Pilot plant scale up techniques used in pharmaceutical industry

1. Pilot Plant Scale up for Semisolid
and Parenterals.
Presented by: khushboo kunkulol.

2. INTRODUCTION:
 In the pilot plant a formulae is transformed into viable, robust product by
development of reliable and practical method of manufacturing that effect
the orderly transition from routine laboratory to routine processing in full
scale production facility .
 So pilot plant is miniature , intermediate plant between laboratory scale
and production plant.

3. Why to build up pilot plant?
 To evaluate the effect on process of large change in the scale of operation and to
gather other data so that good design of larger unit may be made with high
probability of commercial success.
 To produce trial lot quantities of material in question so that its properties may be
critically examined.
 To gather enough data to build a full-scale production facility.
 A pilot plant helps in testing if equipment and control concepts perform as desired
once unit operations are tied together.
 This is very important if recycle streams are involved as the pilot plant will
demonstrate if impurities are building in recycle streams and causing operational
problems.
 To find and examine all by-product and waste. These may not be seen in laboratory
scale.

4.  The majority of parenteral solution are solution requiring a variety of
tankage, piping and ancillary equipment for liquid mixing, filtration,
transfer and related activities.
 The majority of equipment are made up of stainless steel with glass lined
vessel employed for preparation of formulation sensitive to iron or metals.
 The vessels are equipped with external heating jacket and/ or cooling and
various types of agitator depending upon mixing requirement of individual
formulation.
Parenteral

6. Working area for parenteral.
 The incoming goods are stored in special area for quarantine, released and
rejected purpose.
 The cold room is available for temperature sensitive sample.
 Entrance to the warehouse and production area is restricted to authorized
personnel.
 Sampling and weighing of raw material is performed in dedicated sampling
area.
 Storage of final product is done in designated areas in warehouse while they are
awaiting for shipment.
 Several clothing and cleaning procedure in controlled transport zone and
production area ensure the full quality compliance.
 Technical area is located in between production zone and area for research and
formulation.

7. Layout of pilot-plant

8. Facility design:
 To provide the control of microbial, pyrogen and particles
control over production area is essential.
WAREHOUSING:
 All samples should be aseptically taken which mandates
unidirectional airflow and full operator gowning.
 These measures reduce the potential for contamination ingress
into material that are yet to receive any processing at any site

9. Preparation area
The material utilized for production of sterile product moves toward preparation area
through series of progressively cleaner environment.
First material are passed through grade D environment for
presterilization.
Then transfer of material is carried out in air-lock to avoid
cross contamination.
Preparation area are supplied with HEPA filters.
There should be more than 20 air change per hour.
The preparation place is class 100 area.

10. Production area

11. Compounding area:
 The manufacturing of parenteral is carried out in Grade-C controlled environment in which
class 100 unidirectional flow hoods are utilized to provide greater environmental control
during material addition.
 These area are designed to minimize microbial, pyrogen and particulate contamination to the
formulation prior to sterilization.
Aseptic filling room:
 The filling of formulation is performed in class 100 environment.
Capping and crimp sealing area:
 The air supply in capping area should be of class 100.
Corridors:
 They serve to interconnect various rooms, such as filling room, gowning room, air-lock room
are assessed from the corridor.
Air-lock and pass through:
 The air-lock serve as transition point between one environment and other.
 They are fitted with UV lights, spray system, or other device that may be effectively utilized.

12. Formulation Aspects:
Solvent:
 The most widely used solvent for parenteral production is WFI ( water for injection)
 The WFI is prepared by distillation or by reverse osmosis.
 Sterile water for injection is used as vehicle for reconstitution of sterile solid product
before administration and is terminally sterilized by autoclaving.
Solubilizer:
 They are used to enhance and maintain the aqueous solubility of poorly water
soluble drug.
Solubilizing agent used in sterile product include:
 The co-solvent: Glycerine, Ethanol, Sorbitol etc.
 Surfactant: Polysorbate 80, Polysorbate 20, Lecithin.
 Complexing agent: Cyclodexitrine, etc.
They act by reducing dielectric constant property of solvent system thereby reducing
electric conductance of solvent and hence increases solubility.

