Transcript liquids orals

PILOT PLANT
STUDY FOR LIQUID
ORALS
1
LIQUIDS ORALS
Liquid pharmaceuticals encountered in the
pilot plant are defined as non sterile solutions,
suspensions or emulsions. Scale of each of these
present a different set of processing concerns that
must be considered
Liquid orals are the liquid dosage
formulations containing one (or) more active
ingredients with (or) without additives dissolved in
a suitable vehicle, meant for oral administration
2

The physical form of a drug product that is
pourable displays Newtonian or pseudoplastic
flow behaviour and comforts to it’s container at
room temperature.

Liquid dosage forms may be dispersed
systems or solutions.

In dispersed systems there are two or more
phases, where one phase is distributed in
another.

A solution refers two or more substances mixed
homogeneously.
3
TYPES OF ORAL LIQUIDS
SOLUTIONS
EMULSION
SUSPENSION
4
OBJECTIVE
A formula is transformed into a viable
robust product using reliable and practical
method of manufacture that effects the
orderly transition from lab to routine
processing in a full-scale production
5
STEPS INVOLVED IN PILOT PLANT
FOR LIQUID ORAL










Reporting responsibility
Personal requirements
Space requirements
Review of the formula
Raw materials
Relevant processing equipments
Production rates
Process evaluation
GMP consideration
Transfer of analytic method to quality assurance
6
Raw materials
Weighing &
Measuring
Mixing
Distilled
water
Filling
Packing
Pilot Plant Scale-Up
Techniques for
liquid orals
Finished
Product
storage
Quality
Assurance
7
General Consideration:
I. Reporting responsibilities:

The goal of pilot plant scale is to facilitate the
transfer of a product from the laboratory in to
production.

The formulators continue to provide support to
the production even after the transition in to
production has been completed.

There must be good relation between pilot plant
and other departments.
8
II. Personnel requirements:

Have good theoretic knowledge
of pharmaceutics.

Practical experience in liquid
orals manufacturing industry.

Chemical, physical,
biochemical and medical
properties of drugs.

Have the knowledge of
computer, electronics.
9
III. Space requirements:

Administration and information processing
area

Physical testing area

Standard pilot plant equipment floor space

Storage area
10
Administration and information
processing area
11
Physical testing area
12
Standard pilot plant equipment floor
space
13
Storage area
14
IV Review of formula:



A thorough review of each and every steps of
formulation is important
The purpose of each ingredient and its
contribution to the final product should be
studied
If any modification in formula, it should be done
as soon as possible in phase III trials to allow
time to generate meaningful long term stability in
a support of a proposed new drug application
15
V. Raw materials:

One responsibility of pilot plant function is
the approval and validation of the active
ingredient and excipients raw materials
used in the pharmaceutical products.

The quality of the active ingredients needs
to be verified.
16
Formulation consideration:





Solvents
Preservatives
Antioxidants
Solubilizers
Organoleptic agents etc.
17
SOLVENTS
Water
 Alcohol
 Glycerol
 Polyethylene glycol
 Propylene glycol.

18
Water
Compared to ordinary drinking water ,
purified water USP is more free of solid
impurities.
 When evaporated to dryness, it must not
yield greater than 0.001% of residue.
 Purified water is obtained by distillation,
ion-exchange treatment, reverse osmosis
and other relevant method

19
PRESERVATIVES

Preservatives are added to prevent the microbial growth

Preservative are necessary due to chances of microbial
growth

Raw material, processing containers & equipments, the
manufacturing environment, operators, packing materials
& the user.
Phenol, chlorocresol, benzoic acid, etc.

20

Antioxidants: ascorbic acid, sodium
thiosulphate, sodium metabisulphate.

Solubilizers:
active agents
co-solvents
and
surface
 Organoleptic agents etc: colour, flavor,
sweetening agents
21
VI. Relevant processing equipment:

Almost all formulation development work is carried out on
small, relatively simple laboratory equipment.

The equipment that is most economical, the simplest, the
most efficient should be selected

Liquid pharmaceutical processing tanks, kettles, pipes, mills,
filter housings, and so forth are most frequently fabricated
from stainless steel.

Of the three types commonly used in the industry (304, 308,
and 316), type 316 is most often used because it is the least
reactive.

Ease of cleaning should be considered, if multiple products
are to be manufacture in the same equipment.
22
Stages of operations:
1.Tank selection





Material of the tank must not be
additive to the product
The
shape
and
size
of
equipment must be selected
according to the batch size
The
tanks
are
usually
constructed of polished stainless
steel of different grades
Teflon and glass lined tank.
Adequate clean-up procedures
developed.
23
2.Mixing

Simple mixing is essential
increase flow of liquids.
to

If the liquid is of high viscosity, high
electrical stirrer may be used.

Addition of ingredients in proper
order have vital important.

