Pilot plant Scale Up Techniques: General considerations
- 1. PILOT PLANT SCALE UP TECHNIQUES: GENERAL CONSIDERATION Dr. Mahesh Kumar Kataria Professor and Head, Department of Pharmaceutics, Seth G. L. Bihani S. D. College of Technical Education, Sri Ganganagar Email: kataria.pharmacy@gmail.com Dr. Mahesh Kumar Kataria 1
- 2. GENERAL CONSIDERATIONS OR REQUIREMENTS DURING PILOT SCALE UP To have an intermediate batch scale representing procedures used for commercial manufacturing, generally the following should be considered. Dr. Mahesh Kumar Kataria 2
- 3. 1. Reporting responsibilities • Adequate records & reporting arrangement. • Pilot plant functions can be part of the R&D groups with separate staffing. • The formulator who developed the product can take it into the production and continuously provide support even after the transition into production. • Separate pilot plant and technical service group. • Good relationship & effective communication between the pilot plant group and the other groups like R &D, processing, packaging, engineering, QA/ QC and marketing. Dr. Mahesh Kumar Kataria 3
- 4. 2. Personnel Requirement SIGNIFICANCE OF PERSONNEL • Scientists experience in pilot plant, actual production, R&D, formulation and QC. • Knowledge about physical & chemical properties of material and its stability in various dosage form are important. Scientist should have; • Good theoretical knowledge about formulations & practical experience in pharm. industry. • Capable of understanding objectives of formulator and production personnel. • Engineering knowledge as well as scale up. • Appropriate qualification according to the responsibility. • Ability to communicate well, develop and maintain good relationship with other personnel involved in scale up. Dr. Mahesh Kumar Kataria 4
- 5. 3. Space Requirements SIGNIFICANCE OF SPACE REQUIREMENTS The space requirements of a pilot plant are of four types: a. Administrative and information processing • Adequate office & desk space for both the scientists and technicians to facilitate proper documentation of their activities and observations with adequate computers. • Space adjacent to the actual working area with sufficient isolation to avoid any hindrances in the smooth functioning. b. Physical Testing Area • Adequate working area for analysis and physical testing. • In process quality control (IPQC) helps in early identification of production and other type of errors. • Area should provide permanent bench top space for routinely used physical testing equipment like balances, pH meters, viscometers, disintegration apparatus, IR moisture balance etc. Dr. Mahesh Kumar Kataria 5
- 6. ….cont… c. Standard pilot plant equipment floor space • Specific floor space for different equipments required. • Should be as per production line of different dosage forms • Should also be utilized in an effective way. • Equipment used should be preferably portable. • Space for cleaning of the equipment. d. Storage Area • As per GMP two separate storage areas- Approved (for API) and Unapproved area (Excipients) • Different storage area for in-process materials, finished bulk products from pilot plant, packaging materials & materials from experimental scale-up batches made in production. • Controlled environment space for storage of stability samples. • Storage area for packaging materials. Dr. Mahesh Kumar Kataria 6
- 7. 4. Review of the formula: • Close examination of formula to determine its ability to withstand batch-scale and process modifications. • Each aspect require thorough review about the role of each ingredient and its contribution to final product manufactured on the small-scale laboratory. • Important to understand the effect of scale-up process using different size of equipment that may subject the product to different types and degrees of stresses which affect the predetermined quality & specifications of final product. • By reviewing the formula, it can be more readily predicted or recognized all the characteristics related to final formulation. Dr. Mahesh Kumar Kataria 7
- 8. 5. Raw Materials SIGNIFICANE OF RAW MATERIALS • Material (API, excipients etc.) for processing in pilot plant may not be approved and validated. • Materials should meet up with rising needs of the product. • As the batch size increases the variations in micrometrics properties of powder ingredients like particle size, shape, or morphology may resulting in differences in density, static charges, rate of solubility, flow properties and different handling properties of active/inert ingredients. • Approval & validation is the responsibility of pilot-plant. • Single supplier may create problem with respect to price & quality of material so must have alternative suppliers . Dr. Mahesh Kumar Kataria 8
- 9. 6. Relevant Processing Equipment • Economical, simplest & efficient equipment capable of producing product within the proposed specifications are considered for scale up process. • Size of euipments optimum-Too small euipments, the process developed will not scale up, whereas if too big then the wastage of active ingredients. • The ease of cleaning should be considered. 7. Production Rates All parameters should be considered during scale up to decide production rate. The production rate depends upon; • Type of process and equipment • The immediate and future demand of product. • Product loss in equipment • Time required to clean-up equipment between batches • Numbers of batches. Dr. Mahesh Kumar Kataria 9
- 10. 8. Process Evaluation • The knowledge of the effects of various process parameters required for optimization and validation of process. • Optimization performed by monitoring within batch variation of measurable parameters like content uniformity, moisture content, weight variation and compressibility. Dr. Mahesh Kumar Kataria 10
- 11. 9. Preparation of Master Manufacturing Procedure Manufacturing procedures should be presented for easy compliance & understanding for the technicians. The process directions should be; • Specific & unambiguous in form of SOPs. • The weight sheet should clearly identify the chemicals, their quantities and order in which use. • Provide sampling plan and procedure viz. time of sampling, method of sampling and storage of samples. • In-process specifications like addition rates, mixing time, mixing speed, heating and cooling rates, drying temp. etc. and finished product specifications. Proper documentation should be carried out during process. Dr. Mahesh Kumar Kataria 11
- 12. 10. Product stability and uniformity • Each pilot batch should be studied for stability and uniformity of content as per the primary objective of the pilot plant. 11. Good Manufacturing Practice (GMP) Considerations • Compliance of cGMP guidelines is enforced by the FDA during new product or process development. Guidelines provide guidance for manufacturing, testing and QA; • To ensure the safety and consistent quality of finished product. • Clean & hygienic area, controlled environmental conditions to prevent cross contamination, validation of critical process, controlled & clearly defined manufacturing process, qualification & training of personnel, documented procedures in the form of SOPs, MFR, batch processing records (BPR), site master file (SMF) • Emphasize on equipment qualification, regular process review and revalidation, a well-defined technology transfer system, validated cleaning procedures and regularly scheduled preventive maintenance of facilities. Dr. Mahesh Kumar Kataria 12
- 13. 12. Transfer of Analytical Methods to Quality Assurance • Analytical test methods developed at laboratory scale must be transferred to the QA department. • The QA personnel responsible for review the process to make sure that proper analytical instrument is available, trained personal perform the test, reliability of the test and review of assay procedure before transfer. • QA will ultimately be responsible for the release of the product for either clinical studies or commercialization. • QA must be accounted for design of the facility like testing areas, proper product containment areas (quarantine), work-in-process (WIP) areas as well as released material areas. Dr. Mahesh Kumar Kataria 13