Sample Dossier

XYZ PHARMACEUTICAL

PRODUCT REGISTRATION DOSSIER

PARACETAMOL TABLET 500 MG

A Product of Neutral Code

: :

Marketed/ Imported by

:

Date of submission

:

1 Contact :: [email protected]

Website :: http://icpc.biz/PharmaceuticalDossier.aspx

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

:



XYZ PHARMACEUTICAL 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

:



XYZ PHARMACEUTICAL

PART I

SUMMARY OF THE DOSSIER



XYZ PHARMACEUTICAL

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



XYZ PHARMACEUTICAL

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

:



XYZ PHARMACEUTICAL Department of Health Food and Drug Administration Summary Drug Information NAME

APPLICANT

ADDRESS

PHONE/FAX

FOR OFFICIAL USE.

DATE OF APPLICATION: APPLICATION NO.: ASSESSMENT FEES: REGISTRATION CERTIFICATE NO.:

OWNER OF DRUG

DATE OF ISSUE: DATE OF EXPIRY: SALES CATEGORY: VARIATION:

MANUFACTURER



XYZ PHARMACEUTICAL BRAND NAME

COMPOSITION (INCLUDING EXCIPIENTS & COLORING SUBSTANCE)

NON PROPRIETARY NAME

PARACETAMOL BP

DOSAGE FORM

TABLET

STRENGTH

500MG

THERAPEUTIC CATEGORY

ANALGESIC AND ANTIPYRATIC

PRESENTATION(TYPE OF PACKING, PACK SIZE)

1X100T,1X500T,10X10T

INDICATION:

DOSAGE

PARACETAMOL BP 500MG

Relief mild to moderate pain and fever.

: 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.



XYZ PHARMACEUTICAL PROFORMA STATEMENT: S.NO.

TRADE NAME

GENERIC NAME OR FORMULA

INDICATIONS

REMARK

EACH TABLET CONTAINS: 1

PACKING LIFE FOB PRICE MANUFACTURER

PARACETAMOL BP 500MG

ANALGESIC & ANTIPYRETIC

: 1x100T, 10X10T : 3Years from the date of manufacturing : US$ :



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: PARACETAMOL BP ---------500 MG 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



XYZ PHARMACEUTICAL

IA4

QUALITATIVE AND QUANTITATIVE COMPOSITION

EACH TABLETS CONTAINS

I

Nº

Name ACTIVE SUBSTANCE(S)

1.

PARACETAMOL

II

EXCIPIENT(S)

1 2 3 4 5 6 7

Quantity

Unity

Reference

500.00

mg

BP

LACTOSE

23.00

mg

BP

MICRO CRYSTALINE CELLULOSE STARCH

50.00

mg

BP

27.00

mg

BP

5.00

mg

BP

6.00

mg

BP

5.00

mg

USP

4.00

mg

BP

MAGNESIUM STEARATE SODIUM STARCH GLYCOLATE COLLOIDAL SILICON DIOXIDE PURIFIED TALC

...

620.00

:

MG



XYZ PHARMACEUTICAL

CTD Module II & III SUMMARY OF PRODUCT CHARACTERISTICS (SPC)



XYZ PHARMACEUTICAL 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



XYZ PHARMACEUTICAL EACH TABLETS CONTAINS

I

Nº


1.

PARACETAMOL

II

EXCIPIENT(S)

1 2 3 4 5 6 7

Quantity

Unity

Reference

500.00

mg

BP

LACTOSE

23.00

mg

BP


50.00

mg

BP

27.00

mg

BP

5 .00

mg

BP

6.00

mg

BP

5.00

mg

USP

4.00

mg

BP

620.00

MG




XYZ PHARMACEUTICAL

RAW MATERIAL SPECIFICATIONS



XYZ PHARMACEUTICAL SUBJECT: DEPARTMENT:

RAW MATERIAL SPECIFICATION QUALITY CONTROL

MATERIAL NAME: PARACETAMOL BP

SPEC NO: RMS/PARA/2004

EFFECTIVE DATE: REVIEW DATE: Two Years

SR NO 1.

TEST

SPECIFICATION

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. 5.

RELATED SUBSTANCE 4-AMINOPHENOL

Complies the test Complies the test

6. 7. 8. 9.

HEAVY METALS LOSS ON DRYING SULPHATED ASH ASSAY

Complies the test NMT 0.5% NMT 0.1% 99.0-101.0%



XYZ PHARMACEUTICAL SUBJECT

:

DEPARTMENT

:

RAW MATERIAL SPECIFICATION QUALITY CONTROL

MATERIAL NAME :

SPEC NO: RMS/PW/2004

PURIFIED WATER

EFFECTIVE DATE

:

REVIEW DATE

:

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

Two Years



XYZ PHARMACEUTICAL

XYZ PHARMACEUTICAL QUALITY ASSURANCE DPEARTMENT RAW MATERIAL SPECIFICATION Name of Material Sr. no.

: Lactose BP

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 nm)

Not greater than 0.07.

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. Storage:

Black particles

Free from black particles.

Store in well closed containers



XYZ PHARMACEUTICAL

Test

Specifications of Microcrystalline Celiulosel02fMCCP) B.P. 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-


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 %





XYZ PHARMACEUTICAL 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


pH

4.0 to 7.0.

Foreign matter


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 %


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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XYZ PHARMACEUTICAL QUALITY ASSURANCE DPEARTMENT RAW MATERIAL SPECIFICATION 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: Test Sr.

