463 PHT Compendia requirement for parenteral dosage forms Nahla S Barakat, PhD Dept.

of Pharmaceutics College of Pharmacy 1430-2009

1 463 PHT 33-11

Parenteral quality Control

Parenteral articles are preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal. They are prepared by methods designed to ensure that they meet the pharmacopeial requirements for sterility, Pyrogens, Particulate matter and other contaminants

463 PHT

33-

-11

 Nomenclature [DRUG] injection [DRUG] for Injection [DRUG] Injectable emulsion [DRUG] Injectable suspension [DRUG ] for Injectable suspension

463 PHT

33-

-11

 Large-volume intravenous solution: is a single dose injection that is intended for iv use and is packaged in container labeled as containing more than 100 ml Small-volume intravenous injection: is applied to an injection that is packaged in containers labeled as containing 100 ml or less.

463 PHT

33-

-11

 Ingredients
Vehicles and added substances
5

Aqueous vehicles: Types of water: Purified water Sterile Purified water Sterile water for injection Bacteriostatic water for Injection Sterile water for inhalation Sterile water for Irrigation

463 PHT

33-

-11

 Drinking water: may be used in the early stage of chemical synthesis and in the early stages of the cleaning of pharmaceutical manufacturing equipments. Purified water: (USP monograph), is used in the preparation of some bulk pharmaceutical chemicals, do not use purified water in preparations intended for parenteral administration. Must be protected from microbial proliferation. Sterile purified water: Is purified water that is packaged and rendered sterile, contains no antimicrobial agent. It is not for parenteral administration

463 PHT

33-

-11

 Water for injection: is intended for use in the preparation of parenteral solutions and in the preparation of some bulk pharmaceutical chemicals. It must be protected from microbial contamination. It meets the requirements of all of the tests under purified water + Bacterial Endotoxin Test. Sterile water for injection: It is prepared from water for injection that is sterilized and suitably packaged. It contains no antimicrobial agent. It is used as diluents for parenteral products. It is packaged in single dose container not larger than 1-Litre size. Bacterial Endotoxin Test + Particulate Matter Test.
7 463 PHT 33-11

 Bacteriostatic water for injection: is sterile water for injection which contain on or more suitable antimicrobial agents. It is intended to be used as diluent for parenteral products. It is packaged in single or multiple-dose containers, not larger than 30 mL size. NOT FOR USE IN NEWBORNS + Antimicrobial Preservatives-effectiveness Sterile water for irrigation: It contains no antimicrobial agent. It is intended to delivered rapidly. For irrigation only, Not for injection. Packaged in single-dose containers of larger than 1-liter size. - Particulate Matter Test.
8 463 PHT 33-11

 Sterile water for inhalation: Is intended for use in inhalators and in the preparation of inhalation solutions. Not use for parenteral administration. + Bacterial Endotoxin Test.

463 PHT

33-

-11

 Other vehicles: Fixed oil used in non- aqueous injection are of vegetable origin, have no taste, no odour suggesting rancidity, Have a saponification value 185-200, Have an Iodine value between 79-141. Test for: Unsaponifiable matter Free Fatty acid

10

463 PHT

33-

-11

Added substances: Suitable substances may be added to preparations intended for injection to increase stability or usefulness. Observe special care in the choice and use of added substances in preparations for injection that are administered in a volume exceeding 5 ml. The following maximum limit For agents containing mercury and cationic SAA, 0.01% For those of the types of chlorobutanol, cresol, phenol, 0.5% For sulfur dioxide, sulfite, bisulfite, metabisulfite, 0.2%

11

463 PHT

33-

-11

 Substances to prevent the growth of microorganisms must be added to preparations intended for injection that are packaged in multiple-dose containers, except the active ingredients are themselves antimicrobial. Such substances also meet the requirements of Antimicrobial preservatives-effectiveness, and Antimicrobial AgentsContent. The air in the container may be evacuated or be displaced by a chemically inert gas, when specified in the monograph, information regarding sensitivity of the article to oxygen.

