Parenteral production

It is an route of administration other than the oral route, this route of administration bypasses the alimentary canal.

1. Parenteral Production Department of Pharmaceutics | Sagar savale Mr. Sagar Kishor Savale [Department of Pharmaceutics] Mobile No. [phone] Email: [email protected] 2/27/2017 Sagar Kishor Savale 1

2. Department of Pharmaceutics | Sagar savale Parenteral Route It is an route of administration other than the oral route , this route of administration bypasses the alimentary canal. It includes, I.V., I. M., Subcutaneous route for parenteral administration. 2/27/2017 Sagar Kishor Savale 2

3. Advantages Quick onset of action and site specific or targeted activity. It can prevent problem of first pass metabolism or presystolic metabolism. Useful for unconscious or vomiting or diarrhea patients. Duration of action can be prolonged by modifying formulation. Suitable for the drugs which are inactivated in GIT or HCl (GI fluid ). Department of Pharmaceutics | Sagar savale 2/27/2017 Sagar Kishor Savale 3

4. Department of Pharmaceutics | Sagar savale Dis-Advantages Injections may cause pain at the site of injection . Only trained person is required. If given by wrong route , difficult to control adverse effect . Difficult to save patient if overdose . 2/27/2017 Sagar Kishor Savale 4

5. Types of Parenteral Department of Pharmaceutics | Sagar savale Based on types of packaging Single dose units: ampoules, infusions and prefilled disposable syringes. Multiple dose units: multiple dose vials. 2/27/2017 Sagar Kishor Savale 5

6. Based on the production and control Small volume parenterals: volume < 100 ml, single used, no preservative. Large volume parenterals: volume ≥ 100 ml, multiple used, add preservatives. Department of Pharmaceutics | Sagar savale 2/27/2017 Sagar Kishor Savale 6

7. 2/27/2017 Sagar Kishor Savale 7 Based on clinical use Solutions for irrigation Ophthalmic solution Dialysis solution Diagnostic agent Allergenic extracts Implants Department of Pharmaceutics | Sagar savale

8. 2/27/2017 Sagar Kishor Savale 8 Department of Pharmaceutics | Sagar savale Based on physical state of product Sterile solutions Sterile suspensions Sterile emulsions Sterile solids

9. 2/27/2017 Sagar Kishor Savale 9 Department of Pharmaceutics | Sagar savale Route of Administration

10. 2/27/2017 Sagar Kishor Savale 10 Department of Pharmaceutics | Sagar savale Subcutaneous (Hypodermis) injection: Below the skin. Intramuscular injection: Inside the large muscles. Intravenous injection: inside the veins to blood stream.

11. 2/27/2017 Sagar Kishor Savale 11 Intra-arterial injection: Inside the arteries. Intracardiac injection: Inside the Harte veins or cardiac veins. Intrathecal injection: Inside the spinal cord. Department of Pharmaceutics | Sagar savale

12. 2/27/2017 Sagar Kishor Savale 12 Intracisternal injection: Inside the one or two cervical nerve. Intra-articular injection: Inside the articular ends of joints and bones. Intracerebral injection: Inside the cerebrum. Department of Pharmaceutics | Sagar savale

13. 2/27/2017 Sagar Kishor Savale 13 Department of Pharmaceutics | Sagar savale Official Types of Injections Injection: e.g. Insulin Injection USP. For Injection: e.g. Cefuroxime Injection USP. Injectable Emulsions: e.g. Propofol USP.

14. 2/27/2017 Sagar Kishor Savale 14 Injectable Suspension: e.g. Methyl Prednisolone Acetate Suspension USP. For Injectable Suspension: e.g. Imipenem and Cilastatin Injectable Suspension USP. Department of Pharmaceutics | Sagar savale

15. 2/27/2017 Sagar Kishor Savale 15 Department of Pharmaceutics | Sagar savale Requirements of Parenteral Preparations Stability Sterility Free from Pyrogens and Free from foreign particles

16. 2/27/2017 Sagar Kishor Savale 16 Isotonicity Specific gravity Chemical purity Department of Pharmaceutics | Sagar savale

17. 2/27/2017 Sagar Kishor Savale 17 Department of Pharmaceutics | Sagar savale Preformulation Factors pH /pka Solubility Thermal/heat effect Dissociation constant Compatibility studies: FTIR / DSC / TLC/ HPLC Oxidation & reduction particle size

18. 2/27/2017 Sagar Kishor Savale 18 Department of Pharmaceutics | Sagar savale Formulation of Parenteral Products 1.The active drug 2.Vehicles Aqueous vehicle ( e.g. water for injection, water for injection free from CO 2 ). Non-aqueous vehicle ( e.g. Ethyl alcohol, propylene glycol, almond oil ).