Limit

01

Characters

Should Comply as per BP

02

Identification

(C), (D), Should comply as per BP ‘

03

Appearance of solution


04

Acidity or Alkalinity


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

14

Assay

15

Fatty acid composition

Total viable aerobic count not more than 103 micro-organisms per gram, determined by plate count. It complies with the test for Escherichia coli) Should Comply as per BP SHOULD COMPLY AS PER BP



XYZ PHARMACEUTICAL

XYZ PHARMACEUTICAL QUALITY ASSURANCE DPEARTMENT RAW MATERIAL SPECIFICATION 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

03

IDENTIFICATION Appearance of gel


04

PH

5.5 – 7.5

05

Sodium Glycollate


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



XYZ PHARMACEUTICAL

XYZ PHARMACEUTICAL QUALITY ASSURANCE DPEARTMENT RAW MATERIAL SPECIFICATION Name of Material: Purified Sr. TEST PARAMETERS no.

Talc 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 absorption spectrometry)

NMT 2.0%

7.

Calcium (on atomic absorption spectrometry)

NMT 0.9%

8.

Iron (on atomic absorption spectrometry)

NMT 0.25%

9.

Magnesium (on atomic absorption spectrometry)

17.0% to 19.5%

10.

Lead (on atomic absorption spectrometry)

NMT 10 ppm

11.

Loss on ignition (at 1050°c to 1100°c)

NMT 7.0% w/w

12.


Total visible aerobic count is not more than 102 aerobic bacteria and fungi per gram.

Additional test : 1.

Black particles

Free from black particles



XYZ PHARMACEUTICAL

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 (in a 1 in 25 dispersion)

3.5 to 5.5

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

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Name of Material Tested as per

LACTOSE BP 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-Dglucopyranose. 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.



XYZ PHARMACEUTICAL

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) 26 Contact :: [email protected]


XYZ PHARMACEUTICAL

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 .



XYZ PHARMACEUTICAL


MICROCRYSTALLINE CELLULOSE BP BRITISH PHARMACOPEIA

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:



XYZ PHARMACEUTICAL

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 centrifuge. The pH of the supernatant liquid is 5.0. to 7.5.

20 min and

(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. 29 Contact :: [email protected]


XYZ PHARMACEUTICAL

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 microorganisms 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.



XYZ PHARMACEUTICAL

Salmonella Prepare the product to be examined as described in the general method Appendix XVI B2 (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 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. Subculture on a plate of agar medium N and incubate at 35° to 37° for 18 to 72 hours. If no growth of microorganisms 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 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. 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 Contact :: [email protected]


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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 A

such as ATCC 9027 (NCIMB 8626, CIP 82.118): broth medium

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.



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Magnesium Stearate BP BRITISH PHARMACOPEIA

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



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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.



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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.



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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.



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Sodium Starch Glycollate (Type C) BP BRITISH PHARMACOPEIA

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



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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



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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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COLLOIDAL SILICON DIOXIDE 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



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COLLOIDAL SILICON DIOXIDE 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.



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Purified Talc BP BRITISH PHARMACOPEIA

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



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Name of Material Purified Talc BP Tested as per BRITISH PHARMACOPEIA 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. Reference solutions. Into four identical volumetric flasks, each containing 10.0 ml of hydrochloric acid R and 10 ml of lanthanum chloride solution R, introduce respectively



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Name of Material Purified Talc BP Tested as per BRITISH PHARMACOPEIA 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 100.0 ml with water R. 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 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 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 100.0 ml with water R. 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.



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Purified Talc BP BRITISH PHARMACOPEIA

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 administration.

for oral or topical



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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 pressed between the fingers.

which creaks when

■ 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 twoto 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.



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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 1.000 130°Cfor90min.

by drying in an oven at

■ 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 . 47 Contact :: [email protected]


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CONCERNING CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL DOCUMENTATION FOR CHEMICAL ACTIVE SUBSTANCE(S)



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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 paminophenol. 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 49 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 HealthSystem 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. 50 Contact :: [email protected]


XYZ PHARMACEUTICAL 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) daily dose (mg) lb kg 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. 51 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 antiinflammatory 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;36:11961206. 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. 52 Contact :: [email protected]


XYZ PHARMACEUTICAL 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. 53 Contact :: [email protected]


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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 aspirinsensitive 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 antiinflammatory (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, doubleblind, 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 56 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 57 Contact :: [email protected]


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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 onetime 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 58 Contact :: [email protected]


XYZ PHARMACEUTICAL 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, multidose 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 59 Contact :: [email protected]


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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 populationbased, 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 5hydroxyindoleacetic 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 60 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 (1-800-5256115), 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. 61 Contact :: [email protected]


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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: 62 Contact :: [email protected]


XYZ PHARMACEUTICAL 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.



XYZ PHARMACEUTICAL 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). 64 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 P450dependent 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 glutathionederived 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 65 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 66 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 heatregulating 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



XYZ PHARMACEUTICAL 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 69 Contact :: [email protected]


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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 70 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 metabolite Glucuronide Sulfate Mercapturate Cysteine conjugate Free acetaminophen

Range of mean percent 46.8 - 62.2 25.4 - 35.9 2.7 - 5.0 2.1 - 3.0 3.4 - 8.7

TABLE 2. Adult TYLENOL® acetaminophen preparations

Preparation

Strength

Adult single Frequencya dose

Regular Strength TYLENOL Tablets/Caplets

325 mg

650 mg

500 mg

1000 mg

500 mg/15 mL

1000 mg

Every 4 to 6 hb

Extra Strength TYLENOL Tablets/Caplets/Gelcaps/Geltabs Adult Liquid

TYLENOL Arthritis Extended Relief 650 mg 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.

