DDS LEC - Sterile Dosage Forms (start until validation of sterility)

Sterile Dosage Forms

• Pharmaceutical drug preparations that must be free of contamination.

• Must be sterile and pyrogen-free

Personnel

Greatest source of contamination

Parenteral

• Sterile preparations to be administered parenterally

• Parenteral = Para (outside), Enteron (intestine)

• Hypodermic morphine solution

Para

Parenteral

_____ = outside

Enteron

Parenteral

_____ = intestine

Hypodermic Morphine Solution

First recognized parenteral preparation by USP and BP

1. Patient is possibly unconscious/uncooperative

2. When rapid onset of action is wanted

3. Drug is unstable when orally administered

When are sterile dosage forms ideal?

2 Major Parenteral Classifications

1. Small Volume Parenteral

2. Large Volume Parenteral

Small Volume Parenteral

• Injections packaged in containers labeled as containing 100 mL or less

• You can place multiple doses here

• Advantage: Requires little to no manipulation to make it patient-specific

• Disadvantage: Does not offer flexibility in changing volume and concentration; Thawing

• Example: Insulin Injections (Insulin Lispro, NPH Insulin, Insulin Glargine)

Insulin Lispro

Insulin Injection:

• Sold under the brand name Humalog

• Rapid-acting

• Made up of zinc-insulin crystals

• Usually administered subcutaneously

NPH Insulin

Insulin Injection:

• Sold under the brand name Humulin

• Intermediate-acting

Insulin Glargine

Insulin Injection:

• Sold under the brand name Lantus SoloStar

• Long-acting

• Can take effect after 24 hours

• Usually for Type I Diabetes mellitus

Large Volume Parenteral

• Single-dose injection containing more than 100 mL of solution intended for intravenous use

• Typically used as an electrolyte replenisher

• Does not contain bacteriostatic agents

Blow-Fill-Seal (BSF) Technique

Small Volume Parenteral and Large Volume Parenteral can be aseptically-filled using the _____ (Technique).

4 Route of Administration

1. Intravenous Route

2. Intramuscular Route

3. Subcutaneous Route

4. Intradermal Route

Intravenous Route

• Into a vein

• Provides rapid action compared with other routes

  • 1656 - first experimental injection by Christopher Wren

  • 1662 - first recorded injection into man conducted by Johann Daniel Major (thrombus/blood clot & embolism)

  • 1860s - first sterilizable syringe made by Robert Koch

  • 1923 - discovery of the cause of pyrogenic observed by Florence Siebert

• Patient-Centered Analgesia (PCA) - automated IV delivery system

Christopher Wren

• In 1656, the first experimental injection was done by _____.

• He used dogs as test subjects

• He used a mixture of wine & opium

• He developed made-up syringe using bladder & quill

Johann Daniel Major

• In 1662, the first recorded injection into man was made by _____.

• Thrombus (blood clot) & Embolism

Robert Koch

In 1860s, the first sterilizable syringe was made by _____.

Florence Siebert

• In 1923, the discovery of the cause of pyrogenic reactions was observed by _____.

• She saw and proved that the water contained pyrogen, so she made guidelines on how to properly make injections (?)

Patient-Centered Analgesia (PCA)

• Automated IV delivery system

• Stores medications like morphine here

Intramuscular Route

• Into a muscle

• Less rapid but generally longer-lasting than IV administration

  • Can be aqueous or oleaginous preparations

Gluteus Maximus

Ideal intramuscular injection site for adults

Deltoid

Ideal intramuscular injection site for infants

Subcutaneous Route

• Under the Skin

  • For small amounts of medication (1.3 mL to 2.0 mL)

  • Usually the route for Insulin injections

• Ideal Site: Interstitial Tissue of the Upper Arm

Intradermal Route

• Into the Skin

  • Injected into the corium (true skin)

  • Volume limit: 0.1 mL

Official Types (USP) of Injections

1. Injection

2. For Injection

3. Injectable Emulsion

4. Injectable Suspension

5. For Injectable Suspension

Injection

Liquid preparations that are drug substances or solutions

ex. Insulin Injection USP

For Injection

Dry Solids, upon addition of suitable vehicles, yield solutions for injections

ex. Cefuroxime Injectable Emulsion, USP

Injectable Emulsion

Liquid preparation of drug substance dissolved or dispersed in a suitable emulsion

ex. Propofol Injectable Emulsion, USP

Injectable Suspension

Liquid preparation of solid suspended in a suitable liquid medium

ex. Depo-Medrol Injectable Suspension (known NSAID)

