GMP Manufacturing Process - UKM Lecture - PDF

g- non solid : cream - * solid tablet - : GMP MANUFACTURING: PHARMACEUTICAL PRODUCTION PROCESS Azmy A Hamid...

g- non solid : cream - * solid tablet - : GMP MANUFACTURING: PHARMACEUTICAL PRODUCTION PROCESS Azmy A Hamid UKM Lecture 9th December 2024 Credit inputs: PM Dr Ng Shiow Fern Pharmaceutical Manufacturing: The Production Process Welcome to the intricate world of pharmaceutical manufacturing. Today, we'll explore the essential steps involved in producing safe and effective medicines, from raw material procurement to final packaging. Introduction to Pharmaceutical Production Research and Development Quality Assurance Regulatory Compliance Initiating the journey, scientists Maintaining the highest standards, quality Stringent regulations and guidelines meticulously research and develop new assurance systems guarantee the purity govern the entire process, ensuring safety drugs, testing efficacy and safety. and potency of every batch. and efficacy for patients. Raw Material Procurement and Quality Control API Sourcing 4 excepients Testing that has been Pharmaceutical companies verified by Raw materials undergo rigorous NPRA. carefully select suppliers for high- testing to ensure they meet quality raw materials. stringent specifications. Documentation Complete documentation is maintained throughout the process to track material history. - Formulation and Compounding Active Pharmaceutical Ingredients (APIs) Active ingredients are carefully weighed and measured to ensure precise dosage. A- evenly distributed - from mixing , sheering Excipients Inactive ingredients are added for stability, binding, and other purposes. Mixing and Blending Thorough mixing ensures uniform distribution of ingredients for consistency. Dosage Form Preparation 1 Tablets Solid dosage forms, typically compressed powders, for oral administration. 2 Capsules Powder, liquid, or granules encased in a gelatin shell, for swallowing. 3 Liquids Solutions, suspensions, or emulsions for oral, topical, or injectable use. Tableting and Capsule Filling Granulation Compression Capsule Filling Powders are granulated to improve Granules are compressed into tablets Powders or granules are filled into flowability and compressibility. using a specialized machine. capsules using automated machines. tablets → shape of. Coating and Packaging Coating 1 Tablets may be coated to mask taste, improve stability, or enhance appearance. Packaging 2 Tablets, capsules, or liquids are packaged into bottles, blisters, or vials. Labeling 3 Labels with product name, dosage, and other information are applied. Sterilization and Aseptic Processing Sterilization 1 Eliminating microorganisms from products or equipment through heat, radiation, or filtration. more strict r Aseptic Processing ie injectables leg clean room is higher grade 2 Manufacturing processes conducted under sterile conditions to prevent contamination. Quality Control 3 Regular monitoring and testing ensure sterility and safety throughout the process. In-Process Quality Checks 100% Purity Ensuring the product contains only the intended ingredients. 100% Potency Confirming the product's strength and effectiveness. 100% Stability Verifying the product's ability to maintain its quality over time. Regulatory Compliance and cGMP Standards FDA Guidelines Good Manufacturing Practices Quality Auditing (cGMP) The U.S. Food and Drug Administration Regular audits ensure compliance with (FDA) sets strict guidelines for GMP standards are essential for ensuring regulations and internal quality standards. pharmaceutical manufacturing. product quality, safety, and efficacy. Pharmaceutical Semisolids Multiple forms of oral semi solid dosages to deliver the pharmaceutical active ingredients to the intended patients 12 Pharmaceutical semisolids Ointments, creams, and pastes are semisolid dosage forms intended for topical application. Pharmaceutical semisolids are mostly dispersions. Inert, compatibility with active ingredient, stable, patient acceptance. Can be medicated or non-medicated Most of the semisolid preparations are applied to the skin for topical relief of dermatologic conditions, whereas a lesser portion of these preparations are applied to mucous membranes such as rectal and buccal tissue, vaginal/rectal mucosa, external ear lining, nasal mucosa, and cornea. 13  Dispersion Dispersed Continuous type phase phase Examples Cream Liquid Liquid Aqueous cream BP, (oil-in-water, Oily Cream BP water-in oil) Type of Paste Solid Semisolid Zinc and salicylic semisolids paste, coal tar paste Ointment Liquid/ Semisolid Macrogol Ointment Semisolid BPC, Wool Alcohol ointment BP. Gel Solid Liquid Carbomer, hypromellose eye gels _ 14 LIQUID/CREAM / GEL / PASTE / LOTION / Pharma Manufacturing Process https://www.youtube.com/watch?v=aMhgulp8-XM https://www.youtube.com/watch?v=metxHQmIOuk https://www.youtube.com/watch?v=zlDvMY54AEg https://www.youtube.com/watch?v=mRoq0U-LBoU https://www.youtube.com/watch?v=CEI9UiybZ1U 15  16 Industry scale up → for commercial production “…..from lab scale (0.5 kg) study was scaled up to industrial scale (2000 kg, filling 100g tubes at 75 tubes/min)….. “ Scale-Up: the process of developing a reliable and practical method of manufacturing the Product in such designated manufacturing facility to effectuate the orderly transition from laboratory production of the Product to routine full-scale basis By convention, scaling up the production of a new therapy was a linear, iterative process A decade ago, most scale-up would have been a very linear process with lab-scale going to kilo lab-scale to pilot plant-scale and, for successful products, to an in-house existing batch production facility. Now, as manufacturing operations have become more complex, engineering advances in modeling, digitalization, single-use process equipment, and process intensification have made scale-up more systematic, for both small and large molecules. lab bench t pilot scale Flow chart for cream-based products 120 H2O Double reverse Multimedia & Automatic osmosis Sand filter for activated softener dosing purification Storage tank Point Of Use in pre-treatment Raw water tank carbon system system 4000L production area treated since ru Water supply from city water Store in Mixing of water Manual packing warehouse & and raw Filling of in the carton ready for material in products in tube delivery after homogenizer and capping it quarantine. Raw Material QC Testings; Approval? 