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Research J. Pharm. and Tech.

7(2): February 2014

ISSN 0974-3618 www.rjptonline.org

REVIEW ARTICLE

An Updated Review on IPQC Tests for Sterile and Non Sterile Products
V. Shirisha, Somsubhra Ghosh*, B. Rajni, David Banji
Department of Pharmaceutical Analysis and Quality Assurance, Nalanda College of Pharmacy, Cherlapally,
Nalgonda, 508001, A. P, India.
*Corresponding Author E-mail: som_subhra_ghosh@yahoo.co.in

ABSTRACT:
Present study deals with a brief overview of comparative study of quality requirements for in process and finished
product quality control test of IP, BP and USP for some conventional dosage forms. The concept of IPQC refers to the
process of striving to produce a quality product by a series of measures requiring an organised effort in order to
eliminate errors at every stage in the production. Main function of IPQC is monitoring and if necessary adaption of the
manufacturing process in order to comply with the specifications this may include control of equipment and
environment. In process materials should be tested for identity, strength and quality and purity as appropriate and
approved (or) rejected by the quality Assurance department. During the production process rejected in process
materials should be identified and controlled under a Quarantine system designed to prevent their use in
manufacturing. IPQC is done to comply Concurrent Validation also.

KEYWORDS: IPQC, Validation, Quarantine system, In process.

INTRODUCTION (1)
Whenever any production process is going on, it is  Keep a provision for modification of process if
necessary to see that the process is going on as desired. This required.
is required to avoid loss of efforts and resources, in case the  The entire process is described and explained to the
process has not proceeded as desired, and then the whole I.P.Q.C. workers and supervisors before implementing.
processed material may be required to reprocessed or Records of such IPQC training may be kept.
rejected. Therefore, it is an important function of the in
process quality control system to ensure that finished A variable group of tests that are widely used for in process
dosage forms have uniform purity and quality within a control measures characteristics including physical
batch and between batches. appearance, colour, friability, hardness, weight variation,
disintegration time, volume check, viscosity and pH . Such
Steps involved in IPQC (1) in process tests are designed to ensure control of problems
 Identify types of formulations manufacturing or going that can arise during finished dosage form manufacturing
to manufacture, e.g. Tablet, Liquids, Parenteral, and
Ointments etc. Role of USFDA Guidelines in IPQC (1)
 Identify which are the critical steps in the Even though all regulatory guidelines makes passing
manufacturing of the product, where it will be remarks about I.P.Q.C requirements U.S.F.D.A. gives little
necessary to check certain parameters to confirm that more details about this. They are as follows:
the process is in control. Sampling and Testing of in-process materials and drug
 Identify the specifications of the parameters which will products:
confirm the parameters are within control.
 Define the frequency of checking of parameter. To assure batch uniformity and integrity of drug products,
 Create monitoring and control records for all I.P.Q.C. written procedures shall be established and followed that
process. describe in-process controls, and tests, or examinations to
be conducted on appropriate samples of in-process
materials of each batch. Such control procedures shall be
Received on 07.12.2013 Modified on 30.12.2013 established to monitor the output and to validate the
Accepted on 13.01.2014 © RJPT All right reserved
Research J. Pharm. and Tech. 7(2): Feb. 2014; Page 255-265
performance of those manufacturing processes that may be
responsible for causing variability in the characteristics of
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in-process material and drug product. Such control which describes the diameter of an equivalent sphere having
procedures shall include, but are not limited to, the the same rate of sedimentation as that of the symmetric
following, where appropriate: particles Sedimentation of particles may be evaluated by
 Tablet or Capsule weight variation different methods like E.g.: Andersen pipette method
 Disintegration time
 Adequacy of mixing to assure uniformity and Andersen pipette method:
homogeneity Principle:
 Dissolution time and rate The rate setting of particles in a suspension of emulsion
 Clarity, completeness or pH of solutions. may be obtained by stokes .However this equation can be
extended to irregularly shaped particles of various sizes
Valid in-process specifications for such characteristics shall When the power is suspended in a vehicle initially the
be consistent with drug product final specifications and particles of large diameter settled due to heavy weigh After
shall be derived from previous acceptable process average sometime particles of intermediate diameter finally the
and process variability estimates where possible and particles of smaller size settled Hence the study involves
determined by the application of the suitable statistical the sampling during sedimentation at different time
procedures where appropriate. Examination and testing of intervals
samples shall assure that the drug product and in-process
materials conform to specifications. In-process materials Procedure:
shall be tested for identity, strength, quality, and purity as  Prepare 1-2 %suspension of powder in a suitable
appropriate, and approved rejected by the quality control medium.
unit, during the production process, e.g. at commencement  A deflocculating agent can be added for uniform
or completion of significant phases or after storage for dispersion of the suspension.
longer periods.  Transfer the suspension into the Anderson vessel.
 Place the stopper and a shake the vessel to distribute
A. NON-STERILE PRODUCTS (2) the suspension uniformly.
1. Granules (starting materials)  Remove the stopper end the two way pipette and
2. Tablets (finished products) securely suspend the vessel in a constant temperature
3. Capsules in a water bath.
4. Liquid dosage form  At different time intervals 10 ml samples are
withdrawn using two way stop cork and collected in
1. GRANULES: watch glass. Samples were evaporated and weighed.
(2)
a) Appearance : The general appearance of a granule, its  The weight of the amount of particles obtained in each
identity and general elegance is essential for components in time intervals is referred to as weight under size .The
manufacturing, for control of lot-to-lot uniformity and weighs are converted into cumulative weight under
tablet-to-tablet uniformity. The control of general size.
appearance involves the measurement of size, shape, colour,  Particles diameter was calculated from stokes law with
presence or absorbance in (h) in equation being the height liquid above the
lower end of the pipette at the time with drawing
b) Size and Shape : sample.
(1) Sieving: Particle having the size range between 50 and
150 m are estimated by this method. In this method the size 3) Optical microscope: Most direct method here the
is expressed as d sieve which describes the diameter of a particles size and size distribution is determined by
sphere that passes through the sieve aperture as the preparing a suspension and absorbing under, microscope.
asymmetric article .The method directly gives the weight c) Surface area: Surface area of the drug can have a
determination. significant effect upon the dissolution rate it is determined
by Gas adsorption, Air permeability (2)
Method:
Standard sieves of different mesh numbers are available d) Bulk Density and Tapped Density:
commercially as per the specification of IP and USP. The Bulk Density: The bulk density of a powder is the ratio of
sieves are arranged in nest with the coarsest at the top A the mass of an untapped powder sample and its volume
sample 50 gm of the powder is placed on the sieve this including the contribution of the interparticulate void
sieve set is fixed to the mechanical shaker apparatus and volume.
shaken for the certain period of time (20) min The powder
retained on each sieve is weighed it is expressed in terms of Bulk density = Mass of powder (W)/bulk volume (Vb)
arithmetic or geometric mean of the two sieves. It is determined by 3 methods: 1. Measurement in a

