Each raw
material is stored in a separate container having a label attached on it,
indicating
Ø Material name & Internal
Code
Ø Date
Ø QC and QA clearance
Ø Batch no. given by supplier
Ø Expiry date or date beyond
retesting is necessary.
Temperature
and humidity are controlled within 23-27 degree and 45-55%
respectively.
Dispensing
Dispensing
of raw materials is done in a separate area within the raw material store. Raw
material store supredent, Quality Assurance Inspector, Production pharmacist
and Technician for weighing purpose must be present at the time of dispensing.
Each raw material is weighed according to batch requirement and dispensed in a
separate container / package. Dispensing conditions are mostly the same as the
raw material store.
Line
Clearance 1
Quality
Assurance Inspector gives the line clearance
and
dispensed materials are carried form the raw material store to the Sterile
Production Area.
Line
Clearance 2
Quality
assurance inspector check the conditions of the mixing as required and then
gives the clearance for the mixing operation.
Mixing &
Blending
Mixing
is done at 25degree temperature and 35-40 % humidity is maintained during the
mixing process. Specific equipment is used depending upon the batch size.
In-Process
Quality Control of Mixed Ingredients
After the
mixing, sample is sent to the QC lab to check the homogeneity of the mixing and
other different tests needed to be performed to check the quality of the sample
according to the USP mentioned procedures.
Ø Content Uniformity / Blend
Uniformity
Ø Particle size
Preparation
of Water for Injection
Water
required as a solvent (aqeous phase) is treated
by
several methods that provide the characteristics mentioned in the table. These
characteristics must be fulfilled in order to use this water as an excipient
for pharmaceutical purpose.
Removal
of chlorine done by high dosage of UV or filtration through activated Carbon
Media.
Ion Removal
Removal
of ions done by membrane process (reverse osmosis & Nano filtration
membranes), exchange process or distillation process. Ions, particulate matter,
organic compounds and even living organisms are removed in this process.
Bacterial
Control
Bacterial
control is usually applied during the during the processing, storage and even
distribution. Equipments used are UV lights, ozone generation systems and
heating systems for the non-thermal, Chemical and Thermal removal of bacteria
respectively.
Removal of
Specific Impurities
Depending
upon the source of Water different types of impurities can be present in water
that must be removed by proper process e.g., iron, manganese, hydrogen
sulphide, hardness ions, particulate matter, and high conductivity.
Storage
Stored
in special tanks containing ultraviolet lamps. It can be stored for a period up
to a month. Care and hygiene are maintained during the storage and bacterial
control is still incorporated in this stage.
Quality
Control Tests for Water for Injection
·
Sterility
Test
·
Bacterial
Endotoxin Test
·
Pyrogen
Test
Addition of
Solvent in the Rest of Mixed Raw Materials
This
is done under Aseptic Conditions at the temperature of 25 degrees and humidity
maintained at 35 percent.
Specific
equipment for liquid solid mixing is used depending upon the batch size
In-process
Quality Control Test for Parenteral Suspensions before Filling
Appearance
A
graduated transparent glass cylinder is used to check the appearance. The
sediment’s Colour and uniformity is checked during this investigation. Presence
of air pockets or air breaks is noted. Any material coagulated and sticking to
the container wall is checked too.
Density
One
of main parameters in the in-process quality control of this formulation is
Density and Specific Gravity. Entrapped air in the suspension formulation shows
itself in the form of decrease in the density. For the measurements of
densities, the suspension formulation must be uniform throughout the container.
Hydrometers are used to measure the density.
Viscosity
Viscosity
is measured using an Ostwald viscometer. TACA injectable suspension has a
viscosity range of 2-12cps.
Particle Size
Particle
size is checked by optical microscopic method. TACA of 4% (w/v) has a mean
volume diameter of 3-10μm.
pH Value
pH
measured using a pH meter. Triamcinolone acetonide injectable suspension should
have a pH value between 5 and 7.5.
Pourability
Suspension
is checked for the pourability in phases to ensure the proper pourability of
the formulation to avoid any problems or defects during the filling procedure
or during the handling by the patient.
