quality control

1. INPROCESS QUALITY CONTROL
DR .PRACHI VERMA

2. What are IPQC tests?
• These are checks that are carried out before the
manufacturing process is completed.
• The function of in-process controls is monitoring
and if necessary adaption of the manufacturing
process in order to comply with the specifications.
• In-process materials should be tested for identity,
strength, quality and purity as appropriate and
approved or rejected by the quality control unit
during the production process.

3. IPQC Tests
• These are the tests performed between QA and
QC and provides for the authorization of
approved raw materials for manufacturing based
on actual laboratory testing generally called as
IPQC’s such as :
• Physical,
• Chemical,
• Microbiologic and
• Biologic tests.

4. In process Quality Control, IPQC tests are mostly performed
within the production area.
They should not carry any risk for the quality of product.
In process testing enables easier identification of problems.
It some time identifies a defective product batch that can be
corrected by rework, whereas once that batch has been
completed, this may not be possible.
Failure to meet In process control specification indicates
either that procedure were not followed or some factor(S)
out of control.

5. Importance of IPQC
• To minimize human errors.
• Provides accurate, specific and definite description of
the procedure to be employed.
• It is a planned system to identify materials, equipments
process and operations.
• To detect the errors if and when it does occurs.
• To enforce the flow of manufacturing and packing
operations according to established routes and practice.

6. Types of IPQC tests
• A) Physical &Chemical-Identity tests
Quality tests
Purity tests
Potency tests
• B)Biological & Microbiological tests

7. • IDENTITY TESTS : These tests are qualitative
chemical methods used to confirm the actual presence of
compound. For example: Color formation, precipitation
• QUALITY TESTS: These tests are the physical
methods used to measure accurately the characteristic
properties of drug . For example: Absorbance, refractive
index
•

8. • PURITY TESTS: Purity tests are designed to
estimate the levels of all known and significant
impurities and contaminants in the drug substance
under evaluation. For example: Tests for clarity of
solution, acidity/ alkalinity
• POTENCY TESTS: Potency tests are assays that
estimate the quantity of an active ingredient in drug.

9. Various apparatus used
• Disintegration apparatus
• Dissolution apparatus
• Analytical balance Muffle furnace
• Friability testing apparatus
• Bulk density apparatus
• Tablet hardness tester
• Infra red moisture content measuring apparatus
• U.V Spectroscopy
• Abbe Refractometer
• T.L.C. kit
• Karl fisher

10. Tests for evaluation of tablets
Official Tests:
• 1. Weight variation
• 2. Disintegration
• 3. Dissolution
• 4. Drug content
Non-Official Tests:
• 1. Hardness
• 2.friability

11. • 1. General Appearance: The general appearance of a tablet, its
identity and general elegance is essential for consumer acceptance,
for control of lot-to-lot uniformity and tablet-to-tablet uniformity.
The control of general appearance involves the measurement of size,
shape, color, presence or absence of odor, taste etc.
• 2. Size & Shape: It can be dimensionally described & controlled.
The thickness of a tablet is only variables. Tablet thickness can be
measured by micrometer or by other device.
• Tablet thickness should be controlled within a ± 5 % variation of
standard value.

12. • 3.Unique identification marking: These marking utilize some form
of embossing, engraving or printing. These markings include
company name or symbol, product code, product name etc.
• 4. Organoleptic properties: Color distribution must be uniform with
no mottling.
• For visual color comparison compare the color of sample against
standard color.
• 5. Hardness : Tablet requires a certain amount of strength or
hardness and resistance to friability to withstand mechanical shocks
of handling in manufacture, packaging and shipping.
• Hardness generally measures the tablet crushing strength.

13. Why do we measure hardness?
• To determine the need for pressure adjustments on the tableting machine.
• Hardness can affect the disintegration.
•
• So if the tablet is too hard, it may not disintegrate in the required period of
time. And if the tablet is too soft, it will not withstand the handling during
subsequent processing such as coating or packaging.
• In general, if the tablet hardness is too high, we first check its
disintegration before rejecting the batch.
• If the disintegration is within limit, we accept the batch.
• If Hardness is high + disintegration is within a time accept the batch.

