Caps used in the drug industry for primary packaging must ensure the safety of injectable solutions. The steps of transferring these components to a fill line are critical. This paper discusses the validation of aseptic transfer of corks from a processor to a single-use bag using a new system. The study will show that this technology guarantees the maintenance of the sterility of the plugs after transfer performed in ISO 7 or ISO 8 classified environment.
Historical
With respect to the development of new drugs, a number of trends in the industry are changing the landscape. The increase in the manufacture of organic products, an estimated $ 12.6 billion market in 2010 [1], along with vaccines and injectable protein-based drugs, requires advanced aseptic manufacturing conditions. These drugs can not be subjected to terminal sterilization. As a result, health authorities, both European and American, are now recommending the use of insulators for aseptic manufacturing processes to avoid human interaction, which increases the risk of microbiological contamination [ 2].
Upstream of the aseptic filling, there is the critical step of treatment of the stoppers in contact with the drug, including washing, rinsing, siliconization, steam sterilization, drying and maintaining their sterility to the point aseptic filling in ISO 5 environment [3].
The new industrial practices for treating these corks have led to the emergence of new cork formulations and the arrival of new packaging techniques: "Ready to sterilize" (RTS) and "ready to use" components. (RTU). In both cases, all or part of the plug treatment is the responsibility of the component manufacturer. Ready-to-sterilize components are packaged in autoclavable pouches, which reduces user responsibility, except for sterilization. Health authorities have promulgated strict rules for the qualification and validation of third-party processing steps. In particular, the Food and Drug Administration (FDA) is asking manufacturers of primary packaging components to develop more efficient, consistent, validated manufacturing processes that meet Good Manufacturing Practices [2].
More recently, the pharmaceutical and biopharmaceutical industry has also chosen ready-to-use components. It allows users to deport full responsibility for component processing and use these components directly on their aseptic filling lines. The RTU preparation process has been developed to meet the FDA validation request for equipment, manufacturing, product, documentation and test methods as described in 21 CFR § 211.94 [4] . However, the majority of RTU components are sterilized by ³ radiation whose negative impact on the polymer chain of the elastomer is discussed [5].
Despite these new trends, the control of all stages of cork processing remains a reality and the preference for many users. It is on this process that this document focuses its study.
Currently sterilized corks are packaged in pouches via a transfer isolator to maintain the sterility of the components. The Biosafe Biosteam S system allows the user to work in an ISO 7 or ISO 8 [3] rated environment. An insulator represents a heavy investment with validation and complex maintenance ( Figure 1 ).
Biosafe Biosteam S is a system that allows the aseptic transfer of corks for primary packaging from a processing processor of these corks into a sterile Biosafe disposable bag. The innovation of such a system results in the assurance of the maintenance of the sterility of the plugs after transfer in an ISO 7 or 8 classified environment.
Description of the study
The new technology of sterile cork transfer developed by Sartorius Stedim Biotech (SSB) is innovative and not yet framed by ISO standards or the European and American pharmacopoeias [6-8]. This validation plan has been defined in accordance with the regulatory requirements applicable to the sterility testing, bioburden and validation of sterilization processes applied by the drug industries.
The objective of the validation of this aseptic transfer is to demonstrate that the integrity of the entire system is confirmed as well as the sterility of the bag containing the caps ( Figure 2 ).
Justification of the conditions of the study
Sterility is defined in the European Pharmacopoeia and ISO by the phrase: "[the product is] free of viable microorganism" [6; 7]. Since the inactivation curve of a microorganism is exponential, the level of certainty of sterility is the probability that a viable microorganism is present in the product. The purpose of validating a sterilization process is to reduce this probability and to achieve a sterility certainty (SAL) level of 10 -6 .
A terminal sterilization process is based on the exposure of the products to a chemical agent or a physical phenomenon, thus not applicable for an aseptic transfer operation.
