WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Bhusnure et al. World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 2.786

Volume 3, Issue 7, 872-880. Research Article ISSN 2278 4357

CLEANING VALIDATION OF IBUPROFEN ORAL SUSPENSION

Bhusnure O.G.*, Ansari M.M.AW, Gholve S.B., Kazi P.A.

Channabasweshwar Pharmacy College, Depart. of Quality Assurance, Latur(MS), India.

ABSTRACT
Article Received on
22 April 2014, The cleaning validation is to verify the effectiveness of the cleaning
Revised on 20 May
2014, procedure for removal of product residues, degradation products,
Accepted on 09 Jun 2014
preservatives, excipients and cleaning agents so that the analytical
monitoring may be reduced to a minimum in the routine phase. In
*Author for Correspondence addition one need to ensure there is no risk associated with cross
Dr. Bhusnure O.G.
contamination of active ingredients. Cleaning validation is intended to
Channabasweshwar Pharmacy
College, Depart. of Quality
address special consideration and issues pertaining to validation
Assurance, Latur(MS), India. cleaning procedures for equipment used in the manufactured of
pharmaceutical products, radiopharmaceuticals, and biological drugs.
Cross 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.
The cleaning validation is a documented process that proves the effectiveness and
consistency cleaning of pharmaceutical equipments to meet the regulatory requirements.
Manufacturing of Ibuprofen oral suspension and utilizing common facility, where Ibuprofen
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 for two Mfg. batches were
carried out to validate cleaning activity and results from all methods both batches were
complying with acceptance criteria.

Keywords: Ibuprofen Oral Suspension; Cross Contamination; Cleaning Validation.

INTRODUCTION
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

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intervals to prevent malfunctions or contamination that would alter the safety, identity,
strength, quality, or purity of the drug product beyond the official, or other established
requirements. Cleaning validation is a documented process that proves the effectiveness and
consistency in cleaning of pharmaceuticals equipment. It is necessary to have effective
cleaning programs in place because of the regulatory requirements. However, more
fundamental reason and that is a moral requirement to produce products that are as pure and
free from contaminations to the extent that is possible and feasible. Cross contamination and
contamination by foreign material are two types of contamination. 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.
Potential clinically significant synergistic interaction between pharmacologically active
chemicals is a real concern. Inter ingredients used in drug product are generally recognized as
safe or have been shown to be safe for human consumption, the routine use; maintenance
and cleaning for equipment provide the potential for contamination with such items as
equipment parts and lubricants. Chemical cleaning agents and piece of cleaning tools such as
brushes or rags can cause problems ranging from poor pharmaceutical elegance to exceeding
acceptable levels of particulate matter in pharmaceutical products. In addition, some actives
are adversely affected by trace contaminants and may exhibit change in stability or
bioavailability if exposed to such contamination. The second type of contamination is by
foreign material these may be bacterial in nature or could represent parts of the equipment
such as gasket or lining. Maintenance, cleaning and storage condition may provide
adventitious microorganism with the opportunity to proliferate with in processing equipment.
1-5

Cleaning is a challenging task and the design of the cleaning system depending upon the
equipment use (dedicated/multipurpose), manufacture (continuous/batch), cleaning
equipment (manual/automated), preparation (commercial product/clinical supplies), product
formulation i.e., type of materials being removed from the surface, drugs (low risk/high risk),
sterile/non sterile, solids/liquids and solubility (soluble/insoluble) of active ingredients. An
acceptable cleaning system should incorporate the following elements.6-8

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Bhusnure et al. World Journal of Pharmacy and Pharmaceutical Sciences

Now-a-days pharmaceutical industries are increasingly using the multipurpose equipment and
automated clean-in-place procedures; it has become more important to establish evidence that
cleaning procedure is effective. Manufacturing of Ibuprofen oral suspension utilizing
common facility, where Ibuprofen oral suspension could be a possible cross contaminant.
Hence the present study was carried out to validate the cleaning activity from both regulatory
and quality prospective.

OBJECTIVE
To validate the cleaning activity of Ibuprofen oral Suspension from both regulatory and
quality prospective.
To provide documented evidence, so that this Ibuprofen oral suspension would give high
degree of assurance that this specific process will consistently produce meeting its
predetermined specification and quality characteristics.

MATERIAL AND METHODS

All chemicals and reagents used for cleaning validation were of analytical grade. The
instruments in the common facility were cleaned with purified water after production of
Ibuprofen oral suspension. However, Ibuprofen is practically insoluble in water, freely
soluble in acetone & an methanol. Hence the residue level of product changeover for above
products were considered to be both Ibuprofen oral suspension with respect to dosage
strength and solubility criteria and the validation of cleaning activity was carried out by
visual inspection, swab & rinse sampling for chemical residue and similarly swab & rinse
sampling for Microbiological analysis.

Visual inspection [9,10]

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

Acceptance criteria for visual inspection

No quantity of residue should be visible on equipment after cleaning procedure. Spiking
studies of drugs have been determined using 100 g of drugs in which most products are
visible.

Sampling for Chemical Residual Analysis

In order to evaluate a cleaning method it is necessary to sample the product contact surfaces

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of the equipment and establish the level of residuals present.

