169 - Sterility + Stability Studies (answer with term)

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Sterile Dosage Forms

Dosage forms that are free of viable microorganisms and pyrogen free

1. Parenteral Products

2. Ophthalmic Products

3. Solutions for Irrigation

4. Dry Products Ready to be Reconstituted

Examples of Sterile Dosage Forms? [4]

Pyrogen

Fever-producing compounds that are primarily associated with Gram-negative bacteria

Endotoxin

A type of pyrogen and is a component of the exterior cell wall of Gram-negative bacteria

When bacterial pyrogens are injected in sufficient amounts (microgram quantities), the fever produced is accompanied by:

• chills,

• body aches,

• rise in blood pressure

• possibly a state of shock and death

• increased capillary permeability

• a-wide variety of other circulatory changes.

Why avoid pyrogens and endotoxins?

1. Must be free from any viable microorganisms and extraneous materials

2. Must be free from pyrogens and endotoxins

3. Must be of the right pH and isotonicity

4. Must be uniform across units

Quality Control of Sterile DDS [4]

A. Sterility test

B. Particulate matter in injection

[Match the following to the appropriate QC test]

Must be free from any viable microorganisms and extraneous materials

A. Sterility test

B. Particulate matter in injection

C. Pyrogen test

D. Endotoxin test

E. pH

F. Uniformity of Dosage Units

C. Pyrogen test

D. Endotoxin test

[Match the following to the appropriate QC test]

Must be free from pyrogens and endotoxins

A. Sterility test

B. Particulate matter in injection

C. Pyrogen test

D. Endotoxin test

E. pH

F. Uniformity of Dosage Units

Pyrogen Testing (USP <151>)

Designed to limit to an acceptable level the risks of febrile reaction in the patient upon injection of the product

Pyrogen Testing (USP <151>)

The test involves measuring the rise in temperature of rabbits following the intravenous injection of a test solution, and is designed for products that can be tolerated by the test rabbit in a dose not to exceed 10 mL per kg injected IV within a period of not more than 10 minutes.

Use healthy, mature rabbits. House the rabbits individually in an area of uniform temperature between 20° and 23° and free from disturbances likely to excite them. The temperature varies not more than 13° from the selected tem- perature. Before using a rabbit for the first time in a pyrogen test, condition it not more than seven days before use by a sham test that includes all of the steps as directed for Procedure except injection. Do not use a rabbit for pyrogen testing more frequently than once every 48 hours, nor prior to 2 weeks following a maximum rise of its temperature of 0.6° or more while being subjected to the pyrogen test, or following its having been given a test specimen that was adjudged pyrogenic.

Procedure for Pyrogen Testing

Maximum of 8 rabbits, first stage use 3 rabbits, if any of the rabbits exceeded 0.5°C, you have to add 5 more rabbits

• Total temperature change of rabbits should not exceed 3.3°C

Maximum number of rabbits in Pyrogen Testing?

Endotoxin Test

is a test to detect or quantify endotoxins from Gram-negative bacteria using amoebocyte lysate from horseshoe crab (Limulus polyphemus), This can detect the presence of endotoxin and quantify the amount

1. Gel-clot technique (most common)

2. Turbidimetric technique

3. Chromogenic technique

Techniques used in Endotoxin Test [3]

Gel-clot technique

• Endpoint: formation of gel (endotoxin present)

Turbidimetric technique

• Endopoint: presence of turbidity 

Chromogenic technique

• Formation of color

[Bacterial Endotoxin Test]

Endpoint for gel-clot, turbidimetric, and chromogenic technique?

Sterility

 indicates that no contaminating microorganism is found in the sample examined

Sterility Test

USP <71>

Incubation of preparation in suitable medium for not less than 14 day

1. Membrane filtration method

• May filtration matitira sa filter paper ung microbes -> agar plate -> incubation

2. Direct inoculation method

• Mismong diluted ver directly put in the agar plate

2 Methods in Sterility Test

No microbial growth is found.

• If not, check for validity of the test and repeat test as needed

• Check microbial growth in negative control

• Check facility and testing procedure

Acceptance criteria for Sterility test?

Membrane filtration

• Filter the product

• 0.22 um can filter out microorganisms

  • If there are microorganisms that are retained in the filter, it will be placed in a medium (supplied the nutritional needs of the microorganism), incubated (if microorganism is present and alive, it will grow)

Membrane filtration

• Use membrane filters with 0.45μm nominal pore size, 50mm diameter

• Material of membrane filter may vary depending on the preparation tested

• Membrane filter removed after filtration, then inoculated

Direct inoculation

• Quantities prescribed are directly transferred into the culture medium (product NMT 10% of total volume)

• If product is large volume, use concentrated medium taking into account its dilution after addition of product

Direct inoculation

• Sample directly put in the medium (either agarian or broth medium) then we would observe the absence or presence of growth

• We would want the ABSENCE of growth.