(2) Sedimentation (2): Graduated Cylinder, 2. Measurement in a Graduated


Sedimentation method may be used over a size range of 1 Cylinder
to200 m in this method size is expressed as stokes diameter

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Table 1: USFDA Guidelines IPQC Parameters for Pharmaceuticals


Tests to be performed Tablets Capsules Dry Ointment Liquid Ampoules Liquid Powder
Syrup Vials Vials
1.Physical app      
2.Weight variation     
3.Homogeneity   
4.D.T.  
5.Dissolution  
6.Hardness 
7.Friability 
8.Closing length 
9. Cap sealing  
10.Leak test     
11.Volume variation   
12. Clarity of solution   
13.PH   

3. Measurement in a Vessel:  Dry the tests specimen at the temperature and for the
Tap density: The tapped density is an increased bulk time specified in monogram
density attained after mechanically tapping a container  Upon opening the chamber close the bottle promptly
containing the powder sample. and allow it to come to room temperature in
desiccators’ before weighing (w2)
Tap density = Mass of powder (W) / Tapped volume (Vt)  The substance melts at a lower temperature then the
specified for the determination of loss on drying
e) Angle of repose (θ): The flow characteristics are maintain the bottle with it content for 1-2 hrs at a
determined by angle of repose, it is defined as maximum temperature at 5-10 degrees below the melting
angle possible between the surface of a pile of the powder temperature than dry at the specified temperature
and horizontal planes  When the specimen under test is capsules use a portion
θ=Tan-1(h/r) of mixed contents of fewer than4 capsules If it is
h = height of pile : r = Radius of the base of pile tablets use powder from not fewer than 4 tablets grind
The lower the angle of repose the better the flow property to a fine powder Where drying in a desiccators’ is
Rough and irregular surface of the particles gives higher specified exercise particular care to ensure that the
angle of repose desiccant is kept fully effective by frequent
replacement
Table 2: shows angle of repose and powder flow
 Other method employed for moisture content
Angle of repose Powder flow
<25 Flow measurement is Karl fisher method
25-30 Good
30-40 Passable Table 3: Shows compressibility indexand Type of flow
>40 Very poor Compressibility index Type of flow
5-15 Excellent
12-16 Good
f) Moisture content: (2)
18-21 Fair
When there is high moisture content, then there will be 23-25 Poor
greater risk of cohesion and adhesion. Moisture content is 33-38 Very poor
commonly determined by: >40 Extremely poor

Loss on drying: g) Compressibility index:


Mix and accurately weigh the substance to be It demonstrates the relation between the flow and
 If the test specimen is in the form or large crystals compressibility of powder
reduce the particles size to about 2mm by quickly %compressibility = (tapped density-poured density)/tapped
crushing density
 Weight and empty dried glass stopper shallow
weighing bottle h) Hausner ratio: (2)
 Put the test specimen in the bottle replace the cover Hausner predict the flow property of powder by using inter
and accurately weigh the bole and the contents particle friction Hausner ratio = tapped density/powered
 By gentle sideways shaking distributed the test density
specimen as evenly as practicable deep of about 5mm
Table 4: Shows Hausner ratio andtype of flow
generally more than 10 mm in case of bulky materials
Hausner ratio Type of flow
(w1) 1.25 Good flow
 Place the loaded bottle in the drying chamber removing >1.25 Poor flow
the stopper end leaving it also in the chamber

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2) TABLETS: outside these limits or if one individual content is outside


a) Physical Appearance:( 3) the limits of 75-125 % of the average content. If one
The general appearance of a tablet, its identity and generalindividual content is outside the limits of 85 to 115 per cent
elegance is essential for consumer acceptance, for control of
of the average content but within the limits of 75 to 125 per
lot-to-lot uniformity and tablet-to-tablet uniformity. The cent, repeat the determination using another 20 dosage
control of general appearance involves the measurement of units. The preparation complies with the test if not more
size, shape, colour, presence or absence of odour, taste etc.
than one of the individual contents of the total sample of 30
dosage units is outside 85 to 115 per cent of the average
b) Weight variation test (3) content and none is outside the limits of 75 to 125 per cent
Weigh individually 20 units selected at random and of the average content.
calculate the average weight. Not more than two of the
individual weights deviate from the average weight by more d) Disintegration Test : Disintegration test is a measure of
than the percentage shown in the table and none deviates by time required under a given set of conditions for a group of
more than twice that percentage. tablets to disintegrate into particles.

