PILOT PLANT SCALE UP TECHNIQUES FOR THE PARENTRAL …

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Eknath et al. World Journal of Pharmacy and Pharmaceutical Sciences

PILOT PLANT SCALE UP TECHNIQUES FOR THE PARENTRAL

PREPARTIONS

Rahinj Dipali Eknath*, Rokade V. G. and Hingne L. D.

Aditya College of Pharmacy Beed.

ABSTRACT

Pilot scale up techniques for the parentral preparation will provide

guide line forthe manufacture of large scale process and this will play a

pivotal role in large scale manufacturing. The Pilot plant is a relative

term in the sense that pilot plants are typically smaller than full-scale

production plants, but are built in a range of sizes. Also, as pilot plants

are intended for learning, they typically are more flexible, possibly at

the expense of economy. Some pilot plants are built in laboratories

using stock lab equipment, The past two decades particular have

witnessed amazing inventions and innovations in pharmaceutical research, resulting in the

ability to produce new drugs faster than even before. The new drug applications (NDAs) and

abbreviated new drug applications (ANDA) are all-time high. The preparation of several

clinical batches in the pilot plant provides its personnel with the opportunity to perfect and

validate the process.

INTRODUCTION

What is Pilot plant

“Defined as a part of the pharmaceutical industry where a lab scale formula is transformed

into a viable product by the development of liable practical procedure for manufacture.”

R & D Production

Pilot Plant

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 10, Issue 4, 418-433 Review Article ISSN 2278 – 4357

*Corresponding Author

Rahinj Dipali Eknath

Aditya College of Pharmacy

Beed.

Article Received on

23 Jan. 2021,

Revised on 13 Feb. 2021,

Accepted on 05 March 2021

DOI: 10.20959/wjpps20214-18495


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Why conduct Pilot Plant Studies?

A pilot plant allows investigation of a product and process on an intermediate scale before

large amounts of money are committed to full-scale production

It is usually not possible to predict the effects of a many-fold increase in scale

It is not possible to design a large complex food processing plant from laboratory data

alone with any degree of success

Definition

Plant- “it is a place were the 5m’s like money, material, man, method & machine are brought

together for the manufacturing of products.”

Scale up– “The art for designing of prototype using the data obtained from pilot plant

model.”

Objective of scale up

“Find mistakes on small scale and make profit on large scale.”

To produce physically and chemically stable therapeutic dosage forms.

Review of the processing equipment.

Guidelines for productions and process control.

Evaluation and validation.

To identify the critical features of the process.

To provide master manufacturing formula.

Significance of pilot plant

Standardization of formulae.

Review of range of relevant processing equipments.

Optimization and control of production rate.

Information on infrastructure of equipments during the scale up batches physical

spacerequired.

Identification of critical features to maintain quality of a product.

Appropriate records and reports to support GMP.

A pilot plant can be used for

Evaluating the results of laboratory studies and making product and process corrections

and improvements.


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Determining possible salable by-products or waste stream requiring treatment before

discharge.

Providing data that can be used in making a decision on whether or not to proceed to a

fullscale production process; and in the case of a positive decision, designing and

constructing a full-size plant or modifying an existing plant.

Scale up process

Scale-up is defined as the process of increasing the batch size. Scale-up of a process can

also be viewed as a procedure for applying the same process to different output volumes.

Batch size enlargement does not always translate into a size increase of the processing

volume. Inmixing applications, scale-up is indeed concerned with increasing the linear

dimensions fromthe laboratory to the plant size. On the other hand, processes exist (e.g.,

tableting) for which“scale-up” simply means enlarging the output by increasing the speed.

In moving from R&D to production scale, it is sometimes essential to have an intermediate

batch scale. This scale also makes possible the production of enough product for clinical

testing and samples for marketing. However, inserting an intermediate step between R&D

and production scales doesnot in itself guarantee a smooth transition.

