Technology Transfer From R and D to Pilot Plant to Plant for Non-Sterile Semisolids

Technology Transfer
Pilot Plant
scale up
supac guidelines

1. Technology Transfer From R and D to Pilot Plant to Plant for Non-Sterile Semisolids Presented By: Guided By: Mr. Shivshankar k chandapure Dr.Mr.Avinash R Tekade M.pharm (semester-I) ( Professor & HOD Of …. Pharmaceutics Pharmaceutics) Marathwada Mitra Mandal's College of Pharmacy

2. Contents Introduction to technology transfer Importance of technology transfer Pilot plant Scale up of semisolid
SUPAC guidelines Case study References

3. Technology transfer Introduction: A process of successful progress from drug discovery to product development, clinical trials and finally to full scale commercialization. Technology transfer is helpful to develop dosage forms in various ways as it provides efficiency in process, maintains quality of product, helps to achieve standardized process which facilitates cost effective production.

4. Importance of technology transfer in pharmaceutical industry To elucidate necessary information to transfer technology from R and D to actual manufacturing. It provide an opportunity to reduce cost on drug discovery and development. It maintain quality of product and achieve standardization process. Documented evidence of manufacturing process for drug product. Technology transfer includes not only the patentable aspects of production but also includes the business processes, such as knowledge and skills.

5. Reasons for technology transfer Lack of manufacturing capacity. Lack of resources Lack of marketing and distribution capability Exploitation in a different field of application:

6. Pilot plant A pilot plant can be defined as the pre-commercial production system which includes new production technology and produces small volumes of new technology-based products . Pilot plant includes following: Development, Early development activities, Clinical supply manufacture, Technology evaluation Scale up and Trans fer to production site

7. Pilot plant scale up activities The major activities takes place during scale up in early development phase are; Technical aspects of process development, Technical aspects of scale up Organisation- Organisation responsibility Determination of responsibility of technology transfer team . Technology transfer documentation . FDA pre-approval inspection preparation.

8. Objectives of scale up Avoidance of the problems associated with the scale-up. Production and process controls guidelines preparation. To identify the critical features of the process Preparation and providing of Master Manufacturing Formula for manufacturing. Evaluation and Validation for process and equipment. Examination of the formula to assess the batch stability.

9. Significance of scale up Standardization of formulae. Review of range of relevant processing equipment. Optimization and control of production rate. I nformation on infrastructure of equipment during the scale up batches. Information of batches physical space required for equipment. Identification of critical features to maintain quality of a product. Appropriate records and reports to support GMP.

10. Semisolids Introduction: Pharmaceutical semisolid includes Ointments,creams,pastes,gel and rigid foams. They contain one or more active ingredients dissolved or uniformly dispersed in suitable base or in any suitable emulsifier,viscosity increasing agents .

11. The following parameters are to be considered during the scale up of semisolid products; Mixing speed. Mixing equipment (Could be able to move semisolid mass from outside walls to the centre and from bottom to top of the kettle). Motors (Drive mixing system with appropriate handling system at its most viscous stage). Heating and cooling process. Com ponent homogenization. Manufacturing of Semisolids

12. Product transfer. Addition of active ingredients. Working temperature range. Shear during handling and transfer from manufacturing to holding tank to filling lines. Transfer pumps (Easily must move viscous material without applying excessive shear and free of entrapped air). Packaging and storage

13. Mixing equipment Planetary mixer has great function of blending, shearing and dispersing, which suits well in dispersing and blending of materials in solid to solid, solid to liquid, liquid to liquid. Planetary mixer is widely used in chemical, food processing, drug producing, construction materials and light industries.

14. Homogenization process Homogenization is the process of converting non-uniform mixture to a colloidal state or a uniform mixture. It is done by reducing particle size of mixtures or uniform dispersion of the mixtures making the product homogenous..

15. Colloidal mill A colloid mill is a machine that is used to reduce the particle size of a  solid  in  suspension  in a  liquid , or to reduce the droplet size in emulsions. Colloid mills work on the rotor-stator principle: a rotor turns at high speeds

16. Transfer pumps for semisolids

17. SUPAC GUIDLINES (scale up post approved changes) SUPAC represents the changes recommended by the US FDA at the time of scale up or approval of NDA / ANDA. In the process of developing a new drug product, the batch sizes used in the earliest human studies are small and the size of the batches is gradually increased (Scale-up). The scale-up process and the changes made after approval in the composition, manufacturing Process, manufacturing equipment, and change of site have become known as Scale-Up and Post approval Changes, or SUPAC.