At high viscosity the chance of air
entrapment.
24
Air entrapment Minimize:
By reducing agitator speed

By caring out the mixing procedure in
enclosed tank under vacuum

The alternative procedure to the all is
versator
25
Versator
26
3. Dispersion

Suspensions and emulsions
require considerably greater
shear forces
Homogenizer

Laboratory
formulation
is
difficult to duplicate at large
scale

Dispersion
produced
by
colloidal mill or an immersion
homogenizer

Variety of equipment should
evaluated for better results.
Colloidal mill
27
4. Filtration and clarification—



Filtration procedure, requires careful evaluation to
ensure that pilot scale-ups will exhibit the same
degree of clarity as their laboratory counterparts.
During the pilot run the clarity of the filtrate should be
checked periodically, in order to establish schedule
for changing pads, cake, or cartridges, depending on
the type of filtration employed.
In filtration, filter pads are used which is made up of
asbestos and cellulose.
Selection of filtration depends on

The product viscosity

Volumes

Rate requirement
28
5. Transfer and filling

Filling – important parameter in the transfer
of liquids from tank to tank and into
containers.

New batches should not be started until
the previous batches are completely filled
and the tanks are emptied.

Bins and Piping
29
Methods for filling of liquids:
The selection of equipment
depends on characteristic of
liquid such as, viscosity,
type of packaging, surface
tension.

Gravimetric (specific weight)

Volumetric (specific volume)

Constant volume filling
Gravimetric
Volumetric
30
Containers and closures:




Glass
Plastic
It is more important to store the final product in
container until its expiration.
Most oral liquids are packed in either amber or
flint glass containers with plastic or metal caps.
31
VII. Production rates:
The immediate and future market requirements estimating the production rates, selecting the type and
the size of the equipment needed.

Determining the product loss in the equipment during
manufacture.

The time required to clean the equipment between
batches.

The number of batches that will need to be tested for
release.
32
VIII. Process evaluation:Items that should be examined include the following Mixing speed

Mixing time

Rate of addition of solvents, solutions of drug, slurries
etc

Heating and cooling rates

Filter sizes

Filling
33
IX. Preparation of manufacturing
procedures:
The processing directions should be precise and explicit.

The batch records should include addition rates, mixing
times, mixing speeds heating and cooling rates and
temperature should be given.

Finished product specification and release specification
are set; they should be take into consideration.
34
X. GMP considerations:A check list of GMP items
 Equipment qualification
 Process validation
 Regular process review and revalidation
 Relevant written SOP
 Adequate provision for training of personnel
 A well defined technology transfer system
 An orderly arrangement of equipments
35
XI. Transfer of analytic method to quality
assurance:
During the scale up new product the
analytic test methods transferred to the
quality department.

The quality assurance staff should review
the process to make sure that the proper
analysis instrumentation is available and
that personnel are trained to perform tests.
36
Viscosity
It is the internal resistance (or) friction to the
movement of molecules to “FLOW”.

Agents which control viscosity
E.g. Polyvinylpyrrolidine, alginates, carbomers,
and various cellulose derivatives. .
37
Purpose to control Viscosity 1. Improve pour ability.
2. Improve acceptability.
3. Improve palatability.
Equipment
used
for
this
purpose are as followed-
OSTWALD VISCOMETER
By OSTWALD VISCOMETER
(Or)
BY FALLING SPHERE
VISCOMETER.
FALLING SPHERE VISCOMETER
38
Preservative evaluation

Preservative evaluation – should be done in addition to
physical and chemical tests.

Depending on the nature of the product and degree of
protection required the surface of the product can be
over lapped during filling or holding stages with carbon
dioxide or nitrogen.

Bacteriological testing should be done, to know if the
concentration of preservative is to be increased in the
formulation
39
Stability studies:
Physical: Physical instability of liquid formulations involves the
formation of precipitates, less-soluble polymorphs, and adsorption of
the drug substances onto container surfaces, changes in product
appearance.

Chemical: Chemical instability of liquid formulation is mainly due to
interaction between additives, oxidation or some due to interaction
with containers.

Microbiological: It is the most favorable condition for the growth of
microorganism. So studies must me conducted for different
microbiological test. Different preservatives are used to make
product more stable.
40
Type of changes:

Contents: Viscosity, Texture, Color, Odour, pH

Containers: a) Leakage, b) Corrosion, c) Stress
d) cracking

Glass container

Plastic or metal cap
41
REFERENCES:





Leon Lachman, Liberman & Joseph.L, The theory &
practice of industrial pharmacy. 3rd Ed., Vargese
publishing house-1991, 466-75,681-84,703-706.
James Swarbrick, encyclopedia of pharmaceutical
technology Third Edition volume 5.
Herbert A. Lieberman, Martin M. Rieger and Gilbert S.
Banker, pharmaceutical dosage forms: Disperse
system vol 1.
Howard C. Ansel Introduction to pharmaceutical
dosage forms, 4th edition.
www.google.com
42
43