Presentation on – Quality control test of solid dosage form
Submitted by – Moriyom Akhter Department of Pharmacy World University of Bangladesh
QUALITY CONTROL TESTS FOR SOLID DOSAGE FORM
Solid dosage form Oral Solid dosage forms (Tablets and Capsules) are some of the most popular and convenient methods of drug delivery. They can be produced in a non-sterile environment and the process. With the high volume of products produced in this dosage forms, it is important that the unit operations for their production be thoroughly understood. This course focuses on the fundamentals of each processing step (unit operation) required for the manufacture and packaging of tablets and capsules. It will continue with a detailed review all of the major unit operations associated with OSD manufacturing process. This includes: Ingredient Dispensing/Formulation; Blending; Granulation; Drying; Compression/Encapsulation; Coating; Packaging and Miscellaneous Operations. Types of solid dosage form : Tablets, Capsules , Powders, Effervescent, Oral Insufflations Dentifrice Dusting, Lozenges
The development of a solid dosage form will be dependent upon the specific product and process. However, the formula ranges, physical and chemical specifications of the drug substance and excipients, in-process variables, interaction effects of the dosage form ingredients under normal and stress aging conditions, should be confirmed by limited challenge in pilot-scale and productionsize batches. Following specifications must be determined prior to the development of the SDF
QC of Raw Materials
QC for Manufacturing Procedures and Equipment
Granulation/Mix Analysis
In-Process Controls
QC of FDF
QC of packaging & Labelling
QC of raw materials for SDF Characterization of the chemical and physical properties of the drug substance that is API & excipients is one of the most important steps in the development of a solid dosage form. 1.
Chemical properties especially the identification of impurities are very important & they must be identified in visual inspection with color and odor.
2.
Physical characteristics of raw materials must be observed, the quantities and source of materials used and the testing performed. The physical properties of the API and excipients such as solubility, polymorphism, hygroscopicity, particle size, density, etc. must be addressed. They should be able to provide data to demonstrate that dissolution profiles and content uniformity will be satisfactory over a wide range of particle sizes. For example, a manufacturer may establish a specification of 90% of the particles must be less than 300 microns. For validation of this process, one would expect the use of micronized as well as material with particles close to 300 microns in size. In addition to release or dissolution, variation in particle size, particle shape, and/or bulk density can also have an effect on the uniformity of dosage forms, particularly those manufactured by direct compression or direct encapsulation.
3.
QC test for the raw materials of the capsule The gelatin of the capsule shells should be assayed for various physical properties like bloom strength, viscosity and its loss (by atomic force microscopy). Chemical tests like purity, microbial properties, and limits for heavy metals like arsenic, ash content should be determined. The colorants should also be checked for purity, limits for heavy metals, color properties, dye content, subsidiary dye content and color value.
Organoleptic properties: which include color and odor of the API & excipients.
Quality Checks during Manufacturing For manufacturing of the solid dosage form detailed manufacturing directions, specifying equipment and operating parameters must be specified.
The failure to specify the amount of granulating solution, resulting in over wetting and dissolution failures of aged batches to specify the encapsulation machine and operating parameters, such as dosing discs, resulting in weight variation failures the failure to specify the compression machine(s) and operating parameters, resulting in content uniformity failures
Physical Parameters : a. temp, b. time, c. particle size & texture , d. pressure , e. weight f. hardness, g. thickness & diameter , h. disintegration , i. dissolution ( % release) , j. friability, k. moisture content , l. %relative humidity
QC parameter for tablet granulation Granulation may be defined as a size enlargement process which converts small particles into physically stronger & larger agglomerates. Granulation method can be broadly classified into two types: A. WET GRANULATION-Wet granulation process simply involves wet massing of the powder blend with a granulating liquid, wet sizing and drying. B. DRY GRANULATION In dry granulation process the powder mixture is compressed without the use of heat and solvent. Itis the least desirable of all methods of granulation. The two basic procedures are to form a compact of material by compression and then to mill the compact to obtain a granules. The characteristics of a dosage form that make it popular dosage form eg compactness, physical stability, rapid production capability, chemical stability and efficacy are in general dedicated primarily by the qualities of the granulation from which it is made. QC parameters for granulation are 1. Particle size & shape : the particle size of a granulation to affect the average SDF weight, weight variation, disintegration time, granule friability, granulation flowability and the drying rate kinetics of the wet granulation. Particle size profiles are particularly important for the tablet made by a wet granulation process. The size and even the type of granule can affect the pore size in a tablet and have an effect on dissolution.
