Int J Pharm Pharm Sci, Vol 9, Issue 5, 141-151Original Article


DEVELOPMENT AND VALIDATION OF ANALYTICAL METHOD FOR ESTIMATION OF ARIPIPRAZOLE IN SWAB SAMPLES ON PHARMACEUTICAL MANUFACTURING EQUIPMENT SURFACES FOR CLEANING VALIDATION

SUKHPREET KAUR, INDU BALA, ANJOO KAMBOJ*, UPENDRA K JAIN

Chandigarh College of Pharmacy, Landran, Mohali, Punjab (140307)
Email: anjookamboj@gmail.com

Received: 30 Jun 2016 Revised and Accepted: 31 Mar 2017

ABSTRACT

Objective: To validate simple analytical method and its application in the determination of residual aripiprazole in production area equipment and to confirm the efficiency of cleaning procedure.

Methods: The swab sampling and UV method for residual estimation of aripiprazole in swab samples from equipment surfaces after manufacturing of three consecutive batches of aripiprazole 10 mg uncoated tablets were developed and validated.

Results: The swab sampling method was developed and validated in order to obtain the suitable recovery (>90%). The swabs were saturated with acetonitrile. The UV method was developed using UV-Vis spectrophotometer at 255 nm. The calibration curve was linear (r2 =1.0000) over a concentration range of 1-30 µg/ml. The LOD and LOQ were 0.43 µg/ml and 1.32µg/ml, respectively. No interference from swab solution was observed and samples were stable for 24h. The determined concentration varying from 1.00-5.687µg/swab was well below the calculated limit of contamination i.e., 24.2µg/swab or 24.2 µg/25 cm2.

Conclusion: The results obtained from cleaning procedure confirmed that the proposed procedure was able to remove aripiprazole from equipment surfaces below the value of 10 ppm criteria. So the proposed validated UV method with appropriate swab wipe procedure could be applicable for cleaning validation on residues of aripiprazole.

Keywords: Residual estimation, swab sampling, Cleaning validation, Aripiprazole, UV method

© 2017 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijpps.2017v9i5.13788

INTRODUCTION

Cleaning validation is defined as providing a high degree of assurance that a cleaning process removes residues of the active pharmaceutical ingredients of the product manufactured in a piece of equipment, the cleaning aids utilized in the cleaning process and the microbial attributes [1, 2]. All residues are removed to predetermined levels to ensure the quality of the next product manufactured is not compromised by waste from the previous product and the quality of future products using the equipment, to prevent cross-contamination and as a GMP requirement. The U. S. food and drug administration (FDA) have strict regulation about the cleaning validation. For example, FDA requires firms to have written general procedures on how cleaning processes will be validated. Also, FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required. FDA also requires firms to conduct the validation studies in accordance with the protocols and to document the results of studies. The valuation of cleaning validation is also regulated strictly, which usually mainly covers the aspects of equipment design, cleaning process written, analytical methods and sampling. Each of these processes has their related strict rules and requirements. Regarding the establishment of limits, FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. But some limits that have been mentioned by industry include analytical detection levels such as 10 ppm, biological activity levels such as 1/1000 of the normal therapeutic dose and organoleptic levels [3-5].

Sampling sites is based on the difficult clean geometries of the equipment and these locations are inaccessible i.e. their inaccessibility makes them difficult to clean, therefore, before choosing for sampling sites one must be conscious in selecting the desired sampling locations [6]. For validation of cleaning procedure three methods of sampling that are considered to be acceptable, namely direct surface sampling (swab method), indirect sampling (use of rinse solution) and placebo sampling. A combination of the first two methods is generally the most desirable particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling [7, 8].

The cleaning validation is documented evidence with a high degree of assurance that consistently removes the residue of the subjected product below the established acceptance criteria. For the acceptable residual limit, various mathematical formulas and calculations are done based on known daily dose or on toxicological data along with safety factors. Hence the cleaning validation involves three separate activities: (i) establishment of acceptable residue limits for drug, (ii) development and validation of assay method for determination of drug from equipment surfaces and (iii) the development and validation of cleaning procedure that is used to remove drug from the manufacturing surfaces [6, 9-14, 25].

Aripiprazole is an atypical antipsychotic drug. It is primarily used in the treatment of psychotic conditions such as schizophrenia and bipolar disorder. It is commercially available as a tablet or as an oral solution. Tablets are available in 10 mg, 15 mg, 20 mg and 30 mg. Due to low dose profile, it is necessary to prove that the equipment train and production area are clean prior to the development of next product, as per good manufacturing practice.

Fig. 1: Aripiprazole [29]

Aripiprazole (C23H27Cl2N3O2) m. wt 448.385, 7-{4-[4-(2, 3-dichloro-phenyl)-piperazin-1-yl] butoxy}-3, 4-dihydroquinolin-2(1H)-one (CAS registry number: 129722-12-9) is white to off-white crystalline powder, freely soluble in acetonitrile, ethanol, methanol, sparingly soluble in water [29].

