1 IN PROCESS QUALITY CONTROL TESTS OF VARIOUS DOSAGE FORMS

2
3CONTENTS
4In process quality control tests of TABLETS
5In process quality control tests of CAPSULES
6In process quality control tests of INJECTABELS
7In process quality control tests of LIQUID ORALS
8
9IN PROCESS QUALITY CONTROL OF Tablets:
10
11Official Test
12
131. Weight variation test (uniformity of weight)
14Weigh 20 tablet selected at random, each one individually. X1, X2, X3 Xz
15 Determine the average weight. X= (X1+X2 +X3++ Xz)/2
16
17 Limit:
18 Upper limit = average weight + (average weight * % error)
19 Lower limit = average weight - (average weight * % error)
20 The individual weights are compared with the upper and lower limits.
21 Not more than two of the tablets differ from the average weight by more than the % error listed, and no tablet differs by more than
22 double that percentage.
23
24 WEIGHT VARIATION TOLERANCES FOR UNCOATED
25 USP XX-NF standards
Average wt. of tablet(mg) Max. % difference allowed
130 or Less 10%
130-324 7.5%
More than 324 5%
26

27 IP standards
Average wt. of tablet(mg) Max. % difference allowed
84 or Less 10%
84- 250 7.5%
More than 250 5%
28
292. Content Uniformity Test: Randomly select 30 tablets. 10 of these assayed individually. The Tablet pass the test if 9 of the 10 tablets must
30contain not less than 85% and not more than 115% of the labeled drug content and the 10 th tablet may not contain less than 75% and more
31than125 % of the labeled content. If these conditions are not met, remaining 20 tablet assayed individually and none may fall outside of the 85
32to 115 % range.
333. Disintegration test (U.S.P.): It is the time required for the tablet to break into particles, the disintegration test is a measure only of the
34time required under a given set of conditions for a group of tablets to disintegrate into particles it is performed to identify the disintegration of
35tablet in particular time period. Disintegration test is not performed for controlled & sustained release tablets.
36 The U.S.P. device to test disintegration uses 6 glass tubes that are 3 long; open at the top and 10 mesh screen at the bottom end. To test for
37disintegration time, one tablet is placed in each tube and the basket rack is positioned in a 1-L beaker of water, simulated gastric fluid or
38simulated intestinal fluid at 37 2 0 C such that the tablet remain 2.5 cm below the surface of liquid on their upward movement and not closer
39than 2.5 cm from the bottom of the beaker in their downward movement. Move the basket containing the tablets up and down through a
40distance of 5-6 cm at a frequency of 28 to 32 cycles per minute. Floating of the tablets can be prevented by placing perforated plastic discs on
41each tablet.
42According to the test the tablet must disintegrate and all particles must pass through the 10 mesh screen in the time specified. If any residue
43remains, it must have a soft mass.
44
45Liquids used in disintegration
46Water,
47Simulated gastric fluid (pH = 1.2 HCl),
48Or Simulated intestinal fluid (pH = 7.5, KH2PO4 (phosphate buffer) + pancreatic enzyme + NaOH)

49
50Disintegration testing conditions and interpretation
Sr Type of tablets Medium Temperature limit
no.

1 Uncoated Water 37 2 0C 15 minutes or asper individual

monograph
2 Sugar coated Water 37 2 0C 60 minutes or as per individual
If 1 or 2 tablets fail 0.1 N HCL monograph
3 Film coated Water or 0.1N HCL 37 2 0C 30 minutes or as per individual
monograph
4 Enteric coated 0.1 N HCL & 37 2 0C 1 hr in simulated gastric fluid and th
Phosphate buffer pH intestinal fluid or as per individual
6.8 monograph
5 Dispersible/ Effervescent water 37 2 0C LST < 3 minutes or as per individual
monograph
6 Buccal 37 2 0C 4 hr or as per individual monograph
51
52U.S.P. method for uncoated tablets:
53Start the disintegration test on 6 tablets.
54If one or two tablets from the 6 tablets fail disintegrate completely within 15min repeat the same test on another 12 tablet. (i.e. the whole test
55will consume 18 tablets).
56Not less than 16 tablets disintegrate completely within the time
57If more than two tablets (from the 18) fail to disintegrate, the batch must be rejected.
