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REVIEW OF MEDIA FILL TEST VALIDATION FOR STERILE LIQUID PROCESSING

Presentation · January 2017

DOI: 10.13140/RG.2.2.24481.56169

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Nidal Batrawi Hani Naseef - Shtaya

The Advanced Veterinary Manufacturing Co. Birzeit University
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Review in:

Industrial Pharmaceutical
Technology - Master Program

By: Nidal Batrawi

Supervisor: Dr. Hani Shtaya
Jan, 2017
STERILE PRODUCTS MANUFACTURING
• Sterile products manufacturing is subjected to restricted conditions and
requirements in order to reduce potential of microbiological contamination.

• Special facility, process design, special skills and training of the involved
personnel are required.

• Aseptic practices should be used during preparation, and procedures should

be established to reduce the potential of MC. 1
• Sterile products are generally manufactured using two methods:
1. Terminal sterilization.
2. Aseptic processing.
• Terminal sterilization is the sterilization method of choice, where the product
is sterilized in its final sealed container, usually by heat.

• Aseptic processing is used for heat sensitive drug products, the product is
sterilized separately and is filled into pre-sterilized container and closure in a
controlled environment. 1,2
STERILE PRODUCTS MANUFACTURING

• There is a variety of procedures to minimize the risk of microbial contamination

during processing, which should be validated.

• One of these methods is "Media Fill Test", which usually performed in the
development stage of the aseptic processing to estimate the risk of
contamination.

• Media fill test is the simulation of the aseptic processing of the parenteral
product manufacturing using a microbiological growth medium in place of the
product solution.

• Validation of media fill test is performed as prospective validation, including

the process simulation study and qualification of a new or modified clean
room.

• Media fill test is to be re-validated regularly or occasionally. 1

MEDIA-FILL TEST PRINCIPLES:

This process simulation is performed by

exposing the microbiological culture medium
to the same product processing conditions
Tryptic such as contact surfaces, container closure
Soy
Broth system, operational environments. Then,
containers filled with the medium are
incubated under a special conditions to detect
any potential microbiological contamination.

Results are then evaluated to conclude that:

• The process is robust enough to obtain a sterile final product, or,
• The drug product will be contaminated during real operations, and hence the
process and its conditions require more improvement. 5
MEDIA-FILL TEST PRINCIPLES:
Liquid aseptic processing
MEDIA-FILL TEST PRINCIPLES:
Media-Fill Testing Procedure (Process simulation test)

Fail Pass
MEDIA-FILL TEST PRINCIPLES:
• The process simulation test should perfectly simulate the regular aseptic
manufacturing including all steps and worst cases of the manufacturing
process.3
• Selection of the microbiological growth medium depends on formulation of
the drug product, selectivity, concentration and clarity of the medium.3
Aerobic microbiological culture medium such as soybean casein digest
medium (Tryptic Soy Broth) is usually used.
• Anaerobic growth media such as fluid thioglycolate is used in special
circumstances. Moreover, the selected media should induce gram positive
and gram negative bacteria, as well as yeast and mold (non-selective
medium). 5
• Media before and after filling is checked for positive (Growth Promotion
Test) and negative control (Sterility Test).
TEST FREQUENCY:

• A prospective simulation test is performed before starting the real

manufacturing process using three consecutive tests (recommended to be
performed in different days). 4

• Prospective simulation test is performed for new products, processes and

equipment.

• On-going simulation test consists of one simulation test and performed

for the periodic monitoring of aseptic conditions during routine
processing.

• Re-validation is demanded after critical modification of process,

equipment or processing conditions. 4

• Generally, media fill tests should be repeated two times per year. 4
TEST CONSIDERATIONS:
• When designing the test validation study, involve all regular aseptic

manufacturing steps and incorporate worst-case conditions such as:

 Most complex flow of materials

 Longest manufacturing time

 Maximum number of personnel, etc..,. 1

• For aerobic microorganisms detection, don’t use inert gases as nitrogen,

where it will inhibit the growth of aerobic microorganisms, instead, use

sterile filtered air.

• For anaerobic microorganisms detection, an inert gas should be used in the

process simulation, as inert gas will induce the growth of anaerobes. 4

TEST CONSIDERATIONS:
• Dissolve the nutrition medium in water for injection in the same

manufacturing container. If necessary, use the minimum degree of

temperature to dissolve the media. 4

• Personnel including technicians whom are involved in the aseptic

manufacturing process, should be engaged in the process simulation. 5

• The media fill test should be controlled by the QC department.

• Video recording of a media fill test validation maybe a useful aide in

investigating personnel behavior that could negatively affect the aseptic

manufacturing process. 5
MEDIA-FILL TESTING PROCEDURE:

• If all of the starting ingredients are sterile, transfer sterile culture

medium solution into the same sterile container to evaluate aseptically
manufacturing process.

• If some of the starting ingredients are nonsterile, use a nonsterile

medium to make a 3% broth solution.

• Incubate media-filled vials for at least 7 days at 20°C–25°C and further by

7 days at 30C°–35C°.

• Visible turbidity in one or more container on or before the day 14, is an

indication of microbiological contamination and test failure.

• Discuss investigational findings of failure cases with involved personnel

before any re-testing. 1
ACCEPTANCE CRITERIA:
Number of vials used for media fills test validation should be appropriate to
enable a reliable evaluation.
The test target is considered zero microbial contamination.

The following is acceptance criteria for media fill test validation:

• Test size is less than 5000 units:
No contaminated units should be detected.
• Test size is 5,000 to 10,000 units:
One contaminated unit should result in an investigation, including
consideration of a repeat media fill test.
Two contaminated units are considered cause for revalidation, following
investigation.
• When filling more than 10,000 units:
One contaminated unit should result in an investigation;
Two contaminated units are considered cause for revalidation, following
investigation. 3,5
REFRENCES:

1. USP 39 <797> Pharmaceutical Compounding - Sterile Preparations.

2. M. Gibson, Pharmaceutical Preformulation and Formulation: A Practical Guide from

Candidate Drug Selection to Commercial Dosage Form. Interpharm/ CRC, 2004.

3. EU Guidelines to good manufacturing practice, medical products for human and

veterinary use, volume 4, annex 1, manufacture of sterile medicinal products, 2008.

4. PIC/S PI 007-6, Recommendation on the validation of aseptic processes, 2011.

5. FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing -

Current Good Manufacturing Practice, September 2004 Pharmaceutical CGMPs.

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