1. Appearance 2. pH 3. Assay Production Warehouse QC Incoming 4. Microbiology Dispense the weighing storage Sampling 5. Identification raw material process NO 17 Flow chart for liquid-based products Double reverse Multimedia & Automatic osmosis Sand filter for activated softener dosing purification Storage tank Point Of Use in pre-treatment Raw water tank carbon system system 4000L production area Water supply from city water Labelling process Filling and continously Bottle cleaning capping from the Cartoning Quarantine in Mixing water & with blowing machine for capping process for the material method bottle machine 60ml size warehouse Raw Material QC Testings; Approval? 1. Appearance 2. pH 3. Assay Production Warehouse QC Incoming 4. Microbiology Dispense the weighing storage Sampling 5. Identification raw material process NO 18  PROCESS FLOW FOR LIQUID & CREAM PRODUCTS MANUFACTURING Production Request for Raw Materials Process Dispensing Steps Mixing Test either : raw material 1. Appearance putany batik - 2. pH 3. Assay Failed - check specifications Request for Packing & Printed 4. Micro Test QC test Materials Passed Transfer to Holding Tank Filling Checks 1. Appearance Failed 2. Filled Volume IPC Rework Passed Labelling Checks Failed 1. Correct Label IPC Rework 2. Correct Batch No. 3. Correct Mfg & Exp Dates Passed Put into Shippers 19 Production Process Steps…cont. Send Micro & Complete the Documentation Retention Samples Submit Sample to QC Tests 1. Appearance QC Tests REJECT 2. Filled Volume Failed 3. Microbial Test Passed Batch Doc. Documentation Review Analytical Results Micro Results Send to Warehouse Disposal at Release of Products Kualiti Alam 20  *as production manager Production Consideration: Time, Capacity & Outputs (1) MACHINE CAPACITY PACKING SIZE BOTTLE CAPACITY PROCESS TIME Liquid Mixing Tank Produce 800 liter/ process Depend on the product. Average time is 5 hour. Liquid Storage tank Holding 800 liter product Maximum washing capacity 50 Bottle Blowing Machine bottles per minute. Maximum filling rate of 50 bottles Automatic Filling Machine Bottle 60 ml 13,333 Bottle per minute Average time is 5 hours. Capping Machine Max 60 cap/min estimate production , revenue Auto Round Bottle Max 70 label/min Labelling Machine q Auto Cartoning Machine Max 50 Pcs/ min liq mixing tank for bottle of 60Mt if capacity of food / process , use W ran produce 13k bottle w/ n 5 hour 21  Production Consideration: Time, Capacity & Outputs (2) MACHINE CAPACITY PACKING SIZE TUBE CAPACITY PROCESS TIME Dispensing Booth N/A Pump Diameter 20 Min 2ml- Max 160 ml. 4 hours Homogeneous Mixer (2ml to 30 ml), 200 kg Machine Pump Diameter 35 Mixing Tank 100 liter tank 100 liter (20ml to 100 ml), Pump Diameter 45 10 hours (inclusive Cream Filling Machine 20-50 tube/min (30ml to 160 ml), manual packing until complete product) 22 The Production. 23 Cases of Failures in Pharma Manufacturing * mostly man - made Common failures: Product contaminations, process defects, production mistakes, mislabeling etc. Impact: Leads to risk of patient safety being compromised Mitigating Steps: Product Recall 24 Industrial Processing Virtually all liquid and semisolid products involve the unit of * semi-solid :mixi④→ impeller -4,3, → mixer perf operation of mixing. In fact, in many instances, it is the primary unit operation. Component’s blades may be impellers in the form of propellers, turbines, paddles, helical ribbons, Z-blades, or screws. The no. of impellers, the no. of blades per impeller, the pitch (inclination) of the impeller blades, and the location of the impeller can vary and thereby affect mixer performance. 25  To ensure that there is uniformity of composition between the mixed ingredients which may be determined by taking samples from the bulk material and analyzing them, which should represent overall composition of the mixture. Objectives of To initiate or to enhance the physical or mixing chemical reactions e.g. diffusion, dissolution etc. Common problems Mix in a small amount of one substance in a large bulk Segregation and over mixing Mixing that effects the size of the particles * over mixing can also happen - what cause ? protein denatured 26 - why ?  When two or more than two miscible liquids are mixed together, this results in to a solution known as true solution. and oil r water When two immiscible liquids are mixed in the presence of an emulsifying agent, an emulsion is produced. need binding - agent / emulsifying agent When a solid is dissolved in a vehicle, a solution is Mixtures obtained When an insoluble solid is mixed with a vehicle, a suspension is obtained. When a solid or liquid is mixed with a semisolid base, an ointment or a suppository is produced. When two or more than two solid substances are mixed together, a powder is obtained (capsules/tablets) 27  Positive mixtures These types of mixtures are formed when two or more than two gases or miscible liquids are mixed together by means of diffusion process. ( heat ,fore. In this case no energy is required provided the time allowed for solution formation is sufficient. These types of materials do not create any problem in mixing. Mixtures Negative mixtures These types of mixtures are formed when insoluble solids are mixed with a vehicle to form a suspension or when two immiscible liquids are mixed to form an emulsion. heating These mixtures are more difficult to prepare and rie require a higher degree of mixing with external force as there is tendency of the components of these mixtures separate out unless they are continuously stirred. 