Anthony Crasto Scale Up Techniques & Pilot Plant

(1)

Principa

l

Scienti

st,

Process

Research

A Short Presentation

(2)

SCALE-UP--Definition

y

y Act Act of of using results using results obtained from laboratory obtained from laboratory studies for studies for designing adesigning a

prototype

prototype and and a pilot a pilot plant process;construction a plant process;construction a pilot plant pilot plant andand using pilot plant data for designing and constructing a full scale plant using pilot plant data for designing and constructing a full scale plant or modifying an existing plant

or modifying an existing plant

y

y It is a It is a place were place were the 5 Mthe 5 Ms like moneys like money, material, material, man, , man, method andmethod and

machine are brought together for the manufacturing of the products. machine are brought together for the manufacturing of the products.

y

y It is the part of the pharmaceutical industry where a lab scale formulaIt is the part of the pharmaceutical industry where a lab scale formula

is transformed i

is transformed into a nto a viablviable product by e product by developmdevelopment of lient of liable andable and practical procedure

practical procedure of of manufacture.manufacture.

y

y The art for designing of prototype using the data obtained from theThe art for designing of prototype using the data obtained from the

pilot plant model. pilot plant model.

(3)

y

y Define product economics based on projected market size andDefine product economics based on projected market size and

competitive selling and provi

competitive selling and provide de guidance for allowableguidance for allowable manufacturing costs

manufacturing costs

y

y Conduct laboratory studies and scale-up planning at the same timeConduct laboratory studies and scale-up planning at the same time

y

y Define key rate-controlling steps in the proposed processDefine key rate-controlling steps in the proposed process

y

y Conduct preliminary larger-than-laboratory studies withConduct preliminary larger-than-laboratory studies with

equipment to be used in rate-controlling step to aid in plant design equipment to be used in rate-controlling step to aid in plant design

y

y DesigDesign n and construct and construct a a pilot plant including provisions for pilot plant including provisions for processprocess

and environmental controls, cleaning and

and environmental controls, cleaning and sanitizing systems,sanitizing systems, packaging and waste handling systems, and meeting regulatory packaging and waste handling systems, and meeting regulatory agency requirements

agency requirements

y

y Evaluate pilot plant results (product and process) includingEvaluate pilot plant results (product and process) including

Steps in Scale-Up

(4)

API Scale-Up During Research and

Development

y

T

he ultimate g

he ultimate goal of

oal of drug sy

drug synthesis i

nthesis is to

s to scale up from

scale up from

producing milligram quantities in a laboratory to

producing ki

producing kilogram to ton

logram to ton quantities in a plant, all while

quantities in a plant, all while

maintainin

maintaining high quality and reproducibility at the low

g high quality and reproducibility at the lowest

est

cost.

y

The term

process

in the pharmaceutical industry is broad

and can apply to the process development w

and can apply to the process development work that l

ork that leads

eads

to the efficient, reproducible, economical, safe, and

environmentally friend

environmentally friendly synthesis of the active

ly synthesis of the active

pharmaceutical ingredient (API) in a regulated

environment.

4

(5)

Sc

al

eu

p

ne

ed



y

y NN

eeded to make supplies for

y

bench studies,

y

y product charactproduct characterization, erization, purity purity

y

animal studies

y

y toxicology toxicology

y

y pharmacokinetics, ADMEpharmacokinetics, ADME

y

y efficacy efficacy

y

(6)

R

egulations

6

y

Code of Federal Regulations Title 21

y

Part

Part 210 210 and 211 -

and 211 - Good Manufac

Good Manufacturing Prac

turing Practice

tices for

s for

Drugs

y

Part

Part 600 -

600 - 680 Pr

680 Processing

ocessing of Biological mate

of Biological materials

rials

y

Part 8 Part 820 -

20 - Quality Sy

Quality System R

stem Regulations for M

egulations for Medical

edical

Devices

y

(7)

Process flow

(8)

8

(9)

The increasingly stringent regulatory requirem

ents and

the

global nature of

the pharmaceutical business are continuously

presenting new

challenges to the pharmaceutical industr

y

,

resulting in in

creased com

petition and a

need to produce high-

need to produce

high-quality APIs.

quality APIs.

