Production and Scale-up

Techniques- Suspensions and Emulsions

Syam Perla (M.Pharmacy )

syamsundhar222@gmail.com

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Product development

scientist

Small pharmaceutical manufacturing

company

Large organisation

Pilot plant

Scientist is

responsible

for first few

batches

Involve large amount of materials and commercial scale equipment costly to operate

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drug product is developed in the research laboratory at a very small scale

successful in terms of efficacy, safety and stability

needs to be produced at very large scale

but there is substantial difference in the kind of conditions as well as the nature of equipment and facilities between the research laboratory (standard and limited capacity equipments and instruments)and large scale manufacturing

Formulation scientist while developing the product is unable to consider these factors

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thus a lot of problems are encountered in transferring the product directly from laboratory to production scale

In order to study and tackle above product transfer related problems the concept of pilot plant facility has emerged

Pilot plant is a hybrid manufacturing and development facility allows

successful transfer of the experimental formulations obtained in laboratory to

the production scale so that viable and robust product by the development of

a reliable and practical method of manufacture is possible

which may affect the efficacy, safety ,stability and reproducibility of the product

Scale-up:- The art for designing of prototype using the data obtainedfrom the pilot plant model. 4

PILOT PLANT FUNCTIONS

Review of product formula

Selection of raw material

Selection of processing equipments

Scale up batches

documentation

Technology transfer

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Pilot plant operations

Type of organizational structure

Research personnel responsible for initial scale up and initial production runs

The product development scientist is responsible for the scale up and technology transfer

Technology transfer

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Advantages Product scientist knows most about the productVarious product related information stability data etc are best conveyed by formulator

DisavantagesPerson from R&D department is not familierwith the production divisions equipment facilities and operations Time consuming for product scientist

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Pharmaceutical pilot plant controlled by pharmaceutical research

Advantage Scale up runs is under research division

Any scale up problems in the development process corrective measures can be taken up immediately

Provides pilot plant as apart of R&D with separate staffing

This arrangement is designed to provide the research scientist a responsibility to scale up the formulations that have been developed by other formulators with in research and development

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Pharmaceutical pilot plant controlled by production

Product scientist establish practicality of formula and manufacturing procedure in a pilot plant facility

Pilot plant personnel responsibility is process development and technology transfer

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R&D for development and evaluation

Manufactures and suppliers for evaluation of raw materials excipients equipments

Production technology transfer manufacturing support and trouble shooting

QA/QC for raw materials and final product testing

Drug regulatory affairs for documentation and submission of data for various regulatory agencies

Pilot plant inter disciplinary interaction 10

Pilot plant staff and training requirements

RESUME

Good theoretical knowledge

Practical experience

Good communication skills

Formulation experience

Process and equipment experience

Engineer capability

Knowledge in both electronics and computers

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TRAINING OF PILOT PLANT PERSONNEL

Technical skillsCompliance with quality standards compliance with S.O.PSafety and environmental responsibilities

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Sree ramaLARGE

ORGANISATION

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Sree ramaPILOT PLANT LAYOUT

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Design of a pharmaceutical pilot plant facility

A well designed pilot plant facility minimizes the labour, time and cost the key factors

which influence the design of a pilot plant are product type, product quantity and

activity based considerations

Product type Typical requirements

Solid dosage forms Weighing area ,mixing and granulation areas compression and encapsulation area and coating

facility specialized exhaust and dust collector systems

Liquids and semisolids Shear stirring facility, bottle filling facility, purified water facility ,filling and packaging facility

Soft gelatin capsules

Preparation of gelatin mass, gelatin mass storage area ,facility for loading of the gelatin of the

gelatin mass into encapsulation area dedicated temperature and humidity and humidity

controlled area for drying of the capsules

Parenterals

High shear mixing and stirring facility, sterilization and aseptic processing of the in-process and

finished product (aseptic mixing units, special handling units for control of microbial and cross

contamination )

