PILOT PLANT

Prepared By
Md. Khairul Mamun
1
Definitions
Plant:
It is a place were the 5 M’s
like money, material, man,
method and machine are
brought together for the
manufacturing of the
products.
Definitions
The pilot program is a scare up techniques conducted to the
product and its process
• Leaving the development laboratory.
• Accepted by the full production manufacturing unit.

The pilot plant is intermediate sized equipment in between the

laboratory & commercial scale. The R&D personnel develop
the drug dosage forms on a laboratory scale or intermediate
sized pilot plant scale with-
• Exact formulation specification
• Guaranteed adequate physical & chemical stability
• Routine processing in a full scale production facility
Pilot Scale and Scale-Up

R&D Pilot
Scale

Large Scale
Scale-Up
Production
 Primary function /Scopes/ Objectives/Importance of Pilot Plant:

 To formulate a viable, robust product with exact formulation specification

 To determine the compatibility of relevant processing equipment with the
formulation
 To determine whether the formulation parameters are economic, simple &
re1iabe in producing the product
 To determine the availability of the raw materials
 To evaluate the production rate to meet the market demand
 Validation and evaluation of production & process controls
 Evaluation of training, reporting relationships, responsibilities of personnel
 Appropriate records & reports are issued to support GMP’s
 Development & validation of management product reprocessing procedures
 Identification of the critical features of a process
 Development process for formulation

Development batches / laboratory scale batch

Pre-exhibit batch / process qualification batch

Scale up
batches
Exhibit batch

Production scale batch

 Laboratory scale batch

• Early development at laboratory stage.

• It is generally 100-1000 times less than production batch.

• It is 1X (3-10 kg or 3-10 liters or 3000-10000 unit) batch.

Uses
• To support formulation.

• For packaging development.

• For preclinical trial.

Pre-exhibit batch
• It is 1st step in scale up.
• It generally 70 % of the size of the exhibit batch.
• It prepaid with the complete process documentation and fully
validated analytical methodology.

Uses
• To detect any problem arise in manufacture of exhibit batch .
Production batch

• I t is produced during the routine marketing of Product

• I t is 100X batch means :- 300-1000 kg or
300-1000 liters or
300000-1000000 unit
General Consideration
1. Reporting responsibilities
2. Personnel requirements
3. Space requirements
4. Review of the formula
5. Raw materials
6. Relevant processing equipment
7. Production rates
8. Process evaluation
9. Preparation of master manufacturing procedures.
10. Product stability and uniformity
 1. Reporting Responsibility

R & D group with The formulator who developed the

separate staffing product can take into
production and can
theprovide support
even after transition into
production has been completed.
1. Reporting responsibilities
Pilot plant function is a part of research & development group with separate
staffing. This arrangement is designed to provide a hierarchy of responsibility to
scale-UP formulations that have been development by research & development
group. The goal of a pilot plant is to facilitate of a product from 1aboratory scale
to production scale.
And this can be achieved by is good relationship exists between pilot plant
group &other group-
• Research & Development
• Manufacturing
• Packaging
• Engineering
• Marketing
• Administration
• QA /QC
2. Personnel Requirement:-
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.
The group should have some personnel
with engineering knowledge as well as
scale up also involves engineering
principles.
2. Personnel Requirement (Continue):-
a. Qualification
 Have good theoretical, practical & technical knowledge of Pharmaceuticals
 Abi1ity to communicate well in speaking & writing

b. Type & level of education

 Pharmaceutically trained scientists who play rote on physical chemical,
Biochemical & medical attributes of dosage forms.