The objective of this study was to demonstrate the applicability of UV method for estimation of the residues of aripiprazole in cleaning control swab samples from manufacturing surfaces after production of aripiprazole 10 mg uncoated tablets and the efficiency of the cleaning procedure. The analytical method was validated for linearity, accuracy, precision, robustness, ruggedness, LOQ, LOD. The stability of the solutions of aripiprazole was also studied. The studies were carried out as per the established guidelines [15-19, 26]. Also, the swabbing procedure was optimised in order to obtain a suitable recovery of the active ingredient. The cleaning validation was performed on three consecutive batches of finished product-aripiprazole 10 mg uncoated tablets.

MATERIALS AND METHODS

Chemicals and reagents

All the reagents were of analytical grade. Aripiprazole was obtained from Cadila Pharmaceuticals Ltd, Ahmadabad, India. Acetonitrile was obtained from Molychem, Mumbai, India. Swabs were obtained from Himedia Lab. Ltd. Mumbai, India. Stainless steel plates were used in this experimental work. Double distilled water was used throughout the study.

Equipment and instruments

Single rotary tablet compression machine (Shakti, India), UV Spectrophotometer model 1800 (Shimadzu, Japan).

Establishment of cleaning level acceptance criteria for aripiprazole

There are several approaches for the establishment of acceptable residual limit (ARL) calculation. ARL is calculated and compared with different approaches and minimum the value of ARL was selected [7, 8].

  1. Calculation of total carryover limit based on therapeutic or medical dose;
  2. limit of calculation based on 10 ppm criteria (adulteration limit);
  3. Limit of calculation based on visual inspection.

Calculation of total carryover limits based on therapeutic dosage

According to this approach, the safety factor is considered as a risk assessment factor. Many companies have chosen to use a standard safety factor of 1/1000 for all limits calculations. This means that any product, when administered at 1/1000 of its daily therapeutic dose (effective dose), will not cause any toxic effect to the patient if administered by the same route.

The basic principle of cleaning validation is that the patient should not take more than 0.1% of the therapeutic dose (effective dose). The lowest allowable residue level based on pharmacological activity is achieved by using the smallest dosage of the current product and the smallest batch size manufactured using the equipment train. The formula used for the calculation of the lowest allowable residue value is shown:

Where, ARL is the acceptance residual limit, STD is the API smallest therapeutic dose of previous product A (mg/unit dose), SBS is the smallest batch size of any subsequent product (mg) to be manufactured in the small equipment train, SF is the safety factor i.e. 1/1000 or 0.001, MDD is the maximum daily dose of the product to be manufactured in the same equipment train, M is the surface area/swab (25 cm2), SSA is the shared equipment surface area.

Limit of calculation based on 10 ppm criteria

It is stated that not more than 10 ppm of the product will appear in the next batch of product. ARL was calculated on the basis of 10 ppm criterion according to below formula.

Where ARL is the acceptance residual limit, MBS is the minimum batch size in kg of any subsequent product to be manufactured in the same equipment train. (Product B), M is the surface area/swab (25 cm2), SSA is the shared equipment surface area.

Limit of calculation on the basis of visual inspection

Visually equipment surface area must appear clean with no traces of product or any extraneous matter. The VLOD (visually limit of detection) was determined by spiking 5 x 5 cm Stainless steel plates with known amount of drug. The lowest level of aripiprazole residue was visually detected.

Development and validation of UV procedure for assay of aripiprazole residues in swab collected from stainless steel plates

Calibration curve of aripiprazole

A primary stock solution of 1000µg/ml was prepared in acetonitrile by dissolving 10 mg of aripiprazole in 10 ml acetonitrile. For the preparation of different concentrations, aliquots of stock solution were transferred into series of 10 ml volumetric flasks and volume was made with acetonitrile. Different concentrations were prepared in a range of 1-30µg/ml of aripiprazole in acetonitrile and absorbance was measured at 255 nm for standard graph [20].

Validation of developed method as per ICH guidelines

The developed method for estimation of aripiprazole was validated as per ICH guidelines for validation parameters like accuracy, linearity, limit of detection (LOD), limit of quantification (LOQ), selectivity and robustness and ruggedness [18, 19, 28].

Linearity

In order to establish the linearity of the analytical method, a series of dilutions ranging from 1-30μg/ml were prepared. The absorbance values were noted at 255 nm. Linearity curve was plotted against corresponding concentration values. The compliance with beer’s lamberts law (linearity) was found to be in concentration range and noted.

