at 0.33%. The detection limit was determined at 2.1ng/ml, thus the quantification threshold is 14.7 ng/swab. • Analysis of the rinse samples
The residues of the detergent in the final rinse water were established by measuring the conductivity using a conductivity meter type LF325’ (WTW, Weilheim, Germany) in accordance with the specifications of the detergent supplier (4). The samples of the final rinsing water were compared with blank samples of the demineralised water used for rinsing and samples of a 1:1000 dilution of the detergent solution.
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Two criteria are calculated and the most stringent criterion is the acceptance criterion to consider the equipment as clean (8). The first criterion used is the 10 ppm criterion. The acceptable quantity of a product per swab can be calculated as follows: CriterionCriterion = 10 ppm x SB x SURswab = …. µg/swab SURequip x 2 Where: SB = smallest batch size in the equipment SURswab = swabbed surface (standard = 100 cm²) SURequip = total contact surface of equipment (18341 cm²) Factor 2 = swab yield, depending on operator manipulation, recovery, etc. The smallest batch size in the Single Pot Processor for theophylline has been determined to be 12 kg, based on the density of the formulation and the fact that the bowl has to be filled to at least 1/3 of the total volume to have enough impact of the chopper during granulation. From initial trials on recovery of theophylline from the swab tissue it was determined that the recovery is between 95 and 100%. Nevertheless the factor 2 for swab yield has been maintained in the formula for calculating the acceptance criteria to account for any operator influence. The second criterion is the Absolute Mass criterion. The acceptance limit for an active substance is defined as 1 µg/cm². In most cases, the absolute mass criterion is the most stringent and will be used as the acceptance criterion in this study. The acceptance criterion for residual detergent traces is that the conductivity of the final rinsing water should be lower than the conductivity of a 1:1000 dilution of the detergent solution. Mebendazole • Materials
The raw materials for the mebendazole batches were provided in a premixed blend by Janssen Pharmaceutica. For the cleaning cycle three detergents were used (all Ecolab, Belgium)(3): • • •
® P3-Cosa CIP 92, an alkaline detergent containing surfactants, with a pH of 11,5 to 12,5 for a 1% solution of
20°C in deionized water. The alkaline detergent is used in a concentration of 2% (5).
® P3-Cosa PUR 84, a liquid additive for the alkaline detergent, based on complexing agents, surfactants and
sequestrants. It is used together with the alkaline detergent in a concentration of 0,75% (6). P3-Cosa® CIP 72, an acid detergent containing different organic acids. It is used in a concentration of 2% for the neutralization of the alkaline detergent and the removal of the additive (7). • Batch production
All raw materials were loaded into the bowl using the Fill-O-Matic (vacuum) loading system and dry mixed. Water (12 kg) was added using a pressure vessel for granulation of the material. The batches were dried using vacuum and microwaves, and the swinging bowl. The batch was discharged into a drum using a dust-free method. Total production time was 125 minutes
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During the production runs, the Single Pot Processor was kept closed to simulate actual production conditions when working with potent compounds. • Cleaning cycle
The cleaning cycle after the mebendazole runs followed the same basic outline as the cleaning cycle for theophylline, but differs in the following ways: • • • • For the pre-wash, hot water (approximately 60°C) is used For the first cleaning cycle, an alkaline detergent combined with an additive is used. This combination is specifically advised by Ecolab for difficult-to-clean products The rinse with cold water is replaced by a cleaning with the acid detergent to neutralize the alkaline detergent After the rinsing with acid detergent, a ’once-through’ cycle of the TRANSFLO™ system, the product filter, bowl, lid and discharge valve with hot water is executed to remove the traces of the acid detergent The final steps of the cleaning cycle are identical to those of the cleaning cycle for theophylline. The total cleaning cycle takes about 100 minutes, of which 30 minutes are spent for drying and preparing the machine for a next batch (e.g. bringing the temperature of the jacket back down). The volumes of water used during this cleaning cycle are as follows: 175-L hot water and 50-L demineralized water. To evaluate the reproducibility of the cleaning cycle the were three production runs followed by cleaning. Cleaning of the equipment was always performed the day after the production run. • Sampling
Six main areas for sampling were chosen, which are considered to be critical for cleaning: product filter, impeller, chopper, bowl and lid, TRANSFLO™ system and discharge valve. Both stainless steel surfaces and seals were considered (see table). Sampling was done using the swab method by wetting a swab tissue with analytical grade concentrated methanol. The swab surfaces were pre-determined and the exact size was known (8). The same sampling places were selected as for the theophylline cleaning for the same reasons. The only exception was the sampling place in the outlet valve where the piston of the valve was sampled, not the cover. The main reason was to get a better overview of the cleanability of the different parts of the discharge valve. Also for the mebendazole study, samples were taken of the final rinse water to determine residuals of the used detergents. • Analysis of the swab samples
The swab was dried in the sample tube, after which 20 ml of a formic acid/dimethylformamide mixture (1/9; v/v) was added. The tube was shaken for 60 minutes and filtered through an Acrodisc® 0.45 μm filter and 10 μl of the filtrate was injected onto the column. The chromatographic system consisted of an isocratic pump and a variable wavelength UV-detector. The analytical column (100 mm x 4.6 mm ID) was packed with 3.5 μm RP-C18 particles (Xterra, Waters, Milford, Ma, USA). The mobile phase consisted of a mixture of 65% (v/v) demineralised water (with 0.5% (w/v) ammoniumacetate) and 35% (v/v) acetonitrile; its flow rate was 1.0 ml/min. The UV-detector monitored the mebendazole concentration at 312 nm, while the column temperature was kept constant at 35 °C. The system suitability was verified with standard solutions of 0.1 and 5 μg/ml. The detection limit was determined at 1.0 ng/ml, thus the quantification threshold is 20 ng/swab.
