PRODUCT PROFILE

i. Product/Brand Name:

CREAM

ii. Formulation and evidence of competitor availability in the local

or international market:

Product Name: RELIEF CREAM

Company Name: M/s. Polyfine Nutra-Sciences, Peshawar

iii. List of ingredients with strength:

List of ingredients with strength

Each Gram contains:
Capsicum oleoresin (USP)….0.07% w/w
Menthol (USP)……..…….…0.025% w/w
USP/BP Specs

iv. In case of herbal drugs the scientific and species name of plant
along with following:
i. State part used, Nature of the ingredients i.e. powder drugs extracts (aqueous,
alcoholic or any other solvent used for extraction)

ii. In case of standardized extracts state the percentage of active ingredients case
may be.

According to USP & BP.

v. In case of extracts state drug extract ratio if the exract is not
standardized:

vi. Common Name Of Ingredients:

Common Names
Capsicum
Menthol

vii. Recommended use:

 For temporary relief of minor aches and pains of muscles and joints.
viii. Pack Size:
20G Tube packing

ix. Maximum Retail Price:

As per SR

ANNEXURE A
 MASTER FORMULA

MASTER FORMULATION

Specifications

Batch size: 5000 tubes / 5000 packs (kg)

Pack size: 1x1’s = 1’S

Wt. per tube : 20.00 gm

 NET
QTY UNIT O/A
S.No. INGREDIENTS Qty/tube QTY/BATCH

1. Methyl salicylate 4000.00 20.00 kg - 20kg

2. Capsaicin oleoresin 7.500 0.375 kg - 0.0375kg

3. Menthol 1000.00 50.00 kg - 5.00kg

4. Hard paraffin 400mg 1.00 Kg - 1.00Kg

5. White soft paraffin 11696.5mg 22.987 kg - 22.987kg

6. Liquid paraffin 2896 mg 0.928 kg - 0.982kg

20000mg=

20g

Total wt. 100 Kg

7. Empty aluminum tubes 1 5000 # 3% 5150

ANNEXURE B
 MANUFACTURING
PROCESS

INSTRUCTIONS
Before starting each and every step / process, line clearance must be taken from the
1. Quality Assurance department in order to avoid errors / mishaps during manufacturing and
packing processes, so to produce a safe and effective product for consumer
Production pharmacist as well as QA Officer / inspector should exercise precautionary
2.
measures to confirm quality and productivity of in-process + finished product
All the documents must be completely and clearly filled in, signed & dated by the
3.
concerned personnel
Any correction(s) overwriting or changes must be initiated and signed. Use of Blanco /
4.
whiteners is prohibited

5. Any observations or suggestions at any stage must be written in remarks

All the relevant documents associated with the production of the batch should be attached
6.
to the batch file / BPS

PRECAUTIONS
 1 During work must wear proper uniform, gloves and mask

2 Avoid powder spoilage during manufacturing processes

3 Room humidity and temperature: 30% - 45% at 18°C - 28°C

1. LINE CLEARANCE AND IN-PROCESS CONTROL CHECKS

LINE CLEARANCE PARAMETERS

Wearing of personnel protective equipments (PPEs)
1
i.e. Gloves, Mask, Cap and Uniform
Cleanness of Area and machinery i.e. Machine, utensils, Floor, Walls,
2
Ceiling, Windows, Doors of processing area must be cleaned
Satisfactory condition of Light, Humidity and Temperature as per
3
requirement and working, performance of HVAC.
Calibration and working status of the machinery / equipment, i.e.
5
equipments should in working condition and Calibrated properly.
Availability of correct materials with correct identification and release
6
slips
Documents and materials of the previous batch/ process must be
7
removed

Step 1. Pre - Dispensing GMP Checks

Area cleaning and status checks
 Before starting dispensing ensure that:
 Dispensing area is clean & clear from the remains of previous product.
 Related documents of the product to be dispensed are properly filled and available.
 Quantities of the raw materials have been checked to be correct as per their potency against the quantities of standard batch
size.
 Raw materials to be dispensed have been approved by quality assurance department
 Air conditioning and exhaust system is working properly and temperature and relative humidity must be below 45%.
 Labels on raw materials container from the store have been checked for correct material and lot No. to be dispensed.
Equipment / Machine cleaning & status check
 Equipment / Machine (scales/weighing balances, scoops etc.) to be used for dispensing are, clean and clear from the
remains of previous product.
 The weighing balance / scale is calibrated and working properly.
 Plastic bags and containers required for dispensing material are clean and labeled.

 Previous Product: ---------------------------------- Batch No. ----------------------------

Production Officer Date

Step 2. Batch Material Dispensing & Receiving
Operational Procedure
  Based on the Manufacturing order, received from the production department confirm the batch size of the product and
quantities referring to the standard formulation.
 Weighing must be carried out in the presence of a Qualified Pharmacist, Quality Assurance Inspector and a Warehouse
Officer.
 In calculating the quantities give specific attention to the batch size to be manufactured the standard batch size and the
potency of the active material vis-à-vis standard quantity as per formula based on 100% potency.
 Check the calibration record of weighing balance scale.
 On confirming the above detail start dispensing.
 Weigh the ingredients one by one.
 After weighing each item, put a dispensing tag on the plastic bag / container mentioning product name, item name, and batch
number etc.
 At the end of the process, the documents must be signed and filed by authorized Officers.
 Attach one copy of the Manufacturing Order form with Batch Manufacturing Record.
 After weighing is completed, bring the raw material to the manufacturing area and cross –check, the weighs of raw materials
dispensed against the quantities calculated on the basis of their potency and written in the manufacturing order form.

Warehouse Officer Production Officer

Step 3. Pre – Manufacturing GMP checks

Area cleaning and status checks
 Before starting manufacturing ensured that the manufacturing area is clean and cleared from the remains of previous products.
 Storage containers are clean and cleared from the remains of previous product.
 No material other than specified in the Manufacturing order form is present in the mfg.area.
 Related documents of the product to be manufactured are available and the quantity of raw material have been cross checked.
 Air conditioning and exhaust system is working properly and relative humidity must be below 45%.
Equipment / Machine cleaning & status check
 Equipment / Machine (scales/weighing balances, scoops etc.) to be used for dispensing are, clean and clear from the
remains of previous product.
 The weighing balance / scale is calibrated and working properly.
 Plastic bags and containers required for dispensing material are clean and labeled.

 Previous Product: ---------------------------------- Batch No. ----------------------------

Production Officer Date

Swab Test

Machine Name: --------------------------------------------------------------------

Previous Product: --------------------------------------------------------------------
Checked By QA : --------------------------------------------------------------------
Overall results: --------------------------------------------------------------------

Production Officer Date

SPECIFICATION OF IN ACTIVE AND THEIR ROLE

Sr.no Ingredient Specification Rule

1 White soft paraffin USP Emollient; emulsifying

BP Emollient; emulsifying
2 Liquid paraffin
agent; plasticizer

3 Hard paraffin BP Cream base; stiffening agent

Manufacturing Method
Operational Procedure:

 Based on the Manufacturing order, Received from the production department confirm the batch size of
the product and quantities referring to the standard formulation.
 Weighing must be carried out in the presence of a Qualified Pharmacist, Quality Assurance Inspector and
Warehouse Officer.
 Check the calibration record of weighing balance scale.
 On confirming the above detail start dispensing.
 Weigh the ingredients one by one.
 After weighing each item, put the dispensing tag on the plastics bag / container mentioning product name,
item name, and batch number etc.
 At the end of the process, the documents must be signed by the authorized officers.
 Attach one copy of the Manufacturing Order form with Batch Manufacturing Record.
 After weighing is completed, bring the raw material to the manufacturing area and cross-check, the
weighs of raw materials dispensed against the quantities calculated on the basis of their potency and
written in the manufacturing order form.

Manufacturing:
Pre manufacturing GMP Checks:

 Prior to starting the work ensure that section ( cram and cream ) is clean and passed by the Quality
Assurance Department.
 All the equipments and accessories required for manufacturing are clean from previous product
  All personals working in the area are in proper uniform with masks and gloves.
 Before starting work get the line clearance from quality assurance department.

Manufacturing of cream

Material Quantity Unit

White soft paraffin

Liquid paraffin

Hard paraffin

Procedure:

 Melt the oily phase in a steam jacketed homogenizer and mention its temperature up to 90 oc .
 When temperature is reaches upto 50 oc . dissolve Fluticasone Propionate in suitable quantity of ethanol and add to
the cream. Now mix the cream for 30 min . with high speed mixer . when congealing start switch off the high speed
mixer and switch on the homogenizer and mix the cream until congeal .
 When cream congeal intimate the quality assurance for sampling
Filling:

Pre FILLING GMP checks:

 Prior to start work ensure that section (filling area) is clean.

