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Industrial pharmacy 1 Bpharmacy 3rd year

1. WELCOME To our active learning session presentation

2. ACTIVE LEARNING SESSION TOPIC NAME: Parenteral product Production procedure, facilities, aseptic and controls processing. SUBJECT : Industrial Pharmacy I. UNDER THE GUIDENCE OF : MS. Pranita Gaikwad Mam.

3. Participants Mr. Farhan Desai (21) Ms. Komal Dhole (22) Ms. Sakshi Dhole (23) Mr. Sachin Diwane (24) Mr. Soham Dudhgave (25)

4. Contents Introduction Production Procedure Facilities for parental Production Aseptic Processing Control

5. DEFINATION OF PARENTERALS: Definitions:-The term ‘Enteron’ derived from the Greek word 'Para' (outside) & ' (intestine). It means that any dosage form which are given outside the intestine is called parenterals. These preparations are administered by other than oral routes. They are sterile preparations that are given directly into the systemic circulation.Common injection types are intravenous (into a vein), subcutaneous (under the skin), and intramuscular (into muscle).

6. ADDITIVES MEANING EXAMPLES ANTIOXIDANTS The oxidation can be prevented by adding suitable antioxidant Ascorbic acid, Sodium bisulfate buffer Buffers added to maintain pH of solution NaoH , Phosphate Chelating agent Chelating agents are added to chelate & thereby inactivate metals such as copper, iron, zinc present in the formulation. EDTA,Tetra sodium edetate Solubilizing agent These are used to increase the solubility of drugs which are slightly soluble in water. Ethanol,PEG Antimicrobial These agents are added in adequate quantity to prevent the growth of microorganisms during storage and withdrawal of individual doses Phenol,Benzyl Alcohol

7. PRODUCTION PROCEDURES, FACILITIES AND CONTROLS : Parenteral preparations being sterile its production is subject to special requirements in order to minimize risks of microbiological, particulate and pyrogen contamination. Parenteral preparations require stringent controls to minimize microbiological, particulate, and pyrogen contamination due to their sterile nature. Processing involves multiple validated steps, including cleaning, compounding, filtering, sterilization of containers and equipment, filling, stoppering, freeze-drying, terminal sterilization, and final sealing. A proactive approach to quality assurance is crucial,     requiring scientific evaluation and     control of potential risks, with strict adherence     to established and validated manufacturing methods.

8. Overview of Manufacturing of parenteral products

9. Procedure 1.Cleaning of containers, closures & equipments. All the containers, closures & equipment are thoroughly cleaned with detergents with tap water, followed by clean distilled water &finally rinsed with water for injection.
Rubber closures are washed with 0.5% sodium pyrophosphate in water, then removed from the solution, washed with water followed by rinsing with filtered water for injection.
On small scale washing is done manually but on a large scale automatic washing machines (rotary rinsers, automatic washers) are used. 2. Handling & collection of materials The wet, clean containers must be handled in such a way that contamination is not reintroduced. These containers must be protected by a laminar flow of clean air until covered, within a stainless steel box, or within a sterilizing tunnel.

10. 3. Preparation of parenteral products . •The parenteral preparation must be prepared in aseptic condition. •All measurements of quantities should be made as accurately as possible & checked by second qualified person. The ingredients are accurately weighed separately & dissolved in the vehicle as per method of preparation. 4. Filtration After a product has been compounded, it must be filtered, if it is a solution. The solution is passed through bacteria proof filter such as membrane filter, Seitz filter, filter candle & sintered glass filters.

The primary objective of filtration is to clarify a solution

11. 5. Filling the preparation in final containers • The filtered product is filled into final containers such as ampoules, vials, & transfusion bottles, which are previously cleaned & dried.
• The filling is carried out under strict aseptic precautions.
• On small scale, filling is done manually by using hypodermic syringe & needle. On large scale, filling is done by automatic filling machine.

6. Sealing the containers Sealing should be done immediately after filling to prevent contamination.
Ampoules are sealed by melting a portion of the glass neck.
Glass or plastic vials & bottles are sealed by closing the opening with a rubber closure (stopper). 7. Sterilization •The parenteral preparation should be immediately sterilized after sealing in its final container.

12. Parenteral products are sterilized by autoclaving method at different temperature & pressure.
Autoclave: At 115°C to 116°C for 30min
At 121°C for 20min
Hot air Oven: At 160°C for 2 hours. 8. Evaluation of the parenteral preparation
The finished parenteral products are subjected to the following tests, in order to maintain quality control:
1. Sterility test
2. Clarity test
3. Leakage test
4. Pyrogen test
5. Assay.

13. 9. Labelling & Packaging After evaluation of the parenteral preparation, the ampoules, vials & transfusion bottles are properly labelled & packed. The label should state- 1. Name of the preparation
2. Quantity of the preparation
3. Mfg. Lic. No.
4. Batch No.
5. Date of manufacture
6. Date of expiry
7. Storage conditions
8. Retail price
9. Manufacturer’s address The packaging provide ample protection for the product against physical damage from shipping, handling, & storage as well as protecting light-sensitive materials from UV radiation

14. Facilities for Parenteral Production – General Requirements Clean production areas with airlocks for personnel and materials are essential. Separate areas are needed for component preparation, product preparation, filling, and sealing. Critical factors: cleanliness and filtered air quality (Grades A–D). Laminar hood, barrier technology, and automation help maintain sterility. (1) Production Area: Designed to control the environment in critical areas. Operations arranged so that people, product, and components flow in order of increasing cleanliness. (2) Warehouse: Handles receiving (unpacking, sampling, quarantine), storage (spare parts, filters, chemicals, supplies, uniforms), and shipping (with quarantine before dispatch) .

