Plant:- It is a place where the 3 M’s that are Man,
Material and Money are brought together for the manufacturing of products.
Pilot Plant:- It is the part of the pharmaceutical
industry where a lab scale formula is transformed into a viable product by
development of liable practical procedure of manufacturing.
Scale-up:- The art for designing of prototype using
the data obtained from the pilot plant model.
SIGNIFICANCE
Permits close examination of formulae to determine
its ability to withstand batch scale and process modification. Review of Equipment
- most compatible with the formulation & most economical, simple and
reliable in producing product. Raw materials - consistently meet the
specifications required to produce the product can be determined. Production
rate adjustment after considering marketing requirements. Give rough idea
about physical space required and of related functions. Appropriate records
and reports are issued to support good manufacturing practices. Procedure
can be developed and validated.
GENERAL CONSIDERATIONS
1. Reporting Responsibility:-
These are of two
types
a)
The
formulator who developed the product can take into the production and can provide support even after
transition into production has been completed
b)
R &
D group with separate staffing
2. Personnel Requirement:-
Scientists with experience in
pilot plant operations as well as in actual production area are the most
preferable. As they have to understand the intent of the formulator as well as
understand the perspective of the production personnel. Engineering principles
and Knowledge of computers & electronics
3.
Space Requirements:-
Four types
A.
Administration and information processing
Adequate office
and desk space should be provided for
both scientist and technicians. The space should be adjacent to the
working area and adequate Computers.
B.
Physical Testing Area:-
This area should provide permanent
bench top space for routinely used physical - testing equipment.
C.
Standard Pilot-plant Equipment Floor
Space :-
Discreet pilot plant space, where
the equipment needed for manufacturing all types of dosage form is located. Intermediate
– sized and full scale production equipment is essential in evaluating the
effects of scale-up of research formulations and processes. Equipments used
should be made portable where ever possible. So that after use it can be stored
in the small store room. Space for cleaning of the equipment should be also
provided.
D.
Storage Area:-
It should have two areas,
Approved area and Unapproved area
for active ingredient as well as excipient.
Different areas should provided for
the storage of the in-process materials, finished bulk products from the
pilot-plant & materials from the experimental scale-up batches made in the
production. Storage area for the packaging material should also be provided.
4 Review of the formula
A thorough review of the each aspect of
formulation is important. The purpose of each ingredient and it’s contribution
to the final product manufactured on the small-scale laboratory equipment
should be understood. Then the effect of scale-up using equipment that may
subject the product to stresses of different types and degrees can more readily
be predicted or recognized.
5. Raw materials
One purpose/responsibility of the
pilot-plant is the approval & validation of the active ingredient &
excipients raw materials. Raw materials used in the small scale production
cannot necessarily be the representative for the large scale production. Ingredients
may change in particle size, shape or morphology which results in differences
in bulk density, static charges, rate of solubility, flow properties, color,
etc.
6. Equipment:-
The most economical, simplest &
efficient equipment which are capable of producing product within the proposed
specifications are used. The size of the equipment should be such that the
experimental trials run should be relevant to the production sized batches. If too small the process developed will not
scale up. If too big then the wastage of the expensive active ingredients. Ease
of cleaning and Time of cleaning
7. Production
Rates
`The immediate as well as
the future market trends / requirements are considered while determining the
production rates.
8 Process Evaluation
The knowledge of the effects of
various process parameters on in-process and finished product quality is the
basis for process optimization and validation. The purpose of process
validation is to confirm that the selected manufacturing procedure assure the
quality of the product at various critical stages in the process and in finished form.
9. Master Manufacturing Procedures
The three
important aspects
The weight sheet should clearly
identify the chemicals required in a batch. To prevent confusion the names and
identifying numbers for the ingredients should be used on batch records. The
process directions should be precise and explicit. A manufacturing procedure
should be written by the actual operator. Various specifications like addition
rates, mixing time, mixing speed, heating, and cooling rates, temperature,
storing of the finished product samples should be mentioned in the batch record
directions. During the scale-up of a new product, the analytic test methods
developed in research must be transferred to the quality assurance department. Early
in the transfer process, the quality assurance staff should review the process
to make sure that the proper analytic instrumentation is available and that
personnel are trained to perform the tests.
