International Journal of Drug Development and Research

Key words

Ibuprofen, Methocarbamol, Cross Contamination, Cleaning Validation.

INTRODUCTION

Contamination of pharmaceutical product with other pharmaceutically active ingredients and microorganisms are the real concern which questions the integrity and safety of the pharmaceutical product. Drug tragedy of sulfanilamide elixir which killed over 100 people is a classical example of pharmaceutical contamination. In most cases contamination of pharmaceutical products occurs when a common facility is utilized to manufacture many products. Hence regulatory agencies such as the Unites States Food and Drug Administration (USFDA), European Medicinal Evaluation Agency (EMEA), Australia's Therapeutic Goods Administration (TGA) established requirements for cleaning of such instruments/ facility. For example, Code of Federal Regulations (CFR) Title 21, Volume 4, Section 211.67, states: "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" and additionally, Section 211.182 requires that cleaning procedures must be documented appropriately, and that a cleaning and use log should be established [1]. The most common and practical solvent is water being non-toxic, economical, environment friendly and does not leave any residues. Alkaline and acidic solvents are sometimes preferred as it enhances the dissolution of the material, which are difficult to remove; detergent which acts in four ways as wetting agent, solubilizer, emulsifier and dispersant in removing the residues and contaminants from the equipment; and chemical reaction which refers to oxidation and hydrolysis reaction which chemically breaks the organic residues and contaminant to make them readily removable from the equipment. Cleaning should be followed by validation which is documented evidence with a high degree of assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits and ensure no risks are associated with cross contamination of active ingredients or detergent/sanitizer [2, 3].

Production of tablet with Ibuprofen 200 mg and Methocarbamol 500 mg in a common facility, where Ibuprofen and Methocarbamol could be a possible cross contaminant. Hence the present study was carried out to validate the cleaning activity of Ibuprofen and Methocarbamol.

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 200 mg and Methocarbamol 500 mg. However, Ibuprofen is highly soluble in alcohol and Methocarbamol is sparingly soluble in water. Hence the residue level of products changeover for above products were considered to be both Ibuprofen and Methocarbamol with respect to dosage strength and solubility criteria and the validation of cleaning activity was carried out by visual inspection, swab sampling for chemical residue and swab sampling for microbiological analysis.

Visual inspection

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 mcg of drugs in which most products are visible.

Swab sampling for chemical residue [

After cleaning, equipments were visually inspected before sampling. As the Ibuprofen and Methocarbamol are highly soluble in alcohol, swabs were soaked in methanol and samples were collected using 15 parallel and 15 horizontal strokes from the surface of the equipments. Swab sampling was done from pre-determined measured locations. The swab area was around 10 cm x 10 cm (4 inch square). The drug content of the swab samples were analyzed using validated analytical method.

Acceptance criteria for chemical residue

The maximum allowable carryover obtained was 541.24 ppm/swab and 129.9 ppm/swab by 0.001 dose criterions and 10 ppm criterions respectively. The minimum/low level value (129.9 ppm/swab) obtained was taken as an acceptable limit for residue carryover after manufacturing of Ibuprofen 200 mg and Methocarbamol 500mg tablets.

Swab sampling for 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 10 cm x 10 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 50 Colony Forming Unit (CFU) per swab and Total Combined Molds and Yeast Count (TCMY) should not be more than 50 CFU per swab. Testing for pathogens should be nil.

RESULTS AND DISCUSSION

Visual inspection

Visual inspection was done after cleaning of the equipments and there were no visual evidence of the residues and complies with the acceptance criteria. Summary of visual inspection observations are listed in table 1.

Swab sampling for chemical residue

The maximum residual content was found to be 9.98 ppm / swab at Spiral chute of matcon bin and minimum residual content was found to be 0.51 ppm/ swab at charging port of tablet deduster machine. Hence the swab sampling for chemical residue complies with the acceptance criteria and found satisfactory. Summary of swab sampling for chemical residue observations are listed in table 2.

Swab sampling for microbiological analysis

The maximum total aerobic microbial count was found to be 14 CFU/ swab at external surface area of matcon bin and the minimum total aerobic microbial count was found to be 3 CFU/ swab at discharge chute of metal detection machine. Total combined molds and yeast count and pathogens were found to be nil. Hence the swab sampling for microbiological analysis complies with the acceptance criteria and found satisfactory. Summary of swab sampling for microbiological analysis observations are listed in table 3.

CONCLUSION

The cleaning validation of Ibuprofen and Methocarbamol tablets were observed by visual inspection, swab sampling for chemical residue and swab sampling for microbiological analysis. Upon the compiled data, it was concluded that the train of equipments in tablet manufacturing block is completed and the results were found to be satisfactory and there is no chance of cross contamination with Ibuprofen and Methocarbamol to next product.

Conflict of Interest

NIL

Source of Support

NONE

Tables at a glance

Table 1 Table 2 Table 3

Figures at a glance

References

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