PARTICULATE MATTER IN INJECTIONS

Extraneous mobile undissolved particles, other than gas bubbles, unintentionally present in solutions

 irrigating solutions, radiopharmaceutical preparations, for preparations with final filtration step prior to administration (with justification)

Exceptions in PARTICULATE MATTER IN INJECTIONS?

Method 1: Light obscuration particle count test

• Has particle counter

• Preferred, but can be combined with Method 2

Method 2: Microscopic particle count test

• Use if results are not confirmed with method 1, or product has decreased clarity, or viscous preparation

• For preparation with reduced clarity or increased viscosity or those that produce gas or air bubbles

10 microns and above should not be seen

Method 1 and 2 in PARTICULATE MATTER IN INJECTIONS

1. Photostability Testing

2. Selection of Batches

3. Specification

4. Testing Frequency

5. Container Closure System

6. Storage Conditions

7. Evaluation

8. Stability Commitment

9. Statements of Labelling

STABILITY STUDY PROTOCOL

Stability

The ability of a drug to retain its chemical, physical, microbiological and biopharmaceutical properties within specified limits throughout its shelf-life

Stability Studies

Consists of a series of tests in order to obtain an assurance of the stability of a drug product namely maintenance of the specifications of the drug product packed in its specified packaging material and stored in the established storage condition within the determined time period.

A. Photostability Testing

B. Selection of Batches

C. Specification

D. Testing Frequency

E. Container Closure System

F. Storage Condition

G. Evaluation

H. Stability Commitment

I. Statements of Labelling

When we design stability studies we need to perform: [9]

Under ICH Quality Guidelines

·

Q1A(R2) - Stability Testing of New Drug Substances

Q1B - Stability Testing: Photostability Testing of New Drug Substances and Products

Q1C - Stability Testing for New Dosage Forms

Q1D - Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products

Q1E - Evaluation of Stability Data

Q1F - Stability Data Package for Registration Applications in Climatic Zones III and IV

Stability Studies - ICH Quality Guidelines [6]

• Hospital pharmacies are required to respond to therapeutic needs not covered by the pharmaceutical industry simple reconstitutions and/or dilutions of specialized pharmaceutical products

• more complex preparations formulated from pharmaceutical specialties or raw materials

Stability Studies of Hospital Pharmaceutical Preparations

ICH (and ASEAN) guidelines

represent an essential methodological base for the development of medications, but they need to be adapted to reflect the realities of clinical practice, particularly in a hospital environment and in the context of outpatient care.

1. Hydrolysis

2. Oxidation-Reduction

3. Photolysis

4. Racemization and epimerization

Chemical Instabilties [4]

1. Precipitation

2. Sorption

3. Leaching

4. Chelation and complexation leading to insolubility

5. Color changes

Physical Instabilities and Incompatibilities [5]

1. pH

2. Surfactants

3. Temperature

4. Oxygen

5. Light

6. Materials

Factors Affecting the Stability of Preparations [6]

• Data on active ingredient

• API to be used for stability studies should be issued from the same batch

• Packaging items

Formulating the preparation [3]

1. Depends on product's intended use

2. For products used in multiple concentrations: perform stability studies on minimum of two concentrations: one low and one high

3. If the difference between the low and high concentrations is too significant (more than a factor of 10) an intermediate concentration stability study may be considered, depending on the clinical interest.

Choice of concentrations to be tested [3]

• Stability studies should preferably be conducted on a single manufacturing batch

• Must include at least 3 units in the test batch

• Units should be prepared in conditions which reflect the circumstances in which the product is intended to be used

• It is preferable to create one preparation unit per sampling time-point

Number of tests in stability studies [4]

• Temperature (ambient, refrigeration, freezing-thawing, portable infusors)

• Residual moisture

• Light (day/night ambient light)

Storage conditions [3]

• Real-time (up to 1 year)

• Accelerated studies (ICH method is followed)

Duration of study [2]

To, minimum of 5 sampling time points (1/24th, 1/12th, 14, 2 and

3/4 of max duration), maximum duration

Sampling time points

• Depend on the volume and usage of preparation

• It is preferable to prepare a separate preparation unit for each sampling time point, even for multiple doses

Volume sampled on stability studies?

• Assay (stability- indicating) and degradation products

• Tests depending on dosage form

Analysis to be performed in stability studies? [2]