58For Coated tablets:
591. To remove or dissolve the coat, immerse the tablet in distilled water for 5min.
60Put the tablet in the apparatus in water or HCL for 30 min at 37oC (according to the U.S.P). If not disintegrated, put in intestinal fluid.
61 If one or two tablets fail to disintegrate, repeat on 12 tablets. So 16 tablets from the 18 must completely disintegrate within the time, if
62 two or more not disintegrated the batch is rejected.

63
64U.S.P. and B.P Method for Enteric coated tablets:
651. Put in distilled water for five minutes to dissolve the coat.
662. Then put in simulated gastric fluid (0.1M HCL) for one hour.
673. Then put in simulated intestinal fluid for two hours. If one or two tablets fail to disintegrate, repeat this test on another 12 tablets.
68 So 16 tablets from 18 should completely disintegrate. If more than two fail to disintegrate the patch must be rejected.
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724. Dissolution Test:
73ACCORDING TO USP: 7 TYPES
74 a) Basket type (type 1 )- for tablets
75 b) Paddle type (type 2)- for tablets , capsules , modified release products
76 c) Reciprocating cylinder- extended release drug product
77 d) Rotating disc drug product containing low water soluble drug
78 e) Flow through cell-transdermal patches
79 f) Paddle over disc- transdermal patches
80 g) Reciprocating disc extended release drug product
81
82ACCORDING TO I.P: 2 TYPES
83 h) Paddle type
84 i) Basket type
85
861. USP Dissolution apparatus I (Basket method)
87A single tablet is placed in a small wire mesh basket attached to the bottom of the shaft connected to a variable speed motor. The basket is
88immersed in a dissolution medium (as specified in monograph) contained in a 1000 ml flask. The flask is cylindrical with a hemispherical
89bottom. The flask is maintained at 37 0.50C by a constant temperature bath. The motor is adjusted to turn at the specified speed and sample of
90the fluid are withdrawn at intervals to determine the amount of drug in solutions.
91Details of construction of Basket Apparatus
Characteristic USP BP IP
Basket shaft 6.3-6.5 or 9.4-10.1 mm 6.3-6.5 or 9.4-10.1 mm 9.7 0.3 or 6.4 0.1 mm
Basket material (stainless steel) Type 316 Type 316 Type 316
Vent hole 2.0 0.5 mm 2.0 0.5 mm 2.0 mm
Retention Spring 3 tangs 3 tangs 3 tangs
Clear opening 20.2 0.1 mm 20.2 1.0 mm 22.2 1.0 mm
Wire diameter 0.25 mm 0.25-0.33mm 0.254mm
RPM 25-150 100 100
Height of screen 27.0 1.0mm 27.0 1.0mm 27.0 1.0mm
Total height of basket 36.8 3.0mm 37.0 3.0mm 36.8 3.0mm
Height of upper cap 5.1 0.5mm 5.1 0.5mm 5.1 0.5mm
Total height of basket 37.0 3.0mm 37.0 3.0mm 36.8 3.0mm
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962. USP Dissolution apparatus II (Paddle method)
97It is same as apparatus-1, except the basket is replaced by a paddle. The dosage form is allowed to sink to the bottom of the flask before stirring.
98For dissolution test U.S.P. specifies the dissolution test medium and volume, type of apparatus to be used, rpm of the shaft, and time limit of the
99test and assay procedure for. The test tolerance is expressed as a % of the labeled amount of drug dissolved in the time limit.
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01Non-Official Test
02
031. Hardness: Tablet requires a certain amount of strength or hardness and resistance to friability to withstand mechanical shocks of handling
04in manufacture, packaging and shipping. Hardness generally measures the tablet crushing strength.
05Hardness (crushing strength):
06It is the load required to crush the tablet when placed on its edge.
07
08Why do we measure hardness?
09 To determine the need for pressure adjustments on the tableting machine.
10 Hardness can affect the disintegration.
11 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
12 handling during subsequent processing such as coating or packaging.
13 In general, if the tablet hardness is too high, we first check its disintegration before rejecting the batch.
14 If the disintegration is within limit, we accept the batch.
15 If Hardness is high + disintegration is within time accept the batch.
16
17Factors Affecting the Hardness:
18 Compression of the tablet and compressive force.
19 Amount of binder. (More binder more hardness)
20 Method of granulation in preparing the tablet (wet method gives more hardness than direct method, Slugging method gives the best
21 hardness).
