SampleDossier Paracetamol Tabletas

XYZ PHARMACEUTICAL
PRODUCT REGISTRATION DOSSIER
PARACETAMOL TABLET 500 MG
A Product of :
Neutral Code :
Marketed/ Imported by :
Date of submission :
1
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XYZ PHARMACEUTICAL
SCHEDULE
APPLICATION FOR REGISTRATION OF A DRUG
CONFIDENTIAL
DEMOCRETIC REPUBLIC OF---------

MINISTRY OF PUBLIC HEALTH
DIRECTION OF PHARMACY, DRUG & LABORATORY
TECHNICAL DIVISION
SECRETARIAT-GENERAL
PART-I
1. NAME OF APPLICANT :
BUSINESS ADDRESS :
TELEPHONE NUMBER :
FAX :
2. NAME OF PRODUCT
TO BE REGISTERED :
TYPE OF FORMULATION
TO REGISTERED :
PRESENTATION OF
THE PRODUCT :
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3. IDENTIFICATION(PHYSICAL
APPERANCE OF THE PRODUCT :
4. THERAPEUTIC CLASSIFICATION
5(a) NAME OF BUSINESS

ADDRESS OF MANUFACTURER :
(b) COUNTRY OF ORIGIN :
(6) NAME OF LOCAL DISTRIBUTOR :
BUSINESS ADDRESS OF LOCAL

DISTRIBUTOR :
TELEPHONE NUMBER :
FAX NUMBER :
(7) NAME AND SIGNATURE OF

THE AUTHORIZE PERSON :
DATE :
SIGNATURE :
OFFICIAL STAMP :
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PART I
SUMMARY OF THE DOSSIER
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CTD
Module I
ADMINISTRATIVE DATA
(1) SITE MASTER PLAN OF PLANT
(2) COMPANY PROFILE IN SHORT
(3) ATTESTED COPY OF MANUFACTURING LICENCE
(4) ATTESTED COPY OF PRODUCT PERMISSION FROM FDCA
(5) ATTESTED COPY OF COPP
(6) ATTESTED COPY OF WHO/GMP CERTIFICATE
(7) COA OF SAMPLE
(8) ATTESTED COPY OF WHOLE SELL LICENCE.
(9) LETTER OF AUTHORISATION
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MODEL OF LETTER OF AUTHORISATION

COMPANY’S LETTERHEAD
LETTER OF AUTHORISATION
WE, ___________________________________________________________________
PRODUCT OWNER’S NAME AND ADDRESS
HEREBY APPOINT __________________________________________________________
APPLICANT’S NAME AND ADDRESS
TO APPLY FOR REGISTRATION OF OUR PHARMACEUTICAL PRODUCT
PRODUCT NAME,
DOSAGE FORM AND STRENGTH
WITH THE DRUG REGULATORY AUTHORITY IN (STATE COUNTRY) ON OUR BEHALF . THEY
WILL BE THE MARKETING AUTHORISATION HOLDER OF THE REGISTRATION CERTIFICATE
AND BE RESPONSIBLE FOR ALL MATTERS PERTAINING TO THE REGULATION OF THIS
PRODUCT.
SIGNATURE : __________________
Date :
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Department of Health
Food and Drug Administration
Summary Drug Information
NAME ADDRESS PHONE/FAX FOR OFFICIAL USE.
APPLICANT DATE OF
APPLICATION:
APPLICATION NO.:
ASSESSMENT FEES:
REGISTRATION
CERTIFICATE NO.:
OWNER OF DRUG DATE OF ISSUE:
DATE OF EXPIRY:
SALES CATEGORY:
VARIATION:
MANUFACTURER
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BRAND NAME COMPOSITION (INCLUDING

EXCIPIENTS & COLORING
SUBSTANCE)
NON PROPRIETARY NAME PARACETAMOL BP PARACETAMOL BP 500MG
DOSAGE FORM TABLET
STRENGTH 500MG
THERAPEUTIC CATEGORY ANALGESIC AND

ANTIPYRATIC
PRESENTATION(TYPE OF PACKING, PACK 1X100T,1X500T,10X10T

SIZE)
INDICATION: Relief mild to moderate pain and fever.
DOSAGE : Adults: One to two tablets every 4 to 6 hours up to a maximum of 8
tablets daily.
Children 6-12 years: One tablet 3 to 4 times daily as required.
Paracetamol is one of the most common analgesics used in children.

The recommended dose for children is 15mg/kg orally every four
hours.50 The maximum daily dose should be limited to 90mg/kg
up to a total of 4000mg. It can also be used rectally in children
with a dose of
0mg/kg.
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PROFORMA STATEMENT:
S.NO. TRADE NAME GENERIC NAME OR FORMULA INDICATIONS REMARK
EACH TABLET CONTAINS:

1 PARACETAMOL BP 500MG ANALGESIC &
ANTIPYRETIC
PACKING : 1x100T, 10X10T

LIFE : 3Years from the date of manufacturing
FOB PRICE : US$
MANUFACTURER :
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XYZ PHARMACEUTICAL
IA ADMINISTRATIVE DATA
1A1 PROPOSED TRADE NAME OF THE PHARMACEUTICAL PRODUCT
PARACETAMOL TABLET BP 500 MG
EACH UNCOATED TABLET CONTAINS:

PARACETAMOL BP ---------500 MG
EXCIPIENTS---------------------Q.S.
1 A 1.1 NAME OF THE ACTIVE SUBSTANCE(S)
PARACETAMOL BP 500 MG
1 A 1.2 PHARMACOTHERAPEUTIC CLASSIFICATION
ANALGESIC & ANTIPYRATICS
1A2 PHARMACEUTICAL FORM AND STRENGTH
PHARMACEUTIACLS DOSAGE : ORAL TABLET
PARACETAMOL TABLET 500 MG
EACH UN COATED TABLET CONTAINS:

EXCIPIENTS-------------------Q.S.
1 A 2.1 Route of administration
ORAL
1 A 2.2 Container
EACH BOX OF 10 X 10TABLETS
200 BOXES IN EACH CORRUGATED BOX
Shelf-life
36 MONTHS
1 A 2.3 Storage
STORE IN COOL DRY PLACE
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IA4 QUALITATIVE AND QUANTITATIVE COMPOSITION
EACH TABLETS CONTAINS
Nº Name Quantity Unity Reference

I ACTIVE SUBSTANCE(S) :
1. PARACETAMOL 500.00 mg BP
II EXCIPIENT(S)
1 LACTOSE 23.00 mg BP
2 MICRO CRYSTALINE 50.00 mg BP

CELLULOSE
3 STARCH 27.00 mg BP
4 MAGNESIUM 5.00 mg BP
STEARATE
5 SODIUM STARCH 6.00 mg BP
GLYCOLATE
6 COLLOIDAL SILICON 5.00 mg USP
DIOXIDE
7 PURIFIED TALC 4.00 mg BP
... 620.00 MG
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CTD
Module II & III
SUMMARY OF PRODUCT CHARACTERISTICS

(SPC)
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II B SUMMARY OF PRODUCT CHARACTERISTICS (SPC)
II B 1 SUMMARY OF PRODUCT CHARACTERISTICS (SPC)
II B 1.1 Proposed trade name of the pharmaceutical product
PARACETAMOL TABLET BP 500 MG
II B 1.2 Qualitative and quantitative composition
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I ACTIVE SUBSTANCE(S)
II EXCIPIENT(S)

CELLULOSE
4 MAGNESIUM 5 .00 mg BP
STEARATE
GLYCOLATE
DIOXIDE
620.00 MG
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RAW MATERIAL
SPECIFICATIONS
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SUBJECT: RAW MATERIAL SPECIFICATION

DEPARTMENT: QUALITY CONTROL
MATERIAL NAME: SPEC NO: EFFECTIVE DATE:

PARACETAMOL BP RMS/PARA/2004 REVIEW DATE: Two Years
SR TEST SPECIFICATION
NO
1. CHARACTERS A white, crystalline powder.
2. SOLUBILITY sparingly soluble in water, freely soluble in alcohol, very
slightly soluble in ether and in methylene chloride.
3. IDENTIFICATION Complies the test

4. RELATED SUBSTANCE Complies the test
5. 4-AMINOPHENOL Complies the test
6. HEAVY METALS Complies the test
7. LOSS ON DRYING NMT 0.5%
8. SULPHATED ASH NMT 0.1%
9. ASSAY 99.0-101.0%
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SUBJECT : RAW MATERIAL SPECIFICATION
DEPARTMENT : QUALITY CONTROL
MATERIAL NAME : SPEC NO: RMS/PW/2004 EFFECTIVE DATE :

PURIFIED WATER
REVIEW DATE : Two Years
SR NO TEST SPECIFICATION
1. CHARACTERS A clear liquid, colorless and tasteless
2. pH 5.0-7.0
3. Oxidisable substance To comply the test
4. Chloride To comply the test
5. Nitrate To comply the test
6. Sulphate To comply the test
7. Ammonium To comply the test
8. Calcium & Magnesium To comply the test
9. Heavy metal To comply the test
10. Residue on evaporation NMT 0.0001%
11. Microbial contamination To comply the test
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XYZ PHARMACEUTICAL
QUALITY ASSURANCE DPEARTMENT

RAW MATERIAL SPECIFICATION
Name of Material : Lactose BP

Sr.
no. TEST PARAMETERS SPECIFICATION
1. Description White, crystalline powder
2. Solubility Freely but slowly soluble in water
3. Identification
A. I.R. absorption spectrum To comply
B. By TLC To comply
C: Colour test Red colour develops.
D: Test for water To comply
4. Appearances of solutionq Solution is clear and colourless.
5. Acdidty or alkalinity NMT 0.4ml of 0.1M NaOH is required.
6. Specific optical rotation +54.4° to +55.9°
7. Absorbance (at 270 to 300 Not greater than 0.07.

nm)
8. Heavy metals (limit test) NMT 1 ppm
9. Water 4.5% to 5.5%
10. Sulphated ash NMT 0.1%
11. Microbial limit test Complies with the test for Escherichia
coli.
Additional test :
1. Black particles Free from black particles.
Storage: Store in well closed containers
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Specifications of Microcrystalline Celiulosel02fMCCP) B.P.

Test Specifications
Description White or almost white, fine or

granular powder.
Solubility Practically insoluble in water, in

acetone, in ethanol, in toluene, in
dilute acids and in a 50 g/1 solution of
sodium hydroxide.
Identification Complies as per B.P.
pH 5.0 to 7.5 for the supernatant liquid.
Conductivity Ether- Complies as per B.P.
soluble substances Maximum 0.05 %
Water-soluble substances Maximum 0.25 %
Heavy metals Loss on Maximum 10 ppm.
drying Sulphated ash Maximum 7.0 %
Maximum 0.1 %
Microbial contamination Complies as per B.P.
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Specifications of Maize Starch B.P.
Specifications
Test
Description Matt, white to slightly yellowish,

very fine Powder, which creaks when
pressed between the fingers.
Solubility Practically insoluble in cold water

and in ethanol (96 per cent). The
presence of granules with cracks or
irregularities on the edge is
exceptional.
Identification Complies as per B.P.
pH 4.0 to 7.0.
Foreign matter Complies as per B.P.
Oxidizing substances Maximum 20 ppm.
Sulphur dioxide Maximum 50 ppm.
Iron Maximum 10 ppm.
Loss on drying Maximum 15.0%
Sulphated ash Maximum 0.6 %
Microbial contamination Total viable aerobic count NMT 103

bacteria and 102 fungi per gram,
determined by plate count. It complies
with the test for Escherichia coli.
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Name of Material: Magnesium Stearate BP

(A) General Information:
Category Lubricant
Status In-active material
Tested as per BP ’
Sample Size 10 GMS. From each container
Qnty for controlled sample 20 GMS.
Time for Re-testing 1 Year
Retention time for controlled sample 1 year after expiry of the material
(B) Testing Parameters:
Sr. Test Limit
01 Characters Should Comply as per BP
02 Identification (C), (D), Should comply as per BP ‘
03 Appearance of solution Should Comply as per BP
04 Acidity or Alkalinity Should Comply as per BP
05 Chloride NMT 0.1 %
06 Sulphates NMT 0.5 %
07 Cadmium NMT 3 ppm of Cd
08 Lead NMT 10 ppm of Pb
09 Nickel NMT 5 ppm of Ni
10 Loss on drying NMT 6.0 %
11 Magnesium 4.0 – 5.0%
12 Fatty acid composition NLT 40% of stearic acid
Sum of stearic acid & palmitic acid NLT 90%
13 Microbial Contamination
Total viable aerobic count not more than 103
micro-organisms per gram, determined
by plate count. It complies with the test
for Escherichia coli)
14 Assay Should Comply as per BP
15 Fatty acid composition
SHOULD COMPLY AS PER BP
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XYZ PHARMACEUTICAL
XYZ PHARMACEUTICAL

Name of Material: Sodium Starch Glycollate BP

(A) General Information:
Category Lubricant
Status In-active material
Tested as per BP
Sample Size 10 GMS. From each container
Qnty for controlled sample 20 GMS.
Time for Re-testing 1 Year
Retention time for controlled sample 1 year after expiry of the material
(B) Testing Parameters:
Sr. Test Limit

01 Characters Should comply as per BP
02 (A),(B),(C),(D) -should comply as per BP
IDENTIFICATION
03 Appearance of gel Should comply as per BP
04 PH 5.5 – 7.5
05 Sodium Glycollate Should comply as per BP
06 Sodium Chloride NMT 1.0 %
07 Heavy Metals NMT 20 ppm
08 Iron NMT 20 ppm
09 Loss on Drying NMT 7.0 %
10 Microbial Contamination It complies with the test for Escherichia coli and
Salmonella
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XYZ PHARMACEUTICAL

Name of Material: Purified Talc

Sr.
no. TEST PARAMETERS SPECIFICATION
1. Description White coloured fine powder
2. Solubility Practically insoluble in water and in dilute

solutions of acids and alkali hydroxides.
3. Identifications
A: I.R. spectrophotometry To comply
B: Precipitate reaction White, crystalline precipitate is formed.
C: Reaction of Silicates. To comply
4. pH 7.0 to 9.0
5. Water-insoluble substances NMT 0.2%
6. Aluminium (on atomic NMT 2.0%

absorption spectrometry)
7. Calcium (on atomic NMT 0.9%

8. Iron (on atomic absorption NMT 0.25%

spectrometry)
9. Magnesium (on atomic 17.0% to 19.5%

10. Lead (on atomic absorption NMT 10 ppm

spectrometry)
11. Loss on ignition (at 1050°c NMT 7.0% w/w

to 1100°c)
12. Microbial contamination Total visible aerobic count is not more

than 102 aerobic bacteria and fungi per
gram.
Additional test :
1. Black particles Free from black particles
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Specifications of Silicon Dioxide U.S.P
Test Specifications
Description Light, white, nongritty powder of

extremely fine particle size (about 15
nm).
Solubility Insoluble in water and in acid (except

hydro fluoride); soluble in hot
solutions of alkali hydroxides
Identification To comply as per U.S.P.
pH 3.5 to 5.5
(in a 1 in 25 dispersion)
Loss on drying NMT 2.5% w/w
Loss on ignition NMT 2% w/w
Arsenic The limit is 8 ug per g
Organic volatile impurities Meets the requirements
Assay NLT 99% and NMT 100.5% of Si02
24
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Name of Material LACTOSE BP

Tested as per BRITISH PHARMACOPEIA
C12H22O11,H2O 360.3 10039-26-6
Ph Eur
Definition
Lactose monohydrate is the monohydrate of O-b-D-galactopyranosyl-(1®4)-a-D-

glucopyranose. It may be modified as to its physical characteristics and may contain varying
proportions of amorphous lactose.
Characters
A white or almost white, crystalline powder, freely but slowly soluble in water, practically
insoluble in alcohol.
Identification
First identification
A, D.
Second identification
B, C, D.
A. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum

obtained with lactose CRS.
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B. Examine by thin-layer chromatography (2.2.27), using silica gel G R as the coating

substance.
Test solution
Dissolve 10 mg of the substance to be examined in a mixture of 2 volumes of water R and 3

volumes of methanol R and dilute to 20 ml with the same mixture of solvents.
Reference solution (a)
Dissolve 10 mg of lactose CRS in a mixture of 2 volumes of water R and 3 volumes of

methanol R and dilute to 20 ml with the same mixture of solvents.
Reference solution (b)
Dissolve 10 mg each of fructose CRS, glucose CRS, lactose CRS and sucrose CRS in a
mixture of 2 volumes of water R and 3 volumes of methanol R and dilute to 20 ml with the
same mixture of solvents.
Apply separately to the plate 2 ml of each solution and thoroughly dry the starting points.
Develop over a path of 15 cm using a mixture of 10 volumes of water R, 15 volumes of
methanol R, 25 volumes of anhydrous acetic acid R and 50 volumes of ethylene chloride R,
measured accurately since a slight excess of water produces cloudiness. Dry the plate in a
current of warm air. Repeat the development immediately, after renewing the mobile phase.
Dry the plate in a current of warm air and spray evenly with a solution of 0.5 g of thymol R in
a mixture of 5 ml of sulphuric acid R and 95 ml of alcohol R. Heat at 130°C for 10 min. The
principal spot in the chromatogram obtained with the test solution is similar in position, colour
and size to the principal spot in the chromatogram obtained with reference solution (a). The
test is not valid unless the chromatogram obtained with reference solution (b) shows four
clearly separated spots.
C. Dissolve 0.25 g in 5 ml of water R. Add 5 ml of ammonia R and heat in a water-bath at

80°C for 10 min. A red colour develops.
D. It complies with the test for water (see Tests).
Tests
Appearance of solution
Dissolve 1.0 g in water R, heating to 50°C, dilute to 10 ml with the same solvent and allow to
cool. The solution is clear (2.2.1) and not more intensely coloured than reference solution
BY7 (2.2.2, Method II).
Acidity or alkalinity
Dissolve 6.0 g by boiling in 25 ml of carbon dioxide-free water R, cool and add 0.3 ml of
phenolphthalein solution R. The solution is colourless. Not more than 0.4 ml of 0.1M sodium
hydroxide is required to change the colour of the indicator to pink.
Specific optical rotation (2.2.7)
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Dissolve 10.0 g in 80 ml of water R, heating to 50°C. Allow to cool and add 0.2 ml of dilute
ammonia R1. Allow to stand for 30 min and dilute to 100.0 ml with water R. The specific
optical rotation is +54.4° to +55.9°, calculated with reference to the anhydrous substance.
Absorbance (2.2.25)
Dissolve 1.0 g in boiling water R and dilute to 10.0 ml with the same solvent (solution A).
The absorbance of the solution measured at 400 nm is not greater than 0.04. Dilute 1.0 ml of
solution A to 10.0 ml with water R. Examine the solution from 210 nm to 300 nm. At
wavelengths from 210 nm to 220 nm, the absorbance is not greater than 0.25. At
wavelengths from 270 nm to 300 nm, the absorbance is not greater than 0.07.
Heavy metals (2.4.8)
Dissolve 4.0 g in water R with warming, add 1 ml of 0.1M hydrochloric acid and dilute to 20
ml with water R. 12 ml of the solution complies with limit test A for heavy metals (5 ppm).
Prepare the standard using lead standard solution (1 ppm Pb) R.
Water (2.5.12)
4.5 per cent to 5.5 per cent, determined on 0.50 g by the semi-micro determination of water,
using a mixture of 1 volume of formamide R and 2 volumes of methanol R as the solvent.
Sulphated ash
Not more than 0.1 per cent. To 1.0 g add 1 ml of sulphuric acid R, evaporate to dryness on a
water-bath and ignite to constant mass.
Microbial contamination
Total viable aerobic count (2.6.12) not more than 102 micro-organisms per gram, determined
by plate-count. It complies with the test for Escherichia coli (2.6.13).
Storage
Store in an airtight container .
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Name of Material MICROCRYSTALLINE CELLULOSE BP

