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Questions and Answers
Injection of pyrogens can produce beneficial effects.
Injection of pyrogens can produce beneficial effects.
False
Pyrogens are characterized by being heat stable and non-volatile.
Pyrogens are characterized by being heat stable and non-volatile.
True
Depyrogenation refers to the increase of pyrogens in solvents and equipment.
Depyrogenation refers to the increase of pyrogens in solvents and equipment.
False
The ideal pH for parenteral preparations is 7.4.
The ideal pH for parenteral preparations is 7.4.
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Buffers used in non-neutral SVP formulations can include borate buffers.
Buffers used in non-neutral SVP formulations can include borate buffers.
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Reverse osmosis is a method used to achieve depyrogenation in water.
Reverse osmosis is a method used to achieve depyrogenation in water.
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Intravenous (IV) infusions should contain a buffering system.
Intravenous (IV) infusions should contain a buffering system.
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The surface test for surface alkalinity involves titrating with a solution of hydrochloric acid.
The surface test for surface alkalinity involves titrating with a solution of hydrochloric acid.
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In the leaker test, ampoules are visually inspected for leakage after being immersed in a water bath with methylene blue.
In the leaker test, ampoules are visually inspected for leakage after being immersed in a water bath with methylene blue.
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The permeability test for rubber closures assesses the amount of force required to pierce the closure.
The permeability test for rubber closures assesses the amount of force required to pierce the closure.
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Clarity tests for injections assess particles larger than 70 μm in size.
Clarity tests for injections assess particles larger than 70 μm in size.
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The accepted pH range of non-neutral LVP is 2-10.5.
The accepted pH range of non-neutral LVP is 2-10.5.
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Biological testing for plastic containers includes injecting the material into dogs to observe for toxic symptoms.
Biological testing for plastic containers includes injecting the material into dogs to observe for toxic symptoms.
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Injecting hypertonic solutions can cause shrinkage of red blood cells, which is a reversible process.
Injecting hypertonic solutions can cause shrinkage of red blood cells, which is a reversible process.
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The osmotic pressure required to overcome water pressure is related to the concentration of the electrolyte solution.
The osmotic pressure required to overcome water pressure is related to the concentration of the electrolyte solution.
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It is safe to inject non-neutral IV infusions quickly to avoid toxicity.
It is safe to inject non-neutral IV infusions quickly to avoid toxicity.
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Injection of hypotonic solutions could lead to irreversible hemolysis of red blood cells.
Injection of hypotonic solutions could lead to irreversible hemolysis of red blood cells.
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Hypertonic parenteral solutions can be made isotonic through dilution.
Hypertonic parenteral solutions can be made isotonic through dilution.
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Parenteral preparations should always be hypotonic to match blood plasma osmotic pressure.
Parenteral preparations should always be hypotonic to match blood plasma osmotic pressure.
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Intrathecal injections must be hypertonic to ensure safety and avoid serious changes in cerebrospinal fluid tonicity.
Intrathecal injections must be hypertonic to ensure safety and avoid serious changes in cerebrospinal fluid tonicity.
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The slow infusion of a large volume is crucial to allow for rapid neutralization of blood pH.
The slow infusion of a large volume is crucial to allow for rapid neutralization of blood pH.
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Plastic containers made from PVC leach the plasticizer DEHP when storing water.
Plastic containers made from PVC leach the plasticizer DEHP when storing water.
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Type II glass bottles can be reused after washing and autoclaving.
Type II glass bottles can be reused after washing and autoclaving.
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Nitroglycerin can adsorb onto PVC, causing reduced effectiveness.
Nitroglycerin can adsorb onto PVC, causing reduced effectiveness.
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Glass bottles are preferred for storing incompatible materials with plastic due to their chemical inertness.
Glass bottles are preferred for storing incompatible materials with plastic due to their chemical inertness.
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Type I glass bottles are the cheapest option for pharmaceutical use.
Type I glass bottles are the cheapest option for pharmaceutical use.
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Water for injection (WFI) is not free of pyrogens and impurities.
Water for injection (WFI) is not free of pyrogens and impurities.
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Glass bottles require an aeration tube to prevent contamination when used for injections.
Glass bottles require an aeration tube to prevent contamination when used for injections.
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Polyethylene is more compatible with drug formulations compared to PVC.
Polyethylene is more compatible with drug formulations compared to PVC.
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Aqueous solvents constitute a lower proportion of injections than non-aqueous solvents.
Aqueous solvents constitute a lower proportion of injections than non-aqueous solvents.
