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Sterile dosage form
- 1. PRODUCTION LINE SCALING UP, PROCESSING , BATCH RECORD DESIGN Sterile Dosage Forms Alaa Mohamed deabes
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- 3. Sterile Pyrogen free Sterile products are dosage forms of therapeutic agents that are free of viable microorganism. Sterility is absolute term. Pyrogens are substances that produce a fever. The most common pyrogens are endotoxins, produced by G-ve bacteria . Thermostable Sterile Dosage Forms
- 4. Pyrogen Removed byoxidizing to easily eliminated gases or to non volatile solid easily separated by fractional distillation . Several distillation are done , purified sterile , pyrogen free Pyrogen test In vivo ( rabbit ) In vitro Limulus amebocyte lysate LAL
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- 6. Solvent and vehiclefor injections Water for injection WFI Sterile water for injection SWFI Bacteriostatic water for injection Nonaquous vehicle
- 7. Water for injectionWFI Purified by distillation or reverse osmosis
- 8. Water for injectionWFI It is not sterile No added substance. For manufacture of injectable products which are to be sterilized after preparation. Used withen 24 hr after its collection. Collected in sterile and pyrogen free container glass or glass lined.
- 9. Sterile water forinjection SWFI Sterile Pyrogen free No bacteriostatic or other added substance Contain greater amount of solid than WFI Why Diluent for already sterilized and packaged injectable medication Used IV Not used
- 10. Sterile water forinjection SWFI sterilised within 12 hours of collection and distributed in sterile containers It should be packaged only in single dose containers of not larger than 1-litre size
- 11. Bacteriostatic water forinjection Sterile water for injection contain antimicrobial agents . containing 0.9% (9 mg/mL) of benzyl alcohol added as a bacteriostatic preservative . Package is not more than 30 ml of water . can be used in diluting drugs that can subsequently be administered by intravenous, intramuscular, or subcutaneous injection. Why
- 12. Nonaqueous vehicle Substanceliable to hydrolysis Substance insoluble in water Must be non toxic , non irritating without pharmaceutical activity Viscosity & pH must be suitable Misciblity with body fluid Glycerin , PEG , Fixed vegetable oil , Alcohol
- 13. Sterilization • Saturated steamunder pressure • Dry heatclassical • Filteration • Ionizing radiation ( gamma , electron radiation ) • Gas ( ethylene oxide, formaldyde) others
- 14. Microbial destruction D value Zvalue F0 Time required to reduce the bioburden by 90% D = U Log N0 - logNu Exposure time Original bioburden Remaining populaton Diff in temp requried to change D value by 90% Z = T2 –T1 Log D1 –log D2 F0 = D121 ( logN0 – logNu ) Autoclave Z value based on B.stearothermophilius
- 15. Steam sterilization ( autoclaving) 1) Mechanism 2)for what 3) Not for what 4) Air most removed 115.5 for 30 min 121.5 for 20 min 126.5 for 15 min temp Time Most common 121 ±2 °C
- 16. Temperature distribution Heatpenetration On empty & loaded chamber Coldest spot during empty ch to provide the slowest heating location 15 – 20 thermocouples Any deviation more ±2.5 °C ….. Undesirable Depend on the thickness of the container Coldest point in the product load Container similar to formula and put B.S Biological is paced with thermocouples ( location) F0 is determinded Validation of Steam sterilization ( autoclaving)IQ OQ
- 18. Dry heat sterilization 1) Mechanism 2)for what 3) Not for what 160 for 180 min 170 for 60 min De pyrogenation
- 19. Dry heat sterilizationvaldiation Designed as overkill that deliver heat in excess than that required to inactivate 1000 EU of E.Coli endotoxin ( challenge) USP recommends a 3-log reduction in endotoxin using lamulus amebocyte lysate reagent with a senseitivity greater than 0.15 EUml All pervious tests in addition to pyrogen test
- 20. Filtration 1) Mechanism 2) Forwhat 3) Disadvantages Pore size 0.22 micrometer Double filter layer or second filtration Don’t use more than 24 hr * * Membrane filters : cellulose esters , plastic .. Asbestos-containing filters should not be used. Or fiber shedding followed by an aseptic transfer of the sterilized solution to the final containers All filters, tubes, and equipment used "downstream" must be sterile ( autoclave) Filter integrity test filters should not interact with the product
- 21. Radiation 1) Mechanism 2) Forwhat 3) Disadvantages Laws and regulations for protection against radiation must be respected. Radiation doses should be monitored with specific dosimeters
- 22. Aseptic sterilizationTerminal sterilization Drug product & container & closure are first sterilized separately. Each aseptic process can introduce error . Only used when terminal sterilization is not feasible. Product in its final container is sterilized as whole. Can be manufactured under clean rather than aseptic . most common ?? Sterile Dosage Forms
- 25. Air classification system B at rest = A at operation C at rest = B at operation D at rest = C at operation A for high risk operation B surround area A C & D for less critical stages
- 29. For ISO7, particles smaller than 0.5 microns (≥0.1 µm, ≥0.2 µm, ≥0.3 µm) are not taken into consideration. The concentration of particles of ≥0.5 µm and above should be below 352,000, for particles of 1 micron and above 83,200 or lower and for particles of 5 microns and above 2,930 or lower.
