QUALITY ASSURANCE AND IN-PROCESS QUALITY CONTROL IN TABLET PRODUCTION SUBMITTED BYGURBINDER KAUR B.

PHARM

INTRODUCTION


QA is the sum total of organized arrangements made with the object of ensuring that product will be of the Quality required by their intended use. The total control of quality requires the organized effort of an entire company to assure the specified quality in each lot of drug product manufactured.The quality of oral dosage form as well as any drug dosage form must be built in during plant construction,product research ,purchasing of materials,production,testing,labeling,storage and distribution.

QC THROUGOUT PRODUCTION SYSYTEM



layout

Inputs

Conversion Production Processes

Outputs Products and Services

Raw Materials, Parts, and Supplies

Control Charts and Acceptance Tests

Control Charts

Control Charts and Acceptance Tests

Quality of Inputs

Quality of Partially Completed Products

Quality of Outputs

It cannot be assumed that end-product testing alone will ensure product quality The essential qualities of a good compressed tablet are chracterized by a number of specifications.these include appearance,size,shape,thickness,weight,stability ,hardness,dissolution time and disintegration time.

UNIFORMITY OF TABLETS DOSAGE UNITS

1.Weight variation tablet dosage-form

uniformity by weight variation is determined by selecting not less than 30 tablets from each production batch and weighing accurately 10 tablets individually and calculating the average weight. The wt.variation requirements are met if the amount of the active ingredient in each of the 10 tablets under test lies within the range of 85115% of the label claim and the relative standard deviation is less than or equal to 6%.

2.Content uniformity-Tablet dosage-form content uniformity is determined by selecting not less than 30 tablets from each production batch and assaying 10 tablets individually .  if the amount of the active ingredient in the individual tablet is less than required in the assay ,make necessary dilution of the solutions.

DISINTEGRATION TIME


 

1.Uncoated tablets- 1 tablet is placed into each glass tube and a disk is added to each tube.if one or two tablet fails to disintegrate completely,the test is repeated with 12 additonal tablets.not less than 16 of the total tablet tested must disintegrate completely. 2.Plain-coated tablets(a)they are tested by first placing a tablet in each glass tube and immerse in water at room temprature for 5min,disk is added

apparatus is operated for 30 min using simulated gastric fluid (b)if the tablet have not disintegrated completely,they are immersed in a simulated intestinal fluid,if one or two tablet fail to disintegrate completely.the test is repeated with 12 additional tablets

(3)Enteric coated-1 tablet is placed in each glass

tube and basket is immersed in water at room temprature for 5 min if the tablet has a soluble external coating apparatus is operated without adding disk for 1h using simulated gastric fluid.no tab. Should show evidence of disintintegration.Then disk is added and operated using simulated intestinal fluid for 2hr.If one or two tablet fail to disintegrate completely ,test is repeated with

Additional 12 tablet. Not less than 16 of the total 18 tablet must disntegrate completely.

DISSOLUTION TEST
STAGE NUMBER TESTED 6 S1 ACCEPTANCE CRITERIA Each unit is not less than Q+5% Average of 12 units is equal to or greater than Qand no unit is less than Q-15% Average of 24 units is equal to or greater than Q,not more than 2 units are less than Q-15%

S2

S3

12

USP/NF FOR ENTERIC COATED TABLET ACID PHASE TESTING ACCEPTANCE

LEVEL A1 NUMBER ACCEPTANCE CRITERIA TESTED 6 No individual value exceeds 10% dissolved Average of the 12 units is not more han 10% dissolved or no 6 individ.unit is greater than 25% Average of 24 units is not more than 10% dissolved,and no individ.unit is greater than 25%

A2

A3

12

USP/NF ENTERIC COATED BUFFER PHASE TESTING ACCEPTANCE

LEVEL NUMBER TESTED B1 6 B2 6 CRITERIA Each unit not less than Q+5% Average of 12 unitsis equal to orgreater than Q,no unit less than Q-15% Average of 24 units is equal or greater than Q,NMT 2 units less than Q-15%

B3

12

RAW MATERIALS


 

the storage condition of raw materials for tablet manufacturing,particularly hygroscopic substances are important,because of the great number of potential sources of contamination SAMPLING OF RAW MATERIAL Samples of raw materials are to be collected in clean containers using a disinfected sampling,observing aseptic technique for microbiological analysis or clean container for analyticlal lab.