Two possibilities :
• Stoppers are sterilized by moist heat. The sterilization process is validated, with a sterility certainty level (SAL) of 10 -6 [9];
• the bag is sterilized by radiation ³ at a minimum dose of 25 kGy. The sterilization process is validated according to the requirements of the NF EN ISO 11137 standard [10] with a sterility certainty level (SAL) of 10 -6 .
The technical and microbiological qualifications of the processor and pouches ensure the integrity of the complete system before, during and after the split transfer (up to 40 connections-disconnections).
The sterility tests performed on the bags containing the caps (32 units sampled over 3 cycles of sterilization) prove the effectiveness of the aseptic transfer.
Preliminary validations
The global validation program was carried out according to the flowchart of Figure 3 . For better visibility, the following two parts are not described in this article:
• The installation (QI) and operational (QO) qualifications of the Biosafe Biosteam S processor.
• The SAL 10 -6 validation of the wet heat sterilization process of corks.
Validation of test methods
The validations of the methods for estimating the population of microorganisms (biocharge) and the sterility test were carried out according to the requirements of the respective standards NF EN ISO 11737-1 [6] and EP2.6.1 [7]:
• absence of inhibition factors verified by bacteriostasis and fungistasis tests;
• culture conditions applied routinely according to the requirements;
• recovery coefficient according to specifications (≤ 2);
• Relevant sterility test conditions and absence of inhibition phenomenon.
The ammonia leak test method routinely performed on Biosteam S bags was compared with a microbiological integrity test according to the recommendations of ISO 15747 § 4.3 [11].
Validation of the γ radiation sterilization process
The method of sterilization of the bags by γ radiation has been validated at a minimum dose of 25 kGy and a maximum of 45 kGy according to the requirements of standard NF EN ISO 11137 [10]. The method used is the DV 25 for which the selection of the validation method is based on the bioburden estimate of the products (maximum 1000 CFU per bag) with a sterility certainty level (SAL) of 10 -6 .
A bioburden test is performed on ten units of three batches of products (ie thirty units in total), the average is calculated and the verifying dose VD max 25 (SAL 10 -2 ) is obtained.
Experimentation of the verification dose is carried out by exposing ten units of non-sterile products from the same batch to the verification dose VD max 25 . The sterility test performed on these ten units complies with the requirements of the standard (≤ 1 positive test), so the minimum sterilizing dose of 25 kGy is qualified.
The bioburden characterization of products is carried out regularly to identify seasonal variations.
The identification of the strains makes it possible to evaluate the resistance of the natural flora of the products to γ radiation compared with a model. Dose audits are also conducted at the frequency given by standard NF EN ISO 11137 [11] in order to confirm the validity of the sterilizing dose of 25 kGy.
Aseptic Transfer Validation Method
The purpose of this validation is to prove the maintenance of the sterility of corks treated in bulk by moist heat and then packaged in sterile bags. As part of this validation, the door is installed on a processor capacity 250 liters. The components used are vial stoppers 13 mm in diameter.
Justification of validation conditions
The worst case scenario chosen for the validation of aseptic transfer was defined according to several criteria described in Table A.
A Choice of validation conditions
| Criterion | Normal conditions | Configuration chosen for validation |
| Number of wet heat sterilization cycles | 1 cycle per day | 3 consecutive cycles |
| Multiple plug transfers for the same load (number of connections-disconnections) | 10 connections-disconnections * | 20 connections-disconnections and 40 connections-disconnections |
| Transfer environment | ISO class 7 or 8 [3] | Uncontrolled environment |
| Decontamination of the door | Decontamination by alcohol wiping of the door seals between each connection-disconnection | No decontamination of the door seals |
| Handling of bags containing corks | Intermediate storage on shelves in ISo class area 7 | Storage 20 units per carton, without special protection between products |
* Under normal manufacturing conditions, the load of a 250-liter processor is divided into 10 25-liter bags. For this validation, 20 and 40 connections-disconnections are made to consider a partial filling of the pockets.
