2. CONTENTS Introduction Objective Manufacture of sterile preparations Personnel Building and premises Water and steam system Equipment Processing Sterilization Sanitation References 2

3. I NTRODUCTION Sterile pharmaceutical products are very critical and sensitive products. Any failure in quality and purity of these products may directly affect the safety of the patients being treated. Certain elements are required to be in processing of Sterile pharmaceutical products. e.g. :- 1) Trained personnel 2)Layouts of plant 3)SOP 4)Process should be pre-validated 5)Production under guidance of authorized person 6)Use LAF 3

4. O BJECTIVE To review personnel. To review general requirement building and premises. To review equipment. To review the different types of sterilization methods. To review equipment To review processes. 4

5. M ANUFACTURE OF STERILE PREPARATIONS A)C OMPARISON OF VARIOUS GRADES DESCRIBED IN VARIOUS GUIDE LINES :- sr. no. U.S. Federal Standards 209(E) MHRA/ TGA ISO standards Metric grade 1Class100A & B 5 M 3.5 2Class10,000C 7 M 5.5 3Class1,00,000D 8 M 6.5 5

6. C)TYPE OF OPERATION CARRIED OUT IN VARIOUS GRADES FOR ASEPTIC PREPARATION:- Grade Type of operations for aseptic preparations A Aseptic preparation and filling. B Background room conditions for activities requiring Grade -A C Preparation of solutions to be filtered D Handling of components after washing 6

7. PERSONNEL FACTORS ARE REQUIRED TO BE IN PERSONNEL:- 1)Training of persons. 2)Gowning or dress management. 3)some specific requirements for working in sterile products manufacturing area. 7

8. 1)T RAINING OF PERSONS :- Training of persons working in Aseptic Processing area should cover following aspects:- a)Quality and sterility product b)Type of contamination c)Source of contamination d)Control of contamination I)By clean rooms II)By people III)By cleaning and disinfection e)Training on sterilization 8

9. a)QUALITY AND STERILITY PRODUCT:- People working in this area, should be emphasized on the importance of their behavior, knowledge and skills which they utilize for the quality of the product. People should be trained about:- Manufacturing Hygiene Sterilization Process 9

10. 10

11. I. Bacteria-carrying particles from-Skin, Hair, Beard, Gut, Saliva, Nose, Mouth, Throat etc. II. Environment around us III. Water IV. Containers and closure V. Raw material VI. Dusty, dirty premises VII. Uncleaned or wet equipment and containers c) Source of contamination 11

12. d)Control of contamination 1)Control of contamination by clean Rooms:- o Air is supplied under pressure o Use filters o Use different grade or class of clean room. o Surface of walls, floors, ceilings, fittings, work top must be hard, smooth and unbroken. o Wall coated with antifungal epoxy paint layer. o Air locks 12

13. 2)Control of contamination by people:- o High standards of hygiene and cleanliness o Periodic health checks o No eating, chewing, drinking and smoking o No outdoor clothing o Changing and washing procedure o No watches, jewellery and cosmetics o Do not move vigourously 13

14. 3)Control of contamination by cleaning and disinfection:-  SOP of cleaning and disinfection.  Use automatic equipment.  Use vacuum for shucking dust & do not use compressed air.  Cleaning of wall start at the top and work down.  Use right cleaning and disinfectants.  Equipments are clean after use. 14

15. e)Training on sterilization:- Laid-down procedure should be followed. Record should be maintained. Necessary to checked integrity of the products. To ensure the product, materials, equipment are not mixed up after the sterilized. 15

16. 2)G OWNING OR DRESS MANAGEMENT :- Outdoor clothing not in change rooms leading to Grade B and C rooms Change at every working session, or once a day Change gloves and masks at every working session Disinfect gloves during operations Washing of garments – separate laundry facility No outdoor clothing Changing and washing procedure No watches, jewellery and cosmetics 16

17. A REA WISE GOWNING REQUIREMENTS CAN BE TABULATED :- SR. NO ITEMES OF DRESSGREDE A&B GRADE C GRADE D 1Head Gear or hoodYNN 2Nose or Face maskYYN 3One piece boiler suitYYY 4Rubber or plastic shoesYYY 5Shoe cover or bootyYY/N 6Non powder rubber or plastic gloves(sterilized) YY/N 7CapYYY 8Beard maskYYY 9Safety gogglesYNN 17