Swab Sampling Method

Swabbing is the most widely used sampling technique. Swabs may be saturated with solvent
such as methanol or alcohol, facilitating the solubilzation and physical removal of surface
residues. After cleaning, equipments were visually inspected before sampling. As the
Ibuprofen is highly soluble in methanol/alcohol, swabs were soaked in methanol and samples
were collected using 2 parallel and 2 horizontal strokes from the surface of the equipments.
Swab sampling was done from pre-determined measured locations. The swab area was
around 2 cm x 2 cm.

Rinse sampling Method

Used cleaned and dry glass bottle for collection of rinse sample for Ibuprofen analysis hold
the bottles as bottom under sampling grain value of the vessels and opened the cap, rinsed the
bottles for at least thrice with blank purified water 200ml, purified water rinse sample shall be
collected in previously clean bottles without leaving air space (for chemical analysis). Rinsed
the individual item with the required quantity of purified water to ensure that all product
contact surface area shall be covered during rinsing operation.
Closed the cap of bottles to highly & put as status label on it.
Transferred these bottles to quality control for analysis. Along with TRF mentioning
sample detail.
The acceptance criterion for rinse sample was 0.102mg/rinse.

Sampling for Microbiological analysis

Swab Sampling Microbiological analysis
Sterile swabs were used for sampling during microbiological testing. 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 2 cm x 2 cm. 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.

Acceptance criteria for microbiological analysis

Total Aerobic Microbial Count (TAMC) should not be more than(NMT) 50 Colony Forming
Unit (CFU) per swab and Total Combined Molds and Yeast Count (TCMY) should not be

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more than (NMT)50 CFU per swab. Total Aerobic Microbial Count (TAMC) should not be
more than (NMT)100 Colony Forming Unit (CFU) per rinse. Testing for pathogens should be
nil.

Table No.I: Swab Location Description (Sample locations for Ibuprofen residual
analysis & Microbial analysis)
Sample ID Location
C-1 & M-1 Inner side corner of dispensing scoop
C-2 & M-2 Side wall corner of material addition port of manufacturing tank
C-3 & M-3 Manufacturing tank outlet valve
C-4 & M-4 Inside the valve(before ventury and after pump)
C-5 & M-5 Ventury station from inside
C-6 & M-6 Before lobe pump of transfer line, at T joint (near TC clamp)
C-7 & M-7 In transfer line after filter housing at valve joint(TC clamp)
C-8 & M-8 Lobe pump behind and between the lobes
C-9 & M-9 From the filter bag net
C-10 & M-10 1200 L Premix tank outlet valve
C-11 & M-11 Side wall of 300 LSS vessels
C-12 & M-12 Below the blades of silverson Mixer GX-10
C-13 & M-13 Inner bottom side of work head of silverson mixer -DX
C-14 & M-14 Side wall of holding tank near product entry port
C-15 & M-15 Holding tank outlet valve
C-16 & M-16 Transfer Line corner near TC clamp
C-17 & M-17 Bottom side of three-way valve near TC clamp
C-18 & M-18 Inner side bottom corner of product buffer tank
C-19 & M-19 Chevron ring of filling piston
C-20 & M-20 Inner wall of filling needle

RESULT AND DSCUSSION

Sampling location of visual inspection of contact surface of equipments used for Mfg. of
Ibuprofen suspension is as per the Table No I

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

Swab & rinse sampling for chemical residue

All the carryover samples of contact surface of equipments, swab and rinse sampling found to
be less than acceptance criteria. The acceptance criteria for swab sampling and rinse sampling
were NMT 0.256 mg/swab & NMT 0.102 mg/ml respectively. Sampling locations are shown
in Table No-I & results of chemical residue shown in Table No.-II.

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Swab & rinse sampling for microbiological analysis

The maximum and minimum total aerobic microbial count for swab sampling of both batches
where found to be 26 cfu/swab and 17 cfu/swab respectively. Similarly for the rinse sampling
of both batches where maximum and minimum count where 23cfu/ml & 16cfu/ml
respectively. All the result of swab and rinse sampling of microbiological analysis where less
than acceptance criteria. Total combined molds and yeast count was found to be nil and
pathogens were absent at all sampling points. Sampling locations for Microbiological
Analysis are shown in Table-I & results of microbiological analysis is shown in Table No.-
III.

All the chemical & microbial samples were collected & analyzed as approved procedure &
result complies with specified acceptance criteria.

A direct surface sampling (swab sample) & also indirect sampling (rinse sample) were
performed as per procedure give in this approved protocol. All the said samples were
collected & tested for Evaluations of the result for the two batches were carried out by
chemical & microbial analysis. The result of both batches comply with specified acceptance
criteria. No deficiency was reported during cleaning validation execution of Ibuprofen oral
suspension.

Based on the review of test performance the result obtained for the cleaning validation
execution as per the procedure specified in this approved protocol. Prerequisites were verified
with respect to its availability & training found satisfactory.

