Studies in Prospective Process Validation of Cimetidine Tablet Dosage Form

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1 Research Paper Studies in Prospective Process Validation of Cimetidine Tablet Dosage Form Vandana B. Patel l *, Minaxi R. Rathwa l and Kandarp Patel 2 1 Department of Quality Assurance, Baroda college of pharmacy, Vadodara, Gujarat, India 2 Department of Quality Assurance, Centurion Laboratories Pvt. Ltd., Vadodara, Gujarat, India. ABSTRACT The purpose of the research investigation was to study prospective process validation of Cimtidine 400 mg tablet dosage form. Quality cannot be adequately assured by in-process and finished inspections and testing but it should be built in to the manufacturing process. These processes should be controlled in order that the finished product meets all quality specifications. Therefore building of quality requires careful attention to a number of factors, such as the selection of materials, product and process design, control variables, in process control and finished product testing. The critical process parameters were identified with the help of process capability and evaluated by challenging its lower and upper release specifications. Three initial process validation batches of same size, method, equipment & validation criteria were taken. The critical parameter involved in sifting, dry mixing, preparation of granulating agent, wet mixing, wet milling, drying, sizing, lubrication & compression stages were identified and evaluated as per validation plan. Film coating of tablet were evaluated for coating uniformity, coating process efficiency and surface roughness. The spry rate, atomization air pressure, distance of nozzle from tablet bed, inlet air temperature, pan differential pressure,pan speed and % solid content these affect the final film quality of coated tablets. The outcome indicated that this process validation data provides high degree of assurance that manufacturing process produces product meeting its predetermined specifications and quality attributes. Key Words: Prospective Process validation, Cimetidine Tablet, Control variables. INTRODUCTION Validation Principles 1-11 The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. In order to meet this principle, a good understanding of the processes and their performance is important. Quality cannot be adequately assured by in-process and finished product inspection and testing but it should be built into the manufacturing processes. These processes should be controlled in order that the finished product meets all quality specifications. Therefore, building of the quality requires careful attention to a number of factors, such as the selection of quality materials/components, product and process design, control of processes, in-process control, and *Address for correspondence: vbpatel04@yahoo.com finished product testing. Careful design and validation of system and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications. As per the ICH guidelines defines as Process validation: Process validation is the means of ensuring and providing documentary evidence that processes within their specified design parameters are capable of repeatedly and reliably producing a finished product of required quality. Purpose Process validation is intended to establish that the proposed manufacturing process is a suitable one and yields consistently a product of the desired quality. i.e. that the process is suitable and under control. Vol. 2 (4) Oct Dec

2 Importance of Process validation The main advantages to be obtained from validation are assurance of quality and process optimization, both resulting in a reduction of total costs. Assurance of Quality Validation is an extension of the concepts of quality assurance since close control of the process is necessary to assure product quality and it is not possible to control a process properly without thorough knowledge of the capabilities of that process Without validated and controlled processes, it is impossible to produce quality products consistently. End product testing, in the absence of validation, gives little assurance of quality for variety reasons, among which are 1. Very limited sample size. 2. The limited number of tests performed on a sample. For example, it is impractical to test for all potential impurities or contaminants. 