2. Another test which is typically performed on the granulation, particularly when the wet granulation process is used, is loss-on-drying (LOD) and moisture content. If organic solvents are employed, then residual solvent residues are also tested. In the validation of a drying process, LOD levels are determined prior to, during and after drying in order to demonstrate times and levels. As with processing variables, levels (specifications) are established in the development phase with the validation phase used to confirm the adequacy of the process. 3. Disintegration test is also be done for checking disintegration quality of the and assayed is also be done.
product
4. A critical step in the manufacture of an oral solid dosage form is the blending of the final granulation. If uniformity is not achieved at this stage, then one could assume that some dosage units would not comply with uniformity requirements. 5. Organoleptic test is also done which is important for checking the odor and the color of the granules of the product. Granulation is the act or process of forming or crystallizing into grains. Granules typically have a size range between 0.2 to 4.0 mm depending on their subsequent use. Agglomeration or particle size enlargement processes are also used to modify product properties. Agglomeration of powders is widely used to improve physical properties such as wettability, flowability, bulk density and product appearance.
Quality checks during SDF compression SDF specially the tablets are prepared or made by compression. The compression machine are two types single punch, multi punch or multi-station rotary presses. The compression machine are designed with the following basic components
Hopper’s for holding the and feeding granulation to be compressed Dies that define the size and shape of the dosage form Punches for compressing the granulation within the dies Cam tracks for guiding the movements of the punches A feeding mechanisms for moving granulation from hopper into dies. This basic components of the machine must be check during SDF compression.
Factors to be consider during compression Tooling : the shape and size and concavity of the tooling should be examined based on the formulation properties and commercial specifications. For embossed tablet, factors such as the position of the intagliation on the tablet and the intagliation depth and style should be examined to ensure that picking of the intagliation during compression or fill-in of the intagliation during coating does not occur.
Compression Speed: the formulation should be compressed at a wide range of compression speed to determine the operating range of the compressor. Is a force feeder required to ensure that sufficient material is fed into the dies? The speed of the machine can affect fill of the die and tablet weight & it is important to have specific operating directions. Compression/ ejection force : the compression profile for the formulation will need to be determined to establish the optimal compression force to obtain the desired hardness of the product. Quality checks In case of uncoated SDF : Hardness 25Kg (20-30 Kg) , Thickness, Length, Width, Disintegration test, Wt. variation + 3% of Av. Wt. , Friability (10 tabs) NMT 1.0% w/w & also checks frequency during mfg. In case of coated tablet the key areas to be consider 1. Tablet properties, 2. equipment types, 3. coater load, 4. pan speed, 5. spray guns and spray rate, 6. the volume of coating solution, rate and temperature must be controlled.
After coating the QC parameter are Dissolution test, Disintegration test, Hardness test, weight uniformity, moisture content test. The number of applications of coats, volume of coating solution in a specific application, and temperature of the solution during application are all parameters that need to be addressed. For example, the temperature of application and even heat during drying have been found to cause dissolution failures in aged tablets.