 All the equipments and accessories required for manufacturing are clean from previous product.
 All personals working in the area are in proper uniform with mask and gloves.
 Material must be released from quality control department for.
 Before starting work get the line clearance from quality assurance department\

Procedure:

 Transfer the bulk cream and empty aluminum Tube to filling area.
 Adjust the desired weight _________ of tube.
 Send the filled tube to quality assurance department for checking weight variation
 After getting release form quality assurance department fill all the bulk cream in to empty aluminum
tube .
 During filling check the weight of tube after each 15 min and note in weight variation sheet
 When filling is completed clean the al tubes identify the drum and shift it to IPQ and inform quality
Assurance department to take the sample of filled tube for test/analysis.
ANNEXURE C
TEST SPECIFICATION OF
RAW MATERIAL &
FINISH PRODUCT
 TEST SPECIFICATION OF
RAW MATERIAL

Capsicum oleoresin

Capsicum Oleoresin
» Capsicum Oleoresin is an alcoholic extract of the dried ripe fruits of Capsicum
annum var. minimum and small fruited varieties of C. frutescens (Solanaceae). It contains
not less than 8.0 percent of total capsaicins [capsaicin (C18H27NO3), dihydrocapsaicin
(C18H29NO3), and nordihydrocapsaicin (C17H27NO3)].
Caution—Capsicum Oleoresin is a powerful irritant, and even in minute quantities produces
an intense burning sensation when it comes in contact with the eyes and tender parts of
the skin. Care should be taken to protect the eyes and to prevent contact of the skin with
Capsicum Oleoresin.
Packaging and storage— Preserve in tight containers.
Labeling— Label it to indicate that if separation occurs, it should be warmed and mixed before use.

USP Reference standards 11 —

USP Capsaicin RS.
Identification— To about 0.5 g of it in a beaker add 5 mL of water and 10 mL of a mixture of water,
0.2 M potassium chloride, and 0.2 N hydrochloric acid (135:50:13), and mix. Add 5.0 mL of 0.5 M
sodium nitrite and 5.0 mL of 0.02 M sodium tungstate, and mix. Heat at 55 to 60 for 15 minutes,
allow to cool, and filter. To the filtrate add 10 mL of 1 N sodium hydroxide: a bright yellow color is
produced (presence of capsaicin).
Assay—
Mobile phase— Prepare a mixture of methanol and 2% acetic acid (56:44), filter through a 0.5-µm or
finer porosity filter, and degas. Make adjustments if necessary (see System
Suitability under Chromatography 621 ).
Standard preparation— Prepare a solution of USP Capsaicin RS in methanol having a known
concentration of about 0.5 mg per mL. Filter a portion of this solution through a 0.2-µm porosity filter,
and use the filtrate as the Standard preparation.
Assay preparation— Transfer about 1000 mg of Capsicum Oleoresin, accurately weighed, to a 100-mL
volumetric flask, dissolve in and dilute with methanol to volume, and mix. Filter a portion of this
solution through a 0.2-µm porosity filter, and use the filtrate as the Assay preparation.
Chromatographic system (see Chromatography 621 )—The liquid chromatograph is equipped with
a 280-nm detector and a 3.9-mm × 30-cm column that contains packing L1. The flow rate is about 2
mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed
for Procedure: the tailing factor is not more than 2.0; and the relative standard deviation for replicate
injections is not more than 2.0%. Chromatograph the Assay preparation, and record the peak
responses as directed for Procedure: the relative retention times are about 0.9 for
nordihydrocapsaicin, 1.0 for capsaicin, and 1.6 for dihydrocapsaicin; and the resolution, R, between
the nordihydrocapsaicin peak and the capsaicin peak is not less than 1.2.
Procedure— [NOTE—Use peak areas where peak responses are indicated.] Separately inject equal
volumes (about 10 µL) of the Standard preparation and the Assay preparation into the chromatograph,
record the chromatograms, and measure the responses for the three major peaks. Calculate the
percentage of total capsaicins in the portion of Capsicum Oleoresin taken by the formula:
(CP / W)(rU / rS)
in which C is the concentration, in mg per mL, of USP Capsaicin RS in the Standard preparation; P is
the designated purity, in percentage, of USP Capsaicin RS; W is the weight, in mg, of Capsicum
Oleoresin taken to prepare the Assay preparation; rU is the sum of the peak responses for
nordihydrocapsaicin, capsaicin, and dihydrocapsaicin obtained from the Assay preparation; and rS is
the peak response obtained from the Standard preparation.

Menthol
Menthol

C10H20O 156.27

Cyclohexanol, 5-methyl-2-(1-methylethyl)- [1490-04-6].

» Menthol is an alcohol obtained from diverse mint oils or prepared synthetically. Menthol
may be levorotatory (l-Menthol), from natural or synthetic sources, or racemic (dl-Menthol).
Packaging and storage— Preserve in tight containers, preferably at controlled room temperature.
Labeling— Label it to indicate whether it is levorotatory or racemic.
Identification— When it is triturated with about an equal weight of camphor, of chloral hydrate, or of
phenol, the mixture liquefies.

Melting range of l-Menthol 741 : between 41 and 44 .

Congealing range of dl-Menthol 651 — [NOTE—Perform this test preferably in a room having a
temperature below 30 and a relative humidity below 50%.] Place about 10 g of racemic Menthol,
previously dried in a desiccator over silica gel for 24 hours, in a dry test tube of from 18- to 20-mm
internal diameter, and melt the contents at a temperature of about 40 . Suspend the test tube in water
having a temperature of 23 to 25 , and stir the contents of the tube continually with a thermometer,
keeping the bulb of the thermometer immersed in the liquid. Racemic Menthol congeals at a
temperature between 27 and 28 . Shortly after the temperature has stabilized at the congealing point,
add a few mg of dried racemic Menthol to the congealed mass, and continue the stirring: after a few
minutes the temperature of the mass quickly rises to 30.5 to 32.0 .

Specific rotation 781S : between 45 and 51 for l-Menthol; between 2 and +2 for dl-
Menthol.
Test solution: 100 mg per mL, in alcohol.
Limit of nonvolatile residue— Volatilize 2 g, accurately weighed, in a tared open porcelain dish on a
steam bath, and dry the residue at 105 for 1 hour: the residue weighs not more than 1 mg (0.05%).
Chromatographic purity—
System suitability preparation— Dissolve decanol and Menthol in ether to obtain a solution having
concentrations of about 0.05 mg of each per mL.
Test preparation— Dissolve 10 mg of Menthol in 50 mL of ether, and mix. Dilute 25 mL of this solution
with ether to 100 mL, and mix.
Chromatographic system— The gas chromatograph is equipped with a flame-ionization detector and
contains a 1.8-m × 2-mm column packed with 10% phase G16 on support S1AB. The column is
maintained at about 170 , the injection port is maintained at about 260 , and the detector block is
maintained at about 240 . Dry helium is used as the carrier gas at a flow rate of about 50 mL per
minute. Chromatograph the System suitability preparation, and record the peak responses as directed
under Procedure: the retention time of menthol is about 0.7 relative to decanol. In a suitable
chromatogram, the resolution, R, of the 2 peaks is not less than 2.5, and the relative standard
deviation of the ratio of the peak response obtained with menthol to that obtained with decanol is not
more than 2%.
Procedure— Inject about 2 µL of the Test preparation into the gas chromatograph, and measure the
peak responses. The peak response due to menthol is not less than 97% of the sum of all the peak
responses, excluding any due to the ether.
Readily oxidizable substances in dl-Menthol— Place 500 mg of dl-Menthol in a clean, dry test tube,
add 10 mL of a solution of potassium permanganate, prepared by diluting 3 mL of 0.1 N potassium
permanganate with water to 100 mL, and place the test tube in a beaker of water at a temperature
between 45 and 50 . Remove the tube from the bath at intervals of 30 seconds, and mix quickly by
shaking: the purple color of potassium permanganate is still apparent after 5 minutes.
 TEST SPECIFICATION OF
FINISH PRODUCT

Topical and Transdermal Drug Products

INTRODUCTION

Drug products topically administered via the skin fall into two general categories, those applied for local action
and those for systemic effects. Local actions include those at or on the surface of the skin, those that exert their
actions on the stratum corneum, and those that modulate the function of the epidermis and/or the der-mis.
Common products in the former category include creams, gels, ointments, pastes, suspensions, lotions, foams,
sprays, aerosols, and solutions. Creams, oint-ments, and gels generally are referred to as semisolid dosage
forms. The most common drug products applied to the skin for systemic effects are referred to as self-adhering
transdermal drug delivery systems (TDS) or transdermal patches.

Two categories of tests, product quality tests and prod-uct performance tests, are performed with drug products to provide
assurances of batch-to-batch quality, reprodu-cibility, reliability, and performance. Product quality tests are performed to assess
attributes such as assay, identifi-cation, content uniformity, pH, microbial limits, and minimum fill and are part of the compendial
mono-graph. Product performance tests are conducted to as-sess drug release from the finished dosage form.

This Stimuli article provides general information about the test methods that should be employed to ensure the quality and
performance of topical and transdermal drug products. The term topical drug products refers to all for-mulations applied to the
skin except transdermal delivery systems (TDS) or transdermal patches that will be ad-dressed separately.

