Principal Scientist, Process ResearchA Short Presentation

Dec 2011 amcrasto@gmail.com

SCALE-UP--DefinitionAct of using results obtained from laboratory studies for

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

It is the part of the pharmaceutical industry where a lab scale formula is transformed into a viable product by development of liable and practical procedure of manufacture.

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

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Define product economics based on projected market size and competitive selling and provide guidance for allowable manufacturing costs

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

Define key rate-controlling steps in the proposed process

Conduct preliminary larger-than-laboratory studies with equipment to be used in rate-controlling step to aid in plant design

Design and construct a pilot plant including provisions for process and environmental controls, cleaning and sanitizing systems, packaging and waste handling systems, and meeting regulatory agency requirements

Evaluate pilot plant results (product and process) including process economics to make any corrections and a decision on whether or not to proceed with a full scale plant development

Steps in Scale-Up

API Scale-Up During Research and DevelopmentThe ultimate goal of drug synthesis is to scale up

from producing milligram quantities in a laboratory to producing kilogram to ton quantities in a plant, all while maintaining high quality and reproducibility at the lowest cost.

The term process in the pharmaceutical industry is broad and can apply to the process development work that leads to the efficient, reproducible, economical, safe, and environmentally friendly synthesis of the active pharmaceutical ingredient (API) in a regulated environment.

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Needed to make supplies forbench studies,

product characterization, purityanimal studies

toxicology pharmacokinetics, ADME efficacy

clinical studies

Pic is of a 10 lit assembly at ASTAR

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Code of Federal Regulations Title 21Part 210 and 211 - Good Manufacturing

Practices for DrugsPart 600 - 680 Processing of Biological

materialsPart 820 - Quality System Regulations for

Medical Devices Subpart C: Design Controls

Process flow

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The increasingly stringent regulatory requirements and the global nature of the pharmaceutical business are continuously presenting new challenges to the pharmaceutical industry, resulting in increased competition and a need to produce high-quality APIs.

API process development has subsequently gained more attention because of the potential to establish early control over the process at the research and development (R&D) stage by identifying and addressing problematic issues a priori. Thus, a systematic and prospective approach during R&D is key to achieving a successful prospective validation and scale-up.

These activities are important and are frequently under scrutiny by the Food and Drug Administration

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PrerequisitesThe data generated in an R&D laboratory must be accurate, reproducible, and dependable. Therefore, it is imperative to establish and follow standard operating procedures (SOPs) for important activities such as the qualification and calibration of instruments and equipment (e.g., weighing balance, standard weights, temperature indicators, and reference standards). It also is necessary to keep proper detailed records of these qualification and calibration activities and other laboratory experiments, observations, and related analytical data.

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

inconsistent raw material quality and supply;hazardous or nonregulated raw materials;costly raw materials;unsafe or environmentally hazardous reactions;low yields;difficult-to-achieve levels of purity (e.g., for

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

many of these challenges as possible.

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ObjectiveTo try the process on a model of proposed plant

before committing large sum of money on a production unit.

Examination of the formula to determine it’s ability to withstand Batch-scale and process modification.

Evaluation and Validation for process and equipments To identify the critical features of the process.

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Cost. Raw materials, packaging materials, processes, and labor are major cost factors. R&D chemists can help reduce process expenses by:suggesting cheaper alternative reagents or synthetic routes;

reducing raw material consumption (e.g., by conducting process-optimization studies);

shortening process time cycles;recycling materials when possible.

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Environmental friendliness. Today, R&D chemists are expected to use environmentally benign (i.e., green) chemistry. Ideally, high-yielding processes should be developed so that by-products are not pollutants or are treatable to eliminate pollution. Further processing of the spent materials should be attempted to recover the unreacted materials, by-products, and solvents. 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 process step. Gaseous products should be scrubbed effectively. The final spent materials from the scrubber and the other processes should be assessed for their load on the environment and be handled appropriately, causing no environmental damage.

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Process adaptability. R&D chemists should modify their techniques to fit manufacturing environments. For example, to isolate a product, R&D chemists should avoid evaporating the solvents to dryness because it is difficult to follow such procedures in the plant. Instead, a suitable technique such as crystallization or precipitation should be developed because, in such cases, the product can be isolated by centrifugation or filtration in the plant.

Similarly, the purification of a product should be achieved by means of crystallization or selective precipitation because other typical laboratory techniques such as column chromatography have operational limitations at the plant scale.

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

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

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Developing the specificationsIn-house specifications can be developed on the basis of the results of user trials and the CoA of a vendor’s samples.

Process scale-up issues. It is important for R&D chemists to identify potential plant issues and to attempt to address these concerns suitably at the R&D stage. Laboratory studies such as those described below can help address many issues a priori to avoid surprises that might occur in the plant scale-up batches.

Simulating the R&D plant environment. Once the route is finalized, the plant environment in R&D should be simulated as far as possible by:•using reaction vessels of similar type and shape (e.g., material of construction, vessel shape, stirrer type, number of baffles, and diameter:length ratio of the vessel);•using the same charging sequence of the raw materials;•using similar mixing pattern and stirring parameters that are achievable in plant vessels (e.g., similar tip speed or power requirement per unit volume of the reaction mass that can be maintained in R&D);•developing suitable in-process sampling procedures that are feasible in the “controlled” environment of a good manufacturing practice plant;•using similar filtration cloth or medium;•using a similar type of dryer and drying parameters.

