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Long, the process Blow Fill and Seal (BFS) allows a single machine with the production of plastic bottles containing liquids of various kinds: food, pharmaceutical or technical.
Pharmacy, one of the main interest is to aseptically produce sterile liquids sensitive to heat. In this case a sterilizing filtration of the solution is required, the plastic material being sterilized during the extrusion step, the following steps being carried out in aseptic, the machine and its annexes are they usually steam sterilized. This sterilizing filtration is a critical operation for the final product sterility and must meet regulations particularly line 1 Director of Good Manufacturing Practices (GMP). Different implementations of sterilizing filters are possible. All should lead to a mastery of the sterility of the sterile filtration with strategies specific to each company, but each having their limits.
These different options are presented and discussed in the following text.
Guideline for Good Manufacturing Practices (GMP) on sterile products and supplemented by texts on products that can not be sterilized in their final container particularly accurate as:
• The time interval between the beginning of the preparation of the solution and its sterilization or filtration through an antimicrobial filter should be as brief as possible.
• The bioburden (microbial contamination) should be monitored before sterilization. A limit should be set for microbial contamination immediately before sterilization, limit that is based on the effectiveness of the method used (GMP 2014-1 1bis §LD80).
• Since the filtration involves more risks than other sterilization processes, a second filtration through sterile antimicrobial filter, immediately before the distribution, may be recommended. The final sterilizing filtration should be performed as close as possible to the distribution point (GMP 2014-1 1bis §LD111).
• The integrity of the sterilized filter should be checked before use and confirmed immediately after use by an appropriate method such as bubble point tests, diffusion or pressure maintenance.
• The filtration time of a known volume of solution and the pressure difference between the inlet and outlet of the filter should be determined during validation and any significant deviation during the normal manufacturing process noted and discussed. (GMP 2014-1 1bis §LD113).
• The same filter should not be used for more than one working day without this practice has been validated (GMP 2014-1 1bis §LD114)
We must not forget that the sterilizing filters are selected and validated to ensure the effectiveness of sterilizing filtration.
Implementation of sterilizing filters on production lines and fillers BFS
For many years the factories and Excelvision in particular, have developed practices to meet regulatory requirements and ensure the quality and sterility of products.
When the products are filled over a long period, a first sterile filtered into an aseptic storage tank is made to ensure an aseptic product storage.
A second sterile filtration is then carried out on the filler. By convention we call this filter: safety filter.
BFS machine manufacturers typically offer two locations product filters.
Sterilization control principle by sterile filtration
To ensure the effectiveness of the sterile filtration of a sterilizing filter (absolute 0,22μm) 3 main conditions are required:
• Ensure a level of product contamination filter as low as possible by controlling its bioburden,
• Ensure the maintenance during filtration parameters below the maximum validated for pressure, flow and filtration time,
• Perform the verification of the integrity of the filters in place after sterilization as validated parameters (Bubble Point or diffusion test) before and after use.
Possible strategies for controlling the sterilizing filtration
In case the product is filtered on sterilizing filter from the transfer aseptic storage tank control of sterilization by the filter sterilizing should be reached at this stage with control of bioburden before the filtration, respect for filtration parameters validated and filter integrity test before and after use.
The integrity of the security filter placed as close to the filling point then remains to be verified. The advantages and disadvantages related to the implementation of this filter are shown in the tables below.
Case 2 filters before buffer tank
Case 1 1 filter filter before and after buffer vessel
To meet regulatory aspects and ensure control of sterility, design BFS filling although very advanced yet deserves that solutions are proposed to enable the realization of filter integrity testing before use.
The objective is to guarantee the maintenance of circuits in the sterile state upstream and / or downstream of the filter to be controlled.
In current designs, the position upstream of the buffer tank of this security filter allows already to remove the risk of loss sterility downstream of the filter during the implementation of the integrity test. Solutions also exist to avoid loss of sterility at the upstream of the filter in some manufacturers in this situation: for example, by setting up an air filter sterilized product overcoming this filter along the machine.
The filter control as close to the filling point before use requires to be done to ensure the absence of risk for infertility. This requirement must be taken into account in the design of the equipment.
Given our experience (efficiency of the first sterilizing filtration, aseptic maintenance of solutions, filter quality, reliability of sterilization ...) corroborated by the results of Media Fill Test, we continue to question the relevance of a integrity check of the safety filter before use.
The installation required for such controls do not there is a higher risk to the benefit provided?
Jean JAILLOT - EXCELVISION
- European GMP 2014 1 1 bis guidelines for Production of sterile medications paragraph Filtration drugs that can not be sterilized in their final container
- Defining a strategy for the Validation and Qualification of Sterile Filtration Processes of Investigational Medicinal Compounds (Ross W. Acucena Regulatory Consultant, EMD Millipore Provantage March 4, 2014 @ PDA Metro Chapter Dinner)