Table 5: Shows weight variation test of different dosage forms Apparatus:


DOSAGE FORMS AVERAGE. PERCENTAGE The apparatus consists of a basket-rack assembly, a 1-litre
WEIGHT DEVIATION
beaker, a thermostatic arrangement for heating the fluid and
Uncoated film 80 mg(or)µgm 10
coated tablets a mechanical device for raising and lowering the basket in
More than 80mg but 7.55 the immersion fluid at a constant frequency rate. The basket
less than 250 mg rack assembly holds 6 plastic tubes, open at top and the
(or)more bottom of tubes is covered with 10- mesh stainless steel
Capsules, Granules Less than 300mg 10 wire screen. The basket rack is immersed in a bath of
and Powder
300 mg (or)more 7.5
suitable liquid, held at 37±2˚c.For compressed, uncoated
tablets, testing fluid is usually water but sometimes
c) Uniformity of content: monographs refer to use simulated gastric fluid.Tablets are
The test for uniformity of content of single-dose placed in each of 6 cylinders along with plastic disc over
preparations is based on the assay of the individual contents the tablet if mentioned in monograph. Through the use of a
of active substance(s) of a number of single-dose units to mechanical device, the rack moves up anddown in the fluid
determine whether the individual contents are within limits at a specified rate, The volume of liquid is such that the
set with reference to the average content of the sample wire mesh at its highest point is at least 25 mm below the
surface of the liquid, and at its lower point is at least 25 mm
Method: above the bottom. End point of the test is indicated when
Determine the content of active ingredient(s) in each of 10 the tablets are completely disintegrated and any residue
dosage units taken at random using the method given in the remaining is a soft mass with no palpably firm core. The
monograph or by any other suitable analytical method. preparation complies with the test if the time to reach this
Acceptance limits for tablets, suspensions for injection and end point is below a given limit.
ophthalmic inserts:
Limit:
The preparation complies with the test if each individual If 1 or 2 tablets fail to disintegrated, test is repeated using
content is 85-115 % of avg content. The preparation fails to 12 tablets. of the 18 tablets tested, 16 must have
comply with the test if more than one individual content is disintegrated within given period of time.

Table 6: List of Disintegration test of various Tablet dosage forms


Tablets Pre-treatment required Disintegration fluid Temperature (ºC) Plastic discs Standard disintegration
time
1.Uncoated tablets Not required Water 37±2 Required 15-30 mins
2.Coated tablets Water 37±2 Required 60 minutes
a. Film-coated The coated tablets are
(30 in number) immersed in water in order
b. Sugar-coated to remove their outer Water 37±2(for 2 hours) Not required 30 minutes
(60 in number) soluble coating (i)0.1N HCl 37±2
centric-coated (ii)Phosphate Required Tablets do not disintegrate
buffer(pH-6.8) 2hours+as specified in the
individual monograph
3.Effervescent No retreatment required Water 24-26ºC Not required 3minutes
tablets

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e) Hardness Test: (3) tablets and is intended to determine the physical strength of
Hardness of the tablet also termed as its crushing strength. tablets
The hardness of the tablet may be defined as the
compression force required breaking the tablet when such 3) CAPSULES (4):
force is applied diametrically. The tablet is required to Capsules are solid dosage forms in which medicinal agents
posse’s sufficient hardness to resist breakage during the are enclosed in small shell of Gelatin. Capsule shells may
transport, storage or use. The hardness of a tablet is related be hard or soft, depending on their composition.
to its disintegration and has more vital role to play in
controlling the rate of drug release from the tablet. a) Physical appearance:
The general appearance of a capsule, its identity and general
(i) By Manual Testing: Manual testing method was elegance is essential for consumer acceptance, for control of
employed previously. In this, method, the thumb acts lot-to-lot uniformity and capsule uniformity. The control
as a fulcrum, while the tablet is held between the of general appearance involves the measurement of size,
second and third hand fingers. When the pressure is shape, colour, presence or absence of odour, taste etc.
applied the tablet which breaks with a sharp snap
deemed to posses’ sufficient hardness. b) Weight variation test:
(ii) Monsanto Hardness Tester Method :( 3)The Weigh an intact capsule. Open it without losing any part of
instrument measures the force required to break the the shell and remove the contents as completely as possible.
tablet when the force generated by a coil spring is For soft gelatin capsules, wash the shell with a suitable
applied diametrically to the tablet. solvent and keep aside until the odour of the solvent is not
(Iii) Pfizer Hardness Tester: Force required to break tablet perceptible. Weigh the shell. The difference between the
is recorded on dial and may be expressed in key weighing gives the weight of the contents. Repeat the
pounds procedure with another 19 capsules.

