manufacturing of parenterals

SMALL VOLUME AND LARGE VOLUME PARENTERALS. FORMULATION ASPECTS, SEALING, LAYOUT

1. MANUFACTURE OF SMALL VOLUME AND LARGE VOLUME PARENTERALS PRESENTED BY: M.SUPRAJA DEEP, B.PHARMACY, ST.PETERS INSTITUTE OF PHARMACEUTICAL SCIENCES.

2. INTRODUCTION : DEFINITION: Parenteral preparations are pyrogen-free preparations intended to be administered other than oral routes. The term parenteral is derived from two Greek words , Para outside enteron intestine CLASSIFICATION : Based on volume they are classified into two types: Small volume parenterals (SVP’s). 2. Large volume parenterals (LVP’s).

3. SMALL VOLUME PARENTERALS : The volume is generally less than or equal to 100ml. They are supplied in single or multiple doses. They are used to dispense most of the drugs.

4. LARGE VOLUME PARENTERALS : These are supplied for single dose having more than 100 ml. These are delivered through IV route. These generally provide electrolytes, nutrition to the body.

5. FORMULATION ASPECTS : Therapeutic agents. ex: Insulin, Antibiotics, Vaccines, Antipyretics, Analgesics, Dextrose, Nacl, Electrolytes. Vehicles. 1) Water. WFI, BWFI, SWFI. 2) Aqueous vehicles. ex: Ethyl alcohol, PEG, PG. 3) Non-aqueous vehicles. ex: Fixed oils ( corn oil, peanut oil, cotton seed oil.)

6. . Added substances(Additives) 1) Antimicrobials. ex: phenyl mercuric acetate - 0.01% Thiomersal - 0.01% Benzothenium chloride - 0.01% Phenol and cresol - 0.5% 2) Anti oxidants. ex: sodium bisulfide. ascorbic acid – 0.02- 0.1% thiourea - 0.005% 3) Buffers. ex: acetic acid, adipic acid, benzoic acid. 4)Bulking agents. ex: lactose – 0.14- 0.5% mannitol – 0.4 – 2.5%

7. . 5) Chelating agents. ex: Disodium edetate – 0.003 - 0.05 % Tetra sodium edetate – 0.01 % 6) Protectants. ex: sucrose, lactose (2-5%) 7) Solubilizing agents. ex: PEG 300, PG 8) Tonicity adjusting agents. ex: sodium sulfate – 1.1% sorbitol – 2% 9) Surfactants. ex: polyethylene- 0.1 -0.5% sorbitan monooleate-0.05-0.25%

8. VEHICLES: WATER FOR INJECTION(WFI): water that is intended for use in the manufacture of parenteral (i.e. injectable) drugs whose solvent is water. The USP (United States Pharmacopeia) defines this as highly purified waters containing less than 10 CFU/100 ml of Aerobic bacteria. STERILIZED WATER FOR INJECTION (SWFI):   sterile, nonpyrogenic, distilled water in a single dose container for intravenous administration after addition of a suitable solute. It may also be used as a dispensing container for diluent use.

9. . No antimicrobial or other substance has been added. The pH is 5.5 (5.0 to 7.0). BACTERIOSTATIC WATER FOR INJECTION (BWFI): Sterile water containing 0.9% benzyl alcohol that is used to dilute or dissolve medications. The container can be reentered multiple times (usually by a sterile needle) and the benzyl alcohol suppresses or stops the growth of most potentially contaminating.

10. PRETREATMENT OF WATER: The water for injection is most commonly used solvent. Water for injection is the water prepared by reverse osmosis or distillation and contains no added substances. The water must be adequately pretreated to ensure the uniformity and to promote constant quality and high efficiency. Some of the important elements include:

11. . Chlorination or treatment with ozone to suppress the microbial growth throughout the system. Prefiltration through depth filters to remove iron and any suspended matter Injecting a flocculating agent to remove the suspending agents, if any. Water softening by ion-exchange to remove alkaline earth metals, calcium and magnesium, and thus minimize the formation of scale deposits. Ph adjustment to 6.0-6.5 to reduce scale deposits. Deionization by ion exchange resins to removal of ions from feed water. Activated carbon beds for removal of chlorine and organics and then treatment with UV radiation to suppress the microbial growth.