10. Product Stability And Uniformity
The primary objective of the pilot
plant is the physical as well as chemical stability of the products. Hence each
pilot batch representing the final formulation and manufacturing procedure
should be studied for stability.Stability studies should be carried out in
finished packages as well.
GMP CONSIDERATION
¬ Equipment
qualification
¬ Process
validation
¬ Regularly
process review & revalidation
¬ Relevant
written standard operating procedures
¬ The
use of competent technically qualified personnel
¬ Adequate
provision for training of personnel
¬ A
well-defined technology transfer system
¬ Validated
cleaning procedures
¬ An
orderly arrangement of equipment so as to ease material flow & prevent
cross-contamination
¬ ADVANTAGES
Members of the production and
quality control divisions can readily observe scale up runs. Supplies of Excipient
& drugs, cleared by the quality control division, can be drawn from the
more spacious areas provided to the production division. Access to engineering
department personnel is provided for equipment installation, maintenance and
repair.
¬ DISADVANTAGES
The frequency of direct
interaction of the formulator with the production personnel in the
manufacturing area will be reduced. Any problem
in manufacturing will be directed towards it’s own pilot-plant
personnel.
PRODUCT CONSIDERATIONS
v SOLID DOSAGE FORM
Material Handling
Laboratory Scale
Deliver accurate amount to the
destination
Large Scale
Lifting drums
More Sophisticated Methods
-Vacuum Loading System
-Metering Pumps
Prevent Cross Contamination by
Validation Cleaning Procedures.
Dry Blending
Powders should be used for encapsulation or to be granulated prior to
tabletting must be well blend to ensure good drug distribution. Inadequate
blending could result in drug content uniformity variation, especially when the
tablet or capsule is small & the drug concentration is relatively low. Ingredients
should be lumps free, otherwise it could cause flow problems.
3. Granulations
Reasons :-
To improve the flow
properties. To increase the apparent
density of the powder. To change the particle size distribution so that
the binding properties on compaction can
be improved.
Ø
Types
:-
a) Wet Granulation
b) Dry Granulation
c) Direct Compression Method
A small amount potent active ingredient can be
dispersed most effectively in a carrier
granulation, when the drug is dissolved in granulating solution and added
during the granulating process.
Ø
Wet
granulation has been carried out by using,
- Sigma Blades., Heavy-duty planetary
mixture,Tumble Blenders, High Speed Chopper Blades used in mixing of light
powders.
Ø
Multifunctional Processors,dry blending, wet
granulation, drying, sizing & lubricating.
Ø
Effect of Binding Agent.
Drying
Ø
Hot Air
Oven
* air temperature
* rate of air flow
* depth of granulation on the
trays
Ø
Fluidized Bed Dryer
* optimum loads
* rate of airflow
* inlet air temperature
* humidity
Ø
Data
used for small scale batches(1-5 kg) cannot be extrapolate processing conditions for
intermediated scale (100 kg) or large batches.
Reduction In Particle Size
Particle size to particle size distribution is important to the
compression characteristics of a granulation. Compression factors that may
affected by the particle size
distribution are flow ability, compressibility, uniformity of tablet weight,
content uniformity, tablet hardness,
tablet color uniformity.
Ø
Equipments :-
* oscillating granulator a
mechanical sieving device
* a hammer mill
* screening device
Ø
If too large particle size :-
* weight variation
* mottling
If too fines
particle size,weight variation and capping
Both oversized and undersized
granulation can adversely affect tablet content uniformity Lubricants & Gildants are added at final
blend
Blending
Consequent attention should be paid to scale up of the right design is
used and blender loads, mixing speeds, mixing timing are properly established. In
any blending operation segregation and mixing occurs simultaneously, both processes are a function
a particle size, shape, hardness,
density and dynamics of the mixing action.