Test conditions
The steps required to perform a wet heat plug sterilization cycle for validation are described in Figure 4 .
• Three sterilization cycles (123 ° C for 20 minutes) are performed with an Atec 250-liter processor;
• each sterilization load consists of 40 kg of Ø 13 mm plugs;
• in an uncontrolled area, a load is distributed at a rate of 1 kg of plugs per pocket totaling 20 connections-disconnections;
• in an uncontrolled zone, two charges are distributed at a rate of 1 kg of plugs per pocket totaling 40 connections-disconnections;
• no alcohol decontamination of the door seals between each connection-disconnection;
• Bags containing 1 kg of corks are packed in cardboard boxes of 20 units;
• these boxes are transported by truck to the laboratory;
• one in three pouches are sampled for integrity and sterility testing.
Integrity test
The goal is to verify the integrity of the pouch containing the caps by a rapid detection method. The sampling consists of a Biosteam S pouch containing 1 kg of caps on three discharges (total 35 units), which will be tested for integrity.
To detect a leak, the bag containing the plugs is brought overpressure by means of ammonia gas (overpressure of 120 pascals). Bromophenol-impregnated fabric is applied over the entire surface of the product for 5 minutes. Possible leaks are revealed when the fabric turns from yellow to blue.
Sterility test
The objective is to check the sterility of the corks contained in the bag after transfer. The sampling consists of a Biosteam S bag containing 1 kg of plugs out of three (total 32 units). The bags used for this validation were designed as described in Figure 5 to reduce the risk of exogenous contamination when performing sterility tests.
1 liter of sterile sodium chloride (NaCl 0.9%) is injected (1) into the Biosteam S bag containing the caps. Extract (2) is tested by the membrane filtration method (3 and 4) according to the requirements of USP [8] and EP 2.6.1 [7] (no microbial growth after 14 days of incubation) .
Results interpretation
The 35 integrity tests and the 32 sterility tests comply with the requirements. All units sampled over the three sterilization cycles give the expected results in the validation protocol.
The technical and microbiological qualifications of the processor and pouches ensure the integrity of the complete system before, during and after the split transfer: up to 40 connections-disconnections. The integrity and sterility tests carried out on the bags containing the caps prove the effectiveness of the aseptic transfer.
Conclusion
This validation study demonstrates that sterility of primary packaging caps is maintained after transfer using Biosafe Biosteam S technology:
• the process of sterilization of plugs by moist heat with a SAL 10 -6 is validated;
The sterilization method of the γ-radiation bag with an SAL 10 -6 is validated;
• the integrity of the bag containing the caps after transfer is demonstrated;
The maintenance of the sterility of the corks contained in the bag after transfer is demonstrated.
This technology offers prospects for improving aseptic transfer processes, including increased security, ease of use, simplified validation, and reduced investment.
BIBLIOGRAPHIC REFERENCES
PharmPro , Pharmaceutically clean, validated, elastomeric components . November 2007.
FDA , Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Processes. 2004.
NF EN ISO 14644-1: 1999 , Cleanrooms and associated controlled environments - Part 1: Classification of cleanliness of the air.
21 CFR § 211.94 , Code of Federal Regulations title 21 . Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals - Subpart E - Control of Components and Drug Product Containers and Closures - § 211.94 Drug product containers and closures.
PDA Technical Report No. 16 , Effects of gamma irradiation on elastomeric closures . 1992.
NF EN ISO 11737-1: 2006 , Sterilization of medical devices - Microbiological methods part 1 - Estimation of the population of microorganisms on a product.
European Pharmacopoeia 6th edition , Chapter 2.6.1. Sterility.
US Pharmacopeia USP Sterility Tests.
PDA Technical Monograph No. 1 , Industrial moist heat sterilization in autoclaves.
NF EN ISO 11137: 2006 , Sterilization of health care products - Irradiation.
ISO 15747 , Plastic containers for intravenous injection.
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