Action and use Pharmaceutical aid.
DEFINITION
Microcrystalline cellulose is a purified, partly depolymerised cellulose prepared by treating

alpha-cellulose, obtained as a pulp from fibrous plant material, with mineral acids.
CHARACTERS
A white or almost white, fine or granular powder, practically insoluble in water, in acetone, in
ethanol, in toluene and in dilute acids and in a 50 g/l solution of sodium hydroxide.
(1) IDENTIFICATION
A. Place about 10 mg on a watch-glass and disperse in 2 ml of iodinated zinc chloride

solution R. The substance becomes violet- blue.
B. Transfer 1.300 g to a 125 ml conical flask. Add 25.0 ml of water R and 25.0 ml of 1M
cupriethylenediamine hydroxide solution. Immediately purge the solution with nitrogen R,
insert the stopper and shake until completely dissolved. Transfer 7.0 ml of the solution to a
suitable capillary viscometer (2.2.9). Equilibrate the solution at 25±0.1°C for not less than 5
min. Record the flow time, t1, in seconds, between the two marks on the viscometer.
Calculate the kinematic viscosity n1 of the solution using the formula:
t1(k1),
where k1 is the viscometer constant.
Dilute a suitable volume of 1M cupriethylenediamine hydroxide solution with an equal

volume of water R and measure the flow time, t2, using a suitable capillary viscometer.
Calculate the kinematic viscosity n2 of the solvent using the formula:
t2(k2),
where k2 is the viscometer constant.
Determine the relative viscosity hRel of the substance to be examined using the formula:
h1/h2.
Determine the intrinsic viscosity, [h]c, by interpolation, using the Intrinsic Viscosity Table
(Table 315-1 see Cellulose, powdered).
Calculate the degree of polymerisation P using the formula:
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where m is the mass in grams, of the substance to be examined and b is the loss on drying
as a percentage.
The degree of polymerisation is not more than 350.
TESTS
(2) Solubility Dissolve 50 mg in 10 ml of ammoniacal solution of copper tetrammine R. It
dissolves completely, leaving no residue.
(3) pH (2.2.3). Shake 5 g with 40 ml of carbon dioxide-free water R for 20 min and
centrifuge. The pH of the supernatant liquid is 5.0. to 7.5.
(4) Ether-soluble substances Prepare a column using 10.0 g in a tube about 20 mm in
internal diameter. Pass 50 ml of peroxide-free ether R through the column. Evaporate the
eluate to dryness. The residue weighs not more than 5.0 mg (0.05 per cent).
(5) Water-soluble substances Shake 5.0 g with 80 ml of water R for 10 min. Filter with the
aid of vacuum into a tared flask. Evaporate to dryness on a water-bath and dry at 100°C to
105°C for 1 h. The residue weighs not more than 12.5 mg (0.25 per cent).
(6) Starch To 10 g add 90 ml of water R and boil for 5 min. Filter whilst hot. Cool and add to
the filtrate 0.1 ml of 0.05M iodine. No blue colour is produced.
(7) Heavy metals (2.4.8). 2.0 g complies with limit test C for heavy metals (10 ppm).
Prepare the standard using 2 ml of lead standard solution (10 ppm Pb) R.
Method: (2.4.8)
Test C Place the prescribed quantity (usually not more than 2 g) of the substance being
examined in a silica crucible with 4 ml of a 25% w/v solution of magnesium sulphate in 1M
sulphuric acid. Mix using a fine glass rod and heat cautiously. If the mixture is liquid,
evaporate gently to dryness on a water bath. Progressively heat to ignition, not allowing the
temperature to exceed 800°, and continue heating until a white or at most greyish residue is
produced. Allow to cool, moisten the residue with 0.2 ml of 1M sulphuric acid, evaporate,
ignite again and allow to cool. The total period of ignition must not exceed 2 hours. Dissolve
the residue using two 5-ml quantities of 2M hydrochloric acid. Add 0.1 ml of phenolphthalein
solution and 13.5M ammonia dropwise until a pink colour is produced. Cool, add glacial
acetic acid until the solution is decolorised and add a further 0.5 ml. Filter if necessary and
dilute the solution to 20 ml with water.
To 12 ml of the resulting solution add 2 ml of acetate buffer pH 3.5, mix, add to 1.2 ml of
thioacetamide reagent, mix immediately and allow to stand for 2 minutes. Any brown colour
produced is not more intense than that obtained by treating in the same manner a mixture of
2 ml of the test solution obtained above and 10 ml of the 20 ml of solution obtained by
repeating the procedure using the prescribed volume of lead standard solution (10 ppm Pb)
in place of the substance being examined, adding 4 ml of a 25% w/v solution of magnesium
sulphate in 1M sulphuric acid and beginning at the words 'Mix with a fine glass rod…'. The
standard solution exhibits a slightly brown colour when compared to a solution prepared by
treating in the same manner a mixture of 10 ml of water and 2 ml of the solution being
examined.
(8) Loss on drying (2.2.32). Not more than 6.0 per cent, determined on 1.0 g by drying in
an oven at 100°C to 105°C for 3 h.
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Method (2.2.32)
Place the prescribed quantity of the substance being examined in a weighing bottle
previously dried under the conditions prescribed for the substance being examined. Dry the
substance to constant weight or for the prescribed time by one of the following procedures.
(a) In a desiccator The drying is carried out over phosphorus pentoxide at atmospheric
pressure and at room temperature.
(b) In vacuo The drying is carried out over phosphorus pentoxide at a pressure of 1.5 to
2.5 kPa at room temperature.
(c) In vacuo within a specified temperature range The drying is carried out over
phosphorus pentoxide at a pressure of 1.5 to 2.5 kPa within the temperature range specified
in the monograph.
(d) In an oven within a specified temperature range The drying is carried out in an oven
within the temperature range specified in the monograph.
(e) Under high vacuum The drying is carried out over phosphorus pentoxide at a
pressure not exceeding 0.1 kPa at the temperature prescribed in the monograph.
If other conditions are prescribed, the procedure to be used is described in full in the
individual monograph.
(9) Sulphated ash (2.4.14). Not more than 0.1 per cent, determined on 1.0 g.
Method: (2.4.14)
Heat a silica or platinum crucible to redness for 30 minutes, allow to cool in a desiccator and
weigh. Place a suitable quantity of the substance being examined, in the crucible, add 2 ml of
1M sulphuric acid and heat, first on a water bath, then cautiously over a flame and then
progressively to about 600°. Continue incineration until all black particles have disappeared
and then allow to cool. Add a few drops of 1M sulphuric acid, incinerate as before and allow
to cool. Add a few drops of a 15.8% w/v solution of ammonium carbonate, evaporate to
dryness and incinerate carefully. Allow to cool, weigh, incinerate for 15 minutes and repeat
this procedure to constant weight.
(10) Microbial contamination Total viable aerobic count (2.6.12) not more than 103 micro-
organisms per gram and with a limit for fungi of 102 per gram, determined by plate-count. It
complies with the tests for Escherichia coli, for Pseudomonas aeruginosa, for
Staphylococcus aureus and for Salmonella (2.6.13).
(2.6.13)
Escherichia coli
Prepare the product to be examined as described in the general method Appendix XVI B2
(2.6.12) and use 10 ml or the quantity corresponding to 1 g or 1 ml to inoculate 100 ml of
broth medium A, homogenise and incubate at 35° to 37° for 18 to 48 hours. Shake the
container, transfer 1 ml to 100 ml of broth medium G and incubate at 43° to 45° for 18 to 24
hours. Subculture on plates of agar medium H at 35° to 37° for 18 to 72 hours. Growth of red,
non-mucoid colonies of Gram-negative rods indicates the possible presence of E. coli. This is
confirmed by suitable biochemical tests, such as indole production. The product passes the
test if such colonies are not seen or if the confirmatory biochemical tests are negative.
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Salmonella
(2.6.12), but using broth medium A in place of buffered sodium chloride-peptone solution pH
7.0, homogenise and incubate at 35° to 37° for 18 to 24 hours. Transfer 1 ml of the
enrichment culture to 10 ml of broth medium I and incubate at 41° to 43° for 18 to 24 hours.
Subculture on at least two different agar media chosen from agar medium J, agar medium K
and agar medium L. Incubate at 35° to 37° for 18 to 72 hours. The probable presence of
salmonellae is indicated by the growth of cultures having the following appearance:
agar medium J: well-developed, colourless colonies,
agar medium K: well-developed, red colonies, with or without black centres,
agar medium L: small, transparent, colourless or pink or opaque-white colonies, often

surrounded by a pink or red zone.
Transfer separately a few of the suspect colonies to agar medium M in tubes, using surface
and deep inoculation. The presence of salmonellae is provisionally confirmed if in the deep
inoculation but not in the surface culture there is a change of colour from red to yellow and
usually a formation of gas, with or without production of hydrogen sulphide in the agar.
Precise confirmation may be carried out by appropriate biochemical and serological tests.
The product passes the test if colonies of the type described do not appear or if the
confirmatory biochemical and serological tests are negative.
Pseudomonas aeruginosa
broth medium A, homogenise and incubate at 35° to 37° for 18 to 48 hours. Subculture on a
plate of agar medium N and incubate at 35° to 37° for 18 to 72 hours. If no growth of micro-
organisms is detected, the product passes the test. If growth of gram-negative rods occurs,
transfer some material of morphologically different, isolated colonies to broth medium A and
incubate at 41° to 43° for 18 to 24 hours. The product passes the test if no growth occurs at
41° to 43°.
When testing transdermal patches, filter 50 ml of preparation A as described in the general

method Appendix XVI B2 (2.6.12) through a sterile filter membrane and place in 100 ml of
broth medium A and incubate at 35° to 37° for 18 to 48 hours. After incubation spread on
agar medium N.
Staphylococcus aureus
broth medium A, homogenise and incubate at 35° to 37° for 18 to 48 hours. Subculture on a
plate of agar medium O and incubate at 35° to 37° for 18 to 72 hours. Black colonies of
gram-positive cocci, surrounded by a clear zone indicate the presence of S. aureus.
Confirmation may be effected by suitable biochemical tests such as the coagulase test and
the deoxyribonuclease test. The product passes the test if colonies of the type described do
not appear on agar medium O or if the confirmatory biochemical tests are negative.
31
XYZ PHARMACEUTICAL
When testing transdermal transdermal patches, filter 50 ml of preparation A as described in

the general method Appendix XVI B2 (2.6.12) through a sterile filter membrane and place in
100 ml of broth medium A and incubate at 35° to 37° for 18 to 48 hours. After incubation
spread on agar medium O.
Nutritive and selective properties of the media and validity of the test
The tests described hereafter must be performed at least on each lot of dehydrated media.
Proceed as follows. Grow the following test strains separately, in tubes containing suitable
media such as those indicated, at 30° to 35° for 18 to 24 hours:
Staphylococcus aureus such as ATCC 6538 (NCIMB 9518, CIP 4.83): broth medium A,
Pseudomonas aeruginosa such as ATCC 9027 (NCIMB 8626, CIP 82.118): broth medium
A
Escherichia coli such as ATCC 8739 (NCIMB 8545, CIP 53.126): broth medium A
Salmonella typhimurium no strain number is recommended (a salmonella not pathogenic

for man, such as Salmonella abony (NCTC 6017, CIP 80.39), may also be used): broth
medium A.
Dilute portions of each of the cultures using buffered sodium chloride-peptone solution pH
7.0 to make test suspensions containing about 1000 viable micro-organisms per millilitre. Mix
equal volumes of each suspension and use 0.4 ml (approximately 100 micro-organisms of
each strain) as an inoculum in tests for S. aureus, Ps. aeruginosa, E. coli and Salmonellae in
the presence and in the absence of the product to be examined. A positive result for the
respective microorganisms must be obtained.
Total viable aerobic count (2.6.12)

Plate count methods
A. POUR-PLATE METHOD Using Petri dishes 9 cm in diameter, add to each dish 1 ml of

the sample prepared as described in the section 'Preparation of the sample' and 15 ml to 20
ml of a liquefied agar medium suitable for the cultivation of bacteria (such as medium B), or
15 ml to 20 ml of a liquefied agar medium suitable for the cultivation of fungi (such as
medium C) at not more than 45°. If larger Petri dishes are used the amount of agar is
increased accordingly. Prepare for each medium at least two Petri dishes for each level of
dilution. Incubate the plates at 30° to 35° (20° to 25° for fungi) for five days, unless a reliable
count is obtained in a shorter time. Select the plates corresponding to one dilution and
showing the highest number of colonies less than 300 (100 colonies for fungi). Take the
arithmetic average of the counts and calculate the number of colony-forming units per gram
or millilitre.
32
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Name of Material Magnesium Stearate BP

DEFINITION
Magnesium stearate is a mixture of magnesium salts of different fatty acids consisting mainly
of stearic acid [(C17H35COO)2Mg; 591.3] and palmitic acid [(C15H31COO)2Mg; 535.1] and in
minor proportions other fatty acids. It contains not less than 4.0 per cent and not more than
5.0 per cent of Mg (Ar 24.30), calculated with reference to the dried substance. The fatty acid
fraction contains not less than 40.0 per cent of stearic acid and the sum of stearic acid and
palmitic acid is not less than 90.0 per cent.
CHARACTERS
A white, very fine, light powder, greasy to the touch, practically insoluble in water and in
ethanol.
IDENTIFICATION
First identification: C, D.
Second identification: A, B, D.
A. The residue obtained in the preparation of solution S has a freezing point not lower than
53°C.
B. The acid value of the fatty acids is 195 to 210, determined on 0.200 g of the residue
obtained in the preparation of solution S dissolved in 25 ml of the prescribed mixture of
solvents.
C. Examine the chromatograms obtained in the test for fatty acid composition. The retention
times of the principal peaks in the chromatogram obtained with the test solution are
approximately the same as those of the principal peaks in the chromatogram obtained with
the reference solution.
D. 1 ml of solution S gives the reaction of magnesium.
TESTS
Solution S: To 5.0 g add 50 ml of peroxide-free ether R, 20 ml of dilute nitric acid R and 20

ml of distilled water R and heat under a reflux condenser until
33
XYZ PHARMACEUTICAL

dissolution is complete. Allow to cool. In a separating funnel, separate the aqueous layer and
shake the ether layer with two quantities, each of 4 ml, of distilled water R. Combine the
aqueous layers, wash with 15 ml of peroxide-free ether R and dilute to 50 ml with distilled
water R (solution S). Evaporate the organic layer to dryness and dry the residue at 100°C to
105°C. Keep the residue for identification A and B.
Acidity or alkalinity: To 1.0 g add 20 ml of carbon dioxide-free water R and boil for 1 min with
continuous shaking. Cool and filter. To 10 ml of the filtrate add 0.05 ml of bromothymol blue
solution R1. Not more than 0.5 ml of 0.01M hydrochloric acid or 0.01M sodium hydroxide is
required to change the colour of the indicator.
Chlorides: 0.5 ml of solution S diluted to 15 ml with water R complies with the limit test for
chlorides (0.1 per cent).
Sulphates: 0.3 ml of solution S diluted to 15 ml with distilled water R complies with the limit
test for sulphates (0.5 per cent).
Cadmium: Not more than 3 ppm of Cd, determined by atomic absorption spectrometry.
Test solution. Place 50.0 mg of the substance to be examined in a polytetrafluoroethylene

digestion bomb and add 0.5 ml of a mixture of 1 volume of hydrochloric acid R and 5
volumes of cadmium- and lead-free nitric acid R. Allow to digest at 170°C for 5 h. Allow to
cool. Dissolve the residue in water R and dilute to 5.0 ml with the same solvent.
Reference solutions. Prepare the reference solutions using cadmium standard solution (10
ppm Cd) R, diluted if necessary with a 1 per cent V/V solution of hydrochloric acid R.
Measure the absorbance at 228.8 nm, using a cadmium hollow-cathode lamp as a source of
radiation and an air-acetylene flame.
Lead: Not more than 10 ppm of Pb, determined by atomic absorption spectrometry.
Test solution. Use the solution described in the test for cadmium.
34
XYZ PHARMACEUTICAL

Reference solutions. Prepare the reference solutions using lead standard solution (10 ppm
Pb) R, diluted if necessary with water R.
Measure the absorbance at 283.3 nm, using a lead hollow-cathode lamp as a source of
radiation and an air-acetylene flame, depending on the apparatus the line at 217.0 nm may
be used.
Nickel: Not more than 5 ppm of Ni, determined by atomic absorption spectrometry.
Test solution. Use the solution described in the test for cadmium.
Reference solutions. Prepare the reference solutions using nickel standard solution (10 ppm
Ni) R, diluted if necessary with water R.
Measure the absorbance at 232.0 nm, using a nickel hollow-cathode lamp as a source of
radiation and an air-acetylene flame.
Loss on drying: Not more than 6.0 per cent, determined on 1.000 g by drying in an oven at
100°C to 105°C.
Microbial contamination: Total viable aerobic count not more than 103 micro-organisms per
gram, determined by plate count. It complies with the test for Escherichia coli).
ASSAY
Magnesium: To 0.250 g in a 250 ml conical flask add 50 ml of a mixture of equal volumes of

butanol R and ethanol R, 5 ml of concentrated ammonia R, 3 ml of ammonium chloride buffer
solution pH 10.0 R, 30.0 ml of 0.1M sodium edetate and 15 mg of mordant black 11 triturate
R. Heat to 45°C to 50°C until the solution is clear and titrate with 0.1M zinc sulphate until the
colour changes from blue to violet. Carry out a blank titration.
1 ml of 0.1M sodium edetate is equivalent to 2.431 mg of Mg.
Fatty acid composition: Examine by gas chromatography.
35
XYZ PHARMACEUTICAL

Test solution. In a conical flask fitted with a reflux condenser, dissolve 0.10 g of the
substance to be examined in 5 ml of boron trifluoride-methanol solution R. Boil under a reflux
condenser for 10 min. Add 4 ml of heptane R through the condenser and boil again under a
reflux condenser for 10 min. Allow to cool. Add 20 ml of a saturated solution of sodium
chloride R. Shake and allow the layers to separate. Remove about 2 ml of the organic layer
and dry over 0.2 g of anhydrous sodium sulphate R. Dilute 1.0 ml of the solution to 100.0 ml
with heptane R.
Reference solution. Prepare the reference solution in the same manner as the test solution
using 50.0 mg of palmitic acid CRS and 50.0 mg of stearic acid CRS instead of magnesium
stearate.
The chromatographic procedure may be carried out using:
— a fused-silica column 30 m long and 0.32 mm in internal diameter coated with

macrogol 20,000 R (film thickness 0.5 µm),
— helium for chromatography R as the carrier gas at a flow rate of 2.4 ml/min,
— a flame-ionisation detector,
with the following temperature programme:
Inject 1 µl of the reference solution. When the chromatograms are recorded in the prescribed
conditions, the retention time of methyl palmitate relative to that of methyl stearate is about
0.88. The test is not valid unless, in the chromatogram obtained with the reference solution,
the resolution between the peaks corresponding to methyl stearate and methyl palmitate is at
least 5.0.
Inject 1 µl of the test solution. Calculate the percentage content of stearic acid and palmitic
acid from the areas of the peaks in the chromatogram obtained with the test solution by the
normalisation procedure, disregarding the peak due to the solvent.
STORAGE
Store in a well-closed container.
36
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Name of Material
Sodium Starch Glycollate (Type C) BP
DEFINITION
Sodium starch glycollate (type C) is the sodium salt of a cross-linked by physical

dehydration, partly O-carboxymethylated starch. It contains not less than 2.8 per cent and
not more than 5.0 per cent of Na (Ar 22.99), calculated with reference to the substance
washed with alcohol (80 per cent V/V) and dried.
CHARACTERS
A white or almost white, fine, free-flowing powder, very hygroscopic, soluble in water,
practically insoluble in methylene chloride. It gives a translucent gel-like product in water.
Examined under a microscope it is seen to consist of granules, irregularly shaped, ovoid or

pear-shaped, 30 µm to 100 µm in size, or rounded, 10 µm to 35 µm in size; compound
granules consisting of two to four components occur occasionally; the granules have an
eccentric hilum and clearly visible concentric striations; between crossed nicol prisms, the
granules show a distinct black cross intersecting at the hilum; small crystals are visible at the
surface of the granules. The granules show considerable swelling in contact with water.
IDENTIFICATION
A. It complies with the test for pH .
B. Mix with shaking and without heating 4.0 g and 20 ml of carbon dioxide-free water R. The
mixture has the appearance of a gel. Add 100 ml of carbon dioxide-free water R and shake:
the gel remains stable (difference from types A and B). Keep the gel for the tests for
appearance of gel and pH.
C. To 5 ml of the gel obtained in identification test B add 0.05 ml of iodine solution R1. A dark
blue colour is produced.
D. Solution S gives reaction (a) of sodium.
TESTS
Solution S Place 2.5 g in a silica or platinum crucible and add 2 ml of a 250 g/l solution of
sulphuric acid R. Heat on a water-bath, then cautiously over a naked
37
XYZ PHARMACEUTICAL
Name of Material
flame, raising the temperature progressively, and then incinerate in a muffle furnace at
600±25°C. Continue heating until all black particles have disappeared. Allow to cool, add a
few drops of sulphuric acid R and heat and incinerate as described above. Allow to cool, add
a few drops of ammonium carbonate solution R, evaporate to dryness and incinerate
cautiously. Allow to cool and dissolve the residue in 50 ml of water R.
Appearance of gel The gel prepared under identification test B is colourless .
pH The pH of the gel prepared under identification test B is 5.5 to 7.5.
Sodium glycollate Carry out the test protected from light.
Test solution. Place 0.20 g of the substance to be examined in a beaker. Add 5 ml of acetic
acid R
and 5 ml of water R. Stir until dissolution is complete (about 10 min). Add 50 ml of acetone R
and 1 g
of sodium chloride R. Filter through a fast filter paper impregnated with acetone R, rinse the
beaker and filter with acetone R. Combine the filtrate and washings and dilute to 100.0 ml
with acetone R. Allow to stand for 24 h without shaking. Use the clear supernatant liquid.
Reference solution. Dissolve 0.310 g of glycollic acid R, previously dried in vacuo over
diphosphorus pentoxide R, in water R and dilute to 250.0 ml with the same solvent. To 5.0 ml
of this solution, add 5 ml of acetic acid R and allow to stand for about 30 min. Add 50 ml of
acetone R and 1 g of sodium chloride R and dilute to 100.0 ml with acetone R.
Heat 2.0 ml of the test solution on a water-bath for 20 min. Cool to room temperature and
add 20.0 ml of 2,7-dihydroxynaphthalene solution R. Shake and heat on a water-bath for 20
min. Cool under running water, transfer to a volumetric flask and dilute to 25.0 ml with
sulphuric acid R, maintaining the flask under running water. Within 10 min, measure the
absorbance at 540 nm using water R as the compensation liquid. The absorbance of the
solution prepared with the test solution is not greater than that of a solution prepared at the
same time and in the same manner with 2.0 ml of the reference solution (2.0 per cent).
Sodium chloride Not more than 1 per cent. Shake 1.00 g with 20 ml of alcohol (80 per cent
V/V) R for 10 min and filter. Repeat the operation four times. Dry the residue to constant
mass at 100°C and set aside for the assay. Combine the filtrates. Evaporate to dryness, take
up the residue with water R and dilute to 25.0 ml with the same solvent. To 10.0 ml of the
solution add 30 ml of water R
38
XYZ PHARMACEUTICAL
Name of Material
and 5 ml of dilute nitric acid R. Titrate with 0.1M silver nitrate, determining the end-point
potentiometrically , using a silver indicator electrode.
1 ml of 0.1M silver nitrate is equivalent to 5.844 mg of NaCl.
Iron 10 ml of solution S complies with the limit test for iron (20 ppm).
Heavy metals 1.0 g complies with limit test D for heavy metals (20 ppm). Prepare the
standard using 2 ml of lead standard solution (10 ppm Pb) R.
Loss on drying Not more than 7.0 per cent, determined on 1.000 g by drying in an oven at
100°C to 105°C for 4 h.
Microbial contamination It complies with the test for Escherichia coli and Salmonella .
ASSAY
To 0.250 g of the dried and crushed residue obtained in the test for sodium chloride add 80
ml of anhydrous acetic acid R and heat under a reflux condenser for 2 h. Cool the solution to
room temperature. Titrate with 0.1M perchloric acid, determining the end-point
potentiometrically. Carry out a blank test.
1 ml of 0.1M perchloric acid is equivalent to 2.299 mg of Na.
STORAGE
Store in an airtight container, protected from light.
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Name of Material COLLOIDAL SILICON DIOXIDE

Tested as per USP
Molecular Formula:SiO2
Mol. Wt. 60.08
Category: Pharmaceutical aid (tablet excipient).
Description: Light, fine, white, amorphous powder. It has a particle size of about 15 nm.
Solubility: Practically insoluble in water and in mineral acids with the exception of
hydrofluoric acid. Dissolves in hot solutions of alkali hydroxides. When 1 g is shaken
vigorously with 20 ml of carbon tetrachloride for 3 minutes; a transparent gel is produced.
STANDARDS
Colloidal Silicon Dioxide contains not less than 99.0 per cent and not more than 100.5 per
cent of SiO2, calculated with reference to the ignited substance.
Identification: About 20 mg gives the reaction of silicates.
pH: Between 3.5 and 5.5, determined in a suspension of 1 g in 30 ml of carbon dioxide-free

water.
Chloride: To 1.0 g add a mixture of 20 ml of 2M nitric acid and 30 ml of water, heat on a

water-bath for 15 minutes, shaking frequently, dilute to 50 ml with water if necessary, filter
and cool. The filtrate complies with the limit test for chlorides. (250 ppm).
Arsenic: To 2.5 g contained in a round-bottomed flask add 50 ml of 3M hydrochloric acid

and heat under a reflux condenser for 30 minutes. Cool, filter with the aid of suction and
transfer the filtrate to a 100-ml volumetric flask. Wash the filter with several portions of hot
water and add the washings to the volumetric flask. Cool, dilute to volume with water and
mix. To 50.0 ml of the solution add 3 ml of hydrochloric acid; the resulting solution complies
with the limit test for arsenic, (8 ppm).
Heavy metals: Not more than 25 ppm, determined by Method D on 12 ml of a solution

prepared in the following manner. Suspend 2.5 g in sufficient water to produce a semi-fluid
slurry and dry at 140o. When the dried substance is white, break up the mass using a glass
rod, add 25 ml of 1M hydrochloric acid, boil gently for 5 minutes, stirring frequently with the
glass rod, centrifuge for 20 minutes and filter the supernatant liquid through a membrane
filter. To the residue in the centrifuge tube add 3 ml of 2M hydrochloric acid and 9 ml of
water, boil, centrifuge for 20 minutes and filter the
40
XYZ PHARMACEUTICAL
Name of Material COLLOIDAL SILICON DIOXIDE