API process deve

lopment has

subsequently gained

more

attention because of

the potential

to establish early c

ontrol over

the process at the research and development (R&D) stage by

identifying an

d addressing problematic issues

aa

_priori

_{. Thus, a}

systematic and prospective

approach during

R&D is

key to

achieving a successful prospective v

alidation and

scale-up.

These activities are important and

are frequently under scrutiny

by the Food and Drug Administration

(10)

10

(11)

(12)

12

(13)

y

Prerequisites

The data g

The data generated in an R&D

enerated in an R&D laborator

laboratory

y must be

must be

accurat

accurate, reproducible, and d

e, reproducible, and dependable. Therefore, it

ependable. Therefore, it

is imperative to

is imperative to establ

establish and follow standard

ish and follow standard

operating procedures (SOPs) for important activities

such as the qualifica

such as the qualification and calibration of

tion and calibration of

instruments and equipment (

e.g.

, weighing balance,

standard weights, temperature indicators, and

reference

reference standard

standards). It also is necessa

s). It also is necessary to keep

ry to keep

proper

proper detailed

detailed recor

records of

ds of these qualification and

these qualification and

calibration activit

calibration activities and other

ies and other laboratory

laboratory

experiments, observations, and related analytical data.

(14)

y

Process considerations

API development.

Current literature about the API and

Current literature

about the API and about

about

its possible future developments should be

its possible future developments should be kept in one place.

kept in one place.

Chal

Challenges to ov

lenges to overcome at this stage include:

ercome at this stage include:

patent infringement;

y

inconsistent r

inconsistent raw material quality and

aw material quality and supply;

supply;

y

hazardous

hazardous or

or nonregulated

nonregulated raw

raw materials;

materials;

y

costly raw materials;

y

unsafe or environmentally hazardous reactions;

y

low yields;

y

difficult-to-achieve lev

difficult-to-achieve levels of

els of purity (

purity (

e.g.

, for enantiomers);

y

scale-up;

y

difficult-to-handle processes;

y

polymorphism-related issues;

y

stability of

stability of intermediates or products.

intermediates or products.

y

R&D chemists must devise a route that can address as many of

these challenges as possible.

14

(15)

Obj

ective

y

T

To try the process on a model of

o try the process on a model of propos

proposed plant be

ed plant before

fore

committing la

committing large

rge sum of

sum of money on a

money on a produc

production unit.

tion unit.

y

Examinati

Examination of the for

on of the formula to

mula to determine its ability to

determine its ability to

withstand Batch-scale and process modification.

y

Evaluation and V

Evaluation and Valida

alidation for process and equipme

tion for process and equipments

nts

y

(16)

y

C

ost.

Raw materials, packaging

Raw materials, packaging materials, processes

materials, processes,,

and la

and labor

bor are major cost factors. R&D chemis

are major cost factors. R&D chemists can

ts can

help reduce process expenses by:

suggesting che

suggesting cheaper alternative r

aper alternative reagents or synthetic

eagents or synthetic

routes;

y

reducing raw material consumption (e.g., by

conducting process-optimization studies);

y

shortening process time cycles;

y

recycling materials when possible.

16

(17)

y

E

nvironmental friendliness.

T

Today

oday, R&

, R&D che

D chemis

mists are

ts are

expected to use

expected to use environmentally beni

environmentally benign (

gn (

i.e.

, green)

chemistr

chemistryy. Ideally

. Ideally, high-yield

, high-yielding processes shoul

ing processes should be

d be

developed so that

developed so that by-products ar

by-products are not pol

e not pollutants or are

lutants or are

treatable to eliminate pollution. Further processing of the

spent materials s

spent materials should

hould be attempt

be attempted

ed to rec

to recover the

over the

unrea

unreacted

cted materia

materials, by-product

ls, by-products, and solv

s, and solvents. For

ents. For

example, a recovered solvent can be treated so that it can

again match the desired quality specifications and thus be

recycled in the same proc

recycled in the same process step. Gaseous products shou

ess step. Gaseous products should

ld

be scrubbed effectively

be scrubbed effectively. The f

. The final spent material

inal spent materials from the

s from the

scrubber and the other processes should be assessed for

their load on the en

their load on the environment and be handl

vironment and be handled

ed

appropriately

(18)

y

y Process adaProcess adaptabilitptabilityy.. R&D chemists should modifR&D chemists should modify their techniquesy their techniques

to fit manufacturing environments. For example, to isolate a product, to fit manufacturing environments. For example, to isolate a product, R&D chemists should