14. Types of testers
Five types of testers are used.
• Monsanto hardness tester or stokes hardness
tester
• Strong cobb tester
• Pfizer tester- min 4kg
• Erweka tester
• Schleuniger or heberlein tester

15. Friability tests
• It is the tendency of tablets to powder, chip, or fragment
and this can affect the elegance appearance, consumer
acceptance of the tablet, and also add to tablet’s weight
variation or content uniformity problems.
• Friability is a property that is related to the hardness of
the tablet.

16. Friability test
• Roche friabilator
• speed-25 rpm
• Allowable range : 0.5-1 %

17. Weight variation(uniformity of weight
of tablets)
• Take 20 tablets, Weigh individually
• Determine the average weight of 20 tablets=X
• Weight variation =X- individual weight.
• % variation=weight variation/X*100

18. Disintegration tests
• For most tablets , the first important step towards
formation of solution is breakdown of the tablet into
smaller particles or granules , this process is known as
disintegration .
• -Disintegration apparatus : 6 glass tubes- 3inch length
10 mesh screen at the bottom.
• Temperature : 37±2˚C
• Speed – 28-32 rpm .

19. Dissolution
• Dissolution is performed to check the percentage release
from the dosage forms. i.e. Tablet.
• Tablet breaks down into small particles which offers a
greater surface area to the dissolving media.
• Disintegration test does not give assurance that particles
will release drug in solution at an appropriate rate, that’s
why dissolution tests & its specifications developed for
all tablet products

20. Content uniformity test
• The content uniformity test is used to ensure
that every tablet contains the amount of drug
substance intended with little variation among
tablets within a batch.
• 30 Tablets are kept aside . 10 tablets are assayed
. 9 Tablets should have %limit of 85-115%
• If more than 1 Tablet has 85-115% then, 20
Tablets are assayed Not more than 1 Tablet
should have 75-125%.

21. IPQC problems for tablets
Problem Remedy
• Capping
• Lamination
• Pre compression
• Slowing tableting rate
• Reducing final compression
pressure.
• Regranulating materials
• Altering the pressure
adjustment
• Reducing the machine speed
• Proper arrangement of dies
and punches

22. IPQC problems for tablets continued
Problem Remedy
• Picking
• Sticking
• Chipping
• Reduction in liquid application
rate
• Increasing dry air temperature
• Increasing dry air volume
• Reduction in liquid application
rate
• Increasing dry air temperature
&volume
• Replace worn-out punches and
dies
• Add polishing agents

23. Problem Remedy
• Mottling
• Hardness variation
• Weight variation
• Change the solvent system
Change binder system
• Reduce the drying temperature.
• Grind to a small particle size
• Proper adjustment between the
upper and lower punches at the
moment of compression
• Maintaining proper flow of
granules
• Proper mixing of lubricants and
ingredients

24. Mottling chipping

25. IPQC tests for suspensions &
Emulsions

26. • Pharmaceutical suspensions may be defined as
coarse dispersions in which insoluble solids are
suspended in a liquid medium.
• The liquid medium is usually water or a water
based vehicle.
• The insoluble solid may have size range from
0.1 to 100 μm.

27. Classification
1)Based on proportion of solid particles
a)Dilute suspension
b)concentrated suspensions
2)Based on electrokinetic properties of solid particles
a)flocculated suspensions
b)deflocculated suspensions
3)Based on general classes
a)oral suspensions
b)externally applied suspensions
c)Parenteral suspensions

28. IPQC Tests For Suspensions
Appearance- The appearance in a graduated
glass cylinder or transparent glass container is
noted.
It is checked for
 Uniformity of color and appearance of the sediment.
 Any breaks or air pockets in the sediment.
 Any coagulated material adhering to the inside wall of
the container.