28  Neutral Many pharmaceutical products such as pastes, ointments and mixed powders are the examples of neutral mixtures. They are static in their behavior. The components of such products do not have any tendency to mix spontaneously but once mixed, they do not separate out easily. Mixtures Many variations occur within the above explained groups owing to the different physical properties of the components of the mixture like 1. viscosity which might change during mixing 2. the relative densities of the components 3. particle size 4. ease of wetting of solids Chydrophobic / philic) 5. surface tension of liquids 6. proportions of the components 7. the required order of mixing 29 Mixing mechanisms 0 1. Convective - Due to circulating flow of powder during mixing 2. Shear Mixing - The momentum exchange between the powder particles having different velocities - -diff rate move 3. Diffusion - The random motion of powder particles 30 Convective mixing https://www.youtube.com/watch?v=47Rowloh-Wo 31 Shear mixing https://www.youtube.com/watch?v=ylv9F9mESYk 32  Factors to consider: Mixer 1) The physical Selection properties of the material to be mixed. (e.g. density, viscosity, miscibility) 2) Economic considerations (e.g. time and power expenditure) 3) Cost and maintenance of equipment 33 Semisolids Mixer Selection kepekatan Low Viscosity System Intermediate Viscosity system High Viscosity system I based on AFI type of product produced34 Mixer: Low viscosity system Low viscosity emulsions, gels, shampoos, deodorants, injectable products, solutions. Monophasic system of low viscosity are i.e. if given time, mix completely without external agitation. classified as positive mixture. In general, low viscosity system no great problems unless the operational scale is very large. Best mixed by methods that generate a high degree of turbulence and at the same time circulate the entire mass of materials. " E.g. High jets, fluid jets, and high speed propellers. boat " A viscosity of approximately 10 poises may be considered as a practical upper limit for the application of these devices. 35 Mixer: Intermediate viscosity system Immiscible liquid (emulsion) and finely divided solids with liquid of low viscosity (suspensions). Often in single mixing operation, provided that shear forces of sufficient intensity to disrupt aggregates can be generated. Emulsion and suspensions – mixing with turbines of flat blade design. Flat blade turbine of radial flow type less suitable for mixing in large tanks. High speed turbines, fitted with stators to produce increased shearing action are often employed. 36 Mixer: High viscosity systems " " sampan Viscous ointments are effectively mixed by uses paddle mixers, in - shearing action of two surfaces in close which the blades clear proximity, and moving at different velocities with the container walls by a respect to each other. small tolerance. As the % of solid increased, the solid-liquid system takes the consistency of a paste or dough. Sigma blade mixer For thicker paste – kneading, stretching and folding action is employed. and muller mixer are used. For more fluid dispersions, colloid mill may be used. 37 Mixers/Agitators employ a stationary container to hold the material and bring about mixing by means of moving screws, paddles or blades. Mixers designed specifically for semi-solids are usually of heavier construction to handle materials of greater consistency. The agitator arms are designed to give a pulling and kneading action and the shape and movement is such that material is cleared from all sides and corners of the mixing vessel. Eg. Sigma blade Mixer, Planetary Mixer 38 Shear mixers Shear forces are created within the mass of the materials by using agitator. A high-shear mixer can be used to create emulsions and suspensions. Fluid undergoes shear when one area of fluid travels with a different velocity relative to an adjacent area. A high-shear mixer uses a rotating impeller or high-speed rotor, or a series of such impellers or inline rotors, usually powered by an electric motor, to "work" the fluid, creating flow and shear. E.g. Roller mills, Colloid mills, Homogeniser 39 Sigma blade Watch youtube (Sigma Mixer - Design & mixers Operation) : https://youtu.be/1fWI1MIu80k 40  Sigma blade mixers The sigma mixer is one of the most popular used for mixing and kneading high viscosity materials. In mixers handling very viscous materials, it is necessary to promote both lateral and transverse motion of the material. Sigma mixer contains mixing element (Blades) of Sigma type two in numbers which contra rotates inward to achieve end to end circulation and thorough and uniform mixing at close or specified clearance with the container. Advantages Sigma blade mixer creates a minimum dead space during mixing. There is close tolerance between the blades and the sidewalls as well as the bottom of the mixer shell. Disadvantage: Sigma mixers work at a fixed speed. 41 Tangential & Overlapping design 42 Planetary Mixer https://www.youtube.com/watch?v=0gLSInEt6Iw 43  Planetary mixers are used for mixing and beating for viscous and pasty materials, the planetary mixer is still often used for basic operations of mixing and blending in pharmaceutical industry. Uses of planetary mixers: Low speeds are used for dry blending and faster speeds for the kneading action required in wet Planetary granulation. Advantage: Planetary mixers work at Mixer varying speeds. This is more useful for wet granulation and is advantageous over sigma mixers. Disadvantages 1. Planetary mixers require high power. 