Other devices: c) Uniformity of content:


 Strong-Cobb Hardness Tester The preparation complies with the test if not more than one
 Erweka Hardness Tester. individual content is outside the limits of 85-115% of the
 Schleuniger or Heberlein Hardness Tester. average content and none is outside the limits of 75-125
%of the average content. The preparation fails to comply
Acceptance criteria: A force of 4 kg/inch2is considered to with the test if more than three individual contents are
be the minimum requirement for a satisfactory tablet. outside the limits of 85-115% of the average content or if
one or more individual contents are outside the limits of 75-
f) Friability Test: 125 % of the avg content. If two or three individual
The friability of a tablet may be defined as its resistance to contents are outside the limits of 85-115% of the average
shock and abrasion encountered during the process of content but within the limits of 75-125%, repeat the
manufacture, packing, transport and ultimately its usage. determination using another 20 dosage units.
Friability in addition to hardness gives measure of tablets The preparation complies with the test if not more than 3
strength. It is determined through the use of a friabilator. individual contents of the total sample of 30 dosage units
are outside the limits of 85-115 per cent of the average
Method: content and none is outside the limits of 75-125 %of the
A no. of tablets are weighed and placed in tumbling average content.
apparatus where they are exposed to rolling and repeated
shocks resulting from free fall within the apparatus. After d) Closing length:
given no. of rotations, the tablets are weighed. Resistance to The Acceptance criteria 0.2mm
loss in weight indicates ability of tablet to withstand this
type of wear. For tablets with an average weight of 0.65g or e) Moisture permeation test:
less take a sample of whole tablets corresponding to about To assure the suitability of containers for packaging
6.5g and for tablets with an average weight of more than capsules, USP has started some rules and regulations.
0.65 g take a sample of 10 whole tablets. De dusts the According those rules and regulations, the moisture
tablets carefully and weighs accurately the required number permeating feature of capsules packaged in single unit
of tablets. Place the tablets in the drum and rotate it 100 containers is to be determined.
times. Remove the tablets, remove any loose dust from
them and weigh them accurately. Procedure:
For performing this test, one capsule is packaged along with
Criteria: the dehydrated pellets, which have the property of changing
A maximum loss of weight (from a single test or from the colour in the presence moisture. The packaged capsule is
mean of the three tests) not greater than 1.0 per cent is then placed for a certain period of time in an atmosphere of
acceptable for most tablets. If obviously cracked, chipped or known humidity. Any change in the colour of dehydrated
broken tablets are present in the sample after tumbling, the pellets reveals the absorption of moisture. The weight of
sample fails the test. This test is applicable to compressed this capsule is then compared with the weights of the
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capsules under test. The differences in the weights give the c) Leakage Test::
amount of moisture absorbed Ampoules are subjected to leakage test because ampoules
are sealed by fusion. Therefore, there is a chance for a
4) LIQUID DOSAGE FORMS :( 5) incomplete sealing or for microspores to exist, allowing the
It is prepared by dissolving active ingredients or by contents to leak or microorganisms and other contaminants
suspending the drug (if drug is insoluble) or by to enter the ampoules. Method: This test is performed by
incorporating the drug into one of the two phases of oil and immersing the ampoules in a vacuum chamber consisting of
water systems. Liquid dosage form comprises of solution, a dye such as 1% methylene blue solution. A vacuum
suspension and emulsion and a variety of preparation can be (negative pressure) of about 27 inch Hg or more is created
considered under each category. These dosage form are for about 15 to 30 minutes. This negative pressure causes
categorized by their homogene, promote action and easy of the methylene blue solution to enter the ampoules with
Administration. Liquid dosage forms are suitable for both defective sealing. The vacuum is released, ampoules are
internal and external use. This is a general term used to washed externally and observed for the presence of dye in
describe a solution, suspension or emulsion in which the the ampoules. The coloured solution because of the dye in
active ingredient is dissolved or dispersed in a suitable the ampoules confirms the leakage and hence those
liquid vehicle. Liquid dosage forms are 2 types: ampoules are discarded.
(i) Monophasic: a) Syrups, b) Elixirs, c) Tinctures etc.
(ii) Biphasic: a) Suspensions, b) Emulsions. (ii) BIPHASIC LIQUID DOSAGE FORMS:
a) Suspensions:
(i) IPQC TESTS FOR MONOPHASIC LIQUID Pharmaceutical suspensions may be defined as coarse
DOSAGE FORMS: dispersions in which insoluble solids are suspended in
a) Uniformity of content: liquid medium. the insoluble solids may have assize range
Unless otherwise specified, single dose liquids in of 1o to 100 Liquid medium is usually water/water Liquid
suspension form and that contain less than 10 mg or less medium is usually water/water based vehicle Also called
than 10 per cent of active ingredient complies with the “heterogeneous biphasic systems”
following test. For oral liquids containing more than one
active ingredient carry out the test for each active ingredient Physical stability:
that corresponds to the above conditions. Defined as the condition in which the particles in which the
particles remain uniformly distributed throughout the
Method: dispersion without any signs of sedimentation. It is difficult
Determine the content of active ingredient(s) of each of 10 to achieve this condition. Hence the definition can be
containers taken at random, using the method given in the restated as – if the particles settle, they should be easily re
monograph or by any other suitable analytical method of suspend able by a moderate amount of shaking .Therefore
equivalent accuracy and precision. The preparation under the extent of sedimentation and ease of re dispersibility are
examination complies with the test if the individual values to be evaluated by appropriate methods. Drug Content
thus obtained are all between 85-115% of the average value. Uniformity This important testing procedure is best
The preparation under examination fails to comply with the performed using either ‘‘unit of use’’ volume (e.g., 5mL of
test if more than one individual value is outside the limits oral liquid or a spray actuation of an oral inhalation
85-115% of the average value or if any one individual value product) or sampling from a well-mixed dispensing
is outside the limits 75-125 % of the average value. If one container from the top, middle, and bottom of the
individual value is outside the limits 85-115 % but within suspension. Sedimentation Rate, Sediment Volume, and Re
the limits 75-125% of the average value, repeat the suspend ability Simple, inexpensive, graduated cylinders
determination using another 20 containers taken at random. (100– 1000 ml) are useful for determining the physical
The preparation under examination complies with the test if stability of suspensions. They can be used to determine the
in the total sample of 30 contains not more than one settling rates of flocculated and non-flocculated suspensions
individual value is outside the limits 85 -115 % and none is and the sediment height at equilibrium. The falling height
outside the limits 75 -125 % of the average value. of the liquid—sediment interface of the suspension is
determined as a function of time, and the sedimentation rate
b) Uniformity of Weight/Volume: test is repeated periodically during storage. The sediment
The following tests and specifications apply to oral dosage volume at equilibrium should be sufficiently large to
forms and preparations intended for topical use that are support uniform re suspension with gentle agitation. The
packaged in containers in which the labelled net quantity is equilibrium sediment volume should be similar and
not more than 100 g or 300 ml or 1000 units, as the case reproducible batch after batch. Volumetric graduated
may be. For higher labelled quantities the test and limits cylinders are used to determine the ‘‘F’’ or flocculation
given in the standards of Weights and Measures (Packaged ratio, a value that represents the ratio of the sediment
commodities) Rules, may be followed. volume to the original suspension volume at a given time. It
is used to measure the relative degree of flocculation and
physical stability of suspensions.