INACTIVE RAW MATERIAL

CONTAINERS 1 2-8 9-15 6-90 91-150 151-280 NO. OF SAMPLES ALL 2 3 5 8 13

ACTIVE RAW MATERIAL

CONTAINERS 1-5 6-10 11-18 19-28 29-100 NO.SAMPLES ALL 6 7 8 9

INACTIVE OR INERT MATERIAL

A.DILUENT-latose,sucrose,kaolin,dicalcium phosphate etc are common diluents used to make up the major portion of the tablet. Its physical chracterstics,such as colour,odor and foreign material are as important as its chemical purity. Other important specification of diluent are particle size,powder uniformity,water content and microbial limit.

B. BINDERS- water,alcohol,starch paste(1018%),tragacanth(1-3%),sod.alginate etc are commonly used binders. A suitable test such as viscosity,foreign matter,residue on ignition,pH and microbial limit will evaluate the property of binders. C. LUBRICANTS- Mg.sterate,calciium sterate, talc, staeric acid,starch ,mineral oil etc are commonly used lubricants

An accurate particle size determination is recommended.if soluble lubricant is used,a completeness of solution test to assure its water solubility.heavy metal,water content,melting range and microbial limit will avaluate the proprties of lubricants D.DISINTEGRATING AGENTS- potato starch,methylcellulose,alginic acid,microcrystalline cellulose and certain gums

  

are commonly used disintegrants. Tested forForeign matter,water content,microbial limit for starches or alginic acid. Starch has a limit of NMT 14% of water content E.COLOURING AGENTS- approved certified water-souble food,drug and cosmetic(FD&C) dyes or their corresponding lakes are used to colour the tablets.

COLORANTS FD&C Blue#1 D&C green#6 Red #12 LAKES carotene Titanime dioxide

RESTRICTION ON USE Permanent listing for use in foods,drug and cosmetics Provisional listing for use in drug and cosmetics Provisional listing for use in drug and cosmetics with restriction of NMT 0.75mg to be ingested on a daily basis Permanent listing for use in foods.drug and cosmetics Permanent listing for use in drugs and cosmetics.

 

(f) flavoring agents1.flavors or volatile oils are sprayed as an alcoholic solution 2.dry flavors may be used by blending with other tablet constituent They are tested for- referacive index,specific gravity,solubility and alcohol content A GLC chromatogram that can be used as a fingerprint for each specific flavor.

 

(g)sweetening agentsmannitol,lactose,sacchrin etc are commonly used ... Tests like(i)unwanted impurities resulting from synthesis side reaction. (ii)reducing and total sugars in sorbitol (iii)water content,heavy metals,residue in ignition,arsenic melting rangeetc are checked

CONTAINERS
Container component should not interact physically or chemically with tablet product Following features are consideredProperties of container tightness Moisture and vapour tightness regardless of container construction Toxicity,chemical and physical chracterstics of material needed in container construction Compatibility of tablet and container

  

CHRACTERSTICS OF PLASTICS

POLYMER POLYETHLENE POLYSTYRENE POLYPROPYLENE

CLARITY O2 O H L H

N2 L L L

H2O H H H

C T

IN-PROCESS QUALITY ASSURANCE

There is a real and significant differnces between a finished tablet product and manufacturing quality assurance procedure The important function of the in-process quality assurance program to ensure that tablets have uniform purity and quality within a batch and batch-to-batch.

RAW MATERIALS
Quality control must check if any released raw material is to be taken to the production department in its original container,such container should be cleaned Raw material are weighed in an enviromental control weighing area where they are transferred to secondary conatiner that only circulates inside the production department.

