VALIDATION OF TABLET

VALIDATION OF TABLET:

VALIDATION OF TABLET PREPARED BY: PANKAJ LADDHA 10MPH108 M.PHARM SEMESTER II GUIDED BY: Prof.Tejal mehta HOD., Department of pharmaceutics

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Validation Validation simply means, assessment of validity' or action of proving effectiveness. According to European community for medicinal products, validation is 'action of proving', in accordance with the principles of Good manufacturing practices that any procedures, process, requirement, material, activity or system actually leads to expected results.

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There are several important reasons for validating a product and /or process. Manufacturers are required by law to confirm to GMP regulations. Good business dictates that a manufacture avoid the possibility of rejected or recalled batches. Validation helps to ensure product uniformity, reproducibility, and quality. All pharmaceutical scientists, whether in development, quality assurance, production.

PROCESS VARIABLES:

PROCESS VARIABLES In-Process Tests Finished Product Tests Moisture content of “dried granulation” Granulation particle size distribution Blend uniformity Individual tablet/capsule weight Tablet hardness Tablet thickness Disintegration Appearance Assay Content uniformity Tablet hardness Tablet friability Dissolution

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Moisture content of “dried granulation” : Loss on drying (LOD) used to determine whether or not the granulation solvent has been removed to a sufficient level during the drying operation (usually less than 2% moisture). Granulation particle size distribution: An extremely important parameter that affect tablet compressibility, hardness, thickness, disintegration, dissolution, weight variation, and content uniformity. This parameter done by sieve analysis, should be monitored throughout the tablet validation process.

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Blend uniformity: Samples of the blend are taken and analyzed to ensure that the drug is uniformly dispersed throughout the tablet/capsule blend. The proper blend time must be established so that the blend is not under- or over mixed. Individual tablet/capsule weight: The weight of individual tablets or capsules is determined throughout compression /encapsulation to ensure that the material is flowing properly and the equipment is working consistently.

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The individual weight should be within 5% of the nominal weight. Weight fluctuations or frequent machine adjustments suggest that the formulation (e.g., poor granulation flow) is not optimized and/or that the equipment may need maintenance. Tablet hardness: Tablet hardness is determined periodically throughout the batch to ensure that the tablets are robust enough for coating, packing, and shipping and not too hard to affect dissolution.

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Finished Product Tests 1.Appearance: The tablets should be examined for such problems as tablet mottling, picking of the monogram, tablet filming, and capping of the tablets. If the tablets are colored, the color quality needs to be examined. 2. Content uniformity: Samples are taken across the batch profile (beginning, middle, and end) and analyzed to ensure that the dosage forms comply with compendial standards (±15% of the labeled amount) or more stringent internal limits. It will indicate whether there is demixing during the manufacturing operation (i.e., segregation during flow of granulation from a storage bin).

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4. Tablet hardness : A critical parameter for dosage form handling and performance. 5. Tablet friability: Friability is an important characteristic on the tablets’ ability to withstand chipping, cracking, or “dusting” during the packaging operations and shipping. 6. Dissolution: Dissolution is important to ensure proper drug release characteristics (in vitro availability) and batch-to-batch uniformity. 7. Assay: This test will determine whether or not the product contains the labeled amount of drug.

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PROCESS VALIDATION OF TABLETS Tablet Composition Solubility of the drug substance throughout the physiological pH range: Depending on the solubility of the drug, a surfactant may be needed to enhance dissolution. Particle size distribution and surface area: The particle size distribution of the drug may determine what grade of an excipient (e.g., microcrystalline cellulose) to use. Morphology: If the drug is amorphous or has different polymorphs, certain excipients may be used to prevent conversion of the drug to other physical forms.

