PILOT PLANT SCALE
UP TECHNIQUES
[Link] Dr. Shashi Kiran Misra
1 VII sem
Industrial Pharmacy Assistant Professor
University Institute of Pharmacy
CSJMU, Kanpur
PILOT PLANT
OBJECTIVES
1. To try the process on a model of proposed plant before start
of large procedure
2. To study or examine the formula that is used pilot plant or
commercial scale
3. Evaluation replication of process and equipments
NOTE—The pilot plant scale up technique basically identify the
critical feature of the process evaluation parameters and there
by control and assist /help for the preparation of master
formula. 2
STEPS IN PILOT PLANT SCALE UP
1. DEFINE PRODUCT- Economic basis, market size, competition
selling.
2. Conduct lab study.
3. Define key rate controlling step.
4. Conduct preliminary study (pre -formulation study).
5. Design environment control, cleaning and sanitizing system,
packaging, waste handling system and other regulatory
requirements. 3
6. Evaluate pilot plant results (product , process , economy).
GENERAL CONSIDERATION of PILOT
PLANT
⮚ There must be separate staff that include RND group a formulator and
supporting staff.
⮚ Personal Requirement The qualification required for a position in a
pilot plant organisation include a blend of good theoretical knowledge
of pharmaceutics and some practical experience in the pharmaceutical
industry.
⮚ Space requirement:-----
⮚ 1. Administration and information processing,
⮚ [Link] testing area, 4
⮚ [Link] equipment floor space,
⮚ Review of the formula- A throw review of each aspect of formulation must
be conducted. (purpose of each ingredient, equipment configuration)
⮚ Raw material- approved and validate active ingredient and excipient is
required. All the raw material should be cost effective.
⮚ Equipment- It must be economical and simple, must be efficient and
working/ can produce desired product. The size of the equipment should
be such that it can be used for large scale production. The selected
equipment should not be too small or too large.
⮚ Production rate- The immediate and the future market trends or
requirement are considered while determining the production rate.
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⮚ Process evaluation- several parameters should be monitored such as
⮚ 1. Order of mixing of ingredients,
⮚ 2. Mixing speed,
⮚ 3. Mixing time,
⮚ 4. Rate of addition of solvent in formulation,
⮚ 5. Heating and cooling rate,
⮚ 6. Filtration (filter size),
⮚ 7. Prime temperature and time.
⮚ Master manufacturing procedure.--
⮚ 1. Weight sheet
⮚ 2. Processing direction
⮚ 3. Manufacturing procedure
⮚ Product stability and uniformity-
1. Physical and chemical stability,
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2. Process parameter that prepare uniform product,
3. Package stability
PILOT PLANT SCALE UP OF SOLID
FORMULATIONS
Pilot plant scale up technique
1. There is a general consideration regarding for pilot plant staff
members
i) They should have sufficient knowledge regarding new
formulation
ii)They should scale large no of product in efficient way.
2. The design and construction of pilot plant for solid preparation
should be
i) Feasible
ii)Cost effective 7
iii)Easy to maintain and clean
3. The design and construction unit should be installed on the
ground floor that makes easy delivery and shipment.
4. All the preparation should be protected from any kind of
microbial attack
i) Fluorescent lightning feature should be on ceiling
ii) There should be floor drain facility to make
simplify cleaning.
iii) Construction area should be humidity control.
iv) High density concrete floor should be installed.
5. There should be enamel painting on the wall
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PILOT PLANT SCALE UP FOR LIQUID
PREPARATION
QUALITY ASSURANCE FOR LIQUID ORALS
1. Dissolution of drugs in liquid
2. Content uniformity of drug
3. Effect of atmospheric conditions such as temp on uniformity
of liquid preparation.
Suspension -- Low temp high viscosity
High temp low viscosity
Emulsion – As the temp. increases or decreases it will effct on
efficacy of emulsion
Solution - solute solubility enhances as the temperature
increases 9
4. Microbiological control—suspending and emulsifying agent
are prone for microbial attack, water is also good source of
microbe growth.