Tested as per USP
supernatant liquid through the same membrane filter. Wash the residue with small quantities
of water, combine the filtrates and washings and dilute to 50.0 ml with water. To 20.0 ml of
the solution add 50 mg of L-ascorbic acid and 1 ml of strong ammonia solution, neutralise
with 2M ammonia and dilute to 25 ml with water. Use lead standard solution (1 ppm Pb) to
prepare the standard.
Loss on ignition: Not more than 5.0%, determined on 0.2 g by igniting at 900o in a platinum
crucible for 2 hours
Assay: To the residue obtained in the test for Loss on ignition add 0.2 ml of sulphuric acid
and sufficient ethanol (95%) to moisten the residue completely, add 6 ml of hydrofluoric acid
and evaporate to dryness on a hot plate at 95o to 105o, avoiding loss from sputtering. Wash
the sides of the dish with 6 ml of hydrofluoric acid, evaporate to dryness in a well-ventilated
hood, ignite at 1000o, allow to cool in a desiccator and weigh. The difference between the
weight of the final residue and that of the residue obtained in the test for Loss on ignition
represents the amount of SiO2 in the amount of the substance taken for the test for Loss on
ignition.
41
XYZ PHARMACEUTICAL
Name of Material
Purified Talc BP
DEFINITION
Talc is a powdered, selected, natural, hydrated magnesium silicate. Pure talc has the
formula [Mg3Si4O10(OH) 2; Mr 379.3]. It may contain variable amounts of associated minerals
among which chlorites (hydrated aluminium and magnesium silicates), magnesite
(magnesium carbonate), calcite (calcium carbonate) and dolomite (calcium and magnesium
carbonate) are predominant.
CHARACTERS
A light, homogeneous, white or almost white powder, greasy to the touch (non abrasive),
practically insoluble in water, in alcohol and in dilute solutions of acids and alkali hydroxides.
IDENTIFICATION
First identification: A.
Second identification: B, C.
A. Examine by infrared absorption spectrophotometry. The spectrum shows absorption
bands at 3677 ± 2 cm-1, at 1018 ± 2 cm-1 and at 669 ± 2 cm-1. Examine the substance as
discs prepared using potassium bromide R.
B. In a platinum crucible, melt a mixture of 0.2 g of anhydrous sodium carbonate R and 2.0
g of potassium carbonate R. To the melted mass add 0.1 g of the substance to be examined
and heat until the mixture is completely melted. Allow to cool and transfer the melted mass
into an evaporating dish with 50 ml of hot water R. Add hydrochloric acid R until
effervescence ceases. Add 10 ml of hydrochloric acid R and evaporate to dryness on a
water-bath. Allow to cool. Add 20 ml of water R, heat to boiling and filter. (The residue is
used for identification test C). To 5 ml of the filtrate add 1 ml of ammonia R and 1 ml of
ammonium chloride solution R and filter. To the filtrate add 1 ml of disodium hydrogen
phosphate solution R. A white, crystalline precipitate is formed.
C. The residue obtained in identification test B gives the reaction of silicates.
TESTS
Solution S1: Weigh 10.0 g of the substance to be examined into a conical flask fitted with a
reflux condenser, add 50 ml of 0.5M hydrochloric acid gradually while stirring and heat on a
water-bath for 30 min. Allow to cool. Transfer the mixture to a beaker and allow the
undissolved material to settle. Filter the supernatant through medium-speed filter paper into
a 100 ml volumetric flask, retaining as much as possible of the insoluble material in the
beaker. Wash the residue and the beaker with three
42
XYZ PHARMACEUTICAL
Name of Material
Purified Talc BP
quantities, each of 10 ml, of hot water R. Wash the filter with 15 ml of hot water R, allow the
filtrate to cool and dilute to 100.0 ml with the same solvent.
Solution S2: Weigh 0.5 g of the substance to be examined in a 100 ml

polytetrafluoroethylene dish, add 5 ml of hydrochloric acid R, 5 ml of lead-free nitric acid R,
and 5 ml of perchloric acid R. Stir gently then add 35 ml of hydrofluoric acid R and evaporate
slowly to dryness on a hot plate. To the residue, add 5 ml of hydrochloric acid R, cover with
a watch-glass, heat to boiling and allow to cool. Rinse the watch-glass and the dish with
water R. Transfer into a volumetric flask containing 5 ml of a 25.34 g/l solution of caesium
chloride R, rinse the dish with water R and dilute to 50.0 ml with the same solvent.
pH: The pH of the filtrate obtained in the test for water- soluble substances, is 7.0 to 9.0.
Read the pH 1 min after inserting the electrode.
Water-soluble substances: To 10.0 g add 50 ml of carbon dioxide- free water R, heat to

boiling and maintain boiling under a reflux condenser for 30 min. Allow to cool, filter through
a medium-speed filter paper and dilute to 50.0 ml with carbon dioxide-free water R. Take
25.0 ml of the filtrate, evaporate to dryness and heat at 105°C for 1 h. The residue weighs
not more than 10 mg (0.2 per cent).
Aluminium: Not more than 2.0 per cent of aluminium, determined by atomic absorption
spectrometry.
Test solution. To 5.0 ml of solution S2 add 10 ml of a 25.34 g/l solution of caesium chloride
R, 10.0 ml of hydrochloric acid R and dilute to 100.0 ml with water R.
Reference solutions. Into four identical volumetric flasks, each containing 10.0 ml of
hydrochloric acid R and 10 ml of a 25.34 g/l solution of caesium chloride R, introduce
respectively 5.0 ml, 10.0 ml, 15.0 ml and 20.0 ml of aluminium standard solution (100 ppm
Al) R and dilute to 100.0 ml with water R.
Measure the absorbance at 309.3 nm, using an aluminium hollow- cathode lamp as the
radiation source and a nitrous oxide- acetylene flame.
Calcium: Not more than 0.9 per cent of calcium, determined by atomic absorption
spectrometry.
Test solution. To 5.0 ml of solution S2 add 10.0 ml of hydrochloric acid R, 10 ml of
lanthanum chloride solution R and dilute to 100.0 ml with water R.
hydrochloric acid R and 10 ml of lanthanum chloride solution R, introduce respectively
43
XYZ PHARMACEUTICAL
Name of Material
Purified Talc BP
1.0 ml, 2.0 ml, 3.0 ml and 4.0 ml of calcium standard solution (100 ppm Ca) R1 and dilute to
100.0 ml with water R.
Measure the absorbance at 422.7 nm using a calcium hollow- cathode lamp as the radiation
source and a nitrous oxide- acetylene flame.
Iron: Not more than 0.25 per cent of iron, determined by atomic absorption spectrometry.
Test solution. To 2.5 ml of solution S1, add 50.0 ml of 0.5M hydrochloric acid and dilute to
Reference solutions. Into four identical volumetric flasks, each containing 50.0 ml of 0.5M
hydrochloric acid, introduce respectively 2.0 ml, 2.5 ml, 3.0 ml and 4.0 ml of iron standard
solution (250 ppm Fe) R and dilute to 100.0 ml with water R.
Measure the absorbance at 248.3 nm using an iron hollow-cathode lamp as the radiation
source and an air-acetylene flame. Make a correction using a deuterium lamp.
Magnesium 17.0 per cent to 19.5 per cent of magnesium, determined by atomic absorption
spectrometry.
Test solution. Dilute 0.5 ml of solution S2 to 100.0 ml with water R. To 4.0 ml of the solution,
add 10.0 ml of hydrochloric acid R, 10 ml of lanthanum chloride solution R and dilute to
hydrochloric acid R and 10 ml of lanthanum chloride solution R, introduce respectively 2.5
ml, 3.0 ml, 4.0 ml and 5.0 ml of magnesium standard solution (10 ppm Mg) R1 and dilute to
Measure the absorbance at 285.2 nm using a magnesium hollow- cathode lamp as the
radiation source and an air-acetylene flame.
Lead: Not more than 10 ppm of lead, determined by atomic absorption spectrometry.
Test solution. Use solution Sl.
Reference solutions. Into four identical volumetric flasks, each containing 50.0 ml of 0.5M
hydrochloric acid, introduce respectively 5.0 ml, 7.5 ml, 10.0 ml and 12.5 ml of lead standard
solution (10 ppm Pb) R1 and dilute to 100.0 ml with water R.
44
XYZ PHARMACEUTICAL
Name of Material
Purified Talc BP
Measure the absorbance at 217.0 nm using a lead hollow-cathode lamp as the radiation
source and an air-acetylene flame.
Loss on ignition: Not more than 7.0 per cent, determined on 1.00 g by ignition to constant
weight at 1050°C to 1100°C.
Microbial contamination: If intended for topical administration, the total viable aerobic
count (2.6.12) is not more than a total of 102 aerobic bacteria and fungi per gram.
If intended for oral administration, the total viable aerobic count is not more than a total of
103 aerobic bacteria and not more than 102 fungi per gram.
LABELLING
The label states, where applicable, that the substance is suitable for oral or topical
administration.
45
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Maize starch
Definition
Maize starch is obtained from the caryopsis of Zea mays L.
Characters
■ Appearance
Matt, white to slightly yellowish, very fine powder which creaks when
pressed between the fingers.
■ Solubility
Practically insoluble in cold water and in alcohol.
The presence of granules with cracks or irregularities on the edge is
exceptional.
It is tasteless.
Identification
A. Examined under a microscope, using not less than 20 x
magnification and using equal volumes of glycerol R and water R, it
appears as either angular polyhedral granules of irregular sizes with
diameters ranging from about 2 mm to about 23 mm or as rounded or
spheroidal granules of irregular sizes with diameters ranging from about 25
mm to about 35 mm. The central hilum consists of a distinct cavity or two-
to five-rayed cleft and there are no concentric striations. Between crossed
nicol prisms, the starch granules show a distinct black cross intersecting at
the hilum.
B. Suspend 1 g in 50 ml of water R, boil for 1 min and cool. A thin,

cloudy mucilage is formed.
C. To 10 ml of the mucilage obtained in identification test B add 0.04

ml of iodine solution RL An orange-red to dark blue colour is produced
which disappears on heating.
46
XYZ PHARMACEUTICAL
Tests
■ pH (2.2.3)
4.0 to 7.0.
Shake 5.0 g with 25.0 ml of carbon dioxide-free water R for 60 s. Allow
to stand for 15 min.
■ Foreign matter
Examined under a microscope using a mixture of equal volumes of
glycerol R and water R, not more than traces of matter other than starch
granules are present. No starch grains of any other origin are present.
■ Oxidising substances (2.5.30)
Maximum 20 ppm, calculated as H202.
■ Sulphur dioxide (2.5.29)
Maximum 50 ppm.
■ Iron (2.4.9)
Maximum 10 ppm.
Shake 1.5 g with 15 ml of dilute hydrochloric acid R. Filter. The filtrate
Complies with the limit test for iron.
■ Loss on drying (2.2.32)
Maximum 15.0 per cent, determined on 1.000 by drying in an oven at
130°Cfor90min.
■ Sulphated ash (2.4.14)
Maximum 0.6 per cent, determined on 1.0 g.
■ Microbial contamination
Total viable aerobic count (2.6.12) not more than 103 bacteria and 102
fungi per gram, determined by plate count. It complies with the test for
Escherichia coli (2.6.13).
Storage
In an airtight container .
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CONCERNING CHEMICAL,
PHARMACEUTICAL AND
BIOLOGICAL DOCUMENTATION FOR
CHEMICAL ACTIVE SUBSTANCE(S)
48
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DRUG DESCRIPTION
Generic Name
PARACETAMOL TABLET (Acetaminophen)
Physical Properties Of The Chemical Entity1
a. Structural Formula
b. Molecular Formula
C8H9NO2
c. Molecular Weight
151.16
d. Macroscopic Appearance
Acetaminophen is a white, crystalline powder.
e. Solubility
water 1:70
boiling water 1:20
alcohol 1:10
chloroform 1:50
glycerin 1:40
ether slightly soluble
Chemical Properties
a. Structural Similarities/Differences of the Drug to Other Available Compounds or

Groups of Compounds
Acetaminophen is a synthetic, nonopiate, centrally acting analgesic derived from p-

aminophenol. The full chemical name is N-acetyl-p-aminophenol.
b. pKa
The pKa of acetaminophen is 9.51 at 25°C.
c. Stability of the Drug to Temperature, Light, and Moisture
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Acetaminophen is stable to temperature, light, and moisture.
d. pH Range Over Which Drug is Stable in Solution
Acetaminophen is stable at a pH between 4 and 7 at 25°C.
e. pH of Commercially Available Liquid Products
Acetaminophen oral solution (ie, elixir, adult liquid) has a pH of 3.8 to 6.1 and the oral
suspension (ie, infants' drops, children's suspension) has a pH of 5.4 to 6.9.
f. Osmolarity/Osmolality of Commercially Available Solutions
Extra Strength PARACETAMOL acetaminophen Adult Liquid: 3058 ± 152 mmol/kg
Children's PARACETAMOL acetaminophen Elixir: 6040 ± 25 mmol/kg
Because of the nature of suspension formulations, osmolarity of the PARACETAMOL

acetaminophen suspension products cannot be determined.
References
1. Remington's Pharmaceutical Sciences. 23rd ed. Easton, PA: Mack Publishing Company;
1995:1109-1110.
*Permission to use the Product Information Form for the American Hospital Formulary
Service as modified by McNeil Consumer Healthcare has been granted by the American
Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, MD 20814.
The answers to all questions are prepared and furnished by the manufacturer. The answers
were not supplied by the Society nor are they intended to imply the endorsement of the
American Society of Health-System Pharmacists; neither does the Society affirm or deny the
accuracy of the answers contained herein. Copyright© 1985, American Society of Health-
System Pharmacists, Inc., all rights reserved.
INDICATIONS
DOSAGE RANGE
a. Administration
PARACETAMOL acetaminophen products are only administered orally. They are available
in a variety of convenient dosage forms as listed in Tables 2 and 3. For ease of administration
for young children, Infants' f Concentrated Drops are more concentrated than the Children's
PARACETAMOL liquid formulations. Infants' PARACETAMOL Concentrated Drops
labeling instructs consumers to use only the dropper enclosed in the carton to dose the product
and not to use any other dosing device with the product, such as spoons, droppers, or cups that
come with other medicines. The labeling on Children's PARACETAMOL liquid formulations
instructs consumers to use only the measuring cup enclosed in the package to dose the
product and not to use any other dosing device, such as kitchen teaspoons, droppers, or cups
that come with other medicines. PARACETAMOL Arthritis Extended Relief Caplets should
not be crushed, chewed, or dissolved in a liquid.
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b. Adult Dosage
For adults and children 12 years of age and older, the recommended dose of acetaminophen is
650 to 1000 mg every 4 to 6 hours as needed, not to exceed 4000 mg in 24 hours (Table 2).
For extended-release acetaminophen, the dose is 1300 mg every 8 hours as needed, not to
exceed 3900 mg in 24 hours. Some adult products (Extra Strength PARACETAMOL,
PARACETAMOL Arthritis Extended Relief Formula) are not intended for use in children
under 12 years of age.
c. Pediatric Dosage
For children under 12 years of age, the recommended dose of acetaminophen is 10 to 15
mg/kg every 4 to 6 hours,47 not to exceed five doses (50-75 mg/kg) in 24 hours (Table 3).
Age-Related Dosing Schedule
The age-related schedule is based on standard age divisions proposed by the United States
Food and Drug Administration (FDA) and used in the development of an acetaminophen
dosing schedule.47
TABLE 4. Recommended pediatric dosing of acetaminophen by weight and age

(adapted from reference 47, with permission)*
Weight Single Recommended

Agea doseb (mg)
lb kg daily dose (mg)
6-11 2.0 - 5.4 0-3 monthsc 40 200
12 -17 5.5 - 7.9 4-11 months 80 400
18 -23 8.0 - 10.9 12 - 23 months 120 600
24-35 11.0 - 15.9 2-3 years 160 800
36-47 16.0 - 21.9 4-5 years 240 1200
48-59 22.0 -26.9 6-8 years 320 1600
60-71 27.0 - 31.9 9-10 years 400 2000
72-95 32.0 -43.9 11 years 480 2400
* Refer to package label for more specific information related to dosing.
a
For adults and children 12 years of age and older see Table 2.
b
Doses may be repeated every 4 hours but not more than five times daily
c
Data not available to define appropriate adjustments, if any, needed for the
immediate neonatal period. Use of antipyretics in the immediate neonatal period is
extremely limited.
Weight-Related Dosing Schedule
This weight-related dosing schedule was developed and recommended by McNeil Consumer
Healthcare when dosing by weight. The weight-related schedule is based on weight ranges
that are consistent with the use of a standard 80-mg dosage unit.47 Using this method, the
weight-related dosage schedule provides a dose of 10 to 15 mg/kg body weight for a single
dose. The weight-related schedule most closely approximates this dose, so that when possible,
consumers should be instructed to use weight to calculate dose; otherwise, age may be used
(Table 4).
The label for Regular Strength PARACETAMOL acetaminophen products recommends that
children 6 to 11 years old take 325 mg every 4 to 6 hours, not to exceed five doses in 24
hours.
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d. Use of Recommended Doses for Longer Than 10 Days

Clinical studies have evaluated the use of acetaminophen in adult patients with osteoarthritis
of the knee at recommended doses of 4000 mg/d for up to 4 weeks.48,49 Williams and
colleagues50 evaluated the use of acetaminophen in doses up to 2600 mg/d for up to 2 years.
In these studies, acetaminophen was well tolerated.
The package label for adult PARACETAMOL acetaminophen products instructs adults not to
take PARACETAMOL for pain for more than 10 days or for fever for more than 3 days
unless directed by a doctor. The package label for Children's PARACETAMOL products
instructs parents not to administer PARACETAMOL to children for pain for more than 5 days
or for fever for more than 3 days unless directed by a doctor. As with all over-the-counter
(OTC) analgesics, this warning is necessary so that patients and parents will seek appropriate
medical evaluation of their condition if it persists beyond these time periods.
e. Alternate/Concomitant Dosing
Concomitant or alternate dosing with more than one antipyretic agent is not recommended.
There are no studies to support alternate dosing of acetaminophen and ibuprofen or other
nonsteroidal anti-inflammatory drugs (NSAIDs). Studies have demonstrated that single-dose
concurrent administration of aspirin and acetaminophen produced a more prolonged
temperature decrement than when either antipyretic was given alone.51,52
f. Recommended Storage Conditions
Storage requirements for all PARACETAMOL acetaminophen drops, liquids, and solid
formulations are as follows: store at room temperature. It is recommended that high humidity
and excessive heat (ie, ≥ 40°C [104°F]) be avoided for the gelatin-coated formulations (eg,
gelcaps, geltabs). Freezing of the liquid or suspension formulations should be avoided.
g. Expiration Dating Periods for Commercially Available Products
Under room temperature storage conditions, PARACETAMOL acetaminophen solid
formulations are generally stable for 3 years and liquid formulations are generally stable for 2
years from the date of manufacture. Refer to product package for specific expiration date.
References
47. Temple AR. Pediatric dosing of acetaminophen. Pediatr Pharmacol. 1983;3:321-327.
48. Amadio P, Cummings DM. Evaluation of acetaminophen in the management of

osteoarthritis of the knee. Curr Ther Res. 1983;34:59-66.
49. Bradley J D, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an anti-
inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the
treatment of patients with osteoarthritis of the knee. N Engl J Med. 1991;325: 87-91.
50. Williams HJ, Ward JR, Egger MJ, et al. Comparison of naproxen and acetaminophen in a
two-year study of treatment of osteoarthritis of the knee. Arthritis Rheum. 1993;36:1196-
1206.
51. Simila S, Keinanen S, Kouvalainen K. Oral antipyretic therapy: evaluation of benorylate,

an ester of acetyl-salicylic acid and paracetamol. Eur J Pediatr. 1975;121:15-20.
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52. Steele RW, Young FH, Bass JW, Shirkey HC. Oral antipyretic therapy: evaluation of
aspirin-acetaminophen combination. Am J Dis Child. 1972;123:204-206.
SIDE EFFECTS
No information provided.
DRUG INTERACTIONS
Potential Drug-Drug Interactions
Alcohol
The package label for adult TYLENOL® acetaminophen products contains an alcohol
warning that states, "If you consume 3 or more alcoholic drinks every day, ask your doctor
whether you should take acetaminophen or other pain relievers/fever reducers.
Acetaminophen may cause liver damage."
Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive
acetaminophen use, although reports of this event are rare. Although some authors suggest
that alcoholics may be at increased risk from therapeutic doses, reports usually involve cases
of severe chronic alcoholics and the dosages of acetaminophen most often exceed
recommended doses and often involve substantial overdose.108-110 Studies evaluating the
metabolism of doses up to 20 mg/kg of acetaminophen in chronic alcohol abusers and a study
evaluating the effects of 2 days of acetaminophen dosing at 4000 mg daily in chronic
alcoholics undergoing detoxification do not support an increased risk of hepatotoxicity with
recommended doses of acetaminophen.111-115
Healthcare professionals should alert their patients who regularly consume large amounts of
alcohol not to exceed recommended doses of acetaminophen.
Anticonvulsants
Some reports have suggested that patients taking long-term anticonvulsants, who overdose on
acetaminophen, may be at increased risk of hepatotoxicity because of accelerated metabolism
of acetaminophen.137,138 Available data are conflicting. A 7-year retrospective study of
acetaminophen overdose admissions indicates that the overall mortality rate was not
significantly different for patients taking concomitant anticonvulsant medications.139
Hydantoins
At usual oral therapeutic doses of acetaminophen and hydantoins, no special dosage

adjustment or monitoring is generally required. Pharmacokinetic studies indicate that
phenytoin primarily induces the glucuronidation pathway, whereas glutathione-derived
metabolites are not increased in patients on chronic phenytoin therapy.140 Additionally, recent
data demonstrate that phenytoin is metabolized primarily by CYP2C9 and CYP2C19,141
whereas acetaminophen is primarily metabolized by CYP2E1. These data indicate that there
is no increased risk from an acetaminophen overdose in patients on chronic hydantoin
therapy.
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Carbamazepine
At usual oral therapeutic doses of acetaminophen and carbamazepine, no special dosage

adjustment is generally required. Carbamazepine is primarily metabolized by CYP3A4,
whereas acetaminophen is metabolized primarily via CYP2E1.141 It is not known whether
there is increased risk from an acetaminophen overdose in patients on chronic carbamazepine
therapy.
Diflunisal
Professional literature from the manufacturer of diflunisal cautions that concomitant