13. Buffers:
 They are used to maintain pH level of solution in range that provide either
maximum stability of drug against hydrolytic degradation or to obtain optimum
stability and solubility of drug in solution.
Antioxidant:
 The antioxidant act by reacting prefentially with molecular oxygen and
minimizing and/ or terminating the free radical auto-oxidation reaction.
Example: Phenol, m-cresol etc.
Sterilization and depyrogentation:
 Steam sterilization
 Dry-heat sterilization.
 Gas and vapour sterilization.
 Radiation sterilization.
 Sterilization by filtration.

14. Instrumentation:
 Mixer or Homogenizer:

15. The parenteral assembly

16. Filling and closing machinery:

17. Quality assurance:
 The dissolution of drug in solution.
 Potency of drug in suspension.
 Temperature uniformity in suspension.
 Microbial control.
 Product uniformity.
 Final volume.
 Stability.

18. Scale up for semi-solid.
 In general semisolid dosage form are complex formulation having
complex structure.
 Often they are composed of two phases (oil and water) one of
which is continues phase and other is dispersed phase.
 The active ingredient is dissolved in one phase although
occasionally the drug is not fully soluble in the system and is
dispersed in one or both phases thus creating the three-phases
system.
 The physical properties of dosage form depend upon various factor
including the size of dispersed particle coefficient of active
ingredient between phases and product rheology.
 These factors combine to determine the release characteristic of
drug as well as other characteristic such as viscosity.

19. Formulation of semi solid dosage form:
 Ingredient used in preparation of semi-solid dosage form are:
 Active pharmaceutical ingredient.
 Bases
 Preservative
 Humectant
 Antioxidant
 Emulsifier
 Gelling agent
 Permeation enhancer
 Buffer.

20. Suppositories:
The manufacturing of suppositories on laboratory scale usually requires:
 The preparation of molten mass.
 Casting of suppositories in suitable mould.
 Cooling of mould.
 Open and remove suppositories.

21. Critical manufacturing parameter:
 For a true solution the order in which solute is added to solvent is
usually unimportant.
 The same cannot be said for dispersed formulation however, because
dispersed differently depending on to which phase a particulate
substance is added.
 In a typical manufacturing process the critical points are generally
initially separation of one phase system into two phase and the point at
which active ingredient is added.
 Because the solubility of each added ingredient is important for
determining whether a mixture is visually a single homogeneous
phase, such data possibly supported by optical microscopy should
usually be available for review.
 This is particularly important for solute added to formulation at conc.
Near or exceeding that of their solubility at any temperature to which
the product may be exposed.

22.  Variation in manufacturing procedure that occur after either
these event likely to be critical to the characteristic of
finished product.
 This is especially true of any process intended to increase
the degree of dispersion through reducing droplet or particle
size.
 Aging of finished bulked formulation prior to packaging is
critical and should be specifically addressed in-process
validation study.

23. General stability consideration:
 The effect that SUPAC changes may have on the stability of drug product
should be evaluated.
 For SUPAC submission the following point must be considered :
i. In most cases, expect those involving scale-up, stability data for pilot scale
batches will be acceptable to support the proposed change.
ii. Where stability data shows a trend toward potency loss or degrading increase
under accelerated condition, it is recommended that historical accelerated
stability data from a representative pre-change batch be submitted for
comparison.
iii. It is also recommended that under these circumstance all available long term
data on test batches from ongoing studies be provided in supplement.
iv. Submission of historical accelerated and available long term data would
facilitate review and approval of supplement.

24. New era of drug product:
 Health care is one of the important indicator of any
country's development and status of health care indicate
nature of development of country.
 Pharma company are working consistently towards
improvement of health care among people.
 Drug are one of the important component of health care
management.
 The increase in income and change in lifestyle are
contributing to increase expenses of health care
management.

25. Indian pharmaceutical industries:
Evaluation of Indian pharmaceutical sector
 Phase 1-
 In 1901 Acharya Chandra Roy established Bengal chemical and
pharmaceutical work limited in Kolkata and in 1907 alembic chemical
work in Vadodara.
 After independence Hindustan antibiotic ltd was established in 1954.
 Phase 2-
 The private companies like sun pharma established in 1983 and dr. reddy
lab in 1984
 The government also took initiative to export the pharmaceutical product.

26. THANK YOU.