Accuracy

The accuracy of the method was estimated by determination of recovery for three concentrations (corresponding to 80, 100 and 120% of test solution concentration) covering the range of the method. For each concentration, three sets were prepared and absorbances were noted. The drug concentrations of aripiprazole were then calculated

Recovery study of drug from spiked stainless steel plates

Recovery study was prepared on spiked stainless steel plates [20-23] with a predefined 10 cm2 surface area. 5 ml volume of different concentrations of 1, 5, 10, 15 and 20 µg/ml of aripiprazole was spiked onto stainless steel plates with five sets of the concentration of five plates each and was allowed to evaporate. The head of adsorbent swabs was saturated with acetonitrile. The total surface of the plates was successively wiped initially in a horizontal and then in a vertical fashion, starting from the outside towards the centre, with swabs moistened with the appropriate solvent. The head of the swabs was placed into a 10 ml volumetric flask containing 5 ml of the solvent (in which the swab was soaked). Then 5 ml of water was added to each volumetric flask. These volumetric flasks were capped and sonicated for 15 min. The absorbance of the solution was measured with UV-Vis spectrophotometer. The UV maxima in acetonitrile were found to be 255 nm.

Precision: Precision was considered at two levels:

Repeatability (Intra-day repeatability)

The intra-day repeatability was established by analysis 6 different concentrations with three replicates. In intra-day precision, all the replicate was prepared on the same day and statistical validation was carried out. The data is represented as relative standard deviation (% RSD) and with low relative standard deviation (% RSD) values which indicate the good method precision.

Inter-day precision

Day to day precision was carried out by analysis 6 concentration with three replicates. In inter-day precision, all the linearity concentrations were prepared and absorbance was recorded. The low relative standard deviation (% RSD is ±2%) values which indicate the good method precision.

Robustness and ruggedness

Robustness and ruggedness were carried out to evaluate the influence of small but deliberate variations in the experimental conditions for the determination of aripiprazole. Robustness of the method was determined by changing the temperature and ruggedness of the method was determined by changing analyst.

LOD and LOQ

LOD and LOQ of the method were established using the following formulas as per ICH guideline:

Where, σ is the mean standard deviation of y–intercepts of regression lines, S is the slope of the standard curve.

Optimization and validation of cleaning procedure for aripiprazole tablets on compression machine

The cleaning validation was done to demonstrate the effectiveness of the cleaning procedure for residues up to the predetermined acceptance level of aripiprazole in the equipment train [24].

Sampling procedure

To determine the residue of drug remaining in the equipment train after cleaning swab sampling procedure was used. For this procedure, sterile cotton swabs with polypropylene stick in HDPF bottle were used. Before collecting the samples the swabs were dipped in the acetonitrile and completely saturated for 15 min. For all sampling locations, 5 cm × 5 cm swab area was selected and swabbed in described swabbing pattern. The pattern of swabbing and pressure applied was such that it collected the maximum residue present in the selected area. All this operation was done with care and wearing powder free sterile gloves in hands. The swab wiped from selected area was placed in the sterile HDPF containing 5 ml of acetonitrile and capped securely. Each tube was sonicated for 5 min; the extract was collected and analyzed by developed method.

Chemical acceptance criteria

ARL (acceptable residual limit) used to calculate chemical acceptance criteria

Sampling locations

It is important to include the swab samples from the most difficult to clean and worse case locations of the equipment, but the sampling locations were selected such that these were representative of all areas of equipment, even easy to clean surfaces.

In the given piece of equipment, 99% surface was readily accessible, easy to clean and visually friendly category. Only 1% or less equipment surface was hard to clean and it was assumed that the equipment was equally dirty as the hard to clean surface samples obtained.

Following sampling locations were selected for swab sampling of the residual drug from tablet machine after washing (fig. 2; table 1).

Fig. 2: Different sampling locations in the single rotary tablet compression machine [27]


Table 1: Different sampling locations in the single rotary tablet compression machine [27]

S. No. Sampling point location Sampling point name
1. Hopper top cylinder TCM-01
2. Hopper middle cone TCM-02
3. Hopper discharge chute TCM-03
4. Turret TCM-04
5. Chute TCM-05

Optimisation of cleaning procedure

After compression of the tablets of aripiprazole 10 mg the tablet machine was cleaned according to the general procedure used in the industry to clean the pharmaceutical equipment. The samples were collected with cotton swabs by wiping 5 cm×5 cm area of predefined sampling locations. Samples were analyzed and compared w. r. t the predetermined acceptance criteria [24].

Following steps were followed in the cleaning procedure of the tablet machine after compression of the aripiprazole 10 mg tablet.

Validation of cleaning procedures

For validation of cleaning procedure on tablet machine, three consecutive batches of aripiprazole tablet 10 mg were prepared. This validation was done to prove the effectiveness and consistency of the cleaning procedure. Validation was also done to meet the regulatory requirement of the development method. After production of each batch the tablet compression machine was subjected to above cleaning procedure. Visual and chemically inspection results were recorded.

RESULTS AND DISCUSSION

Establishment of cleaning level acceptance criteria for aripiprazole

Swab sampling of area hardest to clean was done from equipment used in the manufacturing and residues were found in mg/ml. the smallest batch sized (SBS) subsequent products were selected for calculating the values of the maximal allowable carryover. ARL was calculated and compared with different approaches and minimum the value of ARL was selected.

