Sterile Pharmaceutical Preparations

Sterile Pharmaceutical Preparations

• Sterile preparations include parenteral preparations, ophthalmic preparations, dialysis solutions, irrigation solutions, radiopharmaceuticals, and plasma expanders.

Parenteral Preparations

• Parenteral preparations are sterile dosage forms delivered to the patient outside the alimentary canal (bypass).
• Definition: "Parenteral preparations are sterile preparations intended for administration by injection, infusion, or implantation into human or animal bodies."
• This method bypasses the digestive system
• Key advantages for administration include:
  • Treating drugs with instability in the gastrointestinal tract (GIT)
  • Addressing poor absorption in the GIT
  • Administering irritating drugs
  • Treating unconscious or uncooperative patients
  • Providing rapid correction of fluid and electrolyte imbalances
  • Addressing patients experiencing nausea and vomiting
  • Offering faster onset of action in emergencies
  • Using lower drug doses and reducing side effects
  • Targeting specific organs
• Key disadvantages include:
  • Invasive and painful nature (lower compliance)
  • Risk of injury from insertion of needles or catheters
  • Difficulties in managing errors
  • Risk of complications from toxic doses, incorrect drugs or contaminants
• Types of injections:
  • Intramuscular (IM): Injections made into muscles (5 ml).
  • Intravenous (IV): Direct injection into the vein.
  • Subcutaneous (SC): Injections made under the skin (1.5 ml, commonly used for insulin).
  • Intradermal (ID): Injections into the skin dermis (for allergic testing, using penicillin).
  • Intraspinal (Intrathecal): Injections through the interthecal spaces into the spinal fluid (for spinal anesthesia).
  • Intraperitoneal (IP): Injection into the peritoneal cavity (commonly for animal studies).

IV Infusion vs IV Injection

• IV injection delivers small-volume parenterals (SVP) directly into a vein.
• IV infusion delivers large-volume parenterals (LVP) via a catheter directly into the vein.

Advantages of IV Infusions

• Parenteral nutrition (PN) and Total Parenteral Nutrition (TPN)
• Correction of fluid or electrolyte imbalances
• Administration of large doses of drugs (antibiotics, chemotherapy)

General Advantages of Parenteral Preparations

• Drugs with instability in the GIT (e.g., insulin, heparin)
• Drugs with poor GIT absorption (e.g., streptomycin)
• GIT irritating drugs
• Unconscious or uncooperative patients
• Rapid correction of fluid and electrolyte imbalance
• Nauseated patients and those vomiting
• Shorter onset of action (emergencies)
• Lower doses and side effects
• Drugs targeting specific organs

General Limitations of Parenteral Preparations

• Invasive and painful procedures
• Trauma from needle/catheter insertion
• Difficulty in addressing mistakes (toxic dose, incorrect drug, contaminants)

Common Types of Injections – Advantages

• Intravenous (IV) Route:
  • Fastest method for systemic administration.
  • Preferred route for emergencies.
  • Enables administration of high doses of fluids, electrolytes, nutrients, and drugs for hospitalized patients.
  • Beneficial for patients with severe GIT problems (e.g., ulcers, intoxication).

Administration and Precautions

• IV route risk: introduction of pyrogens, toxins, and microorganisms into the bloodstream.
• Solutions must be free of particles and air bubbles to prevent embolism which can block blood vessels.
• Suspension or oily injections are not suitable for IV use due to restriction.
• IV administration cannot achieve depot effect.
• Infiltration possible (breakdown or collapse of veins), leading to edema and tissue damage. This requires skilled administration.

Classification of Parenterals

• Pharmaceutical classification:
  • Solutions
  • Suspensions
  • Emulsions
  • Dry powder
• Volume-based classification:
  • Large volume parenterals (LVP)
  • Small volume parenterals (SVP)

How to achieve controlled drug delivery

• Increasing particle size (suspensions) and viscosity (oil solutions and suspensions)
• Use of implants
• Use of less soluble salts (e.g., insulin-Zn)
• Use of crystalline rather than amorphous form (e.g., insulin lente)

Insulin Lente

• Insulin zinc suspension
• An intermediate-acting porcine or human insulin with zinc salt.