MANUFACTURING EQUIPMENT

Quality assurance must ensure that manufacturing equipment be designed, placed and maintained in such way as to faciltate thorough cleaning, be suitable for intended use. It minimize any contamination of drugs and containers during manufacturing They should be thoroughly cleaned and maintained in accordance with specific written directions.

SAMPLING PROCEDURES


Sampling procedure can be based either on attribute inspection that grade the product as defective or nondefective Or inspection by variables for percentage defectives Variable sampling,as compared to attribute sampling required more mathematical understanding and clearical calculation. Variable data can be converted in to attribute.but reverse is not possible

SIZE AND FREQUENCY OF SAMPLES



 

As the percentage of lots in samples is increased: the sampling and sampling costs increase, and the quality of products going to customers increases. Typically, very large samples are too costly. Extremely small samples might suffer from statistical imprecision. Larger samples are ordinarily used when sampling for attributes than for variables.

WHEN TO INSPECT DURING PRODUCTION PROCESS

 

 

Inspect before costly operations. Inspect before operations that are likely to produce faulty items. Inspect before operations that cover up defects. Inspect before assembly operations that cannot be undone. On automatic machines, inspect first and last pieces of production runs, but few in-between pieces. Inspect finished products.

ACCEPTANCE PLAN
An acceptance plan is the overall scheme for either accepting or rejecting a lot based on information gained from samples. The acceptance plan identifies the: Size of samples, n Type of samples Decision criterion, c, used to either accept or reject the lot Samples may be either single, double, or sequential.

SINGLE SAMPLING PLAN

Lot of N Items Random Sample of n Items

N - n Items

c Defectives Inspect n Items Found in Sample c > c c < c n Nondefectives Reject Lot Accept Lot

Replace Defectives

DOUBLE SAMPLING PLAN

Lot of N Items Random Sample of n1 Items Inspect n1 Items n1 Nondefectives Accept Lot (to next slide)

N n1 Items c1 Defectives Found in Sample c 1 > c 2 c1 < c1 c1 < c1 < c2 Reject Lot Continue

Replace Defectives

Cont..

N n1 Items N (n1 + n2) Items Reject Lot (c1 + c2) > c2 c2 Defectives Found in Sample (c1 + c2) < c2 Random Sample of n2 Items Inspect n2 Items

Replace Defectives

Accept Lot

DOUBLE SAMPLING PLAN

 

One small sample is drawn initially. If the number of defectives is less than or equal to some lower limit, the lot is accepted. If the number of defectives is greater than some upper limit, the lot is rejected. If the number of defectives is neither, a second larger sample is drawn. Lot is either accepted or rejected on the basis of the information from both of the samples.

SEQUENTIAL SAMPLING PLAN

Units are randomly selected from the lot and tested one by one. After each one has been tested, a reject, accept, or continue-sampling decision is made. Sampling process continues until the lot is accepted or rejected.

Average outgoing quality (AOQ) Given the actual % of defectives in lots and a particular sampling plan, the AOQ is the average % defectives in lots leaving an inspection station Average outgoing quality limit (AOQL) Given a particular sampling plan, the AOQL is the maximum AOQ that can occur as the actual % defectives in lots varies

FINISHED PRODUCT
Final testing of tablets is made in the quality control lab.these test are designed to determine complaince with specification. The purpose of establishing these specifications and standards is to ensure that each tablet contains the amount of drug claimed on the label.

QUALITY CONTROL ATTRIBUTES

        

1.organoleptic chracters 2.hardness 3.friability 4.Thickness uniformity 5.Weight uniformity 6.moisture content 8.content uniformity 9.dissolution 10.stability of active ingredient in the formula and marketed container

PACKAGING OPERATION
If the quality control lab. Analysis confirms that the product complies with specifications and quality assurance audit of manufacturing operations are satisfactory,the bulk tablet is released to the packaging department . Quality assurance should peiodically check the packaging line and check filled and labelled container for compliance with written specifications

Q.A should also select a finished sample and send it to the analytical control laboratory for final testing