Topical dosage forms include solutions (for which re-lease testing is not indicated), collodion, suspensions,
emulsions (e.g., lotions), semisolids (e.g., foams, oint-ments, pastes, creams, and gels), solids (e.g., powders
and aerosols), and sprays. The physical characteristics of these dosage forms vary widely.
a
Correspondence should be addressed to: Margareth Marques, PhD, Senior Scientist, Documentary Standards Division, US Pharmacopeial Convention,
12601 Twinbrook Parkway, Rockville, MD 20852-1790; tel. 301.816.8106; e-mail [email protected].
b
Deceased.
Therefore, the in vitro release test for those products also may differ significantly and may require different types
of apparatus. At present, a product performance test exists only for semisolid formulations, specifically creams,
ointments, and gels. That test employs the ver-tical diffusion cell (VDC) system. The VDC system is sim-ple to
operate and yields reliable and reproducible results when employed by properly trained laboratory person-nel.

TDS or transdermal patches are physical devices ap-plied to the skin and vary in their composition and meth-
od of fabrication. Therefore, they release their active ingredients by different mechanisms.

GLOSSARY OF TERMS

Definitions of topical drug products, some aspects re-lated to the manufacture of these products, and a glos-
sary of dosage form names commonly used can be found in General Information Chapter Pharmaceutical
Dosage Forms h1151i.

Collodion

Collodion (pyroxylin solution; see USP monograph), is a solution of nitrocellulose in ether and acetone, some-times with the
addition of alcohol. As the volatile solvents evaporate, a dry celluloid-like film is left on the skin. Be-cause the medicinal use of a
collodion depends on the formation of a protective film, the film should be durable, tenacious in adherence, flexible, and
occlusive.

Creams

Creams are semisolid dosage forms that contain one or more drug substances dissolved or dispersed in a suitable base. This
term traditionally has been applied to semi-solids that possess a relatively soft, spreadable consis-tency formulated as either
water-in-oil or oil-in-water emulsions. However, more recently the term has been re-stricted to products consisting of oil-in-water
emulsions or aqueous microcrystalline dispersions of long-chain fatty acids or alcohols that are water washable and more
cosmetically and aesthetically acceptable.

#2009 The United States Pharmacopeial Convention, Inc. All Rights Reserv
emulsions

Emulsions are viscid, multiphase systems in which one or more liquids are dispersed throughout another immis-cible liquid in
the form of small droplets. When oil is the dispersed phase and an aqueous solution is the continu-ous phase, the system is
designated as an oil-in-water emulsion. Conversely, when water or an aqueous solu-tion is the dispersed phase and oil or
oleaginous material is the continuous phase, the system is designated as a water-in-oil emulsion. Emulsions are stabilized by
emulsi-fying agents that prevent coalescence, the merging of small droplets into larger droplets, and, ultimately, into a single
separated phase. Emulsifying agents (surfac-tants) act by concentrating at the interface between the immiscible liquids, thereby
providing a physical bar-rier that reduces the tendency for coalescence. Surfac-tants also reduce the interfacial tension between
the phases, facilitating the formation of small droplets upon mixing. The term emulsion is not used if a more specific term is
applicable, e.g., cream or ointment.

Foams

Foams are emulsified systems packaged in pressurized containers or special dispensing devices that contain dis-persed gas
bubbles, usually in a liquid continuous phase, that when dispensed has a fluffy, semisolid consistency.

Gels

Gels (sometimes called Jellies) are semisolid systems consisting of either suspensions composed of small inor-ganic particles
or large organic molecules interpene-trated by a liquid. When the gel mass consists of a network of small discrete particles, the
gel is classified as a two-phase system (e.g., Aluminum Hydroxide Gel, USP). In a two-phase system if the particle size of the dis-
persed phase is relatively large, the gel mass is sometimes referred to as a magma (e.g., Bentonite Magma, NF). Both gels and
magmas may be thixotropic, forming semisolids after standing and becoming liquid when agi-tated. They should be shaken
before use to ensure homo-geneity and should be labeled to that effect (see Topical Suspensions, below). Single-phase gels
consist of organic macromolecules uniformly distributed throughout a liq-uid with no apparent boundary between the dispersed
macromolecule and liquid.

Lotions

Although the term lotion may be applied to a solution, lotions usually are fluid, somewhat viscid emulsion dosage forms for
external application to the skin. Lotions share many characteristics with creams. See Creams, To-pical Solutions, and Topical
Suspensions, herein.

Ointments

Ointments are semisolids intended for external appli-cation to the skin or mucous membranes. They usually contain less than
20% water and volatiles and more than
50% hydrocarbons, waxes, or polyols as the vehicle. Ointment bases recognized for use as vehicles fall into
four general classes: hydrocarbon bases, absorption bases, water-removable bases, and water-soluble bases.
Each therapeutic ointment possesses as its base one of these four general classes.

Hydrocarbon Bases—Hydrocarbon bases, known also as ‘‘oleaginous ointment bases,’’ are represented by
White Petrolatum and White Ointment (both USP). Only small amounts of an aqueous component can be
incor-porated into these bases. Hydrocarbon bases serve to keep medicaments in prolonged contact with the
skin and act as occlusive dressings. These bases are used chiefly for their emollient effects and are difficult to
wash off. They do not ‘‘dry out’’ or change noticeably on aging.

Absorption Bases—This class of bases may be divided into two groups: the first consists of bases that permit
the incorporation of aqueous solutions with the forma-tion of a water-in-oil emulsion (e.g., Hydrophilic Petrola-
tum and Lanolin, both USP), and the second group consists of water-in-oil emulsions that permit the incor-
poration of additional quantities of aqueous solutions (Lanolin, USP). Absorption bases also are useful as
emollients.

Water-removable Bases—Water-removable bases are oil-in-water emulsions (e.g., Hydrophilic Ointment,

USP), and are more correctly called ‘‘creams’’ (see Creams, above). They also are described as ‘‘water-wash-
able’’ because they may be readily washed from the skin or clothing with water, an attribute that makes them
more acceptable for cosmetic purposes. Some medica-ments may be more effective in these bases than in
hy-drocarbon bases. Other advantages of the water-removable bases are that they may be diluted with water
and that they favor the absorption of serous discharges in dermatological conditions.

Water-soluble Bases—This group of so-called ‘‘grease-less ointment bases’’ comprises water-soluble

constitu-ents. Polyethylene Glycol Ointment, NF is the only pharmacopeial preparation in this group. Bases of
this type offer many of the advantages of the water-remova-ble bases and, in addition, contain no water-
insoluble substances such as petrolatum, anhydrous lanolin, or waxes. They are more correctly called Gels
(see Gels, above).

Choice of Base—The choice of an ointment base de-pends on many factors, such as the action desired, the
nature of the medicament to be incorporated and its bioavailability and stability, and the requisite shelf life of
the finished product. In some cases, it is necessary to use a base that is less than ideal in order to achieve the
sta-bility required. Drugs that hydrolyze rapidly, for example, are more stable in hydrocarbon bases than in
bases that contain water, even though they may be more effective in the latter.

Ophthalmic Ointments

Ophthalmic ointments are semisolids for application to the eye. Special precautions must be taken in the
prep-aration of ophthalmic ointments. They are manufactured from sterilized ingredients under rigidly aseptic
condi-tions, must meet the requirements under Sterility Tests h71i, and must be free of large particles. The
medicinal agent is added to the ointment base either as a solution or as a micronized powder.

Pastes

Pastes are semisolid dosage forms that contain a high percentage (often 50%) of finely dispersed solids with a stiff consistency
intended for topical application. One class is made from a single-phase aqueous gel (e.g., Car-boxymethylcellulose Sodium
Paste, USP). The other class, the fatty pastes (e.g., Zinc Oxide Paste, USP), consists of thick, stiff ointments that do not ordinarily
flow at body temperature and therefore serve as protective coatings over the areas to which they are applied.

Powders
 Powders are solids or mixture of solids in a dry, finely divided state for external (or internal) use.

Sprays

Sprays are products formed by the generation of drop-lets of solution containing dissolved drug for application
to the skin or mucous membranes. The droplets may be formed in a variety of ways but generally result from
for-cing the liquid through a specially designed nozzle as-sembly. One example of a spray dosage form is a
metered-dose topical transdermal spray that delivers a precisely controlled quantity of solution or suspension on
each activation.

Topical Aerosols

Topical aerosols are products that are packaged under pressure. The active ingredients are released in the
form of fine liquid droplets or fine powder particles upon acti-vation of an appropriate valve system. A special
form is a metered-dose aerosol that delivers an exact volume (dose) per each actuation.

Topical Solutions

Topical solutions are liquid preparations, that usually are aqueous but often contain other solvents such as al-
cohol and polyols that contain one or more dissolved chemical substances intended for topical application to the
skin, or, as in the case of Lidocaine Oral Topical Solu-tion USP, to the oral mucosal surface.
 Topical Suspensions

Topical suspensions are liquid preparations that con-tain solid particles dispersed in a liquid vehicle intended
for application to the skin. Some suspensions labeled as ‘‘Lotions’’ fall into this category.

Transdermal Delivery Systems

Transdermal delivery systems (TDS) are self-contained, discrete dosage forms that, when applied to intact skin, are designed
to deliver the drug(s) through the skin to the systemic circulation. Systems typically comprise an outer covering (barrier), a drug
reservoir that may have a drug release–controlling membrane, a contact adhe-sive applied to some or all parts of the system and
the system/skin interface, and a protective liner that is re-moved before the patient applies the system. The dose of these
systems is defined in terms of the release rate of the drug(s) from the system and surface area of the patch and is expressed as
mass per unit time for a given surface area. With these drug products, the skin typically is the rate-controlling membrane for the
drug input into the body. The total duration of drug release from the sys-tem and system surface area may also be stated.