Assignments

• Assignment 1: Investigate different insulin formulations on the market, noting their variable durations and onsets of action.
• Assignment 2: Collect examples of different parenteral drug products, indicating active constituents, doses, labels (excipients), and reconstitution methods.

Specifications of Parenteral Preparations

• Sterility, completely free from microorganisms and contaminants.
• Clarity, absence of foreign particles (dust, glass, fiber).
• Absence of pyrogens (fever-producing toxins).
• Tonicity (osmotic pressure).
• pH.

Methods of Sterilization

• Moist heat sterilization
• Dry heat sterilization
• Ionizing radiation sterilization
• Gaseous sterilization (ethylene oxide)
• Filtration (bacterial filters)

Preservation

• Addition of antimicrobial agents to multi-dose vials to protect from contamination.
• Preservatives not often added to large-volume parenterals (LVPs) because single-dose containers are typically discarded after opening.
• The drug itself may have antimicrobial effects (e.g., methohexital sod).

Preservation - Ideal Preservative Characteristics

• Effective against a wide range of bacteria
• Nontoxic at the concentration employed
• Stable
• Compatible with existing injection components, no interaction detected

Commonly Used Preservatives in Multi-Dose Injections

• Benzyl alcohol
• Chlorocresol
• Cresol
• Methyl paraben
• Propyl paraben
• Phenol
• Thiomersal

Clarity

• Parenteral solutions must be clear, free of foreign particles
• Foreign particles are not biodegradable.

Absence of Pyrogens

• Parenteral solutions must be non-pyrogenic (pyrogen-free)
• Pyrogens are fever-producing endotoxins found in the outer membrane of Gram-negative bacteria
• Pyrogens consist of lipopolysaccharides (Lipid A linked to a central polysaccharide core).

Sources of Pyrogens

• Solvents (water)
• Equipment
• Packaging materials
• Raw materials used

Biological Activity of Pyrogens

• Injection of pyrogens produces toxic effects.
• Contamination of large-volume parenterals (LVPs) can cause serious problems.
• Lipid A affects the thermoregulatory center in the brain (fever).
• High doses activate the coagulation system, leading to shock and death.

Characteristics of Pyrogens

• Water-soluble
• Non-volatile
• Pass through bacterial filters
• Heat-stable

Depyrogenation

• Elimination of pyrogens from solvents, equipment, and raw materials.
• Achieved by removal or inactivation.

Water Depyrogenation

• Distillation (BP) removes non-volatile pyrogens from water
• Reverse osmosis (USP) filters the water under pressure through a semi-permeable membrane.
• Ultrafiltration helps remove pyrogens from solutions.

Packing Materials and Equipment

• Removing pyrogens from surfaces with non-pyrogenic water
• Inactivation of pyrogens by dry heat at 250°C for 30 minutes (for heat-resistant glass).

pH

• Ideal pH of parenteral preparations: 7.4.
• Some drugs necessitate different pH values for stability or solubility.

Non-Neutral SVPs (IM, SC, IV)

• Formulated at suitable pH for stability or solubility, with a low-capacity buffer system.
• Allow rapid neutralization by natural buffer systems.
• Common buffers: acetate, phosphate, and citrate.

Non-Neutral SVPs (cont.)

• Acceptable pH range for tissues: 4-9.
• Exceeding this range can lead to irritation/harm to tissues for injection routes other than IV.

Non-Neutral LVPs

• IV infusions should not include buffering systems due to large volumes needing considerable volumes of buffers and this could be harmful.
• Neutralization of LVP solutions is difficult even with low buffer capacity.

Non-Neutral LVPs (cont.)

• Non-neutral IV infusions should be injected slowly with low infusion rates.

Non-Neutral LVPs (cont.)

• Accepted pH range for non-neutral LVPs: 3-10.5.

Tonicity (Osmotic Pressure)

• Semi-permeable membrane separates water from electrolyte solution causing water to pass from its compartment to the electrolyte solution compartment until equilibrium.
• Pressure required to overcome this water pressure is osmotic pressure.

Tonicity (cont.)

• Parenteral preparations should be isotonic to blood plasma to prevent harmful changes.
• Hypotonic solutions have lower osmotic pressure compared to blood plasma.
• Hypertonic solutions have higher osmotic pressure compared to blood plasma.

Tonicity (cont.)