Another problem associated with the coating process concerns the heat applied to products that are sensitive to heat. For example, it has been shown that estrogen tablets are heat sensitive and have exhibited stability problems. Thus, it is important to control this phase of the process. In case of Capsule manufacturing QC parameters are 1. % purity of gelatin, Viscosity of gelatin solution, Bloom strength of gelatin solution 150-250 gm, film thickness, color, surface, appearance of empty shells, temperature of hot air, for drying of shells, length of capsule & body of the shell, moisture content 12-15% 2. QC Checks During Filling Of Empty Capsule Shells 3. During filling process equipment should be labeled with :-product name, Batch No, Time of starting, Sign During Filling: flow property of granules or powders 4. Weight Variation : For hard gel caps - Limit NMT 2 caps should deviate from avg wt. AVG WT %DEVIATION <300mg 10% >300mg or more 7.5% For soft gel caps: Wg 10 caps Remove inner content by cutting with scissor/blade Wash with solvent & evaporate solvent at room temperature for 30 min Wg the empty shells & calculate % deviation
QC Checks During Manufacturing of lozenges Visual inspection Shape, size, color Weight variation Overprinting logo Uniformity Disintegration Packaging & Labeling POWDERS QC Checks During Powder Manufacturing Particle size & shape, texture powder flow, fluffiness, density, foreign Impurities, moisture. Effervescent Powders: sample powder in 250ml of water produces effervescence & dissolves in 12sec. Dusting Powder: color, texture, density, particle size, flow, fluffiness, spread ability Insufflations: flow, particle size, density Dentifrice: abrasion, texture, particle size, color Powder Flow & Texture Analyzer Powder Flow Analyzer used to measure: Flow, texture, caking, cohesion, speed, granule attrition, compaction & relaxation, dusting surface, friction aggregation, air-entrapment, granulation. Parameters Measured: (principle-slicing, shearing, compaction) speed of rotor blade blade angle path of blade resistance in speed and angle axial force time distance travelled Measured by a sensitive transducer attached to rotor blades.
In process quality control In-process testing is the testing performed on dosage forms during their compression /encapsulation stages to assure consistency throughout these operations. IPQC test are the test which are performed during the product development process or production. IPQC FOR TABLETS: IPQC FOR TABLETS ENVIRONMENTAL CONTROL: Filter condition and changes, humidity and temperature monitoring. Water releases stickers at the point of use for chemical and microbial partly. MATERIALS: checking for name, lot no., weight, particle size, bulk density, color and water content. Balances and scales, sifter and granulator and multi mill with screen. IPQC FOR TABLETS MIXING AND MASSING: Checking for proper equipment and addition of ingredients, mixing time and sampling from top, middle and bottom. Checking of binder temperature, rate and addition time. Massing time and load reading. Wet milling, speed, screen, equipment checking. IPQC FOR TABLETS DRYING: Cleaning condition of an equipment and filter bag. Separate bag for each. Loading uniformity, air temperature, outlet temperature, time of drying. Moisture control and determination. Proper shifting and control of oversize granules. Fine collection and lubrication. Proper mixing for specified product.
IPQC TESTS OF TABLETS Weight variation of tablets. Hardness of tablets. Thickness. Friability. Uniformity of content. Disintegration time. Potency- assay. Dissolution test. Blister sealing test. Content of active ingredients. IPQC TESTS FOR COATED TABLET Moisture content of dried granulation, granulation particle size distribution, blend uniformity, individual tablet/capsule weight , hardness, thickness, disintegration, impurity profile. IPQC TESTS FOR CAPSULES: IPQC TESTS FOR CAPSULES Assay. Weight variation test. Disintegration time. Dissolution time. Moisture test. Bloom strength. Iron test. Hardness and flexibility of shell. Loss on drying. Stability test at different temperature.
IPQC PROBLEMS IN TABLETS: 1. Capping, 2. Lamination, 3. Picking , 4. Mottling , 5. Weight variation, 6. Poor flow 7. Poor mixing, 8. Hardness variation, 9. Double impression
Capping is the partial or complete separation of the top or bottom crowns of a tablet from the main body of the tablet. Lamination is separation of a tablet into two or more distinct layers. Both of these problems usually result from air entrapment during processing. Picking is removal of a tablet’s surface material by a punch. Sticking is adhesion of tablet material to a die wall. These two problems result from excessive moisture or substances Mottling is an unequal color distribution on a tablet, with light or dark areas standing on otherwise uniform surface. This results from use of a drug with a color different from that of the tablet excipients or from a drug with colored degradation products. with low melting temperatures in the formulation IPQC PROBLEMS OF CAPSULES 1. Brittleness, 2. Unusual softness, 3. Atability of ingredients ( soft gelatin ), 4. Color fading / decolorizing, 5. Darkening and widening of capsules, 6. Appearance of dark (soft) spot 7. Improper sealing, locking , mixing, 8. Un-stability of ingredient Organoleptic properties: after compression the product must meet their individual identification that is their color &odor.
QC of FDF 1.