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Analysis of the rinse samples
The samples of the final rinse water were analysed using TOC (Sievers 820 TOC Analyzer, Ionics Instrument Business Group, USA). • Acceptance criteria
Two criteria were calculated and the most stringent criterion was used to consider the equipment as clean (8). The first criterion used was the 10 ppm criterion. The acceptable quantity of a product per swab can be calculated as follows:
CriterionCriterion = 10 ppm x SB x SURswab = …. µg/swab SURequip x 2 Where: SB = smallest batch size in the equipment SURswab = swabbed surface (standard = 100 cm²) SURequip = total contact surface of equipment (18341 cm²) Factor 2 = swab yield, depending on operator manipulation, recovery, etc. The smallest batch size in the ULTIMAPRO™ 75 for mebendazole has been determined to be 8 kg, based on the density of the formulation and the fact that the bowl has to be filled to at least 1/3 of the total volume to have enough impact of the chopper during granulation. The second criterion is the Absolute Mass criterion. The acceptance limit for an active substance is defined as 1 µg/cm². In most cases the absolute mass criterion is the most stringent and will be used as the acceptance criterion in this study. The acceptance criterion for residuals of the detergents is 10 ppm.
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Results and discussion
Theophylline The results of the swab analysis on the theophylline samples are presented in Table I. Table I – Theophylline – sampling places, surfaces, acceptance criteria and results
Sampling Area Productfilter Impeller wingnut Impeller blade Lipseal mixershaft Chopper knife Bowl bottom Bowl seal Transflo™ opening Outlet valve cover Contact surface 1524.5 64.2 349.8 18.4 143.5 100 (sampling area) 106.8 41.1 2932.6 10 ppm Criterion 218 µg 140 µg 763 µg 39 µg 313 µg 327 µg 233 µg 90 µg 327 µg Absolute Mass Criterion 100 µg 64 µg 350 µg 18 µg 143 µg 100 µg 107 µg 41 µg 100 µg Results (µg/swab) 0.2 10.2 6.4 117.8 < 0.1 8.6 5.0 17.0 0.7 0.35 20.31 9.77 0.49 5.2 6.48 0.14* 20.34* 2.49* 52.54* 0.49* 0.59* 7.38* 3.45* 1.22*
165.15 57.18 0.81 2.13 0.69 < 0.07 0.35 0.64 1.31 0.54 11.54 1.93
* results of the batch where the cleaning was executed 1 day after the production run
It can be observed that the results for the product filter, the impeller blade, the chopper knife, the bowl bottom and the outlet valve cover are always very low and very reproducible, even when the cleaning was executed 1 day after the production run. As these areas are large areas in direct contact with the product, it is of major importance that no residues are present on them to avoid contaminating the next batch. The swab results give enough confidence that the cleaning cycle is indeed capable of achieving the necessary level cleanliness for these areas. The results for the impeller wing-nut, the bowl seal and the TRANSFLO™ opening show a wider variation among the different batches, but the observed residues always remain well below the determined acceptance criteria. The reasons for the larger variation can be found in the unpredictability of the water movement in the bowl during cleaning. Depending on this movement, more or less water will come into contact with the wing-nut, will be able to seep through the TRANSFLO™ filter or penetrate in the small gap between the metal surface of bowl and lid to come into contact with the bowl seal. However, for all areas, the largest value observed was still well below the acceptance criteria and gave enough confidence that the cleaning cycle will remove the drug in question. Finally, the results of the lipseal of the mixer shaft show for all batches an amount of theophylline recovered above both acceptance criteria. As already explained in the section on the sampling places, the area was considered critical due to the design of the lipseal and the lack of spray nozzles in the lid of the Single Pot Processor. The problem was initially defined to be a design issue, and the decision has been made to change the design of the lipseal for future machines by improving the accessibility of the seal for the cleaning solution. The results from the trials with mebendazole however show absolutely no problem with the mixershaft lipseal (see below). This seems to indicate that a change in cleaning cycle of use of detergents might also resolve the observed problem. Further investigations are necessary to determine this, but the decision to improve the design still remains.