2. Mechanical heat is built up within the powder mix. 3. Use is limited to batch work only 44  Machines designed for size reduction can be used for mixing although the shear forces are good, the general mixing efficiency is poor. Rotary forms may be used and the colloid mill has a stator and a rotor with conical working surfaces. Roller Mill The rotor works at a speed of the order of 3000 to 15000 r.p.m. and the clearance can be adjusted between 50 and 500 micrometers. A roughly mixed suspension or dispersion is introduced through a funnel and is thrown out between the working surfaces by centrifugal force. 45 Roller mill 46  General Design There are many manufacturers of roller mills, but they all share the following design features shown adjacent picture: - a delivery device to supply a constant and uniform amount of the material to be ground - a pair of rolls mounted horizontally in a Roller mill rigid frame - one roll is fixed in position and the other can be moved closer to or further from the fixed roll - the rolls counter rotate either at the same speed or one may rotate faster; roll surface may be smooth or have various grooves or corrugations - bar; pairs of rolls may be placed on top of one another in a frame. 47 Roller Mill https://www.youtube.com/watch?v=u4_RMAhW4oo https://www.youtube.com/watch?v=dpbQK7D97H4 Advantages: energy efficient uniform particle-size distribution little noise and dust generation Disadvantages: little or no effect on fiber particles tend to be irregular in shape and dimension may have high initial cost (depends on system design) when required, maintenance can be expensive 48 Colloid mill 49 Colloid Mill Watch Colloid Mill video: https://www.youtube.com/watch?v=W2t0uWfHhO4 The main function of the colloid mill is to ensure a breakdown of agglomerates or in the case of emulsions to produce droplets of fine size around 1 micron. The material to be processed is fed by gravity to the hopper or pumped so as to pass between the rotor and stator elements where it is subjected to high shearing and hydraulic forces. Material is discharged through a hopper whereby it can be recirculated for a second pass. Colloid Mills are used in the production of ointment, cream, gels and high viscous fluids for grinding, dispersing and homogenizing in one operation. 50  Homogenisation is a technique used to mill the particles by processing a suspension of solid particles. Used for particle size reduction in pharmaceutical suspensions. Homogeniser Important factors controlling the formation of *for cream emulsions and dispersions are mechanical and/or formulation related. Mechanical forces during homogenisation cause droplet or particle size reduction by shear, turbulence, impact and cavitation. The homogenisers operate using a combination of these forces. 51 Homogeniser High pressure Homogeniser https://www.youtube.com/watch?v=UpvIQwRYe-E 52 Homogeniser Microfluidizer 53 OSD Manufacturing: An Overview Coral solid - ) dosage 54 OSD Manufacturing Aspirin is one of the most popular and commonly used medicines. Historically, this drug had a humble discovery 3500 years ago from the bark of the willow tree, known for its traditional herbal remedy. Similarly, all medicinal drugs originated from natural sources like herbs, plants, roots, bacteria, fungi etc. As science advanced, chemicals were put to use for fetching out the active ingredients from natural sources to produce more potent medicines. With further technological development and with the collaborative efforts of researchers, biologists, physicians and chemists, drug discovery took rapid strides forward, and more throughput screenings and clinical trials began playing a vital role in relieving human pains and suffering. Today, every pharmaceutical manufacturing plant project has a well-proven drug delivery system undergoing a series of well-defined processes. Oral Solid Dosage, which takes the course of tablets, capsules, soft gels, effervescence, gummies, and pills, involves key steps from formulation and development to packaging until the drug becomes ready to be consumed as a final drug product 55 OSD Manufacturing… cont. Oral solid dosage (OSD) products can take several different shapes, and with those different forms comes different production techniques and facility designs. Here’s what is involved with manufacturing an orally-ingested drug product. Small molecules, tablets, capsules, soft gels, effervescence, gummies, and pills. These are all oral solid dosage (OSD) forms, a term that refers to a final drug product therapy that is ingested through the mouth, dissolved in the digestive system, and delivered to the body through absorption into the bloodstream This widely used and well-proven drug delivery system originated in 1842 when Englishman William Brockedon patented tablets of compressed sodium and potassium carbonate. This product was used as a calcium supplement and antacid. Today, oral solid dosage drug products are the most common dose form physicians prescribe for a variety of indications. Oral solid dosage is such a dominant delivery form for three main reasons. It’s relatively easy to administer, it’s easy to distinguish one oral solid dosage product from another, and oral solid dosage manufacturing methods are well understood and well-developed. 56 OSD Manufacturing… cont. Pharmaceutical Semisolids Multiple forms of oral semi solid dosages to deliver the pharmaceutical active ingredients to thesolid Oral intended patients dose (OSD) manufacturing is a cornerstone of the The Importance of Oral Solid Dosage Forms pharmaceutical industry, responsible for producing the most Oral solid dosage forms dominate the common dose forms prescribed today. From tablets and pharmaceutical industry for several reasons: capsules to soft gels and gummies, oral solid dosage forms are a tried-and-true method of drug delivery, with a history that Ease of Administration: Patients find it spans nearly two centuries. This guide will provide an overview convenient to take oral solid drugs, improving about what is it OSD, the manufacturing processes, and the patient compliance. challenges faced by pharmaceutical companies. Distinguishability: Tablets and capsules can be easily distinguished from one another, reducing Oral solid dose (OSD) manufacturing refers to the process of the risk of medication errors. producing drug products that are ingested orally and absorbed through the digestive system. These dosage forms include Established Manufacturing Processes: The tablets, capsules, and other solid forms that are designed to deliver the active pharmaceutical ingredient (API) efficiently to manufacturing processes for oral solid dosage forms are well understood, allowing for efficient the bloodstream. production and quality control. 