Pilot Plant Scale-Up Technique

Pilot Plant Scale-Up Technique

• A plant is a location where resources (money, materials, people, methods, and machines) come together to make products.
• A pilot plant is part of the pharmaceutical industry. It transforms a lab-scale formula into a viable product. It's used for producing small quantities of new tech-based products, developing reliable, practical manufacturing procedures, and is a pre-commercial production process.
• Scale-up is the process of designing a prototype using pilot plant data, increasing batch size, or applying a process to different output volumes.

Objectives of Pilot Plant

• Test the process on a model of a proposed plant before a large investment in a production unit.
• Evaluate the formula's ability to withstand changes in batch scale and process modifications.
• Avoid issues associated with scale-up.
• Outline guidelines for production and process controls.
• Identify process critical features.
• Prepare and provide Master Manufacturing Formula.
• Evaluate and validate processes and equipment.

Scale-Up Steps

• Define product economics based on market size and competitive pricing, ensuring allowable manufacturing costs.
• Conduct lab studies and scale-up planning simultaneously.
• Define critical steps in the proposed process.
• Conduct preliminary large-scale studies using equipment for the critical steps. This supports plant design.
• Design and construct a pilot plant, including process and environmental controls, cleaning, sanitizing systems, and waste management compliant with regulations.
• Evaluate pilot plant results to make necessary corrections to the product and process, evaluate economics and determine whether to continue with large-scale plant development.

Why Conduct Pilot Plant Studies?

• Allow investigation of a product and process on an intermediate scale before committing to large-scale production.
• Help address the difficulty in predicting the effects of large-scale increases in size.
• Useful when large-scale production plants are not possible through lab data alone.

Pilot Plant Uses

• Validate lab study results, adjusting products and processes.
• Produce small quantities of products for sensory, chemical, microbiological evaluation, limited market testing, and stability studies.
• Decide whether to proceed with full-scale production and design/modify existing plants based on pilot plant data.

General Considerations

• Reporting Responsibility: Effective pilot plants require strong relationships between the pilot plant team and other groups (R&D, formulators).

Personnel Requirements

• Ideal personnel have experience in pilot and production plant operations, understanding the formulator's intent and production personnel perspectives. Suitable personnel also have knowledge of engineering principles, computers, and electronics.

Space Requirements

• Pilot plant space is divided into administration/processing, physical testing, standard equipment, and storage areas. Administrative space should be adjacent to working space. Physical testing areas should have permanent benchtops for equipment. Adequate standard equipment space for manufacturing all dosage forms is needed. Portable equipment allows for storage in a dedicated room. Cleaning space for equipment is critical. Storage areas should be for approved versus unapproved active ingredients and excipients; in-process materials, finished bulk products, and pilot plant/scale-up batches. Packaging material needs a designated storage space.

Review of the Formula

• Thoroughly review every aspect of the formulation for understanding their purpose and contribution to the final product using small-scale lab equipment.
• Help predict scaling effects associated with stress testing during equipment changeover.

Raw Materials

• Pilot plants also approve and validate raw materials (active ingredients, excipients). Small-scale production raw materials are not always representative of large-scale production.

Equipment

• Select economical, simple, and efficient equipment suitable for producing the product. Equipment size should match planned production scale. Too small produces insufficient product. Too large wastes expensive active ingredients.

Production Rates

• Determining production rates requires consideration for both immediate and future trends and requirements.

Process Evaluation

• Evaluating drying temperature and time, screen size (solids), filters size (liquids), order of mixing, speed, mixing time, heating and cooling rates, and addition rates of granulating agents, solvents and drug solutions.
• Evaluating process parameters helps optimize and validate processes.

Validation

• The process remains validated if formula, ingredient quality, and equipment configuration stay the same. Annually review and revalidate manufacturing process and quality control information.

Master Manufacturing Procedures

• The main aspects include weight sheets, processing directions, and manufacturing procedures.
• Weight sheets clearly identify chemicals by name and batch number to prevent errors.
• Processing directions are precise and explicit, including addition rates, mixing time/speed, heating/cooling rates, temperature, and storage.
• Manufacturing procedures are written by the actual operators.

Product Stability and Uniformity

• Pilot plants ensure physical and chemical stability of products.
• Every pilot batch representing a final formulation must undergo stability testing.
• Stability testing should also be conducted on finished packaged product.

Transfer of Analytical Method to Quality Assurance

• During scale-up, ensure transfer of analytical test methods from research to the quality assurance department.
• This process should review the process to validate instrumentation availability. Personnel training is crucial for conducting tests correctly.

GMP Considerations

• GMP checklist includes equipment qualification, process validation, preventive maintenance schedules, process review/revalidation, relevant standard operating procedures, competent personnel, training provisions, technology transfer system, and validated cleaning procedures. Well-organized equipment placement is crucial to ease material flow and prevent cross-contamination.