R&D chemists should avavoid evaporating the solvents to drynessoid evaporating the solvents to dryness

because it is difficult to follow such procedures in the plant. Instead, a because it is difficult to follow such procedures in the plant. Instead, a suitable technique such as crystallization or precipitat

suitable technique such as crystallization or precipitation should ion should bebe developed because, in such cases, the product can be isolated by developed because, in such cases, the product can be isolated by centrifugatio

centrifugation or filtration in n or filtration in the plant.the plant.

y

y Similarly, the purification of a product should be achieved by means of Similarly, the purification of a product should be achieved by means of

crystallization or selective precipitation because other typical crystallization or selective precipitation because other typical laborator

laboratory ty techniquechniques such as column chromatoes such as column chromatography hagraphy haveve operational limitations at the plant scale.

operational limitations at the plant scale.

Methods of handling viscous materials in a plant also must be taken Methods of handling viscous materials in a plant also must be taken into ac

into account because the lcount because the large surface area arge surface area of of plant equipmeplant equipment andnt and piping can pose problems during material transfer.

piping can pose problems during material transfer.

y

y Solutions to these problems include performing one-pot reactionsSolutions to these problems include performing one-pot reactions

using a suitable solvent to tr

using a suitable solvent to transfer such materialansfer such materials. In additions. In addition,, reaction

reactions invs involving low temperatures or high pressures could beolving low temperatures or high pressures could be difficult to handle in the plant, and an alternative route should be difficult to handle in the plant, and an alternative route should be considered.

considered.

18

(19)

Developing the specifications Developing the specifications

II_{n-house specifications can be developed on the basis of the results of user}_{n-house specifications can be developed on the basis of the results of user}

trials and the CoA of a vendor¶s samples. trials and the CoA of a vendor¶s samples. Process scale-up issues.

Process scale-up issues. II_{t is important for R&D chemists to identif}_{t is important for R&D chemists to identify}_y

potential plant issues and to attem

potential plant issues and to attempt to address these concerns suitably atpt to address these concerns suitably at the R&D stage. Laboratory studies such as those described below can help the R&D stage. Laboratory studies such as those described below can help address many issues

address many issues a priori a priori to avoid surprises that might occur in the plantto avoid surprises that might occur in the plant scale-up batches.

scale-up batches.

S

S_{imulating the R&D plant environment.}_{imulating the R&D plant environment.} OO_{nce the route is finalized, the plant environment in}_{nce the route is finalized, the plant environment in}

R&D should be simulated as far as possibl

R&D should be simulated as far as possible by:e by:

using reaction vessels of similar type

using reaction vessels of similar type and shape (and shape (e.g.e.g., material of construction, vessel , material of construction, vessel shape, stirrer type,shape, stirrer type,

number of baffles, and diameter:length ratio of the

number of baffles, and diameter:length ratio of the vessel);vessel); using the same charging sequence of the raw

using the same charging sequence of the raw materials;materials; using similar mixing pattern and stirring parameters that are

using similar mixing pattern and stirring parameters that are achievable in plant vessels (achievable in plant vessels (e.g.e.g., similar tip, similar tip

speed or power requirement per unit volume of

speed or power requirement per unit volume of the reaction mass that cthe reaction mass that can be maintained in R&D);an be maintained in R&D); developing suitable in-pr

developing suitable in-process sampling procedures that are feasible in the ocess sampling procedures that are feasible in the ³controlled´ environmen³controlled´ environment of t of aa good manufacturing practice plant;

(20)

W

hy conduct Pilot Plant Studies?