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The plasticizer used in PVC containers is often monitored for human safety in drug storage.
The plasticizer used in PVC containers is often monitored for human safety in drug storage.
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Surfactants are only used in solid dosage forms for improving dissolution.
Surfactants are only used in solid dosage forms for improving dissolution.
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Parenteral preparations can be produced in any environment without strict cleanliness standards.
Parenteral preparations can be produced in any environment without strict cleanliness standards.
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Personnel involved in the production of parenteral solutions require low training and hygiene standards.
Personnel involved in the production of parenteral solutions require low training and hygiene standards.
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HEPA filters can remove 100% of all particles larger than 0.3 μm from the air in sterile production areas.
HEPA filters can remove 100% of all particles larger than 0.3 μm from the air in sterile production areas.
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Laminar flow is a method of sterilization used in IV admixtures.
Laminar flow is a method of sterilization used in IV admixtures.
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IV admixture refers to a combination of one or more sterile products added to an IV fluid.
IV admixture refers to a combination of one or more sterile products added to an IV fluid.
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Quality control testing includes only tests on the whole batch of parenteral solutions.
Quality control testing includes only tests on the whole batch of parenteral solutions.
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Tests on plastic containers are part of the quality control testing for parenteral solutions.
Tests on plastic containers are part of the quality control testing for parenteral solutions.
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Raw materials for parenteral solutions must be of special grade and pyrogen-free.
Raw materials for parenteral solutions must be of special grade and pyrogen-free.
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Glass containers undergo tests for glass alkalinity as part of the quality control process.
Glass containers undergo tests for glass alkalinity as part of the quality control process.
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Study Notes
Sterile Pharmaceutical Preparations
- Sterile pharmaceutical preparations include parenteral preparations, ophthalmic preparations, dialysis solutions/irrigation solutions, radiopharmaceuticals, and plasma expanders.
Parenteral Preparations
- Parenteral preparations are sterile dosage forms delivered outside the alimentary canal.
- Definitions: Para = beyond, enteron = intestine.
- Parenteral preparations are sterile preparations intended for administration by injection, infusion, or implantation into human or animal bodies.
Parenteral Preparations Details
- Includes introduction and definitions, advantages and limitations, types of injections, classifications of injections, specifications and requirements, components of parenteral products, production process, and compendia quality control testing.
Types of Injections
- Intramuscular (IM): injections into muscles (5 ml)
- Intravenous (IV): direct injection into the vein
- Subcutaneous (SC): injections under the skin (1.5 ml, e.g., insulin)
- Intradermal (ID): injections into the dermis (e.g., allergic testing; penicillin)
- Intraspinal (Intrathecal): injection into interthecal spaces of spinal fluid (spinal anesthesia)
- Intraperitoneal (IP): injection into the peritoneal cavity (animal studies)
IV Injection vs. Infusion
- IV Injection: administration of small volume parenterals (SVP) medications by syringe directly into the vein.
- IV Infusion: administration of large volume parenterals (LVP) via a catheter into the vein directly to the blood stream.
Advantages of IV Infusion
- Providing parenteral nutrition (PN) and total parenteral nutrition (TPN) for hospitalized patients.
- Correcting fluid or electrolyte imbalances.
- Administering large doses of drugs (e.g., antibiotics, chemotherapy) continuously.
Advantages of Parenteral Preparations
- Useful for drugs with instability in the gastrointestinal tract (GIT): insulin, heparin, and streptomycin.
- Useful for drugs with poor GIT absorption.
- Useful for GIT irritating drugs.
- Useful for unconscious or uncooperative patients.
- For rapid correction of fluid and electrolyte imbalances.
- Faster onset of action (emergency).
- Lower dose and side effects in some cases.
- Useful for administering drugs targeting specific organs.
Limitations of Parenteral Preparations
- Invasive and painful (lower compliance).
- Traumatic injury from insertion of needles or catheters.
- Difficulty in treating mistakes (toxic doses, incorrect drugs, or contaminants).
Classification of Parenterals
- Pharmaceutical classification: Solutions, suspensions, emulsions, dry powder.
- Volume-based classification: Large volume parenterals (LVP), Small volume parenterals (SVP).
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 SVP.
- Glass neck must be scratched (or self-breaking).
- May release glass particles into solution (filled under vacuum).
Vials
- Multi-dose and single-dose SVP (1–100 ml).
- Glass bottle with rubber cap and aluminum seal covered with plastic cover.