22 Limits:
23 5 kilograms minimum and 8 kilograms maximum. Make hardness test on 5 tablets and then take the average hardness.
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25Five types of testers are used.
26Monsanto hardness tester or stokes hardness tester Strong Cobb tester Pfizer tester- min 4kg Erekat tester Schleuniger or habergeon tester
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282. Thickness Test
29 Thickness of the tablet is inversely proportional to hardness i.e. increase in hardness decrease the thickness & vice versa.
30 Thickness of tablet is measured by Vernier caliper/screw gauge.
31 It is determined for 10tablets.
32 It should be within plus 5% and minus 5% of the standard value.

Vernier caliper

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35IN-PROCESS CONTROL OF CAPSULES
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371) RAW MATERIALS: The gelatine of the capsule shells should be assayed for various physical properties like bloom strength, viscosity, etc.
38.
39
402) MOISTURE PERMEATION TEST: The degree & rate of moisture penetration is determined by packaging the dosage unit together with a
41colour revealing desiccant pellet Expose the packaged unit to known relative humidity over a specified time Observe the desiccant pellet for
42colour change Any change in colour indicates absorption of moisture By measuring pre-test weight & protest weight of pellet, amount can be
43calculated.
44
453) CONTENT UNIFORMITY: 10 capsules are taken and subjected to assay. 9 of 10 capsules should be in the range of 15 %( 85-115%) and
4610 the Capsule in the range of 75-125%. If 2 Capsules are beyond 15% range. Then, 20 tablets are assayed. All capsules should be in the
47range of 25 %( 75%-125 %.)
48
49WEIGHT VARIATION:
50Weigh 20 capsules individually, and determine the average weight. The individual weights should be within the limits of 90%and 110%of the
51average weight. If not all of the capsules fall within the limits, weigh the 20capsules individually remove the contents of each capsule with the
52aid of a small brush Weigh the emptied shells individually
53
54 Net weight of contents (individual) = the weight of shell -respective gross weight.
55
56Determine the average net content from the sum of the individual net weights. Then determine the difference between each individual net
57content and the average net content Limits: Not more than 2 of the differences are greater than 10% of the average net content No case is the
58difference greater than 25% wt. range.
59
60If more than 2, but not more than 6capsules deviate from the average between 10%and 25%, determine the net contents of an additional
6140capsules, determine the average content of the entire 60capsules Determine the 60deviations from the new average Limits: Not more than 6of
62the 60capsules does the difference exceed 10%of the average net content No case does the difference exceed 25%
63
64Viscosity of gelatin solution 25-45 mill poise
65pH of gelatin A=9; B=4.7
66Moisture content 12-15%
67
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69FOR SOFT CAPSULES: Proceed as directed under Hard Capsules, but determine the net weight of the contents of individual capsules as
70follows. Weigh the capsules individually Then cut & open the capsules remove the contents by washing with a suitable solvent Allow the
71solvent to evaporate from the shells at room temperature Weigh the individual shells calculate the net contents.
72
73BLOOM STRENGTH OF GELATIN: Gelatine is weighed into water to typically create a 6.67% solution in standard Bloom bottles the
74mix is then stirred and keep it for 3 hours at room temperature. Bottles are placed in a 65C bath for 20 minutes Allow the Bloom jars to cool
75for 15 minutes at room temperature, they are then conditioned for 16 hours in 10C water bath.
76
77When conducting a gelatine bloom test, the bloom jar is cantered with the probe just above the sample surface. The probe penetrates the gelatine
78to a target depth of 4 mm at a speed of 0.5 mm/s, and then retracts. The peak force is the gel strength in Grams Bloom Chemical tests like
79purity, microbial properties, and limits for heavy metals like arsenic, ash content should be determined. The colorants should also be checked
80for purity, limits for heavy metals, colour properties, dye content, subsidiary dye content and colour value.