administration with acetaminophen produces an approximate 50% increase in plasma levels
of acetaminophen in normal volunteers.142 Acetaminophen had no effect on diflunisal plasma
levels. The clinical significance of these findings has not been established. However, caution
should be used with concomitant administration of diflunisal and acetaminophen and patients
should be monitored carefully.
Isoniazid
Some reports suggest that patients on chronic isoniazid therapy may be at risk for developing
hepatotoxicity from an acetaminophen overdose at doses that would not have been expected
to produce toxicity.143-145 Since patients on isoniazid therapy may develop hepatic effects
from isoniazid alone, data from individual case reports are unclear as to whether chronic
administration of isoniazid may increase the risk of acetaminophen toxicity. Volunteer studies
demonstrate that isoniazid inhibits the formation of the toxic metabolite of acetaminophen
when taken concurrently, indicating that isoniazid could actually protect against
hepatotoxicity from an acetaminophen overdose.146,147 However, it also appears that isoniazid
acetylation genotype may play a role in the activity of CYP2E1,148 and based on acetylation
genotype, inhibition or induction may be present following discontinuation of isoniazid
therapy. In two studies of induction, any evidence suggesting increase of activity was only
seen during a brief period from 12 to 48 hours after discontinuation of isoniazid.147,148
Oral Anticoagulants
Many factors, including diet, medications, and environmental and physical states, may affect
how a patient responds to anticoagulant therapy.142 There have been several reports that
suggest that acetaminophen may produce hypoprothrombinemia (elevated international
normalized ratio [INR] or prothrombin time) when administered with coumarin
derivatives.149-151 In other studies, prothrombin time did not change.152-154 Reported changes
have been generally of limited clinical significance, however, periodic evaluation of
prothrombin time should be performed when these agents are administered concurrently. In
the period immediately following discharge from the hospital or whenever other medications
are initiated, discontinued, or taken regularly, it is important to monitor patient response to
anticoagulation therapy with additional prothrombin time or INR determinations.142
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WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Safety Perspectives, Toxicology, And Special Precautions

a. Safety
Central Nervous System Effects
Acetaminophen at recommended doses has no obvious effects on central nervous system

function.33 In an overdose situation, central nervous system effects are uncommon. Coma or
other evidence of central nervous system depression usually is not present unless the patient
has taken a massive overdose, has taken other central nervous system-active agents
concomitantly, or is experiencing central nervous system effects secondary to fulminant
hepatic failure.
Cross-Reactivity of Acetaminophen With Aspirin and NSAIDs
Most studies do not show any cross-reactivity with the use of acetaminophen in aspirin-
sensitive patients.82-85 In one study, when asthmatic patients who were sensitive to very low
doses of aspirin were challenged with doses of 1000 to 1500 mg of acetaminophen, a
proportion had evidence of decreased pulmonary forced expiratory volume at 1 second
(FEV1), but, in contrast to the aspirin reactions, the reactions to acetaminophen were generally
mild and easily reversed.86 No reactions were seen with acetaminophen at doses of 650 mg or
less. Acetaminophen is recommended as the analgesic/antipyretic of choice in
aspirin/NSAID-sensitive patients.
Gastrointestinal Effects
In recommended therapeutic doses, acetaminophen does not cause gastric irritation, gastric
erosions, occult or overt gastrointestinal blood loss, or ulcers.87,88 In a placebo-controlled,
randomized, double-blind, crossover, endoscopy study in 12 healthy volunteers, 1000 mg of
aspirin evoked a lesion score of 2.5 (possible scores ranged from 0 [no mucosal lesions] to 3
[more than 10 petechiae or free blood in the lumen]), whereas 1000 mg of acetaminophen and
placebo resulted in scores of 1.0 and 0.92, respectively.89 Several case-controlled studies have
established that gastrointestinal bleeding is a significant risk with both regular and occasional
aspirin or NSAID use, whereas acetaminophen is not associated with a risk for
gastrointestinal bleeding.90-92 a case-controlled study evaluating first-time peptic ulcer patients
found no significant risk associated with acetaminophen use prior to gastric ulcer occurrence,
whereas this was not the case with aspirin.93 An American College of Gastroenterology
survey found that OTC aspirin and NSAIDs were used significantly more often by patients in
the gastrointestinal bleeding population than in controls. However, this was not the case with
acetaminophen.94
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Hematologic Effects
A case-controlled, multicenter study established that acetaminophen is not associated with

agranulocytosis or aplastic anemia.95 Although there have been infrequent reports, primarily
letters to the editor, in which thrombocytopenia was noted in patients receiving
acetaminophen, no causality was established.96-101
Hemostatic Effects
In various clinical conditions, acetaminophen may be preferred because it does not have any
immediate or delayed effects on small-vessel hemostasis, as measured by bleeding time. In
normal volunteers receiving a single dose of acetaminophen (975 or 1950 mg) or multiple
doses of acetaminophen (1950 mg daily for 6 weeks), no change in bleeding time or platelet
aggregation was observed.102 In another study, a single 1000-mg dose of acetaminophen was
given to normal volunteers and did not affect bleeding time or platelet aggregation. 103
Patients with hemophilia receiving multiple doses of acetaminophen showed no significant
changes in bleeding time.104,105
Hepatic Effects
In clinical studies in adults, acetaminophen when taken in therapeutic doses of up to 4000

mg/d demonstrated no adverse hepatic effects. Two double-blind, randomized, controlled
trials have demonstrated the safety of acetaminophen with chronic use. In one study, Bradley
and colleagues49 compared acetaminophen (4000 mg/d) with analgesic (1200 mg/d) and anti-
inflammatory (2400 mg/d) doses of ibuprofen for 4 weeks. In the second study, Williams and
associates50 evaluated the relative safety and efficacy of acetaminophen (2600 mg/d)
compared with naproxen (750 mg/d) for up to 2 years. In both of these studies, no clinically
important hepatic events occurred in aceta-minophen-treated patients. In a large clinical study,
Lesko and Mitchell106 enrolled more than 84,000 febrile children in a randomized, double-
blind, acetaminophen-controlled trial to assess the risks of rare but serious adverse events
following use of pediatric ibuprofen. Of the children included in the analysis, 28,130 received
acetaminophen and none experienced serious adverse hepatic effects.
Acetaminophen in massive overdosage may cause hepatotoxicity in some patients. In adults

and adolescents, hepatotoxicity may occur following ingestion of greater than 7.5 to 10 g (ie,
24 regular-strength or 15 extra-strength caplets or tablets) over a period of 8 hours or less.
Fatalities are infrequent (less than 3% to 4% of untreated cases) and have rarely been reported
with overdoses less than 15 g (ie, 45 regular-strength or 30 extra-strength caplets or tablets).
In children, amounts less than 150 mg/kg are highly unlikely to produce hepatotoxicity. In
both adults and children, toxicity associated with acetaminophen is almost invariably caused
by ingestion of quantities of the drug that are significantly above the recommended dosage
range. Hepatotoxicity, ranging from transient sharp transaminase elevations to fatal, fulminant
hepatic failure, is the most common result of clinically significant overdosage.107
Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive
acetaminophen use, although reports of this event are rare. Although some authors suggest
that alcoholics may be at increased risk from therapeutic doses, reports usually involve cases
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of severe chronic alcoholics and the dosages of acetaminophen most often exceed
recommended doses and often involve substantial overdose.108-110 Studies evaluating the
metabolism of doses up to 20 mg/kg of acetaminophen in chronic alcohol abusers and a study
evaluating the effects of 2 days of acetaminophen dosing at 4000 mg daily in chronic
alcoholics undergoing detoxification do not support an increased risk of hepatotoxicity with
recommended doses of acetaminophen.111-115
A report has suggested that hepatotoxicity following greater than the recommended dose of
acetaminophen may be enhanced by both fasting and/or chronic alcohol ingestion.116 Review
of this case series revealed that all patients reported taking overdoses of acetaminophen, most
had reported prolonged periods of fasting, and the majority had a history of the abuse of
alcohol.
Hypersensitivity and Allergy
Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to

acetaminophen are rare and generally are controlled by discontinuation of the drug and, when
necessary, symptomatic treatment.
Pregnancy/Teratogenicity
Acetaminophen labeling, like all OTC medications, instructs consumers who are pregnant or
nursing a baby to contact their doctor before use. Acetaminophen has been used for over 40
years and available data indicate that acetaminophen in therapeutic doses does not adversely
affect the pregnant mother or the fetus.
Transplacental Passage
Analysis of urine samples has demonstrated the passage of unconjugated acetaminophen via
placental transfer.23 When given to the mother in therapeutic doses, acetaminophen crosses
the placenta into fetal circulation as early as 30 minutes after ingestion, although the
difference in serum concentration between maternal and cord blood is not statistically
significant.24 In the fetus, acetaminophen is effectively metabolized by sulfate conjugation.25
Nursing
Maternal ingestion of acetaminophen in recommended analgesic doses does not present a risk
to the nursing infant. Amounts in milk range from 0.1% to 1.85% of the ingested maternal
dose.26-28 These studies have established that, even at the time of peak acetaminophen
concentration in human breast milk, the nursing infant would receive less than 2% of the
maternal dose. Accordingly, breast feeding need not be interrupted because of maternal
medication with recommended doses of acetaminophen.
Overdose
One study that evaluated the subsequent outcome of pregnancy in women who had taken an
acetaminophen overdose during the period from 1984 to 1992 demonstrated no increased risk
for fetal malformation. Acetaminophen overdose alone is not an indication for termination of
pregnancy.117
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Renal Effects
Clinical data have established that acetaminophen in recommended doses is not nephrotoxic.33
In a single-blind study, Prescott and colleagues118 compared the effect of acetaminophen
(4000 mg/d) with indomethacin (150 mg/d) and placebo on renal function in healthy
volunteers. Acetaminophen did not have the adverse renal effects generally associated with
NSAIDs. Edwards and associates119 measured renal function in patients taking at least 1000
mg of acetaminophen daily for at least 1 year. There was no evidence of clinically significant
renal impairment in 18 patients who each consumed a cumulative total of 2 to 30 kg of
acetaminophen over prolonged periods.
Acute nephrotoxicity has been reported following massive overdose either as a sequela of
hepatic failure or, occasionally, in the absence of hepatic failure.120
Some studies suggest an association between the chronic long-term use of acetaminophen and
renal effects. Results, however, are conflicting, limited by recall bias and confounded by the
inability to determine whether analgesic use preceded or followed the onset of renal
disease.119,121-125
A National Kidney Foundation position paper notes that there is negligible clinical evidence
to suggest that the habitual use of acetaminophen causes analgesic nephropathy.126 However,
use of antipyretic analgesic combinations (ie, analgesics that contain aspirin and
acetaminophen combined with caffeine or codeine) in large doses for prolonged periods of
time is thought to be associated with an increased risk of renal papillary necrosis resulting in
analgesic nephropathy.126 The panel concludes that acetaminophen has been preferentially
recommended by physicians to patients with renal failure and that there is no evidence that
occasional use of acetaminophen causes renal injury. In this position paper, acetaminophen
was recommended as the non-narcotic analgesic of choice for episodic use in patients with
underlying renal disease.
b. Use in Certain Disease States or Conditions
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
In therapeutic doses, acetaminophen does not shorten the lifespan of red blood cells127,128 and
does not produce any clinically perceptible destruction of circulating red blood cells.129
Use in Chronic Liver Disease
Acetaminophen can be used in patients with liver disease130 and has been studied in both one-
time single (1500 mg) and multiple doses (4000 mg/d) in adult patients with chronic stable
liver disease.131,132 Benson131 conducted a double-blind, two-period, crossover study that
evaluated the use of 4000 mg/d of acetaminophen for 13 days in patients with stable chronic
liver disease. There were no abnormalities indicative of an adverse reaction to acetaminophen.
Forrest and associates132 compared acetaminophen metabolism following a single 1500-mg
dose in normal subjects, patients with mild liver disease, and patients with severe liver
disease. There were no significant differences in overall 24-hour urinary excretion of
acetaminophen and glucuronide, sulfate, cysteine, and mercapturic acid conjugates of
acetaminophen. Following a single (10 mg/kg) dose of acetaminophen, the pharmacokinetic
profiles in pediatric patients with mild, moderate, or severe liver disease were not
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significantly different.133 Although the plasma half-life of acetaminophen was prolonged in

patients with severe liver disease, there were no significant differences in the 24-hour (adult)
and 36-hour (children) urinary excretion of acetaminophen or its conjugates (eg, glucuronide,
sulfate, cysteine, mercapturic acid).
Use in Renal Disease
Based on available clinical data, acetaminophen can be used in patients with chronic renal
disease without dosage adjustment. In a single-dose study, Prescott and colleagues134
compared the disposition and metabolite kinetics of 1000 mg of acetaminophen in patients
with renal disease and in healthy volunteers. The fractional urinary recovery of
acetaminophen and its conjugates (eg, glucuronide, sulfate, cysteine, mercapturate) was
similar in healthy volunteers and in patients with moderate renal failure. In a 10-day, multi-
dose study, Martin and associates135 evaluated the disposition of acetaminophen 3000 mg
daily in healthy volunteers compared with patients with chronic renal failure. A slight
increase in predose trough acetaminophen levels was noted in patients with renal failure (3.1
µg/mL) compared with controls (1.1 µg/mL), but there was no evidence of accumulation of
the glutathione-derived metabolites of acetaminophen (eg, cysteine, mercapturate). Although
mean daily predose plasma concentrations of sulfate and glucuronide conjugates were higher
in patients with chronic renal disease, these conjugates disappeared rapidly when
acetaminophen was discontinued. There is no significant risk of acetaminophen toxicity in
patients with moderate to severe renal failure.
A National Kidney Foundation position paper notes that physicians preferentially recommend
acetaminophen to patients with renal failure because of the bleeding complications associated
with aspirin in these individuals.126 In this position paper, acetaminophen was recommended
as the non-narcotic analgesic of choice for episodic use in patients with underlying renal
disease.
Use in Older Patients
No adjustment in labeled dosage is necessary for older patients who require acetaminophen
therapy. Those who require therapy for longer than 10 days should consult their physician for
condition monitoring; however, no reduction in recommended dosage is necessary. The
American Geriatrics Society Clinical Practice Guidelines for the Management of Chronic
Pain in Older Persons136 recommend acetaminophen as the drug of choice for relieving mild
to moderate musculoskeletal pain, with the maximum dosage not to exceed 4000 mg daily.
Carcinogenicity/Mutagenicity (Animal)
Various animal bioassays on a weight-of-evidence basis have demonstrated no evidence of

carcinogenic potential for acetaminophen. The International Agency for Research on Cancer
(IARC) found only limited evidence in animals for carcinogenicity and the US National
Toxicology Program (NTP) found no evidence for carcinogenicity in mice and male rats and
only equivocal evidence for carcinogenicity in female rats.161,162 The equivocal results were
based on a few studies with serious methodological problems. Negative results have been
demonstrated in rodent bioassays of acetaminophen.163
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Carcinogenicity (Human)
Although it has been hypothesized that long-term use of analgesics may be associated with a
slight increase in urinary tract tumors and renal cell cancer in man, a number of population-
based, case-controlled studies have shown that it is not likely that acetaminophen use plays a
major role in renal cell cancer.164-166
A comprehensive and conclusive review, accepted by the Committee for Proprietary

Medicinal Products (CPMP) of the European Union, considered the genotoxic and
carcinogenic properties of acetaminophen.167 This review concluded that genotoxic effects of
acetaminophen are not reached at therapeutic dosage.
Reproductive and Teratogenic Effects (Animal)
There was no effect on pregnancy or offspring when acetaminophen was given at dose levels
of 600 mg/kg/d in the diet of male rats for 60 days prior to mating and to female rats from 14
days before mating to the end of pregnancy. An oral dose of 600 mg/kg/d produced no
teratogenicity or embryotoxicity when given from days 6 through 15 of pregnancy. When
acetaminophen was given from day 16 of pregnancy through a 3-week lactation period, no
deleterious effect was noted on pregnancy rate or on percent of live births, but a decrease in
body weight gain and survival rate was noted among offspring of drug-treated females.168,169
In another study, acetaminophen 250 mg/kg/d did not affect fetal length or weight, incidence
of resorptions, or placental weight.170
Potential Laboratory Test Interferences
Using the most current analytic systems, acetaminophen does not cause laboratory test
interferences. However, there are certain methods with which the possibility of laboratory
changes exists, as described below:
Blood Tests
Acetaminophen at recommended doses does not appear to interfere with glucose analysis
using currently marketed blood glucose meters. For further detail, it may be advisable to
contact the specific laboratory instrumentation manufacturer.
Urine Tests
Acetaminophen in therapeutic doses may interfere with the determination of 5-
hydroxyindoleacetic acid (5HIAA), causing false-positive results. False determinations may
be eliminated by avoiding acetaminophen ingestion several hours before and during the
collection of the urine specimen.155
OVERDOSE
Overdose Management
In January 1985, the United States Food and Drug Administration (FDA) approved
acetylcysteine (NAC) as an antidote for the treatment of acetaminophen overdose. Approval
of acetylcysteine for this purpose was based on a nationwide research program conducted by
the Rocky Mountain Poison and Drug Center under the sponsorship of McNeil Consumer
Healthcare. This research clearly demonstrated the efficacy of acetylcysteine, when used early
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in the course of treatment, in reducing morbidity and virtually eliminating mortality

associated with even a massive acetaminophen overdose.
McNeil Consumer Healthcare continues to sponsor a toll-free telephone number (1-800-525-

6115), available 24 hours a day, at the Rocky Mountain Poison and Drug Center. Please do
not hesitate to call this number if you need individualized consultation on managing a patient
with an acetaminophen overdose.
a. Acute Overdose Management
Acute acetaminophen overdose is defined as an ingestion of a toxic amount of acetaminophen
occurring within a period of 8 hours or less.* A number of steps in the management of such
an overdose are important to achieve an optimal clinical outcome. This section outlines basic
steps in managing acute acetaminophen overdose, consistent with FDA-approved labeling of
acetylcysteine. A flowchart outlining a stepwise approach, and a nomogram are provided
(Figures 3 and 4, respectively).
FIGURE 3. Flowchart: Stepwise Management of Acute Acetaminophen Overdose
Assessment
Adults or adolescents ( ≥ 12 years of age), who may have ingested acetaminophen in a
purposeful overdose, independent of the amount reported to have been ingested, should be
referred for evaluation and have a plasma acetaminophen level determined. Any individual
presenting with an unknown amount of acetaminophen ingested or with a questionable or
unreliable history about the time of ingestion should have a plasma acetaminophen level
drawn and be treated with acetylcysteine. (For management of acetaminophen overdose in
young children, see Special Populations, Young Children.)
Estimate as carefully as possible the quantity and dosage form (see also Special
Considerations: Extended-Release Acetaminophen) of acetaminophen ingested and the time
of ingestion. In adults and adolescents, hepatic toxicity may occur following ingestion of
greater than 7.5 to 10 g (ie, 24 regular-strength or 15 extra-strength caplets or tablets) over a
period of 8 hours or less. Fatalities are infrequent (less than 3% to 4% of untreated cases) with
overdoses less than 15 g (ie, 45 regular-strength or 30 extra-strength caplets or tablets).
Gastric Decontamination/Prevention of Absorption

Gastric decontamination should be carried out according to standard treatment guidelines.
a) Activated charcoal should be given during the immediate postingestion period, especially
in the case of a mixed drug overdose. Although there are no data to support the efficacy of
activated charcoal beyond 2 hours, it is reasonable to administer activated charcoal for up
to 4 hours post-ingestion. Administration of activated charcoal will not interfere with

subsequent administration of oral acetylcysteine therapy.
b) Syrup of ipecac given to children during the prehospital phase may reduce subsequent
plasma levels of acetaminophen; however, there is no evidence that syrup of ipecac
administered later than 60 minutes postingestion is useful.
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Determining the Need for an Antidote

Acetaminophen Assay
Plasma or serum acetaminophen levels, determined as early as possible but no sooner than 4
hours following an acute overdose, are essential in assessing the potential risk of
hepatotoxicity. Plasma levels provide a basis for determining the need to initiate or continue
with maintenance doses of acetylcysteine treatment. Therefore, it is important to verify the
time of ingestion as accurately as possible. If there is any question about the time of ingestion,
the earliest possible ingestion time should be assumed.
If an assay for acetaminophen cannot be obtained, it is necessary to assume that the overdose
is potentially toxic. Draw blood immediately for the acetaminophen plasma assay if 4 hours
or more have elapsed postingestion. If less than 4 hours have elapsed postingestion, then wait
until 4 hours to draw blood. Levels obtained before 4 hours cannot be plotted on the
nomogram (Figure 4). If an assay cannot be obtained or if the acetaminophen level is clearly
in the toxic range (ie, above the treatment line on the treatment nomogram), dosing with
acetylcysteine should be initiated and continued for the full course of therapy.
Interpretation of Acetaminophen Assays
Refer to the nomogram in Figure 4 on the following page to plot the initial plasma
acetaminophen level. Values above the Rumack-Matthew line connecting 200 µg/mL at 4
hours with 50 µg/mL at 12 hours are reported to be associated with a potentially increased
risk of hepatotoxicity if the antidote is not administered. In order to err on the safe side, a
treatment line has been established that is 25% below the Rumack-Matthew line. If the initial
plasma acetaminophen level plots above the treatment line, then acetylcysteine treatment is
recommended. If the initial plasma acetaminophen level, determined at least 4 hours
following an overdose, plots below the treatment line described above, the risk of
hepatotoxicity is minimal and acetylcysteine treatment is not necessary and, if already
initiated, can be discontinued.
It is important to verify as closely as possible the timing of the ingestion, using the earliest
possible ingestion time if there is any question about the time of ingestion. Only the initial
acetaminophen level is used in making the decision to initiate or continue acetylcysteine
treatment (see also Special Considerations: Extended-Release Acetaminophen). A complete
course of acetylcysteine should be provided if the initial level is above the treatment line,
even if subsequent acetaminophen levels plot below the treatment line.
FIGURE 4. Single Acute Acetaminophen Overdose Nomogram
Administration of Antidote
Based on clinical experience, if a patient presents soon after the overdose, treatment with
acetylcysteine may be withheld until acetaminophen assay results are available, provided that
initiation of treatment is not delayed beyond 8 hours following the overdose ingestion. In
adults and adolescents, immediately administer acetylcysteine orally or with a nasogastric
tube if 8 hours or more have elapsed from the reported time of ingestion of an acetaminophen
overdose, regardless of the quantity of acetaminophen reported to have been ingested. Do not
await results of assays for acetaminophen level before initiating acetylcysteine.
The following procedures are recommended:

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a) Administer the oral loading dose of acetylcysteine, 140 mg/kg of body weight.
b) Four hours after the loading dose, administer the first of 17 oral maintenance doses, 70
mg/kg of body weight. The oral maintenance dose is then repeated at 4-hour intervals for a
total of 17 maintenance doses. If liver enzymes continue to be elevated, acetylcysteine may be
continued beyond the full course of therapy until liver enzymes are decreasing and
prothrombin time is returning to normal. (Some toxicology authorities have adopted shorter
courses of therapy based on their own specific clinical parameters. Consult a regional poison
control center for these protocols or see page 23 for additional consultation sources.)
c) If the patient vomits the loading dose or any maintenance dose within 1 hour of
administration, repeat the dose.
d) For patients who are persistently unable to retain orally administered acetylcysteine, some
poison control centers recommend aggressive antiemetic therapy or intravenous
administration of acetylcysteine. If more than 8 hours have elapsed post-ingestion and the
patient is persistently unable to retain orally administered acetylcysteine, you may want to
consult a poison control center for protocols on the use of antiemetics or intravenous
acetylcysteine. The intravenous dosage form of acetylcysteine is not approved for use in the
United States, but is recommended by some poison control centers in selected cases.
Other Laboratory Tests
Specific baseline laboratory tests are not necessary in otherwise healthy, asymptomatic
patients with early presentation. In symptomatic patients or patients with increased plasma
acetaminophen levels, obtain aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) levels. Bilirubin, prothrombin time or international normalized ratio (INR), creatinine,
blood urea nitrogen (BUN), blood glucose, electrolyte, and pH levels may be useful,
especially in cases showing evidence of significant toxicity. Repeat the AST (or ALT) level
daily during therapy if the plasma acetaminophen level is in the potentially toxic range. If
AST or ALT levels are abnormal, then bilirubin, prothrombin time or INR, creatinine, BUN,
blood glucose, electrolyte, and pH levels also should be obtained.
Supportive Treatment
a) Monitor for signs and symptoms of incipient hepatic failure and provide appropriate
supportive care.
b) In cases in which fulminant hepatic failure develops, obtain appropriate toxicology or

hepatology consultation. In rare cases, referral to a transplant center may be necessary.
Special Considerations: Extended-Release Acetaminophen
The extended-release form of acetaminophen is composed of one layer containing 325 mg of
immediate-release acetaminophen and another layer containing 325 mg of extended-release
acetaminophen. In cases of overdose, the concern is that absorption of extended-release
acetaminophen is slower than that of immediate-release acetaminophen. As a result, the
plasma acetaminophen level may plot below the treatment line of the nomogram at 4 hours
but may rise above the treatment line with continued absorption.
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a) After an acute overdose with an extended-release acetaminophen product, plasma

acetaminophen concentrations should be measured at least 4 hours after ingestion. Because of
differences in absorption rates, the significance of delayed rising levels is not clear. Some
authorities recommend obtaining a second plasma acetaminophen level 4 to 6 hours after the
first measurement, whereas others do not. Until there is further evidence, it may be prudent to
obtain a second level.
b) If either of the levels plot above the treatment line of the nomogram, acetylcysteine
treatment should be administered.
c) If both levels plot below the treatment line, toxicity is unlikely and acetylcysteine treatment
is not necessary and, if already initiated, can be discontinued.
Special Populations
Young Children ( < 12 Years of Age)
If more than 150 to 200 mg/kg or an unknown amount was ingested, obtain a plasma
acetaminophen level as soon as possible, but not sooner than 4 hours following ingestion. In
children, an acute overdosage of less than 150 mg/kg has not been associated with hepatic
toxicity. In patients referred for plasma acetaminophen levels, gastric emptying with syrup of
ipecac or administration of activated charcoal should be considered. If the plasma
acetaminophen level can be obtained within 8 hours postingestion, initiating acetylcysteine
treatment is not necessary until the result is obtained. However, if the estimated time
postingestion is approaching 8 hours, then acetylcysteine treatment should be initiated
immediately. If the acetaminophen level plots above the treatment line on the nomogram,
acetylcysteine treatment should be initiated and continued for a full course of therapy. Serious
toxicity or fatalities have been extremely infrequent following an acute acetaminophen
overdose in young children, possibly because of differences in the way children metabolize
acetaminophen.
Pregnant Women
Acetylcysteine should not be withheld from pregnant women who have ingested an
acetaminophen overdose. A full course of acetylcysteine treatment should be administered
using the same indications for treatment as described on page 20 in the section entitled
"Determining the Need for an Antidote."
Patients Presenting 24 Hours or More Postingestion
Acetylcysteine may have a role in the management of patients who present more than 24
hours after an acetaminophen overdose. Evidence suggests that acetylcysteine treatment may
improve survival in patients presenting late and may be appropriate almost any time after
overdose ingestion. A well-controlled study has indicated that intravenous acetylcysteine
improves survival in patients with established fulminant hepatic failure, caused by purposeful
overdose of acetaminophen, who presented 36 to 80 hours postingestion. Although the benefit
of acetylcysteine in patients who present more than 24 hours postingestion but without
established fulminant hepatic failure has not been confirmed, patients with demonstrated
hepatic toxicity may receive a full course of acetylcysteine. Contact a regional poison control
center for guidance on managing patients presenting 24 hours or more postingestion (see
Additional Consultation).
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Chronic Alcohol Users

Chronic heavy alcohol users may be at an increased risk of hepatic toxicity from excessive
acetaminophen use, although reports of this event are rare. Reports usually involve cases of
severe chronic alcoholics, and the dosages of acetaminophen most often exceed recommended
doses and often involve substantial overdose. The likelihood of increased risk of
hepatotoxicity in chronic alcohol users following an acute acetaminophen overdose is
unresolved. In these cases, a full course of acetylcysteine treatment should be administered
using the same indications for treatment as described on page 20 in the section entitled
"Determining the Need for an Antidote."
Chronic (Repeated) Overdose
Chronic overdose is defined as an ingestion of toxic amounts of acetaminophen taken for a
period longer than 8 hours.* In these cases, the use of the nomogram is not appropriate.
Hepatotoxicity has been documented in some patients who have reported ingesting repeated
overdoses (greater than the maximum daily recommended dose of 4 g/24 h) of
acetaminophen. In young children, daily doses of more than 150 mg/kg/24 h or more for
several days have been reported to result in hepatic toxicity. Acetylcysteine treatment should
be considered in patients with a history of chronic overdose, especially when signs and
symptoms are consistent with acetaminophen toxicity. For further assistance, consult your
regional poison control center or the Rocky Mountain Poison and Drug Center (see
Additional Consultation).
Additional Consultation
Consult your regional poison control center for additional emergency information or
treatment recommendations. For additional individualized consultation, McNeil Consumer
Healthcare sponsors a toll-free telephone number, 1-800-525-6115, available 24 hours a day,
at the Rocky Mountain Poison and Drug Center.
Clinical Characteristics of Acute Acetaminophen Overdose
The principal toxic effect of a substantial acetaminophen overdose is hepatic injury.
Normally, acetaminophen metabolism involves three separate pathways:
(a) conjugation with glucuronide (glucuronidation);
(b) conjugation with sulfate (sulfation); and (c) metabolism via the cyto-chrome P450-
dependent mixed function oxidative enzyme pathway to form a reactive intermediate
metabolite. The reactive intermediate metabolite formed through the P450 pathway conjugates
with glutathione and is then further metabolized to form cysteine and mercapturic acid
conjugates. Neither acetaminophen glucuronide, acetaminophen sulfate, nor the glutathione-
derived metabolites are toxic. Thus, with normal therapeutic use, toxicity does not occur.
However, following a substantial overdose, the amount of reactive intermediate metabolite

produced may increase markedly. In such a circumstance, the amount of glutathione available
in the liver may become insufficient to conjugate with and detoxify the reactive intermediate
metabolite. It is estimated that when the amount of available glutathione is reduced to
approximately 30% of normal, the reactive intermediate metabolite binds to hepatic cell
macromolecules, producing cellular necrosis. The exact mechanism of hepatocellular damage
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is not known, but is reflected by a rise in serum transaminases. With increasing hepatocellular
necrosis, hepatic dysfunction occurs. In severe cases, this may proceed to hepatic failure.
Signs and symptoms of acetaminophen overdose, during the initial management phase, show
a consistent pattern but are not diagnostic or predictive of risk. The clinical course of
acetaminophen overdose generally occurs in a three-phase sequential pattern:
Phase I
The first phase begins shortly after ingestion of a potentially toxic overdose and lasts for 12 to
24 hours. The patient may manifest signs of gastrointestinal irritability, nausea, vomiting,
anorexia, diaphoresis, and pallor. The larger the overdose, the more likely that these
symptoms are present. Coma or other evidence of central nervous system depression is
usually not present unless the patient has taken a massive overdose or has also ingested toxic
doses of barbiturates, tranquilizers, or other central nervous system depressants, as may be the
case in suicide attempts. In small children, spontaneous vomiting following a substantial
overdose occurs frequently and may play a role in the reduced risk of toxicity in children.
However, these symptoms are not unique to acetaminophen, and unless the possibility of
acetaminophen overdose is considered during this early phase, it may be overlooked. Many
patients with early symptoms never progress beyond the first phase and recover without
additional problems.
Phase II
If toxicity continues or is to ensue, there is a latent phase of up to 48 hours. Initial symptoms
abate and the patient may feel better. However, hepatic enzymes, bilirubin, and prothrombin
time or INR values will progressively rise, with hepatic enzymes often rising to striking
levels. Right upper-quadrant pain may develop as the liver becomes enlarged and tender.
Most patients do not progress beyond this phase, especially if given acetylcysteine treatment.
The subsequent clinical course is characterized by a gradual return of liver function tests to
normal.
Phase III
A few patients will develop serious hepatic necrosis. Signs and symptoms of this third phase
of the clinical course depend on the severity of hepatic damage and usually occur from 3 to 5
days following ingestion. Symptoms may be limited to anorexia, nausea, general malaise, and
abdominal pain in less severe cases or may progress to confusion, stupor, and sequelae of
hepatic necrosis including jaundice, coagulation defects, hypoglycemia, and encephalopathy,
as well as renal failure and cardiomyopathy. Death, if it occurs, is generally a result of
complications associated with fulminant hepatic failure. Mortality rates in patients with toxic
plasma levels who do not receive antidotal therapy are in the range of 3% to 4%. In nonfatal
cases, serial liver biopsies and liver function tests have shown prompt resolution with no
significant residual functional or architectural alterations of the liver.
Acetaminophen Overdose: Summary
Acetaminophen overdose can be effectively managed by focusing on a few basic principles.
As in all cases of poisoning, obtain a careful history and have a high index of suspicion.
When acetaminophen overdose is a possibility, obtain a plasma acetaminophen level and
initiate antidotal therapy. When the antidote, acetylcysteine, is administered using current
recommendations, morbidity is significantly reduced and mortality virtually eliminated. The
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prognosis for patients with acetaminophen overdose is excellent, provided treatment is given
expeditiously and appropriately.
CONTRAINDICATIONS
No information provided.
CLINICAL PHARMACOLOGY
Pharmacologic Classification
a. General
Acetaminophen is an analgesic and antipyretic agent and has been clinically proven to be
effective for the temporary relief of minor aches and pains associated with the common cold,
headache, toothache, muscular aches, backache, for the minor pain of arthritis, for the pain of
menstrual cramps, and for the reduction of fever. Acetaminophen is an effective antipyretic in
infants, children, and adults.
b. Pharmacologic Class
Acetaminophen is a centrally acting analgesic and antipyretic agent.
c. Mechanism of Action
Analgesia
Although the exact site and mechanism of analgesic action is not clearly defined,
acetaminophen appears to produce analgesia by elevation of the pain threshold.2-4 The
potential mechanism may involve inhibition of the nitric oxide pathway mediated by a variety
of neurotransmitter receptors including N-methyl-D-aspartate and substance P.5
Antipyresis
Investigations indicate that endogenous pyrogens produced by leukocytes cause an elevation

of prostaglandin E (PGE) in the cerebrospinal fluid. Fever results when the elevated PGE acts
on the preoptic area of the anterior hypothalamus to decrease heat loss and increase heat gain.
Acetaminophen has been shown to inhibit the action of endogenous pyrogens on the heat-
regulating centers in the brain by blocking the formation and release of prostaglandins in the
central nervous system.6-9 Inhibition of arachidonic acid metabolism is not requisite for the
antipyretic effect of acetaminophen.10 Acetaminophen does not depend upon the activation of
the arginine vasopressin V-1 receptor to induce antipyresis as has been noted in rats treated
with indomethacin and salicylates.11,12 This has been demonstrated in animals by observing a
decrease in both fever and PGE activity following administration of acetaminophen to
unanesthetized cats, and in rabbits and dogs when brain prostaglandin synthetase was
inhibited by the administration of acetaminophen.13,14
d. Pharmacokinetic Data
Absorption
Regular-Release
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Oral acetaminophen is rapidly and almost completely absorbed from the gastrointestinal tract
primarily in the small intestine. This absorption process occurs by passive transport. The
relative bioavailability ranges from 85% to 98%.15
Figure 1 shows the mean pharmacokinetic profile for 24 fasting subjects who received
acetaminophen 1000 mg dosed as liquid or caplets. For individual subjects, maximal plasma
concentrations occurred within 10 to 90 minutes following ingestion and ranged from 8 to 32
µg/mL. Acetaminophen plasma concentrations range from 1 to 4 µg/mL 6 hours after
ingestion.
Extended-Release
Each bilayered acetaminophen extended-release, 650-mg caplet contains 325 mg of

immediate-release acetaminophen on one side and, on the other side, 325 mg of
acetaminophen in a matrix formulation designed to slowly release. In vitro data indicate that
two 650-mg extended-release caplets
FIGURE 1. Mean plasma concentrations of acetaminophen in 24 male subjects following

oral administration of 1000 mg of acetaminophen dosed as either 30 mL of Extra
Strength TYLENOL® acetaminophen Adult Liquid Pain Reliever or as two Extra
Strength TYLENOL® acetaminophen Caplets.
FIGURE 2. Mean plasma concentrations of acetaminophen in 24 male subjects following

oral administration of 1300 mg acetaminophen dosed as either two caplets of
TYLENOL® Arthritis Extended Relief or four Regular Strength TYLENOL®
acetaminophen (two caplets given at 0 and 4 hours).
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(containing a total of 1300 mg of acetaminophen) release 88% and 95% of the drug within 3
and 5 hours, respectively.16 Following administration of a single dose of two 650-mg,
extended-release caplets, the average maximal plasma concentrations occurred within 0.5 to 3
hours following ingestion and ranged from 6.9 to 14.1 µg/mL. Figure 2 shows the mean
pharmacokinetic profile for 24 fasting subjects who received acetaminophen 1300 mg dosed
as two extended-release or four regular-strength caplets (two caplets given at 0 and 4 hours).
Distribution
Acetaminophen appears to be widely distributed throughout most body fluids except fat. The
apparent volume of distribution of acetaminophen is 0.95 L/kg.17 A relatively small
proportion (10% to 25%) of acetaminophen is bound to plasma proteins and binding is only
slightly increased in plasma concentrations associated with overdose.18,19 The sulfate and
glucuronide metabolites do not bind to plasma proteins even at relatively high
concentrations.20
Spinal Fluid
Low protein binding and low molecular weight allow acetaminophen to pass through the
blood-brain barrier. The peak concentration of acetaminophen in cerebrospinal fluid is
reached after 2 to 3 hours.21,22
Placental Barrier
Analysis of urine samples has demonstrated the passage of unconjugated acetaminophen via
placental transfer.23 When given to the mother in therapeutic doses, acetaminophen crosses
the placenta into fetal circulation as early as 30 minutes after ingestion, although the
difference in serum concentration between maternal and cord blood is not statistically
significant.24 In the fetus, acetaminophen is effectively metabolized by sulfate conjugation.25
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Breast Milk
Maternal ingestion of acetaminophen in recommended analgesic doses does not present a risk
to the nursing infant. Amounts in milk range from 0.1% to 1.85% of the ingested maternal
dose.26-28 These studies have established that, even at the time of peak acetaminophen
concentration in human breast milk, the nursing infant would receive less than 2% of the
maternal dose. Accordingly, breast feeding need not be interrupted because of maternal
ingestion of recommended doses of acetaminophen.
Metabolism
Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three
principal separate pathways:
a) conjugation with glucuronide
b) conjugation with sulfate
c) oxidation via the cytochrome, P450-dependent, mixed-function oxidative enzyme pathway

to form a reactive intermediate metabolite, which conjugates with glutathione and is then
further metabolized to form cysteine and mercapturic acid conjugates.29 The principal
cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as
additional pathways.30-32
Two additional minor pathways also are possibly involved in acetaminophen metabolism:33
a) hydroxylation to form 3-hydroxy-acetaminophen
b) methoxylation to form 3-methoxy-acetaminophen.
These metabolites are further conjugated with glucuronide or sulfate.
In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser
extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack
biologic activity.8 In premature infants, newborns, and young infants, the sulfate conjugate
predominates.23,34
Excretion
The biologic half-life of acetaminophen in normal adults is approximately 2 to 3 hours in the

usual dosage range.21,35 It is somewhat shorter in children and somewhat longer in neonates
and in patients with cirrhosis.18 The elimination half-life is approximately 3 hours for the
extended-release product. The elimination half-life of acetaminophen in the cerebrospinal
fluid according to pooled data is 3.2 hours.21
Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate
conjugates in a dose-dependent manner. Table 1 0n the following page shows the mean range
of acetaminophen urinary metabolite values in healthy subjects using therapeutic doses (10
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mg/kg or 1000-mg dose).36-40 Less than 9% of acetaminophen is excreted unchanged in the

urine.37
TABLE 1. Acetaminophen metabolites found in urine
Acetaminophen Range of mean

metabolite percent
Glucuronide 46.8 - 62.2
Sulfate 25.4 - 35.9
Mercapturate 2.7 - 5.0
Cysteine conjugate 2.1 - 3.0
Free acetaminophen 3.4 - 8.7
TABLE 2. Adult TYLENOL® acetaminophen preparations
Adult single
Preparation Strength Frequencya
dose
Regular Strength TYLENOL
Every 4 to 6
Tablets/Caplets 325 mg 650 mg
hb
Extra Strength TYLENOL
Every 4 to 6
Tablets/Caplets/Gelcaps/Geltabs 500 mg 1000 mg
hc,d
500 mg/15 Every 4 to 6
Adult Liquid 1000 mg
mL hd,e
TYLENOL Arthritis Extended Relief
650 mg 1300 mg Every 8 hd,f
Caplets
a
Not to exceed 4000 mg in any 24-hour period.
b
Not to exceed 12 tablets per day.
c
Not to exceed 8 tablets per day
d
Not for use in children under 12 years of age.
e
Not to exceed 8 tablespoons per day.
f
Not to exceed 6 caplets per day.
TABLE 3. Pediatric TYLENOL® acetaminophen preparations
Preparation Strengtha
Infants'TYLENOL Concentrated Drops 80 mg/0.8 mL
Children's TYLENOL Elixir 160 mg/5 mL
Children's TYLENOL Suspension Liquid 160 mg/5 mL
Children's TYLENOL Chewable Tablets 80 mg
Junior Strength TYLENOL Chewable Tablets 160 mg
Junior Strength TYLENOL Caplets 160 mg
a
Dosing to be based on age or weight (approximately 10-15 mg/kg/dose; not to
exceed 5 doses in 24 hours).
Other minor metabolites, each accounting for 4% or less of a therapeutic dose, include sulfate
and glucuronide conjugates of 3-methoxy-acetaminophen, 3-hydroxy-acetaminophen, and 3-
methyl-thioacetaminophen.39,41-43 Slight differences have been seen in ethnically distinct
populations (eg, Asian, Spanish).36,44-46
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Clinical Studies: Therapeutic Comparisons With Other Drugs Or Treatments

a. Antipyresis
In controlled trials, acetaminophen was shown to be superior to placebo.53-56 Tepid sponging
and acetaminophen have been shown to be approximately equivalent for the initial 30 minutes
of treatment, after which acetaminophen is superior. The combination of acetaminophen and
sponging may provide additive benefit, but at the expense of additional discomfort to the
child.54,56. There is no significant difference in antipyresis between equivalent doses of aspirin
and acetaminophen. 51,52,57,58 Comparative clinical studies of the antipyretic efficacy of
acetaminophen and ibuprofen administered in recommended dosages to pediatric patients
suggest that both drugs are effective.59-62 However, results vary depending on the dosage of
each agent administered. Acetaminophen at a dose of 15 mg/kg is equivalent to ibuprofen at a
dose of 10 mg/kg.60 Acetaminophen 10 mg/kg or 12.5 mg/kg does not produce the same
degree of antipyresis as ibuprofen 7.5 mg/kg or 10 mg/kg.59,61,62 Acetaminophen 12.5 mg/kg
is superior to ibuprofen 5 mg/kg.63 In these studies, onset of antipyresis with acetaminophen
generally occurred within 30 to 60 minutes following administration and peak antipyresis was
noted at 2 to 3 hours.
b. Analgesia
Acetaminophen is effective in the treatment of various disorders associated with pain of mild
to moderate intensity. Studies have been performed in a variety of pain models to assess the
overall efficacy of acetaminophen. Clinical research has substantiated efficacy in pain
associated with the following conditions:
Arthritis Pain
At recommended dosages, acetaminophen is well tolerated and effective for the treatment of
minor pain of arthritis. Clinical studies have compared the efficacy of acetaminophen to
placebo, ibuprofen, and naproxen in patients with osteoarthritis of the knee.48-50 In a double-
blind, placebo-controlled study, Amadio and Cummings48 found that 1000 mg of
acetaminophen administered four times daily was significantly more effective than placebo in
relieving tenderness, pain at rest, and pain on motion. In a randomized, double-blind study
comparing acetaminophen (4000 mg/d) with analgesic (1200 mg/d) and anti-inflammatory
(2400 mg/d) doses of ibuprofen, Bradley and colleagues49 reported that acetaminophen was
comparable to both doses of ibuprofen in relieving pain. In a double-blind study lasting up to
2 years that compared the relative safety and efficacy of acetaminophen (2600 mg/d) to
naproxen (750 mg/d), Williams and associates50 noted that acetaminophen was similar to
naproxen in improving pain on motion and in physicians' global assessment of disease
activity.
Acetaminophen taken for 1 month to 2 years is beneficial in relieving osteoarthritic pain and
causes no significant adverse effects. American College of Rheumatology* Guidelines for the
Medical Management of Osteoarthritis, published in 1995, recommend acetaminophen in
doses up to 4000 mg daily as the preferred first-line therapy in patients with symptomatic
osteoarthritis of the knee.64
Headache
Three randomized, multicenter, double-blind, single-dose, placebo-controlled studies have