- Rubber material may include natural or synthetic (butyl rubber).
- Limitations: Incomplete sealing, air contamination, release of rubber particles, adsorption of injection components (preservatives).
Additional Information
- Pre-filled syringes: overcome particle release and air contamination but is expensive and needs special equipment.
- Plastic containers: LVP, single-dose IV infusion bottles (100–1000 ml), polymer (polyethylene, polypropylene, or PVC), additives (plasticizer, opacifier), advantages (handling, transportation), disadvantages (leaching, adsorption).
- Flexible (PVC): absorbs some drugs (e.g. nitroglycerin), no need for air tubing in some cases.
- Semi-Rigid (PE): more compatible, but needs solution aeration for drainage.
Glass Bottles
- Advantages: Transparent, chemically inert, compatible with materials incompatible with plastic.
- Disadvantages: Breakage, need for aeration tube/needle. Also, different types of glass have different properties (Type I: no release of alkalinity, used more often; Type II: alkalinity release).
Solvents for Injection
- Aqueous: Water, co-solvents.
- Non-aqueous: Oil, oily material.
Water for Injection (WFI)
- Potable water may include contamination with: organisms, particles, gases, or minerals.
- WFI is completely free of pyrogens and high chemical purity.
WFI Preparation
- Distillation (BP), filtration, chemical softening, deionization, pH adjustment, reverse osmosis.
Additional Water for Injection Types
- SWFI: packed in sealed containers (single dose) - sterilized by moist heat.
- Bacteriostatic water for injection: contains a bacteriostatic agent (multi-dose).
Co-solvents
- Water-miscible solvents mixed with water in some parenteral preparations (e.g., glycerin, ethyl alcohol, propylene glycol, and PEG 300), commonly enhance drug solubility, or stabilize drugs.
- Higher concentrations of some co-solvents (e.g., ethanol) may be toxic, irritant, and painful.
Non-aqueous Solvents (Oils)
- Solubilization (e.g. digoxin).
- Stabilization (e.g. barbiturates).
- Sustained effect (e.g. steroids)
Additives
- Antimicrobial agents, buffers, tonicity adjusting agents, antioxidants, surfactants.
Antioxidants
- Added for stability purposes.
Surfactants
- Used in parenteral suspensions for wetting, crystal growth prevention, and good syringeability.
- Used in parenteral emulsions.
Production of Parenteral Solutions
- Preparation and filling in clean room environments.
- Raw materials, personnel, and production areas must meet standards to prevent particulate, organism, and pyrogen contamination.
Quality Control Testing and Evaluation (BP)
- I. Tests for container; II. Tests for whole batch; III. Tests for samples of the batch.
- A. Glass test (glass alkalinity).
- B. Test for plastic containers (leaching).
- C. Test for rubber closure (releasing materials, permeability).
Pyrogen Testing:
- Qualitative test: Inject the tested solution to 3 rabbits and measure the increase in rabbit body temperature in 3 hours.
- Increase in body temperature in each rabbit should not exceed 0.6°C.
- Average increase in body temperature for all 3 rabbits should not exceed 1.4°C.
Bacterial Endotoxin Test (LAL test)
- In-vitro test, dependent on gel formation of LAL reagent when pyrogens are added.
- Advantages: rapid, inexpensive.
- Disadvantages: affects by pH, ions, and some positive bacteria/pyrogens might not be detected.
Extractable Volume Tests
- Measures the volume extract from a container.
- Should not be lower than the labeled volume.
- Clarity test for sub-visible particles: direct and microscopical measurement.
Miscellaneous
- Additional assignments were provided which cover the need to investigate different formulations of insulin on the market with varying duration and onset of actions. An additional assignment required to collect market examples of different pharmaceutical forms of parenteral products.
- Sterility, clarity, absence of pyrogens, use of buffers, and injection of non-neutral, hypotonic, and hypertonic solutions.
- Tonicity: isotonicity with respect to blood plasma is critical. Hypertonic solutions can be made isotonic by dilution. Hypotonic solutions can be made isotonic by adding electrolytes or osmotic agents (mannitol or glucose).
- Methods for tonicity adjustment include freezing point depression method, sodium chloride equivalent method, molar concentration method, and serum osmolarity method.
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Description
This quiz covers essential topics in pharmaceutical preparation, including the characterization of pyrogens, the importance of pH in parenteral formulations, and various testing methods for injection clarity and container integrity. Prepare to test your knowledge on the regulatory standards and practices involved in ensuring safe intravenous infusions.