- 30. HEPA Filters High-efficiencyparticulate air (HEPA) filters Can remove at least 99.97 % of dust , pollen , mold , bacteria and any airporn particle 0.3 microgram
- 31. HEPA Filters Aircleanliness is achieved by passing the air through HEPA filters. The more often the air passes through the HEPA filters, the fewer particles are left in the room air. Number of air change with hour = Volume of air filtered by one hour /volume of the room ISO class Average number of air changes per hour ISO 5 240–360 air changes per hour (unidirectional airflow) ISO 6 90–180 air changes per hour ISO 7 30–60 air changes per hour ISO 8 10–25 air changes per hour Conventional building 2–4 air changes per hour
- 32. ISO 5 (A)(100) use unidirectional airflow (not just below a LAFW hood) ISO 5 zone | 240–360 air changes per hour Entry Air lock
- 33. must be takeninto consideration the size of the room, the number of people in the room, the equipment in the room, the processes involved, the heat gain, etc
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- 42. Flow chart ofsterile dosage form IPC Raw material AI + additive +pack Engineering chart Sizing and sieving Ball mill Sieving machine Det of particle size Drying Tray dryer Det of moisture content Weighing Electric balance Douple chek Wt WFI Line
- 43. Flow chart ofsterile dosage formsolution Dissolving Det of sol ,temp, Water quality ,pH Mixing & Dilution Propeller Trubine mixer ( viscous) Propeller Trubine mixer (viscous) Det of sol ,temp SP gravity , volwt PH adjustment pH meterpH determination Filling & sealing sterlization Sterile filteration Aseptic filling F drying Aseptic sealing Filling machine autoclave Sterility , Leakage , Gross Wt , VolWt of* Container suitablity Terminal
- 44. Flow chart ofsterile dosage form Emulsion suspension gel Dissolving & filteration Meta filter Turbine mixer ( viscous) Det of sol ,temp, Water quality ,pH 1 ry emulsion 1 ry suspension Conc gel Collid mill High speed agitator Sterlization for oil ,powder, aq Mixing & dilution PH adjustment Make up to volume Turpine mixer pH meter Filling, Capping , Sealing Rh , Vis, Creaming rate Rh , Vis, Sed rate Rh , Vis , gel stregnth pH determination Dryness Gross Wt Leakage Sterlity test Filling machine
- 45. Flow chart ofsterile dosage formOintment Dissolving & sterilization Oily base melting & sterlization Meta filter Turbine mixer ( viscous) Det of sol ,temp, Water quality ,pH DJ-SH melting tank Aseptic mixing & homogenization DJ-SH melting tank with agitator Aseptic tube filing & sealing & labelling Filling machine Gross Wt- leakage Temp –mix time Homogeneity Oil glob size Wt –clarity – temp
- 46. Flow chart ofsterile dosage form Packaging Labelling , cartoning Package machine Recon of label , carton data, good packaging Inspection of pamphlet & leakage test Intermediate store Quality control Final store Content uniformty Volwt check Viscosity – rheology Clarity Sed rate – cream rate Gel stregnth Consistency Spreading Gritty sensation Strility test
- 47. https://www.sciencedirect.com/topics/chemistry/py rogen http://www.authorstream.com/Presentation/tausif1 991-1795419-design-layout-operational-facilities- sterile-products/ https://www.slideshare.net/shettyuc/cgmps-for- sterile-products https://www.sciencedirect.com/topics/engineering/ terminal-sterilization https://www.sciencedirect.com/topics/agricultural- and-biological-sciences/aseptic-processing Reference
- 48. https://www.google.com/search?q=air+classificatio n+system&source=lnms&tbm=isch&sa=X&ved=0ah UKEwjq0p2QysXhAhUFxhoKHRy_CaYQ_AUIDigB &biw=1366&bih=604#imgrc=ij9hpgPzJYLM6M: http://www.hefilter.com/Industry-News/Common- Types-of-HEPA-Filter.shtml https://www.mecart-cleanrooms.com/learning- center/cleanroom-classifications-iso-8-iso-7-iso-6- iso-5/ https://www.slideshare.net/yuvas2010/377218gmpt rainingsterilefacility Reference