15. (3) Administrative Areas: Designed based on plant requirements.
Offices may be individual or group-based, open or closed.
Should be located near production for efficiency, but supporting offices must be separated to prevent contamination. (4) Environmental Control :
Plant layout must align with HVAC system needs.
The black zone must maintain particle count ≤100 (≥0.5 µ) throughout the upstream work area. The plant is divided into seven environmental control zones: Exterior (Zone 1): Surroundings of the plant; sterile maintenance with pest and weed control. Warehouse (Zone 2): Storage of raw materials and finished products; requires temperature/humidity control and fire safety. General Production & Administration (Zone 3): Well-sealed area for essential personnel and equipment movement. Clean Area (Zone 4): Used for washing, equipment preparation, and product sampling.

16. Weighing, Mixing & Transfer (Zone 5): Controlled environment for operations under cGMP (not aseptic filling). Area (Zone 6) : Controlled zone for aseptic filling; less distinct for non-aseptic processes.
Final Filling Area (Zone 7): Last barrier against contamination; may use laminar flow; stricter control for aseptic than non-aseptic filling. Classification of Clean Rooms:- They are classified as below: Depending upon Grades : Grade Description/ Use Grade A Local zone for high-risk operation (filling zone, stopper bowls, open ampouls , vials) Grade B Background environment for grade A (aseptic preparation, filling) Grade C Clean area for less critical stages in sterile products manufacturing Grade D Clean area for even less critical stages in sterile product manufacturing

17. Cleanroom Depending upon Classes : Class Particle size/ limit Class 1 <3000 particles/ m³ of ≥ 0.5 um Class 2 <3000 particles/ m³ of ≥ 0.5 um ;2000 particles/ m³ of ≥ 0.5 um ; 30 particles/ m³ of ≥10um Class 3 < 1000000 particles/ m³ of ≥1um ; 20000 particles/ m³ of ≥ 0.5 um; 4000 particles/ m³ of ≥10um ; 300 particles/ m³ of ≥ 25um Class 4 < 200000 particles/ m³ of ≥ 0.5 um

18. Depending upon particles per cubic feet : Class Maximum particle count ( ≥ 0.5 um) Minimum particles count ( ≥ 0.5 um) Class 100 100 / ft³ - Class 1000 1000 / ft³ 10 / ft³ Class 10000 10000 / ft³ 65-70 / ft³ Class 100000 100000 / ft³ 700 / ft³

19. Schematic of aseptic area

20. Aseptic area From preparation area the parenteral formulation will be transferred to aseptic filling area.
The parenteral preparations are filtered, filling into final containers & subsequently sealed.

The entry of personnel into aseptic area should be through an air lock.

To maintain sterility, specially trained persons should be selected to work. They required to wear sterile clothes & should be subjected to physical examination at regular intervals to ensure that they are not carrier of any infectious disease. There should be minimum movement in aseptic area.Ceiling, walls & floor of aseptic area should be sealed & painted, so that they can be washed or treated with aseptic solution or sprayed before use.

Stainless steel counters should be fitted on the walls.

Mechanical equipment should be housed in stainless steel cabinet in order to prevent dirt to accumulate on it. Mechanical parts that will come in contact with the parenteral product should be separated so that they can be sterilized.

21. Requirements for design of aseptic area: Aseptic techniques are defined as a set of procedures carried out to obtain an environment with minimal contamination from pathogenic microorganisms. These procedures are carried out under controlled conditions. The main goal of aseptic technique is to provide protection against infections. Site of premises: Aseptic area should be designed at a site away from stairs, lift shafts, corridors and general manufacturing area as these areas are capable of providing routes by which microorganisms may travel. Each stage of the production should be carried out in separate rooms of aseptic area. Store rooms should be adjacent to aseptic area where all sterile equipments and products can be stored.

22. Windows & Doors WINDOWS: Large windows with transparent glass are suitable for aseptic area. These windows should remain closed and ventilation should be provided artificially by air filtration system. These type of windows are used to prevent heat loss from glass material. DOORS: Entrance should have double doors with an air-lock system. In this way, air entering from outside into the aseptic area can be prevented. Even sliding and swing doors can be used.

23. . Floors, walls and bench tops The floor, walls and bench tops should be. Easy to clean Smooth with no cracks and pores Impervious to cleaning agents like disinfectants etc 4. Chemically resistant to solvents, dyes, strong acids or alkalies . FLOORS: It should be made up of the following materials, a) Terrazzo b) Linoleum c) plastics

24. Terrazzo: It is a mixture of cement and marble which is mostly used as flooring material in aseptic area. (b)Linoleum Linoleum of heavy grade is best suited for flooring. It is available in the form of sheets and tiles. (c) Plastics: Polyvinyl chloride of non-slip and matt-finish grade is ideally for aseptic area. The joints of sheets & tiles can be welded

25. Walls and ceiling: They should have surfaces made up of Tiles -they are smooth, non-absorbent in nature and tend to crack on prolonged usage. They can be easily cleaned. Glass paint -this type of paint is applied on smooth plaster. These plaster walls get easily damaged. Plastic laminate - this type of material I used to cover the walls and ceiling of an aseptic room. However, it is expensive