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Material flow and compressibility: A free flowing, highly compressible material such as microcrystalline cellulose may be used for drugs with poor flow or compressibility properties. Hygroscopicity: Special environmental working conditions may be required to ensure that moisture is not picked up during material storage or handling and during the manufacture of the tablet dosage form. Melting point : If the drug has a low melting point, a direct compression formulation may need to be developed instead of a wet granulation formulation to avoid drying the material and potentially melting or degrading the drug. True and bulk density: An excipient (e.g., diluents) that has a similar bulk density as the drug may be selected to minimize segregation, especially with a direct compression formulation .

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Process Evaluation and Selection Mixing or Blending Wet Granulation Wet Milling Drying Milling Tablet Compression Tablet Coating

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Mixing or Blending The following physical properties of the drug and excipients are factors in creating a uniform mix or blend: Bulk density Particle shape Particle size distribution Surface area Materials that have similar physical properties will be easier to form a uniform mix or blend and will not segregate as readily as materials with large differences. Items to consider: Mixing or blending technique Mixing or blending speed

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Mixing or blending time Drug uniformity Excipients uniformity Besides drug uniformity, excipients need to be uniform in the granulation or blend. Two key excipients are: Lubricant Color

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Wet Granulation Wet granulation parameters to be considered during development and validation are: Binder addition Binder concentration Amount of binder solution/granulating solvent Binder solution/granulating solvent addition rate Mixing time Wet Milling Factors to consider are: Equipment size and capacity Screen size Mill speed Feed rate

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Drying The type of drying technique required for the formulation needs to be determined and justified. The type of technique may be dependent on such factor as drug or formulation properties and equipment availability. Changing dryer technique could affect such tablet properties as hardness, disintegration, dissolution, and stability. Parameters to consider during drying are: Inlet/outlet temperature Airflow Moisture uniformity Equipment capability/capacity

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Milling The milling operation will reduce the particle size of the dried granulation. The resultant particle size distribution will affect such material properties as flow, compressibility, disintegration and dissolution. Factors to consider in milling are: Mill type Screen size Mill speed Feed rate

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Tablet Compression Compression is a critical step in the production of a tablet dosage form. The material being compressed will need to have adequate flow and compression properties. Factors to consider during compression are as follows: Tooling Compression speed Compression/ejection force The following in-process test should be examined during the compression stage: Appearance Hardness Tablet weight Friability Disintegration Weight uniformity

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Tablet Coating Tablets may be coated for various reasons. Stability Taste masking Controlled release Product identification Aesthetics Safety–material handling

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Key areas to consider for tablet coating include the following: Tablet properties Equipment type Coater load Pan speed Spray guns Application/spray rate Tablet flow Inlet/outlet temperature and airflow Coating solution Coating weight Residual solvent level

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Appearance testing of the tablets is critical during the coating operation. Items to look for include the following: Cracking or peeling of the coating Intagliation fill-in Surface roughness Color uniformity

EQUIPMENT EVALUATION:

EQUIPMENT EVALUATION Mixer/granulator Blender Dryer Mills Tablet compressor Tablet coater

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Process overview Dispensing Sifting Granulation Drying & sizing Lubrication Compression In-process checking Packing Final product analysis & release

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1.Dispensing i )Check and ensure dispensing booth is clean and line check is given as per current  Standard operating procedure . ii)Check and ensure that balance is not due for calibration. Check for zero error in the balance. iii)Check and ensure that the expire date. iv)Check and ensure that the all materials are issued as per Batch Processing Report

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2.Sifting Check and record the temperature and relative humidity in processing area  temperature  should be 25 ±20° C & RH 45±5%. Check and ensure visually all the equipment and equipment parts are cleaned. Record remarks if any. Check and record the integrity of the sieves before and after sifting through out the processing activity

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3. Granulation Fixed Variable (Monitor) Response (Test) Equipment Mixing speeds Amount of granulation Fluid feed rate granulation Time Load Drug distribution Water/ solvent Appearance (size) Power consumption (amp/torque Control Parameters i )Add ingredient into  vessel then Dissolve. ii)Add the other ingredients into saizoner and mix of 5 minutes using impeller at slow speed. iii)Collect, samples at 3,5 and 7 minutes at 5 different places and subject it to analysis for uniformity in content. iv)Add granulating solution and homogenize at slow speed for about 10 minutes. v)After granulation is over check the Loss of drying the wet granules.

