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INDUSTRIAL PHARMACY II (BP702T) UNIT 1 (IP2)

This unit focuses on the principles and techniques of scaling up pharmaceutical formulations from laboratory to commercial production. It covers pilot plant operations, process optimization, equipment selection, documentation, technology transfer, and quality assurance to ensure consistent, safe, and efficient large-scale manufacturing.

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➢ Plant • A Plant is a place where the 5 M's are brought together for manufacturing a product: o Man o Material o Machine o Method o Money ➢ Pilot Plant • A Pilot Plant is a part of the pharmaceutical industry where a laboratory-scale formula is converted into a viable product by developing a reliable and practical manufacturing process. ➢ Scale-Up • Scale-Up is the process of designing a commercial manufacturing process (prototype) using the data obtained from the pilot plant.
➢ Objectives of Pilot Plant Scale-Up • To test the manufacturing process on a pilot model before investing a large amount of money in commercial production. • To evaluate and validate the manufacturing process and equipment. • To identify the critical steps of the manufacturing process. • To develop production and process control guidelines. • To prepare the Master Manufacturing Formula (MMF) with manufacturing instructions. • To avoid problems during scale-up and commercial production.
➢ General Considerations 1. Reporting Responsibility • The R&D (Research and Development) department should have a separate staff. • The formulator who developed the product should participate in the production process. 2. Personnel Requirements • Scientists should have experience in pilot plant operations and production. • They should understand both the formulator's requirements and the production process. • The team should include personnel with engineering knowledge as well as scale-up involves engineering principles.
3. Space Requirements The pilot plant should have adequate space for: • Administration and information processing • Physical testing area • Standard equipment area • Storage area 4. Review of the Formula • The purpose of each ingredient should be understood. • The role of each ingredient in the final product should be known. 5. Raw Materials • The pilot plant is responsible for the approval and validation of API and excipients. • Raw materials used in the laboratory may not be suitable for large-scale production. • Therefore, raw materials should be evaluated before commercial manufacturing.
6. Equipment • Equipment should be simple, economical, and efficient. • It should be capable of producing a product that meets the required specifications. • The equipment size should be suitable for pilot-scale batches • Very small equipment may not give proper scale-up results. • Very large equipment may lead to wastage of expensive raw materials. 7. Production Rates • Production rate should be decided based on the current market demand. • It should also consider future market requirements.
8. Process Evaluation The following process parameters should be evaluated: • Order of mixing of ingredients. • Mixing speed. • Mixing time. • Rate of addition of granulating agents. • Rate of addition of solvents and drug solutions. • Heating and cooling rates. • Filter size (for liquids). • Screen size (for solids). • Drying temperature. • Drying time.
9. Master Manufacturing Procedures The Master Manufacturing Procedure (MMP) includes: • Weight Sheet o The Weight Sheet should clearly mention all the raw materials required for one batch. • Processing Directions o The Processing Directions should be clear and precise. • Manufacturing Procedure o The Manufacturing Procedure should be prepared by the actual operator. • The batch record should include: o Addition rate o Mixing time o Mixing speed o Heating and cooling rates o Temperature o Storage of finished product samples
10. Product Stability and Uniformity • The main objective of the pilot plant is to ensure the physical and chemical stability of the product. • Every pilot batch should be tested for stability. • Stability studies should also be carried out on the finished packaged product.
➢ GMP Consideration • Equipment qualification • Process validation • Regularly schedule preventive maintenance • Regularly process review and revalidation • Written standard operating procedure • The use of qualified personnel • A well defined technology transfer system • Validation cleaning procedure • An orderly arrangement of equipment.
➢ Pilot Plant Scale-Up Considerations for Solids 1. Material Handling System • Proper material handling is essential in large-scale production. • The correct quantity of each ingredient should be delivered to the required destination. • The selection of the material handling system depends on the properties of the material. • Common material handling systems include: o Vacuum loading system o Drum lifting and tilting devices o Metering pumps o Screw feed system
2. Dry Blending • Powders used for encapsulation or granulation before tableting should be properly blended. • Proper blending ensures uniform distribution of the drug. • Improper blending can cause flow problem, no content uniformity. • The ingredients should be free from lumps to ensure good powder flow. • Equipment used double cone blender, v-blender. • Blending time, blender size, blender loading. 3. Granulation • To improve the flow properties of the powder. • To improve the binding properties during compression. Types of Granulation • Wet Granulation (Binder) • Dry Granulation (Slugging)
4. Drying • In this dry the granules to prevent from moisture • The most common method for drying granules is the circulating hot air oven. • Fluidized Bed Dryer (FBD) is a better alternative to the circulating hot air oven for drying granules. • The important point to be consider during drying is are airflow, air temperature. 5. Reduction of Particle Size • Particle size should be small and uniform for product quality and performance, also for better flow properties • Particle size and particle size distribution are important for tablet compression. • Equipment used for this oscillating granulator, hammer mill, mechanical sieving device.
• Particle size affects: o Flowability o Compressibility o Uniformity of tablet weight o Content uniformity o Tablet hardness 6. Blending • The correct blender design, blender load, mixing speed, and mixing time should be selected. • During blending, mixing and segregation occur at the same time. • These depend on: o Particle size o Particle shape o Hardness o Density o Mixing action • Low-dose active ingredients are generally prepared by direct compression.
7. Slugging • Slugging is used when a dry powder blend cannot be directly compressed due to poor flow properties. • In this process, the powder is first compressed into slugs, which are then processed further for tablet manufacturing. 8. Compression • Compression is the final step in tablet manufacturing. • Tablets are compressed using a high-speed tablet press. 9. Quality Control and Stability • Stability studies • Forced degradation studies according to ICH guidelines • QC Test
➢ Pilot Plant Scale-Up Considerations for Liquid orals • These are liquid dosage form which are taken orally which usually consisting of a solution, emulsion, suspension of one active ingredients in suitable liquid base. • Scale of these pharmaceuticals involve various processing problems that should be evaluate and optimized in a pilot plant scale up study • Liquid dosage forms show Newtonian or Pseudo-plastic flow behaviour. • Liquid dosage forms may be solutions or dispersed systems.
