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Principal Scientist, Process Research A Short Presentation Dec 2011 amcrasto@gmail.com


SCALE-UP--Definition  Act 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.


Steps in Scale-Up  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

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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


API Scale-Up During Research and Development ď‚— The 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.

ď‚— 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. 4


 Needed to make supplies for  bench studies, 

product characterization, purity

 animal 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 21  Part 210 and 211 - Good Manufacturing Practices for Drugs  Part 600 - 680 Processing of Biological materials  Part 820 - Quality System Regulations for Medical Devices 

Subpart C: Design Controls

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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 highquality 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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ď‚— Prerequisites

The 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. 13


 Process considerations

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API 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. 14


Objective  To 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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ď‚— 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 specifications In-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. 19


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 for ď‚— Evaluating the results of laboratory studies and

making product and process corrections and improvements ď‚— 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 ď‚— 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 21


Process Evaluation:-

Drying temp. And drying time

Screen size (solids) Filters size (liquids)

Order of mixing of components

PARAMETERS

Heating and cooling Rates

Mixing speed Mixing time Rate of addition of granulating agents, solvents, solutions of drug etc.

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GMP CONSIDERATION  Equipment qualification  Process validation  Regularly schedule preventative maintenance  Regularly process review & revalidation  Relevant written standard operating procedures  The use of competent technically qualified personnel  Adequate provision for training of personnel  A 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

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Typical Distillation Pilot Plant Setup

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DR ANTHONY CRASTO

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Automated pilot plant, controlled with only one process control system for production of recombinant technical enzymes 30


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CASE STUDY BIO HYDROGEN  Cascade Process  Ethanol fermentation: already existing in Brazil  Biodiesel  Hydrogen fermentation  Methane fermentation

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Crushing Boiler Sugarcane

Bagasse, stover

Ethanol fermentation

Ethanol process

Hydrolysis

Hexose, Pentose, Lignin, Residues

Lignocellulose utilize process

Cane juice

Sugar production

Sugar

Molasses

Sugar process

Distillation Vinasse: residual Xylose, sugars Lignin Hydrogen fermentation

Methane fermentation

Ethanol

Energy

Methane Hydrogen 33


10,000 t/day

Sugar Cane(1 sugar Mill) 3.000 t/day (50% moisture) Crushing Bagasse Hexose 525 t Hydrolysate: Hexose, Pentose, Lignin Pentose 315 t Lignin 210 t Residues: Ash, Char Residues 450 t Cane Juice

Ethanol Fermentation Vinasse Sugar Process Molasses Distillation Biomass

A

Gas for industry Raw material

Hydrogen FermentationHydrogen B Process E. Power C Gas Methane Fermentation Methane D Fuel Process Steam


Pilot Plant Placement

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

01-5 100L Vessel 01-1-4 Stirring device

LAYOUT

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01-3-1 Bioreactor

01-3-6 Flow monitor

01-3-2 Circulation system 37


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)

Temperat : 25ยบC for 50 X 4.6 mmI.D. ure ambient for 50 X 20 mmI.D. Detection : UV at 280 nm

1.Nordihydrocapsaicin 2.Capsaicin 3.Dihydrocapsaicin

Sample

: methanol extract of a commercial cayenne pepper (1 g cayenne pepper/3 mL) 38


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 Eluent Gradient Flow rate Pressure

: : : :

50 X 20 mmI.D. 5 Âľm A) water B) methanol 5%B-95%B 50 mL/min

: âˆź17MPa

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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 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.

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

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SCALEUP TECHNIQUES & PILOT PLANT