Calculation of total carryover limits based on therapeutic dosage

The formula used for the calculation of the lowest allowable residue value is shown:

Where, ARL is the acceptance residual limit, STD is the smallest therapeutic dose of product A (mg/unit dose), SBS is the smallest batch size of any subsequent product to be manufactured in the small equipment train, SF is the safety factor i.e. 1/1000 or 0.001, MDD is the maximum daily dose of the product to be manufactured in the same equipment train, M is the surface area/swab (25 cm2), SSA is the shared equipment surface area.

(1.25L (25% capacity of hopper) x 425 gram/l(average bulk density of subsequent material)=531.25 gm

Tablet weight

SBS (number of dosage unit form/unit batch) =

= 4540.5 tablets

Shared surface area of the tablet compression machine. Covering hopper, turret, discharge chute was calculated 5,484.64 cm2 (table 2).

= 0.0620 mg/swab

= 62µg/swab or 62µg/25 cm2

Table 2: Surface area calculation for tablet machine

S. No. Part name Geometric shape L B R H Formula used Surface area in cm2
1. Hopper
a. Top cylinder Cylinder 23 16 2Лrh 2311.04
b. Middle cone Double radius cone

r1=20.3

r2= 8.2

 14 2Л(r1+r2)/2×h 1239.6
c. Discharge chute Cylinder 5.1 11.5 2Лrh 368.3
2. Turret
Circular

r1=14

r2=9

 Л(rl)2-Л(r2)2 361.1
3. Feed frame
Rectangle 28 15 420
4. Chute
C channel 20.5 8.8 6 Lb+2bh 286
5. Lid of hopper
Circular 8 Лr2 200.96
Total 4986.04
(+ % of area) 498.6
Total 5484.64

L= length, B= breath, R= radius, H= height, Л= 3.14

Limit of calculation based on 10 ppm criteria

ARL was calculated on the basis of 10 ppm criterion according to below formula.

Where ARL is the acceptance residual limit, MBS is the minimum batch size in kg of any subsequent product to be manufactured in the same equipment train. (Product B), M is the surface area/swab (25 cm2), SSA is the shared equipment surface area.

(1.25L (25% capacity of hopper) x 425 gram/l(average bulk density of subsequent material) = 531.25 gm

= 0.531Kg

= 0.0242 mg/swab

=24.2µg/swab or 24.2µg/25 cm2

Limit of calculation on the basis of visual inspection

The VLOD (visually limit of detection) was determined by spiking 5 x 5 cm stainless steel plates with known amount of drug concentration (10-40µg/ml) after evaporation of the sample solution. The lowest level of aripiprazole residues which was visually detected is 40µg/25 cm2.

Since ARL value of 24.2µg/swab was the lowest value out of three values obtained from 3 criterions. Hence 24.2µg/25 cm2 was considered as the acceptable residual limit (ARL) for aripiprazole for residual estimation of the determined concentration of aripiprazole residues in swab sample solution should not be more than ARL (acceptance criteria).

Development and validation of UV procedure for assay of aripiprazole residues in swab collected from stainless steel plates

Calibration curve of aripiprazole in acetonitrile

The stock solution (1000µg/ml) was prepared in acetonitrile by dissolving 10 mg of aripiprazole in 10 ml acetonitrile. From the stock solution, various dilutions were prepared and absorbance was measured at 255 nm [22]. The calibration curve was constructed by plotting absorbance vs concentration with linear regression equation Y = 0.032+0.0006, regression coefficient r2equal to 1 (fig. 3, 4). The high value of correlation coefficient indicates good linearity.

Fig. 3: UV spectrum of aripiprazole in acetonitrile showing absorption maxima at 255 nm


Fig. 4: Calibration curve for aripiprazole

Validation of developed method as per ICH guideline

Linearity

Different aliquots were taken from the stock solution and diluted with acetonitrile to prepare series of concentration ranging from 1-30µg/ml. The absorbance value was noted at 255 nm and plotted against corresponding concentration values. The linearity range was found to be 1-30µg/ml for aripiprazole. Each measurement was carried out in sextet (table 3).

Accuracy

The accuracy of the method was determined by calculating recovery of aripiprazole by standard addition method. A known amount of standard solution of aripiprazole (80, 100, and 120 %) added to pre-quantified separate (10µg/ml) respectively. The amount of aripiprazole was estimated (table 4).

The low value of standard deviation indicates that the proposed method is accurate. Results of recovery studies are given in table 4. The % recovery was found between 95.20%-98.82% which were within the limit of acceptable criteria which indicate indicates that the method has good accuracy for determining aripiprazole [22].

