Anthony Crasto Scale Up Techniques & Pilot Plant

Principall Scienti Principa Scientist, st, Process Research  A Short Presentation Dec 2011 [email protected]

SCALE-UP--Definition y

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 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 M s like money, money, material, 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 i nto a viable viabl e product by development developm ent of liable li able and practical procedure of manufacture. The art for designing of prototype using the data obtained from the pilot plant model.

Steps in Scale-Up y

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Define product economics based on projected market size and competitive selling and provide provi de 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 Desig n 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 correcti corrections ons and a decision decis ion on  whether or not to proceed with a full scale sca le plant development

API Scale-Up During Research and Development y

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goal of drug synthesis sy nthesis is i s to scale up from The ultimate goal producing milligram quantities in a laboratory to producing kilogram ki logram to ton quantities in a plant, all while maintaining maintainin g high quality and reproducibility at the lowest lowest cost. The term process in the pharmaceutical industry is broad and can apply to the process development work work that leads l eads to the efficient, reproducible, economical, safe, and environmentally friendly friend ly synthesis of the active pharmaceutical ingredient (API) in a regulated environment.

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Scal Sc aleu eup p ne need eded ed   y

Needed y

bench studies, y

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product characterization, characterization, purity 

animal studies y

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to make supplies for

toxicology  pharmacokinetics, ADME efficacy 

clinical studies

Pic is of a 10 lit assembly at ASTAR  ASTAR  5

Regulations y

Code of Federal Regulations Title 21 y

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Part 210 and 211 - Good Manufacturing Manufacturing Practice Practicess for Drugs Part 600 - 680 Processing Processing of Biological materials materials Part 820 820 - Quality System System Regulations Regulations for Medical Medical Devices y

Subpart C: Design Controls

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Process flow

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The increasingly stringent regulatory requirements requirements and the global nature of the pharmaceutical business are continuously  presenting new challenges to the pharmaceutical industry industr y, resulting in increased in creased competition competition and a need to produce highquality APIs.  API process development development has subsequently gained more attention because of the potential to establish early control control over the process at the research and development (R&D) stage by  identifying and an d addressing problematic issues a  priori. Thus, a systematic and prospective approach during R&D is key to achieving a successful prospective validation validation and scale-up. These activities are important and are frequently under scrutiny  by the Food and Drug Administration

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Prerequisites The data generated generated in an R&D laboratory laborator y must be accurate, accurate, reproducible, and dependable. d ependable. Therefore, it is imperative to establish establ ish and follow standard operating procedures (SOPs) for important activities such as the qualification qualifica tion and calibration of  instruments and equipment (e.g., weighing balance, standard weights, temperature indicators, and reference standards). standards). It also is necessary necessa ry to keep proper detailed records records of these qualification and calibration activities activities and other laboratory  experiments, observations, and related analytical data. 13

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Process considerations  API development. Current literature about the API and about its possible future developments should be kept in one place. Challenges Chal lenges to overcome overcome at this stage include: patent infringement; inconsistent raw raw material quality and supply; hazardous or nonregulated raw materials; costly raw materials; unsafe or environmentally hazardous reactions; low yields; difficult-to-achieve levels 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 y

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To try the process on a model of proposed propos ed plant before be fore committing large la rge sum of money on a production production unit. Examination Examinati on of the formula for mula to determine its ability to  withstand Batch-scale and process modification. Evaluation and Valida Validation tion for process and equipments equipme nts To identify identif y the critical features features of the process.

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Cost. Raw materials, packaging materials, processes, processes,

and labor la bor are major cost factors. R&D chemists chemis ts can help reduce process expenses by: suggesting cheaper cheaper alternative reagents 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, oday, R&D R&D chemis che mists ts are

expected to use environmentally benign beni gn (i.e., green) chemistry chemistr y. Ideally, Ideally, high-yielding high-yield ing processes should shoul d be developed so that by-products are are not pollutants pol lutants or are treatable to eliminate pollution. Further processing of the spent materials should s hould be attempted attempted to recover recover the unreacted unreacted materials, materials, by-products, by-products, and solvents. 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 process step. Gaseous products should shou ld be scrubbed effectively. effectively. The final f inal spent materials material s from the scrubber and the other processes should be assessed for their load on the environment environment and be handled handl ed appropriately, appropriately, causing no environmental damage.

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Process adaptabilit ada ptability y. R&D chemists should modify modif y their techniques to fit manufacturing environments. For example, to isolate a product, R&D chemists should avoid 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 precipitation should be developed because, in such cases, the product can be isolated by  centrifugation 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 laborator y techniqu techniques es such as column chromatography chromato graphy have have operational limitations at the plant scale. Methods of handling viscous materials in a plant also must be taken into account account because the large l arge surface area of plant equipment equipme nt and piping can pose problems during material transfer.

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Solutions to these problems include performing one-pot reactions using a suitable solvent to transfer transfer such materials. material s. In addition, addition , reactions reaction s involving involving low temperatures or high pressures could be difficult to handle in the plant, and an alternative route should be considered. 18

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 identif y potential plant issues and to attempt attem pt 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 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 possibl e 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 c an be maintained in R&D); developing suitable in-process in-process sampling procedures that are feasible in the ³controlled´ environment 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 plan t allows investigation investigation of a product and process on an intermediate in termediate scale before b efore large amounts of money are committed to full-scale full-s cale production It is usually not possibl pos siblee to to predict the effects of a many-fold increase in scale It is not possible possi ble to design a larg la rgee scale processing plant from laboratory data alone with any degree of success success

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A pilot plant can be used for y

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Evaluating the results of laboratory laboratory studies and making product p roduct and process corrections and improvements Producing small quantities q uantities of product for sensory, sensory, chemical, microbiological evaluations, limited l imited market testing or furnishing furnishing samples to potential customers, shelf-life shelf-l ife and storage stability studies Providing data that that can be used in making ma king a decision on whether or not to proceed to a full-scale production process; and in the case of a positive pos itive decision, designing and constructing constructing a full-size full- size plant or modifying an existing plant 21

Process E valuation:-

Order

Drying temp.  And drying time

Screen size (solids) Filters size (liquids)

of mixing of  components

P ARAMETERS

Heating and cooling Rates

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

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GMP y y y y y y y y y y

CONSIDERATION

Equipment qualification Process validation Regularly schedule schedul e preventative preventative maintenance ma intenance Regularly process process review & revalidation revalidatio n Relevant written written standard stand ard operating procedures The use of competent technically qualified personnel  Adequate provision for training of personnel  A well-defined technology transfer system  Validated  V alidated cleaning clean ing procedures.  An orderly arrangement of equipment so as to to ease material f low & prevent prevent cross- contamination contamination

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SRTM University, Nanded

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Typical Distillation Pilot Plant Setup

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Typical Liquid-Liquid Extraction Pilot PlantSetup PlantSetup

DR ANTHONY CRASTO

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

Pilot plant for processing medicinal and aromatic plants ...

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CASE STUDY BIO HYDROGEN y y y

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Cascade Process Ethanol fermentation: already existing in Brazil Biodiesel Hydrogen fermentation Methane fermentation

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