Media Fill
Current Scenario And Approach
The validation of the media fill or aseptic process simulation is an integral part of sterile pharmaceutical products. The media fill is also known as the aseptic process simulation studies. The study mainly demonstrates that the existing manufacturing practices and processes are robust and there is no chance of contamination. The media fill study mainly includes exposing the microbial growth medium to product contact surfaces of equipment, container closure systems, critical environments, and media fill interventions very closely to simulate the same exposure as per routine product processing.
Author: Mr. Amol P. Mane E-mail: amolmane498@gmail.com
Having overall six years of professional experience in the sterile and non-sterile dosage forms of pharmaceutical manufacturing.
-------------------------------------------------------------------------------------------
Media Fill Simulation Studies:
 |
| Media Fill Simulation Studies |
Presently media fill studies are performed as per risk-based approaches. The entire manufacturing line is assessed through media fill studies. Precautions for minimization of the potential contamination should be taken during all processing stages including the stages before sterilization.
Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill). Selection of the nutrient medium should be made based on the dosage form of the product and selectivity, clarity, concentration, and suitability for sterilization of the nutrient medium.
Objectives of Media Fill:
The primary objective of this media fill study is to assess the sterile products manufacturing lines with respect to the potential chances of contaminant and to meet the regulatory requirements.
Scope of Media Fill:
This article gives a clear idea about the media fill activity in ampoules and vials, liquid injectable manufacturing products. This article is limited to only aseptically manufacturing products. This does not include terminally sterilized products.
Study Rationale For Media Fill:
The media fill study is an important part of sterile manufacturing products. The study was mainly performed to verify the confidence level of routine sterile drug manufacturing processes and practices are in control. The study shall be performed under routine environmental conditions. All routine and non-routine interventions shall be captured during the media fill study. All articles used during the media fill study shall be pre-sterilized through the autoclave. The objective of the study is to ensure, the manufacturing stages of drug products meet all the pre-defined acceptance criteria. WFI shall be used as a vehicle.
The process simulation study shall demonstrate the batch execution procedure as it is designed for the actual product routine manufacturing process. It should also take into account various interventions known to occur during normal production as well as worst-case situations.
Process simulation studies should be performed as initial validation for a new manufacturing line or new facility with three consecutive satisfactory simulation tests per shift and should be repeated at defined intervals. Also, after significant modification to the HVAC- system, equipment, process, and a number of shifts, the media fill simulation studies shall be repeated.
Normally process simulation tests should be repeated twice a year per shift and process. Before going for media fill all the associated equipment, systems, utilities must be in the qualified phase.
Growth Promoting Median Requirement In Media Fill:
For media fill, generally, growth-promoting media is considered. SCDM (Soybean casein digest media) is the best example of growth-promoting media that are used for aerobic media fill simulation study.
Generally, 3% of SCDM (Soyabean casein digest medium) is considered for media fill study. The 3% SCD media is considered for its selectivity, clarity, concentration, and suitability for sterilization at 3% is best. It is noted that the anaerobic media required in such a case of microorganisms are consistently recovered or observed in routine environmental activities. For such kinds of activities, FTM (Fluid Thyoglycolate media) shall be preferred.
Why is 3 SCDM used in media fill simulation studies?
The rationale for selecting the 3% SCDM in media fill is as bellow,
1. The 3% SCD media is giving adequate results for visual verification of the turbidity as it's clear in nature and allows the narrow and broad-spectrum microorganisms for growth.
2. The said media has characteristics like low selectivity, supporting a wide range of microorganisms.
3. The media is easily filtered through the filter of pore size 0.22μ and simulates the routine product filtration activity.
4. The said media passes its growth promotion test within 05 days and meets the industrial practices for passing the growth promotion test.
5. It proves that the 3% of concentration supports the microorganism recovery.
Filling Line during media fill:
The manufacturing process should also be considered to be executed in dedicated manufacturing tanks and filtered in respective holding tanks or vessels. The tanks should possess the CIP/SIP cycles provision prior the batch manufacturing. During batch manufacturing, compressed air shall be used at manufacturing and filtration test. The nitrogen gas (inert gas) is to be avoided in the entire media fill activity, as the nitrogen gas replaces the oxygen and thereby inhibits the aerobic microbial growth of the organism.
Ensure that the pre-GPT of the selected media is passed. Different media lots to be verified in the manufacturing stage. Water temperatures above 60°C shall be considered for media manufacturing as it will reduce the risk of vegetative bacteria and fungi growth, and this will also ensure that the media dissolves more completely, reducing the likelihood of filter blockage. Media should be allowed to cool to < 35°C before usage in process simulation.
The hold time between compounding of the media and filtration of media into a sterile holding vessel should be minimized, based on the process and product simulation. The media shall be filtered through the 0.22μ filter pore size.
Aseptic connections in media fill:
The aseptic connections or assembling of the machine parts is a critical activity in the cleanroom. The movement shall be robotic which minimizes the air-borne particles. The aseptic connections shall be performed to simulate routine batch-related activities. This is to address that, routine batch processing activities like aseptic connection do not increase a microbial count which can trigger the sterility failure of the final product. The settle plate is to be exposed during the activity. The online particulate monitoring system should be operational in this activity.