12. REVERSE OSMOSIS (RO) : This is defined as a process for the separation of solutes from the water by applying pressure on more concentrated solution in contact with semi permeable membrane to give less concentrated solution . The solutes may be charged (ions) or essentially neutral (organics) . Each is excluded or removed by different mechanisms. Charged particles are repelled or excluded due to interfacial tension at the water membrane iinterface .

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14. . Organics are excluded by sieve mechanism so that size and molecular weight are important attributes. The higher the size or molecular weight of a substance, the most efficiently it is excluded. Thus virus, bacteria, and pyrogen are removed by reverse osmosis. The overall system primarily depends on the composition of feed water and the quality of the final water desired. In addition to RO unit, other type of systems may include chlorinators, flocculating agents, filters, water softeners, heat exchangers, active carbon beds, decarbonators, deionizers etc.,

15. DISTILLATION: The action of purifying a liquid by a process of heating and cooling. The process of removal of impurities from the liquid by continuous heating above 100 degrees and at atmospheric pressure cooling simultaneously. This aids in killing the living microorganisms. Prior to distillation, water used as source for WFI should be done with pretreatment Perfect phase change would leave all the impurities behind producing pure water vapor. After this the vapor is condensed to liquid water.

16. . It is maintained at pressure greater than the water of lower purity. The objective is to control the number of organisms per unit volume of water used for final rinses of equipment and containers . After distillation it is filtered and stored in a chemical resistant stainless steel tank at a cold temperature around 5c or at an elevated temperature between 65-85 c to inhibit the microbial growth and pyrogen formation.

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18. CONTAINERS: There are different types of containers used for packing parenteral solutions. They are: 1) Glass containers. Type I Type II Type III NP Generally, glass containers are used in packaging of vials and ampoules. 2) Plastic containers. They are used in packaging of large volume parenterals like saline bags.

19. CLOSURES: The mainly used closures for packing the containers in parenteral preparations are rubber closures. Rubber closures and rubber extractives have been found to influence preservative loss from solution and antimicrobial activity respectively. Generally used rubbers are natural and neoprene rubber. Loss of preservatives like chlorobutanol, methyl paraben, benzyl alcohol, etc was minimal in the presence of butyl rubber.

20. TERMINAL STERILIZATION:  A process whereby a product is sterilized in its final container or packaging, which permits the measurement and evaluation of quantifiable microbial lethality. In principle, the SAL should be less than 10-6. Terminal sterilization refers that the finished product should withstand with steam sterilization cycle for 15minutes. This process helps to assure the sterility of the finished goods.

21. BLOW FILL SEAL (BFS): Blow fill seal technology is most widely used and accepted by USFDA. Polypropylene granules are heated at 200 c to form tube shaped parison Parison reaches the mould forming container by the sterile compressed air. Fill nozzle known as mandrel fills the liquid in the container Followed by sealing neck and filled container is released from the mould.

22. . It takes 10-15 secs of time to produce one container. This method is followed to achieve the contamination rate below 0.1%.

23. . Rommelag’s BFS bottle-pack -321 machine forms 3000 bottles(1000ml) in 1 hr with 6 moulds.

24. PRODUCTION FACILITIES: Clean- up area. Preparation area Aseptic area Quarantine area Finishing and packaging area

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26. COMPARISION: PARAMETERS SVP LVP Volume <= 100 ml 101-1000 ml Route IV, IM, SC IV Dosage unit Single or Multiple Multiple Preservative Used Not used Buffer Used Not used Isotonicity Not essential Must Pyrogenicity Not essential Must Formulations Solution. Emulsion, Suspension. Solution, o/w emulsion. Uses As therapeutic agent, As diagnostic agent. As nutrition, Detoxification, Aid during surgery.

27. REFERENCES: Lachman and Lieberman- parenteral preparations http ://www.ijpbs.com/ijpbsadmin/upload/ijpbs_5163d369bb8f3.pdf http://apps.who.int/phint/pdf/b/Jb.6.2.1.5.pdf http://www.slideshare.net/swapnil_pharmacist/parenteral-preparation-equipments-and-layout http://www.slideshare.net/fatimamuhammad393950/parenterals-48006763 http://www.pharmainfo.net/satyajeethpandey/blog/parenterals http://pharmlabs.unc.edu/labs/parenterals/lvp.htm