➢ Method of preparation • Planning of material requirements. • Liquid preparation. • Filling and packing. • Quality assurance. ➢ Critical Aspects of Liquid Manufacturing • Physical plant. • Heating, Ventilation and Air Conditioning (HVAC) system. ➢ Equipment’s • Mixer • Homogenizer • Filtration assembly • Bottling assembly
➢ General consideration 1. Physical plant • We have to consider the heating, ventilation and air controlling system of liquid orals. • Control physical and chemical stability of ingredients 2. Solution • A solution is a homogeneous mixture of two or more substances. Parameters to be Considered • Tank size • Mixing capacity • Heating and Cooling properties • Filtration equipment’s • Transfer system
➢ Procedure • Raw material • Measured and weighed • Mixing • Filling • Packing • Finished product storage • Quality control test o Dissolution o Stability o Microbiological control o potency
3. Suspension • It is the mixture of solid particles into liquid base. ✓ Parameters to be Considered • avoid air entrapment. • Proper wetting of the suspending agent. • Proper addition and dispersion of the suspending agent. • Selection of equipment according to the batch size. • Time and temperature required for hydration of the suspending agent. • Mixing speed should be controlled; high speed should be avoided as it causes air entrapment. • Mesh size.
4. Emulsion • These are the mixture of two immiscible liquids. ✓ Parameters to be Considered • Homogenizing equipment • Temperature • Mixing equipment • In-process or final product filters • Screens, pumps, and filling equipment • Phase viscosities • Physical properties appearance and viscosity.
➢ Pilot Plant Scale-Up Considerations for Semi-Solids • These are substance that contain both solid and liquid and viscous in nature E.g. Paste, Ointment, gels, creams. ✓ Parameters to be Considered • Mixing speed • Mixing equipment • Motors should be able to handle the product at its highest viscosity. • Heating and cooling process • Component homogenization • Product transfer • Addition of active ingredients • Working temperature range • Pumping rate • Product compatibility • Pumping pressure • Product viscosity
Pump Selection Parameters The following parameters should be considered while selecting the size and type of pump: • Pumping rate • Required pumping pressure • Compatibility of the product with the pump surface • Product viscosity
➢ SUPAC Guidelines • SUPAC stands for Scale-Up and Post-Approval Changes. • It is a set of guideline issued by the US-FDA that explain how to handle changes in drug products after approval. • It includes changes made after approval by the regulatory authority (FDA). These changes may include: o Composition changes o Manufacturing process changes o Manufacturing equipment changes o Site (manufacturing location) changes
➢ Types of SUPAC Guidelines FDA has issued SUPAC guidelines for: 1. SUPAC-IR – Immediate Release solid oral dosage forms. E.g. Tablet, capsules 2. SUPAC-MR – Modified Release solid oral dosage forms. 3. SUPAC-SS – Non-sterile Semisolid dosage forms e.g. Creams, ointments, gels, and lotions. ➢ Guidelines Levels of Change 1. Level 1 (Minor Change) • Minor changes in the formulation. E.g. Change in colour Change in flavour Change in excipients within acceptable limits
2. Level 2 (Moderate Change) • Changes that may affect the formulation quality and performance. E.g. • Change in the technical grade of excipients. • Change in the percentage of excipients. 3. Level 3 (Major Change) • Changes that are likely to have a significant effect on the quality, safety, and performance of the formulation. E.g. Qualitative or quantitative change in excipients of a potent drug formulation.
✓ General Considerations for SUPAC • Collect all relevant data about the formulation composition. • Analyse stability data for any loss of potency or drug degradation. • Review all available long-term stability data of previous batches. • Submit accelerated stability study data, including: o Expiry date o Shelf life o 1st to 3rd month stability data o Production batch details o Other relevant reports • Consider clinical trial data, including time and cost. • Perform physical and chemical tests such as: o Solubility o Particle size o Viscosity o Homogeneity o In-vitro drug release study
❑ Platform Technology • Platform technology is a system that uses a common formulation or manufacturing process to develop multiple pharmaceutical products with only minor modification (Base Procedure) • Platform technology is used to improve the efficiency and quality of drug product development. • It uses an established platform with a risk-based approach to develop new drug products. • It makes use of previous knowledge and data for developing new molecules. • The platform is continuously improved by adding data from each newly developed molecule, making it more reliable and robust.
➢ Designing of Platform Technology • Identify the future market applications that the technology can address. • Determine the core building blocks that can be used for new applications. • Identify what changes are required beyond the existing platform for new applications. • Design the platform in a modular manner to obtain maximum benefits. • Design the platform so that it meets the requirements of future applications.
➢ Applications of Platform Technology 1. Medical Devices • Platform technology helps in the development of medical devices. • It reduces the challenges of new product development. • Modular platforms that have already passed regulatory and safety testing can be used for future product development. 2. Drug Delivery System • Platform technology is used to develop advanced drug delivery systems. • Many pharmaceutical companies (e.g., Cipla) use common platform technologies to improve drug delivery. Examples include: • Sustained Release (SR) formulations • Combination products
3. Examples of Platform Technologies • Nanotechnology • Microspheres • Liposomes • Sustained Release Formulations ➢ Applications • Reusable system one technology applied to different drugs • Predictable performance safety, stability, bioavailability already studies • Reduced time • Use in R and D • Cost in formulation development • Regulatory advantage