19. 2/27/2017 Sagar Kishor Savale 19 Department of Pharmaceutics | Sagar savale

20. 2/27/2017 Sagar Kishor Savale 20 Department of Pharmaceutics | Sagar savale Quality Tests Water for Injection

21. 2/27/2017 Sagar Kishor Savale 21 Department of Pharmaceutics | Sagar savale 3.Adjuvants Solubilizing agents (e.g. Tweens & polysorbates ). Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol ). Buffering agents (e.g. citric acid, sodium citrate ). Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol ).

22. 2/27/2017 Sagar Kishor Savale 22 Department of Pharmaceutics | Sagar savale Chelating agents (e.g. EDTA). Suspending , emulsifying & wetting agents (e.g. MC, CMC). Tonicity factor (e.g. sodium chloride, dextrose).

23. 2/27/2017 Sagar Kishor Savale 23 Department of Pharmaceutics | Sagar savale Processing of parenteral preparation

24. 2/27/2017 Sagar Kishor Savale 24 Department of Pharmaceutics | Sagar savale

25. 2/27/2017 Sagar Kishor Savale 25 Department of Pharmaceutics | Sagar savale Lay out o f Parenteral Manufacturing Area

26. 2/27/2017 Sagar Kishor Savale 26 Department of Pharmaceutics | Sagar savale S T O C K R O O M COMPOUNDING AREA CLEAN UP AREA ASEPTIC AREA QUARANTINE AREA STERILIZATION STORAGE AND TRANSPORT PACKING AND LABELLING

27. 2/27/2017 Sagar Kishor Savale 27 Department of Pharmaceutics | Sagar savale

28. 2/27/2017 Sagar Kishor Savale 28 Qualitative Layout of Parenteral Manufacturing Department of Pharmaceutics | Sagar savale Function Area Square meter Percentage Production 11,094 45.1 Warehouse 7,606 30.9 Utility 1,716 4.1 Quality control 1,716 7.0 Administration 1,018 4.1 Maintenance 1,014 4.5 Employee services 1,014 4.1 Security 39 0.9 Total 24,607 100.0

29. 2/27/2017 Sagar Kishor Savale 29 Department of Pharmaceutics | Sagar savale Parenteral Manufacturing

30. 2/27/2017 Sagar Kishor Savale 30 Department of Pharmaceutics | Sagar savale Manufacturing of Parenteral product (Lyophilized)

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32. 2/27/2017 Sagar Kishor Savale 32 Department of Pharmaceutics | Sagar savale Zones As Per Gazzete o f India 1 st zones as per gazette of India BLACK GRAY WHITE White zone : final step (filling of parenteral ). Grey zone : weighing, dissolution & filtration . Black zone: storage , worst area from contamination view point.

33. 2/27/2017 Sagar Kishor Savale 33 Department of Pharmaceutics | Sagar savale Environmental Control Zone Grouping

34. 2/27/2017 Sagar Kishor Savale 34 1 st Zones As Per The C GMP: Zone 1 : Exterior Zone 7: Filling line Zone 6: Filling area Zone 5 : Weighing, mixing & transfer area Zone 4 : Clean area Zone 3 : General production Zone 2 : Warehouse

35. 2/27/2017 Sagar Kishor Savale 35 Air Handling System (Central Air-Conditioning) Department of Pharmaceutics | Sagar savale

36. 2/27/2017 Sagar Kishor Savale 36 Department of Pharmaceutics | Sagar savale Airborne particulate classification for manufacture of sterile products

37. 2/27/2017 Sagar Kishor Savale 37 Department of Pharmaceutics | Sagar savale Types of operations to be carried out in the various grades for aseptic preparations

38. 2/27/2017 Sagar Kishor Savale 38 Department of Pharmaceutics | Sagar savale Types of operations to be carried out in the various grades for terminally sterilized products

39. 2/27/2017 Sagar Kishor Savale 39 Department of Pharmaceutics | Sagar savale Recommended limits for microbiological monitoring of clean areas “in operation”