1300 mg

Every 4 to 6 hc,d Every 4 to 6 hd,e Every 8 hd,f

TABLE 3. Pediatric TYLENOL® acetaminophen preparations Strengtha Preparation 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 3methyl-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 doubleblind, 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 72 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 doubleblind, 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 73 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 74 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 Rat (1 day old) Rat Mouse Hamster Rabbit Dog NT= not tested. Acute Nephrotoxicity (Rats)

Oral NT 2680-3100 NT 630-770 2640-2800 1180-1450

Intramuscular NT > 600 536-891 > 300, ≤ 548 NT > 66

Subcutaneous > 600, < 700 NT NT NT NT NT

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: 76 Contact :: [email protected]


XYZ PHARMACEUTICAL 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 77 Contact :: [email protected]


XYZ PHARMACEUTICAL 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). 78 Contact :: [email protected]


XYZ PHARMACEUTICAL 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.



XYZ PHARMACEUTICAL

CTD

Module III COMPOSITION



XYZ PHARMACEUTICAL

III A

COMPOSITION QUALITATIVE AND QUANTITATIVE COMPOSITION

EACH TABLETS CONTAINS

I

Nº


1.

PARACETAMOL

II

EXCIPIENT(S)

1 2 3 4 5 6 7

Quantity

Unity

Reference

500.00

mg

BP

LACTOSE

23.00

mg

BP


50.00

mg

BP

27.00

mg

BP


5.00

mg

BP

6.00

mg

BP

5.00

mg

USP

4.00

mg

BP

TOTAL

II A 2

620.00

MG

CONTAINER

Blister of10Tablets Such 10 Strips in Box Such 250 Box In 7 Ply Corrigated Box 20 GSM Paper

Contact :: [email protected]

81 Website :: http://icpc.biz/PharmaceuticalDossier.aspx

XYZ PHARMACEUTICAL

PREPARATION METHOD



XYZ PHARMACEUTICAL

II B METHOD OF PREPARATION II B 1 MANUFACTURING FORMULA (INCLUDING DETAILS OF BATCH SIZE) EACH TABLETS CONTAINS

I

Nº


1.

PARACETAMOL

II

EXCIPIENT(S)

1 2 3 4 5 6 7

Quantity

Unity

Reference

500.00

mg

BP

LACTOSE

23.00

mg

BP


50.00

mg

BP

27.00

mg

BP


5.00

mg

BP

6.00

mg

BP

5.00

mg

USP

4.00

mg

BP

620.00


MG


XYZ PHARMACEUTICAL

BATCH MANUFACTURING & PACKING RECORD TABLET SECTION Page No.: 01 of 30

Product Name: PARACETAMOL TABLTET 500 MG 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.:

Effective Date:

Mfg. Date:

Review Date: Two years

Exp. Date:

1, 00,000 TABS.

Recoverable Residue Added: Kg.

Standard Self Life: 36 months

Tablets

PACKING STYLE: 10X10T Theoretical Yield:

Final Batch Size=100,000 TABLETS

Issue By:

Mfg. Started on:

Date: Mfg. Completed On:

Label Claim: EACH UN COATED TABLET CONTAINS: PARACETAMOL BP ---------500 MG EXCIPIENTS-------------------------Q.S. TENTATIVE BMPR FOR FIRST THREE BATCH

FINAL DOCUMENT VARIFIED BY: ____________________ PRODUCTION HEAD (SIGN & DATE)


_____________ Q.A. HEAD (SIGN & DATE)


XYZ PHARMACEUTICAL

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.



XYZ PHARMACEUTICAL

MATERIAL ISSUING & DISPENSING CHECKING RECORD Sr. No

Label Clai m (mg)

Qty/ Tab. (mg)

INGREDIENTS

Spec.

Item Code

Std. Qty

Ov. %

Qty.

A.R.

Received

NO.

(Kg)

Kg.

DRY MIX 01

500

500

PARACETAMOL (B)*

BP.

1RAA376

50.000

____

02

--

50

MCCP

BP.

1RIM103

5.000

_____

03

--

23

Lactose

BP.

1RIL101

2.300

____

04

--

12

Starch

BP

1RIS105

1.200

____

15.00

Starch

BP

1RIS105

0.500

____

____

Purified Water

BP

1RIP105

Q.S

____

BINDER 05

--

06

LUBRICANTS 07

--

5.00

Magnesium Stearate

BP

1RIM101

0.500

____

08

--

4.00

Talc. (D)$

BP

1RIT101

0.400

____

09

--

6.00

BP

1RIS103

0.600

____

10

--

5.00

Sodium Starch Glycolate Colloidal Sillicon Dioxide

USP

1RIC105

0.500

____

TOT AL

620

(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.



CHE CKE D BY

XYZ PHARMACEUTICAL

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 1000000

=

=

x_______ 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 = (C) x (100 – Cw) Qty. Req./Batch = (Fn) x Batch Size = From 1st A.R.No. 1000000 Now, (G) – (E) =

_____ -_____

x 100 x 100 = x (100 )

x 1000000 =

____ =

Kg. (G) Qty. Req./Batch From 1st A.R.No.

___________Kg. (H) Qty. required From 2nd A.R.No.

Actual Qty. Required = (H) x {C x (100 - Cw)} = {(D) x (100 - Dw)} From 2nd A.R.No. Total Qty. Required / Batch = (E) + ( I ) =

mg / tablet(Fn)

x +

x

=

Kg. ( I ) R.M required From 2nd A.R.No.

.=__________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 :


XYZ PHARMACEUTICAL

EQUIPMENT / AREA / LINE CLEARANCE: GRANULATION Sr. No.

Equipment

Equipment No.

