process validation of pyrazinamide

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PROCESS VALIDATION OF PYRAZINAMIDE 750mg TABLETS Presented By, M.Vamsi Krishna M. Pharm (Industrial Pharmacy) (Reg no:08601038) Under the Guidance of, Mr. V.V.VENKATACHALAM M. Pharm., Reader in pharmacy, Department of Pharmacy, Annamalai University, Annamalai Nagar.

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INTRODUCTION DEFINITION * Establishing Documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. # Validation has action proves that any procedure, process, equipment material, activities or system actually leads to expected results. * US FDA # WHO

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AIM AND OBJECTIVE AIM: To validate the manufacturing process of Pyrazinamide 750mg tablets. OBJECTIVE : To provide assurance that the manufacturing procedure is suitable for intended purpose and consistently meet predetermined specifications and quality attributes, as per specified master formula record.

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To provide documented evidence for the operation sequence and schedule of manufacturing process and to determine the critical parameters and variables in the process of manufacturing of Pyrazinamide 750mg tablets.

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VALIDATION CLASSIFICATION Types of validation Prospective validation Retrospective validation Concurrent validation Process re-validation

ADVANTAGES OF VALIDATION : 

Increased output Reduction in rejections and reworking Reduction in utility cost Avoidances of capital expenditures Reduced testing in-process and in finished goods Easier maintenance of equipment ADVANTAGES OF VALIDATION

BATCH PROFILE : 

Drug : pyrazinamide 750mg I.P Category : antituberculosis No of Batches : 3 Batch size : 2.0 x 100000 Tablets Packing : 10’s blister packing Shelf Life : 24 Months BATCH PROFILE

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PLAN OF WORK   Identification of critical process Preparation of flow chart Challenging the identification variable Preparation of validation protocol Conduct the process validation as per the protocol The challenge variable are checked and to be documented(validation report)

DRY MIXING : 

Mixing is a process that tends to result in a randomization of dissimilar particles on the system. Active ingredients along with diluents are to be well mixed to ensure good distribution. The variables checked in this stage are: - Volume occupancy. Bulk density of dry mix sample. Content uniformity of the dry mix at different time intervals. 28 min,30min. DRY MIXING

PASTE PREPARATION : 

Variables checked at this stage: Water temperature before addition of propyl paraben, methyl paraben starch. Clarity of the solution. Paste temperature before addition to dry mix. PASTE PREPARATION

Wet mixing : 

the prepared binder paste is added to the dry mix in planetary mixer, mixed for 1 minutes at slow speed and continued mixing for 2 minutes at high speed. Pass the wet through multimill using 8mm S.S.sieve. Variables checked in this stage Wet mixing time Mixer speed Loss on drying of wet granules Wet mixing

DRYING : 

The wet mass dried in FBD at a temperature of 50o c for about 45 minutes or in a tray drier at a temperature of 50o c for 8 hours till the LOD of the granules is less than 3.0%sieve the dried trough multi mill using 3.0 S.S. sieve. The variables checked at this stage are: Time taken to attain the in-let temperature. Temperature at the end of drying. In-let and out-let temperature at the end of drying. Airflow and % opening of flap. Total drying time. DRYING

BLENDING : 

In any blending operation, both the segregation and mixing take place simultaneously. Both the process are function of particle size, shape, and density and of the dynamics of the mixing action. Therefore the characteristics of the different particles to be helps to make a full-production operation successful and more efficient. Sifted granules are loaded in a clean and dry S.S planetary mixer for 30 minutes. The variables recorded at this stage are: Volume occupancy of the granules in the mixer. Mixer speed/RPM. Tapped density and untapped density. Particle distribution using #20, #40, #60, #80, and#100 sieves. Loss on drying of the lubricated granules (not more than 3.5%). BLENDING

COMPRESSION : 

During the compression the compression machine performs the following. Filling of empty die cavity with granules. Pre-compression of granules. Compression of granules. Ejection of the tablet from the die cavity and take off compressed tablet. Compression about 10kg of granules each at. Lower hardness (about 5kg/sq.cm)/higher thickness (about6.4mm) Target hardness (about 7kg/sq.cm)/ Lower thickness (about6.1mm) Higher hardness (about9.5kg/sq.cm)/lower thickness (about6.1mm) COMPRESSION

COMPRESSION : 

Compressed about 10kg of granules each at. Slow speed (10 RPM) Medium speed (20RPM) High speed (28 RPM) COMPRESSION

PACKING : 

Leak test. Random samples after final packing are collected and checked for the physical defects of the tablets. PACKING

The result for pre compression was within range, according to specification : 

1. Group weight of 20 tablets 15.60g±2.5%(15.99 -15.21) 2. Thickness (mm) 5.9 to 6.5mm  3.Hardness Not less than 5kg/sq.cm 4. Friability Not more than 3% w/w 5.Dissolution (By UV) Not less than 80.0% in 30 min. 6.Assay (By UV) Each un coated tablet contains Pyrazinamide: 735mg -765mg The result for pre compression was within range, according to specification

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Graphical representation of dissolution profile

CONCLUSION : 

Dry mixing time Based on the results of the content uniformity for the sample collected from planetary mixer at predestinated location at different intervals of 28, 30, and 32 minutes, the predetermined dry mixing time of 30minutes, is thus validated, results are satisfactory. Blending time Based on the results of content uniformity for the sample collected from octagonal blender at predesignated location at different intervals of 25, 30 and 35 minutes, the predetermined blending time of 30 minutes, is thus validated, parameters were found to be appropriate and meet the acceptance criteria. CONCLUSION

CONCLUSION : 

Compression parameters Based on the in-process compression parameters were found to be appropriate and meet the acceptance criteria In process parameters, dissolution profile Based on the, monitoring and recording in process compression parameters for the samples collected at the machine speed 10, 20,and 28 RPM, the minimum and maximum speed 10 and 28 and RPM respectively are validated. CONCLUSION

CONCLUSION : 

As the indirect method of finding the optimum force is correlating the same with thickness/hardness, which in turn has the direct effect on the in process compression parameters the force, which gives the hardness of NLT 5kg/sq.cm, is thus validated. CONCLUSION

CONCLUSION : 

The manufacturing process consistently yielded a product which is in conformance with the approved finished product specification. All the key process parameters are studied and found acceptable for the manufacture of PYRZINAMIDE 750 mg Tablets. Thus the manufacturing process of PYRZINAMIDE 750 mg Tablets is successfully stands validated. CONCLUSION

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Thank you