Appearance: - Size, shape, and thickness: This is important to facilitate packaging and to decide which tablet compressing machine to use.
2.
Organoleptic properties: which include color and odor of the tablets.
3.
Assay
Weight uniformity and content uniformity: The tablet should include the correct dose of the drug. Dissolution test: Drug should be released from tablet in a controlled time Weight variation, thickness & diameter: The appearance of tablet should be elegant & its weight, size & appearance should be consistent. Hardness & friability: The tablet should show sufficient mechanical strength to withstand fracture & erosion during manufacture & These factors must be controlled & handling during production and verified after production, hence called In-process control.
4. Packaging and labeling
PHARMACOPOEIAL QUALITY CONTROL TESTS According to BRITISH PHARMACOPOEIA QUALITY CONTROL TEST
FOR ALL TABLETS: Content of active ingredients Disintegration (coated, uncoated & effervescent tablet) Uniformity of weight Uniformity of content Dissolution test Uniformity of dispersion (for dispersible tablet) Tablet diameter
Uniformity of active ingredient It is measured to ensure a constant dose between drug and Ingredients Traditionally, dose variation between tablets is tested in two separate tests 1- Weight uniformity 2- Content uniformity If the drug forms greater part of the tablet, any variation in the tablet weight obviously indicates a variation in the active ingredient.(Weight uniformity test). if the drug is potent (USP specifies 50 mg of the active ingredient or less),the excipients form the greater part of the tablet weight and the correlation between the tablet weight and amount of the active ingredient can be poor, in this case another test(Content uniformity)must be performed. A critical step in the manufacture of an oral solid dosage form is the blending of the final granulation. If uniformity is not achieved at this stage, then one could assume that some dosage units would not comply with uniformity requirements. A. 1. 2.
Weight Variation (uniformity of weight) of tablets: Weigh 20 tablet selected at random, each one individually . X1, X2, X3… Xz Determine the average weight. X= (X1+X2 +X3+…+ Xz)/20 Limits according to U.S.P · Weight of tablet 130 mg or less then %error = ±10% · Weight of tablet 130-324 mg then %error = ±7.5% · Weight of tablet 324 mg or more then %error = ±5%
B. Content uniformity
USP defines content uniformity test for tablets containing 50mg or less of drug substance in case of uncoated tablets and for all sugar coated tablets regardless to the drug content. USP design: Ten tablets are individually assayed for their content(according to the method described in the individual monograph) The requirements for content uniformity are met if the amount of the active ingredient in each tablet lies within the range of 85 -115 % of the label claim. Upper limit = average weight + (average weight * %error) Lower limit = average weight - (average weight * %error) The individual weights are compared with the upper and lower limits.
Dissolution test Tablet into solution per unit time under standardize condition is called dissolution test. Media used in dissolution testing purified water, simulated gastric fluid, simulated intestinal fluid or others. The most commonly used apparatus for dissolution are USP apparatus I (basket) and USP apparatus II (paddle). APPARATUS-1 (BASKET TYPE): A single tablet is placed in a small mesh basket attached to the bottom of the shaft connected to motor. The basket is immersed in a dissolution medium in a variable speed. The flask is (as specified in monograph) contained in a 1000 ml flask. cylindrical with a hemispherical bottom. The flask is maintained at 37±0.5 0 C by a constant temperature bath. The motor is adjusted to turn at the specified speed and sample of the fluid are withdrawn at intervals to determine the amount of drug in solutions.
APPARATUS-2(PADDLE TYPE): It is same as apparatus-1, except the basket is replaced by a paddle. The tablet is allowed to sink to the bottom of the flask before stirring. For dissolution test U.S.P. specifies the dissolution test medium and volume, type of apparatus to be used, rpm of the shaft, time limit of the test and assay procedure. The test tolerance is expressed as a % of the labeled amount of drug dissolved in the time limit .
Disintegration test It is the time required for the tablet to break into particles, the disintegration test is a measure only of the time required under a given set of conditions for a group of tablets to disintegrate into particles. Liquids used in disintegration Water, simulated gastric fluid (PH = 1.2 HCl), or Simulated intestinal fluid (PH = 7.5, KH2PO4 (phosphate buffer) + pencreatin enzyme +NaOH)
Procedure : Start the disintegration test on 6 tablets. If one or two tablets from the 6 tablets fail disintegrate completely within 30min repeat the same test on another 12 tablet. (i.e. the whole test will consume 18 tablets). Not less then 16 tablets disintegrate completely within the time if more then two tablets (from the 18) fail to disintegrate, the batch must be rejected.
