Cleaning Validation of Paracetamol Tablets as a Dosage Formulation

 

Hapse  S.A.*, Bhagat B.V., Wagh V.S. and Kadaskar P.T.

Department of Quality Assurance Technique, Padmashree Dr. Vithalrao Vikhe Patil College of Pharmacy, Ahmednagar. Maharashtra.  414111.

 

ABSTRACT:

Cross1 contamination is one of the major problems focused in manufacturing of drugs utilizing common facility which leads to inferior quality of final product and cause considerable loss to the company. Contamination of one batch product with significant levels of residual active ingredients from a previous batch and contamination by microorganisms are the real concern. Cleaning and decontamination is one of the major and critical activity in pharmaceutical operations. The concept of purity and safety are directly related to the cleaning operations. Cleaning programmers are necessary simply to prevent our manufactured products from being contaminated. These  are cross-contamination of one product into another , product contamination by a foreign material and microbial contamination   The cleaning validation is a documented process that proves the effectiveness and consistency cleaning of pharmaceutical equipments to meet the regulatory requirements. Manufacturing of paracetamol and other tablets utilizing common facility, where paracetamol could be a possible cross contaminant. Hence the present study was carried out to validate the cleaning activity from both regulatory and quality prospective. Visual inspection, Swab sampling for chemical residue and for microbiological analysis were carried out to validate cleaning activity and results from all methods were complying with acceptance criteria.

 

KEYWORDS: Paracetamol, sodium lauryl sulphate; Cross contamination; Cleaning validation

 

 

INTRODUCTION:

Pharmaceutical2 products could be contaminated due to several factors such as cleaning agents, microorganisms, dust and particulates, product residue, etc. The objective of cleaning validation is to provide documented evidence that specific cleaning process will consistently clean to predetermined limits to prevent contamination that could adversely affect the safety, efficacy, purity and quality of the products. The objective of Cleaning Validation of Equipment, utensils and components is to establish sufficient documented evidence to assure that the cleaning procedures can reproducibly remove residue of the product being handled below established acceptance limit. The quantity of residue of the previous product if, within the acceptance limit will not affect quality and Safety of the subsequent product to be manufactured by using same equipment and facility. The possible contaminants may be product residues, cleaning agent residues and breakdown, airborne matter, lubricants, ancillary material, decomposition residues, bacteria, mould and pyrogens3. Cross contamination with active ingredients is a real concern. The Code of Federal Regulations states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug . It is necessary to have effective cleaning programs in place because of the regulatory requirements.. Cross contamination is usually through an active ingredient from one product carrying over into subsequent manufactured product.


However, carryover of other product components such as excipients can also be problematic and may degrade the final quality of product. Contamination of one batch of product with significant levels of residual active ingredients from a previous batch obvious problems posed by subjecting consumes or patients to unintended contaminants. Manufacturing of Paracetamol tablets 500 mg and other tablets using common facility, where paracetamol could be a possible cross contaminant. Hence the present study was carried out to validate the cleaning activity from both regulatory and quality prospective.

 

EXPERIMENTAL:

Cleaning of equipments:4

The equipments were cleaned with purified water as cleaning agent and then with 2% sodium lauryl sulphate in water as cleaning agent as the Paracetamol is sparingly soluble in water. Hence the residue level of product changeover for above products was considered to Paracetamol with respect to dosage strength and solubility criteria. The compression machine (LABPRESS )is cleaned in place with certain parts like hopper, feeder, feeder plate, punches and dies were cleaned out of place with water pre rinse and then washed with 2% SLS, finally rinsed with purified water and dried off with compressed air.

 

Visual inspection:

Equipments were cleaned using water and after cleaning, equipments were visually checked for presence of residues.