Biologically derived products sterile manufacturing areas, extensive air handling equipment and environmental controls

Product type: the type of dosage form developed, evaluated and manufactured in a pilot

plant facility and the technology that is going to be employed have an important bearing

on the design of pilot plant

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Batch size: a pilot plant is supposed to be designed to manufacturewide array of batch sizes meant for different purposes such as productdevelopment, analytical development, and stability testing which aretypically few kg or liters in size a pilot plant facility must be operatedunder good manufacturing practices

Activity based considerations: guidelines for the maintenance of thepilot plant must be exactly the same as that of manufacturing facilityideally large scale equipment in the pilot plant should approach 25-100% of the capacity of full scale equipment

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Layout of a pharmaceutical pilot plant

Layout must compliance with cGMP guidelines following factors must be taken intoaccount

a) Space requirements and allocation

b) Process flow

c) Construction

d) Safety and environmental considerations

e) Operational costs

Space requirements and allocation

generally a pilot plant facility has following four types of space requirements.

major considerations in assessing the

floor space requirements are

a) Space for equipment

b) Provision for additional portable equipments

c) Dedicated equipment cleaning area

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Storage facility there should be a separate and appropriate space for storage various purposes

a) Storage of active ingredients and excipients

b) Storage of in-process materials, finished bulk products from the pilot plant

c) Storage of stability samples in controlled environment

d) Storage of packing materials in bulk

Testing facility this area

should provide permanent

bench top space for

routinely used physical

testing equipments

Documentation and

administration

effective monitoring and

documentation of each specific

activity is extremely important18

Process flow plan

a) Materials flow

b) Controlled access for the materials and components used in

manufacturing clinical supplies

c) Sampling of potent substances (specially designed rooms with air locks)

d) Receipt, sampling ,solvent dispensing and quarantine storage of

flammable solvents also need consideration

e) Temporary handling of flammable waste products as well as other waste

material

Ware house layout the ware house layout of a pilot plant facility depends

on the manufacturing capacity type of the product to be manufactured and

the storage requirements, requirements of special storage conditions

Personnel flow: size of rest room,

locker growing and shower areas

a proper provision in the layout

must be made for the cleaning,

disposal and storage

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Construction features taken into consideration

a) High density concrete floors should be installed

b) the walls in the packaging area should be enamel cement

finish

c) connections between the wall and window frames need to be

carefully constructed to prevent moisture damage and

enhance cleanability

d) light fixtures should be washable and allow for easy

maintenance

Building systems and utilities

The pilot plant HVAC system (heating ,ventilation and air conditioning)

It functions to maintain constant temperature and humidity it must be

suitable to consistently produce a quality product

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Processed air arrangements for specialized gases and breathing

air are also required for certain specialized process or handling

of some sensitive materials

Control systems controlling and monitoring of air, temperature

as well as relative humidity is the prime concern the other area

where monitoring and control may be desirable include

exhaust duct monitoring for lower explosives limits in solvent

processes

Water used during processing of the

product as well as for cleaning of

equipments and areas water quality is

divided into two types compendial

(USP Purified water and water for

injection)and noncompendial water

(portable water)

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Safety and environmental considerations

Environmental discharges

Necessary provisions are always incorporated in the

pilot plant layout for isolation and pretreatment or

an alternate means of disposal of waste water will

likely be required if highly potent or toxic compounds are to be processed in the pilot plant

Handling of certain special (potent or toxic) materials

Certain specific arrangements in the building layout are

required to maintain a safe environment inside and

outside the facility

a) light and dark room conditions with lights of specific

wave length for photosensitive materials

b) Humidity controls for moisture sensitive materials

c) Temperature controls for thermo sensitive materials

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Operational costs

Operational costs for maintaining sterile product facility is much more expensive to

operate than a pilot plant manufacturing solid oral dosage forms

Maintenance, calibration, engineering housekeeping, security, validation, QA,

microbiology, QC shipping receiving and training can be shared

Handling and prevention of

explosives

Explosions are unavoidable thus

the pilot plant layout must

include arrangements for

suppressing, isolating or venting

an explosion in such a way to

protect operators and minimize

damage to the equipment and

facility.