Operation SOP

Cleaning SOP

E/01 E/02 E/03 E/04 E/25 E/26 E/01-E,F

T0201 T0202 T0203 T0204 T0103 T0104 T0210

T0205 T0206 T0207 T0208 T0103 T0104 T0210

Done By

Checked By

GRANULATION: I 1 2 3 4 5 6 7

Sifter Planetary Mixer Fluid Bed Dryer Multi Mill Yard Balance (300 kg.) Two Pan Balance(5 Kg) Sieve 20,40 #

ENVIRONMENT CONTROL 1. Temperature °C :

LIMIT Date & Time:

2. Relative Humidity:

Date & Time:

(50% ±5 Rh)

Date & Time:

( 10-15 PSI )

40%.

3 Differential Pressure:

(27°C ±3°C )

4 DETAILS OF PREVIOUS PRODUCT: Name of Previous product : Batch No. : LINE CLEARANCE (AREA & MACHINERY.) Done By

: Production Chemist

Date & Time.

Q.A. Chemist

Date & Time.

Checked by :



XYZ PHARMACEUTICAL

cePRE MANUFACTURING CONTROL OPERATIONS: 1 2 3 4

Use proper uniform, gloves, Mask, & safety goggles, while handling raw materials. For operation & cleaning of machines follow respective SOP‘s. Obtained line clearance from Quality Assurance department before starting the activity. 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. No.

PROCESS

1.

WEIGHING AND CHECKING :

DATE

TIME

DONE BY

CHECKED BY

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.



XYZ PHARMACEUTICAL

SR. NO.

PROCESS

DATE

TIME

DONE 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



XYZ PHARMACEUTICAL

SR. NO. 6.0

PROCESS

DATE

TIME

DONE BY

CHECKED BY

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).



XYZ PHARMACEUTICAL

Sr. No.

PROCESS

9.0

MILLING:-

DATE

TIME

DONE BY

CHECKED BY

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 NO.

GROSS WT. Kg.

TARE WT. Kg.

NETT 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.


XYZ PHARMACEUTICAL

SR. NO.

PROCESS

DATE

TIME

DONE

CHECKED BY

BY

10.0

FINAL MIXING : (LUBRICATION ) Sieve integrity Checked by (sign) Ok (Before) 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 NO.

GROSS WT. Kg.

TARE WT. Kg.

NETT 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. :



XYZ PHARMACEUTICAL

TEST REQUEST Bulk sample drawn by (Sign): Date

Quantity:

:

Time

Gms. :

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.



XYZ PHARMACEUTICAL

TABLET COMPRESSION PROCESS: -

ENVIRONMENT CONTROL

1.

Temperature:

2.

Compression started Date :

COMPRESSION MACHINE NO.:

Date & Time:

(27°C ±3°C)

Relative Humidity:

Date & Time:

(50% ±5 Rh)

3.

Differential Pressure:

Date & Time:

4

DETAILS OF PREVIOUS PRODUCT: Name of Previous product: Batch No. :

Sr. No. 1

Equipment Used

C.

(10 to 15 PSI)

Production Chemist:

Equipment No.

Ope.SOPNo.

Rotary Tablet Compr. Machine1 E/05 T0301 (16 stn.) 3 Punch Set :16/32” mm Round E/07 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 5 Single Pan Balance (Analytical) E/27 Q0502 6 Disintegration Test Apparatus E/11 QO504 7 Vernier caliper E/09 QO517 8 Hardness Tester E/08 QO514 9 Friability Test Apparatus E/10 QO503 10 De-duster E/33 T0304 LINE CLEARANCE (AREA & MACHINERY.) Done By : _______________ Production Chemist Date & Time. Checked by : _______________ Q.A. Chemist Date & Time.

Clean. SOP No. T0302

Done by

Check by

T0303

T0105 Q0502 QO504 QO517 QO514 QO503 T0304

Checking integrity of Die-Punch Upper Punch Checked by

Lower Punch

Dies

:



XYZ PHARMACEUTICAL



INITIAL COMPRESS CHECK RECORD:

No. of Punch Weight in mg. No. of Punch Weight in mg.

1

2

3

4

5

6

11

12

13

14

15

16

7

8

9

Max. wt. Min. wt. Avg. wt. Max. Limit Min. Limit 

PRECAUTIONS: Check the department as well as machine for cleanliness & line clearance. Confirm release for compression. Operator should wear full sleeve hand gloves and nose mask. Machine & Floor should be kept in clean condition. Affix a status label indicating Product Name, B. No., stage, date. etc. 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) (1) (2) (3) (4) (5) (6)

 Sr. No.

IN-PROCESS PERAMETERS TO BE CHECK DURING COMPRESSION :

PARAMETER

LIMITS

WEIGHT OF 20 TABLETS

GM. ± 3 %

INDIVIDUAL WEIGHT OF TABLET

MG. ± 5 %

DISINTEGRATION TIME

NMT 15 MIN.

THICKNESS

MM ± 0.2 MM

HARDNESS

2-5

1.

CHECKING FREQUENCY Every 30 minutes. Every 2 hours.

2.

Every 2 hours.

3.

Every 2 hours.

4.

Every 2 hours.

5.


KG/CM².


10

XYZ PHARMACEUTICAL Every 2 hours.

6. FRIABILITY


NMT 1 %.


XYZ PHARMACEUTICAL

DATE

TIME

Wt .of 20 tabs . gm ± 3%


D.T.

Hardness

NMT

Kg/cm².

Thickness ± 0.2 mm.

Friability

Checked

NMT 1.0 %

By & Sign.

15 MIN


XYZ PHARMACEUTICAL

FRIABILITY % = c x 100 a

FRIABILITY – 1 Date :

FRIABILITY – 2

Time :

Date :

Time :


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. :

Diff. :

c.