3. The limited sensitivity of the test. Process Optimization The optimization of a process for maximum efficiency, while maintaining quality standards, is a consequence of validation. Literal meaning of word to optimize is To make as effective, perfect or useful as possible. The optimization of the facility, equipment, systems, and processes results in a product that meets quality requirements at the lowest cost. Reduction of quality costs Quality costs are divided in to four categories. They are: a) Preventive costs. b) Appraisal costs. c) Internal failure costs. d) External failure costs. E.g.: of internal failure costs: Any validated and controlled process will result in fewer internal failures like Fewer rejects Reworks Re-tests Re-inspection Process validation makes it possible to do the job right the first time. Also, a scientifically studied and controlled process makes it unlikely that defective products will be dispatched to market thus no recalls or market complaints. Safety Validation can also result in increased operation safety. eg: gaues used on equipment that designed to operate at certain temperature and pressures must be reliable i.e. they must be calibrated. Validation Master Plan A validation master plan is a document that summarises the company s overall philosophy, intentions and approaches to be used for establishing performance adequacy. The Validation Master Plan should be agreed upon by management. Validation in general requires meticulous preparation and careful planning of the various steps in the process. In addition, all work should be carried out in a structured way according to formally authorized standard operating procedures. All observations must be documented and where possible must be recorded as actual numerical results. The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The main elements of it being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in the validation master plan. It should comprise all prospective, concurrent and retrospective validations as well as re-validation. The Validation Master Plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOP s and validation protocols and reports. The validation protocols for equipment and systems are normally divided into three segments: Installation Qualification, Operational Qualification and Performance Qualification, abbreviated as IQ, OQ, PQ. For systems and equipment, Performance Qualification is often synonymous with Validation. Depending on the function and operation of some equipment, only IQ/OQ are required. For equipment whose correct operation is a sufficient indicator of its function, and that are monitored and/or calibrated on a regular schedule (e.g. ph meter, incubator, centrifuge, freezer), the installation and operational qualifications are performed. Systems such as air, water, steam, and major equipment which perform critical support processes, such as sterilization (autoclave, oven), depyrogenation (oven or tunnel), or lyophilization, require installation, operational and performance qualifications. Each IQ, OQ, and PQ protocol provides the specific procedure to follow, information to be recorded, a set of acceptance criteria, and a list of materials, equipment and documents needed to perform the validation. TYPES OF PROCESS VALIDATION Prospective validation Concurrent validation Retrospective validation Re-validation Vol. 2 (4) Oct Dec

3 1) Prospective Validation The objective of the prospective validation is to prove or demonstrate that the process will work in accordance with validation protocol prepared for the pilot production trials. Prospective validation should normally be completed prior to the distribution and sale of the medicinal product. In Prospective Validation, the validation protocol is executed before the process is put into commercial use. During the product development phase the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical parameters that may affect the quality of the finished product. A series of experiments should be designed to determine the criticality of these factors. Each experiment should be planned and documented fully in an authorized protocol. All equipment, production environment and the analytical testing methods to be used should have been fully validated. Master batch documents can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined. Using this defined process a series of batches should be produced. In theory, the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. Some considerations should be exercised when selecting the process validation strategy. Amongst these should be the use of different lots of active raw materials and major excipients, batches produced on different shifts, the use of different equipment and facilities dedicated for commercial production, operating range of the critical processes, and a thorough analysis of the process data in case of Requalification and Revalidation. During the processing of the validation batches, extensive sampling and testing should be performed on the product at various stages, and should be documented comprehensively. Detailed testing should also be done on the final product in its package. Upon completion of the review, recommendations should be made on the extent of monitoring and the in-process controls necessary for routine production. These should be incorporated into the Batch manufacturing and packaging record or into appropriate standard operating procedures. Limits, frequencies and actions to be taken in the event of the limits being exceeded should be specified. 