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in electrical resistance is observed between the two


IPQC tests for suspensions: electrodes. The resulting voltage pulses which are
a) Appearance: proportional to the particle size, are amplified and are
The appearance of the suspension is noted and determined measured and counted. Particles below 0.2 m can also
the uniformity of sedimentation and also determined the detected by this method.
breaks or air pockets in the sediment.
Significance of Particulate Matter Detection:
Method: The presence of foreign particles in intravenous solutions
The appearance is noted in a graduated glass cylinder or may cause obstruction of small blood vessels leading to
transparent glass container. severe consequences like emboli, infusion, and infusion
phelebitis. The presence of particulate matter implies that
Photo microscopic Examination: the product is of inferior quality.
The microscope can be used to distinguish between
flocculated and non-flocculated particles and to determine Table 7: shows the microscopic count of particle size
changes in the physical properties and stability. Sufficient Particle Method Small volume Large volume
fields and samples should be examined to make these Size injectables injectables
≥10µ Microscope 3000parts/container 12parts/ml
determinations. count
≥25µ Microscope 3000parts/container 2parts/ml particles
Method: count
Microscopic can be used to estimate and detect change in
particle size distribution and crystal shape of suspension. Microscopic count method (or) membrane filtration
The dilution of suspension for microscopic examination method:
should be made with supernatant external phase rather than A measured sample solution is filtered through a membrane
with purified water. Individual particle size distributions filter. The collected particles on the surface of the filter are
can be accurately determined, using Suitable electron then counted with the help of a microscope at 100X
instrumentation, for example, a Coulter Multisizer II or the magnification. The whole method is carried out under
Elzone 280 PC systems .General methods for particle size. aseptic conditions. However, it is a time consuming
process.
b) Colour, Odour and Taste:
These characteristics are especially important in orally d) Uniformity of Volume:
administered suspensions. Variation in colour Pour completely the contents of each container into
Photomicrograph of a flocculated steroid suspension calibrated volume measures of the appropriate size and
indicates poor distribution and/or differences in particle determine the volume of the contents of the 10 containers.
size. Variations in taste, especially of active constituents,
can often be attributed to changes in particle size, crystal Acceptance Criteria:
habit, and subsequent particle dissolution. Changes in The given % allowance for uniformity of vol according to
colour, odour, and taste can also indicate chemical I.P: If this requirement is not met, test is done on 10
instability additional containers. The average net volume of the
contents of the 20 containers is not less than the labelled
Method: amount, and the net volume of the contents of not more
By visualisation as product and by testing the drug products than1 of the 20 containers is less than 91 per cent or more
pH Value as the presence of H+ ions in the suspension than 109 per cent of the labelled amount where the labelled
preparation. The pH value of aqueous suspensions should amount is 50 ml or less (or) less than 95.5 per cent or more
be taken at a given temperature and only after settling than 104.5 per cent of the labelled amount where the
equilibrium has been reached, to minimize ‘‘pH drift’’ and labelled amount is more than 50 ml but not more than 2oo
electrode surface coating with suspended particles. pH ml
defined as the presence of H+ ions in the suspension
preparation. Immerse the electrodes in the solution under Table 8: Shows labelled volume and percentage allowance
examination and measure the pH at 25º ± 2º (pH range:-4.5- S. No Labelled vol of % allowance
7.2) container
1. ≤50ml 91-109% of labelled vol
2. 50-200 ml 97-103% of labelled vol
c) Determination of Particle Size:
Coulter counters method: e) Viscosity:
This electronic method is used to detect the particles and A Brookfield viscometer with a heli path attachment
also determine the particle size. The sample solution is (Stoughton, MA) is a useful rheological instrument for
added to an electrolyte solution. This solution is drawn measuring the settling behaviour and structure of
through a small orifice of the device. Positive and negative pharmaceutical suspensions and for characterizing the
electrodes are present one on either side of an orifice. As properties sand stability of flocculated suspensions. The
the particle passes through the orifice, it displaces its own viscometer should be properly calibrated to measure the
volume of electrolyte and at the same moment, an increase
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apparent viscosity of the suspension at equilibrium at a DEGREE OF FLOCCULATION:


given temperature to establish suspension reproducibility It is defined as β = F/Fα
Sedimentation volume of flocculated system
f) Density : = Sedimentation volume of deflocculated system
Specific gravity or density of the suspension is an important
parameter. A decrease in density often indicates the β = VU/Vα
presence of entrapped air within the structure of the
suspension. Ultimate sedimentation volume of flocculated system
Ultimate sedimentation volume of deflocculated system
Method: If F = Fα, then β will be one. If β value is nearer to one, then
Density measurements at a given temperature should be suspension does not represent flocculated suspension. It
made using well-mixed, uniform suspensions; precision indicates it is deflocculated suspension.Higher the value of
hydrometers facilitate such measurements. It is determined β, greater the physical stability.
by using pyknometer or density bottle.
i) Re dispersibility:
Density (D) =Mass/Volume Re dispersibility can be estimated by shaking the
suspension with hands or by some mechanical device which
g) Particle Size Measurement: is stimulated with motion of human arm. Suspension is
Recently with respect to the importance of particle size placed in 100ml graduated cylinder. After storage and
distribution in terms of particle characterization and product sedimentation, cylinder is rotated through 360 at 20 rpm.
physical stability testing, The end point is taken when base of cylinder is clear of
sediment. The time required / no of revolutions is noted.
Method:-1) The shorter the time/ lower the no of revolutions, greater or
Light-Scattering methods for particle detection called faster redispersibility.
photon correlation spectroscopy (PCS).
(2) By using single particle optical sensing (SPOS) j) Determination of zeta potential :( 5)
(3) With the help of laser diffraction (LD) This can be determined by using ‘zeta meter’ which
(4) Also by the ultrasound attenuation (UA) determines by measuring electrophoretic mobility of
particles in suspension
h) Extent of sedimentation: Z = 4πnv/Εe
It is quantitatively expressed by 2 parameters: Where, n = viscosity of suspension
Sedimentation volume, Degree of flocculation E = applied electric field
Sedimentation volume: F = VU / V = ultimate volume of ε = dielectrical constant
sediment / initial volume of suspension Where F is V = velocity of particle
sedimentation volume , F’ can assume a value of ‘1’, when
there is no sedimentation (VU =VO) , ‘F’ can also assume a Table 9: Shows zeta potential and stability behaviour
value of ‘zero’, when sedimentation is complete (VU = 0) , Zeta potential (mV) Stability behaviour
‘F’ value lies between the limits 0 and 1, In general higher 0 to ±5 Rapid coagulation / flocculation
±10 to ±30 Incipient stability
the sedimentation volume better is physical stability , A ±30 to ±40 Moderate stability
series of suspensions can be prepared using different ±40 to ±60 Good stability
suspending agents or varying concentrations of same > ±61 Excellent stability
suspending agent. These formulations are transferred into
100 ml measuring cylinders. At different time intervals, b) Emulsion: IPQC test for Emulsion:
sedimentation level in ml is measured. A plot is drawn by a) Appearance: The appearance or the emulsion is noted
taking time on x-axis and VU/VO on y-axis. At zero time, and determined the uniformity of emulsion. The appearance
this ratio is equal to one as VU/VO. As the time elapses, is noted in transparent glass container
sedimentation levels decrease. Then the curve moves b) Colour, odour and taste method: These characteristics
downward to right of time axis and goes on. After sometime are especially for orally administered emulsion. Variation in
colour indicates the poor distribution in particle size. Colour
by direct visualisation method and taste by in vivo method.
c) Miscibility emulsion: An emulsion will only mix with a
liquid that is miscible with its continuous phase therefore an
o/w type emulsions miscible with water aw/o emulsion with
an oil.

Staining evaluation method: For evaluation of emulsion


the staining test is performed. A dry filter paper
impregnated with cobalt chloride turns from blue to pink on
exposure to stable o/w emulsion .Limit May fail if emulsion
Figure no. 1 Shows extent of sedimentation. is unstable and breaks in presence of electrolyte.
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Research J. Pharm. and Tech. 7(2): February 2014

IPQC test for parenterals:


Dye Test: Method: Oil –soluble dye is used. O/w a) Uniformity of content: Unless otherwise stated in the
emulsions are pales in colour than w/o emulsion and vice- individual monograph, suspensions for injection that are
versa. If examined microscopically, an o/w emulsion will presented in single dose containers and that contain less
appears as coloured globules on a colourless background than 10 mg or less than 10 per cent of active ingredient
while aw/o emulsion will appear as colourless globules comply with the following test for injection containing
against a coloured background more than one active ingredient carry out the test for each
active ingredient that corresponds to the above conditions
Limit: May fail if ionic emulsifier are present not more .The test for Uniformity of content should be carried out
than2.O only after the content of active ingredient(s) in a pooled
sample of the preparation has been shown to be within
d) Determination of zeta potential: This can be accepted limits of the stated content. Determine the content
determined by using ‘zeta meter’ which determines by of active ingredient(s) of each of 10 containers taken at
measuring electrophoretic mobility of particles in random, using the method given in the monograph or other
suspension. suitable analytical method of equivalent accuracy and
precision. The preparation under examination complies with
Z = 4πnv/Εe the test if the individual values thus obtained are all
between 85 and 115 per cent of the average value. The
Where, n = viscosity of suspension preparation under examination fails to comply with the test
E = applied electric field if more than one individual value is outside the limits 85 to
ε = di electrical constant 115 per cent of the average value or if any one individual
V = velocity of particle value is outside the limits 75 to 125 percent of the average
value. If one individual value is outside the limits 85 to 115
Table 10: List of zeta potential and stability behaviour per cent but within the limits 75 to125 per cent of the
Zeta potential (mV) Stability behaviour average value, repeat the determination using another 20
0 to ±5 Rapid coagulation / flocculation containers taken at random. The preparation under
±10 to ±30 Incipient stability
±30 to ±40 Moderate stability examination complies with the test if in the total sample of
±40 to ±60 Good stability 30 containers not more than one Individual value is outside
> ±61 Excellent stability the limits 85 to 115 per cent.

e) Determination of globule size: Size of globule is b) Clarity test for (particulate matter method):
increased over long storage period i.e. it causes Particulate matter is defined as presence of unintentional
coalescence. So to prevent it, globule size should be small. undesirable extraneous, mobile and undissolved substances
Globule size is determined by:- (other than gas bubbles) within the parenteral preparations.
a) Coulter counter method: in this method, particle Presence of particulate matter could make the user to
diameter is measured and also frequency (no of globules per conclude that it is of inferior quality. It has been suggested
ml) is determined. that as erythrocytes have a diameter of approximately
b) Microscopic method: in this method, diameter of 4.5µm, particles of more than 5µ should be the basis of
globule is measured under a microscope. evaluation. If the particle size more than RBC, then it cause
c) Laser diffraction sizing method: Size of globule is obstruction of blood vessels leading to severe consequences
determined using laser diffraction. like emboli in the vital organs of humans and animals.
f) Rheological method: This method ensures flow property
of emulsion so as to ensure its stability. Low viscosity of Table 11: Permissible limits(Maximum limits) for particulate
emulsions causes increase in rate of creaming leading to matter According to IP
Particle size(µm) (Maximum no of particles/ml)
instability. Determination of viscosity is done by using
10 50
brook field viscometer. A graphical plot of viscosity against 25 5
time on a log-log scale indicates a linear relationship. This 50 Nil
leads to an estimation that viscosity changes with time.
Visual method:
B. STERILE PRODUCTS: The field containers are examined by holding the neck of
1) Parenterals:(6) The term parenteral refers to inject able the containers against strong illuminated screen. The
routes of administration. It derives from Greek word Para containers are slowly inverted and rotated and the contents
(outside) and enter on (intestine) and denotes the routes of are examined for the presence of any foreign particles.
administration other than oral route. They are injected Black surface is used for the detection of light coloured
directly into body tissue through the primary protective particles and white surface for dark coloured particles. If
system of human body, the skin and mucous membranes; so any foreign particle is visible, then that container is
they must be exceptionally pure and free from physical, discarded.
chemical biological contaminants.

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Research J. Pharm. and Tech. 7(2): February 2014

Microscopic Count Method (or Membrane Filtration


Method):
A measured sample solution is filtered through a membrane
filter. The collected particles on the surface of the filter are
then counted with the help of a microscope at 100X
magnification the whole method is carried out under aseptic
conditions. However, it is a time consuming

Light Obscuration Method:


This method uses an electronic instrument that produces a
light beam of high intensity. The solution is allowed to pass
under this bright light. If the particle present in the solution
passes through, a shadow cast is produced due to the
obstruction of light by the particle. The particles are
measured and counted automatically by the device means of
the shadow castings.
Figure No 3. Shows coulter counter Apparatus

Table 13: shows particle size method of different volume


injectables by coulter counters method
Particle Size Method Small volume Large volume
injectables injectables
≥10m Microscope 3000parts/container 12parts/ml
count
≥25m Microscope 3000parts/container 2parts/ml particles
count

Significance of Particulate Matter Detection:


• The presence of foreign particles in intravenous
solutions may cause obstruction of small blood vessels
Figure 2: Shows light obscuration method
leading to severe consequences like emboli, infusion,
and infusion phelebitis.
Limits for Sub visible Particulate Matter in Inject able • The presence of particulate matter implies that the
Preparations as prescribed in I.P. product is of inferior quality.