Tablet Diameter Tablet diameter is also an important test. We use Pfizer tester for checking the diameter of the tablet, screw guage and calliper are also used. Tablet thickness can be measured by micrometer or by other device. Tablet thickness should be controlled within a ± 5% variation of standard value.
Tablet thickness Tablet thickness is an important qc test for tablet packaging. Very thick tablet affects packaging either in blister or plastic container. Tablet thickness is determine by the diameter of the tablet. Pfizer tester is used for checking tablet thickness.
Hardness (crushing strength) test It is the load required to crush the tablet when placed on its edge. Why do we measure hardness? To determine the need for pressure adjustments on the tablet machine. Hardness can affect the disintegration. So if the tablet is too hard, it may not disintegrate in the required period of time. And if the tablet is too soft, it will not withstand the handling during subsequent processing such as coating or packaging. >In general, if the tablet hardness is too high, we first check its disintegration before rejecting the patch. And if the disintegration is within limit, we accept the patch. >If H. is high + disintegration is within time è accept the batch. Factors Affecting the Hardness: Compression of the tablet and compressive force. Amount of binder. (More binder à more hardness) Method of granulation in preparing the tablet (wet method gives more hardness than direct method, Slugging method gives the best hardness). Limits: 5 kilograms minimum and 8 kilograms maximum. Make hardness test on 5 tablets and then take the average hardness.
Friability test It is the tendency of tablets to powder, chip, or fragment and this can affect the elegance appearance, consumer acceptance of the tablet, and also add to tablet’s weight variation or content uniformity problems. Friability is a property that is related to the hardness of the tablet. An instrument called friabilator is used to evaluate the ability of the tablet to withstand abrasion in packaging, handling, and shipping. Procedure: 1. Weigh 20 tab altogether = W1 2. Put these tablets in the friabilator and adjust the instrument at 100 rpm (i.e. = 25 rpm for 4 min) 3. Weigh the 20 tablets (only the intact ones) = W2 4. Friability (% loss) = It must be less than or equal to1% but if more we do not reject the tablets as this test is non-official. Perform this test using 20 tablets that were used first in the weight variation test
QC of capsule Quality control should be carried out during all stages of manufacturing operation which is the primary requirement of good manufacturing practices.
Empty hard capsules According to Japanese Pharmacopoeia, the test called ‘purity’ uses five capsules which are tested individually. Each is placed in a 100 ml conical flask and shaken vigorously after adding 50 ml of water 37C throughout the test. The capsule passes the test if it completely dissolves within 10 mins giving odorless, neutral (or slightly acidic).
Weight variation For hard capsules: Accurately weigh 10 capsules. By suitable means the contents of each capsule should be removed. The weights of emptied shells should be recorded individually. The difference of both the weights will yield the net weight of the contents. Then calculate acceptance value. For soft capsules: pre weigh 10 capsules. Cut the capsules by suitable means (either scissors or any open blade) remove the contents by washing with a suitable solvent and let the solvent evaporate by placing them at room temperature for about 30 mins. Weigh the individual shells. Calculate the acceptance value
Content uniformity
Hard capsules containing 25 mg or more of the drug contents should meet content uniformity requirements. Assay 10 capsules individually and calculate the acceptance value. The requirement is met if the acceptance value of 10 capsules is less than or equal to 15%. If acceptance value is greater than 15% or is about 25 % then, test the next 20 units and calculate the acceptance value. The 30 capsules if less than or equal to 15% and no individual unit is 1-25*0.01 nor more than 1+25*0.01. Calculation of acceptance value: (Reference value-mean of individual contents ) + acceptability constant * sample standard deviation
Disintegration: The disintegration of capsules is different from those of tablets because the determination of end point is difficult owing to the adhesive nature of shell. The shell pieces after disintegration may agglomerate forming large mass of gelatin taking more time to dissolve and may adhere to the mesh thus, blocking the holes. According to USP, place one dosage unit in each of the tubes of the basket with water or any other specified medium (depends on individual monograph) maintained at 37 + 2C. Attach a removable wire cloth with a plain square weave of 1.8-2.2 mm of mesh aperture and a wire diameter of 0.60-0.655 mm to the surface of upper rack of the basket assembly.