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82
83IN PROCESS QUALITY CONTROL OF INJECTABLES
84
85Environmental control pH Viscosity Osmolality (occasionally) Conductivity measurement Temp for heat sterilized product Volume filled
86Leakage test Clarity test Pyrogen test Sterility tests
87
881.EVIRONMENTAL CONTROL: Traffic control: A carefully designed arrangement to control and minimize the traffic Personnel should be
89permitted to enter aseptic areas only after following rigidly prescribed procedures Surface disinfection Personnel: must be inherently neat,
90orderly, reliable and alert should be in good health
91
92Air control: HEPA (High Efficiency Particulate Air): It is composed of glass fibres and filters. It is 99.97% efficient, Removes particles of
930.3m size & larger. Velocity is 10020 ft. /min.
94
952. PH MEASUREMENT:
962 different types of methods used in the measurement of pH.
97 a. 1. Dip a piece of pH paper into the sample.
98 b. 2. PH meter pH meter
99
00Viscosity and consistency directly relates with stability of solutions. Viscosity is measured by viscometer. The personnel working in the filling
01area should have complete control on filling equipments.
02
033. VISCOSITY:
04
054. CONTROL ON VOLUME FILLED:
06
075. OSMOLALITY (Occasionally):
08Osmolality is a count of the number of particles in a fluid sample. The osmolality of a solution can be measured using an ohmmeter. The most
09commonly used instrument in modern laboratories is a freezing point depression ohmmeter freezing point depression ohmmeter
10
11Measured by using conduct meter. It is also necessary measure the conductivity of the vehicle used in sterile preparations. The conductivity of
12the pure water is 0.055 S/cm (micro-Siemens/cm).
13
146. CONDUCTIVITY MEASUREMENT:
15It is important to maintain the constant temperature during heat sterilization of products. The temperature changes may cause some undesirable
16changes like change in potency, change in is tonicity etc. The temperature can be determined normal thermometer, digital thermometer.
17
187. TEMPERATURE FOR HEAT STERILIZED PRODUCTS:
19A) VISUAL INSPECTION
20B) BUBBLE TEST
21C) DYE TEST
22
238. LEAKAGE TEST: Leakage test is employed to test the package integrity. By Three Methods:
24
259. CLARITY TESTING:
26Clarity testing is carried out to check the particulate matter in the sample. It is practically impossible that every unit of lot is perfectly free from
27visible particulate matter, that is, from particles that are 30 to 40 m and larger in size. USP limits for large volume infusions: Particle Size
28Particles limit 10m and larger/ml 50 25m and larger/ml 5
29
30I) VISUAL INSPECTION BY NAKED EYE: II) INSTRUMENTAL METHODS: each injectable is inspected visually against white and
31black backgrounds. The white background aids in detection of dark coloured particles. The light or reflective particles will appear against the
32black back ground. Also called as the particles count method particles counting may be based on any one of the following principles: change in
33electrical resistance light absorption light scattering.
34
3510. STERILITY TEST: The test method for sterility of the product:
361 .Membrane filtration
372. Direct inoculation of the culture medium
38
391. Membrane filtration Solutions to be examined must be introduced and filtered under aseptic conditions all steps of this procedure are
40performed aseptically in a Class 100 Laminar Flow Hood pore size of 0.45 m effectiveness established in the retention of micro-organisms the
41size of filter discs is about 50 mm in diameter
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43
442. DIRECT INOCULATION:
45
4611. PYROGEN TEST:
47Main test: group of 3 rabbits are taken preparation and injection of the product: warming the product dissolving or dilution duration of injection:
48not more than 4 min the injected volume: not less than 0.5 ml per 1 kg and not more than 10 ml per kg of body mass determination of the initial
49and maximum temperature all rabbits should have initial T: from 38.0 to 39.8 C
50
51The Result of Pyrogen Test:
52The Result of Pyrogen Test: No. of Rabbits Individual Tempt. Rise (c) Tempt. Rise in group (c) Test 3 rabbits 0.6 1.4 Passes If above not
53passes 3+5 = 8 rabbits 0.6 3.7 Passes If above test not passes perform the test again If above test not passes, the sample is said to be pyrogenic
54
55LAL TEST:
56Limulus gametocyte lysate (LAL) test to detect or quantify endotoxins of gram-negative bacterial origin reagent: amoebocyte lysate from
57horseshoe crab (Limulus Polyphemus). LAL reacts with bacterial endotoxin. It involves 3 methods: Gel clot method turbid metric method
58Chromogenic method
59
60IN-PROCESS CONTROL OF LIQUID ORALS
61
62These are of two types:
631. Monophasic liquids Ex: Solutions, Syrups, and Elixirs, etc.
642. Biphasic liquids Ex: Emulsions, Suspensions
65
661. MONOPHASIC LIQUIDS:
67CLEAN AND PURIFIED VEHICLE (WATER): Quality control technicians test the water frequently to ensure that it is clean and pure
68before the syrup is made. The syrup is also thoroughly filtered before filling in bottles.