TDS work by diffusion: The drug diffuses from the drug reservoir, directly or through the rate-controlling mem-
brane and/or contact adhesive if present, and then through the skin into the general circulation. Typically,
modified-release systems are designed to provide drug delivery at a constant rate so that a true steady-state
blood concentration is achieved and maintained until the system is removed. Following removal of the system,
blood concentration declines at a rate consistent with the pharmacokinetics of the drug.

PRODUCT QUALITY TESTS—GENERAL

The International Conference on Harmonization (ICH) Guidance Q6A (available at www.ich.org) recommends specifications
(tests, procedures, and acceptance criteria) to ensure that commercialized drug products are safe and effective at release and
during shelf life. Tests that are universally applied to ensure safety and efficacy in-clude description, identification, assay, and
impurities.

Description—A qualitative description of the dosage form should be provided. The acceptance criteria should
include the final acceptable appearance. If color changes during storage, a quantitative procedure may be
appro-priate. It specifies the content or the label claim of the article.

Identification—Identification tests are discussed in Pro-cedures under Tests and Assays in the General Notices and
Requirements. Identification tests should establish the identity of the drug or drugs present in the article and should discriminate
between compounds of closely re-lated structure that are likely to be present. Identity tests should be specific for the drug
substances. The most con-clusive test for identity is the infrared absorption spec-trum (see Spectrophotometry and Light-
scattering
 and Spectrophotometric Identification Tests h197i). If no suitable infrared spectrum can be obtained, other analy-tical techniques
can be used. Near infrared (NIR) or Ra-man spectrophotometric methods also could be acceptable as the sole identification
method of the drug product formulation (see Near-infrared Spectrophotome-try h1119i and Raman Spectroscopy h1120i).
Identifica-tion solely by a single chromatographic retention time is not regarded as specific. However, the use of two chro-
matographic procedures for which the separation is based on different principles or a combination of tests in a single procedure
can be acceptable. See Chromatog-raphy h621i and Thin-layer Chromatographic Identification h201i.

Assay—A specific and stability-indicating test should be used to determine the strength (content) of the drug
product. See Antibiotics—Microbial Assays h81i, h621i, or Assay for Steroids h351i. In cases when the use of
non-specific assay is justified, e.g., Titrimetry h541i, other sup-porting analytical procedures should be used to
achieve overall specificity. A specific procedure should be used when there is evidence of excipient interference
with the nonspecific assay.

Impurities—Process impurities, synthetic by-products, and other inorganic and organic impurities may be pres-
ent in the drug substance and excipients used in the manufacture of the drug product. These impurities are
controlled by the drug substance and excipients mono-graphs. Organic impurities arising from the degradation
of the drug substance and those arising during the man-ufacturing process of the drug product should be moni-
tored.

In addition to the universal tests listed above, the fol-lowing tests may be considered on a case-by-case basis:

Physicochemical Properties—These are properties such as pH h791i, Viscosity h911i, and Specific Gravity h841i.

Uniformity of Dosage Units—This test is applicable for TDS and for dosage forms packaged in single-unit con-
tainers. It includes both the mass of the dosage form and the content of the active substance in the dosage
form. The test can be performed by either content uni-formity or weight variation (see Uniformity of Dosage
Units h905i).

Water Content—A test for water content should be in-cluded when appropriate (see Water Determination
h921i).

Microbial Limits—The type of microbial test(s) and ac-ceptance criteria should be based on the nature of the drug substance,
method of manufacture, and the in-tended use of the drug product. See Microbiological Ex-amination of Nonsterile Products:
Microbial Enumeration Tests h61 i and Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms
h62i.

Antimicrobial Preservative Content—Acceptance cri-teria for preservative content in multidose products should be established.
They should be based on the lev-
els of antimicrobial preservative necessary to maintain the product’s microbiological quality at all stages
throughout its proposed usage and shelf life (see Antimi-crobial Effectiveness Testing h51i).

Antioxidant Preservative Content—If antioxidant pre-servatives are present in the drug product, tests of their
content normally should be determined.

Sterility—Depending on the use of the dosage form, e.g., ophthalmic preparations, sterility of the product
should be demonstrated as appropriate (see Sterility Tests h71i).
 PRODUCT QUALITY TESTS FOR TOPICAL DRUG

PRODUCTS

General product quality tests such as identification, as-say, content uniformity (uniformity of dosage units),
im-p u r i t i e s , p H , w a t e r c o n t e n t , m i c r o b i a l l i m i t s , antimicrobial preservative content,
antioxidant preserva-tive content, and sterility should be performed for topical drug products as described
above. In addition, specific tests for topical dosage forms, as described below, also should be conducted.

Viscosity—Rheological properties such as viscosity of semisolid dosage forms can influence their drug
delivery. Viscosity may directly influence the diffusion rate of drug at the microstructural level. Yet semisolid
drug products with relatively high viscosity still can exhibit high diffu-sion rates when compared to semisolid
products of com-paratively lower viscosity. These observations emphasize the importance of rheologic
properties of semisolid do-sage forms, specifically viscosity, on drug product perfor-mance.

Depending on its viscosity, the rheological behavior of a semisolid drug product may affect its application to treatment site(s)
and consistency of treatment and thus the delivered dose. Therefore, maintaining reproducibil-ity of a product’s flow behavior at
the time of release is an important product manufacturing control to maintain and demonstrate batch-to-batch consistency. Most
semisolid dosage forms, when sheared, exhibit non-Newtonian behavior. Structures formed within semisolid drug products
during manufacturing can show a wide range of behaviors, including shear thinning viscosity, thixotropy, and structural damage
that may be irreversi-ble or only partially reversible. In addition, the viscosity of a semisolid dosage form is highly influenced by
such fac-tors as the inherent physical structure of the product, product sampling technique, sample temperature for vis-cosity
testing, container size and shape, and specific methodology employed in the measurement of viscosity.

A variety of methods can be used to characterize the consistency of semisolid dosage forms, such as penetro-metry,
viscometry, and rheometry. With all methods sig-nificant attention is warranted to the shear history of the sample. For
semisolids, viscometer geometries typically fall into the following categories: concentric cylinders, cone-plates, and spindles.
Concentric cylinders and spin-dles typically are used for more fluid, flowable semisolid
dosage forms. Cone-plate geometries are more typically used when the sample size is small or the test samples
are more viscous and less flowable.

When contemplating what viscosity parameter(s) to test, one must consider the properties of the semisolid
drug product both ‘‘at rest’’ (in its container) and as it is sheared during application. The rheological properties of
the drug product at rest can influence the product’s shelf life, and its properties under extensive shear can in-
fluence its spreadability and, therefore, its application rate that will affect the safety and efficacy of the drug
product. Further, although it is necessary to precisely control the temperature of the test sample during the vis-
cosity measurement, one should link the specific choice of the temperature to the intended use of the drug prod-
uct (e.g., skin temperature for external application ef-fects).

Because semisolid dosage forms frequently display non-Newtonian flow properties, formulators should give
close attention to the shear history of the sample being tested, such as the shear applied during the filling
opera-tion, shear applied dispensing the product from its con-tainer, and shear introducing the sample into the
viscometer. The point of reemphasizing this aspect is that considerable variability and many failures to meet
speci-fications can be directly attributed to a lack of attention to this detail rather than a change of viscosity (or
flow properties) of the drug product.

Tube (Content) Uniformity—Tube uniformity is the de-gree of uniformity of the amount of active drug sub-stance
among containers, i.e., tubes containing multiple doses of the semisolid topical product. The uni-formity of
dosage is demonstrated by assay of top, mid-dle, and bottom samples (typically 0.25–1.0 g) obtained from a
tube cut open to withdraw respective samples for drug assay.
 Various topical semisolid products may show some physical separation at accelerated storage temperatures because
emulsions, creams, and topical lotions are prone to mild separation due to the nature of the vehicle.

The following procedure should be followed for test-ing tube uniformity of semisolid topical dosage forms:

1. Carefully remove or cut off the bottom tube seal and make a vertical cut up the face of the tube. Then carefully cut the tube
around the upper rim and pry open the two ‘‘flaps’’ to expose the semisolid.

2. At the batch release and/or designated stability time point remove and test 0.25- to 1.0-g samples from the
top, middle, and bottom of a tube. If assay values for those tests are within 90.0% to 110.0% of the la-beled
amount of active drug, and the relative stan-dard deviation (RSD) is not more than 6%, then the results are
acceptable.

3. If at least 1 value of the testing described above is outside 90.0% to 110.0% of the labeled amount of drug and none is
outside 85.0% to 115.0% and/or the RSD is more than 6%, then test an additional 3 randomly sampled tubes using top,
middle, and bot-tom samples as described. Not more than 3 of the 12 determinations should be outside the range of 90%
to 110.0% of the labeled amount of drug, none should be outside 85.0% to 115.0%, and the RSD should not be
not more than 7%.