40. 2/27/2017 Sagar Kishor Savale 40 Department of Pharmaceutics | Sagar savale The air classification limits stated by USFDA

41. 2/27/2017 Sagar Kishor Savale 41 Department of Pharmaceutics | Sagar savale Critical Area

42. 2/27/2017 Sagar Kishor Savale 42 Department of Pharmaceutics | Sagar savale ISO 14644-1 Cleanroom Standards

43. 2/27/2017 Sagar Kishor Savale 43 Department of Pharmaceutics | Sagar savale

44. 2/27/2017 Sagar Kishor Savale 44 Department of Pharmaceutics | Sagar savale

45. 2/27/2017 Sagar Kishor Savale 45 Department of Pharmaceutics | Sagar savale Biological  indicators (BIs) are the most accepted means of monitoring the sterilization process because they directly determine whether the most resistant microorganisms (e.g., Geobacillus or Bacillus species) are present rather than merely determine whether the physical and chemical conditions necessary for sterilization are met. Because spores used in BIs are more resistant and present in greater numbers than are the common microbial contaminants found on patient care equipment, an inactivated BI indicates that other potential pathogens in the load have also been killed. Biological indicators (BIs)

46. 2/27/2017 Sagar Kishor Savale 46 Department of Pharmaceutics | Sagar savale Biological indicators (BIs)

47. 2/27/2017 Sagar Kishor Savale 47 Department of Pharmaceutics | Sagar savale Biological  indicators (BIs) are used for determination of Bacillus species. BIs such as, ethylene oxide, ethylene chlorohydrin, ethylene hydroxide and halogenated ethylenehydrine. BIs was determined by Z value and D Value.

48. 2/27/2017 Sagar Kishor Savale 48 Department of Pharmaceutics | Sagar savale Z value and D Value Z value is define as Temperature is required to higher death rate. D value is define as reduction of microbial population by 90 % of the factor 10. D value is 10 factor greater than Z value. e.g. D value is 121 ºc as the Z value is 10 ºc.

49. 2/27/2017 Sagar Kishor Savale 49 Department of Pharmaceutics | Sagar savale Sterile area : the area which are used to kill the all microorganisms. Techniques Celerity study Sterility study Leakage study Pyrogen study LAL test Assay for content uniformity study

50. 2/27/2017 Sagar Kishor Savale 50 Department of Pharmaceutics | Sagar savale Aseptic area: the area which are used to kill the pathogenic microorganisms. Techniques: HEPA filter integrity test Air flow pattern Air velocity study Heat sensitization study Heat distribution study

51. 2/27/2017 Sagar Kishor Savale 51 Department of Pharmaceutics | Sagar savale Quality Control of Parenteral Preparations

52. 2/27/2017 Sagar Kishor Savale 52 Department of Pharmaceutics | Sagar savale Quality Assurance The planned and systematic activities implemented in a quality system so that quality requirements for a product or service will be fulfilled . Quality Control is a procedure or set of procedures intended to ensure that a manufactured product or performed service adheres to a defined set of quality criteria or meets the requirements of the client or customer.

53. 2/27/2017 Sagar Kishor Savale 53 Department of Pharmaceutics | Sagar savale In Process Quality Control Test Conductivity measurement Volume filled Temperature for heat sterilized product Environmental control tests Visual inspection

54. 2/27/2017 Sagar Kishor Savale 54 Department of Pharmaceutics | Sagar savale Environmental Control Traffic control Surface disinfection personnel Air control (HEPA filters)

55. 2/27/2017 Sagar Kishor Savale 55 Department of Pharmaceutics | Sagar savale Volume Filled An injection container is filled with a volume in slight excess of the labeled size Determination of filled volume: 10 mL or more 1 container 3-10 mL 3 containers Less than 3 mL 5 containers

56. 2/27/2017 Sagar Kishor Savale 56 Department of Pharmaceutics | Sagar savale Leakage Test visual inspection bubble test  dye tests  vacuum ionization test

57. 2/27/2017 Sagar Kishor Savale 57 Department of Pharmaceutics | Sagar savale Clarity Test Clarity test is carried out to check the particulate matter in the sample . It is practically impossible that every unit of lost is perfectly free from visible particulate matter , that is ,from particles that are 30 to 40 micrometer and large in size. USP limits for large volume infusions Particle size Particle limit 10 mm (or) larger/ml 50 25 mm (or) larger/ml 5