2 ) Concurrent Validation Concurrent Validation means establishing documented evidence a process does what it is supposed to do based on data generated during actual implementation of the process. Concurrent validation may be the practical approach under certain circumstances. It is important in these cases when the systems and equipment to be usedhave been fully validated previously. The justification for conducting concurrent validation must be documented and the protocol must be approved by the Validation Team. A report should be prepared and approved prior to the sale of each batch and a final report should be prepared and approved after the completion of all concurrent batches. It is generally considered acceptable that a minimum of three consecutive batches within the finally agreed parameters, giving the product the desired quality would constitute a proper validation of the process. 3) Retrospective Validation Retrospective Validation means establishing documented evidence a process does what it is supposed to do based on review and analysis of historical data. In many establishments, processes that are stable and in routine use have not undergone a formally documented validation process. Historical data may be utilized to provide necessary documentary evidence that the processes are validated. The steps involved in this type of validation still require the preparation of a protocol, the reporting of the results of the data review, leading to a conclusion and recommendation. Retrospective validation is only acceptable for well established detailed processes that include operational limits for each critical step of the process and will be inappropriate where there have been recent changes in the formulation of the product, operating procedures, equipment and facility. The source of data for retrospective validation should include amongst others, batch documents, process control charts, maintenance log books, process capability studies, finished product test results, including trend analyses, and stability results. For the purpose of retrospective validation studies, it is considered acceptable that data from a minimum of ten consecutive batches produced be utilized. When less than ten batches are available, it is considered that the data are not sufficient to demonstrate retrospectively that the process is fully under control. In such cases the study should be supplemented with data generated with concurrent or prospective validation. 4) Re-Validation Re-validation is usually performed to the confirmation of initial validation for a Periodic review. Re-validation provides the evidence that changes in a process and /or Vol. 2 (4) Oct Dec

4 the process environment that are introduced do not adversely affect process characteristics and product quality. Documentation requirements will be the same as for the initial validation of the process. Revalidation becomes necessary in certain situations. Change Control Clearly defined procedure is required in order to control any changes in the production processes. These procedures should control all the planned changes and ensure the presence of sufficient supporting data that show that modified process will result in a product of the desired quality. Significant changes to process (e.g. mixing time, drying temperature, etc.), using new equipments with different operating parameters, etc may require the pre-approval of the process. If a change is proposed in any of the procedures, product, processes, or equipment which may impact the quality, appropriate written procedures should be in place. All changes must be formally requested, documented and proposed changes was scientifically assessed and, depending on the changes, the need of re-validation will be determined. Phases of Process Validation Phase 1 Pre-Validation Phase or the Qualification Phase, which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, Equipment Qualification, master production documents, Process Capability. Phase 2 Process Validation Phase (Process Qualification phase) designed to verify that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under the "worst case" conditions. Phase 3 Validation Maintenance Phase requiring frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including Change Control procedures. VALIDATION PROTOCOL A written plan stating how validation will be conducted, including test parameters, product characteristics, production and packaging equipment, and decision points on what constitutes acceptable test results. This document should give details of critical steps of the manufacturing process that should be measured, the allowable range of variability and the manner in which the system will be tested. In the case where a protocol is altered or