12

463 PHT

33-

-11

Volume in container An injection container is filled with a volume in slight excess of the labeled size
Labeled size 0.5 mL 1 mL 2 mL 5 mL 10 mL 20 mL 50 mL or more Mobile liquid 0.1 mL 0.1 mL 0.15 mL 0.3 mL 0.5 mL 0.6 mL 2% Viscous liquid 0.12 mL 0.15 mL 0.25 mL 0.5 mL 0.7 mL 0.9 mL 3%

Determination of filled volume: 10 mL or more 1 container 3-10 mL 3 containers Less than 3 mL 5 containers
13 463 PHT 33-11

 Take up individually the content of each container into a dry hypodermic syringe fitted with 21-guage needle, 2.5 cm length. Discharge the contents of the syringe into a dry cylinder or in dry tared beaker, weigh the solution. The content of two or three containers (each 1 or 2-mL) may be pooled for the measurement using separate dry syringe. The volume is not less than the labeled volume in the case of containers examined individually, or in the case of pooled samples, is not less than the sum of the labeled volumes of the containers taken collectively. For injections containing oil, warm the containers and shake them thoroughly and remove the content. Cool to 25 C before measuring the volume.
14 463 PHT 33-11

PARTICULATE MATTER IN INJECTIONS

Particulate matter in injections and parenteral infusions consists of mobile undissolved particles, other than gas bubbles, unintentionally present in the solutions. For the determination of particulate matter, two procedures, Method 1 (Light Obscuration Particle Count Test) and Method 2 (Microscopic Particle Count Test), are specified hereinafter. When examining injections and parenteral infusions for subvisible particles Method 1 is preferably applied. However, it may be necessary to test some preparations by the light obscuration particle count test followed by the microscopic particle count test to reach a conclusion on conformance to the requirements.
15 463 PHT 33-11

 When Method 1 is not applicable, e.g. in case of preparations having reduced clarity or increased viscosity, the test should be carried out according to Method 2, Emulsions, colloids, and liposomal preparations are examples. Similarly, products that produce air or gas bubbles when drawn into the sensor may also require microscopic particle count testing. If the viscosity of the preparation to be tested is sufficiently high so as to preclude its examination by either test method, a quantitative dilution with an appropriate diluents may be made to decrease viscosity, as necessary, to allow the analysis to be performed

16

463 PHT

33-

-11

METHOD 1. LIGHT OBSCURATION PARTICLE COUNT TEST Use a suitable apparatus based on the principle of light blockage which allows an automatic determination of the size of particles and the number of particles according to size.

17

463 PHT

33-

-11

General precautions The test is carried out under conditions limiting particulate matter, preferably in a laminar-flow cabinet. Very carefully wash the glassware and filtration equipment used, with a warm detergent solution and rinse with abundant amounts of water to remove all traces of detergent. Immediately before use, rinse the equipment from top to bottom, outside and then inside, with particle-free water. Take care not to introduce air bubbles into the preparation to be examined, especially when fractions of the preparation are being transferred to the container in which the determination is to be carried out.

18

463 PHT

33-

-11

Method Mix the contents of the sample by slowly inverting the container 20 times successively. If necessary, cautiously remove the sealing closure. Clean the outer surfaces of the container opening using a jet of particle-free water and remove the closure, avoiding any contamination of the contents. Eliminate gas bubbles by appropriate measures such as allowing to stand for 2 min or sonicating. For large-volume parenterals, single units are tested. For small-volume parenterals less than 25 ml in volume, the contents of 10 or more units is combined in a cleaned container to obtain a volume of not less than 25 ml;

19

463 PHT

33-

-11

 the test solution may be prepared by mixing the contents of a suitable number of vials and diluting to 25 ml with particlefree water or with an appropriate particle-free solvent when particle-free water is not suitable. Small volume parenterals having a volume of 25 ml or more may be tested individually. Remove four portions, each of not less than 5 ml, and count the number of particles equal to or greater than 10 m and 25 m. Disregard the result obtained for the first portion, and calculate the mean number of particles for the preparation to be examined.

