Sterile Injectable Preparations Quiz

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Questions and Answers

What is the primary standard for sterile preparations intended for injections, infusions, or implantation?

General monograph in USP

General monograph in JP

General monograph in BP (Ph.Eur.monograph 0520) (correct)

General monograph in FDA

Which source of particulate matter is classified as intrinsic in injectable preparations?

Dust from the environment

Skin flakes from personnel

Rubber from packaging materials (correct)

Microorganisms found in nature

What is the acceptable limit for sub-visible particles in sterile injectable preparations as per the provided data?

3000/300 per container

6000/600 per container (correct)

5000/500 per container

1000/100 per container

Which quality test is focused on assessing the presence of bacterial endotoxins in sterile products?

Bacterial endotoxins test Signup and view all the answers

What material can contribute to extrinsic particulate matter in injectable preparations?

Glass from vials Signup and view all the answers

Which of the following test methods measures the average particle count in sterile preparations?

<788> Signup and view all the answers

Which type of particulate originates from the formulation components of sterile preparations?

Undissolved material Signup and view all the answers

What is the expected specification for the visibility of particles in a lyophilized powder intended for intravenous use?

Free of visible particles Signup and view all the answers

What is the maximum allowable average number of sub-visible particles for solutions of infusion/injection with a volume of ≤ 100 mL that are ≥ 25 µm in size?

< 600 Signup and view all the answers

For solutions of infusion/injection greater than 100 mL, what is the maximum permissible number of particles ≥ 10 µm per mL?

< 12 Signup and view all the answers

What is the required uniformity of weight criterion for co-coated tablets weighing more than 80 mg but less than 250 mg?

NMT 7.5% Signup and view all the answers

In the uniformity of content test for powders for parenteral administration, what constitutes a pass for the batch?

All 10 units within 85-115% of average content. Signup and view all the answers

What is the weight criteria for powder formulations for parenteral routes with an average mass over 40 mg?

NMT 10% deviation. Signup and view all the answers

What is the threshold for the initial testing pass in terms of units being outside the acceptable range for average content when testing 30 units in total?

NMT 1 outside 85-115% and none outside 75-125%. Signup and view all the answers

Which of the following represents an allowable deviation percentage for capsules weighing 300 mg or more?

7.5% Signup and view all the answers

For powders intended for eye-drops weighing less than 300 mg, what is the maximum allowed percentage deviation from the average mass?

10% Signup and view all the answers

What is the correct sequence of steps for ensuring uniformity of weight in pharmaceutical preparations?

Empty, rinse, dry, and weigh contents. Signup and view all the answers

What is the minimum volume that should be extracted from a multi-dose container with one unit?

≥ 10 mL Signup and view all the answers

What is the recommendation for the temperature of oily and viscous preparations before measuring the volume?

Between 20-25 °C Signup and view all the answers

Which syringe size is specified for extracting the volume to be measured?

NMT three times the volume Signup and view all the answers

What should the volume extracted from individual containers be relative to the nominal volume?

No less than the nominal volume Signup and view all the answers

What is the required syringe specification for a volume less than or equal to 2 mL?

Multiple syringes and separate containers Signup and view all the answers

Which type of preparation follows the same process and criteria as the single dose preparation?

Cartridges and pre-filled syringes Signup and view all the answers

How should a volume for infusions be measured?

Empty into a dry cylinder occupying at least 40% of the volume Signup and view all the answers

What gauge needle is specified for the syringe used in the extraction process?

21-gauge needle Signup and view all the answers

In single dosage preparations, what should the sum of the volumes be when using five containers for a volume less than or equal to 3 mL?

No less than the sum of nominal volumes Signup and view all the answers

What is the purpose of shaking suspensions and emulsions before withdrawal?

To ensure even distribution of contents Signup and view all the answers

What is the purpose of the Limulus Amebocyte Lysate (LAL) test?

To evaluate the endotoxin-initiated clotting cascade Signup and view all the answers

How is the endotoxin limit calculated according to the formula provided?

By calculating the ratio of threshold pyrogenic dose to the maximum recommended dose Signup and view all the answers

Which of the following statements is true regarding animal selection for pyrogen testing?

Healthy adult rabbits must weigh no less than 1.5 kg. Signup and view all the answers

In what condition should the environment for the rabbits in pyrogen testing be maintained?