4. For very small tubes (e.g., 5 g or less), test only top and bottom samples, and all values should be within the
range of 90.0% to 110.0% of the labeled amount of drug.

pH—When applicable, semisolid drug products should be tested for pH at the time of batch release and desig-
nated stability test time points for batch-to-batch moni-toring. Because most semisolid dosage forms contain
very limited quantities of water or aqueous phase, pH measurements may be warranted only as a quality con-
trol measure, as appropriate.

Particle Size—Particle size of the active drug substance in semisolid dosage forms is determined and controlled
at the formulation development stage. When applicable, semisolid drug products should be tested for any
change in the particle size or habit of the active drug substance at the time of batch release and designated
stability test time points (for batch-to-batch monitoring) that could compromise the integrity and/or performance
of the drug product, as appropriate.

Ophthalmic Dosage Forms—Ophthalmic dosage forms must meet the requirements of Sterility h71i. If the speci-fic ingredients
used in the formulation do not lend them-selves to routine sterilization techniques, ingredients that meet the sterility requirements
described under Sterility h71i, along with aseptic manufacture, may be employed. Ophthalmic ointments must contain a suitable
substance or mixture of substances to prevent growth of, or to de-stroy, microorganisms accidentally introduced when the
container is opened during use, unless otherwise direc-ted in the individual monograph or unless the formula itself is
bacteriostatic (see Added Substances under Ophthalmic Ointments h771i). The finished ointment must be free from large
particles and must meet the re-quirements for Leakage and for Metal Particles in h771i. The immediate containers for ophthalmic
ointments shall be sterile at the time of filling and closing. It is man-datory that the immediate containers for ophthalmic ointments
be sealed and tamper-proof so that sterility is assured at time of first use.

PRODUCT QUALITY TESTS FOR TOPICAL DRUG PRODUCTS

General product quality tests such as identification, as-say, content uniformity (uniformity of dosage units), im-p u r i t i e s , p H
, w a t e r c o n t e n t , m i c r o b i a l l i m i t s , antimicrobial preservative content, antioxidant preserva-tive content, and sterility
should be performed for topical drug products. In addition, specific tests for topical dos-age forms, such as viscosity, tube
(content) uniformity, and particle size also should be conducted. For details, see General Chapter Product Quality Tests: Topical
and Transdermal Drug Products h3i.
#2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
 STIMULI TO THE REVISION PROCESS
Pharmacopeial Forum Stimuli articles do not necessarily reflect the policies

Vol. 35(3) [May–June 2009] of the USPC or the USP Council of Experts 755
 PRODUCT PERFORMANCE TEST FOR TOPICAL DRUG PRODUCTS

A performance test for topical drug products must have the ability to measure drug release from the finished
dosage form. It must be reproducible and reliable, and although it is not a measure of bioavailability, the perfor-
mance test must be capable of detecting changes in drug release characteristics from the finished product. The
lat-ter have the potential to alter the biological performance of the drug in the dosage form. Those changes may
be related to active or inactive/inert ingredients in the for-mulation, physical or chemical attributes of the finished
formulation, manufacturing variables, shipping and stor-age effects, aging effects, and other formulation factors
critical to the quality characteristics of the finished drug product.

Product performance tests can serve many useful pur-poses in product development and in postapproval drug product
monitoring. They provide assurance of equiva-lent performance for products that have undergone postapproval raw material
changes, relocation or change in manufacturing site, and other changes as detailed in the FDA Guidance for Industry—SUPAC-
SS: Nonsterile Semisolid Dosage Forms, Manufacturing Equipment Adden-dum, Dec 1998, available at http://www.fda.gov/cder/
guidance/1722dft.pdf.

Vertical Diffusion Cell Method

Theory—The vertical diffusion cell (VDC) system is a sim-ple, reliable, and reproducible means of measuring
drug release from semisolid dosage forms. A thick layer of the test semisolid is placed in contact with a
reservoir. Diffu-sive communication between the delivery system and the reservoir takes place through an inert,
highly perme-able support membrane. The membrane keeps the prod-uct and the receptor medium separate
and distinct. Membranes are chosen to offer the least possible diffu-sional resistance and not to be rate
controlling. Samples are withdrawn from the reservoir at various times. In most cases, a five- to six-hour time
period is all that is needed to characterize drug release from a semisolid, and when this is the case samples
usually are withdrawn hourly.

After a short lag period, release of drug from the semi-solid dosage form in the VDC system is kinetically de-scribable by
diffusion of a chemical out of a semi-infinite medium into a sink. The momentary release rate tracks the depth of penetration of
the forming gradient within the semisolid. Beginning at the moment when the receding boundary layer’s diffusional resistance
p
assumes dominance of the kinetics of release, the amount of the drug released, M, becomes proportional to t (where t = time)
for solution, suspension, or emulsion semisolid sys-tems alike. The momentary rate of release, dM/dt, be-comes proportional to 1/
pt, which reflects the slowing of drug release with the passage of time. The reservoir is kept large so that drug release is into a
medium that re-mains highly dilute over the entire course of the experi-

ment relative to the concentration of drug dissolved in the semisolid. In this circumstance, drug release is said to
take place into a diffusional sink.

When a drug is totally in solution within the dosage form, the amount of drug released as a function of time
can be described by:

where:
M = amount of drug released into the sink per cm2 Co = drug concentration in releasing matrix

D = drug diffusion coefficient through the matrix.

p
A plot of M vs t will be linear with a slope of

The following equation describes drug release when the drug is in the form of a suspension within the
dosage form:

where

Cs = drug solubility in the releasing matrix

Dm = drug diffusion coefficient in the semisolid matrix

Q = total amount of the drug in solution and suspended in the matrix.

When Q>>Cs, the previous equation simplifies to:

p
p A plot of M vs t will be linear with a slope of 2QDmCs.

Coarse particles may dissolve so slowly that the mov-ing boundary layer recedes to some extent behind the
p
particles. That situation introduces noticeable curvature in the t plot because of a particle size effect. During
re-lease rate experiments, every attempt should be made to keep the composition of the formulation intact
over the releasing period.

In Vitro Drug Release Using the VDC—A VDC system is used to determine in vitro release of semisolid (cream, ointment, and
gel) preparations. Typically, 200–400 mg of a cream, ointment, or gel is spread evenly over a suitable synthetic inert support
membrane. The mem-brane, with its application side up, is placed in a vertical diffusion cell (typically of 15-mm diameter
orifice), e.g., a Franz cell. The release rate experiment is carried out at 32

1 8C, except in the case of vaginal creams for which the temperature should be 37 1 8C. Sampling generally is performed
over 4–5 hours, and the volume sampled is replaced with fresh receptor medium. To achieve sink conditions, the receptor
 medium must have a high ca-pacity to dissolve or carry away the drug, and the recep-tor media should not exceed 10% of Cs
(drug solubility in

The releasing matrix) at the end of the test. The test is done with groups of 6 cells. Results from 12 cells, 2 runs
of 6 cells, are used to document the release rate.

Application of Drug Release—The drug release results can be utilized for purposes such as ensuring
product sameness after scale-up and post-approval related changes or successive batch release
comparison.

The VDC assembly consists of two chambers, a donor chamber and a receptor chamber, separated by a donor
compartment and held together by a clamp (see Figure 1). This type of cell is commonly used for testing the in vitro
release rate of topical drug products such as creams, gels, and ointments. Alternative diffusion cells that con-form to the
same general design and size can be used.
Stimuli to the Revision Process

The VDC body normally is made from borosilicate glass, although different materials may be used to manu-
facture the body and other parts of the VDC assembly. None of the materials should react with or absorb the
test product or samples.

In the donor compartment, the semisolid dosage form sample sits on a synthetic membrane within the cavity
of the dosage compartment that is covered with a glass disk.

The diameters of the orifices of the donor chamber and the dosage compartment, which defines the dosage
delivery area for the test, should be sized within 5% of the specified diameter. The receptor chamber orifice
should never be smaller than the orifice of the donor chamber and should be fabricated to the same size as the
donor chamber orifice. The design of the VDC should facilitate proper alignment of the dosage compartment
and receptor orifices.
Figure 1. Vertical diffusion cell. (All measurements are expressed in mm unless noted otherwise).
The thickness of the dosage compartment normally is 1.5 mm. This thickness should be sized within 10% of the
specified thickness.

The cell body should be manufactured consistently, with uniform height and geometry. Cells should appear the
same, and their internal receptor volumes should fall within 20% of their specified volume.

Volume—Before conducting testing, determine the true volume of each receptor chamber in the VDC. The vol-ume
of each VDC should be determined with the internal stirring device in place.

Temperature—The temperature of the receptor media during the test should remain within 1.0 8C of the tar-get
temperature (typically 32 8C).

Speed—The rotational speed tolerance is 10% from the target speed (normally 600–800 rpm). The speed se-lected
should ensure adequate mixing of the receptor media during the test.

Sampling Time—Samples should be taken at the speci-fied times within a tolerance of 2% or 2 min, which-ever is
greatest.

Qualification—Unless otherwise specified in the indivi-dual monograph, the qualification of the apparatus is de-
monstrated by verifying the test temperature and speed requirements are met, along with a performance verifica-
tion test (PVT). The PVT is passed if two tests of 6 cells comply with FDA’s SUPAC-SS requirements of a 90% con-
fidence interval. The PVT is performed by one analyst testing the specified reference standard in duplicate. The first
test with 6 cells is performed and is defined as the reference. The second test of 6 cells is defined as the test. The
PVT is passed if the second test passes the 90% confidence interval with reference to the first refer-ence test.