29. • Photo microscopic examination.
• The microscope can be used to estimate and detect
changes in particle size distribution and crystal shape.
• Its usefulness can be enhanced by attaching a polaroid
camera to the microscope to permit rapid processing of
photomicrographs.
• This can be used to distinguish between flocculated and
non-flocculated particles and to determine changes in
the physical properties.

30. • Color, odour and taste:
• These characteristics are especially important in orally
administered suspensions.
• Variation in color often indicates poor distribution
and/or differences in particle size.
• Variation in taste, especially of active constituents can
often be attributed to changes in particle size, crystal
habit and subsequent particle dissolution.
• Changes in color, odour and taste can also indicate
chemical instability.

31. Viscosity & Particle size
• .DETERMINATION OF VISCOSITY : The
viscometers used are cone and plate viscometers ,
Brookfield viscometer.
• 2.DETERMINATION OF PARTICLE SIZE : It is
performed by optical microscopy and Coulter
counter apparatus .
• 3. DETERMINATION OF PHASE
SEPERATION(for emulsions): Phase separation
may be observed visually Or by subjecting the
emulsions to various stress conditions like boiling,
temperature variations .

32. Viscosity
Stability of a suspension is solely dependant on
the sedimentation rate of dispersed phase which
is dependant on the viscosity of the dispersion
medium.
The viscosity of the dispersion medium is
measured before mixing with dispersed phase
and also viscosity after mixing is determined
using Brook field viscometer.
The calculated values are compared with standard
values and if any difference is found necessary
corrective action is taken to get optimized
viscosity.

33. Content Uniformity
• For proper dosing of the dosage form it is necessary
that the active ingredient is uniformly distributed
throughout the dosage form.
• So samples are withdrawn from the dispersed phase
after micronization and after mixing with dispersion
medium,assayed to find out degree of homogeneity.
• If any discrepancy is found out it is suitably corrected by
monitoring the mixing step to ensure a reliable dosage
formulation.

34. Content Uniformity
• 10 capsules are taken and subjected to assay .
• 9 of 10 capsules should be in the range of ±15%(
85-115%) and 10th Capsule in the range of 75-
125 %.
• If 2 Capsules are beyond ± 15% range . Then, 20
capsule are assayed.
• All capsules should be in the range of ±
25%(75%-125%.)

35. Particle size distribution
• Optimum size of drug particle in the dispersed
phase plays a vital role in stability of final
suspension.
• So this test is carried out to microscopically
analyse and find out particle size range of drug
then it is compared with optimum particle size
required.
• If any difference is found,stricter monitoring
of micronization step is ensured.

36. Particle size measurement
Particle size can be measured by
a)optical microscopy
b)sedimentation method
c)conductivity method(coulter counter method)

37. Electrical conductivity
• )ELECTRICAL CONDUCTIVITY; Electrical
conductivity measurement is a tool for the
evaluation stability shortly after preparation.
APPARATUS: Nuro amperometer

38. IPQC problem for emulsions
Problem Remedy
• Creaming
• Cracking
• Reduce globule size
• Reduce the difference in
density between internal and
external phase
• Increasing the viscosity
• Adding emulsifying agent
• Preventing decomposition or
precipitation of emulsifying
agent

39. Problem Remedy
• Flocculation
• Coalescence
• Phase inversion
(Change of emulsion type from
o/w to w/o or vice versa)
• Use of emulgent
• increase emulsifier
• Keeping the concentration of
internal phase between 30-60
• Storing emulsion in cool place
• Using proper emulgent in
adequate concentrations.

40. IPQC tests for Parenterals

41. What are parenterals?
• A parenteral dosage form can be defined as a sterile drug
product which is presented in the form of solution,
suspension, emulsion, or reconstituted lyophilized
powder, suitable for administration by injection through
skin or mucous membrane.