%

Time :

FRIABILITY – 6

FRIABILITY – 5


%

% =

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 % =


XYZ PHARMACEUTICAL



RECORD OF WEIGHT VARIATION (FREQUENCY EVERY 2 HOURS. ) Av. wt. per Tab. = 620 mg Limit: 5 % (_589 mg to 651mg) Date: Time: Date: Time: INDIVIDUAL WEIGHT – 1 INDIVIDUAL WEIGHT – 2 No Weight in No Weight No Weight No Weight in Mg. in Mg. in Mg. Mg. 1 11 1 11 2 12 2 12 3 13 3 13 4 14 4 14 5 15 5 15 6 16 6 16 7 17 7 17 8 18 8 18 9 19 9 19 10 20 10 20 Weight of 20 Tabs. Av. Wt. Per Tablet: Max mg & Min Sign :_______________

Weight of 20 Tabs Av. Wt. Per Tablet: Max mg & Min Sign :_______________

gm mg mg

gm mg mg

Date: Time: INDIVIDUAL WEIGHT – 3 No Weight No Weight in Mg. in Mg. 1 11 2 12 3 13 4 14 5 15 6 16 7 17 8 18 9 19 10 20

Weight of 20 Tabs. Av. Wt. Per Tablet: Max mg & Min Sign :_______________

gm mg mg

Weight of compressed tablets with yield. Drum No. 1.

Gross wt. Kg.

Tare wt. Kg.

(A) Theoretical batch size = (B) Weight of granules transferred = (C) Weight of compressed tablets = (D) Recoverable residue = (E) Rej. for destruction = C+ D X 100 % Yield = --------------------- = B (Limits : NLT 98.00%) Note : If yield is less than limit, investigate.

Net wt. Kg.

2.

Total weight : Rejection Destroyed by :


Kg. Kg. Kg. Kg. Kg. % w/w.

Kg Checked by :

Date :


XYZ PHARMACEUTICAL

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 No.

Gross wt. Kg.

Tare wt. Kg.

Net wt. Kg.

1.

Rejection for Destruction: = Destroyed By: Pankaj 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. QTY

IHS IHS

2PTC376 2PLC376

1000 1030

IHS

2CBC376

20

NO 1. 2.

Plastic small tin

A.R.NO.

QTY. RECEIVED

CHECKED BY

Printed labels 3. Corrugated box SR.

NAME OF THE

NO. 1.

MACHINE

EQUIPMENT NO.

CAPACITY

SOP NO. OPERATION

Coding M/C

E/20

HAND

T0503

Box Strapping M/C

E/21

HAND

T0504

SOP.NO. CLEANING T0503

2.


T0504


XYZ PHARMACEUTICAL 

PRECAUTIONS :

1. 2. 3. 4. 5.

Environment control (Packing room):-Temp: 27C±3C Humidity: 50% ± 5 % R.H. Over printing on carton and catch cover should be done in advance. “Release Notice” from Q.C. department is to be confirmed before packing operation started. “Line clearance” should be performed as per SOP no. Q0737 (Equipment) Over printing should be checked carefully by packing supervisor and department in charge and counter Checked by Q.C. department. Leak test should be performed before starting packing line and confirmed for sealing as per SOP no.Q0714 Rejection and recoverable rejection strips should be kept in separate with proper label. Reconciliation of packing material should be done after packing is finished. Rejection material should be destroyed and carried to scrap and record accordingly.

6. 7. 8.



LINE CLEARANCE CHECK LIST :

SR. No. 1.

OBSERVATION

CHECKS

CHECKED BY PRODUCTION Q.A

General Cleanliness Machine / Equipment Cleanliness ( Visual Checking ) previous product / material Stereo of previous product Check print matter on carton Status label on packing line Release status of issued packing material BMPR Status Log Card entry Line Clearance label

2. 3. 4. 5. 6. 7. 8. 9. 10.

Note : Line Clearance is required if work continues for next day. 

CODING MATTER ON LABELS :

PROCESS

DATE

TIME FROM TO

CHECKED BY PROD.

APPROVED 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



XYZ PHARMACEUTICAL

CODING DETAILS ON LABELS

PRINTED BY

CHECKED

APPROVED

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. :

BATCH No. :

MAXIMUM RETAIL PRICE Rs. : (INCLUSIVE ALL TAXES)

MFG. DATE :

EXP. DATE :

CHECKED BY (PROD) :

APPROVED BY (Q.A) :



XYZ PHARMACEUTICAL

REMARKS :

Date

Time

Qty. Packed Checking

Counting

Labeling

7plyouter corr.box filling

Total Qty. Packed = Total Qty. sent to B.S.R. =

CHECKED BY PRODUCTION


Tablet Control Sample:

:

Tablet

Tablet

PPROVED BY : Q.A


XYZ PHARMACEUTICAL

PACKING MATERIAL RECONCILIATION: Packing Material Qty. Required (A) Qty. Issued (B) Qty. Used (C) Quantity Destroyed (D) Qty. Returned (E) Total Consumption (F) C+D Difference B-(F+E) % Deviating (B-F)X100 B Acceptance criteria:

Printed Labels

Plastic tin

Online Rej.

For Labels ± 3.0%.

CHECKED BY

:

APPROVED BY :

PRODUCTION Qty. packed

:

Retain sample Qty. : Qty. Transferred to Finished goods Warehouse: Goods transfer slip no. :


Q.A

Tablet

Date : Date :


XYZ PHARMACEUTICAL

BATCH RECONCILLIATION RECORD: 1. Actual Batch Size

:

2. Samples For Analysis

:

2.1 Granules For Bulk Analysis

: 0.050

2.2 Qty. Of Inprocess Sample

100000 100

: 100

Gm =

Tablet 80

Tablets.