58. 2/27/2017 Sagar Kishor Savale 58 Department of Pharmaceutics | Sagar savale Instrumental Methods This is also called as the particle count method particle counting may be based on any one of the following principles; change in Electrical resistance Light absorption Light scattering

59. 2/27/2017 Sagar Kishor Savale 59 Leaker Test Department of Pharmaceutics | Sagar savale

60. 2/27/2017 Sagar Kishor Savale 60 Pyrogen Test Department of Pharmaceutics | Sagar savale 1. LAL test 2. Rabbit test

61. 2/27/2017 Sagar Kishor Savale 61 Department of Pharmaceutics | Sagar savale LAL Tester

62. 2/27/2017 Sagar Kishor Savale 62 Department of Pharmaceutics | Sagar savale Criteria For Limulus Test Result LAL TUBE TEST SAMPLE/CONTROL RESULT 1 Negative control (pyrogen free saline) Should be -Ve 2 Positive control (pyrogen ) Should be +Ve 3 Positive internal control (test sample tainted with exdotoxins) Should be +Ve 4 Test Sample May be +ve or -Ve

63. 2/27/2017 Sagar Kishor Savale 63 Department of Pharmaceutics | Sagar savale Sterility Test

64. 2/27/2017 Sagar Kishor Savale 64 Methods For Testing Department of Pharmaceutics | Sagar savale 1 . Membrane Filtration Method 2. Direct Inoculation Method

65. 2/27/2017 Sagar Kishor Savale 65 Department of Pharmaceutics | Sagar savale Media suitable for Sterility tests are: Fluid thioglycollate medium Soya-bean casein digest medium Wash the filters with fluids to remove inhibitory properties, cutting the membranes aseptically into equal parts and transferring one of the parts to each type of culture medium used. The media are then incubated under prescribed conditions. Membrane Filtration Method

66. 2/27/2017 Sagar Kishor Savale 66 Department of Pharmaceutics | Sagar savale Parenteral Preparation Culture Medium This Method Is Only Used When Membrane Filtration Is Not Possible The Sample Is Inoculated Directly Into The Media Or The Device Is Placed Directly Into The Media. Result: If No Growth In The Media Then Test Is Positive. Direct Inoculation Method

67. 2/27/2017 Sagar Kishor Savale 67 Department of Pharmaceutics | Sagar savale Lyophilization or freeze drying Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The process consists of three separate, unique, and interdependent processes; Freezing, Primary drying ( sublimation ), and Secondary drying ( desorption ).

68. 2/27/2017 Sagar Kishor Savale 68 Department of Pharmaceutics | Sagar savale The advantages of Lyophilization Ease of processing a liquid, which simplifies aseptic handling. Enhanced stability of a dry powder. Removal of water without excessive heating of the product. Enhanced product stability in a dry state. Rapid and easy dissolution of reconstituted product.

69. 2/27/2017 Sagar Kishor Savale 69 Department of Pharmaceutics | Sagar savale Disadvantages of Lyophilization Increased handling and processing time. Need for sterile diluent upon reconstitution. Cost and complexity of equipment.

70. 2/27/2017 Sagar Kishor Savale 70 Department of Pharmaceutics | Sagar savale The Lyophilization process generally includes the following steps Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI ). Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter. Filling into individual sterile containers and partially stoppering the containers under aseptic conditions. Transporting the partially stoppered containers to the lyophilizer and loading into the chamber under aseptic conditions.

71. 2/27/2017 Sagar Kishor Savale 71 Department of Pharmaceutics | Sagar savale Freezing the solution by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or pre-freezing in another chamber . Applying a vacuum to the chamber and heating the shelves in order to evaporate the water from the frozen state . Complete stoppering of the vials usually by hydraulic or screw rod stoppering mechanisms installed in the lyophilizers.

72. 2/27/2017 Sagar Kishor Savale 72 Department of Pharmaceutics | Sagar savale There are many new parenteral products, including anti- infectives , biotechnology derived products, and in-vitro diagnostics which are manufactured as lyophilized products. Additionally , inspections have disclosed potency, sterility and stability problems associated with the manufacture and control of lyophilized products.

73. 2/27/2017 Sagar Kishor Savale 73 Department of Pharmaceutics | Sagar savale