57  Understanding Oral Solid Dosage forms The most common oral solid dosage forms are tablets and capsules. Both forms are comprised of an active pharmaceutical ingredient (API), which can also be called a drug substance, and dry powder ingredients. Tablet forms are made through compression and can either be coated, meaning they have an extra layer to create a smooth surface, or uncoated. Capsules are created through a coating process, where the drug substance and dry ingredients layer around a seed material. 0 0 Each of these forms can have variable bioavailability and rate of release. Depending on the therapeutic use of the OSD product, it will have an immediate, sustained, controlled, or extended-release. These factors influence drug manufacturing platforms and the equipment and technology used in the manufacturing process. * objective : The overall goal for OSD processing regardless of the type of product is to create a formulation that ensures each dose–a single tablet or capsule–is consistent. Each one has a repeatable distribution of ingredients, and there is a consistency of dissolution and bioavailability to ensure that the drug product is safe and effective. 58 Tablet Manufacturing Process * not continuous process tukarfromonetempat to - , another 59 Tablet manufacturing process flow 1 Request for 7 Mill/Blend IPQC raw material Complete Dispensing Sieving Documentation Active Excipient Dispensing Sample to QC 4 Micro & Sieve/Mill IPQC Retention Weigh station Compression 8 QC Holding station 5 QC Reject 2 Blend/Sieve/Mill Coating Warehouse Batch Document Chemistry Data 3 Micro Data 6 Documentation Granulate IPQC Review Release of Fluid bed dry Packing products n = Key Quality Control activities Primary OSD Manufacturing Unit Operations One of the unique aspects of oral solid dosage manufacturing is that the typical unit operations (steps in the process) are very well defined and relatively unchanged over the past century. Although the unit operations may involve various equipment and technologies, there is a well-defined progression from raw materials into the final product. * Note: This matrix illustrates the basic production flow from left to right. The boxes along the top represent the unit operation activity. This can vary with specialized drug products and unique applications, but this flow is the norm. 61 Formulation & Development The process begins with formulation followed by development, wherein the active pharmaceutical ingredient (API) is combined with suitable excipients to create a stable and effective dosage form. Formulation development is carried out with an effective approach to attain the desired drug release profiles, enhanced bioavailability, and significant regulatory compliance. In the case of highly potent API, specialised technology is employed to reach a good solubility level with ensured therapeutic efficacy. All in all, the excipients and API must be well understood to have a well-defined formulation. 62 The Ingredient Dispensing and Formulation Unit Operation The first unit operation is the Primary process equipment for introduction of the various ingredient dispensing ingredients and raw materials into the manufacturing process. and formulation: This starts with accurately weighing the APIs, excipients, Dust control/ operator/ fillers, and miscellaneous environment protection system materials, and then dispensing (LEV, downflow booth, isolation) them into the process vessel. Sifting size reduction and/or Handling powders typically milling systems produces dust, so ingredient dispensing must occur in a Process feed and receipt controlled and contained material handling technology environment. This may include (lifts/manipulators/etc) local exhaust ventilation (LEV) One key challenge of ingredient dispensing and formulation is the enclosures, downflow booths, fact that ingredients and materials come from raw material suppliers isolators, or other containment Scales and weigh devices in a wide range of containers and packaging types. and process control devices. For example, materials can arrive in various sized bags, drums, Wash-in-place or clean-in-place boxes, and supersacks, among other options. This means material systems handling equipment like lifts, inverters, and manipulators will be required in this operation, which also requires consideration for safety and ergonomics. 63  Granulation Granulation is a continuous manufacturing process in which the powdered API and excipients are agglomerated into granules to improve the flowability, compressibility, and uniformity of the powder mixture. The core granulation methods for pharma manufacturing comprise wet granulation, dry granulation, and direct compression, which are selected depending on the operational conditions, formulation properties and requirements. Dry granulation – This economical method is most suited when the temperature and moisture- sensitive compounds need to be critically controlled. The granulation technique involves slugging, i.e. compressing the small, dry particles into larger granules to form a tablet of the right ingredient ratio with the right amount of excipient. * premix concept Wet Granulation – This one is regarded as a superior method for its ability to work without special excipients and for providing content uniformity. The procedure is adaptive and reproducible and calls for perfect dispersion and preparation of granules. The quick processing time makes dealing with soluble low-dose medication easier. Direct Compression – Direct compression is a simplified and shorter process of ingredient mixing that works well with heat and moisture-sensitive APIs and allows for tablets to disintegrate into particles of API instead of granules, as in the case of wet granulation. This method also helps avoid extreme compaction pressure during tablet production. 