Preparation of large volume and small volume parenteral

Preparation of large volume and small volume parenteral

1. Large and Small Volume Parenteral Mr. Sangram Maskar . Ashokrao mane college of Pharmacy, Peth Vadgaon.

2. Parenteral The term of Parenteral derived from Greek words: Para means : Outside Enteron: Intestine Denotes route of administration other than Oral route Sterile

3. Introduction Definition Of Large Volume Parenteral: The large Volume solution applies to an Injection that is intended for intravenous use and is packed in container holding 100 mL or more (As per USP). “LVP”s Means sterilized aqueous phase drug products packed in single dose container with a capacity of 100 mL or More. Definition Of Small Volume Parenteral: An Injection that is packed in container labeled as containing 100 mL or less.

4. Types Formulation Solution Injection Lyophilized Injection Emulsion Suspension Dry powder

5. Parameter SVP LVP Volume 100 mL or less 101-1000 mL Routes IV, IM and SC IV-LVP & Non IV-LVP Dosage Unite Single or Multiple Single Perseverative Used Not used Buffer Used Not used Formulation Solution, Emulsion & Suspension Solution and O/W nutrient emulsion Isotonicity Not essential Must

6. GENERAL PROCEDURE D ispending of Material Cleaning and Washing of Container, Closures Preparation of Solution Sterilization (Filtration) Filling Packaging

7. Formulation of parenteral product In preparation of Parenteral product the following substance are added to make stable preparation: The Active drug Vehicles Aqueous vehicles (Water for Injection, Water for Injection free from Co2) Non aqueous vehicles ( Ethyl alcohol, propylene glycol, almond oil) Antimicrobial Preservative: Maintain the stability of the product during storage e.g Chlorobutanol 0.5%

8. pH Buffer system Conc % 3.5-5.7 Acetic acid - acetate 0.22 2.5-6.0 Citric acid- citrate 0.5 6.0-8.2 Phosphoric acid – phosphate 0.8-2 8.2-10.2 Glutamic acid- Glutamate 1-2 Buffer: Added to maintain pH results in stability of drug against hydrolytic degradation or enhance the solubility of drug in solution.

9. Antioxidant: Antioxidant function by preferentially with molecule Oxygen and minimize or terminate the free radical auto-oxidation e.g. Reducing agent : Ascorbic acid,0.002-0.1%, Thiourea 0.005 % Tonicity Adjuster: Electrolytes : Nacl Non electrolytes: Dextrose Injection 5 % Tonicity can measurement by “Osmometer” Other Ingredient: Bulking agent: For freeze dried preparation eg Mannitol, dextrose, Lactose sucrose. Suspending agent: Carboxy methyl cellulose, sorbitol Emulsifying agent: Polysorbate 80

10. Container closure system Material: Glass, plastic, metals. Containers: Vial, Ampoules, cartridges, syringes, sterile pouches. Closure: flip-off seals, rubber stoppers, plungers.

11. Equipment's used Manufacturing Tanks/ reactors Autoclave Glassware’s isolators Holding vessels Washing machine, filling machine, sealing machine. Lyophilizer Visual inspection machine Packing machines

12. Production Facilities of Parenterals: The production area where the parenteral preparations are manufactured can be divided into five section: Clean up area : It is not aseptic area All the parenteral products must be free from foreign particles and microorganism Clean up area should be withstand moisture, dust & detergent. This area should be kept clean so that contamination may not carried out into aseptic area.

13. Preparation area: In this area the ingredients of the paracentral preparation are mixed & preparation is made for filling operation. It is not essentially aseptic area but precaution are required to prevent ant contamination from outside. Aseptic area: The parenteral preparation are filtered filled into final container & sealed should be in aseptic area. The entry of personal into aseptic area should be limited & through an air lock. Celling, wall & floor of that area should be sealed.

14. The air in the aseptic area should be free from fiber, dust & microorganism. The High efficiency particulate air filter (HEPA) is used for air. UV lamp are fitted in order to maintain sterility. Clean Area Classification (0.5 um particles/ft3 ) ISO Designation > 0.5 µm particles/m3 Microbiological Active Air Action Level sc (cfu/m3 ) Microbiological Settling Plates Action Level sc,d (diam. 90mm; cfu/4 hours) 100 5 3,520 Less than 1 Less than 1 1000 6 3,5200 7 3 10,000 7 3,52000 10 5 1,00000 8 35,20,000 100 50

15. Quarantine area: After filling, sealing & sterilization the parental product are held up in quarantine area. Randomly samples were kept for evaluation. The batch or product pass the evaluation tests are transfer into finishing or packaging area. Finishing & packaging area: Parenteral products are properly labelled and packed. Properly packing is essential to provide protection against physical damage. Ampoules should be packed in partition boxes.

16. Criteria for parenterals Raw Material testing In process testing Semi finished testing Finished product testing

17. Chemical : Physical testing Color , Appearance, Clarity. Analytical testing PH test Assay test Relative substance, Impurities , Particulate matter, Viscosity, Density, Specific Gravity, Fill volume, Moisture content, Leak test. Biological testing Sterility test BET Bioburden test

18. Assay : Assay is performed according to method given in the monograph of that parental preparation in Pharmacopoeia. Assay is done to check the quantity of medication present in the parental preparation. Sterility Test: It is a procedure carried out to detect and conform absence of any viable form of microbe in or on pharmacopeia preparation or product. Method of sterility testing Method 1 membrane filtration method Bubble point test WIT

19. Method 2 Direct inoculation method Suitable for samples with small volumes. Suitable method for aqueous solution and oily liquids. Direct Inoculation of the culture medium suitable quantity to be examined is transferred directly into the appropriate culture medium & incubate for not less than 14 days.

20. Clarity Test: Particulate matter is defined as unwanted mobile insoluble matter other than gas bubble present in the product. If the particle size of foreign matter is larger than the size of R.B.C. it can be block the vessel. The permit limits of particulates matter as per I.P are follows Particle size in µm Maximum number of particles per mL 10 50 25 5 50 Nil

21. Leakage test: The sealed ampoules are subjected to small cracks which occur due to rapid temperature changes or due to mechanical shocks. Filled sealed ampoules. Dipped in 1% methyl blue solution under negative pressure in Vacuum chamber. Vacuum released colored enter the ampoules Defective sealing

22. Pyrogen test: Pyrogen = ‘Pyro” (Greek = Fire) + “Gen” (Greek = Beginning) Fever production, metabolic by-product of microbial growth and death. Bacterial Pyrogens are called “Endotoxins” Gram negative bacteria produce more potent endotoxin than gram positive and fungi. Limulus amebocyte lysate (LAL) test another method for the determination of pyrogenic endotoxins. In this method, the test solution is combined a cell lysate from the amebocyte (Blood cell) of horse shoe crab Any endo toxin that might be present will be coagulated with protein fraction of amebocyte & results in the formation of gel. This consider to be simple, Rapid and greater sensitivity that the rabbit test.

23. Stability (Reference Q1A R1) Study Long term Intermediate Accelerated Storage condition (For Room temp product) 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 30°C ± 2°C/65% RH ± 5% RH 40°C ± 2°C/75% RH ± 5% RH Minimum time period covered by data at submission 12 months 6 months 6 months Storage condition (For 2 to 8 °C Product) 5°C ± 3°C  NA 25°C ± 2°C/60% RH ± 5% RH Minimum time period covered by data at submission 12 months  NA 6 months Storage condition (For freezer Product) - 20°C ± 5°C NA   NA Minimum time period covered by data at submission 12 months  NA  NA