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The conductivity of the samples of the final rinsing water was consistently lower then the conductivity of the 1:1000 dilution of the detergent solution, and in fact equalled the conductivity of the blank samples of demineralized water. These results indicate that the rinsing steps of the CIP cycle are capable of removing all detergent traces from the machine. Mebendazole The results of the swab analysis on the mebendazole samples are presented in Table II. Table II – Mebendazole – sampling places, surfaces, acceptance criteria and results
Sampling area Productfilter Impeller wingnut Impeller blade Lipseal mixershaft Chopper knife Bowl bottom Bowl seal Transflo™ opening Outlet valve - piston Contact surface (cm²) 1524.5 64.2 349.8 18.4 143.5 150 (sampling area) 106.8 41.1 50 10 ppm Criterion 218 µg 140 µg 763 µg 39 µg 313 µg 327 µg 233 µg 90 µg 109 µg Absolute Mass Criterion 100 µg 64 µg 350 µg 18 µg 143 µg 150 µg 107 µg 41 µg 50 µg Results (µg/swab) <QT <QT <QT <QT <QT 20 13 2 <QT <QT <QT 2 <QT <QT 11 23 8 <QT <QT <QT 5 <QT 2 47 31 5 <QT
Of the nine places sampled, four areas were always below the quantification limit for mebendazole (= 20 ng/swab). These areas are the product filter surface, the impeller wingnut, the lipseal of the mixer shaft and the piston of the outlet valve. These results differ with the results obtained with theophylline, especially regarding the lipseal, which was a major problem area during the cleaning validation of theophylline. This result for the lipseal seems to indicate, as already mentioned above, that the problem observed for theophylline is not so much a design issue and might be influenced by the use of detergents, or the water-solubility of the drug substance. Also the results for the impeller blade, the chopper knife and the TRANSFLO™ opening are consistently low, indicating an excellent reproducibility of the cleaning cycle for these areas. The results observed for the bowl bottom and the bowl seal are slightly higher than the results obtained for the other sampling areas. All results however remain well below the acceptance criteria and show a good reproducibility. The results obtained during the cleaning validation for mebendazole provide sufficient proof and confidence that the CIP system of the Single Pot Processor is also capable of cleaning water-insoluble drugs. The TOC measurements of the final rinsing water samples showed a TOC content of on average 6,26 ppm. The TOC content of the blank samples was always lower then 1 ppm. These results indicate that there are remains of the detergent in the bowl but, as the actual value found is lower then the acceptance criterion, the removal of detergent by the final rinsing step is found to be acceptable.
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The cleaning validation study on the ULTIMAPRO™ 75 has shown that the CIP system of this equipment is capable of removing both the water-insoluble mebendazole and the water soluble theophylline from the machine to a level well below the generally accepted acceptance criteria. Although certain areas show a larger variation in results then others, the reproducibility of the cleaning cycle can be considered good as results for all sampling areas were always consistent.
We would like to thank Prof. Remon, Prof. Chris Vervaet and Dr. Geert Vergote of the Laboratory of Pharmaceutical Technology of the State University of Ghent for the use of their analytical equipment and their kind assistance during the execution of the analyses on the theophyline samples. We would also like to thank Dr. Lieven Baert and Dr. Filip Kiekens of Johnson & Johnson Pharmaceutical Research & Development, department of Janssen Pharmaceutica NV in Beerse for supplying the raw materials for the mebendazole batches and for the use of their analytical equipment and their kind assistance during the execution of the analyses on the mebendazole samples.
1. 2. 3. 4. 5. 6. 7. 8. Cleaning Validation Handbook, Ecolab 2002 – CD-Rom Cleaning and Cleaning Validation, H. Stahl, 2000 – internal communication D.Rohsner and W.Serve, The Composition of Cleaning Agents for the Pharmaceutical Industry, Pharm. Eng. Vol. 15 N°2, March/April 1995 Product data sheet P3-Cosa
® ® ®
CIP 95, Ecolab CIP 92, Ecolab
Product data sheet P3-Cosa
Product data sheet P3-Cosa PUR 84, Ecolab Product data sheet P3-Cosa® CIP 72, Ecolab PDA Technical Report No. 29, Points to Consider for Cleaning Validation, PDA Journal of Pharmaceutical Science and Technology, Vol. 52, N° 6, Supplement, 1998
by Griet Van Vaerenbergh Product Manager Single Pot Processing GEA Pharma Systems nv Griet.firstname.lastname@example.org
This paper was originally published in the February 2004 issue of Pharmaceutical Technology Europe
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