Zeta
Potential
Zeta
Potential is measured using a zeta sizer and acceptable range of zeta potential
is -20 to +20 mv.
Treatment
of Ampoules
Ampoules made of
type 1 glass provided by the supplier are used for the filling purposes and
they require specific treatment before filling preparation.
Ø Colour: Colourless transparent
ampoules
Ø Dimensions: 10.75 x 70 x
0.50mm
Line
Clearance 3
Quality
Assurance inspector also inspects the process of Ampoules treatment and
specific conditions e.g. the speed of the washing machine and even the number
of persons required in a particular area are checked by QAI and ultimately if
all the requirements are fulfilled then Process is continued.
Washing
Automatic
ampoule washer is used for cleaning the containers. Ampoules are washed at a speed
of 250 ampoules per minute by an automatic machine. There are some specific
gripping techniques used in this machine that hold the ampoules and then invert
them in order for the cleaning process. Pressurized as well as positive
pressure nozzles are used to do the washing of the ampoules. Cleaned ampoules are
then collected in a tray after they are washed through a feeding path in a
straight position.
There
are 6 washing stations in the machine and 3 needles for the air removal and 3
needles for the water removal are present in each station. Cleaning agents are
hold and pumped by three pumps with three 25 litre tanks are also present in
the machine. Gripper cassettes are also present in each station that holds the
ampoules and turn them in the neck down position. Feeding and exiting the
machine is done totally automatically
Stainless steel 316 is used to manufacture all the
internal surfaces that helps in preventing the corrosion. FDA approved
materials are required to make the other parts that are not made with the
Stainless steel 316. CGMP standards are used to make the fabrication and
materials and their quality is guaranteed by them.(Lee, Shin,
Kim, Eun, & Surgery, 2013)
Sterilization
of Ampoules
Sterilization
of ampoules is done for 13 minutes at 115 degrees.
After
that they are cooled at -30 to -40 degrees for some time and then exposed to
the conditions for primary freeze drying for about 6 hours.
Storage
Ampoules
then are stored under aseptic conditions in airtight area and controlled
temperature and humidity.
Filling &
Sealing of Ampoules
Line Clearance 4
Here
the aseptic conditions are checked and then allowed to start the filling
process and a small sample is tested after filling for the required volume ,
weight variation, particle contamination and leaker test and oxygen content
test are also performed to judge the accuracy of the filling and sealing
procedure, If everything is under-controlled then the line clearance is given
for the batch filling and sealing operation.
Performance
Qualification of Filling Machine
Weight
Variation test: 10 containers must be within 85-115% of target content or NMT 1
out of 30 containers outside of the 85-115% and no unit must be outside the
75-125%.
Filling
Volume Accuracy: It
should be within plus minus 1 % of adjusted volume.
Particle
Contamination
This
test is performed according to the USP test for particulate matter.
Leaker Test
Leak
is detected by submerging the ampoule in deeply coloured dye solution (0.5-1%
methylene blue). Capillaries of less than 15 um cannot be detected by this
method.
Oxygen Content
If
the filler produces a nitrogen purge, the head space gas should be analyzed for
oxygen content.
Operation
Ampoules
are filled using an automatically filling and sealing machine. Ampoules that
are already sterilized are loaded on a tray and then tray is loaded into the
slant hopper unit directly. Ampules are delivered to the eccentric ampoule rack
that continuously moves in single or two or four or six, one by one.(Kupiec,
2004)
Quality
Control Tests of the Filled Ampoules
Following Tests
are performed on the filled ampoules according to USP Specifications (Akers, Larrimore, &
Guazzo, 2002; Deshmukh, Salunkhe, Deshmukh, & Shete, 2015)
Ø Deliverable Volume
Ø Leaker test
Ø Clarity Test
Ø Pyrogen Test
Ø Sterility Test
Ø Content Uniformity Test
Labelling of Ampoules
Ampoule
labelling machine is that prints the label horizontally on the ampoules. This
specific label contains all the required information according to the
guidelines for labeling of parenterals (Deshmukh
et al., 2015).
