1. DESIGNING A MULTIPRODUCT PLANT FOR RECOMBINANT BIOPHARMACEUTICALS. MAJOR CONSIDERATIONS Biotec India International, 2003

2. Why a Multiproduct Plant (MPP)? Recombinant Biopharma Products (rBP) have, in general, similar steps in their production process. Recombinant Biopharma Products (rBP) have, in general, similar steps in their production process. One MPP is more economical than two or more separate plants. One MPP is more economical than two or more separate plants. It is possible to reduce up to 40% of the total investment.It is possible to reduce up to 40% of the total investment. A MPP reduces the number of high qualified personnel. A MPP reduces the number of high qualified personnel. Can achieve better control. Can achieve better control.

3. Why not a MPP? Regulatory agencies are more concerned with cross contamination in MPP than in dedicated plants. Regulatory agencies are more concerned with cross contamination in MPP than in dedicated plants. Need to produce in campaign. Need to produce in campaign. It is necessary to have a higher stability for the Active Principles & intermediary products in the processes.It is necessary to have a higher stability for the Active Principles & intermediary products in the processes. Less flexibility for the production management.Less flexibility for the production management.

4. Recombinant biopharma products (rBP). More than 90% of the approved rBP are proteins, most of them of human origin. Therefore they are treated as biological. More than 90% of the approved rBP are proteins, most of them of human origin. Therefore they are treated as biological. In future rBP can be DNAs or other nucleic acid biomolecules.In future rBP can be DNAs or other nucleic acid biomolecules. Biomolecules are more labile. Biomolecules are more labile. Biomolecules are more difficult to characterize and control. Biomolecules are more difficult to characterize and control. There is an intrinsic variability in the biological response.There is an intrinsic variability in the biological response.

5. Timeline for launching a new rBP. From lab to market Biotechnology have reduced the time line from R&D upto the market for a new product. (10-12 years). Biotechnology have reduced the time line from R&D upto the market for a new product. (10-12 years). Production cell engineering Process engineering Plant design and Production Market CT I & IICT III

6. Engineering a rBP Production Cell Genes Structure: coding sequences & regulatory sequences. Structure: coding sequences & regulatory sequences. Coding sequences are read by an universal genetic code. (95% true)Coding sequences are read by an universal genetic code. (95% true) Regulatory sequences are more differentiated.Regulatory sequences are more differentiated. Prokaryotes ≠ Lower Eukaryotes ≠ Mammals ≠ Plants Prokaryotes ≠ Lower Eukaryotes ≠ Mammals ≠ Plants Start Stop Regulatory sequences Coding sequences General structure of a gene

7. Engineering a rBP Production Cell Vectors Auto-replicative multicopy plasmids (mostly used in bacteria) Auto-replicative multicopy plasmids (mostly used in bacteria) Integrative plasmids (More used in yeasts) Integrative plasmids (More used in yeasts) Bacteriophages Bacteriophages Viruses (Integrative or not, higher eukaryotes) Viruses (Integrative or not, higher eukaryotes) Artificial chromosomes. (Yeast mainly) Artificial chromosomes. (Yeast mainly)

8. Engineering a rBP Production Cell Hosts Prokaryotes (Bacteria, mainly E. coli). Prokaryotes (Bacteria, mainly E. coli). Lower eukaryotes (yeast). Lower eukaryotes (yeast). Higher Eukaryotes cell lines (Mammalians, Insects) Higher Eukaryotes cell lines (Mammalians, Insects) Living Organisms (Transgenic animals & plants) Living Organisms (Transgenic animals & plants)

9. Regulatory Considerations Are the rBP parenterals?. Are the rBP parenterals?. Have few sense to use a Plant designed to produce a parenteral drug for producing a non parenteral (np) one. Plant should be designed according to the highest requirements and then, production cost for the np will run over.Have few sense to use a Plant designed to produce a parenteral drug for producing a non parenteral (np) one. Plant should be designed according to the highest requirements and then, production cost for the np will run over. Cleaning Validation. Cleaning Validation. Additional to the cleaning procedure between batches, inter-campaign cleaning procedure should be validated.Additional to the cleaning procedure between batches, inter-campaign cleaning procedure should be validated. No traces of the previous product. No traces of the previous product. No traces of the previous host.!!!! No traces of the previous host.!!!!

10. Scale of the rBP production. Are Are the commercial scale of the products similar?. DifferenceDifference of scale must be under a factor of approximately 20. Ex. Ex. Positive: Interferon and G-CSF Negative: Interferon & Insulin Insulin plant must be designed for not less than 50 kg of protein. Interferon Plant 10 gram is a good commercial scale.

11. Are the bioproducts coming from the same HOST? Different host -> different equipment design. Different host -> different equipment design. Geometry of fermentorsGeometry of fermentors Disruption devices.Disruption devices. Different skills of the personnel for bacteria or yeast then from MCL. Different skills of the personnel for bacteria or yeast then from MCL. Equal host is easier to validate inter- campaigns cleaning procedures. Equal host is easier to validate inter- campaigns cleaning procedures. Environmental aspects depend of the hosts. Environmental aspects depend of the hosts. Effluents treatmentEffluents treatment

12. Formulation Section Purification Section Live Section MPP Design Recommendations General production scheme of a rBP Support Activities Section QC & QA Section

13. Plant Design Recommendations Sectioned Plant Sectioned Plant Live Section Steps 1-3Live Section Steps 1-3 Purification Section Steps 3-XPurification Section Steps 3-X Formulation & Filling Section Steps X+1Formulation & Filling Section Steps X+1 Support Activities SectionSupport Activities Section QC & QA SectionQC & QA Section Each Section should have independent: Personnel & material entrance,Personnel & material entrance, Differentiated HVAC systems,Differentiated HVAC systems, Differentiated treatment of supplies, RM, Uniforms etc.Differentiated treatment of supplies, RM, Uniforms etc.

14. Actual layout of a MPP PANHEBER BIOTEC LALRU PUNJAB

15. Advantages of Sectioned MPP? Each section can be used in an independent way. Each section can be used in an independent way. Different batches.Different batches. Different products Simultaneously !!!Different products Simultaneously !!! One MP Live Section for 2 or more dedicated purification Section. One MP Live Section for 2 or more dedicated purification Section. Design of Intermediary products. Design of Intermediary products. It is recommended that at final step on each section an stable well identify intermediary product can be establish.