Recovery study of drug from spiked stainless steel plates

Recovery study was prepared on spiked stainless steel plates with a predefined 10 cm2 surface area. 5 ml volume of different concentrations of 1, 5, 10, 15 and 20 µg/ml of aripiprazole was spiked onto stainless steel plates with five sets of the concentration of five plates each and was allowed to evaporate. The head of adsorbent swabs was saturated with acetonitrile.

The total surface of the plates was successively wiped initially in a horizontal and then in a vertical fashion, starting from the outside towards the centre, with swabs moistened with the appropriate solvent. The head of the swabs was placed into a 10-ml volumetric flask containing 5 ml of the solvent (in which the swab was soaked). Then 5 ml of water was added to each volumetric flask. These volumetric flasks were capped and sonicated for 15 min.

The absorbance of the solution was measured with UV-Vis spectrophotometer at 255 nm. The % recovery with spiked stainless steel plates was found between 88.75-98.12% which is well within the acceptance criteria with %RSD value well in limit i.e. less than 2%. Hence indicates method has good accuracy for determining aripiprazole (table 5).

Table 3: Linearity data for aripiprazole

Drug conc. (µg/ml) mean±SD (n=6) Drug recovered (µg) % recovery
1 0.032±0.002 0.996 99.68
5 0.160±0.001 4.986 99.93
10 0.320±0.004 10 100
15 0.48±0.002 14.98 99.87
20 0.640±0.003 20 100
25 0.797±0.016 24.91 99.65
30 0.960±0.001 29.99 99.98
Mean 99.89
Standard Deviation 0.174
% Relative Standard Deviation 0.174

n=6 each measurement was repeated in sextet, Data is expressed in mean±SD.

Table 4: Recovery study for aripiprazol

Amt of sample (µg/ml) Amt of std. drug added (µg/ml)

Mean

(n=3)

 SD % RSD Drug recovered (µg) % Recovery
10 8 0.549 0.0005 0.105 17.13 95.20
10 10 0.629 0.0006 0.110 19.65 98.29
10 12 0.696 0.001 0.240 21.74 98.82
Mean 97.44
Standard Deviation 1.952
% Relative Standard Deviation 2

Each measurement was repeated three times independently, Data is expressed in mean±SD.

Table 5: Result obtained for the recovery of aripiprazole form spiked 180-grit stainless steel plate samples

Drug spiked (µg) Absorbance (n=5) Drug recovered (µg) % Recovered
1 0.032 0.981 98.12
  0.031 0.95 95
  0.029 0.887 88.75
  0.03 0.918 91.87
  0.032 0.981 98.12
5 0.155 4.825 96.5
  0.153 4.762 95.25
  0.154 4.793 95.87
  0.152 4.731 94.62
  0.156 4.856 97.12
10 0.305 9.512 95.12
  0.309 9.637 96.37
  0.307 9.575 95.75
  0.311 9.7 97
  0.31 9.66 96.68
15 0.461 14.38 95.91
  0.464 14.48 96.54
  0.463 14.45 96.33
  0.465 14.51 96.75
  0.466 14.54 96.95
20 0.618 19.29 96.46
  0.615 19.2 96
  0.617 19.26 96.31
  0.619 19.32 96.62
  0.62 19.35 96.78
Mean 95.87
Standard Deviation 1.924
% Relative Standard Deviation 2

Each measurement was repeated five times. (n=5)

Precision

Precision was investigated by analyzing the different concentration of aripiprazole (20µg/ml) in independent replicates on the same day (intra-day) and on consecutive days (inter-day).

Repeatability

The intra-day and inter-day precisions of the proposed method was determined by performing swabbing which involved spiking aripiprazole on stainless steel surface, recovering the aripiprazole with swabs and desorbing the swabs into extraction solution diluent as described earlier in accuracy study and analyzing corresponding responses on the same day and on different days over a period of one week for different concentration of standard solution of aripiprazole (20µg/ml). Results were reported in table 6, 7. The results indicate that the % RSD values were 0.09 and 0.079 for Intraday and Interday precision respectively which were within the prescribed limits of ICH guidelines indicate good precision.

Table 6: Repeatability analysis of aripiprazole (Intraday precision)

Drug Conc (µg/ml) Mean absorbance (n=3) SD % RSD Drug recovered (µg) % recovery
20 0.637 0.0005 0.090 19.90 99.54
20 0.637 0.0015 0.239 19.89 99.48
20 0.637 0.0005 0.090 19.90 99.54
20 0.637 0.001 0.156 19.88 99.43
20 0.638 0.001 0.156 19.91 99.59
20 0.638 0.0005 0.090 19.93 99.69
Mean 99.55
Standard Deviation 0.089
% Relative Standard Deviation 0.090

Each measurement was repeated three times. (n=3), Data is expressed in mean±SD.