Observe the capsules for a time limit (specified in individual monograph), at the end of prescribed time, all of the capsules must have been disintegrated excluding the fragments from the capsule shell. If 1 or 2 capsules fail, the test should be repeated on additional of 12 capsules. Then, not fewer than 16 of the total 18 capsules tested should disintegrate completely.
Dissolution test Place each of the capsules in the apparatus 1, excluding air bubbles from the surface of the capsule. Operate immediately at specified rate within specified dissolution medium at 37 + 0.5C. Aliquots should be withdrawn at specified time points mentioned in individual monograph. The requirements are met if the quantity of active ingredients dissolved conforms the following: 1) At stage 1 (S1): When 6 capsules are tested, amount of each of the dissolved content should not be less than +/- 5% of the mentioned in monograph. 2) At stage 2 (S2): when 6 capsules are tested, the average of 12 (both from step 1and 2) should be equal to or greater than 15% and no capsule should be than 15%. 3) At stage 3 (S3): when 12 capsules are tested, the average of 24 capsules (all 1,2 and 3 steps) should be equal to or greater than the amount mentioned in the monograph, not more than two units are less than 15% and no unit s less than 25%.
Machine output The manufacturing machine’s output should be monitored continuously via the dimensional correctness during each lot production. The color of the capsules should be checked against a standard strip; in case of any changes the gelatin solution should be adjusted by adding standardized dye solutions which can be ensured via thin layer chromatography.
Moisture content Moisture content can be monitored with the aid of data the drying kilns can be adjusted.
Loss on drying Determination of loss on drying via the oven method consumes more time. To prevent this advanced methods like infrared balances, humidity meter etc.
Sorting of defects After electronic or manual inspection, they are sampled by quality control inspectors. The results should meet the inspection plan, if not the capsules should be resorted or rejected depending upon frequency of faults.
Printing inspection Quality inspectors sample the lot and are inspected for quality of print. The results will again be compared with the inspection plan and in case if it does not match then, either capsules should be resorted or rejected depending upon number of faults present.
Final inspection After the capsules are placed in final containers, samples are checked for various parameters like dimensions, physical defects and color. These samples are also subjected to various microbial tests also.
QC parameter for SDF packaging and labeling Pharmaceutical manufacturers have to pack & required labeling their medicines before they can be sent out for distribution. Every pharmaceutical preparation must comply with the labeling requirements established under Good Manufacturing Practice. The label should include: (1) the name of the pharmaceutical product; (2) the name(s) of the active ingredient(s); INNs should be used wherever possible; (3) the amount of the active ingredient(s) in each capsule and the number of capsules in the container; (4) the batch (lot) number assigned by the manufacturer; (5) the expiry date and, when required, the date of manufacture; (6) any special storage conditions or handling precautions that may be necessary; (7) directions for use, warnings, and precautions that may be necessary; and (8) the name and address of the manufacturer or the person responsible for placing the product on the market. Tablets should be able to withstand handling, including packaging and transportation, without losing their integrity. Moisture-sensitive forms, such as effervescent tablets, should be stored in tightly closed containers or moisture-proof packs and may require the use of separate packages containing water-adsorbent agents, such as silica gel.
Capsules should be kept in well-closed containers. They should be protected from light, excessive moisture, or dryness, and should not be subjected to temperatures above 30 °C. Additional special packaging, storage, and transportation recommendations are specified in the individual monograph. The type of packaging will depend on the formulation of the medicine. There are generally two types of packing:1.Strip sealing 2.Blister packing - 'Blister packs' are a common form of packaging used for a wide variety of products. They are safe and easy to use and they allow the consumer to seethe contents without opening the pack. IPQC CHECKS ON PACKING LINE: Strips- number of strips Appearance of strips Text of strips & leak test Inspection of overprinting, logo, labeling are checked with the standard shade cards. Defective ones are sorted out & rejected. Packaging - sealing, printing
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