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FULL SCALE MANUFACTURING

PILOT PLANT

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Preparation of relevant documents and technology transfer to productionDocuments and reports prepared in pilot plant

Lab note books

Scale up report

Validation protocol and report

Master manufacturing instructions a) weighment sheet : exact quantities of raw materials

b) Stepwise manufacturing instructions : for each unit operation

c) Clearly specified time points: for sampling in process and finished products

Pilot plant transfers the technology to the shop floor for routine

mfg of the product at commercial scale

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Liquid pharmaceuticals encountered in the pilot plant are defined as non sterile

solutions ,suspensions or emulsions

are the most straight forward to scale up require tanks of adequate size and suitable mixing

capability and heating/cooling capabilities for rapid dissolution all equipment must be of

suitable nonreactive , sanitary materials and to be designed and constructed to facilitate easy

cleaning. Liquid processing tanks ,kettles pipes mills filter housing and so forth are most

fabricated from stainless steel

Stainless steel used in the industry type (308 and 316 ) most often used in the industry is 316

because of its unreactive nature

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Disadvantage surface alkalinity of the stainless steel

minimized by pre reacting the stain less steel with an

acetic acid or nitric acid this procedure is known as

passivation may need to be repeated at periodic

intervals

Interaction with metallic surfaces can be minimized by

the use of glass or polytetrafluoro ethylene liners.

Although these are highly inert surface materials they

have the obvious disadvantages of cracking breaking

flacking and peeling which results in product

contamination27

suspensions require more attention during scale up studies than dosimple solutions because of additional processing needs

Addition and dispersion of suspending agents

Lab scale sprinkling the material into the liquid vortex

Production scale require vibrating feed systems

Powder materials tends to clump during the process or that is difficult

to disperse

but these can be successfully incorporated by making a slurry with the

portion of the vehicle by using high shear mixer or powder blender

this converts a bulky material which is difficult to handle because of

static charges to a dense readily wettable powder which is mucheasier to handle 28

Mixing at too high speed can result in the

incorporation of an excessive amount of air

into the product

Removal of Air bubbles is

difficult and time consuming

If air bubbles are not removed physical and

stability problems(reproducibility of filling )

Air can be removed using a

vacuum unit such as the versator

Product is drawn

into a vacuum

chamber through

an inlet line

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In preparing pharmaceutical suspensions the type of

mixers , pumps and mills and the horse power of the

motors should be carefully selected based on scale up

performance

example use of an

appropriate type of mixer

is important because if the

mixer is undersized obvious

problems of inadequate

distribution or excessive

production time result

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where it is spread on to

the center of high speed

rotating disc.

The centrifugal force produced by the

rotation of the disc causes the product

to form a thin film on the disc surface

as the film thins and moves toward the

outer edge of the vacuum chamber the

entrapped air is drawn off

deaerated product is collected from

the outer edge of the vacuum

chamber

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Selection of filters the mesh size

chosen must be capable of

removing the unwanted foreign

particulates but should not filter

out any of the active ingredients

If suspensions are not constantly mixed or recirculated during transfer process

they may settle out and there by adversely affect the uniform distribution of the

active ingredient 32

processing parameters of emulsions include temperature

mixing equipment homogenizing equipment final product

filters pumps and filling equipment

Mixing equipment are more likely to lead to air entrapment.

So use of vessels can be operated with the contents under a

controlled vacuum avoids the problem of unwanted aeration

Filtration equipment the unwanted particulates are most

efficiently removed by filtering the separate oil and water

phase before emulsification33

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Sree rama

Created by SYAM PERLA

References N.K.Jain Pharmaceutical

Product Development pgno 379-418

Theory and Practice Of Industrial

Pharmacy Leon Lachman, Herbert

A. Lieberman pgno 681-710

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