Filling Operations in Media Fill:
Below mentioned parameters shall be considered during the media fill activity.
1. Frequency and number of runs for media fill study:
As per regulatory requirements, there shall be three successful runs to be performed at initial validation. At the initial stage, the smallest and largest container sizes shall be qualified with the three different independent runs.
If any addition of the new pack size same shall be qualified with three runs. Different container sizes play an important role in the media fill activity. Many organizations are following the media fill bracketing approach through the in-house documentation and scientific justification about selecting the container size with respect to the media fill runs.
2. Media Fill Batch Size and no. of Runs Requirement:
On the basis of commercial product batch size, Media Fill batch size should be selected. As per different guidelines, Batch size should be considered as 10000 units for the product batch size of 5000 units or more. The batch size should be 5000 units or equal to the product batch size; if the batch size is 5000 units or lower. It is expected that the batch size should be large enough to represent a routine operation, worst case interventions, cover potential contact surfaces, and accurately assess the potential for commercial batch contamination sources.
3. Container closure configuration :
The container closure configuration shall be assessed through the opening/mouth of the container and fill volume to be 70% of the actual container size and shall stimulate the entire surface area of the container. The scientific consideration is as follows,
a. There must be enough medium in the container to contact all the container-closure seal surfaces when the container is inverted and swirled.
b. There must be enough medium in the container to allow for the detection of microbial growth.
c. There should be enough head space volume considering the growth-promoting capability of the media to support aerobic microorganisms.
4. Filling Machine Speed During Media Fill:
The machine shall be run with maximum, minimum, and at optimum speed. The speed shall be considered through routine operating speed or the speed qualified at the stage of the machine qualification. For a small neck container, the maximum speed is considered as a worst-case and for the largest container with a wide neck, minimum speed shall be considered as a worst-case.
Media Fill Interventions:
The media fill is considered as the critical activity, in which routine and non-routine activities shall be simulated in the form of interventions. The activity shall represent a worst-case covering all the manipulations.
For the execution of interventions, an approved list of allowed interventions, both inherent and corrective, should be prepared as a procedure or as part of the media fill protocol. The same shall be executed and respective trays shall be separated with proper identification and numbering of respective intervention. Corrective actions – These are performed to correct or adjust an aseptic process during its execution. (e. g.Container breakage, toppling of the container, stopper jam, change in filling needle, change in filling pistons, machine breakdown, power failure, etc
Inherent interventions – These are the normal and planned activities that occur during the aseptic filling process. (e.g. fill volume adjustment, rubber stopper charging, aluminum seals charging, flame adjustment, EM, etc.
Incubation Criterion For Media Fill:
After completion of the media filling, the same containers shall be visually inspected. The inspected containers shall be incubated for 07 days at 20-25°C considered as a first incubation. The containers shall be arranged in inverted positions for the first three days and upright for the next four days. Post visual inspection shall be performed after the completion of 1st 07 days. Again, arrange the trays in an inverted position for three days and an upright position in the next four days considered second incubation. The temperature shall be maintained at 30-35°C. Visual inspection shall be performed by a qualified microbiologist.
In case of contaminated unit/s observed, the microorganisms should be identified to Genus level; however, practical efforts should be made preferably for species-level to assist in the determination of the likely source of the contaminant.
Environmental Monitoring Programm:
A planned documented environmental monitoring program shall be performed thorough the media fill activity. The viable, non-viable environmental monitoring shall be performed as per the frequency given in the media fill protocol. Finger dabs shall be taken at every exit during the media fill activity.
Media Fill Acceptance Criteria:
The target should be zero growth and the following should apply:
• When filling fewer than 5000 units, no contaminated units should be detected.
• When filling 5,000 to 10,000 units:
a) One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill;
b) Two (2) contaminated units are considered cause for re-validation, following an investigation.
• When filling more than 10,000 units:
a) One (1) contaminated unit should result in an investigation;
b) Two (2) contaminated units are considered cause for re-validation, following an investigation.
Documentation Criterion for Media Fill:
The respective media fill BMR, SOP, Environmental monitoring records, temperature monitoring records, Pre and post Growth promotion test records, Media fill reports. Respective change controls, deviations, are compiled together as a course of the documentation. This record shall be used in sterility failure investigations as well as for the regulatory review inspection. If possible, media fill videos shall be considered as evidence.
References for Media Fill:
1. FDA, Guidance on sterile drug products produced by Aseptic Processing (Sept -2004).
2. EU, EU GMP Annex 1: Manufacture of Sterile Medicinal Products (Nov 2009).
3. PIC/s, Recommendation on the Validation of Aseptic Process, PI 007-6 (Jan-2011).
4. PDA, Process Simulation for Aseptically Filled Products, TR 22 (Revised 2011) IVT Network, A Risk
Matrix Approach for Media Simulation Trials (Jul 2016).
5. https://www.pharmaceuticalonline.com/doc/non-invasive-headspace-analysis-for-automated-media-fill-microbial-inspection-0001
Comments
Post a Comment
If you have any doubt please let me know. Thank you.