Tablets.

2.3 Tablets For Finished Product Analysis : 120

Tablets.

2.4 Retain Samples

3X100Tablets.

:

3. Qty. Of Recoverable Residue:

Gm. =

4 Quantity Transferred To Finished Goods Warehouse

Tablets. :

5. Total Quantity Destroyed : At Granules Stage:

Tablets. Kg.

At Compression Stage 6.

Tablets.

Kg.

Percentage Yield (2 + 3 + 4 ) ------------------- X 100 (1 )

Note: If Yield Is Less Than CHECKED BY : PRODUCTION


=

% ( Limits : NLT 97.0% ) Please Investigate. APPROVED BY : Q.A


XYZ PHARMACEUTICAL

DEVIATION REPORT



XYZ PHARMACEUTICAL

FLOW CHART FOR MANUFACTRUING PROCESS OF TABETS

R.M.

WEIGHING

SHIFTING

MIXING

GRANULATION

SEMI DRYING

SIFTING QUALITY CONTROL FINAL DRYING

PACKING

LUBRICATION

COMPRESSION



XYZ PHARMACEUTICAL

Finished product specification



XYZ PHARMACEUTICAL

FINISHED PRODUCT SPECIFICATION QUALITY ASSURANCE DEPARTMENT FINISHED PRODUCT SPECIFICATION Issue No : 01 First Issue Date:

Revision No Revision Date:

Specification No : 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 500 mg.

PARACETAMOL BP Sr

Test / Parameter

Uncoated

Finished Product Requirement

Bulk 01

Description

02 03 04 05 06 07 08 09

Wt. Of 20 tablets Av. Wt. Of tablet Friability Thickness Diameter Hardness Uniformity of weight Identification

10 11

Disintegration Time Assay of PARACETAMOLE NA = NOT APPLICABLE Issued By Q.A. Chemist


Off white Coloured granule 12.400 gm 0.620 gm NA NA NA NA NA R.T. of sample should same as sample in assay test NA 97.0 – 103.0 %

white, round, uncoated tablet

,

12.400 gm 0.620 gm N.M.T. 1.0% 4.7 mm ( ± 0.4 mm ) 12.7 mm ( ± 0.1 mm ) 3.5 – 7.0 kg/cm2 ± 5.0 % R.T. of sample should same as sample in assay test NMT 8 Mins 97.0 – 103.0 %

Checked By Q.A. Incharge

Pharmacopial NA NA NA NA NA NA NA ± 7.5% R.T. of sample should same as sample in assay test NMT15Mins 90.0 – 110 %

In-House Awhite colour round, un coated tablet. 12.400 gm (±5.0 %) 0.620gm (±5.0 %) NA 4.7 mm ( ± 0.4 mm ) 12.7 mm ( ± 0.1 mm ) NA ± 5.0 % R.T. of sample should same as sample in assay test NMT 10 Mins 95.0 – 105.0 %

Approved By Q.A. Manager


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Method Of Analysis of Finished Products



XYZ PHARMACEUTICAL

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). Contact :: [email protected]


XYZ PHARMACEUTICAL

SUBJECT

:


DEPARTMENT

:

QUALITY CONTROL.

PRODUCT NAME

:

PARACETAMOL TABLETS

GENERIC NAME

:


FPS NO.

:

FPS/PARA-500/01

EFFECTIVE DATE

:

01/01/2004

SUPERSEDES : --PAGE NO.

: 02 / 05

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.



XYZ PHARMACEUTICAL

SUBJECT

:


DEPARTMENT

:

QUALITY CONTROL.

PRODUCT NAME

:

PARACETAMOL TABLETS

GENERIC NAME

:


FPS NO.

:

FPS/PARA-500/01

SUPERSEDES : ---

EFFECTIVE DATE

:

01/01/2004

PAGE NO.

: 03 / 05

In the chromatogram obtained with solution (2) the area of any peak corresponding to 4aminophenol 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.



XYZ PHARMACEUTICAL

SUBJECT

:


DEPARTMENT

:

QUALITY CONTROL.

PRODUCT NAME

:

PARACETAMOL TABLETS

GENERIC NAME

:


FPS NO.

:

FPS/PARA-500/01

SUPERSEDES : ---

EFFECTIVE DATE

:

01/01/2004

PAGE NO.

7.

: 04 / 05

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 finelypowdered 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



XYZ PHARMACEUTICAL

SUBJECT

:


DEPARTMENT

:

QUALITY CONTROL.

PRODUCT NAME

:

PARACETAMOL TABLETS

GENERIC NAME

:


FPS NO.

:

FPS/PARA-500/01

EFFECTIVE DATE

:

01/01/2004

SUPERSEDES : --PAGE NO.

: 05 / 05

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.



XYZ PHARMACEUTICAL

QUALITY CONTROL DEPARTMENT TABLET PHYSICAL TEST REPORT 01 02 03

Batch No. Name of Product Description

04

Wt. of 20 Tablets

Gms.

05

Av. Wt. of Tablet

Gm.

06

Desintegration Time

Mins

07

Diameter / Length

mm

08

Thickness

Mm

09

Width

mm

10

Friability

%

11

Hardness

Kg/Cm²

12

Uniformity of weight

01

Mg

06

Paracetamol Tablet BP White colour round uncoated Tablet.

Mg

Secs.

mm

11

Mg.

16

Mg.

12

Mg.

17

Mg.

13

Mg.

18

Mg.

14

Mg.

19

Mg.

15

Mg.

20

Mg.

. 02

Mg

07

Mg .