modified after its approval, appropriate reasoning for such a change must be documented. The validation protocol should be numbered, signed and dated, and should contain as a minimum the following information: Objectives, scope of coverage of the validation study. Validation team membership, their qualifications and responsibilities. Type of validation: prospective, concurrent, retrospective, re-validation. Number and selection of batches to be on the validation study. A list of all equipment to be used; their normal and worst case operating parameters. Outcome of IQ, OQ for critical equipment. Requirements for calibration of all measuring devices. Critical process parameters and their respective tolerances. Description of the processing steps: copy of the master documents for the product. Sampling points, stages of sampling, methods of sampling, sampling plans. Statistical tools to be used in the analysis of data. Training requirements for the processing operators. Validated test methods to be used in in-process testing and for the finished product. Specifications for raw and packaging materials and test methods. Forms and charts to be used for documenting results. Format for presentation of results, documenting conclusions and for approval of study results. According to Indian GMP (Good Manufacturing Practice), validation study is an essential part of GMP required to be done as per predetermined protocols. Prospective process validation is carried out during the development stage by means of risk analysis of the production process which is broken down into individual steps. These are then evaluated on the basis of past experience to determine whether they might lead to critical situation The risk is evaluated, the potential causes are investigated and assessed for probability & extent, the teal plan are drawn up, & priorities are set. The trial are then performed and evaluated & overall assessment is made. If the end results are acceptable the process is considered to be satisfactory. Unsatisfactory processes must be modified & improved until a validation exercise proves them to be satisfactory. This form of validation is essential in order to limit the risk of Vol. 2 (4) Oct Dec

5 error occurring on the production scale. The present work deals with identification of critical stage and their consequent evaluation by challenging its upper and lower specifications. MATERIALS Cimetidine (JIANGSUGUO.TAI INT L Group), Starch (Maize Starch) (Maize products), PVP K-30 (Koje polymer), Sodium benzoate (Navyug pharmaceuticals), Talcum (Gangotri inorganic pvt Ltd), Magnesium stearate (Komal pharmaceuticals), sodium starch glycolate (Rosswell Industries) and D.M. Water were used in the study, Unique coat FCAQ (Titanium dioxide) white (Cocoon Pharma coating & Excipient) was used for coating. All raw materials used were of BP grade and chemicals used in the analysis were of analytical grade. Machinaries Machineries and equipments used were as Sifter, Scoops, Oscillating Granulator (Cadmach Machinery co. pvt. ltd),rapid mixing granulator [RMG] (250L, Kevin make), Tray Dryer ( Manish Metal),octagonal blender (240L, Ganson Ltd), compression machine 31 station double rotatory (SHAMDEW), UVvisible spectrophotometer (Shimadzu), six stage dissolution rate test apparatus IP/BP/USP (Electrolab),Weighing balance (Shimadzu), hardness tester (Vishal Hardness testing),disintegration and friability test apparatus (Electo lab), Thickness tester, IR Moisture balance(rajdhani Scientific Instts.co) Evaluation of Tablet The critical parameters considered during the process validation of Cimetidine 400 mg tablets are Dry Mixing Wet granulation Drying Lubrication Compression Coating Strip Packing Weight variation, Hardness Test, Friability, Assay, Dissolution Study. Dry Mixing The dry-mixing step involves mixing of active ingredients with other additives using Rapid Mixer Granulator (RMG). The content of Cimetidine in the dry mix shall be tested, to validate dry mixing process. Mixing speed and mixing time are the critical variables that determine content uniformity. Mixing speed is kept constant, mixing time shall be studied to validate dry mixing step. In dry mixing stage 3 batches like PVB 1, PVB 2 and PVB 3 are considered for validation. Each sides sampled from top (RS1T, RS2T, RS3T), middle (RS1M, RS2M, RS3M),bottom (RS1B RS2B RS3B)layer of RMG in polyethylene bag for QC analysis of assay. Refer sampling plan of RMG as shown in figure.1 Dry mixing results of all the batches are well within the acceptance criteria. Fixed parameters Time interval studies: after 30 minutes Measured response: Description, blend uniformity Acceptance criteria: Not less than 95% and not more than 105% of the Label claim WET GRANULATION Binding solution* was added in to sifted raw material and mix it for 30 min in RMG Finally complete the granulation by running impeller and Chopper