Table 7: Repeatability analysis of aripiprazole (Interday precision)

Drug conc. (µg/ml) Mean absorbance (n=3) SD % RSD Drug recovered (µg) % Recovery
20 0.640 0.002 0.331 19.99 99.95
20 0.639 0.0007 0.110 19.97 99.85
20 0.639 0.0007 0.110 19.95 99.75
20 0.64 0.0014 0.220 19.98 99.90
20 0.639 0.0014 0.221 19.97 99.85
20 0.640 0.0028 0.441 19.99 99.95
Mean 99.880
Standard Deviation 0.078
% Relative Standard Deviation 0.079

Each measurement was repeated three times. (n=3), Data is expressed in mean±SD.

Robustness and ruggedness

In robustness, the drug content was analyzed under the experimental variables like a slight change in the temperature (25˚C, 18˚C). In ruggedness analyst to analyst, variation was considered. As the % RSD values was found to less than 2%, so method proves its robustness and ruggedness (table 8-10). This gives the confidence that API residues are stable and the residues concentration do not change in swab solutions during cleaning validation.

LOD and LOQ

The sensitivity of the method for estimation was determined in terms of the limit of detection (LOD) and limit of quantitation (LOQ). The LOD value of LOD was found to be 0.43µg/ml and LOQ was found to be 1.32µg/ml (table 11).

Optimization and validation of cleaning procedure for aripiprazole tablets on compression machine

Cleaning procedure validation was done to check the effectiveness of cleaning procedure.

Chemical acceptance criteria

ARL (acceptable residual limit) used to calculate chemical acceptance criteria

= 23.18µg/cm2

Table 8: Room temperature (25 ˚C) variation study for aripiprazole

Drug conc. (µg/ml) Mean absorbance (n=3) SD % RSD Drug recovered (µg) % recovery
20 0.638 0.002 0.313 19.91 99.59
20 0.635 0.002 0.314 19.83 99.17
20 0.635 0.002 0.314 19.84 99.22
20 0.641 0.002 0.312 20.02 100.1
20 0.641 0.001 0.156 20.01 100.0
20 0.640 0.002 0.312 19.99 99.95
Mean 99.68
Standard Deviation 0.418
% Relative Standard Deviation 0.419

Each measurement was repeated three times independently. (n=3), Data is expressed in mean±SD.

Table 9: 18 ˚C temperature variation study for aripiprazole

Drug conc. (µg/ml) Mean absorbance (n=3) SD % RSD Drug recovered (µg) % recovery
20 0.633 0.001 0.157 19.77 98.86
20 0.632 0.001 0.158 19.75 98.76
20 0.633 0.001 0.157 19.76 98.81
20 0.634 0.001 0.157 19.79 98.96
20 0.631 0.001 0.158 19.72 98.60
20 0.632 0.002 0.316 19.74 98.70
Mean 98.78
Standard Deviation 0.126
% Relative Standard Deviation 0.128

Each measurement was repeated three times independently. (n=3), Data is expressed in mean±SD.

Table 10: Analyst to analyst variation study for aripiprazole

Drug Conc. (µg/ml) Mean absorbance (n=3) SD % RSD Drug recovered (µg) % recovery
20 0.636 0.0035 0.555 19.87 99.35
20 0.636 0.0007 0.111 19.87 99.35
20 0.634 0.0007 0.111 19.80 99.04
20 0.632 0.0007 0.111 19.74 98.73
20 0.637 0.0007 0.110 19.90 99.51
20 0.639 0.0014 0.221 19.95 99.75
Mean 99.29
Standard Deviation 0.357
% Relative Standard Deviation 0.360

Each measurement was repeated three times independently. (n=3), Data is expressed in mean±SD.

Table 11: Regression analysis data and summary of validation parameters for proposed method

Parameters Aripiprazole
Linearity 1-30 (µg/ml)
Regression equation Y=0.032x+0.0006
Slope 0.032
Intercept 0.0006
Correlation coefficient 1
LOD (limit of detection) (µg/ml) 0.43
LOQ (limit of quantitation) (µg/ml) 1.32
Precision (% RSD)
Interday (n=6) 0.079
Intraday (n=6) 0.090

Optimization of cleaning procedure

Samples were analyzed and compared with respect to the pre-determined acceptance criteria.

Validation of cleaning procedure

For validation of cleaning procedure, the three consecutive batches of aripiprazole tablets 10 mg were formulated and evaluated (according to each cleaning level condition) by the developed analytical method. The level of drug residue obtained from visual inspection and chemical inspection was evaluated against the ARL level. The level of drug residue obtained after final washing (of three batches) was less than the pre-calculated ARL value hence, it was concluded that the established procedure is responsible to achieve the expected cleanliness. The concentration of drug was found to be highest at turret (5.166 µg/swab) but within the ARL value i.e., 24.2µg/swab (table 14, 15; fig. 4).