03

Mg

08

Mg .

04

Mg

09

Mg .

05

Mg

10

Mg .

Lower Wt.

Mg.

Heigher Wt.

Mg.

Range

%

To

%

Pharmacopial Limit : ± 4 / 5 / 7.5 / 10 %



XYZ PHARMACEUTICAL

Uniformity of wt. Standards Analyst :

: Complies / Does Not Complies as per I.P./B.P./U.S.P./ In-House Date :

Name of Test

:

Reference Reason for revision Supersedes

: : :

Approved By:

QUALITY ASSURANCE DEPARTMENT STANDARD OPERATING PROCEDURE Uniformity of Weight SOP No. (tablets) BP'2005 Effective Date NA Review Date NA Page No.

: : 01/01/07 : 01/12/08 : 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.



XYZ PHARMACEUTICAL

CHEMIST

QA/QC IN CHARGE

Prepared by

Checked by

MANAGER

Approved by

Name of Test

:


: : :

QUALITY ASSURANCE DEPARTMENT STANDARD OPERATING PROCEDURE Friability of Uncoated SOP No. Tablets BP'2005 Effective Date NA Review Date NA Page No.

: QC/SOP/109 : 01/12/05 : 01/12/06 : 1 of 2

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.



XYZ PHARMACEUTICAL

Fig. 17G-1 Tablet friability apparatus Dimensions in mm



XYZ PHARMACEUTICAL

Name of Test

:


: : :

QUALITY ASSURANCE DEPARTMENT STANDARD OPERATING PROCEDURE Friability of Uncoated SOP No. Tablets BP'2005 Effective Date NA Review Date NA Page No.

: QC/SOP/109 : 01/12/05 : 01/12/06 : 2 of 2

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. Contact :: [email protected]


XYZ PHARMACEUTICAL

Indicate the number of tablets used.



XYZ PHARMACEUTICAL

QUALITY ASSURANCE DEPARTMENT STANDARD OPERATING PROCEDURE Name of Test Reference Reason for revision Supersedes

: : : :

Description In-House NA NA

SOP No. Effective Date Review Date Page No.

: : : :

QC/SOP/115 01/12/01 01/12/02 1 of 1

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.



XYZ PHARMACEUTICAL

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. 12A1).



XYZ PHARMACEUTICAL

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



XYZ PHARMACEUTICAL

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



XYZ PHARMACEUTICAL

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.



XYZ PHARMACEUTICAL

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.



XYZ PHARMACEUTICAL

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)



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.



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.



XYZ PHARMACEUTICAL

PART II F

STABILITY TESTS ON THE FINISHED PRODUCT



XYZ PHARMACEUTICAL

ACCELERATED STABILITY PROTOCOL PRODUCT NAME LABEL CLAIM

: :

CONDITION

:

DESCRIPTION

:

PARACETAMOL TABLET BP 500 MG Each Uncoated tablet ontains: PARACETAMOL BP………. 500mg. EXCIPIENTS…………………Q.S. Temperature 40°C ±2.0°C Humidity : 75%, ±5.0 %

BATCH NO MFG. DATE

: :

R400227 Sep’2004

EXP. DATE

:

Aug’2007

white, round, Uncoated tablet.

PACK STYLE

:

10X10TABLETS IN BLISTER

Months

Description

Disintegration Time NMT 15 Mins.

Dissolution NLT 75.0 %

Initial

White Round, uncoated tablet. White Round,Uncoated tablet. White Round,Uncoated tablet. White Round, Uncoated tablet. White Round, Un coated tablet.

06 Mins. 40 Secs.

Min.: 92.35 %

Assay 95.0 – 105.0 % 100.37 %

06 Mins. 51 Secs.

Min.: 90.31 %

100.24 %

07 Mins. 11 Secs.

Min.: 89.34 %

99.31 %

07 Mins. 24 Secs.

Min.: 88.30 %

98.56 %

07 Mins. 30 Secs.

Min.: 85.29 %

98.04 %

01 02 03 06

Analysed By

Remarks

Sample complies as per InHouse Specification Sample complies as per InHouse Specification Sample complies as per InHouse Specification Sample complies as per InHouse Specification Sample complies as per InHouse Specification

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


Website :: http://icpc.biz/PharmaceuticalDossier.aspx 131

XYZ PHARMACEUTICAL

ACCELERATED STABILITY PROTOCOL PRODUCT NAME LABEL CLAIM

: :

CONDITION

:

DESCRIPTION

:

Months

Initial 01 02 03 06

PARACETAMOL TABLET BP 500 MG Each Uncoated tablet contains: PARACETAMOL BP…….. 500mg. EXCIPIENTS……………….Q.S. Temperature 40°C ±2.0°C Humidity : 75%, ±5.0 %

BATCH NO MFG. DATE

: :

R400228 Nov’2004

EXP. DATE

:

Oct’2007

White round, Uncoated tablet.

PACK STYLE

:




round, Uncoated

07 Mins. 12 Secs.

Min.: 94.20 %

Assay 95.0 – 105.0 % 100.67 %

round, Uncoated

07 Mins. 42 Secs.

Min.: 92.35 %

100.51 %

round, Uncoated

08 Mins. 22 Secs.

Min.: 93.45 %

99.39 %

round,

Uncoated

08 Mins. 34 Secs.

Min.: 92.03 %

98.33 %

round, Uncoated

08 Mins. 49 Secs.

Min.: 90.40 %

97.03 %

Description

White, tablet. White, tablet. White, tablet. White tablet. White, tablet.