at slow speed at till suitable dough mass is obtained. * Binder solution preparation: Takeout P.V.P.K, Sodium benzoate and hot water in S.S vessel and mix properly and prepared solution. In another vessel add Starch and D.M water and mix and make slurry, then add above solution in slurry and made a paste. Drying Drying of wet granules for 4 to 6 hours at C temperature till the loss on drying is NLT % w/w at 105 C. (Outlet temperature would be approx.30ºc to 40 C). The level of moisture in the granules is important factor. If level of moisture is more in granules then blend will have poor flow & distribution characteristics. If level of moisture in blend is less it will produce tablet with capping, high friability and chipping problems. During drying the desired LOD will be maintained in the granules which will influence the quality parameters like tablet hardness, flow properties, physical properties during compression. Drying of granules in Tray dryer controls the level of moisture. Inlet temperature of is most critical variable for the same. LOD is checked at regular interval to establish the correlation with outlet temperature. In dry stage of different time interval of each batch should be considered for validation. After mixing completed of above material take 5 gm sample material from three sides (starting from left corner, center, right corner). Drying results of the batches are well within the acceptance criteria. Results of Loss on drying were shown in Table 5. Acceptance criteria: NMT 2%w/w. Lubrication This step involves mixing of Lubricating agent with drug granules & other blending material. The purpose of blending is to get a uniform distribution of granules and lubricating agent. This is followed Vol. 2 (4) Oct Dec

6 by mixing of the granules with lubricant to get good flow and anti-adhesion property of the blend. Mixing speed and time are critical variables in this process. Mixing speed is kept constant & mixing time of blender should be studied for validate blending process. Mixing time is critical since under mixing would result in non-uniform distribution of drug and poor flow whereas over mixing will result affect the uniformity of mixing and leads to non-uniform distribution of drug. Compression of Tablets For compression of tablets involves consistent flow of properly lubricated, granules in the hopper to dies where the granules were compressed in to tablets. Compression carried out as per batch manufacturing recorded. Collect the sample at various stage and speed. i.e. at maximum RPM, minimum RPM, optimum RPM and at start, middle and end of compression process and carry out testing of content uniformity and physical parameters such as hardness, thickness, friability etc. In compression stage three batches i.e. Batch No PVB 1, PVB 2 and PVB 3 shall be considered for validation. Compression results of all the batches are well within the acceptance criteria. Results of the compression at different speed, low weight at optimum speed, high weight at optimum speed, initial, middle and end of the compression were shown in table no.9 Tablets were compressed using 12.5mm, round Punch, Upper punch & lower Punches plain. Each 635 mg tablet contains 400mg Cimetidine. The specifications for tablet was average weight 627 mg( ±5%), hardness NLT 3kg/cm, thickness mm,friability NMT 1%w/w, DT NMT 15 min, Assay %,Dissolution NLT 80%. Coating Coating is to be carried out as per batch manufacturing record. Samples are collected at the end of coating stage and carried out the testing of content uniformity and identification tests, inlet temperature, outlet temperature, solid content, physical parameters such as hardness, thickness, friability, etc. In coating stage three batches i.e. Batch No PVB 1, PVB 2 and PVB 3 should be considered for validation. Coating results of all the batches are well within the acceptance criteria. Results are shown in Table no. 10 and 11. *Coating solution preparation: Take D.M water, add unique coat FCAQ white, slowly to it stir for 45 minutes. Homogenize the mixture by passing through nylon cloth. STRIP PACKING Packing is to be done as per batch packing record. In packing stage three batches i.e. Batch No PVB 1, PVB 2 and PVB 3 shall be considered for validation. Packing results of all the batches are well within the acceptance criteria. Weight Variation Twenty tablets were randomly selected from each batch and individually weighed. The average weight and standard deviation of 20 tablets was calculated. The batch passes the test for weight variation test if not more than two of the individual tablet weight deviate from the average weight by more than the percentage shown in Table 12 Thickness Twenty tablets were randomly selected from each batch and there thickness and diameter was measured by using digital vernier caliper. Results are shown in Table 13. Hardness The crushing strength Kg/cm2 