64 The Granulation and Drying Unit Operation The granulation Primary process and drying unit equipment for operation begins to combine the granulation & various ingredients drying: and raw materials to create the Granulator appropriate granule characteristics for Dryer a compressible or Solution preparation encapsulated drug and delivery systems product. (for the wet This includes granulation process) dispensing Size reduction ingredients into the granulation train and/or milling (wet or dry) and systems Space can be one key challenge during this unit operation. Granulation and drying processes generally working the Process feed and require tall spaces, especially when using gravity to feed and receive. materials to receipt material achieve the desired If manufacturers want to fit this process into an existing facility, it will often require renovations and results.. handling technology upgrades. It is also possible to separate the two operations into different rooms, but integrated granulation Scales and drying is more efficient. Wash-in-place or clean-in-place NOTE: Occasionally, materials are pre-blended (via a blending operation) prior to the granulation and drying step systems 65 Blending After granulation, the granules may undergo blending with additional excipients, such as diluents, disintegrants, and lubricants. Blending ensures a homogeneous distribution of API and excipients throughout the mixture, enhancing content uniformity and tablet-to-tablet consistency. The prime objective of the blending process is to ensure the adequacy of mixing the ingredients through various mixing equipment/blenders such as octagonal blenders, V blenders, bin blenders, conta blenders etc. 66  The Blending Unit Operation The blending unit operation Primary process equipment for combines the active blending: ingredients and excipients Blender (fixed station, portable, and/or lubricants to achieve a or intermediate bulk container homogenous distribution of ingredients. type) Containment and dust collection This process may occur more solutions than once in the overall Process feed and receipt operation. For example, a material handling technology manufacturer might pre-blend materials prior to granulation Scales and post-blend (or final Wash-in-place or clean-in-place blend) prior to compression. systems One of the biggest blending challenges is loading and unloading the blender. If done improperly, this step can be inefficient. Furthermore, it can introduce contaminants into the formulation, generate dust, and separate the blend. With fixed station blenders (i.e., twin shells, slants, double cones, and ribbons) do a complete evaluation of the upstream and downstream process to determine optimal solutions. One solution is to use an intermediate bulk container (IBC) or an in-bin blending system. The blend happens in the same transfer container that is used upstream and downstream of the blending process. Discharge only occurs once, which reduces the chance for material segregation and improves containment control. Another consideration for blending is designing the process with a through-the-wall configuration. In this instance, the drive mechanism for the blender is outside the GMP blending space, and only the product container portion of the system is in the process room. This allows for smaller rooms and quicker cleaning and turn over. 67 Compression Compression is known to be one of the most challenging steps as it can have a direct bearing on the hardness of the tablet and, resultantly, on the dosage form integrity and bioavailability. It includes compressing the granules or blending them into tablets using a high- speed mechanical device – a tablet press. The compression process involves precise squeezing of ingredients to reach a required tablet shape, viz. round, oval, or scored. The compressed tablets must determine the physical and chemical properties of the tablet while ensuring appropriate hardness, thickness, and weight. 68 The Compression and/or Encapsulation Unit Operation The compression and/or Primary process equipment for encapsulation unit operation compressing/encapsulating: creates the final dosage form Tablet press or encapsulator that patients receive. Metal check, deduster, polisher This step compresses or Tablet tester (to check weight, encapsulates the formulation thickness, and hardness) into the end product: a tablet Containment and dust collection or capsule. solutions Process feed and receipt material handling technology Scales Wash-in-place or clean-in-place systems As is the case with the granulation unit operation, the compression and encapsulation process generally requires tall spaces, especially to use gravity to feed and receive. Again, if this unit operation is going into an existing facility, thoroughly review and evaluate the layout and configuration to achieve a safe and efficient compression/encapsulation operation. A high hat around the tablet press or encapsulator, with a lower ceiling for the rest of the room, can solve this problem, too. This allows for the desired gravity feed from the IBC or transfer bin, but also avoids a high ceiling for the whole room, which minimizes air and cleaning requirements. 