69
70LIGHT TRANSMITTANCE TEST: A light transmittance meter is a newer tool that is used to check syrup colour. In a light transmittance
71meter, a syrup sample is checked for colour by passing light through the sample. The percent of light transmission is compared to light
72transmission rates set for different grades.
73
74VISUAL INSPECTION: The ingredients and the final products are carefully examined for purity and for appearance. Physical appearance of
75products for patient adherence and compliance is critical so it should be Good looking, Elegant in appearance.
76PH MEASUREMENT: The measurement and maintenance of pH is also very important step in the Quality control testing. Generally there are
772 different types of methods used in the measurement of pH. The simplest and cheapest is to dip a piece of pH paper into the sample. By using
78pH meter (for greater accuracy)
79
80DETERMINATION OF SUCROSE CONCENTRATION (FOR SYRUPS ONLY): If the concentration of Sucrose in the syrup is very high
81it may crystallize the syrup, less sucrose concentrations give favour for the microbial growth. For the determination sucrose in syrup, HPLC and
82UV -spectroscopy are used.
83DETERMINATION OF ALCOHOL CONCETRATION (FOR ELIXIRS ONLY): Elixir usually contains 5 to 40% alcohol. Distillation,
84Specific gravity.
85
86BIPHASIC LIQUIDS:
871. EMULSIONS
882. SUSPENSIONS
89
903. DETERMINATION OF VISCOSITY: Determination of viscosity is done to assess the changes that might take place during aging. The
91viscometers used are cone and plate viscometers, Brookfield viscometer. 2. DETERMINATION OF PARTICLE SIZE: It is performed by
92optical microscopy and Coulter counter apparatus.
93
944. DETERMINATION OF PHASE SEPERATION (for emulsions): Phase separation may be observed visually or by measuring the volume
95of the separated phases. Or by subjecting the emulsions to various stress conditions like boiling, temperature variations, etc.
96
975. STABILITY OF SUSPENTIONS:
98SEDIMENTATION METHOD: The measurement of sedimentation volume is the most important parameter in the evaluation of stability of
99suspensions.
00RHEOLOGICAL METHOD: The viscosity of the suspension is studied at different time intervals by using a good quality of viscometer
01
02ELECTRO KINETIC METHOD: The determination of surface electric charge or zeta potential of suspension is helpful to find out the
03stability of suspension.
04MICROMERITIC METHOD: The stability of a suspension depends on the particle size of the dispense phase. A change in particle size
05distribution & crystal habit may be studied by microscopy & counter coulter method.
06
07IPQC TESTS OF SUSPENSIONS:
08
09FINAL QUALITY CONTROL OF SUSPENSIONS:
10Microscopic photography for crystal growth
11Sedimentation rate
12Sedimentation volume
13Redispersibility and Centrifugation tests Rheological measurement
14Stress test -Freeze-Thaw temperature cycling Compatibility with container and cap liner Torque test
15
16UNIFORMITY OF CONTENT:
17Suspension that contain less than 10 mg or less than 10 per cent of active ingredient comply with the following test. Empty each container and
18carry out the test on the active ingredients. Determine the content of active ingredient(s) of each of 10 containers taken at random using the
19method given in the monograph or by any other suitable analytical method. The preparation complies with the test if the individual values thus
20obtained are all between 85 to 115 per cent of the average value. The preparation fails to comply with the test if more than one individual value
21is outside the limits 85 to 115 per cent of the average value or if any one individual value is outside the limits 75 to 125 per cent of the average
22value.