of prepared tablets was determined for 10 tablets of each batch by usingvishal tablet hardness tester. The average hardness and standard deviation was determined. The results are shown in Table 14. Friability Twenty tablets were weighed and placed in the Electro lab friabilator and apparatus was rotated at 100 rpm. After revolutions the tablets were deducted and weighed again Table 12 The percentage friability was measured using the formula, % F = {1-(Wt/W)} 100 Where, % F = friability in percentage W = Initial weight of tablet Wt = weight of tablets after revolution. Assay Cimetidine was estimated by using U.V. Spectrophotometer as per the British pharmacopoeia method at 218nm & 260 nm formulation Samples was Subjected to U.V spectroscopy. Weight and finely powder 20 tablets. Shake a quantity of the powdered tablets containing 0.1 g of Cimetidine with 300 ml of 0.05M Sulphuric acid for 20 minutes, add sufficient 0.05M Sulphuric acid to produce 500ml and filter (Whatman filter). Dilute 5ml of filtrate to 100ml with 0.05M Sulphuric acid ( solution A). Prepare a 0.001% w/v solution of Cimetidine in 0.05M Sulphuric acid (solution B) Measured the absorbance of solution A and B at the maximum at 218 nm and at 260 nm. Calculate the content of Cimetidine (C 10 H 16 N 6 S) using the difference between the absorbencies of Vol. 2 (4) Oct Dec

7 solution A and B at the two wavelengths and the declared content of C 10 H 16 N 6 S in Cimetidine. In-Vitro Dissolution Studies In Vitro dissolution study was carried out using USP II apparatus (paddle apparatus) in 900 ml of 0.1N HCl for 60 minutes. The temperature of the dissolution medium was kept at 37± 0.5 o C and the basket was set at 100 rpm. 10 ml of sample solution was withdrawn at specified interval of time and filtered through Whatman filter paper. The absorbance of the withdrawn samples was measured at 218 nm and at 260 nm using UV visible spectrophotometer. RESULTS All the results are tabulated in Table 1-14 CONCLUSION Quality cannot be adequately assured by in-process and finished inspections and testing but it should be built in to the manufacturing process. These processes should be controlled in order that the finished product meets all quality specifications. The quality system regulation defines process validation by establishing evidence that a process consistently produces a result or product meeting its predetermined specifications. The goal of quality system is to consistently produce products that are suitable for their intended use. In this study prospective process validation was carried out for one product. In tablet dosage form, critical parameters were taken up for validation studies. In tablet dosage form, the critical parameters are Dry mixing Granulation Drying Lubrication Compression Coating Dry Mixing The dry-mixing step involves mixing of Cimetidine with other additives using Rapid mixer granulator. The content uniformity of Cimetidine has to be established during validation of dry mixing process. The mixing of the active ingredient depends on the mixing of drug during mixing. Hence it is a critical step to be validated. Drying The drying step involves drying of wet mass. Moisture in granules is important factor. If moisture is more in granules it will lead to poor flow and sticking problem. If moisture is less it will lead to capping, high friability and chipping. During drying the quality parameters like tablet hardness, flow properties of granules, physical properties of tablets during compression should be taken in to consideration. The inlet temperature of the Tray dryer is controlled during the drying process and the outlet temperature is monitored and correlated with the corresponding LOD of the granules under drying. Lubrication The blending of three batches was performed and the samples at the designated locations were drawn after 20, 25, 30 minutes of blending for determining the content uniformity and RSD values of Cimetidine. The RSD values meet the acceptance criteria at 8minutes of blending. From the analytical results it is clear that the drug distribution pattern in the blend is almost homogeneous at 8 minutes of blending. Hence the blending time of 30 minutes as mentioned in the BMR stands was validated. Compression The compression for all the three batches has been validated for Startup, high RPM, low RPM, low weight at target speed, high weight at target speed, Initial, Middle, and End cycle of compression. The physical parameters, results of content uniformity and dissolution of the tablets were well within the acceptable limits. The results are comparable among all the three batches. Coating The coating of all three batches has been validated for pan load, Pan RPM, Inlet & outlet temperature, gun distance, atomization air pressure and spray rate. The results are comparable among all the three batches. Aqueous film coating of the tablets is