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During the production of a drug in sterile liquid form, heat sterilization of the product in its container, should always be preferred. However, the thermal sensitivity of the active ingredient sometimes makes this impossible. Filtration, combined with aseptic processing conditions, offers an alternative widespread in the pharmaceutical industry. The document Guidance for Aseptic Production of Sterile Drug by FDA Aseptic Process 2004 (1) and the technical report Sterilizing filtration of liquids PDA 2008 (3) offer the opportunity to take stock of best practices for validation of filtration.
Objective validation of a filtration step
The sterile filtration must retain all viable organisms, except viruses, present in a liquid formulation. Validation aims to prove, with a high level of confidence that the filtration process is reliable and reproducible one step, to release a drug in the pre-established specifications (2).
The validation must demonstrate that the retention of the filter is not disturbed by the fluid or pharmaceutical by the process conditions. It must establish that the filter does not alter the composition of the drug by adsorbing the active substance or by adding foreign substances.
Establishment of a validation master plan
It defines the overall strategy, resources and responsibilities. It will include protocols approved and final test results. The FDA admits that the qualification testing of filters can be made on a reduced scale, by partners (suppliers of filters or external labs). The pharmaceutical industry remains responsible for the approval of protocols, their implementation, the signature of the final report and its maintainability.
Defining the functionality of a filter
The U.S. and EU GMP (4) insist on controlling the organic contamination throughout the process. The online process must be designed to minimize the bioburden prior to sterile filtration. Often, it is close to 0 with an upper limit up to 10 ml ufc/100 (5). If exceeded, use a filter found "bioburden reduction" to reduce the level of contamination is necessary. There is desirable but not imperative, that this filter is similar (polymer construction) that the filter identified as "sterilization" to prevent the duplication of some studies (adsorption, chemical compatibility). However, their functionality must be clearly defined because it will have a major impact on the level of validation performed.
Double sterile filtration and filter integrity test before and after sterilization
These issues recur. Strictly speaking, if the solution has to be filtered and controlled low bioburden, a single sterile filtration, properly validated nearest filling point is sufficient. However, the doubling of this stage is suggested by the authorities without ever being taxed. A comprehensive risk analysis taking into account the nature of the product line design (process or conventional insulator; autoclave or SIP), the location of the filtration (Grade A, B or C) and process conditions ( long ....) must justify its implementation or not. Similarly, achieving an integrity check after sterilization and before filtration should be discussed. Simple solutions exist to highlight a defect that may occur during the critical phase of the sterilization filter.
Qualifying performance of a sterilizing filter (PQ)
- Test for bacterial retention
The manufacturers describe the sterilizing filters by standard method ASTM F838 with at least 107 Brevundimonas diminuta per cm ² of membrane and defined test conditions (duration, pressure, temperature, flow, report filtered volume / unit area filter). However, the actual conditions of use in the pharmaceutical industry are sometimes unfavorable. The FDA then asked to simulate the small scale of these adverse conditions and document that the filter produces many sterile effluent. On the other hand, the physicochemical characteristics of the product may influence the retention capacity of the filter. For this reason, direct inoculation of B. Diminuta in the pharmaceutical formulation, will always be better in the test (3). If it turns out that a microorganism smaller than B.diminuta is highlighted in the characterization of the bio-load, the FDA recommends conducting the study with this organism.
- Determination of substances extractable
The drug manufacturer is required to document the nature, quantity and toxicity of extractables generated by all materials in contact with the product (attached, hose, filter ...) or by processing conditions (contact time, method of sterilization, temperature). The extractables are often present in small quantities compared to active compounds. This complicates their detection. In this case, the FDA accepts a study based on the use of pure solvents representative of the pharmaceutical and simulating the worst conditions. The extracted substances were identified and quantified. Their biological and toxicological compliances are then tested vis-à-vis Class VI tests for plastics and mouse defined by the USP.
- Determination of specific parameters of integrity
The Bubble Point tests or broadcast are dependent wetting liquid. The specifications of filters are usually provided with hydrophilic water. In some cases (difficulty rinsing end filtration test performance during the process), it is necessary to verify the integrity using the filtered product itself. Parameters can be determined in the laboratory and will be confirmed during the performance qualification.
- Chemical compatibility
The filter is placed in contact with the pharmaceutical product by simulating the worst conditions. Compliance and visual weight of the filter and the integrity and flow are then compared to specifications.
Conclusion
A risk analysis leads to consider carefully the sterilizing filtration. To complete the validation of a new line of aseptic packaging, qualification sterilizing filter performance that we have just described is only a first step. She accompanied the IQ / OQ of equipment and instruments and sterilization procedures (SIP / Autoclave) and integrity test (PQ). Finally, a training program and periodic evaluation of operators will be established. This comprehensive approach must ensure a high level of assurance of sterility in an aseptic process and successfully pass the next regulatory audit.
Bibliography
1: FDA, Guidelines on Sterile Drug Products Produced by Aseptic Processing, Center for Drug Evaluation & Research (CDER) & Center for Biologics Evaluation and Research (CBER) and Office of Regulatory Affairs (ORA). Washington, D.C., September 2004
2: FDA, Guidelines on General Principal of Process Validation, Center for Drug Evaluation & Research (CDER) & Center for Biologics Evaluation and Research (CBER) and Office of Regulatory Affairs (ORA). Washington, D.C., September 2004
3: Technical report N° 26, Sterilizing Filtration of Liquids, revision 2008, PDA Journal of Pharmaceutical Science and Technology, December 2008 62(S5)
4: EU Guidelines to GMP for Manufacture of Sterile Medicinal Products: Annex 1. Brussels, February 2008
5: Note for Guidance on Manufacture of the Finished Dosage Form- 3AQ2a. CPMP EMEA Brussels, May 1996
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