Validation of the Cleaning in Place of the coating pan PERFIMA, IMA

1. Introduction

1.1 Cleaning specifications

2.1.2 Phosphates

The phosphates determination was carried out using the “Phosphates Limit Essay” (Ph Eur IV 2002).
100 mL of the solution were added with 4 ml of sulphomolybdic reagent, shaken and added with 0.1 mL of stannous chloride solution.
The standard was prepared in the same manner using 2 mL of phosphate standard solution (5 ppm PO₄) and 98 ml of water. The colour of 20 mL of each solution was compared after 10 minutes.
The colour of any test solution should not be more intense than that of the standard. Sulphomolybdic reagent was prepared as follow: dissolve with heating 2.5 g of ammonium molybdate in 20 mL of water. Dilute 28 mL of sulphuric acid in 50 ml of water, then cool. Mix the two solutions and dilute to 100 mL with water. Stannous chloride solution was prepared as follow: immediately before use, dilute 1 volume of stannous chloride solution with 10 volumes of diluted hydrochloric acid.
Stannous chloride solution was prepared as follow: heat 20 g of tin with 85 mL of hydrochloric acid until no more hydrogen is released. Allow to cool.
Store the solution over an excess of tin, protected from air. Phosphate standard solution (5 ppm PO₄) was prepared as follow: a quantity of monobasic phosphates potassium corresponding to 0,716 g of KH₂PO₄ is dissolved in water and made up to a volume of 1000 mL. 1 volume of this solution is diluted to 100 with water immediately before using.
Besides the visual comparison with the reference standard, as described in European Pharmacopoeia, the phosphates concentration was quantified spectrofotometrically at 340 nm.

2.1.3 pH

The determination of pH value was done at second decimal digit with potentiometric method.

2.1.4 Total Organic Carbon (TOC)

The determination of the total contents in organic carbon was performed according to USP 28.

3. Test A

3.1 Test conditions

3.1.1 Machine set-up

The pan was loaded with a small tablet batch (50 kg) to mimic a worst case scenario (more losses). The film coating was sprayed by means of 3 Schlick ABC guns (nozzle diameter 1.2 mm) installed on a PCA arm.
The coating solution had the following composition:

First of all the spray line was filled with the coating solution, then a preheating phase was performed. The coating time was approximately 1 hour to achieve a 3% weight gain using the standard coating solution.
The pan was unloaded in a semiautomatic way at the end of the coating step. The spray line was cleaned by spraying hot water inside the empty pan (approx. 5-8 L) and then the guns were positioned inside the pan for the CIP.
The reservoir connected to the peristaltic pump was dismantled and cleaned manually.

3.1.2 Tablets production

The tablets used for the coating process had the following composition:

3.1.3 Description of the cleaning procedure

As a detergent for the washing phase ANTOS PH (DK Ausiliari Chimici, Ozzano Emilia, Italy) was used. This detergent contains phosphoric acid, which offers the opportunity to check the efficacy of the rinsing through the analysis of phosphates with the “Phosphates limit essay” according to Ph Eur IV 2002. The washing cycle developed through the following phases:

1. pre-washing
   The pre-washing phase aimed to remove from the machine surfaces most of the residual material. In this phase 435 L of hot (50 °C) tap water, at the pressure of 4 bar and with a flow of 40 L/min were used.
2. washing with detergent
   435 L of detergent solution at 1% w/v in hot tap water, at the pressure of 4 bar and with a ow of 40 L/min were employed for removing all soluble and insoluble materials.
3. rinsing
   This phase was divided into 2 steps and had the aim to remove completely the detergent. 435 L of demineralized water pumped at a pressure of 4 bar for each cycle were used, for a total of 870 L.
4. drying
   During this final phase the pan, rotating at 18 rpm, was dried with hot air (temperature 80 °C, absolute humidity 5.8 g/kg), for 30 minutes with a flow of 3000 m³/h.

3.2 Samples recovery and preparation

To assess the efficacy of the washing procedure, the following samples were taken:

a) Solution samples

The pH value was measured for each sample. In order to determine the fluorescein content, all samples were diluted with an appropriate volume of buffer solution pH 8 (FU XI) to dissolve completely the marker.
The rinsing samples were analyzed also to determine phosphates content and total organic carbon (TOC).

b) Metallic surfaces swab sampling
Swab sampling was carried out using a hydrophilic cotton swab of 24 cm² impregnated with 1 mL of a NaHCO₃ 0.5% (w/v) solution. Table I lists the parts of the machine sampled along with the relevant surface.

Table I: pan sampled area

Swabs were extracted with 20 mL of a buffer solution pH 8. The obtained solutions were filtered (0.45 μm) and analyzed by HPLC.
The process of extraction of fluorescein from swabs was previously validated (mean recovery: 98.9%).

3.3 Results

3.3.1 Visual check

The visual check with ambient and UV light (253 nm) did not evidence visible residues.

