PROCESS DEVELOPMENT FACILITIES AND PILOT PLANT MANUFACTURING AND PRODUCTION OF BIOLOGICAL PRODUCTS (ERT 455) PROCESS DEVELOPMENT FACILITIES AND PILOT PLANT WEEK 15 Munira Mohamed Nazari School of Bioprocess Engineering UniMAP

TOPIC OUTLINE Primary and Secondary Processing,  Process Development,  Small-Scale Pilot Facilities, Physical Manipulation Pilot Plants, Filling and Packing Pilot Plants

SMALL-SCALE PILOT FACILITIES Chemical Synthesis Physical Manipulation Manufacturing Final Dosage Form Filling Packing Building Design Controls & Instrumentation

Chemical Synthesis ??? Is purposeful execution of chemical reactions to get a product. This happens by physical and chemical manipulations usually involving one or more reactions. In modern laboratory usage, this tends to imply that the process is reproducible, reliable, and established to work in multiple laboratories. A chemical synthesis begins by selection of compounds that are known as reagents or reactants. Various reaction types can be applied to these to synthesize the product, or an intermediate product. This requires mixing the compounds in a reaction vessel such as a chemical reactor. Many reactions require some form of work-up procedure before the final product is isolated.

There are two main types of processes used to manufacture pharmaceuticals: chemical synthesis based on chemical reactions, and bioprocessing based on the ability of microorganisms and cells to produce useful substances. Chemical synthesis can be used to produce pharmaceutical products with relatively low molecular weights in large volumes in short timespans. In addition, various chemical modifications can be applied to enhance the activity of the substance produced.

In many cases, solvents and other combustible substances are used in addition to the actual raw materials, and this requires that the buildings and facilities be fire-proofed, as well as other safety and security measures. Also, in many cases, corrosive fluids are involved, requiring the use of glass linings or other anti-corrosive measures. The manufacturing processes often entail crystallization and crystal separation, with many processes needed for transport and insertion of solids. In general, pharmaceutical plants produce many different products, and production lines must be kept separate from one another to prevent cross-contamination of products.

Chemical Synthesis (con’t…) Reaction Equipment SSPF with capacities that range from 20 – 100 L usually required for chemical synthesis stages. Glass equipment is usually used  to provide a high level corrosion resistance so that particular processes can took part.

Chemical Synthesis (con’t…) Solid Handling Equipments Most pharmaceutical intermediates are in solid form. Therefore, simple filters, centrifuges & dryers are required. The equipments  corrosion resistant & mobile (allowing the equipment to be connected to reaction equipment) The equipment will be replicate to be used on production scale that have similar modus operandi. The problem of small scale solid handling equipment is that it suffer from problem that much of product may be held up in the equipment that cause the production yield to be low.

A laboratory centrifuge is a piece of laboratory equipment, driven by a motor, which spins liquid samples at high speed. There are various types of centrifuges, depending on the size and the sample capacity. Function - to separate substances of greater and lesser density.

Chemical Synthesis (con’t…) Multi-purpose Equipment Multi-purpose equipments are sometimes provide so that it could be used for reactions, filtration and drying process. The advantage of this type of equipment is that it reduces handling. Therefore it also reduce the exposure of operators to chemicals. Although the equipment is complex, it usually compromise & the result is not cost effective and less optimal. not cost effective and less optimal. tidak kos efektif dan kurang optimum.

Chemical Synthesis (con’t…) Solvents As most of chemical syntheses use flammable solvent, it is necessary if the SSF be a flameproof area. These facilities normally located within laboratory complexes and thus it is appropriate if flameproof area is being separated from safe areas. This may be accomplished b using pressurized air locks and use pressurization of safe areas. A flameproof drum handling and storage area is build outside from the building to reduce ventilation need as SSF uses large number of solvents (that is handled in drum)

Chemical Synthesis (con’t…) Methods of transferring solvents: Require a safely transferring from drums to manufacturing equipment. One method involve moving the drums from drum store to dispensary area, where the require quantity is decanted into safe solvent container before it is transferred to reaction area. For some cases, intermediate containers could be use to transfer liquid from drum area to dispensary. Solvent recovery facilities are hardly find in the SSF unless one or more solvent is used in a large quantity and can be recovered using the equipment used for chemical processes.

Chemical Synthesis (con’t…) Toxicity Chemical intermediate that contains active pharmaceutical ingredient are often highly potent. The designation of facility must ensure the safety of operating personnel. This may covered by the building design, use of fume cupboard, local extract ventilation, glove-boxes, rapid transfer ports, contained transfer coupling and air suits. LEV is a system that uses extract ventilation to prevent or reduce the level of airborne hazardous substances from being breathed by people in the workplace, which draws pollutants away from a process or operation that is likely to release a hazardous substance into the air and which consists of an inlet, such as a hood, slot, booth or cabinet placed around or close to the point of release of the substance. This device is connected via ducting to the inlet of a fan or air mover. The extracted air is usually discharged to the atmosphere or returned elsewhere in the workplace, having first been cleaned to make it safe for release.

Chemical Synthesis (con’t…) Fume cupboard Ventilation device that is designed to limit exposure to hazardous or noxious fumes, vapors or dust. Is typically a large piece of equipment enclosing five sides of a work area, the bottom of which is most commonly located at a standing work height. Designed to address goals of: protect the user. protect the product or experiment. protect the environment.