Low dose active ingredients – directly compressed.
Ø
Equipments
:-
* Planetory type mixer
* Twin shell mixture
* Cone type
Ø
Over
loading in blender –
Retards the free flow of granules, reduce the
efficiency cause content un-uniformity
Ø
If the load is to small –
powder blend slides rather
than roll in blender and improper mixing
Slugging
A dry powder blend that cannot be directly compressed because of poor
flow properties may in some instances be processed using a slugging operation.
Ø
Instruments :-
Tablet press – which operates at
pressure of 15 tons, compared with a
normal tablet press, which operates at pressure of 4 tons or less.
Compression
The ultimate test of the tablet formulation and granulation can be
compressed on a high-speed tablet press.
Ø
Steps involved during compression,
* Filling empty die cavity with
granulation
* Pre compression of granules
* Compression of granules
* Ejection of tablet from the
die cavity
Ø
Compression characteristics can be evaluated
by press speed equal to normal
production speed.
Ø
Then
detect the problems such as,
* sticking to punch surface
* tablet hardness
* capping
* weight variation
Ø
Granules must be delivered at adequate rate.
Ø
During compression, the granules are
compacted, and in order for a tablet to form, bonds within the compressible
materials must be formed.
TABLET COATING
Equipments :-
* conventional coating pan
* perforated pans of
fluidized-bed coating column
Ø
Types :-
1. Sugar coating
2. Film coating
Ø
Tablet must be sufficiently hard to withstand
the the tumbling to which they are
subjected while coating.
Ø
Operation conditions to be established for pan
or column operation are optimum tablet
load, operating tablet, bed temperature, drying air flow rate, temperature,
solution application rate.
CAPSULES
To produce capsules on high-speed equipment, the powder blend must have,
* uniform particle size
distribution
* bulk density
* formation of compact of the
right size and of sufficient
cohesiveness to be filled
into capsule shells.
Ø
Equipments :-
1. Zanasi or Mertalli –
Dosator(hollow tube)
2. Hoflinger – Karg – Tamping
pins
Ø
Weight variation problem can be encountered
with these two methods.
Ø
Overly lubricated granules – delaying
disintegration.
Ø
Humidity
affect moisture content of –
* granulation
* on the empty gelatin capsules
Ø
Empty gelatin capsules have a recommended
storage condition of 15-25 ºC temperature & humidity 35-65 % RH.At high
humidity – capsule swells make separation of the capsule parts difficult to
interfere with the transport of the capsule
through the process.
Ø
At low humidity – capsule brittle increased
static charge interfere with the encapsulation
operation.
LIQUID ORALS
Ø
Simple
solutions are the straight forward to scale up but they require tanks of adequate size and
suitable mixing capability. Most
equipment has heating or cooling
capabilities to effect rapid
disollution of components of the system.All the equipments must be made up of
suitable non-reactive material and be
designed and constructed to facilitate easy cleaning. Liquid pharmaceutical processing tank,
kettles, pipes, mills, filter houses
etc. are most frequently fabricated from
stainless steel Two types of steel –
1. 308
2. 316
Stainless steel is most non reactive,
however it does react with some acidic pharmaceutical liquids, this problem can
be minimized by PASSIVATION. Interaction with metallic surfaces can be
minimized by use of glass or Teflon coating. Although
they are highly inert materials, they have the disadvantages of cracking,
breaking and flaking with resultant product contamination.
SUPPOSITORIES
The manufacturing of
suppositories on a laboratory scale usually involves,
* The preparation of a molten
mass
* The dispersion of drug in the
molten base
* casting of suppositories in a
suitable mold
* cooling of the mold
* opened & remove the
suppositories
More no. of moulds & large size Pan for
melting of drug & base.
On occasional,
scale-up or manufacture of a product may need to be done at an outside,
contract manufacturer.The reasons for considering contract manufacture include
the needs for additional manufacturing capacity, high specialized technology or
specialized equipment's.
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