3.3.2 Analytical results

Analytical results are reported in Figures 2, 3, 4 and in Tables II, III, IV.

Analysis of the discharged water

The fluorescein concentration in the pre-washing, washing and rinsing water is presented in Figure 2.
It can be observed that the fluorescein concentration dropped well below 1 ppm at the end of the pre-washing phase.

Figure 2: fluorescein concentration in pre-washing, washing and rinsing water

In the rising phase (Figure 3), a general trend toward a progressive diminution of the fluorescein concentration in each phase can be evidenced. At the end of this phase the tracer concentration leveled around 0.0005 ppm.

Figure 3: fluorescein concentration in rising water

pH, Phosphates and Total Organic Carbon (TOC) concentration

To further evaluate the characteristics of the water discharged during and at the end of washing operation, the pH value, phosphates concentration (indicating the residual detergent) and total organic carbon (TOC) were evaluated. As illustrated in Figure 4, the pH of the discharged water, went down during the washing procedures because of the presence of acid detergent, thus turned to be very close to neutral value (7) in the samples relevant to the rinsing phases.

Figure 4: pH variations during pre-washing, washing and rinsing steps

Phosphates concentration is presented in Table II. The values obtained for all samples were above Ph Eur IV limits (0.1 ppm), except for the last one.
It is possible, however, to note a progressive reduction of phosphate concentration. A value lower than Ph Eur IV limit was attained with the sample PC4, indicating that the rinsing procedure was able to eliminate completely detergent residues.

Table II: phosphate concentration in rinsing water.

Table III shows the carbon concentration in rinsing, tap and demineralized waters. All values of TOC are higher then the value of TOC reported on FUI XI for depurated water (0.5 ppm/500 ppb), although a trend toward a progressive reduction of TOC value can be clearly evidenced for the rinsing water samples. 

The final rising sample attains a TOC value not significantly different from those of tap and demineralized water used in the CIP process.

Table III: carbon concentration in rinsing waters

Swabbing of the metallic surfaces

Table IV reports the amount of fluorescein found in different parts of the machine per unit of sampled surface. It can be observed that in all cases, the amount recovered was very low and well below the specific limit required from the adopted guideline

Round door’s inflatable seal2.4 x 10^-3

4. Test B

4.1 Test conditions

Machine set-up and conditions used during the production phase were the same adopted in TEST A (paragraph 3.1.1 and 3.2.2) with the only difference that fluorescein was not added in the filmforming mixture.

4.2 Samples preparation

A sample of 10 tablets was taken from the pan.
The tablets were weighed and grinded.
Then 3 powder samples, each one corresponding to the mean weight of one tablet, were accurately weighed. Each powder sample was dissolved in 20 mL of a buffer solution pH 8 (FU XI), left under magnetic stirring for 60 minutes, then filtered three times.
The obtained solutions were analyzed by HPLC for fluorescein quantification.

4.3 Results

The concentration of fluorescein found in the placebo tablets was around 0.02 ppm (5.72×10^-3 μg per tablets). This value is 500 times lower than that established by specific n°2 (paragraph 1.1) as maximum acceptable limit (10 ppm).

5. Test C

5.1 Test conditions

5.1.1 Pan preparation for recovery test
A powder mixture containing 50 g of HPMC E 5,50 g of PEG 6000 and 250 g of fluorescein was dispersed in ethanol and distributed inside the pan, to simulate the material accumulation during a normal production. Then, a complete cleaning cycle was performed as described for the TEST A (paragraph 3.1.4).

5.2 Samples preparation

The water coming from each cleaning phases (pre-washing, washing and rinsing) was collected in eleven tanks and alkalinized to pH 8 with NaOH pellets in order to assure complete fluorescein dissolution.
Samples, opportunely diluted, were analyzed by HPLC for fluorescein quantification.

5.3 Results

The total amount of fluorescein recovered from pre-washing, washing and rinsing waters was 256 g, which represents 102.4% of the theoretical quantity put inside the pan.

6. Conclusions

In general, it must be underscored that the cleaning of a coating pan represents a difficult task, as many issues should be taken into account in order to obtain a satisfactory result. In particular, the main problem that should be addressed is related to the difficulty of removing from the pan surface nebulized, composite, cohesive material, often containing water insoluble components. In the present cleaning validation trial we selected a tracer practically insoluble in acidic solutions and we used an acidic detergent in order to test the worst-case scenario. The results obtained indicate that the selected tracer can be almost completely eliminated after the first step of the cleaning procedure and that, at the end of the washing procedure no residual left inside the pan. The water discharged at the end of the CIP procedure had characteristics comparable to those of the supplied water in terms of pH and phosphate content and TOC values.
The results of the placebo trial indicate lack of cross contamination between subsequent productions. The recovery trial clearly showed the complete elimination of the tracer from the pan.
Therefore, it can be concluded that the CIP system of the Perfima pan should be considered effective and reliable.