• Injection of hypertonic solutions can cause painful tissue reactions, RBC shrinkage (reversible in IV), damage to delicate nerve cells.
• Intrathecal injections must be isotonic to prevent damage to the spinal cord and cerebrospinal fluid.
• IV injections of hypotonic solutions can cause RBC haemolysis (irreversible and fatal).

Hypertonic Parenteral Solutions

• Hypertonic solutions for injection can be made isotonic by dilution.
• IM and SC hypertonic injections might cause mild pain.
• Hypertonic IV infusions should be administered slowly via a central catheter.

Comment

• In some cases, hypertonic IV infusions are deliberately administered, particularly in cases of TPN where high concentrations of nutrients (e.g., 25% dextrose) are required.

Hypotonic Parenteral Solutions

• Made isotonic by adding electrolytes like sodium chloride or other osmotic agents (e.g., mannitol, glucose).
• Mannitol and glucose may be incompatible with some drugs.
• Solutions are made isotonic with 0.9% NaCl.

Tonicity Adjustment

• Calculate solute amount and dilution using methods:
  • Freezing point depression method
  • Sodium chloride equivalent
  • Molar concentration
  • Serum osmolarity

Lecture Quiz

• Comparing SVPs and LVPs regarding sterility, clarity, pyrogen absence, buffer use, non-neutral solutions, hypotonic solutions, and hypertonic solutions.

Components of Parenteral Products

• Container (packaging)
• Active constituent
• Solvent
• Additives

Packaging (Containers)

• Glass ampoules
• Rubber-stoppered vials
• Glass and plastic bottles
• Glass and plastic syringes
• Prefilled syringes

Packing Materials

• Glass
• Rubber
• Plastic

Ampoules

• Single-dose glass container for SVPs.
• Glass neck should be scratched (or self-breaking).
• May release glass particles into the solution (filled under vacuum).

Vials

• Multi-dose and single-dose SVPs (1-100 ml)
• Glass bottle with a rubber cap and sealed aluminum cover coated with plastic.
• Rubber material might be natural or synthetic (butyl rubber).

Vial Limitations

• Incomplete sealing in multi-dose vials.
• Air contamination during production.
• Release of rubber particles into the solution
• Adsorption of injection components (preservatives).

Pre-filled Syringes

• Advantage: solving problems of particulate release and air contamination.
• Limitation: Cost and specific machine requirement for manufacturing.

Plastic Containers

• LVP single-dose IV infusion bottles (100-1000 ml)
• Polymers (polyethylene, polypropylene, or PVC) + additives (plasticizer, opacifier).

Plastic Containers – Disadvantages

• Leaching of some drugs from the plastic (fat emulsions, paclitaxel, amiodarone hydrochloride, blood).
• Drug adsorption onto PVC (e.g., nitroglycerin).
• Low clarity and inspection potential.

Flexible (PVC)

• Adsorb some drugs (nitroglycerin)
• No need for air tubes (solutions drain by gravity).

Semi-Rigid (PE)

• More compatible.
• Needs aeration for solution drainage.

Glass Bottles

• Advantages: transparent, chemically inert, can be used with incompatible plastic materials.
• Disadvantages: Breakage during transport, need for aeration tube or needle due to contamination risks

Glass Bottles (Chemical Composition)

• Consists of silicon dioxide and other oxides.
• Three types:
  • Type III (soda lime glass): Releases alkalinity with water.
  • Type II (sulphated glass): Treated with sulfur oxide to neutralize alkalinity.
  • Type I (borosilicate glass): Doesn't release alkalinity; multiple use, more expensive.

Glass (cont.)

• Type II glass cannot be reused due to removed internal layer after multiple washes and autoclaving.

Solvents for Injection

• Aqueous (water, co-solvents)
• Non-aqueous (oils, oily materials).

Grades of Water

• Water for injection (WFI): Potable water with no organisms, particles, dissolved gases/minerals; highly purified. Commonly used as a vehicle or solvent in parenteral products.
• WFI preparation methods include: Distillation, filtration, chemical softening, deionization, pH adjustment, and reverse osmosis.

WFI (cont.)

• Packed in sealed containers and sterilized by moist heat for single-dose use.
• Used to dissolve or dilute products before administration.

Bacteriostatic Water for Injection (SWFI)

• WFI containing a bacteriostatic agent, used in multi-dose vials.