Chemical Synthesis (con’t…) Glove box Sealed container that is designed to allow one to manipulate objects where a separate atmosphere is desired. Built into the sides of the glove box are gloves arranged in such a way that the user can place their hands into the gloves and perform tasks inside the box without breaking containment. Two types of glove boxes: allows a person to work with hazardous substances, such as radioactive materials. allows manipulation of substances that must be contained within a very high purity inert atmosphere, such as argon or nitrogen. Part or all of the box is usually transparent to allow the user to see what is being manipulated.

Chemical Synthesis (con’t…) Environmental Considerations Chemical synthesis route is highly complex (in some cases more than 20 intermediates are made before the active pharmaceutical ingredient is prepared) Facilities must be equipped with waste streams so that all waste could be handled properly. Widely large variety of chemicals produced in a low volumes usually precludes usage of an on-site effluent treatment plant. Liquids and solids must be categorized in groups that can be mixed together for disposal.

Chemical Synthesis (con’t…) Vapor & gaseous emission are being treated depending on their quantity & toxicity. Vapors can be condensed by using a low temperature system  using liquid nitrogen cooling system for economical matter at small scale. For gaseous emission, solvent, acid or alkali scrubbing system may be required. Choice of equipment depends on : Chemical used Flexibility required

PHYSICAL MANIPULATION A process that does not involve chemical reaction but change the purity of the material. Involves: crystallization, filtration, chromatography, milling, drying or blending. This process is required to fulfill one or more of these requirements: Crystal morphology Moisture content Specific particle size change the purity of the material. menukar ketulenan bahan

PHYSICAL MANIPULATION (cont..) Equipment used for process such as crystallization, filtration & centrifugation may be as same as the one used for chemical synthetic process. Some other equipment is used to carry out other particular operation such as milling, micronization or granulation. Equipments need to be mobile to achieve maximum flexibility. As many organic solids are explosive, it is likely the most appropriate method to be used inert gas blanketing.

MANUFACTURING THE FINAL DOSAGE FORM Liquid, Gels Creams & Syrup Equipment used for chemical synthesis may be suitable for blending operations. Advantage: using equipment placed near to filling equipment  possible to run the formulated product directly. Choice depends on the nature of the product & overall facilities available. Solids For solid final dosage form  solid mixing system is required. Usually required a second manufacturing stage beyond formulation  production Machinery is highly specialized & designed to carry out a particular task

FILLING Process of putting the finished product into primary container (bottle, blister pack etc.) Small quantity: hand operated bench machine Individual machines separate and manually moving filled pack from one place to another Large quantity: automatic machine Integrated filling lines (filling-check weighing-washing) connected together.

PACKING Process of putting the product (primary packaging) into secondary packaging. Clinical trials : packing by hands If more than 1000 containers: semi-automatic packing machine Chosen packs will be tested on clinical trials – (sampling)

BUILDING DESIGN CHANGING ROOM Personnel dressed in suitable clothing No cross contamination, no active material out of the building EQUIPMENT STORE Not damaged during storage Use GMP pallets Unit must be numbered, have log book & signature PORTABLE EQUIPMENT Width of corridors Size of doors, lifts, transfer hatches

BUILDING DESIGN (con’t…) OFFICES Write up area out of the main development area. Offices between changing area to reduced time. ENVIRONMENTAL CONTROL Controlled environment to prevent cross contamination. Need to supply every room with high quality air. LABORATORY Necessary to have in-house laboratory. Close to production to reduce time. Maybe inside controlled area.

BUILDING DESIGN (con’t…) Engineering workshop Must be close to process room Tools are not lost Source of contamination Movable walls Services through ceiling Movable walls in high quality environment cleaning Equipment Specific area Automated washing machines Communication Intercom systems, visual pannels, CCTV system,etc.

BUILDING DESIGN (con’t…) Airlocks / pressure regimes To prevent contamination of product & cross contamination. Flammable vapor contact with non-flameproof equipment. Active compound contact with operator. Building services Water (purified, portable, cooling), air (compress, breathing), vacuum. Air conditioning with temperature and humidity control. Services for solvents used in high volumes.

BUILDING DESIGN (con’t…) A containment building, in its most common usage, is a steel or reinforced concrete structure enclosing a nuclear reactor. It is designed, in any emergency, to contain the escape of radiation to a maximum pressure in the range of 60 to 200 psi ( 410 to 1400 kPa). The containment is the fourth and final barrier to radioactive release (part of a nuclear reactor's defence in depth strategy), the first being the fuel ceramic itself, the second being the metal fuel cladding tubes, the third being the reactor vessel and coolant system.

CONTROLS & INSTRUMENTATION Depend on the quantity of products and equipment used. Considerations: Equipment compatible with environment Instrumentation suitable for in-house calibration Control systems should be short, simple and flexible

THANK YOU Happy Holidays!! Merry Christmas & New Year Good Luck for Your Exam…

Differentiate contamination and cross-contamination. [20m] Propose four advantages of GMP standard application for food processing industry. [20m] Differentiate contamination and cross-contamination. [20m] Explain why parameters below need to be qualified in HVAC system. Temperature [20m] Room pressure [20m] Explain why we need to design proper material storage and handling process in pharmaceutical industry. [20m]