Pilot plant design

A pilot plant design should support three key strategic objectives

Formulation and process development.

Clinical supply manufacture.

Technology evaluation, scale up and transfer.

Attributes playing a key role in achieving the above objectives are

cGMP Compliance.

A flexible highly trained staff.

Equipment to support multiple dosage form development.

Equipment at multiple scales based on similar operating principles to those in Production

The pilot plant design should be according to cGMP norms. The layout should be according

to the need for flexibility, restricted access, personnel flow and material flow.


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The facility and equipment should be able to capture critical process information .Adequate

space required to carry out each function smoothly (eg., cleaning of pilot plant equipments) .

The final design should result in a facility that support the key strategic objectives and should

have low maintenance and operating costs.

Although the pilot plant design must simulate the manufacturing environment in which the

new product will ultimately be produced , there are many differences in operation because of

the specific objectives of the two types of facilities i.e. the pilot plant facilitates product

development activities , whereas the manufacturing plant routinely fabricates products for the

market place.

Scale up techniques

Scale up: The art for designing of prototype using the data obtained from the pilot plant

model.


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General considerations

1. Reporting responsibilities

R & D group with The formulator who

separate staffing developed the product can take into

the production and can provide

Support even after transition into

Production has been completed

2. Personnel requirements

Personnel should have– 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

Personal requirement


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3. Space requirements

Administration and information process:

Adequate office and desk space should be provided for both scientist and technicians.

The space should be adjacent to the working area.

1. Administration & information process

Adequate office and desk splace should be provided for both scientists and technicians

The space should be adjacent to the working area.

Computers

2. Physical testing area

This area should provide permanent bench top space for routinely used physical- testing

equipment.


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3. Standard pilot-plant equipment floor space

Discreet pilot plant scale, where equipment needed for manufacturing

All types of dosage form is located

Equipment used should be made portable where ever possibleSo that after use it can be

stored in small store room

Space for the cleaning of the equipment should be also provided

4. 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.

5. 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.


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6. Raw materials

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

ingredient & excipients raw materials.

Raw materials used in the small scale production cannot necessarily be the representative

for the large scale production

7. Equipment

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.

8. Production rates

The immediate as well as the future market trends/requirements are considered while

determining the production rates.

9. Process evaluation

Parametrs Order of mixing of components Mixing speed Mixing time Rate of addition of

granulating agents, solvents, solutions of drug etc. Heating and cooling Rates Screen size

(solids) Drying temp. And drying time.


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Why to carry out process evaluation?

The knowledge of the effects of various process parameters as few mentioned above fform

the basis for process optimization

9. Master manufacturing procedures

The three important aspects

1. Weight sheet

2. Processing directions

3. Manufacturing procedure

Master manufacturing procedures

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.

The process directions should be precise and explicit.

A manufacturing procedure 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 record directions

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 as raw materials.

GMP Consideration

Equipment qualification

Process validation

Regularly process review & revalidation

Relevant written standard operating procedures

The use of competent technically qualified personnel

A well-defined technology transfer system .

Validated cleaning procedures.


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An orderly arrangement of equipment so as ease material flow.

& prevent cross contamination.

Transfer of analytical methods to quality assurance: Analytical methods developed in

research must be transferred to QA department. Transfer process includes –-

1. Review the process to make sure that proper analytical instrument is available.

2. Personnel should be trained to perform the test.

3. Reliability of the test should be checked.

4. At last assay procedure should be reviewed before transfer.

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

The frequency of direct interaction of the formulator with the production personnel in the

manufacturing area will be reduced.

Anyproblemin manufacturing will be directed towards it’sown pilot-plant personnel's.

General flow chart


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General stability consideration for general guidance on conducting stability studies, see

the FDA Guideline for Submitting Documentation for the Stability of Human Drugs and

Biologics.

A commitment should be included to conduct long-term stability studies through the

expiration dating period, according to the approved protocol.

