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Cleaning Validation Practices Using a Single Pot Processor

Cleaning Validation Practices Using a Single Pot Processor

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11/30/2013

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Technical Article
Single Pot Processing
GEA Pharma Systems
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 drugcompounds: 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, withoutoperator 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 substancesto a level well within generally accepted regulations.
Introduction
Concern regarding the cleanability of pharmaceutical processingequipment and operator exposure to active pharmaceutical ingredients(API) has been growing steadily recently, driven mainly by theincreasingly strict regulations regarding operator safety and theoccurrence of more potent active compounds. These concerns have ledto most process equipment on the market these days being equippedwith integrated Clean-In-Place (CIP) systems. This article examines theeffectiveness of the CIP system in a Single Pot Processor anddescribes 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 65% DMV (The Netherlands)- PVP K25 5% BASF (Germany)- Theophylline 30% 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).
 
 
GEA Pharma Systems
 
Batch production
 All raw materials were loaded into the bowl of the UltimaPro™ 75 (single pot Processor used during this study) using the
Fill-O-Matic 
(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 adust-free method.Total production time was 50 minutes. The processor was kept closed throughout to simulate actual production conditions whenworking with potent compounds.
 
Cleaning cycle
The cleaning cycle starts with a pre-wash of the product feed tube, the
RANSFLO
system, the liquid addition system and thebowl 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 thebowl with the detergent solution. The bowl and lid are then cleaned by using the mixer and chopper at high speed. The cleaningsolution is discharged and the discharge valve is cleaned afterwards with hot water and detergent. Consequently, the differentmachine parts are rinsed with cold water in the following order: T
RANSFLO
™ system, product filter, bowl and lid and dischargevalve. 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 processair. Finally, the machine is dried using vacuum, T
RANSFLO
™ 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 nextbatch (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. Cleaningwas always performed immediately after a production run, except for one batch that was held for one day between productionand cleaning.
 
Sampling 
Six main areas for sampling were chosen that are considered to be critical for cleaning: product filter, impeller, chopper, bowland lid, T
RANSFLO
™ 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 pre-determined 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 closestcontact with the product, especially during swinging. Although a rinse sample for a filter would give a better indication of thecleanliness, 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 islikely 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 onthe impeller blades, both front surface and back surface, it was decided to swab the blade completely, although the surface ismuch larger than 100 cm².
 
 
GEA Pharma Systems
The lipseal of the impeller shaft was considered to be a critical part in the Single Pot Processor because it is not flush with thelid and no spray balls are available in the lid for this size of machine. The intention of including this part in the cleaning validationstudy 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 directcontact 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 areabecause of the possibility that water could infiltrate the small gap between the two metal surfaces of bowl rim and lid rim.Finally, the T
RANSFLO
™ opening was included to assess the possibility of water seeping through the T
RANSFLO
™ filter and beingtrapped. At the end of the cleaning cycle samples of the final rinse water were collected to determine whether the detergent had beenremoved.
 
 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. Thetube was vortex-mixed for 10 s, homogenised in an ultrasonic bath for 1 minute and 250
μ
l of the solution was injected onto thecolumn. The chromatographic system consisted of an isocratic pump (L-7110), a variable wavelength UV-detector (L-7400) anda 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
μ
m RP-C18 particles (Licrosphere, Merck,Darmstadt, Germany). Samples were manually injected using a syringe-loaded injector (Valco six-channel injector, ValcoInstruments, Houston, TX, USA) and a loop of 250 µl. The mobile phase consisting of 50% (v/v) MeOH and 50% (v/v) distilledwater was degassed before use; its flow rate was 1.0 ml/min. The UV-detector monitored the theophylline concentration at 280nm. All experiments were run at ambient temperature. Stock solutions of theophylline at a concentration of 100
μ
g/ml wereprepared 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). Thewithin-day variability (n=5) was 0.28%, while the inter-day variability over the above-mentioned concentration range wasdetermined 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 thefinal rinsing water were compared with blank samples of the demineralised water used for rinsing and samples of a 1:1000dilution of the detergent solution.

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