 

Swab Sampling for chemical residue5 :

After cleaning, equipments were visually inspected before any sampling and swab was collected using direct surface sampling or swab sampling. In this use 0.5’’, polyester, polypropylene swab stick for swab sampling. Take sufficient quantity of swab stick in a beaker and wash them thoroughly by soaking in 10 ml (for each swab) of swabbing media (to be used for swab sampling).Repeat the washing 10 times by discarding the wash every time and dry at 40°C.Wear the hand gloves and take the pretreated swab in a test tube bearing identification  label and 10 ml of swabbing media. Allow the pretreated swab to soak completely in the swabbing media. Take out the swab from swabbing media and squeeze the tip against inner surface of the test tube to remove excess swabbing media in such a manner that excess swabbing media drips inside the test tube. Hold the stem of swab and wipe the hard to clean identified surface area of individual equipment, of 4 square inch with 5 firm unidirectional, horizontal strokes as illustrated in figure No.1 without touching head of the swab. Use SS frame to cover the 4 square inch area. At the end of each stroke, lift the swab carefully. Do not swab the area in a zigzag or random manner. Place the swab in the respective test tube, rotate it for 1-2 minutes and squeeze the tip of the swab against inner surface of the test tube to remove excess swabbing media in such a manner that excess swabbing media drips inside the test tube. Hold the stem of swab and wipe the same test surface area, of 4 square inch with 5 firm unidirectional, vertical strokes as illustrated in figure No.1 and 2

 

 

 

At the end of each stroke, lift the swab carefully. Place the swab in the respective test tube, rotate it for 1-2 minutes and squeeze the tip of the swab against inner surface of the test tube to remove excess swabbing media in such a manner that excess swabbing media drips inside the test tube, mix well. In case of uneven surfaces / contours swab an approximate 4 sq. inch area. If any organic solvent is used as swabbing media, then wipe the swabbed surface area of equipment with lint free cloth soaked in purified water and then using dry lint free cloth. After collecting the swab, close the test tube properly with paraffin film and send it in the laboratory for testing. Analyse the sample as per respective Standard Test Procedure. Record the collection of sample in the individual protocol. The swabbing pattern is as per displayed in figure no.1 and figure no.2.The actual swab along with swabbing technique is shown in figure 3 and 4..

(a)

(b)

Fig (3) :Spectra of swab sample of Turret  1(a) and Rinse sample of  chute2,(b)scanned in the range 200-400nm

(c)

 (d)

Fig(4) Spectra of swab sample of Hopper1(c) and Rinse sample of Lid 2 (d)scanned with in range of 200-  400nm

 

Rinse sampling6:

Large area or parts of equipment which could not be swabbed should be rinse sampled or directly extracted by solvents. Tubes, nozzles, pipes or containers with surfaces those are not reasonably accessible for direct surface sampling have to be rinsed with a solvent. The compound to be sampled should be freely soluble in the solvent. In this use clean and dry conical flask for collection of rinse sample. Flush the equipment with required quantity of water. During flushing collect about 50 ml of rinse water for analysis for content of previous product. Close the flask properly with paraffin film and send it in the laboratory for testing. Analyze the sample as per respective Standard Test Procedure. Record the collection of sample in the individual protocol.

Results of chemical residues-Table no.1

S. No.

Equipments

Sampling Point

Observations (ppm / swab)

1

Labpress rotary tablet press machine

(8 station)

Turret (location - I)

2.06

Turret (location - II)

4.74

Discharge port - I

4.14

Feeder frame - I

3.52

Hopper - I

4.04

Hopper lid- I

4.00

2

Tablet Deduster

Machine

 

Charging port

4.38

Spiral assembly

4.40

Discharge port 2.6

2.77

Inner Surface - Hose pipe - II (White)

1.5

3

Metal Detection

Machine

Discharge chute 3.