Analysed By

Remarks



Q.A. INCHARGE Contact :: [email protected]


XYZ PHARMACEUTICAL ACCELERATED STABILITY PROTOCOL PRODUCT NAME LABEL CLAIM

: :

CONDITION

:

DESCRIPTION

:

Months

Initial 01 02 03 06

PARACETAMOL TABLET BP 500MG Each Uncoated tablet contains: PARACETAMOL BP………. 500 mg. EXCIPIENTS…………………Q.S. Temperature 40°C ±2.0°C Humidity : 75%, ±5.0 %

BATCH NO MFG. DATE

: :

R400229 Dec’2004

EXP. DATE

:

Nov’2007

White, round, Uncoated tablet.

PACK STYLE

:




Uncoated

07 Mins. 03 Secs.

Min.: 92.32 %

Assay 95.0 – 105.0 % 100.21 %

round, Uncoated

07 Mins. 12 Secs.

Min.: 90.33 %

99.35 %

round, Uncoated

07 Mins. 46 Secs.

Min.: 88.36 %

98.21 %

round, Uncoated

08 Mins. 22 Secs.

Min.: 85.16 %

98.03 %

round, UNcoated

09 Mins. 23 Secs.

Min.: 84.36 %

97.22 %

Description

White tablet. White, tablet. White, tablet. White, tablet. White, tablet.

round,

Analysed By

Remarks


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



XYZ PHARMACEUTICAL

PRODUCT NAME LABEL CLAIM

: :

CONDITION

:

DESCRIPTION

:

Months Initial 06 12 18 24 36

REAL TIME STABLITY PROTOCOL PARACETAMOL TABLET BP 500MG Each Uncoated tablet contains: PARACETAMOL BP ………500mg. EXCIPIENTS……………….Q.S. Temperature 30°C ±2.0°C Humidity : 40%, ±5.0 % White , round, Un coated tablet.



Un coated

06 Mins. 40 Secs.

Min.: 92.35 %

Assay 95.0 – 105.0 % 100.37 %

round,

Un coated

06 Mins. 22 Secs.

Min.: 93.85 %

99.51 %

round,

Un coated

07 Mins. 34 Secs.

Min.: 90.34 %

99.03 %

round,

Un coated

08 Mins. 22 Secs.

Min.: 88.35 %

97.84 %

Un coated

08 Mins. 46 Secs.

Min.: 85.36 %

97.34 %

Un coated

08 Mins. 51 Secs.

Min.: 84.16 %

97.24 %

Description White, tablet. White, tablet. White, tablet. White tablet. White tablet. White, tablet.

round,

round, round,

BATCH NO MFG. DATE

: :

R400227 Sep’2004

EXP. DATE

:

Aug’2007

PACK STYLE Analysed By

:

10X10 TABLETS IN BLISTER Remarks

Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification

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 Contact :: [email protected]


XYZ PHARMACEUTICAL

PRODUCT NAME LABEL CLAIM

: :

CONDITION

:

DESCRIPTION

:

Months

Initial 06 12 18 24 36

REAL TIME STABLITY PROTOCOL PARACETAMOL TABLET BP 500MG Each Uncoated tablet contains: PARACETAMOL BP………. 500 mg. EXCIPIENTS………………..Q.S. Temperature 30°C ±2.0°C Humidity : 40%, ±5.0 % White, round, Un coated tablet.



round, Un coated

07 Mins. 12 Secs.

Min.: 94.20 %

Assay 95.0 – 105.0 % 100.67 %

round, Un coated

08 Mins. 21 Secs.

Min.: 92.03 %

98.35 %

round, Un coated

08 Mins. 54 Secs.

Min.: 90.49 %

97.06 %

Uncoated

09 Mins. 20 Secs.

Min.: 89.03 %

96.06 %

round, Un coated

09 Mins. 12 Secs.

Min.: 85.36 %

95.19 %

09 Mins. 34 Secs.

Min.: 84.89 %

95.06 %

Description

White, tablet. White tablet. White, tablet. White, tablet. White, tablet. White, tablet.

round,

round,

Uncoated

BATCH NO MFG. DATE

: :

R400228 Nov’2004

EXP. DATE

:

Oct’2007

PACK STYLE Analysed By

:

10X10TABLETS IN BLISTER Remarks

Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification


Q.A. INCHARGE Contact :: [email protected]


XYZ PHARMACEUTICAL REAL TIME STABLITY PROTOCOL PRODUCT NAME LABEL CLAIM

: :

CONDITION

:

DESCRIPTION

:

PARACETAMOL TABLET BP 500MG Each Uncoated tablet contains: PARACETAMOL BP……….. 500mg. EXCIPIENTS…………………Q.S Temperature 30°C ±2.0°C Humidity : 40%, ±5.0 % White, round, Un coated tablet.

Months

Description



Initial

White, round, Un coated tablet. White, round, Un coated tablet. White, round, Un coated tablet White, round, Un coated tablet. Pink, round, biconvex, Film coated tablet. White, round, Un coated tablet.

07 Mins. 03 Secs.

Min.: 92.32 %

Assay 95.0 – 105.0 % 100.21 %

08 Mins. 24 Secs.

Min.: 90.36 %

100.54 %

09 Mins. 10 Secs.

Min.: 86.34 %

100.03 %

09 Mins. 23 Secs.

Min.: 82.06 %

99.05 %

09 Mins. 40 Secs.

Min.: 80.34 %

98.36 %

09 Mins. 34 Secs.

Min.: 78.36 %

98.06 %

06 12 18 24 36

BATCH NO MFG. DATE

: :

R400229 Dec’2004

EXP. DATE

:

Nov’2007

PACK STYLE

:


Analysed By

Remarks Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification Sample complies as per In-House Specification

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



Sample Dossier

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