Table No-II: Result of chemical residue

Sr. Equipment/Accessories Swab Applicability Result
No Name sample ID Swab Rinse Swab Rinse
number Batch I Batch Batch Batch
1. Ibuprofen dispensing scoop C-1 ND ND NA NA
2. 10 KL Manufacturing Tank C-2; C-3 ND ND ND ND
3. Ventury C-4 ;C-5 ND ND ND ND
4. Product Transfer Line (From
C-6 ;C-7 ND ND ND ND
manufacturing To Holding)
5. Lobe Pump C-8 ND ND NA NA
6. 1000 Micron filter bag C-9 ND ND NA NA
7. 1200 Lpremix tank C-10 ND ND ND ND
8. 300 LSSvessl C-11 ND ND ND ND
9. Silversion Mixer GX-10 C-12 ND ND NA NA
10. Silversion Mixer DX C-13 ND ND NA NA

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11. 10 KL holding tank C-14; C-15 ND ND ND ND

12. Product Transfer Line (from
C-16 ;C-17 ND ND ND ND
Holding to Filling)
13. Filling Machine product Buffer
C-18 ND ND ND ND
tank
14. Filling cylinder/piston C-19 ND ND NA NA
15. Filling needle/nozzle C-20 ND ND ND ND
NMT 0.256 NMT 0.102
Acceptance Criteria
mg/Swab mg/Rinse
ND=Not detected, NA=Not applicable

Table No-III: Result of Microbial Analysis

Sr. Equipment/Accessories Swab Applicability Result

No Name Sample ID Swab Rinse CFU/Swab CFU/ml (Rinse)
number Batch I Batch II Batch Batch
I II
19cfu/ 19cfu/
Ibuprofen dispensing scoop M-1 NA NA
swab swab
19cfu/ 19cfu/ 19cfu/ 19cfu/
10 KL Manufacturing Tank M-2; M-3
swab swab ml ml
M-4 24cfu/ 24cfu/ 17cfu/ 17cfu/
Ventury before ventury
swab swab ml ml
19cfu/ 19cfu/ 17cfu/ 17cfu/
Ventury section M-5
swab swab ml ml
M-6 17cfu/ 17cfu/ 18cfu/ 18cfu/
Product Transfer Line
swab swab ml ml
From manufacturing to 21cfu/ 21cfu/ 18cfu/ 18cfu/
M-7
Holding swab swab ml ml
23cfu/ 23cfu/
Lobe Pump M-8 NA NA
swab swab
25cfu/ 25cfu/
1000 Micron filter bag M-9 NA NA
swab swab
21cfu/ 21cfu/ 19cfu/ 19cfu/
1200 Lpremix tank M-10
swab swab ml ml
24cfu/ 24cfu/ 23cfu/ 23cfu/
10. 300 LSSvessl M-11
swab swab ml ml
25cfu/ 25cfu/
11. Silversion Mixer GX-10 M-12 NA NA
swab swab
20cfu/ 20cfu/
12. Silversion Mixer DX M-13 NA NA
swab swab
20cfu/ 20cfu/ 16cfu/ 16cfu/
M-14
swab swab ml ml
13. 10 KLholding tank
26cfu/ 26cfu/ 16cfu/ 16cfu/
M-15
swab swab ml ml

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Transfer Line corner near M-16 26cfu/ 26cfu/ 18cfu/ 18cfu/

14.
TC clamp swab swab ml ml
Bottom side of three way 21cfu/ 21cfu/ 18cfu/ 18cfu/
15. M-17
valve near TC clamp swab swab ml ml
20cfu/ 20cfu/ 22cfu/ 22cfu/
16. Product Buffer tank M-18
swab swab ml ml
17. Filling cylinder/piston M-19 ND ND NA NA
Filling needle/nozzle M-20 21cfu/ 21cfu/ 21cfu/ 21cfu/
18.
swab swab ml ml
NMT 50 NMT 100
Acceptance Criteria
CFU/Swab CFU/Rinse
ND=Not detected, NA=Not applicable, NMT= Not more than

CONCLUSION
The cleaning validation studies of Ibuprofen oral suspension was observed by visual
inspection, swab and rinse sampling for chemical residue and similarly swab & rinse
sampling for microbiological analysis. The result revealed that (1) There were no visual
residues on the equipments (2) Chemical residues were below acceptance criteria (3) Total
aerobic microbial count(TAMC) were below acceptance criteria (4) Total combined molds
and yeast count was Nil and (5) Pathogens were absent. Upon the compiled data, it was
concluded that the train of equipments in liquid manufacturing block is completed and the
results were found to be satisfactory and there is no cross contamination of Ibuprofen oral
suspension to next product. Based on the summary report & data obtained it can be concluded
that, the cleaning procedure used for the cleaning product contact surface of manufacturing &
filling equipments & utensils were found effective with respect to residue contaminants of
previous product & potential microbial contaminants.

AKNOWLEDGEMENT
The authors are very thankful to Wockhardt Limited, MIDC, Aurangabad, India for the
support, guidance and facility extended for this work. They are also grateful to the principal,
Channabasweshwar Pharmacy College, Latur(MS), India for allowing to carry out this work
at company.

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4. Jos A. Morales Snchez, BioPharm International, 19, 1 (2006).

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