Table 12: Shows particle size method in different volume c) Leakage Test :(8)
injectables Ampoules are subjected to leakage test because ampoules
Particle Method Small volumes Large volume are sealed by fusion. Therefore, there is a chance for a
size injectable injectables incomplete sealing or for microspores to exist, allowing the
≥10µ Light 6000parts/container 25parts/ml contents to leak or microorganisms and other contaminants
Obscuration
≥25µ Light 6000parts/container 3parts/ml
to enter the ampoules.
Obscuration
Method: This test is performed by immersing the ampoules
Coulter Counter Method :(7) in a vacuum chamber consisting of a dye such as 1%
This electronic method is used to detect the particles and methylene blue solution. A vacuum (negative pressure) of
also determine the particle size. The sample solution is about 27 inch Hg or more is created for about 15 to 30
added to an electrolyte solution. This solution is drawn minutes. This negative pressure causes the methylene blue
through a small orifice of the device. Positive and negative solution to enter the ampoules with defective sealing. The
electrodes are present one on either side of an orifice. As vacuum is released; ampoules are washed externally and
the particle passes through the orifice, it displaces its own observed for the presence of dye in the ampoules The
volume of electrolyte and at the same moment, an increase coloured solution because of the dye in the ampoules
in electrical resistance is observed between the two confirms the leakage and hence those ampoules are
electrodes. The resulting voltage pulses which are discarded. Detection of leakage is more effective when the
proportional to the particle size, are amplified and are ampoules are subjected to autoclaving in the presence of a
measured and counted. Particles below 0.2 m can also dye. This method has the advantage that, both detection of
detected by this method. leakage and sterilization can be done in a single operation.
The advantages of this test are: High accuracy of inspection,
High speed of processing

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Research J. Pharm. and Tech. 7(2): February 2014

d) Extractable volume: Where the nominal volume does CONCLUSION:


not exceed 5 ml, the containers comply with the Unless otherwise stated in s IPQC test we can minimise
Requirements of Method 1 and where the nominal volume cost, time, material, repetition of processes. We can also get
is greater than 5 ml, the containers comply with the total details and properties of different dosage forms. We
requirements of Method 2. Suspensions should be shaken can improve the quality of products and minimise the
before the contents are withdrawn; oily injections may be repetitive usage of instruments, so we must conduct this
warmed but should be cooled to 25º before carrying out the IPQC test. During the processing of any pharmaceutical
test. dosage forms, further investigation on IPQC test of
different dosage forms are going on to improve the quality
Method 1 Use 6 containers, 5 for the test and 1 for rinsing of product. All the tests are mentioned above are also
the syringe used. Inspect the 5 containers to be used in the carried out for finished doses form also. In case of IPQC
test visually and ensure that each contains approximately test all test are carried out with repetition within 15 /30 min
the same volume of the preparation. difference generally. Type of IPQC test and frequency is
determined by Q.A persons of the respective company. As a
Using a syringe with a capacity not exceeding twice the part of concurrent validation IPQC test are done.
volume to be measured and fitted with a suitable needle,
take up a small quantity of the liquid under examination REFERENCES:
from the container reserved for rinsing the syringe, and 1. Available at:www.yogipandya/ipqc-solid dosage forms: 2013.
discharge it from the syringe whilst the needle is pointing 2. Available at: http//Krishnakanth. B, In process Quality control
upwards so as to expel any air. Withdraw as much as test for Tablets R.S Bhat (2010), 2-9.
possible the contents of one of the containers reserved for 3. Leon Lachman, Herbert A. Liberman, Joseph L. Kanig: The
the test and transfer, without emptying the needle, to a dry Theory and practice of industrial pharmacy, Varghese publishing
house, 3rd ed. 296, 297, 298, 299, 300,301. 302, 392, 484, 485,
graduated cylinder of such capacity that the total combined 490, 492, 494, 529, 531, 673, 674, 675.
volume to be measured occupies not less than 40 per cent of 4. Loyd V. Alle Jr. Nicholas G. Popovich, Howard C. Ansel,
the nominal volume of the cylinder. Repeat the procedure Ansel’s Pharmaceutical dosage forms and drug delivery system,
until the contents of the 5 containers have been transferred Lippincott Williams and Wilkins, 8th ed.; 218,219,234,235,
and measure the volume. The average content of the 5 236.237,238,388,392,463,464.
5. Nikunj Vora, Vikas, In Process Quality Control A review,
containers is not less than the nominal volume and not more
International Journal of Industrial Pharmacy and Technology
than 115 per cent of the nominal volume. 1(4), 2012, 2000-2019.
6. Indian Pharmacopeia, Volume II; 659-660.
Method 2: Transfer the contents of not less than 3 7. Manohar A. Potdar, Pharmaceutical Quality Assurance,
containers separately to dry graduated cylinders such that 2006,Nnirali Prakashan , 6.7-6.8 .
the volume to be measured occupies not less than 40 per 8. British Pharmacopeia, Volume I; A 90,141.143.
9. United States of Pharmacopeia Volume I; 311,312,313,369.
cent of the nominal volume of the cylinder and measure the
volume transferred. The contents of each container are not
less than the nominal volume and not more than 110
percent of the nominal volume.

e) Sterility testing:(9) However, a satisfactory result only


indicates that no contaminating viable microorganisms have
been found in the sample examined in the conditions of the
test. If the number of micro-organisms present in a given
amount of the article under examination is large, the
probability of detecting them increases. Very low levels of
contamination cannot be detected on the basis of random
sampling of a lot.

The test must be carried out under aseptic conditions


designed to avoid accidental contamination of the product
during testing. For achieving these conditions, a grade A
laminar airflow cabinet or an isolator is recommended.

The test environment has to be adapted to the way in which


the tests are performed. Precautions taken for this purpose
should not adversely affect any micro-organisms, which are
to be revealed in the tests.

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