Flow Chart and Manufacturing Procedure of Dextromethorphan Hydrobromide, Chlorphenamine Maleate & Phenylephrine Hydrochloride Flavoured Dispersible Tablets
Bill of Material
|Quantity in kg|
|Dextromethorphan Hydrobromide and Chlorphenamine Maleate complex||12.12*#|
|Phenylephrine Hydrochloride complex||8.08**#|
|Mannitol (Pearlitol SD200, Roquette)||42.80|
|Silica, Colloidal Anhydrous||2.00|
|Sunset Yellow Lake Colour||0.80|
|Citric Acid Monohydrate||3.06@|
|Colour Lake of Sunset Yellow||0.10|
|Silica, Colloidal Anhydrous||0.50|
*Given quantity of Dextromethorphan Hydrobromide and Chlorphenamine Maleate complex is based on assay (ODB) of Chlorphenamine Maleate in the complex = 100.00 % W/W, L.O.D = 0.00 % W/W
**Given quantity of Phenylephrine Hydrochloride complex is based on assay
(ODB) = 100.00 % W/W, L.O.D = 0.00 % W/W
# Taken 1.0 % extra to compensate loss during processing.
@ Taken 2.0 % to compensate for loss during processing`
- Manufacturing Procedure :
- Manufacturing procedure in brief comprise of following steps:
- Step – I:-MILLING : Mill Citric Acid Monohydrate through comminuting mill fitted with 5 mm perforated sieve at hammer forward orientation and at medium speed and sift through vibro sifter fitted with sieve of mesh size 100 & divide in two lots (2.0 + 1.0 kg).
- Step – II:-SIFTING : Sift Dextromethorphan Hydrobromide and Chlorphenamine Maleate complex , Phenylephrine Hydrochloride complex, Mannitol , Silica, Colloidal Anhydrous, Indion 294 , Talc, Magnesium Stearate, Croscarmellose Sodium, Pharmaburst B2 through Vibro Sifter fitted with sieve of mesh size 40 collect the sifted material in IPCs.
- Step – III:-SIFTING : Sift Sunset Yellow Colour Lake through Vibro Sifter fitted with sieve of mesh size 100 collect the sifted material in IPCs.
- Step – VI:Take Citric Acid Monohydrate (2.0 kg) from step- I and manually mix with the bulk of step – III for 2-3 minutes.
- Step – V:DRY MIXING : Perform dry mixing of materials of step – II & step -IV in Blender’s bin. ( mix for 10 minutes at 6 rpm)
- Step – VI:SLUGGING : Slug the mass of step – V in Roll-Compactor, adjust and record Feed screw rate (rpm) and speed of rollers (rpm) and weigh the slugs.
- Step – VII: DESLUGGING : Mill the mass of step – VI by Multimill/ Comminuting mill fitted with 3.0 mm Screen at knife forward orientation and at slow speed
- Step – VIII: SIFTING :Sift the milled mass through Vibro Sifter fitted with sieve of mesh size 16 and pass the retention through comminuting mill fitted with 3.0 mm Screen at knife forward orientation and at slow speed , repeat the above process till all the material of step- VII passed through sieve of mesh size 16 .
- Step – IX:SIFTING :
- a) Sift the material of step – VIII through Vibro Sifter fitted with sieve of mesh size 60,collect and weigh the retention.
- b) If the retention of step IXa is more than or equal to 80 % proceed for lubrication step.
- Manufacturing procedure in brief comprise of following steps:
If the retention percentage is less than 80 % then repeat process steps (7.1.6 to 7.1.8) for retention until retention % is equal or more than 80 % ,if it is equal or more 80 % then directly proceed for next step
- Step – X:SIFTING/LUBRICATION OF GRANULES :
- a) Sift Colour Lake of Sunset Yellow through Vibro Sifter fitted with sieve of mesh size 100
- b) Sift Silica, Colloidal Anhydrous , Orange Flavour , Aspartame, Talc, Magnesium Stearate, Croscarmellose Sodium through Vibro Sifter fitted with sieve of mesh size 40.
- c) Geometrically mix Citric acid monohydrate of step -I with step -X a&b manually for 3-5 minutes.