C. No. of personnel
 It’s depends on number of products.
3. Space Requirements
A Pilot plant has the following 4 types of space requirements-

Space Requirements

Administration Standard Storage area

Physical
and information testing area equipment

processing floor space

a. Administration and information process:

 Adequate office & desk space (for scientist, technicians)

 An area where 3-4 people can meet and discuss.
 Space for computer terminal (for conventional data entry)
 Retreva1 and archives for stability data protocols and
historical files.
b. Physical testing area:-

 Adequate working area in which

samples can be laid out and examined.
 Permanent bench- top space for
physical testing equipment’s (balances,
pH meter, Viscometer)
C. Standard pilot-plant equipment floor space:-
I. Discreet pilot plant space, where the equipment needed for
manufacturing all types of dosage form is located. (Solid, semisolid ,
liquid, sterile products)
II. Separate areas according to GMP for
API, excipient, packaging materials, retained samples, experimental
production batches, shell room, bottles, closure, tubes, vials, ampoules.
III. Intermediate – sized and full scale production equipment is essential in
evaluating the effects of scale-up of research formulations and processes
IV. Equipment used should be made portable where ever possible. So that
after use it can be stored in the small store room.
V. Space for cleaning of the equipment should be also provided.
d. Storage Area:-
 It should have two areas divided as approved
and 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 packing material should
also be provided.
4. Review of the formula:-
A thorough review of the each aspect of
formulation is important.
The purpose of each ingredient and it’s
contribution to the final product
manufactured on the small-scale laboratory
equipment should be understood.
Then the effect of scale-up using
equipment that may subject the product to
stresses of different types and degrees can
more readily be predicted, or recognized.
5. Raw materials:-

One purpose/responsibility of the pilot-plant is the approval &

validation of the active ingredient & excipients raw materials.

Why?
Raw materials used in the small scale production cannot
necessarily be the representative for the large scale production

21
5. Raw materials (continue):-
Approved & Validation of the active
and excipients raw materials used in
pharmaceutical product is an
important function of the pilot plant.
Because the raw materials used in
large scale formulation traits may not
be the representative of large volume
shipments of materials used in large
scale production. The evaluation of
alternative suppliers depend on the
several batches of product of
alternative material that their
performance in the formulation &
stability of finished products relative
to the standard product
6. Relevant processing Equipment:-
 Based on the known processing characteristics of the product, the
equipment that promises to the most economical. The simplest, the
most efficient and the most capable of consistently producing
product within the proposed specifications should be evaluated.
 The size of this equipment should be such that experimental trials
can be run that are meaningful & relevant to the production sized
batches that will eventually be made.
6. Relevant processing Equipment (contin):-
 The most economical and the 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 the equipment is too small the process
developed will not scale up. Whereas if
equipment is too big then the wastage of the
expensive active ingredients.
 7. Production Rates:-
 The immediate & future market requirements
must be considered when determining the
production rates & tile type & size of
production equipment needed.
 The size of this equipment should be such that it
is properly utilized. The equipment & process
should be chosen so as to produce batches at a
frequency that takes in to Consideration

 Product loss in the equipment during manufacture

 The time required to clean the equipment between
batches
 The number of batches needs to be tested before
release
8. Process Evaluation:-

Order of mixing of
Drying temp. components Mixin
And drying time g
speed

Mixin
Screen size PARAMETERS g time
(solids)

Rate of addition of
Filters size granulating agents,
Heating and cooling solvents,
(liquids)
Rates solutions of drug
etc.
8. Process Evaluation:-
The purpose of process validation is to confirm that the
selected manufacturing procedure assures the quality of the
product at various critical stages in the process and in the
finished product.
The following points should be examined—
a. Order of addition of materials (amount)
b. Mixing speed
c. Mixing time
d. Rate of addition of granulating agents (solvents,
solution of drugs, slurries etc)
e. Heating and cooling rates
f. Filter sizes (Liquids)
g. Screen sizes (Solids)
h. Drying temperature
i. Drying time
Why to carry out process evaluation????
T h e knowledge of the effects of various process parameters as
few mentioned above form the basis for process optimization
and validation.
9.Preparation of master manufacturing
procedure:-
The three important aspects