multivariate process. Speed of pan was taken 4,5, 6 was effective for coating. Spray rate was maintained to between 16 to18 gm/min. Atomizing pressure 2 bar was constant maintained otherwise lower pressure sticking and picking was observed. and higher pressure formation of dust. Solid content was almost up to12% did not affect the tablet but after affect the surface of the tablet. Higher solid content form a droplets and unequal distribution of the solution noted. Rotating pan speed was improved the mixing of the tablet and distribution of the coating solution. Rotating pan speed was 4 to 6 rpm maintained otherwise sticking of the tablet. Higher pan speed problem of friability was observed. film coating of the tablet direct related to the tablet parameter increased weight up to 1 to 3 % of specified weight, Disintegration time almost double after coating of tablets. Vol. 2 (4) Oct Dec

8 Strip packing Here, various measured parameter for packing process are machine speed, sealing & forming, temperatures, knurling & cutting,pocket formation.strip packing process involves packing of tablets in aluminum foil. Temperature of sealing rollers, speed of machine is critical variables. Adequate sealing roller temperature is essential to get proper sealing, less temperature will lead to improper sealing which cause leakage and higher temperature will result in burning or spoilage of aluminum foil. Speed of the machine is influenced by following parameters. Proper sealing of strip pack configuration of strip pack Leak test and strip appearance are carried out to establish the above variables during blister packing operation. Calculated the % yield and record. Process Sifting Dry Mixing Granulation Drying Dry Screening Blending & Lubrication Compression Coating Process control variables Table 1: Process Control Variables Variable Sieve size Load, Speed of Mixer, Mixing Time Speed of Mixer & chopper, Mixing Time,Temp. of Binder, Quantity of Purified Water used Initial air drying, Inlet air temperature, Outlet temperature, Drying time Sieve size, Screen size, Milling speed Load, Mixing Time Speed of compression,compression force, Average weight, Uniformity of weight, Diameter, Thickness,Hardness,Friability, Disintegration time, Dissolution Pan Load (Kg),Pan Speed, Inlet Temperature, Outlet Temperature, Tablet bed temperature,atomizing air pressure, Spray rate S. No. Ingredients Table 2: Details of Raw Materials Pharmacopeial status Theoretical Quantity Mg/tab. Actual Quantity Quantity Per Batch(kg) MIXING 1 Cimetidine BP Lactose BP Starch(maize starch) BP BINDING 4 Starch BP P.V.P.K USP Sodium Benzoate BP LUBRICATION 7 Talcum BP Magnesium stearate IP/BP Sodium starch Glycolate BP COATING 10 Unique Coat FCAQ Universal (Titanium IH Dioxide) White 11 D.M. Water IH ml ml L Total P.V.P.=Polyvinyl pyrrolidone, D.M= Demineralized Water Table 3: Equipments to be used During Validation Processing Stage Weight verification Sifting Dry Mixing Drying Dry screening and Milling (Sizing of dried granules) Blending & Lubrication Compression Assay testing Processing Equipments Weighing Balance Mechanical sifter Rapid Mixer granulator Tray Dryer Oscillating Granulator Multimill Octagonal Blender RMG Double station rotary compression machine U.V spectrophotometer Vol. 2 (4) Oct Dec

9 Table 4: Dry Mixing Process results PVB1 PVB2 PVB Assay results after completion of mixing process SD% Table 5: Wet Mixing Results S. Process Batch no. No. parameter PVB1 PVB2 PVB3 1 Impeller Slow speed till wet dough 2 Chopper Mass is obtained. 3 Impeller motor amperage at the end of wet granulation 18A 18.2A 18.6A 4 Speed of Impeller during Slow Slow Slow discharging speed speed speed 5 Total Granulation time (min) 30 min 30 min 30 min 6 % assay result after completion of process 98% 97.91% 98.58% Table 6: Drying Stage Result. Loss on Drying LOD (%w/w) Time After 4 hours After 5 hours After 6 hours Layer T M B T M B M B PVB PVB PVB T = Top M = Middle B = Bottom Table: 7 Lubrication Stage Result Sample % Assay location of octagonal blender After 20 min After 25 min After 30 min PVB1 PVB2 PVB3 PVB1 PVB2 PVB3 PVB1 PVB2 PVB3 BS BS BS BS BS BS BS BS BS SD% RSD% Table 8: Sizing Stage Result Batch no: % fine Bulk Density PVB PVB PVB Vol. 2 (4) Oct Dec