A uniform temperature between 20-23° ±3° C Signup and view all the answers

What is the threshold pyrogenic dose (K) for intravenous administration of endotoxin?

5.0 IU per kilogram of body mass Signup and view all the answers

What is the recommended procedure for sterilizing glassware before pyrogen testing?

Wash with water for injections and heat at 200 °C for 1 hour Signup and view all the answers

Which route of administration has the lowest threshold pyrogenic dose for endotoxin?

Intrathecal Signup and view all the answers

Which organisms are known to produce pyrogens that can induce fever in humans?

Pseudomonas and Viruses Signup and view all the answers

What is the primary method suggested for the removal of pyrogens from water?

Distillation Signup and view all the answers

What is the purpose of depyrogenation in relation to glass containers?

To eliminate residual pyrogens Signup and view all the answers

Which of the following statements about the LAL test is accurate?

The gel-clot technique results in the formation of a gel. Signup and view all the answers

At what temperature should glassware be sterilized to eliminate pyrogens?

250°C Signup and view all the answers

Which technique is NOT employed for the detection of endotoxins in the LAL test?

Fluorescent technique Signup and view all the answers

Which of the following is an essential step in preparing amoebocyte lysate for testing?

Dissolving in water or a specified buffer Signup and view all the answers

Which statement is true regarding the sources of pyrogens?

Water can frequently be a source of pyrogens. Signup and view all the answers

What aspect does the maximum valid dilution relate to in endotoxin testing?

It defines the highest dilution permissible for effective endotoxin detection. Signup and view all the answers

What characteristic of pyrogens makes them a significant concern in the pharmaceutical industry?

They are heat-resistant and not destroyed by typical sterilization methods. Signup and view all the answers

Study Notes

Sterile Products Manufacture - Quality Evaluation

Dr. Laura Urbano, F154 Hillside House, [email protected], 01707 281372
Quality evaluation of sterile products is covered

Learning Objectives

Critically understand the quality requirements for sterile products and compare them to pharmacopeial standards
Understand the sources of particulates and endotoxins in sterile manufacturing
Review the rationale, techniques, and acceptable limits for quality tests relating to sterile products

Sterile Preparations

General monograph in BP (Ph. Eur. monograph 0520) defining sterile preparations for injection, infusion, or implantation in human/animal bodies
Excipients, containers, preservatives, and water for injections are included in the definition

Quality Tests for Compliance

Tests for particulate contamination (sub-visible particles, 2.9.19) -covered in a workshop
Test for sterility (2.6.1)
Consistency of formulated preparations (Appendix XII C)
Uniformity of dosage units (2.9.40)
Uniformity of content (2.9.6)
Extractable volume of parenteral preparations
Tests for bacterial endotoxins (2.6.14) -Tests for pyrogens (2.6.8)

Types and Sources of Particulate Matters in Injectable Preparations

Table listing sources (intrinsic/extrinsic) of particulate matters in injectable preparations including dust, fibers, biologics (e.g., insect parts, microorganisms, pollens), hair, fibers from anthropogenic origin, skin, paint/coating chips, metal, rust, minerals, polymers, glass, extraneous material (e.g., from rubber stopper components)
Additional table providing intrinsic/extrinsic classification of particulate matters from packaging materials and solution/Formulation components, including rubber, silicone, glass, polymers, precipitates, oligomers, degradants, agglomerates, undissolved material, glass lamellae, silica, rubber, plastic, metal, and filter/consumables.

Summary of Available Data

Data summary for sterile injection applications submitted to USFDA between September 2010 and July 2011, including dosage route, container type, container volume, subvisible particle limit, method, 210 µm particle average ± SD, 225 µm particle average± SD, visible particle results (stability batches) and comments regarding conformity.

Techniques for Sub-Visible Particles

Light Obscuration Particle Count Test: Apparatus measures light blockage to determine particle size and numbers; calibration with spherical particles (10 and 25 µm); particle-free water as a dispersion medium; laminar-flow cabinet for a particle-free environment, determination of 5 samples for particulate contamination, and environment should be suitable for particle counting.
Microscopic Particle Count Test: Suitable binocular microscope and filter assembly used to retain particulate contamination; Membrane filter is used for examination. Other requirements are the same as in the Light Obscuration Particle Count Test method.

