pilot plant and basic scale up techniques of pharmaceutics formulation and devlopment

1. PILOT PLANT AND SCALE UP TECHNIQUES
SUBMITTED BY
Mr. BHUNESHWAR SAHU
M.PHARM (1ST SEM)
PHARMACEUTICS

2. CONTENTS
 Definition
 Significance
 General Considerations
 GMP Considerations
 Product Considerations
 Advantages
 Disadvantages
 References

3. DEFINITIONS
 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.

4. 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.

5. GENERALCONSIDERATIONS
1. Reporting Responsibility:-
R & D group with The formulator who
separate staffing developed the product can
take into the production
and can provide support even after
transition into production has been
completed

6. 2. Personnel Requirements:-
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
* Knowledge of computers & electronics

7. 3. Space Requirements:-
Administration and Physical testing area Standard equipment Storage
information processing floor space
area

8. a)AdministrationAnd Information Process:-
 Adequate office and desk space should be provided
for both scientist and technicians.
 The space should be adjacent to the working area.
 Computers.
b) Physical Testing Area:-
 This area should provide permanent bench top space
for routinely used physical - testing equipment.

9. 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.

10. d) StorageArea:-
 It should have two areas,
1.Approved area and
2.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.

11. 4. 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 result in differences in bulk
density, static charges, rate of solubility, flow
properties, color, etc.

12. 5. 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
 Time of cleaning

13. 6. Production Rates:-
 The immediate as well as the future market
trends / requirements are considered while
determining the production rates.

14. 7. Process Evaluation:-
Order of mixing of components
Drying temperature and drying time
Mixing speed
Mixing time
Rate of addition of granulating agents,
solvents, solutions of drug etc.
Screen size (solids)
Filters size (liquids)
Heating and cooling Rates

15. 8.Master Manufacturing Procedures:-
 The three important aspects
Weight sheet Processing & Sampling directions
Manufacturing procedure

16. 9. Product StabilityAnd 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.

17. 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

18. ADVANTAGES
 Members of the production and quality control
divisions can readily observe scale up runs.
 Supplies of excipients & 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.

19. 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.

20.  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.

21. 2. 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.

22. 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.

23.  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.

24.  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.
 Multifunctional Processors,
 dry blending, wet granulation, drying, sizing &
 lubricating.
 Effect of Binding Agent.

25. 4. Drying
 Hot Air Oven
 * air temperature
 * rate of air flow
 * depth of granulation on the trays
 Fluidized Bed Dryer
 * optimum loads
 * rate of airflow
 * inlet air temperature
 * humidity
 Data used for small scale batches(1-5 kg) cannot be
 extrapolate processing conditions for intermediated scale
 (100 kg) or large batches.

26. TABLET COATING
 Equipments :-
 * conventional coating pan
 * perforated pans of fluidized-bed coating column
 Types :-
 1. Sugar coating
 2. Film coating
 Tablet must be sufficiently hard to withstand the the
 tumbling to which they are subjected while coating.
 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.

27. 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.
 Equipments :-
 1. Zanasi or Mertalli – Dosator(hollow tube)
 2. Hoflinger – Karg – Tamping pins
 Weight variation problem can be encountered with these
 two methods.
 Overly lubricated granules – delaying disintegration.

28.  Humidity affect moisture content of –
 * granulation
 * on the empty gelatin capsules
 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.
 At low humidity – capsule brittle increased static charge
 interfere with the encapsulation operation.

29. SEMI SOLID PRODUCTS
 The main difference of semi solid formulation with
 comparison to suspensions, liquids and emulsions
is their
 higher viscosity.
 Viscosity renders certain aspects of the scale-up of
semi
 solid products more critical.
 Equipments :-
 * blenders
 * mixers
 * pressure filling equipments

30. 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.

31. EMULSIONS
 Manufacturing of liquid emulsion products entails
 specialized procedures as result scale up into production
 equipment involves extensive process development and
 validation.
 Equipments :-
 * mixing equipment
 * homogenizing equipment
 * screens
 * pumps
 * filling equipment
 High shear mixers may lead to air entrapment, this
 problem can be avoid by carrying out operation under
 controlled vacuum.