Procedure—Unless otherwise specified in the individual monograph, degas the medium using an appropriate
technique. With the stirring device in place, fill the VDC with the specified media and allow time for it to come to a
temperature of 32 8C. If necessary, saturate the mem-brane in the specified media (generally receptor media) for
30 min. Place the membrane on the dosage compart-ment and invert. Apply the material that will be tested into the
cavity of the dosage compartment, and spread the material out to fill the entire cavity of the dosage compartment.

Assemble each of the prepared dosage compartments to each VDC with the membrane down and in contact with the receptor
media. During this application it is im-portant to ensure that there are no bubbles under the membrane. When all dosage
compartments and the re-maining components are in place, turn on the stirring de-vice, which constitutes time zero.

Follow the specified sampling procedure and collect an aliquot from each VDC for analysis. Ensure that during the sampling
process bubbles are not introduced into the cell. Exercise care during sampling and replenishment of the medium in order not to
introduce bubbles.
With some cells it is acceptable to have up to three bubbles under the membrane if the bubbles are less than 1 mm
in diameter. With some cells, bubbles may be re-moved from the receptor chamber during the test by tip-ping the
cell as long as this process is required only one time per position.

Calculation of Rate (Flux) and Amount of Drug

Released
 Creams and ointments are considered extended-release preparations. Their drug release largely depends on the formulation and
method of preparation. The re-lease rate of a given drug product from different manu-facturers is likely to be different. It is assumed
that the drug release of the product is linked to the clinical batch.

Unless otherwise specified in the individual mono-graph, the release requirements are met if the following have
been achieved:

The Amount Released (mg/cm2) at a given time (t1, t2, etc.) is calculated for each sample as follows:

where
Au = Area of the current sample
As = Average area of the standard
Cs = Concentration of the standard, mg/mL
Vc = Volume of the diffusion cell, mL
AR = Amount released, mg/cm2
Ao = Area of the orifice, cm2
Vs = Volume of the sample aliquot, mL.

For each cell the individual amount released is plotted vs time, and the slope of the resulting line (rate of drug
release, flux) is determined. The average of 6 + 6 slopes represents the drug release of the dosage form and
serves as the standard for the drug product.

Application of Drug Release

The drug release results can be utilized for purposes such as ensuring product sameness after SUPAC-SS–re-
lated changes or successive batch release comparison. This is illustrated by the following example where the in-
itial drug batch is referred to as Reference Batch (R) and the changed or subsequent batch is referred to as Test
Batch (T). The individual amount released from R is plotted vs time, and the resulting slope is determined. These
are the reference slopes. The process is repeated to determine the test slopes.
 The T/R Ratios are calculated for each Test-to-Refer-ence Slope. This is most easily done by creating a table in which the Test
Slopes are listed down the left side of the table and the Reference Slopes are listed across
top of the table. The T/R ratios are then calculated and entered in the body of the table where the rows and col-
umns intersect (Table 1).

After the T/R Ratios have been calculated they are or-dered from lowest to highest. The 8th and 29th T/R
Ratios are extracted and converted to percent (multiply by 100). To pass the first stage these ratios must fall
within the range of 75% to 133.33%.

If the results do not meet this criterion, the FDA SUPAC-

SS guidance requires that 4 more tests of 6 cells each must be run, resulting in 12 additional slopes per
product tested. The T/R ratios are calculated for all 18 slopes per product tested. All 324 individual T/R Ratios
are calcu-lated and ordered lowest to highest. The 110th and the 215th ratios are evaluated against the
specification of 75% to 133.33%.

No third stage is suggested.

PVT Method for USP Hydrocortisone Cream

Reference Standard

Materials and Equipment

USP Hydrocortisone Cream Reference Standard; 25-mm, 0.45-mm hydrophilic polysulfone [NOTE—a suitable filter is Tuffryn
available from www.pall.com] membrane filters; vacuum filtration apparatus consisting of a filter holder with a medium or fine-
porosity sintered glass holder base, funnel with a 250-mL capacity, and mag-netic stirrer; small and smooth jeweler’s forceps;
depres-sion porcelain color plate; Diffusion Cell System with 6 diffusion cells and temperature control circulator; and sampling
syringe or device and collection vials.

Procedure

Receptor Medium Preparation

Mix 60 mL of USP Alcohol with 140 mL of water to pre-pare a 30% alcoholic media. Degas the media by filtering through a 47-
mm, 0.45-mm membrane by vacuum filtra-tion. Assemble the filtration apparatus placing a mag-netic stir bar (approximately 1in
0.25 in) in the receiving flask. Place the apparatus on a magnetic stirring plate, and spin the bar at a moderate rate. Apply
vacuum and pass the media through the filter while stirring. After all media have passed through the filter, continue stirring while
maintaining a vacuum for 2 min. Applying vacuum and stirring beyond 2 min may change the composition
of the water–alcohol media. Care should be taken to en-sure that the period of time that the media is under vac-uum after the
filtration is complete is limited to 2 min.

Immediately transfer the degassed receptor medium to a suitable receptor medium bottle and stopper. Place the receptor
medium bottle in the jacketed beaker and allow the media to equilibrate for 30 min before use.

Preparation of Apparatus
 Set the circulating bath to a temperature (typically 32.5 8C) that will maintain the temperature in the diffu-sion cells at 32 8C
during the test. Place the appropriate magnetic stirrer in each diffusion cell. Allow the system to equilibrate for at least 30 min
before beginning the test.

Sample Preparation

Carefully lift one membrane at its very edge with jew-eler’s forceps. Place the membrane on a paper tissue, and blot any extreme
excess solution (a slight excess solution is desired). Carefully place the membrane in the center of the dosage compartment. Place the
dosage compart-ment, with the membrane centered on the underside, onto a tissue and press down on the compartment. Ap-ply an
appropriate amount of Hydrocortisone Cream Ref-erence Standard (between 200 mg and 400 mg) on top of the membrane and inside of
the dosage compartment cavity. Use a spatula to carefully smooth the material over the membrane, filling the entire cavity of the dosage
compartment. Wipe any excess material from the surface of the dosage compartment. Repeat for a total of 6 sam-ple preparations.

Performing the Test

Fill the diffusion cells with receptor media, and allow time to equilibrate to 32 8C. Ensure that the stirrers are not rotating and
that there is a positive meniscus cover-ing the complete top of each diffusion cell. Place the glass disk on top of the dosage
compartment against the sample. Place the dosage compartment/glass disk as-sembly on the top of the diffusion cell, avoiding
bubbles. Inspect under the membrane for bubbles. Assemble the cell. Repeat for each cell.

Begin the test according to the following test para-meters: temperature: 32 8C; stir speed: 600–800 rpm; to-tal
test time: 6 h; sampling times: 1, 2, 3, 4, and 6 h.

Table 1. Calculation of T/R Ratios

RS1 RS2 RS3 RS4 RS5 RS6

TS1 TS1/RS1 TS1/RS2 TS1/RS3 TS1/RS4 TS1/RS5 TS1/RS6

TS2 TS2/RS1 TS2/RS2 TS2/RS3 TS2/RS4 TS2/RS5 TS2/RS6

TS3 TS3/RS1 TS3/RS2 TS3/RS3 TS3/RS4 TS3/RS5 TS3/RS6

TS4 TS4/RS1 TS4/RS2 TS4/RS3 TS4/RS4 TS4/RS5 TS4/RS6

TS5 TS5/RS1 TS5/RS2 TS5/RS3 TS5/RS4 TS5/RS5 TS5/RS6

TS6 TS6/RS1 TS6/RS2 TS6/RS3 TS6/RS4 TS6/RS5 TS6/RS6

Sampling Procedure

At each of the stated sampling times, collect a sample from each cell as follows:

Stop the stirrer 30 sec before sampling. Repeat sam-pling procedure for each cell in order from 1 to 6. After the
sixth cell has been sampled, resume the stirrer rotation.

High-performance Liquid Chromatography (HPLC) Hydrocortisone Analysis

USP Hydrocortisone Cream Reference Standard; ace-tonitrile, HPLC grade; water, HPLC grade; USP alcohol,
95%; 47-mm, 0.45-mm hydrophilic polysulfone mem-brane filters [NOTE—a suitable filter is Tuffryn available from
www.pall.com]; HPLC System with UV detector capable of 10-mL injections; 50 mm 3.9 mm column that contains 5
mm packing L1.

Procedure

Mobile Phase Preparation

Prepare and degas a sufficient volume of mobile phase to complete the analysis of the samples collected. For each 1 L of mobile
phase mix 200 mL of acetonitrile with 800 mL of water. If necessary, adjust the mobile phase composition to achieve an approximate
retention time of 7 min for the hydrocortisone peak.