Criteria for Acceptability

Criteria for solutions for infusion/injection (>100mL): average numbers <25 per mL (size≥10 µm) and <3 per mL (size ≥ 25 µm)
Criteria for solutions for infusion/injection (≤100mL): average numbers <6000 per container (size ≥ 10 µm) and <600 per container (size ≥ 25 µm)

Consistency of Formulated Preparations

Uniformity of weight: Procedures for measuring consistency of weight involve: removing labels, washing and drying containers; rinsing containers with water and then alcohol; drying at 100-105°C for 1 hour; weighing container contents, and measuring deviation from average mass.
Uniformity of weight (mass): Standards related to deviation from the average mass, based on the pharmaceutical form (e.g., tablets, capsules, granules, powders, suppositories) are provided.
Uniformity of content: Method involves chemical analysis of individual contents in a sample of 10+20 units for calculating percent content and deviation from the average content. Criteria includes all 10 units within the 85-115% of the average content; if any units outside 85-115% but are within 75-125% more units must be tested.

Extractable Volume of Parenteral Preparations

Single Dose Containers: Procedures for measuring extractable volumes and criteria for volume measurements using syringes and cylinders.
Multi Dose Containers: Similar procedures and criteria apply for multi-dose containers, including measuring extractable volume.
Cartridges and Pre-filled Syringes: Same process as single dose containers
Infusions: Volume be measured for determining occupancies at least 40% of cylinder.

Endotoxins

Appendix XIV C: Test for Bacterial Endotoxins (LAL Test). Used to detect bacterial endotoxins from the outer membrane of gram-negative bacteria using amoebocyte lysate.
Appendix XIV D: Test for Pyrogens. Detects pyrogens, i.e., heat-resistant lipopolysaccharides from gram-positive bacteria, mycobacteria, fungi, and viruses. The significance of endotoxins in the pharmaceutical industry is addressed. The bacteria that induce pyrogens and cause fever in humans are also discussed.

Pyrogens

Prevention is key for pyrogens removal.
Primary source is water.
Pyrogens are destroyed by distillation process, but also exist in water used for cleaning containers & closures.
Sterilization methods using dry heat (glass) and washing with pyrogen-free water (rubber closures).
Chemical raw materials used in parenteral formulations should be crystallized using pyrogen-free water or other solvents.

Endotoxin Methods

LAL tests (Appendix XIV C): Depyrogenate all glassware at 250°C for 30 minutes before the test. Components of LAL test are listed, including reagents & solvents.
Procedure for dissolving product in water for bacteria endotoxin test. pH must be adjusted to 6-8
Endotoxin Detection Methods: Gel-clot, turbidimetric, chromogenic methods are detailed.

LAL Tests (Appendix XIV C) - Maximum Valid Dilution

Describes the maximum dilution (MVD) allowed for determining endotoxins in a sample, correlating it to the endotoxin limit and concentration of the test solution (λ).
Defined A as labelled lysate sensitivity or lowest concentration in a calibration curve, and K/M as the endotoxin limit where K represents the threshold pyrogenic dose per kg of body mass, and M is the maximum recommended dose per kg of body mass.

Endotoxin Limits

Lists endotoxin limits (K values, in IU) based on different routes of administrations (Intravenous, Intravenous for radiopharmaceuticals, Intrathecal, Parenteral).

Pyrogen Testing

Appendix XIV D: Describes the selection criteria for rabbits and the preparation of the test animals (age, sex, weight, diet).
Material requirements include glassware, syringes, and needles, along with the sterilization process.
Describes pyrogen tests, including temperature recording before and after injection; pre-test measurement of temperature after pyrogen-free NaCl injection; injection of test substances; sample preparation (0.5–10mL/kg body weight) and measurement of body temperature over 3 hours.
Lists the criteria for passing (temperature variation < 1.15 °C) and failing (>2.65°C), and what to do if sum of temperature increases is between 1.15 and 2.65°C.

Pyrogen Testing - Different Methods

Rabbit Pyrogen Test (RPT): Measures the raise in body temperature after injection of a drug. In-vivo testing.
Monocyte Activation Test (MAT): Detects pyrogens by measuring cytokines released by blood monocytes. In-vitro testing.

References & Resources

Aulton's Pharmaceutics (2013)
Langille (2013) study on particulate matter in injectable drug products
Current BP and USP standards

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Description

Test your knowledge on the standards and quality control for sterile injectable preparations. This quiz covers topics such as particulate matter, quality tests, and specifications for injectable pharmaceuticals. Perfect for students and professionals in pharmaceutical sciences.