anthony crasto scale up techniques & pilot plant

8/3/2019 Anthony Crasto Scale Up Techniques & Pilot Plant

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Principal Scientist, Process Research

A Short Presentation

Dec 2011

[email protected]


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SCALE-UP--Definition

y

Act of using results obtained from laboratory studies for designing aprototype and a pilot plant process;construction a pilot plant andusing pilot plant data for designing and constructing a full scale plantor modifying an existing plant

y It is a place were the 5 Ms like money, material, man, method andmachine are brought together for the manufacturing of the products.

y It is the part of the pharmaceutical industry where a lab scale formulais transformed into a viable product by development of liable andpractical procedure of manufacture.

y The art for designing of prototype using the data obtained from thepilot plant model.


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API Scale-Up During Research and

Developmenty The ultimate goal of drug synthesis is to scale up from

producing milligram quantities in a laboratory toproducing kilogram to ton quantities in a plant, all while

maintaining high quality and reproducibility at the lowestcost.

y The term process in the pharmaceutical industry is broadand can apply to the process development work that leads

to the efficient, reproducible, economical, safe, andenvironmentally friendly synthesis of the activepharmaceutical ingredient (API) in a regulatedenvironment.

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Scaleup needed

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y Needed to make supplies for

y bench studies,

y

product characterization, purityy animal studies

y toxicology

y pharmacokinetics, ADME

y efficacy

y clinical studies

Pic is of a 10 lit assembly at ASTAR


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Regulations

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y Code of Federal Regulations Title 21

y Part 210 and 211 - Good Manufacturing Practices for

Drugsy Part 600 - 680 Processing of Biological materials

y Part 820 - Quality System Regulations for MedicalDevices

y

Subpart C: Design Controls


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Process flow

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y PrerequisitesThe data generated in an R&D laboratory must beaccurate, reproducible, and dependable. Therefore, itis imperative to establish and follow standardoperating procedures (SOPs) for important activities

such as the qualification and calibration ofinstruments and equipment (e.g., weighing balance,standard weights, temperature indicators, andreference standards). It also is necessary to keep

proper detailed records of these qualification andcalibration activities and other laboratoryexperiments, observations, and related analytical data.

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y Process considerationsAPI development. Current literature about the API and aboutits possible future developments should be kept in one place.Challenges to overcome at this stage include:patent infringement;

y inconsistent raw material quality and supply;y hazardous or nonregulated raw materials;y

costly raw materials;y unsafe or environmentally hazardous reactions;y low yields;y difficult-to-achieve levels of purity (e.g., for enantiomers);y scale-up;y

difficult-to-handle processes;y polymorphism-related issues;y stability of intermediates or products.y R&D chemists must devise a route that can address as many of

these challenges as possible.

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y Cost. Raw materials, packaging materials, processes,

and labor are major cost factors. R&D chemists canhelp reduce process expenses by:suggesting cheaper alternative reagents or syntheticroutes;

y reducing raw material consumption (e.g., byconducting process-optimization studies);

y shortening process time cycles;

y recycling materials when possible.

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y Process adaptability. R&D chemists should modify their techniquesto fit manufacturing environments. For example, to isolate a product,R&D chemists should avoid evaporating the solvents to drynessbecause it is difficult to follow such procedures in the plant. Instead, asuitable technique such as crystallization or precipitation should bedeveloped because, in such cases, the product can be isolated bycentrifugation or filtration in the plant.

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

crystallization or selective precipitation because other typicallaboratory techniques such as column chromatography haveoperational limitations at the plant scale.

Methods of handling viscous materials in a plant also must be takeninto account because the large surface area of plant equipment andpiping can pose problems during material transfer.

y Solutions to these problems include performing one-pot reactionsusing a suitable solvent to transfer such materials. In addition,reactions involving low temperatures or high pressures could bedifficult to handle in the plant, and an alternative route should beconsidered.

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Why conduct Pilot Plant Studies?yA pilot plant allows investigation of a product and

process on an intermediate scale before large

amounts of money are committed to full-scaleproduction

y It is usually not possible to predict the effects of amany-fold increase in scale

y It is not possible to design a large scale processingplant from laboratory data alone with any degreeof success

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A pilot plant can be used fory Evaluating the results of laboratory studies and

making product and process corrections andimprovements

y Producing small quantities of product for sensory,

chemical, microbiological evaluations, limitedmarket testing or furnishing samples to potentialcustomers, shelf-life and storage stability studies

y Providing data that can be used in making a decision

on whether or not to proceed to a full-scaleproduction process; and in the case of a positivedecision, designing and constructing a full-size plantor modifying an existing plant

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Process Evaluation:-

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PARAMETERS

Order of mixing of

components Mixing

speed

Mixingtime

Rate of addition of

granulating agents,

solvents,

solutions of drug etc.