18. 3) SOME SPECIFIC REQUIREMENTS :- Restrict number of people in aseptic area. Drug sensitivity test for employees. Medical check-up. Psychological persons. 18

19. BUILDING AND PREMISES Design:-  avoid unnecessary entry of supervisors and control personnel  operations observed from outside In clean areas, all exposed surfaces:-  smooth, impervious, unbroken  permit cleaning and disinfection  no uncleanable shelves, cupboards, equipment  proper installation of pipes and ducts, no unsealed openings 19

20. Changing rooms:-  designed as airlocks  effective flushing with filtered air  separate rooms for entry and exit desirable  hand washing facilities  interlocking system for doors  visual and/or audible warning system 20

21. W ATER AND STEAM SYSTEM :- PEURIFIED WATERWATER FOR INJECTION 1) Clear, colorless, odourless, tasteless. 2) pH- 5 to 7.5 3) Residue on evaporation : not more than 0.001%. 4)Conductivity :nmt4.3µ /cm².4)Conductivity :nmt1.1µ /cm²at 20°C 5)Microbial count-Maximum 100CFU/ml. 5)Microbial count:- a)Bacteria :- 10CFU/100ml. b)Fungi :- Nill  Pure steam:- 21

22. EQUIPMENT I. Type of equipment II. Materials of construction III. SOP IV. Validation of equipment 22

23. I. Type of equipment a) Washing machine b) Sterilizers e.g. Dry het sterilizers, autoclave c) filling machines for ampules and vials d) Plugin and sealing machine for ampules and vials e) Labelling machine II. Materials of construction 23

24. III. Validation of equipment Equipments validated before use Record should be maintained IV. SOP calibration, cleaning, operations and maintenance 24

25. P ROCESSING 1)Starting materials:- Microbiological contamination should be minimal. 2)Area monitoring and control:- Viable /Non-viable particulate mater, air velocity, presser differentials, Temp., relative humidity, personnel hygienic, Light level. 3)Equipment Control:- Validation – should not compromise the processes. New processing procedures validated revalidation after significant changes and regular intervals 25

26. 4)Discipline in Aseptic processing area 5)Washing and sterilization of primary containers:-  as short as possible  time limit validated 6)Solution preparation and Filtration:-  as short as possible  maximum time set for each product 26

27. 7)Filling, Sealing and Inspection:-  Takes place in Grade A & B.  Equipment validation.  I.P.Q.C. inspection.  Medically fit workers.  Labeling of filled & sealed container. 27

28. S TERILIZATION Methods of sterilization:- 1)Moist or dry heat 2)Irradiation (ionizing radiation) 3)Sterilizing gaseous agents (e.g. ethylene oxide) 4)Filtration 28

29. 1)Sterilization by moist or dry heat:- I) Sterilization by dry heat:- For non-aqueous liquids, dry powders, equipment Air circulation in the chamber Positive pressure in chamber to prevent entry of non-sterile air validation 29

30. II)Sterilization by moist heat (autoclave):- Water-wettable materials only, and aqueous formulations Items are wrapped Temperature, time and pressure monitored Quality of the steam – no contamination 30

31. III) Sterilization by radiation :- Suitable for heat-sensitive materials and products ‹ confirm suitability of method for material ‹ ultraviolet irradiation not acceptable 31

32. IV)Sterilizing by gaseous agents:- Only when no other method is suitable E.g. ethylene oxide, hydrogen peroxide vapour Validation: also prove the gas has no damaging effect on product Time and conditions for degassing Direct contact with microbial cells essential Humidity and temperature equilibrium 32

33. V)Sterilizing by filtration :- Through a sterile filter of 0,22 µm or less, into previously sterilized containers remove bacteria and moulds not all viruses or mycoplasmas Consider complementing with some degree of heat treatment 33

34. S ANITATION Frequent, thorough cleaning of areas necessary Written SOP Regular monitoring to detect resistant strains of microorganisms Chemical disinfection Monitoring of disinfectants and detergents Frequent monitoring in areas where aseptic operations are carried out settle plates, volumetric air samples, surface sampling (swabs and contact plates) sampling methods should not contaminate the area 34

35. REFERENCES 1. “Pharmaceutical quality assurance,”by prof. Manohar A.Potdar,nirali prakashan pageno.13.1-13.60 2. www.newagepublishers.com 3. Whglib.doc.who int/trs/who 4. www.fda gov/ucm 5. www.extemp.je sterile preperat 6. bookGoole.com/.com pharmacutical 35

36. T HANK YOU 36