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4. Drying and sizing Fixed Variable (Monitor) Response (Test) Bowl charge Inlet/ exhaust air temperature Particle size distribution Porosity of filter bags Product temperature Densities Bowl sieve Drying time Loss on drying Air volume Humidity of incoming air ( dew point) Humidity of exhaust air Assay ( for heat sensitive materials ) i )Check and ensure the integrity of the Fluidized bed drying bag. ii)Initially dry the wet granules with air for 10 minutes, Dry the granules are per batch process report instruction.

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iii)Check the Loss of drying of granules; it should not be not more than 1% at 70°C for 15 minutes. iv)Check and ensure the dried granules are not stored above 25°C before the milling is started. v)Check and ensure the integrity of the sieves before and after sieving. vi)Pass the granules through 16 mm mesh sieve, break the oversize granules using mill fitted with 2mm screen. vii)Collect the granules in poly bags, and check for flow properties viii)Check the weight of sifted and dried granules

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5. Milling Variable Response Screen size Milling speed Feed rate Particle size distribution Loose/ tapped densities 6.Powder blending Variable Response Blending time Blender speed Intensifier bar Content uniformity Assay Particle size distribution Powder flow

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7.Lubrications Variable Response Blending speed Blending time Method of addition Particle size distribution Loose / tapped densities Flow properties Tabletting characteristics ( Friability, hardness) i )Perform the pre mixing and final mixing as per Batch process report instruction ii)During the final mixing before i.e., before adding the remaining quantity of the  lubricant mix for 15 minutes.

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iv)Collects sample at 5,10,15 minute's intervals form top, middle, bottom and v)Composite and subject it to analysis for assay. vi)After adding the remaining quantity of lubricant mix for 5 minutes. vii)Collects sample at 3,5,7 minutes interval form top, middle, bottom and viii)Composite and subject it to analysis for assay and content uniformity. ix)Check the weight of the final blend and record

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8.Compression i )Check and ensure the temperature and relative humidity of the compression room  is not more than 25°C and Relative Humidity not more than 50%. ii)Check and ensure the compression machine is cleaned iii)Collect 40 tablets and inspect for Appearance, weight, thickness, friability and hardness every 1 hour. iv)Tablets weight variation shall be y mg. hardness shall be (IP) kg/cm 2 , thickness. v)Collect 40 tablets by " Bracketign " i.e. by increasing this speed of the compression machine form the target speed and by reducing from the targeted speed.

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vi)Collect 10 tablets during initial, middle and end of the compression process and  subjective it to analysis for content uniformity and perform the assay also. 9 . Coating i )Check and ensure the coating pan and other equipment's are cleaned. ii)Check and ensure that the tablets is deducted, the speed of the coating pan, inlet and exhaust air temperature, spray rate, spray type, temperature of the coating solution. iii)After coating   is   completed , samples   are   collected   for dissolution testing and weight variation.

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10. Labeling and packing Check and record the temperature air the heating roller and sealing roller . Check and record that the over printing instructions on labels and cartons. Check and verify that price overprinted on label and carton is as per current price list. After ensuring the proper labeling of tablets, check, for correctness of cartons packing for the same

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11.Finished product analysis and release Finished product needs to be analyzed as per in-house specification product released only after pre­determined specifications and quality attributes. Needs to be released only after pre-determined specifications

REFERENCES::

REFERENCES: Nash A.Robert,Wachter H.Alfrad “Pharmaceutical Process Validation” Third Edition,volume 129, Marcel Dekker, Inc, New York, 2003,159-180. http://www.pharmainfo.net/reviews/guidelines-general-principles-validation-solid-liquid-and-sterile-dosage-forms

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