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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.
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
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
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.
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
Visual inspection
Visual inspection was done after cleaning of the equipments shows that there was no visual
evidence of the residues.
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.
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.
REFERENCE
1. I.R. Berry and R.A.Nash, Pharmaceutical Process Validation, Marcel Dekker, New York,
p.500, 541(2003).
2. J.A. Thomas, J. Validation Technol., 6, 522 (2000).
3. R.J. Forsyth and D.V.Haynes, Pharm. Technol., 22, 104 (1998).