5. Final volume –if solution is stored for long time – then
sorption or permeation or leaching is possible in plastic
container
6. Stability- (Accelerated stability studies) the preparation are
kept in variable temp and humidity zones , then we check the
potency and uniformity of preparation.
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STAGE OF LIQUID PREPERATION
Raw material
Measuring and weighing
Mixing
Filling
Packing
Finished product storage
Quality assurance
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INGREDIENTS OF LIQUID PREPARATIONS
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PILOT PLANT SCALE UP OF SEMISOLID
DOSAGE FORM
-Semisolids are complex formulation, consisting two
phases- (external and internal)
eg cream, ointment, gels
-Partition coefficient plays important role to distribute
active ingredient into other phase
-Physical properties factors- size, interfacial tension,
partition coefficient, etc. they play a role in movement of
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API from one phase to another phase.
PARAMETERS FOR SEMISOLID PREPARATION
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SUPAC – SCALE UP AND POST
APPROVAL CHANGES
The scale up and changes whatever made after taking
approval from governing body (FDA), such as composition,
manufacturing process, manufacturing equipment, site
change, all comes under SUPAC.
FDA has issued various guidance for SUPAC changes
for
1)SUPAC-IR (Immediate release),
2)SUPAC- MR (modified release),
3)SUPAC-SS (non-sterile semi solid
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dosage form, cream, ointment, gel and
lotions)
LEVEL OF CHANGE
MINOR/ LEVEL 1 MODERATE/ LEVEL 2 LEVEL 3
Change of color flavor, These changes could The changes that are
expression of excipient effect to the likely to have change
in formulation level. formulation, quality total formulation
and assurance. quality and
performance of
formulation
Change in technical Eg, any qualitative or
grade in excipient, quantitative excipient
there percentage. Eg, change in a potent drug
avicel 102, avicel 100 formulation, the drugs
that not need
dissolution criteria
when change in level 16
2.
SUPAC – IR --- - The change in component and
conjugation. - The site of manufacture.
- The scale up of manufacture.
- The manufacturing
process and equipment.
SUPAC – MR --- - Component and composition of
non- release controlling excipient.
- Focus on changes on
concentration of that excipient.
- Remove that
excipient if possible. 17
GENERAL CONSIDERATION FOR SUPAC CONSIDERATION
1. All the relevant data regarding composition of formulation.
2. Stability data analysis. – any trend of potency lost, - any degrading
condition,
3. All available long term circumstances data that influence batches
4. Submission of previous accelerated stability studies for better
understanding that must include – expiration date, - shelf life, - over
ages, of 1 st to 3 month study. Details of production patches and any
other report. Clinical trial study/ time and expense associated with
these trials
5. Variety of physical and chemical test commonly performed for
semisolid preparation (solubility , particle size, viscosity, homogeneity)
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in vitro release study
PLATEFORM
TECHNOLOGY
Plateform technologies are considered a valuable
tool to improve efficiency and quality in drug
product development. It is the risk based systematic
approach that is based on prior knowledge. These
technologies are designed to modify drug molecule
and dosage for their better action
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Key feature of platform technology
- It is robust and versatile.
- It improves chemical stability and solubility of the active
molecule.
- Stable simply and solvent free technologies offer preparation of
various formulations successfully.
- Reformulation of drug near patent expiration.
- Development of drugs that are not prepared and left over for
preparation of formulation.
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- New administration rules for a variety of molecules
Example- Argos therapeutics is an immune oncology
company that develops immunotherapies for the treatment
of cancers. The company has developed ARCELIS®
technology for mutation of various antigens through
capturing complete genome, patient’s dendritic cell cells of
tumors etc., and applies suitable approach for the
management of cancerous diseases. The technology
reduces associated toxicity of those formulations by
including suitable adjuvants
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REFERENCES
Leon Lachman et al. The theory and practice of industrial pharmacy. Pilot Plant
Scale-Up Techniques.
Scaling Up Manufacturing Processes : A Technology Primer : Supplement To
Pharmaceutical Technology 2005 .
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