Standard Preparation

Obtain a portion of appropriately dried Hydrocorti-sone Cream Reference Standard. Prepare a stock hydro-
cortisone standard solution at a concentration of approximately 0.20 mg/mL in USP alcohol. A solution of 20 mg
hydrocortisone in 100 mL of USP alcohol is sug-gested for the stock standard preparation. Prepare a working
standard solution by making a 5-fold dilution of the stock standard in a solution of 30:70 USP alco-hol/water
mixture. For example, dilute 2 mL to 10 mL.

Chromatographic Conditions

Wavelength—242 nm; flow rate: 1 mL/min; injection

volume: 10 mL; run time: 10 min; column: 50 mm

3.9 mm C-18, 5-mm (Symmetry); mobile phase: 20/80 acetonitrile/water. Begin the analysis by making 5 replicate
injections of the working hydrocortisone stan-dard solution for system suitability.
System Suitability Requirements—Relative standard deviation: < 2%; tailing factor: NMT 1.5. Make single in-
jections of each of the samples obtained during the in vi-tro release testing. Bracket injections of samples with
single standard injections after the analysis of the 2-h samples, 4-h samples, and 6-h samples. Calculate the re-
sults as specified.

Other Test Systems

Other diffusion-type cell devices are available as poten-tial apparatus for drug release testing from topical/der-mal drug products.
However, only limited data are available for these devices. USP will consider these de-
vices for inclusion in this General Chapter after they are validated and collaborative study data have been evalu-
ated. The devices currently include:

Modified Holding Cell—A sample of semisolid dosage form is placed in an inert holding cell with a suitable membrane separating
the dosage form from the recep-tor medium. The holding cell is positioned at the bottom of a modified, reduced-volume dissolution
vessel of the USP Apparatus 2 type and is stirred with a mini paddle.

USP Apparatus 4 (Flow-through Cell) with a Trans-cap Semisolid Cell—A sample of the semisolid dosage form
is placed in the trans-cap cell with a suitable mem-brane separating the dosage form from the receptor me-dium.
The trans-cap cell with membrane facing upward is inserted into the 22.6-mm flow cell of USP Apparatus 4 (Flow-
through Cell).

Extraction Cell—A sample of the semisolid dosage form is placed in an inert extraction cell with a suitable mem-
brane separating the dosage form from the receptor me-dium. The test is performed using the USP Apparatus 2
assembly with the extraction cell positioned at the bot-tom of the dissolution vessel.

Product Quality Tests for Transdermal Delivery

Systems

TDS are physical devices that deliver their active ingre-dient at a fixed rate over a prolonged period of time, e.g., from days to as
long as one month. Their methods of de-livery or release mechanisms vary significantly because of differences in their composition
and fabrication. TDS sys-tems can be categorized as (1) liquid form, fill, and seal systems, (2) peripheral adhesive systems, or (3)
matrix systems. The latter two categories include the subcate-gories of monolithic, matrix, multi-laminate, and drug-in-adhesive
systems. Moreover, recent advances in the design of novel transdermal drug delivery systems has expanded the list of basic TDS
categories further, includ-ing, systems that employ iontophoresis, heat-assisted drug delivery, or micro-needles.

In all three principal TDS categories, the drug is in solu-tion or suspension. Factors that can influence drug re-lease and,
therefore, the performance of TDS dosage forms include changes in formulation composition invol-ving the adhesive, solvents,
viscosity-modifying agents, permeation enhancers, and changes in the dosage form’s semipermeable film or laminate.

The product quality tests for transdermal drug delivery system include assay, content uniformity, homogeneity,
and adhesive test.

Uniformity of dosage units—This test is applicable for transdermal systems and for dosage forms that are pack-
aged in single-unit containers. It includes both the mass of the dosage form and the content of the active sub-
stance in the dosage form. It can be done by either con-tent uniformity or weight variation (see h905i).
 Assay of excipient(s) critical to the performance of the product should be considered; e.g., residual solvent con-
tent can affect certain patche
Adhesive Test—Three types of adhesive tests generally are performed to ensure the performance of the TDS dosage forms.
These are the peel adhesion test, tack test, and shear strength test. The peel adhesion test measures the force required to peel
away a transdermal patch at-tached to a stainless steel test panel substrate at panel an-gles of 908 or 1808 following a dwell time
of 1 min and peel rate of 300 mm/min.

The tack test is used to measure the tack adhesive properties of TDS dosage forms. With this test a probe
touches the adhesive surface with light pressure, and the force required to break the adhesion after a brief per-
iod of contact is measured.

The shear strength or creep compliance test is a meas-ure of the cohesive strength of TDS dosage forms.
Two types of shear testing are performed: dynamic and static. During dynamic testing the TDS is pulled from
the test panel at a constant rate. With the static test the TDS is subjected to a shearing force by means of a
suspended weight.

Leak Test—A test that is discriminating and capable of detecting sudden drug release, such as leakage, from
the TDS should be performed. Although form, fill, and seal TDS are more likely to display leak problems, all
TDS should be checked for sudden drug release (dose dumping) during release testing of the dosage form.

Product Performance Tests for TDS

As with topical drug products, a performance test for transdermal drug products also must have the ability to measure drug
release from the finished dosage form, must be reproducible and reliable, and must be capable of detecting changes in drug
release characteristics from the finished product. Again, the latter have the potential to alter the desired pharmacologic effect(s) of
the active ingredient. Such changes could be related to active or in-active/inert ingredients in the formulation or physical dosage
form, physical or chemical attributes of the fin-ished preparation, manufacturing variables, shipping and storage, age, and other
critical-to-quality character-istics of the finished dosage form.

When based on sound scientific principles, product performance tests can be used for pre- and postmanufac-turing purposes
such as during the product research and development phase, as a basic quality control tool, for demonstrating product similarity,
or for demonstrating compliance with FDA guidelines (e.g., approval and postapproval changes in the dosage form).

In vitro drug release methods for transdermal patches include USP Apparatus 5 (Paddle over Disk Method),
Ap-paratus 6 (Rotating Cylinder Method), or Apparatus 7 (Reciprocating Holder Method). In general, it has been
found that Apparatus 5, a modified paddle method, is simpler and is applicable for most types, sizes, and
shapes of TDS
 Apparatus 5 (Paddle over Disk Method)

Apparatus—Use the paddle and vessel assembly from Apparatus 2 as described in Dissolution h711i, with the
addition of a stainless steel disk assembly (1) designed for holding the transdermal system at the bottom of the
vessel. Other appropriate devices may be used, pro-vided they do not absorb, react with, or interfere with the
specimen being tested (2). The temperature should be maintained at 32 0.5 8C. During the test maintain a
distance of 25 2 mm between the paddle blade and the surface of the disk assembly. The vessel may be cov-
ered during the test to minimize evaporation. The disk assembly for holding the transdermal system is designed
to minimize any dead volume between the disk assembly and the bottom of the vessel. The disk assembly
holds the system flat and is positioned so that the release surface is parallel with the bottom of the paddle blade
(see Figure 2).
 Fig. 2. Paddle over Disk. (All measurements are expressed in mm unless noted otherwise.)

Apparatus Suitability Test and Dissolution Medium— Proceed as directed for Apparatus 2 in h711i.

Procedure—Place the stated volume of the Dissolution Medium in the vessel, assemble the apparatus without
the disk assembly, and equilibrate the medium to 32

0.5 8C. Apply the transdermal system to the disk assem-bly, ensuring that the release surface of the system is as flat as possible.
The system may be attached to the disk
by applying a suitable adhesive (3) to the disk assembly. Dry for 1 min. Press the system, release surface side up, onto the adhesive-
coated side of the disk assembly. If a membrane (4) is used to support the system, it should be applied in such a way that no air bubbles
occur be-tween the membrane and the release surface. Place the disk assembly flat at the bottom of the vessel with the re-lease
surface facing up and parallel to the edge of the paddle blade and surface of the Dissolution Medium. The bottom edge of the paddle
should be 25 2 mm from the surface of the disk assembly. Immediately start operation of the apparatus at the rate specified in the
monograph. At each sampling time interval, withdraw a specimen from a zone midway between the surface of the Dissolution Medium
and the top of the blade, not less than 1 cm from the vessel wall. Perform the analysis
on each sampled aliquot as directed in the individual monograph, correcting for any volume losses, as neces-sary. Repeat the test with
additional transdermal systems.

Sampling Time—The test time points, generally three, are expressed in hours. Specimens should be
withdrawn within a tolerance of 15 min or 2% of the stated time; select the tolerance that results in the
narrowest time interval.

In Vitro Release Criteria—Unless otherwise specified in the individual monograph, the requirements are met if the
quantities of active ingredient released from the sys-tem conform to Acceptance Table 1 for transdermal drug delivery
systems. Continue testing through the three lev-els unless the results conform at either L1 or L2.

Acceptance Table 1

Level Number Criteria

L1 6 No indi vi dual value li es outside the s tated r ang e.

Stimuli
Tested

The average value of the 12 units (L1 + L2) lies within the stated range.

to
L2 6 No in-
dividual value is outside the stated range by more than 10% of the
average of

the
the stated range.

Revision
more than 2 of the 24 units are outside the stated range by more than 10% of

The average value of the 24 units (L1 + L2 + L3) lies within the stated
L3 12 range. Not
Process
the average of the stated range, and none of the units is outside the
stated
range by more than 20% of the average of the stated range.