Table 12: Chemical inspection results of various steps and time of cleaning on turret

Active drug content (µg/ml)
Sampling location Initial after tablet production
TCM-04 44.43
45.68
45.218
Avg. (n=3) 45.11

TCM-04= turret; IPA=isopropyl alcohol, each measurement was repeated three time independently. (n=3)

Table 13: Chemical inspection results of various steps and time of cleaning on different parts of tablet compression machine

Active drug content (µg/ml)
Sampling location Initial after tablet production After wiped with dry cloth After rinse with potable water After rinse with purified water for 3 min
2 min 4 min 6 min
22.56 11.15 6 5.062 4.593 4.281
23.34 13.18 6.312 7.25 4.281 2.406
23.81 12.87 6.312 5.062 3.968 2.562

Average

(n=3)

 23.23 12.40 6.208 5.791 4.280 3.083
TCM-02 43.65 10.06 6.312 6 3.187 2.25
44.59 10.84 6.156 5.531 3.5 2.875
44.75 11.78 7.093 4.75 4.437 3.5

Average

(n=3)

 44.33 10.89 6.520 5.427 3.708 2.875
TCM-03 16.15 9.593 8.031 3.968 3.5 2.406
17.25 11 9.125 3.968 3.812 1
16.62 11.93 9.75 3.187 4.437 1.156

Average

(n=3)

 16.67 10.84 8.968 3.707 3.916 1.520
TCM-05 33.96 21 5.531 5.218 3.656 2.562
34.28 22.40 6.468 4.437 3.343 3.031
34.43 21.62 6 4.281 3.968 2.875

Average

(n=3)

 34.22 21.67 5.999 4.645 3.655 2.822

TCM-01= hopper top cylinder; TCM-02=hopper middle cone; TCM-03= hopper discharge chute; TCM-04= turret; TCM-05=chute, each measurement was repeated three time independently. (n=3)

Table 14: Visual inspection results of tablet compression machine after cleaning

S. No. Areas for visual observation Visually clean: Yes/No (n=3)
Batch-1 Batch-2 Batch-3
1. Doors Yes Yes Yes
2. Hopper Yes Yes Yes
3. Turret Yes Yes Yes
4. Discharge chute Yes Yes Yes

Each measurement was repeated three time independently. (n=3)

Table 15: Chemical inspection results of tablet compression machine after cleaning

S. No. Sampling location Active drug content (µg/swab) (n=3)
Batch-1 Batch-2 Batch-3
1. TCM-01 4.281 2.406 2.562
2. TCM-02 2.25 2.875 3.5
3. TCM-03 2.406 1 1.156
4. TCM-04 4.75 5.687 5.062
5. TCM-05 2.562 3.031 2.875

TCM-01= hopper top cylinder; TCM-02=hopper middle cone; TCM-03= hopper discharge chute; TCM-04= turret; TCM-05=chute, each measurement was repeated three times independently. (n=3)


Fig. 5: Comparation of chemical residue content of three batches at various locations of tablet compression machine after cleaning, TCM-01= hopper top cylinder; TCM-02=hopper middle cone; TCM-03= hopper discharge chute; TCM-04= turret; TCM-05=chute

Hence the developed cleaning method removes even traces of residue of drug present on the instrument. Analytical method developed was found to be linear, precise, accurate and sensitive to detect even small quantity of drug residue in view of cleaning validation. Cleaning standard operating procedure provides sufficient removal of the residues from equipment surfaces and totally excludes the risk of cross contamination.

CONCLUSION

Cleaning procedure was optimized by changing the variables and determination of drug residues on different parts of tablet machine in different steps of cleaning. Cleaning validation was executed on tablet compression machine. Three consecutive batches of aripiprazole tablets were formulated for cleaning validation study. The chemical residue of the drug at various parts of the equipment surfaces was found within the predefined acceptance criteria.

Swab sampling and UV method were developed and validated for the quantitative estimation of aripiprazole residues on stainless steel surfaces of plant equipment after manufacturing of aripiprazole 10 mg uncoated tablets to demonstrate cleaning validation. Methods with appropriate swab wipe procedure were found to be selective, accurate, precise and linear. No interference from swab solution was observed and samples were stable during analysis for residual estimation. Hence, the results obtained confirm that the cleaning procedures used are able to remove residues from equipment surfaces and well below the calculated limit of contamination.

The swab sampling and UV method can be used in other pharmaceutical quality control laboratories to apply successfully in cleaning validation for quantitative estimation of aripiprazole residues after manufacturing of aripiprazole uncoated tablets.

CONTRIBUTION

Ms. Sukhpreet Kaur (Research Scholar) performed practical work. Ms. Indu Bala has supervised the practical work and compiled it. Dr. Anjoo Kamboj has helped in the compilation of results and prepared the manuscript. Dr. Upendra K Jain has worked as an overall supervisor.