been conducted by McNeil (unpublished), which evaluated the efficacy of acetaminophen in
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the tension headache model. In the first study, patients were treated with acetaminophen 1000
mg, ibuprofen 200 mg, ibuprofen 400 mg, or placebo. The active treatments were more
effective than placebo, and neither strength of ibuprofen was different from acetaminophen;
however, ibuprofen 400 mg was significantly more effective than ibuprofen 200 mg in
patients' overall evaluation. The second study compared the efficacy of acetaminophen 1000
mg, naproxen 375 mg, and placebo. Acetaminophen and naproxen were rated significantly
higher than placebo but were not different from each other. The third study evaluated
acetaminophen 1000 mg, naproxen sodium 440 mg, and placebo. Both active treatments were
significantly better than placebo. Naproxen sodium was significantly more effective than
acetaminophen for patients with baseline pain of moderate severity. However, comparisons of
patients with severe baseline pain were not significantly different between the active
treatment groups.
Post-Oral Surgery Pain
Several dose-ranging studies have assessed the efficacy of acetaminophen in post-oral surgery
pain.
Two double-blind, single-dose studies (unpublished) evaluated patients who had undergone
oral surgery and were experiencing moderate to severe pain. In these studies, acetaminophen
650 mg and 1000 mg was superior to placebo in all summary measures for moderate pain. For
more severe pain, acetaminophen 1000 mg was superior to acetaminophen 650 mg. In two
randomized studies, acetaminophen 2000 mg did not provide greater analgesia compared with
acetaminophen 1000 mg.65,66
Three studies (unpublished) compared the relative analgesic efficacy of acetaminophen,

aspirin, and placebo in patients experiencing pain following dental surgery. Two double-
blind, single-dose studies demonstrated that acetaminophen 975 mg and 1000 mg were
significantly better than aspirin 650 mg in relieving pain. In a third study, acetaminophen
1000 mg and aspirin 1000 mg were significantly more effective than placebo but were not
different from each other.
Several studies have compared the analgesic efficacy of acetaminophen and ibuprofen
following dental surgery. Most studies showed that both active treatments were effective
compared with placebo, but in some studies ibuprofen 400 mg provided greater pain relief
than acetaminophen 1000 mg in patients with moderate to severe baseline pain.67,68
In another study, patients were randomized to receive 500 mg of diflunisal or 1000 mg of

acetaminophen prior to oral surgery. Both treatments were effective and the difference in
mean overall pain scores between the two regimens was not significantly different.69
Quiding and colleagues70 evaluated the analgesic efficacy of a two-dose regimen of codeine
60 mg compared with acetaminophen 1000 mg in patients undergoing surgical removal of a
third molar tooth. Acetaminophen 500 mg was used as the control. After two doses,
acetaminophen 1000 mg was superior to acetaminophen 500 mg, and the efficacy of codeine
60 mg corresponded approximately to acetaminophen 500 mg.
Two randomized, double-blind studies (unpublished) evaluated the onset of analgesia using
acetaminophen 1000 mg, naproxen sodium 220 mg and 440 mg, and placebo in patients who
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experienced moderate to severe postoperative dental pain. The first study found that all active
treatments were more effective than placebo, and no difference for onset of pain relief
between the active treatments was observed. The second study demonstrated that all active
treatments had shorter time to onset of pain relief and were more effective than placebo.
Episiotomy Pain
Postpartum patients receiving a single 600-mg dose of acetaminophen reported a degree of

relief greater than with either salicylamide or placebo and equivalent to the same dose of
aspirin.71 Kantor and associates72 compared the effects of single doses of acetaminophen 600
mg and aspirin 600 mg or 1200 mg in postpartum patients. The three active treatments were
significantly superior to placebo. In a double-blind evaluation comparing acetaminophen,
propoxyphene, propoxyphene/acetamino-phen combination, and placebo, acetaminophen
alone was comparable to the propoxyphene combination and superior to both propoxyphene
alone and placebo.73 The analgesic efficacies of acetaminophen 650 mg, ibuprofen 200 mg,
and placebo were evaluated in a randomized, double-blind study (unpublished) involving
hospitalized postpartum patients with moderate to severe pain due to episiotomies. Both
active treatments were superior to placebo, whereas ibuprofen was significantly better than
acetaminophen.
Orthopedic Surgery
McQuay and colleagues74,75 performed two studies comparing the analgesic equivalence and
efficacy of varying doses of ketorolac, bromfenac, and acetaminophen in patients who had
elective orthopedic surgery. In the first study, patients were treated with placebo plus one of
the following: acetaminophen 500 mg, acetaminophen 1000 mg, ketorolac 5 mg, ketorolac 10
mg, or ketorolac 20 mg. Acetaminophen 1000 mg was significantly superior to
acetaminophen 500 mg. Ketorolac 20 mg was superior to acetaminophen 500 mg and
ketorolac 5 mg and 10 mg but was not superior to acetaminophen 1000 mg.75 In the second
study, patients were randomized to receive placebo, acetaminophen 1000 mg, bromfenac 5
mg, bromfenac 10 mg, or bromfenac 25 mg. In terms of analgesic efficacy, bromfenac 10 mg
was similar to acetaminophen 1000 mg.74
Menstrual Pain/Dysmenorrhea
A randomized crossover study (unpublished) in primary dysmenorrhea compared the effect of

acetaminophen 1000 mg four times daily, ibuprofen 400 mg three times daily, and placebo in
patients with a history of recurrent moderate to severe dysmenorrhea. The two active drugs
were comparable in the treatment of primary symptoms of dysmenorrhea, and both were
superior to placebo.
Post-Immunization Muscle Aches and Pain
Aoki and associates76 evaluated the effect of acetaminophen on the incidence of adverse
effects and immunogenicity of whole-virus influenza vaccine in healthcare workers. Hospital
personnel volunteers were randomly assigned to acetaminophen 325 mg, acetaminophen 650
mg, or placebo. Capsules were taken at the time of the vaccination, and 4, 8, and 12 hours
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after vaccination. Acetaminophen 650 mg significantly reduced the incidence of sore arm and
nausea without affecting antibody response.
Cancer Pain
Wallenstein and Houde77 found 600 mg of acetaminophen or aspirin to be approximately

equivalent and significantly superior to salicylamide and placebo for pain relief in patients
with cancer. Moertel and colleagues78 compared acetaminophen 650 mg, codeine 65 mg,
aspirin 650 mg, pentazocine 50 mg, propoxyphene 65 mg, and ethoheptazine 75 mg in the
treatment of cancer pain. On the basis of mean pain relief scores, neither propoxyphene nor
ethoheptazine was statistically superior to placebo. Acetaminophen was superior to placebo
and comparable to codeine, aspirin, and pentazocine for pain relief.
Sore Throat
The analgesic efficacy of acetaminophen also has been demonstrated in pain associated with
tonsillectomy, tonsillitis, and sore throat.79-81
Toxicology
A number of acute, subacute, and chronic toxicity studies in animals show that the toxic
effects of acetaminophen appear only at extremely high doses.
Acute Toxicity (Multiple Animal Models)
See Table 5.
Subacute Toxicity (Rats)
Oral doses of up to 1000 mg/kg/d or intramuscular doses of up to 100 mg/kg/d were given to
rats for 13 days or 30 days, respectively. No drug-related changes were seen in mortality rate
or necropsy findings compared with controls.
Subacute Toxicity (Dogs)
After acetaminophen (20 and 63 mg/kg/d) was given intramuscularly for 4 weeks to dogs,
mortality rate, laboratory determinations, and gross necropsy observations were not
significantly different from control values. Slight thyroid hyperplasia was seen on
histopathologic examinations in the six high-dose dogs, slight renal tubular cell cloudy
swelling was noted in three high-dose and one low-dose dog, and slight liver glycogen
depletion was found in one control, three high-dose, and two low-dose animals.156
Chronic Toxicity (Rats)
Acetaminophen, 200 mg/kg/d, given to rats once a day by gavage for 28 weeks produced no
changes in weight gain, gross pathology, or histologic findings in liver, kidney, heart, or
lungs.157 Acetaminophen incorporated into the diet of rats for 100 days showed that the
minimum dose that caused death in all rats was 1060 mg/kg/d, the dose that caused death in
50% of rats was 765 mg/kg/d, and the maximum dose that caused no deaths was 413 mg/kg/d.
At or near the LD50 (100 days), histologic findings included areas of hepatic necrosis, some
renal tubular degeneration, and testicular atrophy.158
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TABLE 5. Acute toxicity (LD50 mg/kg) of acetaminophen
Species Oral Intramuscular Subcutaneous

Rat (1 day old) NT NT > 600, < 700
Rat 2680-3100 > 600 NT
Mouse NT 536-891 NT
Hamster 630-770 > 300, ≤ 548 NT
Rabbit 2640-2800 NT NT
Dog 1180-1450 > 66 NT
NT= not tested.
Acute Nephrotoxicity (Rats)
Renal tubular lesions were observed in rats given single doses of acetaminophen in the lethal
range of 2000 to 7000 mg/kg, and similar lesions were found in rats given 500 to 4000 mg/kg
daily for up to 100 days. Attempts to produce renal damage with single nonlethal doses of
acetaminophen have been unsuccessful.159
Chronic Nephrotoxicity (Rats)
In studies using rats, rabbits, and dogs, 50 to 400 mg/kg/d of acetaminophen for 13 to 40
weeks failed to produce any significant renal abnormalities, with no evidence of interstitial
nephritis or papillary necrosis.159
Renal lesions have occurred in rats given 300 mg/kg/d for periods of up to 32 weeks in the
presence of experimentally induced renal infection, whereas the same dose of acetaminophen
failed to cause renal lesions in rats without pyelonephritis.160
* The American College of Rheumatology is an independent professional, medical, and

scientific society that does not guarantee, warrant, or endorse any commercial product or
service.
CONSUMER
IMPORTANT NOTE:
This is a summary and does not contain all possible information about this product. For
complete information about this product or your specific health needs, ask your health care
professional. Always seek the advice of your health care professional if you have any
questions about this product or your medical condition. This information is not intended as
individual medical advice and does not substitute for the knowledge and judgment of your
health care professional. This information does not contain any assurances that this product is
safe, effective, or appropriate for you.
ACETAMINOPHEN - ORAL
COMMON BRAND NAME(S): Panadol, Tylenol
USES:
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This drug is used to treat mild to moderate pain (e.g., headaches, cold/flu aches and pains) and
to reduce fever.
HOW TO USE:
Take this product by mouth as directed. Follow all directions on the product package. If you
are uncertain about any of the information, consult your doctor or pharmacist.
For suspensions, shake the bottle well before each dose. Measure the liquid medication with
the provided dose-measuring spoon/dropper to make sure you have the correct dose. Do not
use a household spoon.
For rapidly-dissolving tablets, chew or allow to dissolve on the tongue, then swallow with or
without water. For chewable tablets, chew thoroughly before swallowing.
If you are using sustained-release tablets, swallow the medication whole. Do not crush, chew,
or break the tablets. Doing so can destroy the long action of the drug and may increase side
effects.
There are many brands and forms of acetaminophen available. Read the dosing instructions
carefully for each product because the amount of acetaminophen may be different between
products. Do not take more acetaminophen than recommended. (See also Side Effects and
Precautions sections.)
Do not take this medication for fever for more than 3 days unless directed by your doctor. For
adults, do not take this product for pain for more than 10 days (5 days in children) unless
directed by your doctor. If the child has a sore throat (especially with high fever, headache, or
nausea/vomiting), consult the doctor promptly.
Pain medications work best if they are used as the first signs of pain occur. If you wait until
the symptoms have worsened, the medication may not work as well.
Tell your doctor if your condition persists or worsens or if you develop new symptoms. If you
think you may have a serious medical problem, seek immediate medical attention.
SIDE EFFECTS:
Tell your doctor immediately if any of these rare but very serious side effects occur: easy
bruising/bleeding, new signs of infection (e.g., fever, persistent sore throat).
If your doctor has directed you to use this medication, remember that he or she has judged
that the benefit to you is greater than the risk of side effects. Many people using this
medication do not have serious side effects.
If you do not have liver problems, the maximum dose of acetaminophen for adults is 4 grams
per day (4000 milligrams). The maximum dose of acetaminophen for children is based on
age/weight (check product package for details). Taking more than the maximum daily amount
may cause serious (possibly fatal) liver disease. Seek immediate medical attention if you have
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any of the following symptoms of liver damage: persistent nausea/vomiting, yellowing

eyes/skin, dark urine, stomach/abdominal pain, extreme tiredness.
A very serious allergic reaction to this drug is rare. However, seek immediate medical
attention if you notice any symptoms of a serious allergic reaction, including: rash, itching,
swelling, severe dizziness, trouble breathing.
This is not a complete list of possible side effects. If you notice other effects not listed above,
contact your doctor or pharmacist.
Contact your doctor for medical advice about side effects. The following numbers do not
provide medical advice, but in the US you may report side effects to the Food and Drug
Administration (FDA)
PRECAUTIONS:
Before taking acetaminophen, tell your doctor or pharmacist if you are allergic to it; or if you
have any other allergies.
If you have any of the following health problems, consult your doctor or pharmacist before
using this product: liver disease, regular use/abuse of alcohol.
Acetaminophen may cause liver damage. Daily use of alcohol may increase your risk for liver
damage, especially when combined with acetaminophen. Ask your doctor or pharmacist for
more information.
Liquid forms of this product may contain sugar. Caution is advised if you have diabetes. Ask
your doctor or pharmacist about using this product safely.
This children's form of this medicine may contain aspartame. If you have phenylketonuria
(PKU) or any other condition that requires you to restrict your intake of aspartame (or
phenylalanine), consult your doctor or pharmacist about using this drug safely.
Tell your doctor if you are pregnant before using this medication.
Acetaminophen passes into breast milk. Consult your doctor before breast-feeding.
DRUG INTERACTIONS:
If you are taking this product under your doctor's direction, your doctor or pharmacist may
already be aware of possible drug interactions and may be monitoring you for them. Do not
start, stop, or change the dosage of any medicine before checking with your doctor or
pharmacist first.
Before using this product, tell your doctor or pharmacist if you use any of the following
products: anti-seizure medications (e.g., phenytoin, carbamazepine, phenobarbital), "blood
thinners" (e.g., warfarin), isoniazid, phenothiazines (e.g., chlorpromazine).
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Acetaminophen is an ingredient in many nonprescription products and in some combination

prescription medications. Read the labels carefully before taking other pain relievers, fever
reducers, or cold products to see if they also contain acetaminophen. Consult your pharmacist
if you are uncertain whether your other prescription or nonprescription products contain
acetaminophen. (See also maximum daily dose information in Side Effects section.)
This medication may interfere with certain medical/laboratory tests (including urine 5-HIAA),
possibly causing false test results. Make sure laboratory personnel and all your doctors know
you use this drug.
This document does not contain all possible interactions. Therefore, before using this product,
tell your doctor or pharmacist of all the products you use. Keep a list of all your medications
with you, and share the list with your doctor and pharmacist.
OVERDOSE:
If overdose is suspected, contact your local poison control center or emergency room
immediately. US residents can call the US National Poison Hotline at 1-800-222-1222.
Canada residents can call a provincial poison control center. Symptoms of overdose may
include: nausea, vomiting, increased sweating, yellowing eyes/skin, dark urine, severe
stomach/abdominal pain, extreme tiredness.
NOTES:
Acetaminophen does not cause the stomach and intestinal ulcers that NSAIDs such as aspirin,
ibuprofen, and naproxen may cause. However, acetaminophen does not reduce swelling
(inflammation) like the NSAIDs do. Consult your doctor for more details and to see which
medication might be right for you.
MISSED DOSE:
If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip
the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.
STORAGE:
Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and
moisture. Do not store in the bathroom. Keep all medicines away from children and pets.
Do not flush medications down the toilet or pour them into a drain unless instructed to do so.
Properly discard this product when it is expired or no longer needed. Consult your pharmacist
or local waste disposal company for more details about how to safely discard your product.
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CTD
Module III
COMPOSITION
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III A COMPOSITION QUALITATIVE AND QUANTITATIVE COMPOSITION

II EXCIPIENT(S)

CELLULOSE
STEARATE
GLYCOLATE
DIOXIDE
TOTAL 620.00 MG
II A 2 CONTAINER
Blister of10Tablets
Such 10 Strips in Box
Such 250 Box In 7 Ply Corrigated Box
20 GSM Paper
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PREPARATION METHOD
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II B METHOD OF PREPARATION
II B 1 MANUFACTURING FORMULA (INCLUDING DETAILS OF BATCH SIZE)


II EXCIPIENT(S)

CELLULOSE
STEARATE
GLYCOLATE
DIOXIDE
620.00 MG
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BATCH MANUFACTURING & PACKING RECORD
TABLET SECTION
Product Name: PARACETAMOL TABLTET 500 MG Page No.: 01 of 30
Generic Name: PARACETAMOL TABLTET 500 MG
Product Code: FPA376 MFC. No. : MFC/ FPA376 Mfg. Lic. No. :
Std. Batch Size: BMPR.No: BMPR/ FPA376 Batch No.:
1, 00,000 TABS.
Effective Date: Mfg. Date:
Recoverable Residue Added: Review Date: Two years Exp. Date:
Kg. Standard Self Life:

36 months
Tablets PACKING STYLE: 10X10T
Theoretical Yield:
Final Batch Size=100,000 TABLETS Issue By: Date:
Mfg. Started on: Mfg. Completed On:
Label Claim:
EACH UN COATED TABLET CONTAINS:

EXCIPIENTS-------------------------Q.S.
TENTATIVE BMPR FOR FIRST THREE BATCH
FINAL DOCUMENT VARIFIED BY:
____________________ _____________
PRODUCTION HEAD Q.A. HEAD
(SIGN & DATE) (SIGN & DATE)
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PRE-MANUFACTURING AND PACKING CONTROL OPERATION:
1 Carry out all the activities related to equipment cleaning and material handling strictly as per respective
standard operation procedure and cleaning schedule.
2 Maintain labels of in process stages.
3 Label all equipments and areas with status and product label and display prominently,
4 Label all the recoverable and non-recoverable materials clearly and prominently.
Dispose the materials as per standard operating procedure.
5 Get QA clearance before beginning of each operation.
6 All personnel must observe stipulated gowning code for respective area.
7 Protective mask, surgical gloves and any other safety provisions must be followed.
8 Check and record temperature and humidity of every room.
9 Any deviation /from the MFC must be done with prior approval of QA by deviation request.
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MATERIAL ISSUING & DISPENSING CHECKING RECORD
Sr. Label Qty/ INGREDIENTS Spec. Item Code Std. Ov. Qty. A.R. CHE
Clai Tab. Qty % CKE
No Received NO.
m (mg) D BY
(Kg)
(mg) Kg.
DRY MIX
01 500 500 PARACETAMOL 1RAA376 50.000 ____

(B)* BP.
02 -- 50 MCCP BP. 1RIM103 5.000 _____
03 -- 23 Lactose BP. 1RIL101 2.300 ____
04 -- 12 Starch BP 1RIS105 1.200 ____
BINDER
05 -- 15.00 Starch BP 1RIS105 0.500 ____

06 ____ Purified Water BP 1RIP105 Q.S ____
LUBRICANTS
07 -- 5.00 Magnesium Stearate BP 1RIM101 0.500 ____

08 -- 4.00 Talc. (D)$ BP 1RIT101 0.400 ____
09 -- 6.00 Sodium Starch BP 1RIS103 0.600 ____

Glycolate
10 -- 5.00 Colloidal Sillicon USP 1RIC105 0.500 ____
Dioxide
TOT 620
AL
(B)* = Quantity maintain on 100% Assay. Qnty. to be calculated on basis of % Assay.
(D)$ = Quantity to be compensates on increasing quantity of active material.
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1) RAW MATERIAL REQUIREMENT CALCULATION :
(I) PARACETAMOL: (For Single A.R.No.)

Theoretical Qty.PARACETAMOL required per batch =L.claim x B.Size =_______Kg/ Batch
1000000 (T)
 Qty. of PARACETAMOL required per tablet = L.Claim x 100 x 100

Assay X (100-water)
= 100 x 100___
x ( 100 - )
= mg. (A)
= (A) x Batch Size = x_______

1000000 1000000
= Kg. / Batch (B)*
(I-A) PARACETAMOL: (For Double A.R.No.)