- d) Geometrically mix the granules of step X c with step – IX then transfer the bulk to Blender’s Bin and Blend for 10 minutes at 6 rpm.
- Step – XI: WEIGHING :Weighing of lubricated granules is done by using a calibrated balance and calculate the actual .
- SAMPLING : Inform to IPQA Department through In-process Analytical Request to collect the sample of blended granules of step – XI, IPQA personnel send the sample to Quality Control Department for testing as per In-process Specification.
- Step – XII:COMPRESSION : After getting approval from IPQA Department, compress the lubricated blend of step XI, into tablets of required specification using 37 station compression machine fitted with round dies, plain punches (12.00 ± 0.05 mm).
Description : Orange coloured , round, plain, flavoured uncoated tablets.
Average Weight : 600 mg
Uniformity of mass : Individual mass of 20 tablets should not deviate by more than 5.0 % of the average weight.
Friability : NMT 2.0 %w/w
Diameter : 12.00 ± 0.05 mm
Thickness : 4.60 ± 0.20 mm
Disintegration time : Not more than 3 minutes
Uniformity of Dispersion : Shall Comply with the test
Hardness : 30 – 60 N
- IPQA CHECKS : Carry out in-process control /check as per SOP.
- SAMPLING : Inform to IPQA Department through In-process Analytical Request to collect the sample of tablets for analysis as per approved in process specification.
- WEIGHING : Collect the Compressed tablets in HDPE containers lined with double poly ethylene bags & weigh and calculate the final yield of Compressed Tablet.
PACKAGING : After getting approval from IPQA Department, pack the approved tablets of step XII as per approved BPR.
Critical Process Steps and Process Parameters for Validation with Justification:
|Process Step||Process Parameters||Justification|
|DISPENSING||% RH & Dispensing aids||Influence the stability and manufacturing of product|
|SIFTING||Sieve size, sifting time and integrity of sieve.||To evaluate the sifting time during sifting process|
|DRY-MIXING||Dry-mixing time, and Blending rpm.||After completion of sifting, the process of dry mixing is evaluated for Homogeneity of drugs through sampling of the mixed blend after 10 minutes at 6 rpm. Blending is done using Conta Blender. This process step is evaluated for adequate blending time assessment through the determination of blend uniformity analysis of samples collected from different location. It can influence both the content uniformity & assay of product.|
|SLUGGING||Feed screw rate (rpm), Speed of rollers (rpm).||To record and evaluate the variability of critical process variables for process step of slugging to achieve granules of desired properties.|
|DESLUGGING/ MILLING||Feed rate of slugs. Milling speed, Blade orientation and Screen size.||Effective deslugging is achieved by adjusting the feed rate to 10.0 kg/ 10-20 minutes.|
|SIFTING||Sieve size, sifting time and integrity of sieve.||To record and evaluate the variability of critical process variables during sifting.|
|LUBRICATION/ BLENDING||Blender speed (rpm) and Blending time etc.||After addition of sifted Post granulation ingredients to the granules; blending is done using Conta Blender. This process step is evaluated for adequate blending of the lubricant by sampling of the blended granules from different locations from the blender bin after 8 minutes of blending at 6 rpm. The assessment is taken through the determination of blend uniformity analysis in samples collected from different locations. The blend to be monitored for Bulk Density & Tapped Density, angle of repose, Compressibility Index and Hausner Ratio on the composite sample collected after 10 minutes at 6 rpm to determine the flow properties of the blended granules. Sampling is done by using suitable sampling thief.|
|COMPRESSION||Machine Speed, Description, Average Weight, Uniformity of Weight, Diameter Thickness, Disintegration time, Uniformity of dispersion, Hardness, Friability etc.||Tablets are Compressed using 37 Station Double Rotary Compression Machine. This process is evaluated through sampling the compressed tablets from both sides (left & right) produced at different intervals (Start, Middle and towards the end of compression). Samples are checked for the determination of Description, Average Weight, Uniformity of Weight, Diameter Thickness, Disintegration time, Uniformity of dispersion, Hardness, Friability against the established specifications at IPQA Laboratory
Compressed tablets are subjected for the determination of Uniformity of dosage units (by content uniformity & Dissolution.
One composite sample is subjected for complete analysis as per the established