Apparatus 6 (Rotating Cylinder Method)

Apparatus—Use the vessel assembly from Apparatus 1 as described in h711 i, but replace the basket and shaft with a stainless steel
cylinder stirring element and main-tain the temperature at 32 0.5 8C during the test. The shaft and cylinder components of the stirring
element are fabricated from stainless steel to the specifications shown in Figure 3. The dosage unit is placed on the
cylinder at the beginning of each test. The distance between the in-side bottom of the vessel and the cylinder is
maintained at 25 2 mm during the test.
 STIMULI TO THE REVISION PROCESS
Stimuli articles do not necessarily reflect the policies Pharmacopeial Forum
762 of the USPC or the USP Council of Experts Vol. 35(3) [May–June 2009]
Stimuli to the Revision Process

Fig. 3. Cylinder Stirring Element (5). (All measurements are expressed in cm unless noted otherwise.)

Dissolution Medium—Use the medium specified in the individual monograph (see h711i).

Procedure—Place the stated volume of the Dissolution Medium in the vessel of the apparatus specified
in the in-dividual monograph, assemble the apparatus, and equi-librate the Dissolution Medium to 32 0.5
8C. Unless otherwise directed in the individual monograph, prepare the test system before the test as
follows:

Remove the protective liner from the system, and place the adhesive side on a piece of Cuprophan (4) that is not less
than 1 cm larger on all sides than the system. Place the system, Cuprophan-covered side down, on a clean surface, and
apply a suitable adhesive (3) to the ex-posed Cuprophan borders. If necessary, apply additional adhesive to the back of
the system. Dry for 1 min. Care-fully apply the adhesive-coated side of the system to the exterior of the cylinder so that
the long axis of the system fits around the circumference of the cylinder. Press the Cuprophan covering to remove
trapped air bubbles. Place the cylinder in the apparatus, and immediately ro-tate at the rate specified in the individual
monograph. Within the time interval specified, or at each of the times stated, withdraw a quantity of Dissolution Medium
for analysis from a zone midway between the surface of the Dissolution Medium and the top of the rotating cylin-der, not
 less than 1 cm from the vessel wall. Perform the analysis as directed in the individual monograph, correct-ing for any
volume losses as necessary. Repeat the test with additional transdermal drug delivery systems.

Sampling Time—Proceed as directed for Apparatus 5.

In Vitro Release Criteria—Unless otherwise specified in the individual monograph, the requirements are met if the quantities of
active ingredient released from the sys-tem conform to Acceptance Table 1 for transdermal drug delivery systems. Continue
testing through the three lev-els unless the results conform at either L1 or L2.

Apparatus 7 (Reciprocating Holder Method)

Apparatus—The assembly consists of a set of volumetri-cally calibrated or tared solution containers made of glass or other
suitable inert material (6), a motor and drive as-sembly to reciprocate the system vertically and to index the system horizontally to
a different row of vessels auto-

matically if desired, and a set of suitable sample holders [see Figure 4 (2) and Figures 5a and 5b). The solution con-tainers are
partially immersed in a suitable water bath of any convenient size that permits maintaining the tem-perature, T, inside the containers
at 32 0.5 8C or within the allowable range, as specified in the individual mono-graph, during the test. No part of the assembly, includ-
ing the environment in which the assembly is placed, should contribute motion, agitation, or vibration beyond that due to
the smooth, vertically reciprocating sample holder.

An apparatus that permits observation of the system and holder during the test is preferable. Use the
size con-tainer and sample holder specified in the individual monograph.
 Stimuli to the Revision Process
Fig. 4. Reciprocating Disk Sample Holder (7).
 Fig. 5a. Transdermal System Holder—Angled Disk.

#2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
 STIMULI TO THE REVISION PROCESS
Stimuli articles do not necessarily reflect the policies Pharmacopeial Forum
764 of the USPC or the USP Council of Experts Vol. 35(3) [May–June 2009]

Fig. 5b. Transdermal System Holder—Cylinder.

Stimuli to the Revision Process

Sample Preparation A—Attach the system to be tested to a suitable sample holder with 2-cyano acrylate glue.

Sample Preparation B—Press the system onto a dry, un-used piece of Cuprophan (4), nylon netting, or equiva-
lent with the adhesive side against the selected substrate, taking care to eliminate air bubbles between the
substrate and the release surface. Attach the system to a suitably sized sample holder with a suitable O-ring so
that the back of the system is adjacent to and centered on the bottom of the disk-shaped sample holder or cen-
tered around the circumference of the cylindrical-shaped sample holder. Trim the excess substrate with a sharp
blade.

Sample Preparation C—Attach the system to a suitable holder as described in the individual monograph.

Dissolution Medium—Use the Dissolution Medium speci-fied in the individual monograph (see h711i).

Procedure—Suspend each sample holder from a verti-cally reciprocating shaker so that each system is continu-ously immersed
in an accurately measured volume of Dissolution Medium within a calibrated container pre-equilibrated to temperature, T.
Reciprocate at a fre-quency of about 30 cycles/min with an amplitude of about 2 cm, or as specified in the individual monograph,
for the specified time in the medium specified for each time point. Remove the solution containers from the bath, cool to room
temperature, and add sufficient solu-tion (water in most cases) to correct for evaporative losses. Perform the analysis as directed
in the individual monograph. Repeat the test with additional drug deliv-ery systems as required in the individual monograph.

Sampling Time—Proceed as directed for Apparatus 5.

In Vitro Release Criteria—Drug release should be mea-sured at least at 3 time points, first time point around 1 hour, second
around 50% of total drug release, and third around 85% drug release. Unless otherwise specified in

the individual monograph, the requirements are met if the quantities of the active ingredients released from the
system conform to Acceptance Table 1 under Dissolu-tion h711i for transdermal drug delivery systems, or as
specified in the individual monograph. Continue testing through the three levels unless the results conform at
either L1 or L2.
ANNEXURE D
 SHELF LIFE AND
STORAGE

CREAM
BATCH NO. BATCH SIZE MFG. DATE EXP. DATE

The applied drug is tested under the following conditions for the period of 6 months.
1. At room temperature (25° C)
2. At refrigerator
3. At dark place
4. In sun light
5. At external temperature (35-40° C)
For 1st week, the drug is analyzed every day then after every week.

1ST MONTH
Description Appearance Identification %age Purity
At room temperature
Complies Complies Complies
(25° C)
At Refrigerator Complies Complies Complies
At dark place Complies Complies Complies
In sun light Complies Complies Complies

2ND MONTH
Description Appearance Identification %age Purity
At room temperature
Complies Complies Complies
(25° C)
At Refrigerator Complies Complies Complies
At dark place Complies Complies Complies
In sun light Complies Complies Complies

3RD MONTH
Description Appearance Identification %age Purity
At room temperature
Complies Complies Complies
(25° C)
At Refrigerator Complies Complies Complies
At dark place Complies Complies Complies
In sun light Complies Complies Complies

4TH MONTH
Description Appearance Identification %age Purity
At room temperature
Complies Complies Complies
(25° C)
At Refrigerator Complies Complies Complies
At dark place Complies Complies Complies
In sun light Complies Complies Complies

5TH MONTH
Description Appearance Identification %age Purity
At room temperature
Complies Complies Complies
(25° C)
At Refrigerator Complies Complies Complies
At dark place Complies Complies Complies
In sun light Complies Complies Complies
6TH MONTH
Description Appearance Identification %age Purity
At room temperature
Complies Complies Complies
(25° C)
At Refrigerator Complies Complies Complies
At dark place Complies Complies Complies
In sun light Complies Complies Complies

ANNEXURE E
 RECOMMENDED
CONDITIONS FOR USE

i. Dosage form

CREAM/CREAM
ii. Recommended route of administration

TOPICAL

iii. Recommended Dose

Adult dose: Apply on skin 2 -3 times a day or as directed by

physician
Child dose: N/A

iv. Indications

As a Supportive therapy for;

PAIN AND INFLAMMATION OF SKIN.

v. Recommended duration of use , if any

As advised by the physician

vi. Risk information ,including any caution ,warning,
contraindication or known adverse reactions associated
with its use

Cautions:
» Store at room temperature
» Protect from Heat, Light & Moisture

» Keep out of the reach of the children

 » Before using this medicine, consult your doctor or pharmacist

Warning:
There is no interaction of it with any drug or food.

Contra-Indications:
There is no known Contra-indication of it.

Side Effects:
No major known side effects.
 ANNEXURE F

PACKAGING
&
LABELING

The Artwork of the label and Unit carton and Patient information Leaflet is
attached

ANNEXURE G
FEE DEPOSIT RECEIPT

ATTACHED WITH
COVER LETTER

ANNEXURE I
 UNDERTAKING

UNDERTAKING

I undertake and certify that the contents stated above are correct and true to the
best of my knowledge

For & on behalf of

PHARMASPEC LABORATORIES (PVT.) LTD
 UNDERTAKING FOR BRAND NAME

PHARMASPEC LABORATORIES (PVT.) LTD hereby undertake that:

1). the brand name, label and packaging of this product applied for Enlistment does
not resemble to any of the products in market.
2). the applied product’s formulation / composition are not already enlisted for us.

For & on behalf of

PHARMASPEC LABORATORIES (PVT.) LTD