69 Coating In the tablet coating process, a thin layer of coating material is applied to the tablet surface to achieve the desired properties of dosage form over the uncoated variety. Equipment such as auto coaters for granulation line bring effectiveness to the coating operation by serving multiple purposes, such as protecting the drug from environmental factors, improving swallowability and product stability, providing taste masking, or modifying drug release characteristics The amount of coating on the surface of a tablet is critical to the effectiveness of the oral dosage form. 70 Tablet Coating One of the final steps in the Primary process equipment for OSD manufacturing process coating: is tablet coating. After a core Tablet coater with a process air tablet has been compressed, handler a film or functional coat is applied to the tablet. Solution preparation and delivery system This improves the taste and In-process testing devices makes the tablet easier to Process feed and receipt swallow. A functional coating material handling technology is also common. This is an additional active ingredient Scales applied to the outside of the Wash-in-place or clean-in- tablet. place systems Tablets must be safely and efficiently loaded into and discharged from the equipment without damaging them. Ergonomic assist devices or using gravity to assist with movement are both effective solutions for discharging tablets to and from bins. 71  * Primary Routes OSD Manufacturing Platforms OSD drug products typically consist of a dry powder formulation that includes the drug substance or API, various excipients, and intermediates and fillers. Where they differ is the final form and the individual characteristics of the ingredients, such as particle size, bulk density, flowability, among other factors. As such, different products require different processing methods and platforms. The final dose form requirements also dictate which processing platform is used. 72 Wet Granulation A platform and process that involves a combination of liquids and solids, via a variable intensity motive force (typically high shear or low shear mixing in a granulator) working the powders and creating a dense granule that can be compressed or encapsulated. Wet granulation is the process of joining powder particles together to create a larger particle, known as a granule. The granules can be composed of particles that are either the same or dissimilar materials depending upon the formulation ingredients. In the wet granulation process, granules are joined together using a binder solution, often aqueous, that is sprayed into the process. The two primary types of wet granulation are high shear and low shear. In the case of high shear, the binding solution is introduced to the dry particles in a vessel that has a motor-driven blade or impeller system that creates a variable intensity (or high shear force) interaction. The most common piece of equipment for this process is a vertical or horizontal (top drive or bottom drive) high shear granulator. In the case of low shear, the binding solution is introduced to the dry particles in a vessel, via a spray atomization configuration that creates a softer (or low shear force) interaction. The most common piece of equipment for this process is a fluid bed granulator. 73  Reasons for Wet Granulation Main Equipments Dust reduction: reduces fine particles for better Granulator: This is a system that creates the dust control during processing motion and energy to integrate solids and liquids efficiently and under control. Improved flowability: improves the overall flowability of powders, which is more Solution delivery system: This is the device conducive to downstream processing that delivers the granulating liquid to the requirements powders. It generally consists of a solution delivery tank, pump system, piping, and spray Particle size and uniformity control: can nozzles. predetermine the final granule size and create a consistent distribution of ingredients Dryer: A fluid bed dryer removes the liquids and dries the powders after the wet granulation Compaction enablement: good granulation process creates the desired granule helps hold the granules together when they are characteristics. compressed into a tablet core Controlled solubility characteristics: increases control of the dissolution profiles Increased bulk density: a key process parameter control for specific body absorption 74 Wet Granulation 75 Dry Granulation * premix → more restricted of drug thatyou can produced but time save easy , A platform and process that involves a combination of solids only, via a variable intensity motive force (typically high force compaction in a roller compactor) working the powders and creating a dense granule that can be compressed or encapsulated. Dry granulation is the process of joining powder particles together to create a very dense larger particle or granule. In the dry granulation process, a high-motive force joins the granules and compacts the powders without the use of an additional binder. A dry granulator system incorporates press rolls and milling to compact the particles. Adjusting the distance between the rolls creates a variable intensity (or high shearing force compaction) interaction. A roller compactor is the most common piece of equipment. 76  Reasons for Dry Granulation Main Equipment Dust reduction: reduces fine particles for better Roller compactor: This creates the motion and dust control during processing energy to integrate and compact the solids efficiently and under control. Improved flowability: improves the overall flowability of powders, which is more It performs three sub-operations: feeding in conducive to downstream processing and compacting the particles, creating a ribbon requirements of the compacted granules, and sizing them. Particle size and uniformity control: can predetermine the final granule size and create a consistent distribution of ingredients Compaction enablement: good granulation helps hold the granules together when they are compressed into a tablet core Controlled solubility characteristics: can define and control the dissolution profiles Increased bulk density: a key process parameter control for specific body absorption 77 Dry Granulation 78 Direct Compression A- simpler A platform and process that involves a combination