Co-solvents

• Water-miscible solvents (e.g., glycerin, ethanol, propylene glycol).
• Increase solubility and act as stabilizers for certain drugs.

Non-aqueous Solvents (Oils)

• Used for drugs like digoxin (solubilization).
• Stabilize water-hydrolysable drugs (e.g., barbiturates).
• Provide sustained drug effects (e.g., steroids).

Major Class of Non-Aqueous Solvents

• Fixed vegetable oils (e.g., corn oil, cottonseed oil, peanut oil, sesame oil).
• Must be labeled.
• May cause sensitivity reactions.
• Mineral, volatile, and animal oils are generally not used in injections.

Additives

• To provide effective, safe, and elegant preparations.
• Antimicrobial agents
• Buffers
• Tonicity-adjusting agents
• Antioxidants
• Surfactants

Antioxidants

• Added for stability.
• Oxidized preferentially during product shelf life.

Surfactants

• Used in parenteral suspensions (preventing crystal formation and improved syringeability).
• Also used in parenteral emulsions with examples such as Sorbitan monooleate or polyoxyethylene sorbitan monooleate

Production of Parenteral Solutions

• Produced in a high-standard clean room and aseptic environment,
• Avoiding mistakes that cause contamination (microorganisms, pyrogens, particulate matter).

Production of Parenteral Solutions – Raw Materials

• Special, pyrogen-free grades for injections

Production of Parenteral Solutions – Personnel

• High training level
• Good hygiene practices
• Special clothing (fiber and sterile)

Production of Parenteral Solutions – Production Area

• Sterile rooms fitted with laminar flow hoods and HEPA filters for air purification.
• Removes 99.97% of particles larger than 0.3 µm along with all microbial contaminants.

Note on Laminar Flow

• Laminar flow isn't sterilization, it maintains a contamination-free area, crucial for IV admixtures.

Quality Control Testing and Evaluation (BP)

• This process involves testing for containers, the entire batch, and samples within the batch.

Tests for the Container

• Glass containers
• Plastic containers
• Rubber closures

Glass Tests

• Surface alkalinity
• Total alkalinity

Plastic Container Tests (Leaching)

• Chemical testing (color, pH, turbidity, and UV)
• Reducing substances testing
• Biological testing on new plastics

Rubber Closure Tests

• Release testing (chemicals upon autoclaving)
• Permeability testing (force to pierce)

Resealing Test

• Efficiency of vial resealing as a multi-dose container.

Fragmentation Test

• Measuring the amount of rubber fragments inside/inside a vial.

Tests for the Whole Batch

• Leaker test
• Clarity test

Leaker Test

• Ensures proper sealing of ampoules.
• Immersing ampoules in a methylene blue solution after autoclaving.
• Reject visibly-colored ampoules.

Clarity Test

• Tests the presence of particles exceeding 50 µm and rejects products with visible particles.

Tests for Samples of the Batch

• Sterility tests (referring to microbiology)
• Pyrogen tests (detailed steps with examples in following sections)
• Extractable volume tests (measuring the extractable volume of a container vs. the labelled volume).
• Clarity tests (measuring and evaluating presence of sub-visible particles)

Pyrogen Testing (Rabbit Pyrogen Test)

• Qualitative test to detect various pyrogens.
• Involves injecting the solution into three rabbits and monitoring body temperature changes.
• Pyrogens increase body temperature by 0.6°C or more in any rabbit.
• All rabbits combined readings don't exceed 1.4°C within 3 hours.

Pyrogen Testing (cont.) – Advantages

• Reacts similarly to human reactions.
• Detects all types of pyrogens

Pyrogen Testing (cont.) – Disadvantages

• Costly
• Time-consuming procedure
• Low sensitivity
• Injection components can sometimes interfere.

Bacterial Endotoxin test

• LAL (Limulus Amebocyte Lysate) test: An in-vitro test on gel formation when pyrogens are added to the LAL reagent.
• LAL agent contains clotting proteins, while pyrogens aid in the clotting process.

LAL Test (cont.) Advantages

• Quick and less expensive than rabbit test
• Can quantify endotoxins

LAL Test (cont.) Disadvantages

• Many variables (pH, ions in solution) can affect the outcome.
• Does not detect pyrogens from gram-positive bacteria.