For Injectable Suspension

Dry solids that, upon addition of a suitable vehicle, yield preparation which conforms for injectable suspension

ex. Imipenem (antibiotic) + Cilastatin (suicidal drug) for Suspension, USP

USP Waters

1. Purified Water, USP

2. Water for Injection (WFI), USP

3. Sterile Water for Injection (SWFI)

4. Bacteriostatic Water for Injection (BWFI)

Purified Water, USP

Prepared by distillation, ion exchange methods or by reverse osmosis

Solid Limit: 1 mg/100 mL

Water for Injection (WFI), USP

• Purified water which is free of pyrogen

• Very sensitive

• Good for 24 hours

• Solid Limit: 0.85 mg/ 150 mL

Sterile Water for Injection (SWFI)

• Sterilized Water for Injection

• Packaged in a single-dose container not larger than 1L

Bacteriostatic Water for Injection (BWFI)

• Sterilized Water for Injection with Bacteriostatic Agent

• Packaged in prefilled syringes or vials (containing NMT 30 mL of the water)

• Note: If more than 5mL of water is needed, SWFI is the preferred water to be used.

Aqueous Vehicles

1. Sodium Chloride Injection, USP

2. Bacteriostatic Sodium Chloride Injection, USP

3. Ringer Solution, USP

Sodium Chloride Injection, USP

• Sterile isotonic solution of sodium chloride

• NO antimicrobial agent

• Contains 154 mEq each of Sodium and Chloride ions per liter

Bacteriostatic Sodium Chloride Injection, USP

• Contains one or more suitable antimicrobial agent

• Packaged in containers NMT 30 mL

Ringer Injection, USP

• Sterile solution of 3 Chloride Salts

  • CaCL2, KCl, NaCL

Fixed Vegetable Oils

• Non-Aqueous Vehicle

• Must remain clear when cooled to 10 deg C to ensure stability

• ex. CoCoPeSe

  • Cotton Seed Oil

  • Corn Oil

  • Peanut Oil

  • Sesame Oil

Examples of Fixed Vegetable Oils

Cotton Seed Oil

Corn Oil

Peanut Oil

Sesame Oil

Sterilization

Destruction of all living organism and their spores or complete removal from the preparation

Steam Sterilization

• Conducted in an autoclave and employs pure steam under pressure

• Method of choice for majority of sterile products

• AKA moist-heat sterilization

• Conditions: 121ºC, 15 PSI, 15 mins

• Mechanism Behind: Protein Denaturation

3 Stages of Steam Sterilization (Moist-Heat Sterilization)

1. Heat up or Preconditioning (30 mins)

2. Sterilization (15 mins)

3. Steam Removal or Cooldown Stage (45-60 mins)

Moist Heat Sterilization

Conditions:

• 10-lb pressure; 115.5ºC (30 mins)

• 15-lb pressure; 121.5ºC (20 mins)

• 20-lb pressure; 126.5ºC (15 mins)

Dry Heat Sterilization

• Carried out in ovens

• Destroys microorganisms by oxidation due to high heat

• Conditions: 150ºC - 170ºC for 2 hours

• Effective for sterilizing glassware and surgical instruments

Gas Sterilization

• Gases Used: Ethylene oxide, Peracetic acid, Chlorine dioxide, Vapor-phase Hydrogen peroxide

• Effective for heat- and moisture-labile preparations

• Duration: 4 to 16 hours of exposure

• Mechanism: Gas interferes with bacterial metabolism process

Sterilization by Filtration

• Physical removal of microorganisms by adsorption on the filter medium

• Millipore Filter - thin plastic membrane of cellulosic esters with millions of pores per square inch

Millipore Filter

Thin plastic membrane of cellulosic esters with millions of pores per square inch

Sterilization by Ionizing Radiation

• Utilizes Gamma Radiation

• Mechanism: Uses radiation to alter chemicals of the cell to promote formation of deleterious chemicals capable of destroying the cells

Biologic Indicator

(Validation of Sterility)

Preparation of a specific microorganism resistant to a particular sterilization

Thermal Death Time

(Validation of Sterility)

Time required to kill a particular organism under a specified condition

ex. Bacillus stearothermophilus, Bacillus subtilis, Bacillus pumilis

Bacillus Stearothermophilus

Organism killed by:

Steam sterilization and Ethylene oxide sterilization

Bacillus Subtilis

Organism killed by:

Dry Heat sterilization and Ionizing Radiation

Bacillus Pumilis

Organism killed by:

Ionizing Radiation

Bacterial Endotoxin Test (BET)

• Test to detect or quantify endotoxins from Gram-negative bacteria using amoebocyte lysate from the horseshoe crab (Limulus polyphemus or Tachypleus tridentatus)

• Can also be called Limulus Ameobocyte Lysate Test (LAL Test)

• Reaction Time: 15-60 mins

• Should be a clear, colorless solution