1.30

Machine Inlet chute

2.55

 

Table no:2 Result of microbiological assay

Sr. no

Equipment

Sampling point

Observations 

(CFU/Swab)

TCMY and

Pathogens

1

Labpress Rotary Tablet Press Machine(8 Station)

Turret(location 1)

03

NIL

Turret(location 2)

04

NIL

Discharge port-1

02

NIL

Feeder frame -1

05

NIL

Hopper-1

05

NIL

Hopper lid-2

07

NIL

Inner surface of hose pipe-1

05

NIL

2

Tablet Deduster Machine

Charging port

05

NIL

Discharge port

04

NIL

Inner surface hose pipe

05

NIL

3

Metal Detection Machine

Discharge chute

06

NIL

Inlet chute

05

NIL

(e)                                                                                                        (f)

Fig (5)Spectra of swab sample of discharge chute(e) and swab sample of feeder frame(f)

 

Acceptance7 criteria were calculated using 0.001 dose criterions and 10 ppm criterions. The maximum allowable carryover obtained was 34.88 ppm/swab and 158. 3 ppm/ swab by 0.001 dose criterions and 10 ppm criterions respectively. The minimum/low level value (34.88 ppm/swab) obtained was taken as an acceptable limit for residue carryover after manufacturing of Paracetamol 500mg tablets.

 

SWAB Sampling for microbiological analysis9:

Sterile swab was used for swabbing. Swab samples were collected from the measured surface areas of the equipments which was different from area for chemical residue testing. The swab area was around 10 cm x 10 cm10. After swab sampling, each swab sample was placed inside a properly labeled and sealed sterile test tube and analyzed for aerobic microbes, mold, yeast and pathogens using established methods. After swab sampling, swab area was sanitized with 70% isopropyl alcohol.

 

RESULTS AND DISCUSSION:

Visual inspection:

Visual inspection was done after cleaning of the equipments shows that there was no visual evidence of the residues.

 

Swab Sampling for chemical residue:

The maximum and minimum carryover of paracetamol was found to be 8.77 ppm / swab and 1.30 ppm / swab respectively which were less than acceptance criteria. The results of chemical residue are as in Table 1.

 

Swab Sampling for microbiological analysis:11

The maximum and minimum total aerobic microbial count was found to be 7 CFU / swab and 3 CFU / swab respectively which were less than acceptance criteria. Total combined molds and yeast count was found to be nil and pathogens were absent at all sampling points. The results of microbiological analysis were tabulated in Table- 2.

 

CONCLUSION:

The cleaning validation studies of Paracetamol 500 mg tablet was observed by Visual inspection, swab sampling for chemical residue and swab sampling for microbiological analysis. The result showed that there were no visual residues on the equipments and chemical residues were below acceptance criteria The total aerobic microbial count were below acceptance criteria and total combined molds and yeast count was nil and pathogens were absent.

 

REFERENCES:-

1.        Galatowitsch S. The Importance of  Cleaning Validation. Cleanrooms. 2000; 14(6): 19-22.

2.        Parenteral Drug Association. Points to  Consider for Cleaning Validation. Technical Report No. 29, 1998.

3.        Cleaning Validation in Active  Pharmaceutical Ingredient manufacturing  plants by Active pharmaceutical  ingredients committee. September 1999.

4.        FDA, Guide to inspections of validation  of cleaning process division of  investigations, Office of regional  operations and Office regulatory affairs. July 1993.

5.        Gavlick WK, Ohlemeier LA, Kaiser HJ. Analytical Strategies for Cleaning Agent  Residue Determination. Pharm Tech.  1995; 19: 136-144.

6.        Kaiser HJ, Tirey JF, LeBlanc DA   Measurement  of  Organic and Inorganic  Residues Recovered from Surfaces. J  Valn Tech. 1999; 6(1): 424-436.

7.        I.R. Berry and R.A.Nash, Pharmaceutical Process Validation, Marcel Dekker, New York, p.500,    541(2003)

8.        J.A. Thomas, J. Validation Technol., 6, 522 (2000)

9.        R.J. Forsyth and D.V.Haynes, Pharm. Technol., 22, 104 (1998)

10.     José A. Morales Sánchez, BioPharm International, 19, 1 (2006)

11.     A. Hamid Mollah, BioPharm International, 21, 1 (2008).

 

Received on 02.08.2011

Accepted on 30.08.2011        

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(5): Sept.-Oct. 2011, 215-219