20

463 PHT

33-

-11

 Evaluation For preparations supplied in containers with a nominal volume of more than 100 ml, apply the criteria of test 1.A. The preparation complies with the test if the average number of particles present in the units tested does not exceed 25 per mL equal to or greater than 10 m and does not exceed 3 per mL equal to or greater than 25 m.

21

463 PHT

33-

-11

 For preparations supplied in containers with a nominal volume of less than 100 ml, apply the criteria of test 1.B. The preparation complies with the test if the average number of particles present in the units tested does not exceed 6000 per container equal to or greater than 10 m and does not exceed 600 per container equal to or greater than 25 m. If the average number of particles exceeds the limits, test the preparation by the Microscopic Particle Count Test.

22

463 PHT

33-

-11

METHOD 2. MICROSCOPIC PARTICLE COUNT TEST The microscope is equipped with an ocular micrometer calibrated with an objective micrometer, a mechanical stage capable of holding and traversing the entire filtration area of the membrane filter, two suitable illuminators to provide episcopic illumination in addition to oblique illumination, and is adjusted to 100 10 magnifications.

23

463 PHT

33-

-11

 Test 2.A Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL. The preparation complies with the test if the average number of particles present in the units tested does not exceed 12 per mL equal to or greater than 10 m and does not exceed 2 per mL equal to or greater than 25 m. Test 2.B Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of less than 100 ml. The preparation complies with the test if the average number of particles present in the units tested does not exceed 3000 per container equal to or greater than 10 m and does not exceed 300 per container equal to or greater than 25 m.
24 463 PHT 33-11

Pyrogen testing Is designed to limit to a acceptable level the risks of febrile reaction in the patient to the injectable administration of the product concerned. It involves measuring the rise in temperature of rabbits following i.v injection (into ear vein) of a test solution in a dose 10 ml/kg within 10 min.

25

463 PHT

33-

-11

 Use temperature-sensing probe to measure the rabbit s body temp. 30 min before the injection of the test dose. (use three rabbits). Do not use a rabbit for pyrogen test more frequently than once every 48 hours, do not use any rabbit having a temp. exceeding 39.8C. Record the temp. at 30-min intervals between 1 and 3 hours subsequent to the injection.

26

463 PHT

33-

-11

Consider any temp. decrease as zero rise. If no rabbit show a rise in temp. of 0.5 or more its respective control temp. i.e the product is pyrogen-free. If any rabbit show rise in temp. of 0.5 or more, continue the test using 5 other rabbits. If not more than 3 rabbits of the 8 rabbits show individual rise in temp. of 0.5 or more and if the sum of the 8 individual maximum temp. rises doesnt exceed 3.3C ; the material is pyrogen-free

27

463 PHT

33-

-11

Packaging
containers for injections

The container is made of material that permits inspection of the contents. Containers are closed by fusion or by application of suitable closures.

28

463 PHT

33-

-11

 Elastomeric closures for Injections are made of materials obtained by vulcanization (cross-linking) polymerization, polyaddition, or polycondensation of macromolecular organic substances (elastomers). Closure formulations contain natural or synthetic elastomers and inorganic and organic additives to aid or control vulcanization, impart physical and chemical properties or color, or stabilize the closure formulation. Such closure are typically used as part of a vial, bottle, or prefill syringe package system.

29

463 PHT

33-

-11

 Criteria for the selection of an elastomeric closure should also include a careful review of all the ingredients to assure that no known or suspected carcinogens, or other toxic substances are added. Definition An elastomeric closure is a packaging component that is, or may be, in direct contact with the drug.

30

463 PHT

33-

-11

Functionality tests
Includes: penetrability, fragmentation, self-sealing capacity Functionality tests are performed on closures intended to be pierced by a hypodermic needle. The self-sealing capacity is required only for closures intended for multiple-dose containers. The needle specified for each test is a lubricated long bevel hypodermic needle*. * Sterile hypodermic needle with an external diameter of 0.8mm (21 Gauge).