CONFLICT OF INTERESTS

Declared none

REFERENCES

  1. Agalloco J. Points to consider in the validation of equipment cleaning procedures. J Pharm Sci Tech 1992;46:168-75.
  2. Venugopal S. Designing of cleaning validation program for active pharmaceutical ingredients. World J Pharm Res 2014;3:3819-44.
  3. FDA. Guide to inspections of validation of cleaning processes; 1993.
  4. Leblan C, Destin A. Establishing scientifically justified acceptance criteria for cleaning validation of finished drug products. AAPS PharmSciTech 1998;22:136-48.
  5. Appleby C. Principal of cleaning validation. Global Quality Operation; 2010. p. 1-24.
  6. Lodhi B, Padamwari P, Patel A. Cleaning validation for the pharmaceuticals, biopharmaceuticals, cosmetic and nutraceuticals industries. J Innovations Pharm Biol Sci 2014;1:27-38.
  7. Grobin AW. Cleaning verification/validation of pharmaceutical manufacturing equipment from a laboratory perspective. Southern California Pharmaceutical Discussion Group; 2013.
  8. Mollah AH. Cleaning validation of biopharmaceutical manufacturing at Genentech, Inc. Part 2. Biopharm; 2008. p. 21.
  9. Pawar HA, Banerjee ND, Pawar S, Pawar P. Current perspectives on cleaning validation in the pharmaceutical industry: a scientific and risk-based approach. Int J Pharm Phytopharm Res 2011;1:8-16.
  10. Kumar S, Bharat P. A review on the concept of cleaning validation in pharmaceutical industry. Int Res J Pharm 2012;3:17-9.
  11. Waghmare PV, Chinchole AS, Poul BN, Bhusnure OG. A brief review on cleaning validation and its significance in pharmaceutical industry. Int J Pharm Sci 2013;4:165-92.
  12. Ghosh A, Dey S. Overview of cleaning validation in pharmaceutical industry. Int J Pharm Quality Ass 2010;2:26-30.
  13. APIC. Cleaning validation in active pharmaceutical ingredient manufacturing plant. A guide to Cleaning Validation in API Plants; 1999.
  14. Asgharian R, Hamedani FM, Heydari A. Step by step how to do cleaning validation. Int J Pharm Sci 2014;5:3345-66.
  15. Ravichandran V, Shalini S, Sundram KM, Rajak H. Validation of analytical methods–strategies and importance. Int J Pharm Pharm Sci 2010;2:18-22.
  16. Daksh S, Goyal A, Pandiya CK. Validation of analytical methods–strategies and significance. Int J Res Dev Pharm Sci 2015;4:1489-7.
  17. Lavanya G, Sunil M, Eswarudu MM, Eswaraiah MC, Harisudha K, Naga B. Analytical method validation: an updated review. Int J Pharm Sci Res 2013;4:1280-6.
  18. ICH. Harmonised tripartite guideline, validation of analytical procedures, text and methodology Q2 (R1); 2005.
  19. Geetha G, Karanam NGR, Kumar BV, Raja MG. Analytical method validation: an updated review. Int J Adv Pharm Biol Chem 2012;1:64-71.
  20. Yanamadala G, Gupta VR, Kumar PP, Lavanya N. Cleaning validation for residual determination of valganciclovir hydrochloride on stainless steel surface of pharmaceutical manufacturing equipment using HPLC-Dad method. Int J Res Pharm Chem 2013;3:782-9.
  21. Patel S, Kamath K, Shabaraya R. Evaluation of cleaning method validation techniques of ciprofloxacin. Int J Pharm Chem Sci 2012;1:1118-27.
  22. Sandeep K, Induri MSR, Sudhakar M. Validated spectro-photometric quantification of aripiprazole in pharmaceutical formulations by using the multivariate technique. Adv Pharm Bull 2013;3:469-72.
  23. Kathiresan K, Prathyushal Y, Moorthil C, Sha NAD, Krishnan K, Manavalan R. Cleaning validation of ibuprofen and methocarbamol tablets. Int J Drug Dev Res 2011;3:300-6.
  24. Dhoka MV, Vaidya PD, Pande AV, Arora AA. Development and validation of analytical method for estimation of cefixime in swab samples. Int J Chem Tech Res 2010; 2:1918-23.
  25. Rubashvili I, Karukhnishvili N, Loria K, Dvali N. Cleaning validation for estimation of active ingredients’ residues of vicazid uncoated tablets (pyrantel 100 mg/mebendazole 150 mg) on surfaces of pharmaceutical manufacturing equipment using swab sampling and HPLC method. Int J Pharmacol Pharm Sci 2015;7:158-69.
  26. Ivaturi KV, Yu SK, Mulla U, Reddy M. Method development and validation of cleaning procedure for fenbendazole residual determination in manufacturing. Asian J Plant Res 2016;9:316-29.
  27. www.tabletpress.co.in/tabletpress_mini_singlerotary.html. [Last accessed on 20 May 2016]
  28. Theivarasu C, Ghosh S, Indumathi T. UV spectrophotometric determination of carvedilol in pharmaceutical formulations. Asian J Pharm Clin Res 2010;3:64-8.
  29. https://en.wikipedia.org/wiki/Aripiprazole. [Last accessed on 20 May 2016]

How to cite this article