Assay of Raw material (Cn) & (Dn)
(C) – Assay of PARACETAMOL From 1st A.R.No. : ____________%
(Cw) – Water of PARACETAMOL From 1st A.R.No. : ____________%
(D) – Assay of PARACETAMOL From 2nd A.R.No. : ____________%
(Dw) – Water of PARACETAMOL From 2nd A.R.No. : ____________%
(E) – Available Stock ofPARACETAMOL From 1st A.R.No. : ________________ Kg.
Quantity of PARACETAMOL Required,

From 1st A.R.No. = L.Claim x 100 x 100 = x 100 x 100 = mg / tablet(Fn)
(C) x (100 – Cw) x (100 - )
Qty. Req./Batch = (Fn) x Batch Size = x ____ = Kg. (G) Qty. Req./Batch
From 1st A.R.No. 1000000 1000000 From 1st A.R.No.
Now, (G) – (E) = _____ -_____ = ___________Kg. (H) Qty. required From 2nd A.R.No.
Actual Qty. Required = (H) x {C x (100 - Cw)} = x x = Kg. ( I ) R.M required

From 2nd A.R.No. {(D) x (100 - Dw)} From 2nd A.R.No.
Total Qty. Required / Batch = (E) + ( I ) = + .=__________Kg. (B)*
 Deduction quantity of Talcum required: (B)* – T = _____-_______= _______kg (P)
 Inactive Raw material Calculation Adjusted for increasing Active addition :
 Theoretical qty. of Talcum require/ batch = ______________Kg. ( C )
 Actual quantity of Talcum require / batch = C – P =___________Kg (D)$


CHECKED BY : Production : Q.A :
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EQUIPMENT / AREA / LINE CLEARANCE:
GRANULATION
Sr. Equipment Equipment Operation Cleaning Done By Checked By

No. No. SOP SOP
GRANULATION: I
1 Sifter E/01 T0201 T0205
2 Planetary Mixer E/02 T0202 T0206
3 Fluid Bed Dryer E/03 T0203 T0207
4 Multi Mill E/04 T0204 T0208
5 Yard Balance (300 kg.) E/25 T0103 T0103
6 Two Pan Balance(5 Kg) E/26 T0104 T0104
7 Sieve 20,40 # E/01-E,F T0210 T0210
ENVIRONMENT CONTROL LIMIT

1. Temperature °C : Date & Time: (27°C ±3°C )
2. Relative Humidity: 40%. Date & Time: (50% ±5 Rh)
3 Differential Pressure: Date & Time: ( 10-15 PSI )
4 DETAILS OF PREVIOUS PRODUCT:

Name of Previous product :
Batch No. :
LINE CLEARANCE (AREA & MACHINERY.)
Done By :
Production Chemist Date & Time.
Checked by :
Q.A. Chemist Date & Time.
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cePRE MANUFACTURING CONTROL OPERATIONS:
1 Use proper uniform, gloves, Mask, & safety goggles, while handling raw materials.
2 For operation & cleaning of machines follow respective SOP‘s.
3 Obtained line clearance from Quality Assurance department before starting the activity.
4 Always take care to avoid cross contamination of material.
Any deviation from the MFR must be done with prior approval of Q.A on deviation request
Sr. PROCESS DATE TIME DONE CHECKED
No. BY
BY
1. WEIGHING AND CHECKING :
Check the weight of all (active/inactive) raw materials and their name,
Control no., Mfg. date, Exp. date, as per Store’s Requisition Cum Issue
Slip.
2. SIFTING:
Note:
PassPARACETAMOL through 20# sieve.
Pass MCCP, Lactose Starch Through 30#
Sieve integrity Checked
(b) Before use: Date:
(c) After Use: Date:
3.0 MIXING:
Transfer above sifted material (STEP-2) in planetary mixer bowl and

mix for 10 minutes at slow speed.
4.0 PREPARATION OF GRANULATING PASTE:
Take 8 Lits purified water in s.s. vessel. Boil it. Take starch & Add
Purified water and make slurry with stirring.add this starch slurry in Boil
Mix well for homogeneous.
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SR. PROCESS DATE TIME DONE

NO.
BY
5.0 RECOVERABLE RESIDUE :
Machine setting granules, tablets, inspection rejections
and other recoverable Residues are to be added in
nex
1. Mill the tablets using 2.0 mm sieve in Multimill
Mill Knives forward.
2 Blend with the granules during Dry Mixing
3 “Recoverable Residues” should not be more than 5% w/w of Batch Size.
4 Retest recoverable Residue after was six month & use with in one year.
5 Record the details of Reprocessible materials added with details of Batch No.,
Mfg., Dt.,Exp. Dt. And respective qty. added.
6. Check the granules LOD % in IR Moisture balance.
Batch No.
MFG. DATE EXP.DATE
Total Qty:
5.8 Screen Inspected by :
Before Use :
After Use
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SR. PROCESS DATE TIME DONE CHECKED

NO.
BY BY
6.0 GRANULATION:
Slowly add paste (step4) to the dry mixed powder in PLM and
granulate for 10 minutes at slow speed. Check the mass for
binding. Add Purified Water BP if required. Note down qty. of
Purified Water BP added.
Added qty of Purified water BP : 12.0liter
Actual Time : min.
7.0 DRYING :
Transfer above binded mass (step 4.5) in FBD 30KG trolley 1

&2
Trolley 1. Dry using hot air 40°C (without starting Heater.)
till Mass is dry
For about 30 min
trolley 2 Dry using hot air 40°C (without starting Heater.) till
Mass is dry
For about 30 min
8.0
L.O.D. Observed : (NMT 3% )
DRY SIEVING :
Sift the dried granules through 20# sieve in Sifter and collect
sifted granules in a poly bag kept in a plastic drum.
Sieve integrity Checked by : (before)
Sieve integrity Checked by : ( after).
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Sr. PROCESS DATE TIME DONE CHECKED

No. BY
BY
9.0 MILLING:-
Collect the over size granules and mill using 2 mm sieve, knife
forward and at slowest speed through Multi Mill. Collect the
milled granules and add to the sifted granule of
( step 7)
Screen inspected By:
Before Use:__________
After Use:_________
Weigh the total granules obtained.
Theoretical Wt. : Kg
DRIED GRANULES RECONCILIATION
DRUM GROSS TARE NETT

NO. WT. Kg. WT. Kg. WT. Kg. 1. Theo. wt. of granules: Kg.
2. Actual wt. of granules: Kg.
3. Percentage yield:
(Yield should not be less than98.5%)
Remarks: If any deviation in % yields, investigate.
Total Wt. : Kgs.
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SR. PROCESS DATE TIME DONE CHECKED

NO. BY
BY
FINAL MIXING : (LUBRICATION )

Sieve integrity Checked by (sign) Ok (Before)
10.0 sift following material through 40 # after mixing
Magnesium Stearate BP
Talc BP Sodium Starch Glycolate BP
on Sifter and collect in a poly bag.
Sieve integrity Checked By Ok (After)
Transfer dry granules (Step-7), lubricant in PLM add
Reprocessible material and lubricate for 10 minutes at slow
speed.
LUBRICATED GRANULES RECONCILIATION
DRUM GROSS TARE NETT

NO. WT. Kg. WT. Kg. WT. Kg. 1. Theo. wt. of lubricated
granules : Kg.
2. Actual wt. of granules : Kg.
3. Percentage yield : %
( Yield should not be less than 98.5%)
Remarks: If any deviation in % yields, investigate.

Total Wt. :
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TEST REQUEST
Bulk sample drawn by (Sign): Quantity: Gms.
Date : Time :
Affix “UNDER TEST SLIP” from Q.C. Dept on drum(s) and tightly close the drum(s).
Q.C. RESULTS
1. Assay : % (Limit: 95.0% to 105.0%)
2. Moisture of granules : % (Limit : NMT 3% )
Q.C. Release given by : Date Time :
Affix a suitable label on drum when batch sample is approved by Q.C.
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TABLET COMPRESSION PROCESS: - Compression started Date :
ENVIRONMENT CONTROL COMPRESSION MACHINE NO.:
1. Temperature: C. Date & Time: (27°C ±3°C)
2. Relative Humidity: Date & Time: (50% ±5 Rh)
3. Differential Pressure: Date & Time: (10 to 15 PSI)
4 DETAILS OF PREVIOUS PRODUCT:

Name of Previous product:
Batch No. : Production Chemist:
Sr. Equipment Used Equipment No. Ope.SOPNo. Clean. Done Check
No. SOP No. by by
1 Rotary Tablet Compr. Machine1 E/05 T0301 T0302
(16 stn.)
3 Punch Set :16/32” mm Round E/07 T0303 T0303
Upper Punch 16/32” mm Round
Lower Punch . 12.7 mm Round
Die: 12.7 mm Round
4 Two Pan Balance (Analytical) E/25 T0105 T0105
5 Single Pan Balance (Analytical) E/27 Q0502 Q0502
6 Disintegration Test Apparatus E/11 QO504 QO504
7 Vernier caliper E/09 QO517 QO517
8 Hardness Tester E/08 QO514 QO514
9 Friability Test Apparatus E/10 QO503 QO503
10 De-duster E/33 T0304 T0304
LINE CLEARANCE (AREA & MACHINERY.)
Done By : _______________
Production Chemist Date & Time.
Checked by : _______________
Q.A. Chemist
Date & Time.
Checking integrity of Die-Punch
Upper Punch Lower Punch Dies

Checked by :
95
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 INITIAL COMPRESS CHECK RECORD:
No. of 1 2 3 4 5 6 7 8 9 10
Punch
Weight in mg.
No. of Punch 11 12 13 14 15 16
Weight in mg.
Max. wt.
Min. wt.
Avg. wt.
Max. Limit
Min. Limit
PRECAUTIONS:
(1) Check the department as well as machine for cleanliness & line clearance.
(2) Confirm release for compression.
(3) Operator should wear full sleeve hand gloves and nose mask.
(4) Machine & Floor should be kept in clean condition.
(5) Affix a status label indicating Product Name, B. No., stage, date. etc.
(6) The containers will be stored on pallets in rows with the maximum height of 2 containers. Particular batch
will be segregated by a partition. The containers will be placed in such a way that all the container labels
are facing the individual inspecting the batch.
(7) The compressed tablets are stored in the poly-bags in the containers to approximately 80 to 90% of the
holding capacity of the poly-bag to facilitate proper tying with twine.
(8) Follow the respective SOPs of equipment.
(9) Environment control: Room Temp. : (27ºC ±3ºC) Humidity: 50% ±5%Rh)
 IN-PROCESS PERAMETERS TO BE CHECK DURING COMPRESSION :
Sr. CHECKING
No. PARAMETER LIMITS FREQUENCY
1. Every 30 minutes.
WEIGHT OF 20 TABLETS GM. ± 3 %
2. Every 2 hours.
INDIVIDUAL WEIGHT OF TABLET MG. ± 5 %
3. Every 2 hours.
DISINTEGRATION TIME NMT 15 MIN.
4. Every 2 hours.
THICKNESS MM ± 0.2 MM
5. Every 2 hours.
HARDNESS 2-5 KG/CM².
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6. Every 2 hours.
FRIABILITY NMT 1 %.
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DATE TIME Wt .of 20 D.T. Hardness Thickness Friability Checked

tabs
NMT Kg/cm². ± 0.2 mm. NMT 1.0 % By & Sign.
.
15 MIN
gm ± 3%
98
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FRIABILITY % = c x 100
a
FRIABILITY – 1 FRIABILITY – 2 FRIABILITY – 3
Date : Time : Date : Time : Date : Time :
a. Wt.of 20 Tab(before): a. Wt.of 20 Tab(before): a. Wt. of 20 Tab(before):
b. Wt.of 20 Tab (after): b. Wt.of 20 Tab (after) : b. Wt. of 20 Tab (after) :
c. Diff. : c. Diff. : c. Diff. :
% % = %
FRIABILITY – 4 FRIABILITY – 5 FRIABILITY – 6
Date : Time : Date :______ Time :______ Date :______ Time :______
a. Wt. of 20 Tab(before): a. Wt. of 20 Tab(before):____g a. Wt.of 20 Tab(before):_____g
b. Wt. of 20 Tab (after) : b. Wt. of 20 Tab (after) :____g b. Wt. of 20 Tab (after):______g
c. Diff. : c. Diff. : ______g c. Diff. : ______g
% = % = % =
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 RECORD OF WEIGHT VARIATION (FREQUENCY EVERY 2 HOURS. )

Av. wt. per Tab. = 620 mg Limit: 5 % (_589 mg to 651mg)
Date: Time: Date: Time: Date: Time:
INDIVIDUAL WEIGHT – 1 INDIVIDUAL WEIGHT – 2 INDIVIDUAL WEIGHT – 3
No Weight in No Weight No Weight No Weight in No Weight No Weight
Mg. in Mg. in Mg. Mg. in Mg. in Mg.
1 11 1 11 1 11
2 12 2 12 2 12
3 13 3 13 3 13
4 14 4 14 4 14
5 15 5 15 5 15
6 16 6 16 6 16
7 17 7 17 7 17
8 18 8 18 8 18
9 19 9 19 9 19
10 20 10 20 10 20
Weight of 20 Tabs. gm Weight of 20 Tabs gm Weight of 20 Tabs. gm

Av. Wt. Per Tablet: mg Av. Wt. Per Tablet: mg Av. Wt. Per Tablet: mg
Max mg & Min mg Max mg & Min mg Max mg & Min mg
Sign :_______________ Sign :_______________ Sign :_______________
Weight of compressed tablets with yield.
Drum Gross wt. Tare wt. Net wt. (A) Theoretical batch size = Kg.
No. Kg. Kg. Kg. (B) Weight of granules transferred
1. = Kg.
(C) Weight of compressed tablets
= Kg.
2. (D) Recoverable residue = Kg.
(E) Rej. for destruction = Kg.
C+ D X 100
% Yield = --------------------- = % w/w.
B (Limits : NLT 98.00%)
Note : If yield is less than limit, investigate.
Total weight : Kg
Rejection Destroyed by : Checked by : Date :
100
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CORE TABLETS INSPECTION.
Inspected By : Date & Time Supervised By.
Remark :Take 100 Tablets for inspection of physical parameters such as mottling , capping, sticking,
Picking, softening of tablets. If deviation that occurs more than 2 % take whole batch for
inspection
WEIGHT OF INSPECTED TABLETS
Drum Gross Tare Net
No. wt. Kg. wt. Kg. wt. Kg. Rejection for Destruction: =
Destroyed By: Pankaj
1.
Recoverable residue = Kg.
2.
Total weight : Kg
PACKING:
 PACKING MATERIAL REQUISITION WITH SPECIFICATION :
Packing Material Issue Date: 4/12/08
SR. ITEM SPEC. ITEM CODE STD. A.R.NO. QTY. CHECKED

QTY RECEIVED BY
NO
1. Plastic small tin IHS 2PTC376 1000

2. IHS 2PLC376 1030
Printed labels
3.
Corrugated box IHS 2CBC376 20
SR. NAME OF THE EQUIPMENT CAPACITY SOP NO. SOP.NO.

NO.
NO. MACHINE OPERATION CLEANING
1. T0503
Coding M/C E/20 HAND T0503
2.
Box Strapping M/C E/21 HAND T0504 T0504
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 PRECAUTIONS :
1. Environment control (Packing room):-Temp: 27C±3C Humidity: 50% ± 5 % R.H.
2. Over printing on carton and catch cover should be done in advance.
3. “Release Notice” from Q.C. department is to be confirmed before packing operation started.
4. “Line clearance” should be performed as per SOP no. Q0737 (Equipment)
5. Over printing should be checked carefully by packing supervisor and department in charge and counter
Checked by Q.C. department.
6. Leak test should be performed before starting packing line and confirmed for sealing as per SOP no.Q0714
7. Rejection and recoverable rejection strips should be kept in separate with proper label.
8. Reconciliation of packing material should be done after packing is finished. Rejection material should be
destroyed and carried to scrap and record accordingly.
 LINE CLEARANCE CHECK LIST :
SR. No. OBSERVATION CHECKED BY

CHECKS PRODUCTION Q.A
1. General Cleanliness
Machine / Equipment Cleanliness
2.
( Visual Checking )
3. previous product / material
4. Stereo of previous product
5. Check print matter on carton
6. Status label on packing line
7. Release status of issued packing material
8. BMPR Status
9. Log Card entry
10. Line Clearance label
Note : Line Clearance is required if work continues for next day.
 CODING MATTER ON LABELS :
DATE TIME CHECKED APPROVED

PROCESS FROM TO BY PROD. BY Q.A
a) Set Labels printing m/c as per SOP No.T0503-01
Obtain Line clearance from Q.A.
Approved the label for coding matter by
Q.A.
b) Now start Labels printing m/c as per SOP
No..T0503-01
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CHECKED APPROVED
CODING DETAILS ON LABELS PRINTED BY
BY PROD BY Q.A
BATCH NO. :
MFG. DATE :
EXP. DATE :
MAXIMUM RETAIL
PRICE Rs. :
(INCLUSIVE ALL TAXES)
 SPECIMEN OF PRINTED LABELS :
NAME OF PRODUCT : PARACETAMOL TABLET 500MG MFG.LIC.No. :

MAXIMUM RETAIL
BATCH No. : PRICE Rs. :
(INCLUSIVE ALL TAXES)
MFG. DATE : EXP. DATE :
CHECKED BY (PROD) : APPROVED BY (Q.A) :
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REMARKS :
Date Time Qty. Packed

Checking Counting Labeling 7plyouter
corr.box filling
Total Qty. Packed = Tablet
Total Qty. sent to B.S.R. = Tablet Control Sample: Tablet
CHECKED BY : PPROVED BY :
PRODUCTION Q.A
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PACKING MATERIAL RECONCILIATION:

Packing Printed Labels Plastic tin
Material
Qty.
Required (A)
Qty.
Issued (B)
Qty.
Used (C)
Quantity Online Rej.
Destroyed (D)
Qty. Returned
(E)
Total
Consumption (F)
C+D
Difference
B-(F+E)
% Deviating
(B-F)X100
B
Acceptance criteria: For Labels ± 3.0%.
CHECKED BY : APPROVED BY :
PRODUCTION Q.A
Qty. packed :
Retain sample Qty. :

Qty. Transferred to Finished goods Warehouse: Tablet Date :
Goods transfer slip no. : Date :
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BATCH RECONCILLIATION RECORD:
1. Actual Batch Size : 100000 Tablets.
2. Samples For Analysis : 100 Tablet
2.1 Granules For Bulk Analysis : 0.050 Gm = 80 Tablets.
2.2 Qty. Of Inprocess Sample : 100 Tablets.
2.3 Tablets For Finished Product Analysis : 120 Tablets.
2.4 Retain Samples : 3X100Tablets.
3. Qty. Of Recoverable Residue: Gm. = Tablets.
4 Quantity Transferred To Finished Goods

Warehouse : Tablets.
5. Total Quantity Destroyed : At Granules Stage: Kg.
At Compression Stage Kg.

6. Percentage Yield
(2 + 3 + 4 )
------------------- X 100 = % ( Limits : NLT 97.0% )
(1 )
Note: If Yield Is Less Than Please Investigate.
CHECKED BY : APPROVED BY :
PRODUCTION Q.A
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DEVIATION REPORT
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FLOW CHART FOR MANUFACTRUING PROCESS OF TABETS
R.M. WEIGHING SHIFTING MIXING GRANULATION
SEMI DRYING
SIFTING
QUALITY CONTROL
FINAL DRYING
PACKING
LUBRICATION
COMPRESSION
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Finished product specification
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FINISHED PRODUCT SPECIFICATION

QUALITY ASSURANCE DEPARTMENT
FINISHED PRODUCT SPECIFICATION
Issue No : 01 Revision No Specification No :

First Issue Date: Revision Date: Page 1 of 1
Dosage Form: Tablet
Product Name:PARACETAMOLE TABLET 500 MG

Generic Name: PARACETAMOLE TABLET 500MG Tested as per : BP
Mfg. Lic. :
CATEGORY: ANALGESIC & ANTI PYRETICS.
Self-Life: 3 years or depending upon the self-life of active ingredient, which ever is less
Storage Condition: In a cool & dry place.
EACH UN COATED TABLET CONTAINS

PARACETAMOL BP 500 mg.
Sr Test / Parameter Uncoated Finished Product Requirement

Bulk
Pharmacopial In-House
01 Description Off white white, round, , NA Awhite colour round,
Coloured uncoated tablet un coated tablet.
granule
02 Wt. Of 20 tablets 12.400 gm 12.400 gm NA 12.400 gm (±5.0 %)
03 Av. Wt. Of tablet 0.620 gm 0.620 gm NA 0.620gm (±5.0 %)
04 Friability NA N.M.T. 1.0% NA NA
05 Thickness NA 4.7 mm ( ± 0.4 mm ) NA 4.7 mm ( ± 0.4 mm )
06 Diameter NA 12.7 mm ( ± 0.1 mm ) NA 12.7 mm ( ± 0.1 mm )
07 Hardness NA 3.5 – 7.0 kg/cm2 NA NA
08 Uniformity of weight NA ± 5.0 % ± 7.5% ± 5.0 %
09 Identification R.T. of sample R.T. of sample should R.T. of sample R.T. of sample should
should same as same as sample in should same as same as sample in
sample in assay test sample in assay assay test
assay test test
10 Disintegration Time NA NMT 8 Mins NMT15Mins NMT 10 Mins
11 Assay of 97.0 – 103.0 % 97.0 – 103.0 % 90.0 – 110 % 95.0 – 105.0 %
PARACETAMOLE
NA = NOT APPLICABLE
Issued By Q.A. Chemist Checked By Q.A. Incharge Approved By Q.A. Manager
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Method Of Analysis of
Finished Products
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SUBJECT : FINISHED PRODUCT METHOD OF ANALYSIS.

DEPARTMENT : QUALITY CONTROL.
PRODUCT NAME : PARACETAMOL TABLETS
GENERIC NAME : PARACETAMOL TABLETS BP 500 MG
FPS NO. : FPS/PARA-500/01 SUPERSEDES : ---
EFFECTIVE DATE : 01/01/2004 PAGE NO. : 01 / 05
1. Description:
White round flat bevel, uncoated tablet with break line on one side.
2. Average weight : 620.00mg + 5%

Hardness : NLT 3.0 Kg/ cm2
Thickness : 4.7 mm + 0.4MM
Friability : NMT 1.0%
3.Disintergration :
NMT 15 MIN
Place one tablet in each of the six tubes of the basket, add a disc to each
tube and operate the apparatus using water maintained at 37°+ 2 c as the
immersion fluid. at the end of 15 minutes, lift the basket from the fluid and
completely. It one or two on 12 additional tablets, not less than 16 of the total
of 18 tablets disintegrate completely.
4.Identification
Extract a quantity of the powdered tablets containing 0.5 g of Paracetamol with 20 ml of
acetone, filter, evaporate the filtrate to dryness and dry at 105°. The residue complies with the
following tests.
A. The infrared absorption spectrum, Appendix II A, is concordant with the
reference spectrum of paracetamol (RS 258).
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B. Boil 0.1 g with 1 ml of hydrochloric acid for 3 minutes, add 10 ml of water and cool; no
precipitate is produced. Add 0.05 ml of 0.0167M potassium dichromate; a violet colour is
produced slowly which does not turn red.
C. Melting point, about 169°
5. 4 - AMINOPHENOL
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
Solution (1) contains 0.001% w/v of 4-amino-phenol in methanol (15%). For solution (2)
shake a quantity of the powdered tablets containing 1.0 g of Paracetamol with 15 ml of
methanol , dilute to 100 ml with water and filter.
The chromatographic procedure may be carried out using (a) a stainless steel column (20 cm
× 4.6 mm) packed with stationary phase C (10 µm) (Nucleosil C18 is suitable), (b) 0.01M
sodium butanesulphonate in a mixture of 0.4 volume of formic acid, 15 volumes of methanol
and 85 volumes of water as the mobile phase with a flow rate of 2 ml per minute and (c) a
detection wavelength of 272 nm.
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In the chromatogram obtained with solution (2) the area of any peak corresponding to 4-
aminophenol is not greater than the area of the peak in the chromatogram obtained with
solution (1). In the chromatogram obtained with solution (2) peaks with a long retention time
may occur due to excipients (0.1%)
6. Dissolution :
Comply with the dissolution test for tablets and capsules, Appendix XII D, using Apparatus II.
Use as the medium 900 ml of phosphate buffer pH 5.8 and rotate the paddle at 50 revolutions
per minute. Withdraw a sample of 20 ml of the medium and filter. Dilute the filtrate with 0.1M
sodium hydroxide to give a solution expected to contain about 0.00075% w/v of Paracetamol.
Measure the absorbance of this solution, Appendix II B, at the maximum at 257 nm using
0.1M sodium hydroxide in the reference cell. Calculate the total content of paracetamol,
C8H9NO2, in the medium taking 715 as the value of A(1%, 1 cm) at the maximum at 257 nm.
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7. Related Substance:
Carry out the method for thin-layer chromatography, Appendix III A, using silica gel GF254 as
the coating substance and a mixture of 10 volumes of toluene, 25 volumes of acetone and 65
volumes of chloroform as the mobile phase. Pour the mobile phase into an unlined tank,
immediately place the prepared plate in the tank, close the tank and allow the solvent front to
ascend 14 cm above the line of application. Apply separately to the plate 200 µl of solution (1)
and 40 µl of each of solutions (2), (3) and (4). For solution (1) transfer a quantity of the finely-
powdered tablets containing 1.0 g of Paracetamol to a ground-glass-stoppered 15 ml
centrifuge tube, add 5 ml of peroxide-free ether, shake mechanically for 30 minutes, centrifuge
at 1000 revolutions per minute for 15 minutes or until a clear supernatant liquid is obtained
and use the supernatant liquid. For solution (2) dilute 1 ml of solution (1) to 10 ml with ethanol
(96%). Solution (3) contains 0.0050% w/v of 4´-chloroacetanilide in ethanol (96%). For
solution (4) dissolve 0.25 g of 4´-chloroacetanilide and 0.10 g of paracetamol in sufficient
ethanol (96%) to produce 100 ml. After removal of the plate, dry it in a current of warm air and
examine under ultraviolet light (254 nm). Any spot corresponding to 4´-chloroacetanilide in the
chromatogram obtained with solution (1) is not more intense than the spot in the
chromatogram obtained with solution (3). Any secondary spot in the
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chromatogram obtained with solution (2) with an Rf value lower than that of 4´-
chloroacetanilide is not more intense than the spot in the chromatogram obtained with solution
(3). The test is not valid unless the chromatogram obtained with solution (4) shows two clearly
separated principal spots, the spot corresponding to 4´-chloroacetanilide having the higher Rf
value.
8.Assay :
Weigh and powder 20 tablets. Add a quantity of the powder containing 0.15 g of Paracetamol
to 50 ml of 0.1M sodium hydroxide, dilute with 100 ml of water, shake for 15 minutes and add
sufficient water to produce 200 ml. Mix, filter and dilute 10 ml of the filtrate to 100 ml with
water. Add 10 ml of the resulting solution to 10 ml of 0.1M sodium hydroxide, dilute to 100 ml
with water and measure the absorbance of the resulting solution at the maximum at 257 nm,
Appendix II B. Calculate the content of C8H9NO2 taking 715 as the value of A(1%, 1 cm) at the
maximum at 257 nm.
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QUALITY CONTROL DEPARTMENT