Production batches, and to report the results in subsequent annual reports.

Scale-up for parenterals

Injectables

The majority of the parenteral solutions are solutions requiring a variety of tankage,

piping and ancillary equipment for liquid mixing, filteration, transfer and related

activities.

The vessels can be equipped with external jackets for heating and/or cooling and various

types of agitators, depending upon the mixing requirements of the individual formulation.

Working area of a parenteral pilot plant

Incoming goods are stored in special areas for Quarantine, Released and Rejected status.

A cold room is available for storage of temperature-sensitive products. Entrance into the

warehouse and production areas is restricted to authorized personnel.


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Sampling and weighing of the raw material is performed in a dedicated sampling area and

a central weighing suite, respectively.

The route for final products is separated from the incoming goods; storage of final

products is done in designated areas in the warehouse while they are awaiting shipment.

Several clothing and cleaning procedures in the controlled transport zone and production

area ensure full quality compliance

In addition, a technical area is located in between the production zone and the area for

formulation development.

Here, the water for injection equipment is located, as well as the technical installation of

the lyophilizer.

Facility design: To provide the control of microbial, pyrogen and particlecontrols over

the production environment are 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 materials that are yet to receive any processing at any site.

Preparation area: The materials utilized for the production of the sterile products move

toward the preparation area through a series of progressively cleaner environments.

Preparation area


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Compounding area

The manufacture of parenterals is carried out in class 10,000 (Grade C) controlled

environments in which class 100 unidirectional flow hoods are utilized to provide greater

environmental control during material addition.These areas are designed to minimize the

microbial, pyrogen, and particulate contamination to the formulation prior to sterilization.

Aseptic filling rooms

The filling of the formulations is performed in a Class 100 environment.

Capping and Crimp sealing areas: The air supply in the capping line should be of Class

100.

Corridors: They serve to interconnect the various rooms. Fill rooms, air locks and

gowning rooms are assessed from the corridor.

Aseptic storage rooms.

Air-locks and pass-throughs

Air locks serve as a transition points between one environment and another.

They are fitted with the UltraViolet lights, spray systems, or other devices that may be

effectively utilized for decontamination of materials.

Formulation aspects

Solvent

The most widely used solvent used for parenteral production is water for injection.

WFI is prepared by by distillation or reverse osmosis. Sterile water for injection is used as a

vehicle for reconstitution of sterile solid products before administration and is terminally

sterilized by autoclaving

Solubilizers

They are used to enhance and maintain the aqueous solubility of poorly watersoluble drugs.

Solubilizing agents used in sterile products include:

1. Co-solvents: glycerine, ethanol, sorbitol, etc.

2. Surface active agents: polysorbate 80, polysorbate 20, lecithin.

3. Complexing agents: cyclodextrins etc.


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They act by reducing the dielectric constant properties of the solvent system, There by

reducing the electrical, conductance capabilities of the solvent and thus increase the

solubility.

Antimicrobial preservative agents

Buffers

They are used to maintain the pH level of a solution in the range that provides either

maximum stability of the drug against hydrolytic degradation or maximum or optimal

solubility of the drug in solution.

Antioxidants

Antioxidants function by reacting prefentially with molecular oxygen and minimizing or

terminating the free the free radical auto-oxidation reaction. Examples phenol (0.065-0.5%),

m-cresol (0.16-0.3%) etc.

CONCLUSION

From the above finding it was concluded that the Pilot scale up techniques is one of

theimportant tool for the optimization of large scale production.

The parameters will play a important, role the development of pilot scale up techniques to

large scale production soliddosage form.

In order to scale up and transfer a process successfully from laboratory scale to pilot scale

and multiple commercial manufacturing scales, a thorough understanding of the integration

of scale factors, facility design, equipment design and process performance is necessary.

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PILOT PLANT SCALE UP TECHNIQUES FOR THE PARENTRAL …