42. IPQC tests for finished products
There are mainly five Quality control test for the
parenterals are performed.
1) LEAKER TEST
2) CLARITY TEST
3) PYROGEN TEST
4) STERILITY TEST
5) CONTENT UNIFORMITY TEST

43. Leaks in parenterals: Why are they
important?
• Leaks can be due to incomplete and defective Sealing, Rubber-
stoppering and Crimping, Cracks and Pinholes in packaging.
• Leaks can cause loss of product (evaporation, seeping of liquid,…).
• Leaks and cracks can cause loss of headspace gas leading to
product decay.
• Leaks can cause microbial/physicochemical contamination of the
product.
• Leaks can pose hazards to those handling the product (product
contact, breakage of packaging,…).
• Particularly in case of parenteral preparations, leaks can cause
loss of sterility.
• Leaks due to cracks, pinholes, incomplete seals,… are all critical
defects which can lead to complaints, recalls and damages to the
reputation and finances of a company.

44. Leaker tests
Leaker test for ampoules is intended to detect incompletely sealed
ampoules so that they can be discarded in order to maintain sterile
condition of the medicines.
Tip seals are more likely to be incompletely closed than pull seals.
Open capillaries or cracks at the point of seal result in LEAKERS.
• Presence of capillary pores or tiny cracks can cause microbes or
other dangerous contaminants to enter the ampoules or package or
may lead to the leakage of contents to outside. This may cause
contamination of the sterile contents and also spoilage of appearance
of the package.
• Changes in temperature during storage can cause expansion and
contraction of the ampoule or package and thereby causing
interchange of its contents if an opening exists.

45. • Leaker tests are 4 types :
• a) visual inspection
• b) bubble test
• c) dye test
• d) vacuum ionization test

46. Visual Inspection
• Visual inspection is the easiest leaker test method to
perform.
• The method is used for the evaluation of large volume
parenterals.
• To increase the sensitivity of the method the visual
inspection of the sample container may be coupled with
the application of vacuum to make leakage more readily
observable.
• Advantage:
• This method is simple and inexpensive.
• Disadvantage: less sensitive
• Sensitivity is increased by applying pressure/vacuum

47. Bubble test
• The test package is submerged in liquids.
• A differential pressure is applied on the container.
• The container is observed for bubbles.
• Sometimes, surfactant added liquid is used for
immersion of test package.
• Any leakage is evident after the application of
differential pressure as the generation of foaming in
immersion liquid.
• The method is simple and inexpensive.
• The location of the leaks can be observed in this
method.

48. Dye test
• The leaker test is performed by immersing the ampoules
in a dye solution, such as 1% Methylene blue, and
applying at least 25 inches of vaccum for a minimum of
15 mins.
• Detection of leaker is prominent when ampoules are
immersed in a bath of dye during autoclaving as this has
advantage of accomplishing both leaker detection and
sterilization in one operation.

49. • The dye test is widely accepted in industry and is
approved in drug use.
• The test is inexpensive and is requires no
special equipment required for visual dye
detection.
• However, the test is qualitative, destructive and
slow.
• The test is used for ampoules.

50. Vacuum Ionization test
• Vacuum ionization test is useful for testing leakage
in the vials or bottles sealed under vacuum.
• This test is used for testing of the lyophilized
products.
• High voltage, high frequency field is applied to vials
which to cause residual gas, if present to glow.
• Glow intensity is the function of headspace vacuum
level.
• The blue glow is the indicative of vacuum while the
purple glow indicative of no vacuum.

51. CLARITY TEST (PARTICLE
CONTAINMENT TEST)
• Definition: Clarity is a relative term, its mean a clear
solution having a high polish conveys to the observer
that the product is of exceptional quality and purity.
• Clarity test is carried out to check the particulate matter
in the sample.
• It is practically impossible that every unit of lot is
perfectly free from visible particulate matter ,that is,
from particles that are 30 to 40 micrometer and large in
size.

52. TYPES OF TEST:
• Particulate matter can be detected in parenteral product by two
methods, 1. Test for visible particles 2. Test for sub visible particles
• Test for Visible particles
• Visual inspection by naked eye: The test is intended to provide a
simple procedure for the visual assessment of the quality of
parenteral solutions as regards visible particles.
• In visual inspection, each injectable is inspected visually against
white and black backgrounds.
• The white background aids in detection of dark colored particles.
• The light or reflective particles will appear against the black
background.