TABLET PHYSICAL TEST REPORT
01 Batch No.
02 Name of Product Paracetamol Tablet BP
03 Description White colour round uncoated Tablet.
04 Wt. of 20 Tablets Gms.
05 Av. Wt. of Tablet Gm.
06 Desintegration Time Mins Secs.
07 Diameter / Length mm
08 Thickness Mm mm
09 Width mm
10 Friability %
11 Hardness Kg/Cm²
12 Uniformity of weight
01 Mg 06 Mg 11 Mg. 16 Mg.
.
02 Mg 07 Mg 12 Mg. 17 Mg.
.
03 Mg 08 Mg 13 Mg. 18 Mg.
.
04 Mg 09 Mg 14 Mg. 19 Mg.
.
05 Mg 10 Mg 15 Mg. 20 Mg.
.
Lower Wt. Mg. Heigher Wt. Mg.
Range % To %
Pharmacopial Limit : ± 4 / 5 / 7.5 / 10 %
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Uniformity of wt. : Complies / Does Not Complies as per I.P./B.P./U.S.P./ In-House

Standards
Analyst : Date : Approved By:

STANDARD OPERATING PROCEDURE
Name of Test : Uniformity of Weight SOP No. :
(tablets)
Reference : BP'2005 Effective Date : 01/01/07
Reason for revision : NA Review Date : 01/12/08
Supersedes : NA Page No. : 1 of 1
Weigh individually twenty units taken at random or, for single-dose preparations presented in
individual
containers, contents of twenty units, and determine the average weight (mass). Not more
than two of the
individual weights (masses) deviate from the average weight (mass) by more than the
percentage deviation
shown in Table 12G-1 and none deviates by more than twice that percentage.
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CHEMIST QA/QC IN CHARGE MANAGER
Approved by
Prepared by Checked by

Name of Test : Friability of Uncoated SOP No. : QC/SOP/109
Tablets
This test is intended to determine, under defined conditions, the friability of uncoated tablets,
the phenomenon
whereby tablet surfaces are damaged and/or show evidence of lamination or breakage when
subjected to
mechanical shock or attrition.
Apparatus
Use a drum with an internal diameter between 283 and 291 mm and a depth between 36 mm
and 40 mm, made
of a transparent synthetic polymer with polished internal surfaces and not subject to static
build-up (see Fig.
17G-1). One side of the drum is removable. The tablets are tumbled at each turn of the drum
by a curved
projection with an inside radius between 75.5 mm and 85.5 mm that extends from the middle
of the drum to the
outer wall. The drum is attached to the horizontal axis of a device that rotates at 25 ± 1 r/m.
Thus, at each turn
the tablets roll or slide and fall onto the drum wall or onto each other.
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Fig. 17G-1 Tablet friability apparatus

Dimensions in mm
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Name of Test : Friability of Uncoated SOP No. : QC/SOP/109
Tablets
Method
For tablets weighing up to 0.65 g each, take a sample of twenty tablets; for tablets weighing
more than 0.65 g
each, take ten tablets. Place the tablets on a sieve no. 1000 and remove any loose dust with
the aid of air pressure
or a soft brush. Accurately weigh the tablet sample and place the tablets in the drum. Rotate
the drum 100 times
and remove the tablets. Remove any loose dust from the tablets as before. If no tablets are
cracked, split or
broken, weigh the tablets to the nearest milligram.
Generally the test is run once. If the results are doubtful or if the mass loss is greater than
1%, repeat the test
twice and determine the mean of the three tests. A maximum loss of 1% of the mass of the
tablets tested is
considered to be acceptable for most products.
For tablets having a diameter of 13 mm or greater, problems of reproducibility may be

encountered due to
frequent irregular tumbling. In such cases, adjust the drum so that the tablets may fall freely
and do not bind
together when lying next to each other, adjusting the drum so that the axis forms a 10° angle
with the base is
usually satisfactory.
Expression of the results
The friability is expressed as the loss of mass and it is calculated as a percentage of the
initial mass.
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Indicate the number of tablets used.
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Name of Test : Description SOP No. : QC/SOP/115

Reference : In-House Effective Date : 01/12/01
1 Observe the sample immediately after receipt.
2 Observe the sample on the piece of paper under sufficient light.
3 Observe the sample of black and white particles and foreign matters.
4 Observe the sample for colour and odor.
5 Observe the sample for clarity for liquid samples.
6 Record your observations in the worksheet.
7 Inform your immediate supervisor in case of any abnormal observation.
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Disintegration Time (Ref: BP).
Disintegration Uncoated tablets comply with the test for disintegration of tablets and
capsules (2.9.1). Use
water R as the liquid medium. Add a disc to each tube. Operate the apparatus for 15 min,
unless otherwise
justified and authorised, and examine the state of the tablets. If the tablets fail to comply
because of adherence to
the discs, repeat the test on a further six tablets omitting the discs. The tablets comply with
the test if all six have
disintegrated.
Apparatus
a. A rigid basket-rack assembly supporting six cylindrical glass tubes 75.0 to

80.0 mm long, 21.5 mm in
b. internal diameter and with a wall thickness of about 2 mm (see Fig. 12A-
1).
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Fig. 12A-1 Apparatus for the Disintegration of Tablets and Capsules
Dimensions in mm
(b) A cylindrical disc for each tube, each 20.55 to 20.85 mm in diameter and 9.35 to 9.65
mm thick, made
of transparent plastic with a relative density of 1.18 to 1.20, pierced with five holes, each 2
mm in diameter, one
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in the centre and the other four spaced equally on a circle of radius 6 mm from the centre of
the disc. Four
equally-spaced grooves are cut in the lateral surface of the disc in such a way that at the
upper surface of the disc
they are 9.5 mm wide and 2.55 mm deep and at the lower surface 1.6 mm square.
(c) The tubes are held vertically by two superimposed transparent plastic plates 90 mm
in diameter and 6
mm thick, perforated by six holes. The holes are equidistant from the centre of the plate and
are equally spaced
from one another. Attached to the under side of the lower plate is a piece of woven gauze
made from stainless
steel wire 0.635 mm in diameter and having nominal mesh apertures of 2.00 mm.
(d) The plates are held rigidly in position

and 77.5 mm apart by vertical metal rods at the periphery and a
metal rod is also fixed to the centre of the upper plate to enable the assembly to be attached
to a mechanical
device capable of raising and lowering it smoothly through a distance of 50 to 60 mm at a

constant frequency of
between 28 and 32 cycles per minute.
(e) The assembly is suspended in the specified liquid medium in a suitable vessel,
preferably a 1000-ml
beaker. The volume of liquid is such that when the assembly is in the highest position the
wire mesh is at least
15 mm below the surface of the liquid and when the assembly is in the lowest position the
wire mesh is at least
25 mm above the bottom of the beaker and the upper open ends of the tubes remain above
the surface of the
liquid.
(f) A suitable device maintains the temperature of the liquid at 36° to 38°.
The design of the basket-rack assembly may be varied provided that the specifications for
the glass tubes and
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wire mesh are maintained.
Method
Unless otherwise stated in the individual monograph, introduce one tablet or capsule into
each tube and, if
prescribed in the appropriate general monograph, add a disc to each tube. Suspend the
assembly in the beaker
containing the specified liquid and operate the apparatus for the specified time. Remove the
assembly from the
liquid. The tablets or capsules pass the test if all six have disintegrated.
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DISSOLUTION TEST FOR TABLETS AND CAPSULES (As per BP’2002)

Use Apparatus 1 unless otherwise directed. All parts of the apparatus that may come into
contact with the
preparation being examined or with the dissolution medium are chemically inert and do not
adsorb, react or
interfere with the preparation being examined. All metal parts of the apparatus that may
come into contact with
the preparation or the dissolution medium must be made from stainless steel, type 316 or
equivalent or coated
with a suitable material to ensure that such parts do not react or interfere with the preparation
being examined or
the dissolution medium.
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No part of the assembly, including the environment in which the assembly is placed,
contributes significant motion, agitation or vibration beyond that due to the smoothly rotating
element.
An apparatus that permits observation of the preparation being examined and the stirrer
during the test is preferable.
Apparatus 1
An assembly consisting of the following:
A cylindrical vessel, A, made of borosilicate glass or any other suitable transparent material,
with a hemispherical bottom and with a nominal capacity of 1000ml.The vessel has a flanged
upper rim and is fitted with a lid that has a number of openings, one of which is central.
A motor with a speed regulator capable of maintaining the speed of rotation of the paddle
within 4% of that specified in the individual monograph. The motor is fitted with a stirring
element which consists of a drive shaft and blade forming a paddle, B (see Fig. 7.3.2)
129
XYZ PHARMACEUTICAL
The blade passes through the diameter of the shaft so that the bottom of the blade is flush
with the bottom of the shaft. The shaft is positioned so that its axis is within 2 mm of the axis
of the vessels and the lower edge of the blade is 23 to 27 mm from the inside bottom of the
vessel. The apparatus operates in such a way that the paddle rotates smoothly and without
significant wobble.
A water -bath set to maintain the dissolution medium at 36.5° to 37.5° . The bath liquid is
kept in constant and smooth motion during the test. The vessel is securely clamped in the
water-bath in such a way that the displacement vibration from other equipment, including
the water circulation device, is minimised
Dissolution medium: Use the dissolution medium specified in the individual monograph. If
the medium is a buffered solution, adjust the solution so that its pH is within 0.05 units of the
pH specified in the monograph. The dissolution medium should be deaerated prior to testing.
Time: Where a single time specification is given in the monograph, the test may be
concluded in a shorter period if the requirement for the minimum amount dissolved is met. If
two or more times are specified, specimen are to be withdrawn only at the stated times,
within a tolerance of ± 2%.
Method: Introduce the stated volume of the dissolution medium, free from dissolved air, into
the vessel of the apparatus. Warm the dissolution medium to between 36.5° and 37.5° .
Unless otherwise stated use one tablet or capsule.
When Apparatus 1 is used, allow the tablet or capsule to sink to the bottom of the vessel
prior to the rotation of the paddle. A suitable device such as a wire of glass helix may be
used to keep horizontal at the bottom of the vessel tablets or capsules that would otherwise
float. Care should be taken to ensure that air bubbles are excluded from the surface of the
tablet or capsule. When Apparatus 2 is used, place the tablet or capsule in a dry basket at
the beginning of each test. Lower the basket into position before rotation. Operate the
apparatus immediately at the speed of rotation specified in the individual monograph. Within
the time interval specified, or at each of the times stated, withdraw a specimen from a zone
midway between the surface of the dissolution medium and the top of the rotating blade or
basket, not less than 10mm from the wall of the vessel. Except in the case of single
sampling, add a volume of dissolution medium equal to the volume of the samples
withdrawn. Perform the analysis as directed in the individual monograph. Repeat the whole
operation five times. Where two or more tablets or capsules are directed to be placed
together in the apparatus, carry out six replicate tests.
130
XYZ PHARMACEUTICAL
For each of the tablet or capsule tested, calculate the amount of dissolved active ingredient
in solution as a percentage of the stated amount where two or more tablets or capsules are
placed together, determine for each test the amount of active ingredient in solution per tablet
or capsules and calculate as a percentage of the stated amount. If the results do not conform
to the requirements at stage S1 given in the accompanying acceptance table (Table 1),
continue testing with additional tablets or capsules through stages S2 and S3 unless the
result conform at stage S2.
Where capsule shells interfere with the analysis, remove the contents of not less than 6
capsules as completely as possible, and dissolve the empty capsule shells in the specified
volume of the dissolution medium. Perform the analysis as directed in the individual
monograph. Make any necessary correction.
Correction factors should not be greater than 25% of the stated amount.
TABLE 1- Acceptance Table
Stage Number Tested Acceptance
S1 6 Each unit is not less than D* + 5%
S2 6 Average of 12 units (S1 +S2) is equal to or

greater than D, and no unit is less than D -
15%.
S3 12 Average of 24 units (S1+S2+S3), Is equal t
or greater than D, not, More than 2 units
are less than D - 15% and no unit is less
than D - 25%
*D is the amount of dissolved active ingredient specified in the individual monograph,
expressed as a percentage of the stated amount.
131
XYZ PHARMACEUTICAL
PART II F
STABILITY TESTS ON THE FINISHED

PRODUCT
132
XYZ PHARMACEUTICAL
ACCELERATED STABILITY PROTOCOL

PRODUCT NAME : PARACETAMOL TABLET BP 500 MG BATCH NO : R400227
LABEL CLAIM : Each Uncoated tablet ontains: MFG. DATE : Sep’2004
PARACETAMOL BP………. 500mg.
EXCIPIENTS…………………Q.S.
CONDITION : Temperature 40°C ±2.0°C EXP. DATE : Aug’2007
Humidity : 75%, ±5.0 %
DESCRIPTION : white, round, Uncoated tablet. PACK : 10X10TABLETS
STYLE IN BLISTER
Months Description Disintegration Time Dissolution Assay Analysed By Remarks

NMT 15 Mins. NLT 75.0 % 95.0 –
105.0 %
Initial White Round, uncoated 06 Mins. 40 Secs. Min.: 92.35 % 100.37 % Sample complies as per In-
tablet. House Specification
01 White Round,Uncoated 06 Mins. 51 Secs. Min.: 90.31 % 100.24 % Sample complies as per In-
02 White Round,Uncoated 07 Mins. 11 Secs. Min.: 89.34 % 99.31 % Sample complies as per In-
03 White Round, Uncoated 07 Mins. 24 Secs. Min.: 88.30 % 98.56 % Sample complies as per In-
06 White Round, Un coated 07 Mins. 30 Secs. Min.: 85.29 % 98.04 % Sample complies as per In-
CONCLUSION: From the data observed in above table are carried out as per In-House Specification & it is evident that the
Product is within permissible limit.
CHECKED BY
Q.A. INCHARGE

131
XYZ PHARMACEUTICAL

PRODUCT NAME : PARACETAMOL TABLET BP 500 MG BATCH NO : R400228
LABEL CLAIM : Each Uncoated tablet contains: MFG. DATE : Nov’2004
PARACETAMOL BP…….. 500mg.
EXCIPIENTS……………….Q.S.
CONDITION : Temperature 40°C ±2.0°C EXP. DATE : Oct’2007
Humidity : 75%, ±5.0 %
DESCRIPTION : White round, Uncoated tablet. PACK : 10X10TABLETS
STYLE IN BLISTER

NMT 15 Mins. NLT 75.0 % 95.0 –
105.0 %
Initial White, round, Uncoated 07 Mins. 12 Secs. Min.: 94.20 % 100.67 % Sample complies as per In-
01 White, round, Uncoated 07 Mins. 42 Secs. Min.: 92.35 % 100.51 % Sample complies as per In-
03 White round, Uncoated 08 Mins. 34 Secs. Min.: 92.03 % 98.33 % Sample complies as per In-
CHECKED BY
Q.A. INCHARGE

132
XYZ PHARMACEUTICAL
PRODUCT NAME : PARACETAMOL TABLET BP 500MG BATCH NO : R400229
LABEL CLAIM : Each Uncoated tablet contains: MFG. DATE : Dec’2004
PARACETAMOL BP………. 500 mg.
EXCIPIENTS…………………Q.S.
CONDITION : Temperature 40°C ±2.0°C EXP. DATE : Nov’2007
Humidity : 75%, ±5.0 %
DESCRIPTION : White, round, Uncoated tablet. PACK : 10X10TABLETS
STYLE IN BLISTER

NMT 15 Mins. NLT 75.0 % 95.0 –
105.0 %
Initial White round, Uncoated 07 Mins. 03 Secs. Min.: 92.32 % 100.21 % Sample complies as per In-
06 White, round, UNcoated 09 Mins. 23 Secs. Min.: 84.36 % 97.22 % Sample complies as per In-
CHECKED BY
Q.A. INCHARGE

133
XYZ PHARMACEUTICAL
REAL TIME STABLITY PROTOCOL

LABEL CLAIM : Each Uncoated tablet contains: MFG. DATE : Sep’2004
PARACETAMOL BP ………500mg.
EXCIPIENTS……………….Q.S.
CONDITION : Temperature 30°C ±2.0°C EXP. DATE : Aug’2007
Humidity : 40%, ±5.0 %
DESCRIPTION : White , round, Un coated tablet. PACK : 10X10 TABLETS
STYLE IN BLISTER
NMT 15 Mins. NLT 75.0 % 95.0 –
105.0 %
Initial White, round, Un coated 06 Mins. 40 Secs. Min.: 92.35 % 100.37 % Sample complies as per In-House
tablet. Specification
06 White, round, Un coated 06 Mins. 22 Secs. Min.: 93.85 % 99.51 % Sample complies as per In-House
18 White round, Un coated 08 Mins. 22 Secs. Min.: 88.35 % 97.84 % Sample complies as per In-House
CHECKED BY
Q.A. INCHARGE

134
XYZ PHARMACEUTICAL

LABEL CLAIM : Each Uncoated tablet contains: MFG. DATE : Nov’2004
PARACETAMOL BP………. 500 mg.
EXCIPIENTS………………..Q.S.
CONDITION : Temperature 30°C ±2.0°C EXP. DATE : Oct’2007
Humidity : 40%, ±5.0 %
DESCRIPTION : White, round, Un coated tablet. PACK : 10X10TABLETS
STYLE IN BLISTER
NMT 15 Mins. NLT 75.0 % 95.0 –
105.0 %
18 White, round, Uncoated 09 Mins. 20 Secs. Min.: 89.03 % 96.06 % Sample complies as per In-House
36 White, round, Uncoated 09 Mins. 34 Secs. Min.: 84.89 % 95.06 % Sample complies as per In-House
CHECKED BY
Q.A. INCHARGE
135
XYZ PHARMACEUTICAL

LABEL CLAIM : Each Uncoated tablet contains: MFG. DATE : Dec’2004
PARACETAMOL BP……….. 500mg.
EXCIPIENTS…………………Q.S
CONDITION : Temperature 30°C ±2.0°C EXP. DATE : Nov’2007
Humidity : 40%, ±5.0 %
DESCRIPTION : White, round, Un coated tablet. PACK : 10X10TABLETS
STYLE IN BLISTER

NMT 15 Mins. NLT 75.0 % 95.0 –
105.0 %
tablet Specification
24 Pink, round, biconvex, Film 09 Mins. 40 Secs. Min.: 80.34 % 98.36 % Sample complies as per In-House
coated tablet. Specification
CHECKED BY
Q.A. INCHARGE

136

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XYZ PHARMACEUTICAL

PRODUCT REGISTRATION DOSSIER

PARACETAMOL TABLET 500 MG

APPLICATION FOR REGISTRATION OF A DRUG

DEMOCRETIC REPUBLIC OF---------

5(a) NAME OF BUSINESS

(b) COUNTRY OF ORIGIN :

(6) NAME OF LOCAL DISTRIBUTOR :

BUSINESS ADDRESS OF LOCAL

(7) NAME AND SIGNATURE OF

SUMMARY OF THE DOSSIER

(1) SITE MASTER PLAN OF PLANT

(2) COMPANY PROFILE IN SHORT

(3) ATTESTED COPY OF MANUFACTURING LICENCE

(4) ATTESTED COPY OF PRODUCT PERMISSION FROM FDCA

(5) ATTESTED COPY OF COPP

(6) ATTESTED COPY OF WHO/GMP CERTIFICATE

(7) COA OF SAMPLE

(8) ATTESTED COPY OF WHOLE SELL LICENCE.

(9) LETTER OF AUTHORISATION

MODEL OF LETTER OF AUTHORISATION

PRODUCT OWNER’S NAME AND ADDRESS

HEREBY APPOINT __________________________________________________________

APPLICANT’S NAME AND ADDRESS

TO APPLY FOR REGISTRATION OF OUR PHARMACEUTICAL PRODUCT

OWNER OF DRUG DATE OF ISSUE:

BRAND NAME COMPOSITION (INCLUDING

NON PROPRIETARY NAME PARACETAMOL BP PARACETAMOL BP 500MG

DOSAGE FORM TABLET

THERAPEUTIC CATEGORY ANALGESIC AND

PRESENTATION(TYPE OF PACKING, PACK 1X100T,1X500T,10X10T

INDICATION: Relief mild to moderate pain and fever.

DOSAGE : Adults: One to two tablets every 4 to 6 hours up to a maximum of 8

Children 6-12 years: One tablet 3 to 4 times daily as required.

Paracetamol is one of the most common analgesics used in children.

S.NO. TRADE NAME GENERIC NAME OR FORMULA INDICATIONS REMARK

EACH TABLET CONTAINS:

PACKING : 1x100T, 10X10T

PARACETAMOL TABLET BP 500 MG

EACH UNCOATED TABLET CONTAINS:

1 A 1.1 NAME OF THE ACTIVE SUBSTANCE(S)

1 A 1.2 PHARMACOTHERAPEUTIC CLASSIFICATION

ANALGESIC & ANTIPYRATICS

1A2 PHARMACEUTICAL FORM AND STRENGTH

PHARMACEUTIACLS DOSAGE : ORAL TABLET

PARACETAMOL TABLET 500 MG

EACH UN COATED TABLET CONTAINS:

1 A 2.1 Route of administration

EACH BOX OF 10 X 10TABLETS

200 BOXES IN EACH CORRUGATED BOX

IA4 QUALITATIVE AND QUANTITATIVE COMPOSITION

EACH TABLETS CONTAINS

Nº Name Quantity Unity Reference

2 MICRO CRYSTALINE 50.00 mg BP

SUMMARY OF PRODUCT CHARACTERISTICS

II B SUMMARY OF PRODUCT CHARACTERISTICS (SPC)

II B 1 SUMMARY OF PRODUCT CHARACTERISTICS (SPC)

II B 1.1 Proposed trade name of the pharmaceutical product

PARACETAMOL TABLET BP 500 MG

II B 1.2 Qualitative and quantitative composition

EACH TABLETS CONTAINS

Nº Name Quantity Unity Reference

2 MICRO CRYSTALINE 50.00 mg BP