23If one individual value is outside the limits 85 to 115 per cent but within the limits 75 to 125 per cent of the average value, repeat the
24determination using another 20 containers taken at random. The preparation complies with the test if in the total sample of 30 containers not
25more than 3 individual values are outside the limits 85 to 115 per cent and not more than one is outside the limits 75 to 125 per cent of the
26average value
27
28DOSE AND UNIFORMITY OF DOSE OF ORAL DROPS:
29Into a graduated cylinder, introduce by means of the dropping device or by means of measuring device the number of drops usually prescribed
30for one dose.
31The dropping speed does not exceed 2 drops per second. Weigh the liquid, repeat the addition, weigh again and carry on repeating the addition
32and weighing until a total of 10 masses are obtained. No single mass deviates by more than 10 per cent from the average mass. The total of 10
33masses does not differ by more than 15 per cent from the nominal mass of 10 doses. If necessary, measure the total volume of 10 doses. The
34volume does not differ by more than 15 per cent from the nominal volume of 10 doses.
35STORAGE: Store Oral Liquids or powders and granules for the preparation of Oral Liquids in well-closed containers at temperatures not
36exceeding 30c.
37LABELLING: The label should contain the name of any added antimicrobial preservatives.
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43IPQC Tests for Emulsions:
44
45IPQC Tests for Emulsions
46Appearance- Color, odour, taste.
47Identity test
48Drug content. Homogeneity by product assay.
49Rheology. Stability.
50Clarity. QC of water.
51pH Compatibility of product and container/closure.
52Breaking and cracking.
53
54IPQC TESTS OF SEMISOLOIDS
55A) OINTMENTS
561) PHYSICAL TESTS:
57
58a) TEST OF RATE OF ABSORPTION:
59Diadermic ointments are those from which the drug moves into deeper skin tissues and finally into the systemic circulation. Such ointments
60should be evaluated for the rate of absorption of drugs. The ointment should be applied over a definite area of the skin by rubbing. At regular
61intervals of time, serum and urine samples should be analyzed for the quantity of drug absorbed. The rate of absorption i.e., the amount of drug
62absorbed per unit time should be more.
63b) TEST OF NON-IRRITANCY:
64The bases used in the formulation of ointments may cause irritation or allergic reactions. Non-irritancy of the preparation is evaluated by patch
65test. In this test 24 human volunteers are selected. Definite quantity of ointment is applied under occlusion daily on the back or volarforearm for
6621 days. Daily the type of pharmacological action observed is noted. No visible reaction or erythema or intense erythema with edema and
67vesicular erosion should occur. A good ointment base shows no visible reaction.
68c) TEST OF RATE OF DRUG RELEASE:
69A clean test tube is taken and the internal surface is coated with the preparation as a thin layer. Saline or serum is poured into the test tube. After
70a certain period of time, the saline is analyzed for the quantity of the drug. The amount of drug when divided by the time period gives the rate of
71drug release.
72d) TEST OF RHEOLOGICAL PROPERTIES:
73The viscosity of the preparation should be such that the product can be easily removed from the container and easily applied to the skin. Using
74cone and plate viscometer the viscosity of the preparation is determined.
75e) TEST OF CONTENT UNIFORMITY:
76The net weight of contents of 10 filled ointment containers is determined. The results should match each other & with the labelled quantity. This
77test is also called minimum fill test.
78
792) MICROBIOLOGICAL TESTS
80
81a) TEST OF MICROBIAL CONTENT:
82Micro-organisms like pseudomonas aeruginosa & staphylococcus aureus may contaminate the preparation & finally infect the skin. So
83ointments should be tested for the absence of such micro-organisms. Solutions of different samples of the preparation are made. Each sample is
84inoculated into separate volumes of 0.5 ml of rabbit's plasma under aseptic conditions and incubated at 37 0 C for 1-4 hours. No formation of
85the clot in the incubated mass indicates the absence of the micro-organisms.
86TEST OF PRESERVATIVE EFFICACY:
87b) Using pour plate technique the number of micro-organisms initially present in the preparation are determined. Solutions of different samples
88of the preparation are made and mixed with Tryptone Azolectin (TAT) broth separately. All cultures of the micro-organisms are added into each
89mixture, under aseptic conditions. All mixtures are incubated. The number of micro-organisms in each sample are counted on 7th, 14th, 21st
90and 28th days of inoculation.
91MICROBIAL LIMITS: On 14th day, the number of vegetative cells should not be more than 0.1% of initial concentration.
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