Heating and cooling

Rates

Filters size

(liquids)

Screen size

(solids)

Drying temp.

And drying time


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GMP CONSIDERATION

y Equipment qualification

y Process validationy Regularly schedule preventative maintenance

y Regularly process review & revalidation

y Relevant written standard 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 Validated cleaning procedures.

y An orderly arrangement of equipment so as to ease material f low& prevent cross- contamination

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SRTM University, Nanded 24


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Typical Distillation Pilot Plant Setup 27


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Typical Liquid-Liquid

Extraction Pilot PlantSetup

DR ANTHONY CRASTO 28


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Pilot plant for processing medicinal

and aromatic plants ...

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CASE STUDY BIO HYDROGEN

y Cascade Process

y Ethanol fermentation: already existing in Brazil

y Biodiesel

y Hydrogen fermentation

y Methane fermentation


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BIO HYDROGEN PROCESS

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Sugarcane

Sugar

BoilerBoiler

Sugar

production

Molasses

Ethanol

fermentation

Bagasse,

stover

Cane

juiceCrushing

Hydrogen

fermentation

Methane

fermentation

Vinasse:

Xylose, Lignin

Vinasse:

residual sugars

Distillation

Sugar process

Ethanol processEthanol

Hydrolysis

Hexose,Pentose,

Lignin,

Residues

Hydrogen

Methane

Lignocellulose utilize process

Energy

Sugarcane

Sugar

BoilerBoiler

Sugar

production

Sugar

production

Molasses

Ethanol

fermentation

Ethanol

fermentation

Bagasse,

stover

Cane

juiceCrushingCrushing

Hydrogen

fermentation

Hydrogen

fermentation

Methane

fermentation

Methane

fermentation

Vinasse:

Xylose, Lignin

Vinasse:

residual sugarsVinasse:

Xylose, Lignin

Vinasse:

residual sugars

DistillationDistillation

Sugar process

Ethanol processEthanol

HydrolysisHydrolysis

Hexose,Pentose,

Lignin,

Residues

Hydrogen

Methane

Lignocellulose utilize process

Energy


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Sugar Cane

Crushing

Cane Juice

Sugar Process Molasses

Bagasse

Hydrolysate: Hexose, Pentose, LigninResidues: Ash, Char

Ethanol Fermentation

Distillation

Vinasse

BiomassHydrogen Fermentation

Methane Fermentation

Hydrogen

Process E. Power

Methane

Process Steam

A

B

C

D

10,000 t/day

(1 sugar Mill)

3.000 t/day

(50% moisture)

Hexose 525 t

Pentose 315 tLignin 210 t

Residues 450 t

Gas for industry

Raw material

Gas

Fuel

Overall Process Flow


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Pilot Plant Placement 35


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LAYOUT 36

01-5 100L Vessel

01-1-1Tank for raw material preparation

01-1-6 Stirring device

01-1-4 Stirring device


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Conclusion

The various process considerations described in this article

can help chemists understand and adopt a systematic and

prospective approach in research and development to havedocumented and controlled synthetic processes.

This approach willhelp manufacturers meet product-quality

objectives consistently and build a good basis for achieving

thegoals of prospective validation and scale-up activities.


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Referencesy The theory & practice of industrial pharmacy by Leon Lachman, Herbert A. Lieberman, Joseph L.

kenig, 3rd edition, published by Varghese Publishing house.

Impurities: Guidelines for Residual Solvents, Q3C, recommended by ICH on July 17, 1997.

y Process ChemistryinthePharmaceutical Industry, K.G. Gadamasetti, Ed. (Marcell Dekker, Inc., NewYork, NY, 1999), p. 389.

y Internet databases such as Cole-Palmer Chemical compatibility database, ARO chemicalcompatibility, eFunda O ring material compatibility with chemicals, Varidisk chemical compatibility

information, Flowline Chemical compatibility database and DMRTM fluid compatibility table byDaemar Inc.

y Physicians DeskReference (Thomson PDR,Montvale, NJ, 1997).

y S. Ahuja, Chiral Separations: Applications andTechnology (ACS Publications,Washington, DC, 1996),p. 4.

y G. Chawla and A. Bansal, Challenges in Polymorphism of Pharmaceuticals, Scrip 5(1), 9 (Jan.Mar.2004).

y N. Yoswathananont et al., ANovel Three-Component Pseudo-Polymorphism in the CholamideInclusion Crystals Promoted by the Combination of Organic Guest and Water, Chem. Lett. 12, 1234(2002)

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MyOwn Scaleup Site and Thanks

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https://sites.google.com/site/anthonycrastoscaleup/home

anthony crasto scale up techniques & pilot plant

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