Manufacturing Standard Operating

Weight sheet
directions procedure (SOP)
9.Preparation of master manufacturing
procedure (Continue):-
Criteria/basis
• Chemical Weigh sheet (MO/PO: manufacturing order)
• Manufacturing directions (BMR/BPR)
• Standard operating procedure (SOP)
MO/PO should contain
• Product name, -Batch no
• Identifications of chemicals
• Dispensing dates, -Batch size
• Amount of chemicals
• Sign of responsible people (IPC)
9.Preparation of master manufacturing
procedure (Continue):-
 The weight sheet should clearly identify the chemicals required
In a batch. To prevent confusion the names and identifying nos.
For the ingredients should be used on batch records.
 T h e manufacturing directions should be precise and explicit.
 A Standard operating procedure (SOP) should be written by the
actual operator
 Various specifications like addition rates, mixing time, mixing
speed, heating, and cooling rates, temperature, storing of the
finished product samples should be mentioned in the batch
9.Preparation of master manufacturing
procedure (Continue):-
BMR/BPR
It shou1d be precise
Language should be easy (Understand by production operators)
Each and every step of manufacturing should he clearly specified
Should contain
 Product name
 Batch number &
 Batch Size
 Identification of Chemicals
9.Preparation of master manufacturing
procedure (Continue):-
BMR
 Amounts of chemicals
 Order of mixing & time of mixing
 Speed of mixing (RMP-Rotation per minute)
 Sampling direction
 In process and finished product specification In case of coated tablet
 Types of coating
 Coating material (name, amount & volume of coating Solution)
 Order of mixing
 Spray rate
 Machine RPM
 Drying temperature and time
 Exhaust arid inlet air temperature
 Inlet Humidity
9.Preparation of master manufacturing
procedure (Continue):-

SOP (Standard Operating Procedure)

 How to operate the instrument
 It should be precise
 Language should be easy
 Every step of should be clearly
mentioned
10. Product stability and 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.
GMP consideration
Equipment qualification
 Process validation
 Regularly schedule preventative maintenance
 Regularly process review & revalidation
 Relevant written standard operating procedures
 T h e use of competent technically qualified personnel
 Adequate provision for training of personnel
 A well-defined technology transfer system
 Validated cleaning procedures.
 A n orderly arrangement of equipment so as to ease material
flow & prevent cross- contamination
Significance of pilot plant:-

 Examination of formulae.
 Review of range of relevant processing equipment.
 production rate adjustment.
 Idea about physical space required.
 Appropriate records and reports to support GMP.
 Identification of critical features to maintain quality.
A pilot plant can be used for
 Evaluating the results of laboratory studies and making
product and process corrections and improvements.
 Producing small quantities of product for sensory, chemical,
microbiological evaluations, limited market testing or
furnishing samples to potential customers, shelf-life and
storage stability studies.
 Providing data that can be used in making a decision on
whether or not to proceed to a full-scale production process;
and in the case of a positive decision, designing and
constructing a full-size plant or modifying an existing plant.
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.
Disadvantages
 T h e frequency of direct interaction of the formulator with
the production personnel in the manufacturing area will be
reduced.
 A n y problem in manufacturing will be directed towards its
own pilot-plant personnel's.
Pilot Plant design for Tablets
i. The primary responsibility of the pilot plant staff
is to ensure that the newly formulated tablets
developed by product development personnel
will prove to be efficiently, economically, and
consistently reproducible on a production scale.
ii. The design and construction of the pharmaceutical
pilot plant for tablet development should
incorporate features necessary to facilitate
maintenance and cleanliness.
iii. If possible, it should be located on the ground
floor to expedite the delivery and shipment of
supplies.
Pilot Plant design for Tablets
Extraneous and microbiological contamination must be guarded against
by incorporating the following features in the pilot plant design:
1. Fluorescent lighting fixtures should be the ceiling flush type.
2. The various operating areas should have floor drains to simplify
cleaning.
3.The area should be air-conditioned and humidity controlled.
4. High -density concrete floors should be installed.
5.The walls in the processing and packaging areas should be enamel
cement finish on concrete.
6. Equipment in the pharmaceutical pilot plant should be similar to that
used by production division- manufacture of tablets.