31

463 PHT

33-

-11

Penetrability Procedure Fill 10 suitable vials to the nominal volume with water, fit the closures to be examined, and secure with a cap. Using a new hypodermic needle for each closure, pierce the closure with the needle perpendicular to the surface. Requirement The force for piercing is no greater than 10 N (1 kgf) for each closure, determined with an accuracy of 0.25 N (25 gf).

32

463 PHT

33-

-11

Fragmentation Closures for Liquid Preparations Fill 12 clean vials with water to 4 mL less than the nominal capacity. Fit the closures to be examined, secure with a cap, and allow to stand for 16 hours. Closures for Dry Preparations Fit closures to be examined into 12 clean vials, and secure each with a cap. Procedure Using a hypodermic needle fitted to a clean syringe, inject into each vial 1 mL of water while removing 1 mL of air. Repeat this procedure 4 times for each closure, piercing each time at a different site. Use a new needle for each closure, checking that it is not blunted during the test.

33

463 PHT

33-

-11

 Filter the total volume of liquid in all the vials through a single filter with a nominal pore size no greater than 0.5 m. Count the rubber fragments on the surface of the filter visible to the naked eye. Requirement: there are no more than 5 fragments visible. This limit is based on the assumption that fragments with a diameter 0.5 m are visible to the naked eye. In case of doubt, the particles are examined microscopically to verify the nature and size.

34

463 PHT

33-

-11

Self-Sealing Capacity Procedure Fill 10 suitable vials with water to the nominal volume. Fit the closures that are to be examined, and cap. Using a new hypodermic needle as described above for each closure, pierce each closure 10 times, piercing each time at a different site. Immerse the 10 vials in a solution of 0.1% (1 g per L) methylene blue, and reduce the external pressure by 27 kPa for 10 minutes. Restore to atmospheric pressure, and leave the vials immersed for 30 minutes. Rinse the outside of the vials. Requirement None of the vials contain any trace of blue solution.

35

463 PHT

33-

-11

Type of glass containers: Type I, II: Soda-lime glass is suitably dealkalized are usually used for packaging neutral and acidic parenteral preparations. Type III is soda-lime glass containers are not used for parenteral preparations. Type NP glass: for packaging nonparenteral articles, for oral and topical use.

36

463 PHT

33-

-11

 Powdered glass Test: Use crushed glass containers in 250-ml conical flask, add 50 ml high purity water, cap the flask with borosilicate glass beaker Place the containers in the autoclave and close it securely hold temperature at 1212rC for 30 min., counting from the time this temperature is reached. cool the flask, decant the water from the flask into a clean vessel, and wash the residual powdered glass with high purity water, add 5 drops methyl red solution, titrate immediately with 0.02 N sulfuric acid . Record the volume of 0.02N Sulfuric acid used to neutralize the extract from 10 g of the prepared specimen of glass.
37 463 PHT 33-11

 Water attack at 121C Rinse 3 or more containers with high purity water Fill each container to 90% of its capacity with high purity water Cap all the flasks with borosilicate glass beaker, place in the autoclave at 121 C for 60 min Type General mL of 0.02 N acid
description I II III NP
38

High resistant borosilicate glass Treated soda lime glass Soda lime glass

1.0 0.7 0.2 8.5

All purpose glass 15.0

463 PHT 33-11

Labels and labeling

The label states the name of the preparation (in case of a liquid preparation) The percentage content of drug in a specified volume (in case of dry preparation) The route of administration Storage condition Expiration date Name of the manufacturer The lot number

39

463 PHT

33-

-11

 Containers for injection that are intended for use as dialysis, or irrigation solution are labeled to indicate that the contents are not intended for use by iv infusion Injection intended for veterinary use are labeled to that effect The containers are so labeled that a sufficient area of the container remains uncovered for its full length to permit inspection of the contents

40

463 PHT

33-

-11