10 Table 9: Illustrated the Result of the Compression Process. Parameter Speed PVB -1 PVB -2 PVB -3 Specification Appearance Minimum ok ok ok White colored, round shape, biconvex, tablets with Maximum ok ok ok Plain on both side. Optimum ok ok ok Minimum ± 4.2 ± 4.2 ± 3.7 Select 20 tablets at random, weigh each one Uniformity of Maximum ± 3.4 ± 4.7 ± 3.2 individually and obtain an average weight. Not more weight than two of the individual weights deviate from the (%) Optimum ± 2.4 ±3.6 ± 2.6 average weight by more than ± 5% Thickness (mm) Minimum Maximum mm to 5.45mm Optimum Hardness Minimum 5 to 7 4 to 6 4 to 6 (kg/cm 2 ) Maximum 4 to 8 5 to 7 4 to 6 Not less than 3 kg/cm2 Optimum 5 to 7 5 to 7 4 to 6 Disintegration Minimum Time (min) Maximum Not more than 15 minutes Optimum Friability Minimum (%w/w) Maximum Not more than 1.0 % w/w. Optimum Assay (%w/w) Minimum Maximum % to % Optimum Minimum Dissolution Maximum Not less than 80 % of the labeled amount (%) Optimum Yield of batch % to % Table 10: Coating Stage Result S.No Parameters PVB1 PVB2 PVB3 Limits 1 Speed of pan RPM 2 Hot air temperature ºC ± 5ºC 3 bed temperature ºC ± 5ºC 4 Total Coating time 3 hours 3 hours 3 hours To be recorded 5 Room Temperature ºC ± 2ºC 6 Relative Humidity % ± 5% Table 11: Coating Stage Tablet Result Parameter PVB -1 PVB -2 PVB -3 Specification Appearance ok ok ok White colored, round shape, biconvex, coated tablets with Plain on both side. Thickness (mm) mm ( ±0.2 mm) Hardness (kg/cm 2 ) 5 to 6 5 to7 4to 6 Not less than 3 kg/cm2 Disintegration Time Not more than 30minutes (min) Assay (%w/w) % to % Dissolution (%) Not less than 70 % Vol. 2 (4) Oct Dec

11 Table 12: Weight variation Results of Tablets Sample. No. PVB 1 PVB 2 PVB Maximum Minimum Average Table 13: Thickness results Sample. No. PVB 1 PVB 2 PVB Average Maximum Minimum Table 14: Hardness test results Sample. No. PVB 1 PVB 2 PVB Average Maximum Minimum Vol. 2 (4) Oct Dec

12 . BS1 BS2 BS3 BS4 BS9 BS5 BS6 BS7 BS8 Fig. 1: Illustrative diagram of octagonal blender and sampling locations RS1T RS2T RS3T RS1M RS2M RS3M \ RS1B RS2B RS3B Fig. 2: Illustrative diagram of RMG and sampling locations. Comperision of thickness for three batches 5.35 T h ic k n e s s r e s u lt s Num ber of Samples PVB 1 PVB 2 PVB 3 Fig. 3 Vol. 2 (4) Oct Dec

13 Comperision of weight variation for three batches R e s u l t s samples PVB 1 PVB 2 PVB 3 Fig. 4 Comperision of Hardness for three batches R e s u l t s o f h a r d n e s s Samples PVB 1 PVB 2 PVB 3 Fig. 5 REFERENCES 1. Guidelines on General Principles of Process Validation, Food and Drug Administration, Maryland, 1993; Manoher A Potder, Pharmaceutical Quality Assurance, Nirali Prakashan 8.1to Health Canada / Health Products and Food Branch Inspectorate, Validation Guidelines for Pharmaceutical Dosage Forms (GUI-0029).2009; UK Orange Guide, Guide to Good Pharmaceutical Manufacturing Practices. United Kingdom. 1983; Validation Guidelines for Pharmaceutical Dosage Forms (GUI-0029) 2009; Guidelines for Process Validation of Pharmaceutical Dosage Forms, Drug Sector Saudi Food & Drug Authority, Kingdom of Saudi Arabia Asian guidelines on process validation, page no: A WHO guide to good manufacturing practice requirements, part: 2 validation 2 to 6,9. 9. Leon Lachman,Herbert A. Liberman and Joseph L. Kanig, The Theory and Practice of Industrial Pharmacy, , Berry I. Nash, Manual of Process validation, Marcel Dekker, New York, 1993;2: Satyabrata Jena, Arjun G, Anil Kumar Ravipati NV, Satish Kumar D, Vinod. KR and David Banji. Industrial process validation of solid dosage forms. International Journal of Pharmaceutical Sciences Review and Research. 2010;4(2): R. Raghunandanans R. Validation aspect of solid dosage forms, Journal of pharmaceutical technology, Chapter 8, Process Validation of Solid Dosage Form- Tablet. 13. Validation of solid dosage forms the FDA view, 1989;15(6-7): Paolo Colombo, Instituto Techanica Farmaceutica, Univercity of Pharma,Via M.d Azelglio 85,43100, pharma, Itly,Validation of tablet formulation, Viral kumar kishorbhai patel. Process Validation: An Essential Process In Vol. 2 (4) Oct Dec

14 Pharmaceutical Industry. 16. Michel D Tousey. Sticking and picking: Some causes and remedies, Journal of Tablet and capsule Yeli Zhang, Yuet Law and Sibu Chakrabarti. Physical Properties and Compact Analysis of commonly used Direct Compression Binders,Journal of AAPS pharmascitech Douglas McCormick. Evolutions in Direct Compression. Journal of Pharmaceutical Technology. 2005; Odeku OA, Awe OO, Popoola B, Odeniyi MA, and Itiola OA. Compression and Mechanical Properties of Tablet Formulations, Journal of Pharmaceutical Technology. 2005; Rohokale BS, Jadhav VM and KadamVJ. Studies in prospective process validation of Metformin HCl tablet dosage formulation,journal of Pharma Tech Research. 1999;2: Robert A Nash. Process validation: 17 year Retrospective of solid dosage Forms. 1996;22(1): Rohkale BS, Jadav VM and Kadam VJ.Studies in optimization of non-aqueous film coating parameters, International Journal of Pharma. Research and Development. 2010;2(7) Navin Sheth, Sunny Shah, Arti Potder and Anand Shah. Studies in optimization of aqueous film coating parameters, International Journal of Pharmaceutical Sciences and Nanotechnology Rang HD, Dale MM, Ritter JM and Moore PK. Pharmacology 5th ed. Elsevier India Pvt Ltd., New Delhi. 2006: British Pharmacopoeia, volume: Goyal RK, Anita A, Maheta, Balaraman R, Mahesh D and Burande.Elements of Pharmacology Fifth edition,b.s. Shah Prakashan, Vol. 2 (4) Oct Dec