53. • Test for Sub visible particle
• This test is performed to check particulate
contamination of injections and infusions consists of
extraneous, mobile un-dissolved particles, other than gas
bubbles, unintentionally present in the solutions.
• This is further divided into two methods:
• 1. Method 1 ((Light Obscuration Particle Count Test)
• 2. Method 2 (Microscopic Particle Count Test)

54.  Test for packing containers
• For glass containers
• Water attack test
• Powder glass test
For plastic containers
• Leakage test,
• collapsibility test,
• transparency test,
• water vapor permeability test.
 Inspecting for label check
 Uniformity of contents

55. Volume
• After filling the containers they are checked for
the correct volume filling.
• Check for fill volume is by visual inspection.
• This is important for small volume parenterals
where the volume is less .
• By keeping the container against a bright
background we can check for the fill volume.
• After conforming for the correct fill volume then
they are lacked and labelled and sent to the ware
house.

56. PH
• Checking the bulk solution, before filling for drug
content, pH, color, clarity and completeness of
solution
• The pH of a formulation must be considered from
following standpoint: 1) the effect on the body when
the solution is administered 2) the effect on stability
of the product 3) the effect on container-closure
system.
• pH measurement- pH is measured by using a pH
meter . pH meter is initially calibrated with
respective buffer capsule then the pH of the
preparation is measured.

57. Content uniformity
• The weight of 10 individual sterile units is noted and the
content is removed from them and empty individual
sterile unit is weighed intern.
• Then net weight is calculated by subtracting empty
sterile unit weight form gross weight.
• The content of active ingredient in each sterile unit is
calculated by performing the assay according to the
individual monographs.
• The content in 10 sterile units is calculated by
performing the assay. The dose uniformity is met if the
amount of active ingredient is within the range of 85-
115.0% of label claim as determine by the content
uniformity method or weight variation method.

58. Documentation
• Document is a paper that provides information
especially of an official or legal nature, written
report or record.
• Documentation is a method of preparing a
written material, which describes the process in
terms of specifications, instructions etc.
Documentation and records are essential for
obtaining accreditation, certification of ISOs and
approvals by Federal Bodies.

59. • Importance Of Documentation of Records
• Provide working details necessary for manufacturing,
packaging and QC.
• Reduce the risk of mistakes inherent in verbal
communication
• Help in tracing the deviation from the expected yields.
• Help in decreasing the batch to batch variations so that
the quality of product kept within the limit of
acceptability.
• Considered as history of batch operations.
• Self inspection of procedures in order to achieve better
control of operations and improvement of product
design

60. • Important areas of documentation
• Particulars with respect to their storage, stability &
handling.
• Instructions of all manufacturing & packaging
procedures, preferably batch wise are documented
so that no further calculations are required at the
work of floor level.
• Instructions for non product related operations
such as cleaning & disinfections, maintenance of
equipment, monitoring of working conditions use of
specific conditions.
• Records such as batch manufacturing record, batch

61. • batch packaging record, test record for no
product related operations as indicate.
• Procedures for testing for e.g. physical,
chemical, microbiological. Etc. to be followed.
• Specifications of starting material packaging
materials and product for the compliance by the
quality control department.

62. • Document, Document, Document!!!
• According to FDA: “If it is not documented . . . it
did not happen!” or, it’s a rumor!”

63. IPQC problems for Parenterals
Problem Remedy
• Leakage of ampoule
• Perforation in filter leading to
defective filtration
• Discard the ampoules
• Use new ampoules with
proper sealing
• Changing the filter

64. Problem Remedy
• presence of Foreign particles
• Fibre
• PH
• Leaching
• Membrane filtration
• Optical and visual inspection
• Use of buffers
• Internal coating of glass
container

65. THANK YOU