18. SUPAC guidline defines The level of changes – Minor, Moderate and Major Changes. Test – Application test, in vitro dissolution and in vivo Filing – Annual report, changes being effected supplement and Prior Approval Supplement. The level of changes may impact on formulation and quality performance in following levels; Level 1: unlikely to have detectable Impact. Level 2: could have significant impact. Level 3: likely to have significant impact.

19. These guidelines provide recommendations for post approval changes in; The components or composition change, The site of manufacture change, The scale-up of manufacture change The manufacturing (process and equipment) change.

20. Scale-Up of an Oil/Water Cream Containing 40% Diethylene Glycol Monoethy Ether Drug development and industrial pharmacy 26 (1), 71-77, 2000 The purpose of this study was to scale up an oil/water (o/w) cream formulation containing 40% diethylene glycol monoethyl ether (DGME), developed via 300-g laboratory batches in a 2 5-2 fractional factorial design, to 7-kg batch sizes in a Brogli-10 homogenizer. The o/w cream was manufactured via a standard phase-inversion process in the Brogli-10 homogenizer. Partitioning studies of DGME were conducted in test tubes at ambient temperature and after 24 hr at 70°C in a convection oven.  Phase height was measured by vernier calipers. Microscopy studies of excipients with and without treatment with water or a DGME/water mixture were conducted with a Nikon microscope after equilibration at 35°C for 24 hr. During creation of the 7-kg pilot-scale batches, congealed material was observed between the sweep agitation blade and the discharge port, where the Brogli-10 homogenizer is not temperature jacketed.

21. Factors that increased the amount of congealed material were higher temperatures during primary emulsification and longer cooling times. Partitioning studies revealed that DGME resides in the aqueous external phase of this formulation.  Microscopy studies revealed that DGME in the external phase of this cream has a profound impact on the solubility of certain solid, waxy excipients (e.g., cetyl alcohol and polyoxyethylene-2-stearyl ether) at 35°C. From this study, it appears that DGME resides in the external phase of the o/w cream. During manufacturing, it is hypothesized that the presence of DGME in the external phase alters the solubility of certain solid, waxy excipients in the formula such that they no longer primarily reside in the internal oil phase. On cooling, these materials precipitate or congeal in the external phase. The fractional factorial experimental design at the 300-g laboratory scale did not predict the issues encountered during scale-up. Differences between laboratory scale and pilot plant scale that explain why this phenomenon was not seen during laboratory scale are differences in cooling times, nonjacketed or “cold spots” in the Brogli-10 homogenizer, and a low proportion of congealed material in relation to the total batch size (<1.5%).

22. References 1) Leon Lachman,Herbert A.Liberman,:Industerial pharmacy.Special Indian edition 2009 page no.681 2) Michael Levin,Pharmaceutical process scale up ,Second edition ,volume 157 3) Roop K Khar, Farhan J Ahmad, A Vashishtha, S. Harder, GV Buskirk, JV Battista. PilotPlant Scale-up and Production Management. In: Roop K Khar, SP Vyas, Farhan J Ahmad, Gaurav K Jain, Editors. Industrial Pharmacy. 4th edition. New Delhi: CBS Publishers & Distributors Pvt Ltd, 2013. pp. 947-1002.

23. 4) Dhobale AV, Mahale AM, Shirsat M, Pethkar S, Chakote V. Recent Advances in Pilot Plant Scale Up Techniques - A Review. Indo Am J Pharm Res 2018; 8(4): 1060-1068. 5) Mounica NVN, Sharmila RV, Anusha S, Evangeline L, Nagabhushanam MV,Nagarjunareddy D, et al. Scale up and Postapproval changes (SUPAC) Guidance for Industry: A Regulatory note. Int J Drug RegulAff 2017; 5(1): 13-19. 6)Shayne Cox Gad, Pharmaceutical Manufacturing Handbook ,Publisher ;A John Wiley and Sons ;67-80.

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