y

A pilot plant allows inv

A pilot plan

t allows investigation of

estigation of a product and

a product and

process on an in

process on an intermediate

termediate scale b

scale before large

efore large

amounts of

amounts of money are

money are committed

committed to full-s

to full-scale

cale

production

y

It is usually not pos

It is usually not possibl

sible t

e to predict the effects of a

o predict the effects of a

many-fold increase in scale

y

It is not possi

It is not possible to

ble to design a la

design a larg

rge scale processing

e scale processing

plant from

plant from laboratory data alone with any degree

laboratory data alone with any degree

of

of succ

success

ess

20

(21)

A pilot plant can

b

e used for

y

Evaluating the results of l

Evaluating the results of laboratory studies and

aboratory studies and

making p

making product and process corrections and

roduct and process corrections and

improvements

y

Producing small q

Producing small quantities of

uantities of product for sensory

product for sensory,,

chemical, microbiological evaluations, l

chemical, microbiological evaluations, limited

imited

market

market testing or furnishin

testing or furnishing samples to potential

g samples to potential

customers, shelf-l

customers, shelf-life

ife and storage stability studies

and storage stability studies

y

Providing data t

Providing data that can be used in ma

hat can be used in making a decision

king a decision

on whether or not to proceed to a full-scale

production process; and in the case of a pos

production process; and in the case of a positive

itive

decision, designing and constr

(22)

Process

E

valuation:-

valuation:-22

22

P

P_ARAMETERS_ARAMETERS

O

O_{rder of mixing of}_{rder of mixing of} components

components _Mixing_Mixing speed speed Mixing Mixing time time

Rate of addition of Rate of addition of granulating agents, granulating agents,

solvents, solvents,

solutions of drug etc. solutions of drug etc. Heating and cooling

Heating and cooling Rates Rates Filters size Filters size (liquids) (liquids) Screen size Screen size (solids) (solids) Drying temp. Drying temp. And drying time And drying time

(23)

GM

_{P C}

_ON_ON

_SIDERATI

_ON_ON

y

Equipment qualification

y

Process validation

y

Regularly schedul

Regularly schedule preventativ

e preventative ma

e maintenance

intenance

y

Regularly proc

Regularly process review & revalidatio

ess review & revalidation

n

y

Relevant writt

Relevant written stand

en standard operating procedures

ard operating procedures

y

The use of competent technically qualified personnel

y

Adequate provision for training of personnel

y

A well-defined technology transfer system

y

V

Validated clean

alidated cleaning

ing procedures.

procedures.

y

An orderly

An orderly arrangement of equipment so as t

arrangement of equipment so as to ease material f

o ease material f low

low

&

(24)

SRTM University, Nanded

(25)

(26)

26

(27)

(28)

T

y

pical Liquid-Liquid

Extraction

Pilot Plant

Setup

DR ANTH

(29)

(30)

Automated

Automatedpilot plantpilot plant, controlled with only one pr, controlled with only one process control system for ocess control system for production of production of

Anthony Crasto Scale Up Techniques &amp; Pilot Plant

Principa

Principa

l

l

Scienti

Scienti

st,

st,

Process

Process

Research

Research

A Short Presentation

SCALE-UP--Definition

SCALE-UP--Definition

Steps in Scale-Up

Steps in Scale-Up

API Scale-Up During Research and

API Scale-Up During Research and

Development

Development

T

T

he ultimate g

he ultimate goal of

oal of drug sy

drug synthesis i

nthesis is to

s to scale up from

scale up from

producing milligram quantities in a laboratory to

producing milligram quantities in a laboratory to

producing ki

producing kilogram to ton

logram to ton quantities in a plant, all while

quantities in a plant, all while

maintainin

maintaining high quality and reproducibility at the low

g high quality and reproducibility at the lowest

est

cost.

cost.

The term

The term

process

process

in the pharmaceutical industry is broad

in the pharmaceutical industry is broad

and can apply to the process development w

and can apply to the process development work that l

ork that leads

eads

to the efficient, reproducible, economical, safe, and

to the efficient, reproducible, economical, safe, and

environmentally friend

environmentally friendly synthesis of the active

ly synthesis of the active

pharmaceutical ingredient (API) in a regulated

pharmaceutical ingredient (API) in a regulated

environment.

environment.

Sc

Sc

al

al

eu

eu

p

p

ne

ne

ed

ed

ed

ed

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Anthony Crasto Scale Up Techniques & Pilot Plant