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 scale processing plant from laboratory data alone with any degree of success

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A pilot plant can be used forEvaluating 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

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Process Evaluation:-

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PARAMETERS

Order of mixing of components Mixing

speed

Mixing time

Rate of addition of granulating agents,

solvents,solutions of drug etc.

Heating and coolingRates

Filters size (liquids)

Screen size(solids)

Drying temp.And drying time

GMP CONSIDERATION

Equipment qualificationProcess validationRegularly schedule preventative maintenanceRegularly process review & revalidationRelevant written standard operating proceduresThe use of competent technically qualified personnelAdequate provision for training of personnelA well-defined technology transfer system Validated cleaning procedures.An orderly arrangement of equipment so as to ease

material flow & prevent cross- contamination

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SRTM University, Nanded 24

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Typical Distillation Pilot Plant Setup 27

DR ANTHONY CRASTO 28

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Automated pilot plant, controlled with only one process control system for production of recombinant technical enzymes

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CASE STUDY BIO HYDROGEN

Cascade ProcessEthanol fermentation: already existing in

BrazilBiodiesel

Hydrogen fermentationMethane fermentation

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Sugarcane

Sugar

BoilerBoiler

Sugar production

Molasses

Ethanol fermentation

Bagasse, stover

Cane juice

Crushing

Hydrogen fermentation

Methane fermentation

Vinasse: Xylose, Lignin

Vinasse: residual sugars

Distillation

Sugar process

Ethanol process Ethanol

Hydrolysis

Hexose, Pentose, Lignin,

Residues

HydrogenMethane

Lignocellulose utilize process

Energy

Sugarcane

Sugar

BoilerBoiler

Sugar production

Sugar production

Molasses

Ethanol fermentation

Ethanol fermentation

Bagasse, stover

Cane juice

CrushingCrushing

Hydrogen fermentation

Hydrogen fermentation

Methane fermentation

Methane fermentation

Vinasse: Xylose, Lignin

Vinasse: residual sugars

Vinasse: Xylose, Lignin

Vinasse: residual sugars

DistillationDistillation

Sugar process

Ethanol process Ethanol

HydrolysisHydrolysis

Hexose, Pentose, Lignin,

Residues

HydrogenMethane

Lignocellulose utilize process

Energy

Sugar CaneCrushing

Cane Juice

Sugar Process Molasses

BagasseHydrolysate: Hexose, Pentose, Lignin

Residues: Ash, Char

Ethanol Fermentation

DistillationVinasse Biomass

Hydrogen Fermentation

Methane Fermentation

HydrogenProcess E. PowerMethaneProcess Steam

A

B

C

D

10,000 t/day(1 sugar Mill)

3.000 t/day(50% moisture)

Hexose 525 tPentose 315 tLignin 210 t

Residues 450 t

Gas for industryRaw material

GasFuel

Pilot Plant Placement 35

LAYOUT 36

01-5 100L Vessel

01-1-1Tank for raw material preparation01-1-6 Stirring device

01-1-4 Stirring device

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01-3-1 Bioreactor

01-3-2 Circulation system

01-3-6 Flow monitor

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1.Nordihydrocapsaicin2.Capsaicin3.Dihydrocapsaicin

Eluent : A) methanol/water/TFA (50/50/0.1)B) methanol/TFA (100/0.1)10-30%B (0-5 min), 30%B (5-10 min)

Temperature

: 25ºC for 50 X 4.6 mmI.D.ambient for 50 X 20 mmI.D.

Detection

: UV at 280 nm

Sample : methanol extract of a commercial cayenne pepper(1 g cayenne pepper/3 mL)

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Axial Compression Technology to semi-prep column (20 mm i. d. and 30 mm i. d.). The column bed is compressed adequately by attaching the end assembly newly designed. It provides proper bed density (10% higher than conventional columns) and bed uniformity. The combination of technology acquired by long our experience with DAC column, the advanced technique of slurry packing, and new hardware design offers an outstanding durability and efficiency

Column : 50 X 20 mmI.D. 5 µm

Eluent : A) water B) methanol

Gradient

: 5%B-95%B

Flow rate

: 50 mL/min

Pressure

: ∼17MPa

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ConclusionThe various process considerations described in this article can help chemists understand and adopt a systematic and prospective approach in research and development to have documented and controlled synthetic processes. This approach will help manufacturers meet product-quality objectives consistently and build a good basis for achieving the goals of prospective validation and scale-up activities.

References 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.

Process Chemistry in the Pharmaceutical Industry, K.G. Gadamasetti, Ed. (Marcell Dekker, Inc., New York, NY, 1999), p. 389.

Internet databases such as Cole-Palmer Chemical compatibility database, ARO chemical compatibility, eFunda O ring material compatibility with chemicals, Varidisk chemical compatibility information, Flowline Chemical compatibility database and DMRTM fluid compatibility table by Daemar Inc.

Physician’s Desk Reference (Thomson PDR,Montvale, NJ, 1997). S. Ahuja, Chiral Separations: Applications and Technology (ACS

Publications,Washington, DC, 1996), p. 4. G. Chawla and A. Bansal, “Challenges in Polymorphism of

Pharmaceuticals,” Scrip 5(1), 9 (Jan.–Mar. 2004). N. Yoswathananont et al., “A Novel Three-Component Pseudo-Polymorphism in the

Cholamide Inclusion Crystals Promoted by the Combination of Organic Guest and Water,” Chem. Lett. 12, 1234 (2002)

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