Packaging of
the Ampoules
Within
the raw material store packaging store section is separate area where the
primary, secondary, and tertiary materials for packing are stored. They are
dispensed when given the line clearance by the Quality Assurance inspector and
carried to the packaging section where each ampoule is packaged in single unit
container and entire batch is packages in tertiary containers (Akers et al., 2002).
Finished
Product Tests
Appearance
of Phases, Colour & Crystal Determination
A
graduated transparent glass cylinder is used to check the appearance. The
sediment’s Colour and uniformity is checked during this investigation. Presence
of air pockets or any breaks is noted. Any material coagulated and sticking to
the container wall is checked too.
Sedimentation
Volume
TACA
Injectable suspension must have a degree of flocculation greater than 5.
Measurement
of Zeta Potential
Zeta
Potential Measurement is done in the same way as described above in the IPQC.
Re-Dispersibility
Upon
settling the particles of the formulation, they should be easily redispersible.
Rheological
Measurement
Preparation
must have good flow properties for the good syringablity and pourability
properties.
pH Value
Triamcinolone
acetonide injectable suspension should have a pH value between 5 and 7.5.
Universal
Tests for Triamcinolone Acetonide Injectable Suspension (USP)
Description
Triamcinolone Acetonide occurs as White to cream
colored particles suspended in the aqueous phase.
Identification
of Triamcinolone Acetonide Suspension
As per USP identification test is performed to
confirm the presence of active ingredient.
Assay
Assay
is performed as per USP Monograph specifications.
Triamcinolone acetonide injectable
suspension contains not less than 90.0 percent and not more than 115.0 percent
of the labeled amount of C24H31FO6.
Sterility
Test
Sterility test is performed according to USP by the
membrane filtration method and no growth of microorganisms should be observed
in the product (Akers
et al., 2002).
Bacterial
Endotoxin Test
TACA Injectable suspension contains not more than 4.4
USP Endotoxin Units per mg of triamcinolone acetonide by testing according to
the requirements for the bacterial endotoxin test (Williams, 2007).
Foreign
& Particulate matter Test
The limits for the foreign and particulate matter
test for this formulation are the following: all the tested units must not
contain more than 6000 average number of particles equal to or greater than 10
micrometer and should not be more than 600 particles per container equal to
greater than 25 micrometer (Akers
et al., 2002).
Container
Contents
Upon individual examination of the containers the
volume of each container should not be less than nominal value or in case of
the containers having a nominal volume of 2 ml or less, should not be less than
the sum of the nominal volumes of the containers taken together (Deshmukh et al., 2015).
Labeling
FDA is responsible for ensuring the compliance with
the current regulation to label a product. The date
beyond use or expiry date must be present on both the container and package
label. Package label must also contain the storage conditions that are
recommended if the container is packaged. All other requirements as well as
storage conditions must be indicated on the container label if the container is
not packaged individually. National and international requirements must be
fulfilled during the labelling of the Formulation (Deshmukh et al., 2015).
Specific
Test for Parenteral Suspensions (USP)
Uniformity
of Dosage Unit
Content
Uniformity test is applied on the 10 containers first. If the criteria is not
met then 20 more containers are selected and overall content uniformity is
checked in 30 containers.
Acceptance value is calculated by
the: Av= ⋮M-x⋮+ Ks where x-bar
is mean of assay values and K is constant and s is standard deviation while M
is the reference value.
Criteria
The acceptance value should be less than or equal to
15. All the assay values must be in the range in between the upper and lower
limits.
Antimicrobial
Preservatives
Antimicrobial preservative should not be more than 20
% of the labelled amount.
Storage
in Warehouse
Finished products then are placed in the warehouse
from where they will be shipped to the distributors.
Conditions
for the storage in the warehouse are the
Ø Temperature:
23-27 degrees
Ø Humidity:
35-45 %
Conclusion
Various in- process quality Control parameters are
there to be controlled during the manufacturing of the Triamcinolone Acetonide
that effect the quality of the final suspension formed. Quality assurance is
the main factor involved that must be able to optimize the production by
controlling the process and ensures the best quality of each process and the
intermediate after each step. Industrial requirements including the area,
personal flow as well as material flow must be fulfilled in order to maximize the
output by using the quality raw materials that must be tested for their
properties after receiving from the supplier