of solids Main Equipment only, via a low-intensity motive force (typically gentle tumbling in a blender) to homogeneously combine the A tumble blender: This is a vessel that rotates to powders capable of being compressed or encapsulated. compress the ingredients inside. Charging and discharging equipment: This loads The direct compression process homogeneously combines material into the blender and then removes it. ingredients, without directly changing or impacting the starting granules. It is a mixing process that uniformly blends the powders through particle movement and rotation. The most common piece of equipment is a tumble blender, which can be configured in various ways. Reasons for Direct Compression Ingredient combination and homogeneity No physical changes to the particles 79 Direct Compression 80  A platform and process that involves a combination of liquids and solids, via low-intensity motive force (typically atomized liquid to powder coating in a fluid bed processor) to coat the Particle powder granules for encapsulation. Coating The particle coating process applies an active drug and/or sealer onto an individual granule or bead (like grain sugar) to create a capsule dosage form. A liquid and solid suspension is sprayed onto the face of the bead material to achieve the proper coating characteristics. A spray atomization configuration creates a soft and consistent interaction between the solution and dry particles in a vessel. The most common piece of equipment is a fluid bed coater. 81  Benefits of Particle Main Equipment Coating Process Fluid bed coater: Similar to the equipment used in other A low abrasion, smooth surface processes, It creates the motion Good flowability and energy to integrate solids and liquids efficiently and under Masks taste and smell control. But instead of Protects against light, air, and compressing the dry powder moisture molecules together, the fluid bed coater creates layers of the Multi-layer compositions are ingredients. impervious to separation Solution delivery system and Systematic release of active dryer: These serve the same ingredients purposes as they do in the other Delayed dissolving processes and are usually the same machines. 82 Packaging The packaging of medicines must be done with utmost care. Once the tablets are manufactured and coated, they go through critical packaging to avoid contact with external components like heat, air, and water, which may alter the drugs’ properties. This requires primary packaging, where the tablets are placed in blister packs, bottles, or other suitable containers. Secondary packaging, such as labelling and cartoning, is also performed to provide information and protect the product during distribution. The selection of the package begins with the determination of the product’s physical and chemical characteristics. 83 Quality Assurance Quality Control (QAQC) QA. QC. Quality assurance involves implementing a Throughout the manufacturing processes, quality comprehensive quality management system control is crucial in ensuring product quality and encompassing all OSD manufacturing compliance with regulatory standards. aspects. The quality control process in a pharmaceutical It includes establishing standard operating manufacturing plant project takes into procedures (SOPs), documentation control, consideration the raw materials, in-process deviation management, change control, and samples, and finished products for various compliance with regulatory guidelines. parameters, including identity, purity, potency, dissolution, and physical attributes. All these processes necessitate the need for pharmaceuticals to meet all the quality It identifies the distinct areas of the material like control standards in order to further meet appearance, usability, compatibility and their intended use. dimension. 84 Process Validation. Process validation is conducted to demonstrate that the manufacturing processes consistently produce OSD forms of the desired quality. It necessitates conducting tests to ensure the reliability and reproducibility of the manufacturing processes that have an impact on the quality of the products. The tests include viz. validation studies, including equipment qualification wherein a series of tests are conducted to ensure reliable performance of each piece of equipment: User Requirement Specification (URS), Design Qualification (DQ), Factory Acceptance Test (FAT) at manufacturers’ site, Site Acceptance Test (SAT) at the user site, Installation Qualification (IQ), Operation Qualification (OQ) and Performance Qualification (PQ). Process qualification is an act to conform to the standard compliances and evaluate the process sustainability, and cleaning validation aims to establish a high degree of assurance for due prevention and control of product contaminants. 85 Continuous OSD Manufacturing Increasingly, OSD manufacturers are moving toward a modern continuous processing operation. This approach integrates the individual batch unit operations and processing steps into a single continuous process, which can reduce cost and time, as well as produce higher quality products. Rather than manually transferring in-process work from process to process and unit operation to unit operation, continuous manufacturing (CM) feeds material through all the operations in a single equipment train that is also a closed process. This eliminates many of the ergonomic issues associated with moving the product and ingredients, the contamination risks associated with an open process, testing and quality control errors that human operators make, and production delays that come from all these aspects. Not only does this shorten production time and improve quality, but the processing capacity is more readily adjustable to accommodate changing demands. Continuous manufacturing uses the same processing platforms as traditional batch processing for wet and dry granulation, as well as direct compression. 86 87 Thank You. 88