Sterile Product Manufacturing Research Articles

Validation of a Sporicidal Bio-Decontamination Process for use in Pharmaceutical Isolators in an NHS Aseptic Manufacturing Unit

The recently published revision of EU GMP Annex 1 Manufacture of Sterile Medicinal Products includes a requirement for pharmaceutical isolators to undergo a bio-decontamination process of the interior which should be automated, validated and controlled within defined cycle parameters and include a sporicidal agent. It is widely accepted that the easiest way to achieve this is by converting Hydrogen Peroxide (H2O2) liquid into a state that will diffuse readily through the closed isolator chamber leading to bio-decontamination of all surfaces which it comes into contact with. The technology to do this has been around for years and can be validated to give a high level of assurance of surface bio-decontamination comparable with sterilization when used on surfaces in the isolator critical work zone. This type of activity is routinely used in large-scale sterile manufacturing that takes place in the pharmaceutical industry where the amount of materials and timescales involved make this viable. In the NHS, aseptic preparation and manufacture of sterile products is carried out in isolators both for immediate use and for stock in anticipation of demand. Automated bio-decontamination systems are available but their use is much less than in the pharmaceutical industry and reliance is still placed on manual spraying and wiping of surfaces with disinfectant agents such as alcohol and hydrogen peroxide. This brings a degree of variability and is more difficult to validate. For sterile manufacturing units holding an MHRA Specials Manufacturing licence the expectation is that proper consideration is given to using an automated bio-decontamination process or there is justification for not doing it. For units preparing products for immediate use there is not the same expectation but as standards are improved, it is reasonable to assume it may become the case in the future. To use this type of process requires it to be integrated into the isolator, meaning either buying a new isolator or retrofitting to an existing one. The relatively high cost of this is a barrier to pharmacy department aseptic units using the technology. There is a range of bio-decontamination systems on the market from Devea (www.devea environnement.com)which are claimed to be suitable for use in hospital pharmacy clean room facilities. One model from this range, the Phileas Genius is a simple, stand-alone battery powered unit that generates vapourized hydrogen peroxide of particle size 5-10 µm from 7.4% solution using novel spinning disc technology. This generator can be transferred into and out of any closed isolator work zone through the transfer hatch (as long as the hatch door is wide enough) and can be used to do pre-programmed cycles (called zones) to routinely decontaminate inner surfaces.

Study of Establishing a Contamination Control Strategy using a Quality Risk Management for Manufacture of Sterile Products

Manufacturers engaging in Good Manufacturing Practice (GMP) for a sterile product are required to establish a Contamination Control Strategy (CCS) to prevent product contamination. Domestic and overseas regulations including the EU GMP Guideline “Annex.1 Manufacture of Sterile Products” mention the importance of establishing a CCS; however, despite mentioning a risk management method, the Annex does not describe a specific implementation method. Sterile product manufacturers should take measures to prevent product contamination by establishing an appropriate CCS. Therefore, this study presents a method for establishing a CCS strategy, as required by various guidelines, using the quality risk management method presented in ICH Guideline Q9. In this study, when establishing a CCS strategy by applying the quality risk management method, it was possible to confirm factors affecting product contamination through Cause and Effect Analysis, and the degree to which each factor influences product contamination through Failure Mode and Effect Analysis. Based on these results, when establishing product contamination countermeasures, manufacturers can identify the items requiring improvement and evaluate the strength of these measures. Finally, the manufacturers can establish a CCS at the level required by the relevant guidelines. This study is meaningful in providing a method for establishing a CCS that can be applied by sterile product manufacturers in the future by presenting a CCS using the quality risk management method.

Barrier Technologies proposed text from PHSS Annex 1 focus group for revision of clauses/ section in version 12 of Annex 1 through the targeted consultation process.

The PHSS are one of the eleven EC appointed commenting platforms in the targeted consultation process on Annex 1, with version 12 how in the process of review and commenting. Two sections of Annex 1 are considered by the PHSS to need significantly more clarity and differentiation of technologies and approaches to qualification. This article has a focus on Barrier technologies with a follow up article and Webinars also planned for the section on Qualification of Cleanrooms and clean-air devices (that includes classification). It is considered the current section in Annex 1 version 12 does not fully differentiate Isolators and Restricted Access Barriers (RABS) and their set-up for use in sterile product manufacturing. The following is recommended replacement text (in draft) that a PHSS Annex 1 Focus group have prepared to put forward to the EC/EMA as part of overall commenting on Annex 1 version 12 that has a deadline for submission on 20 July 2020.

Analysis of the methods for projection of spaces for good manufacturing practice

BACKGROUND: In this Paper we will present the evolution of the best practice for biobanks, the technical and medical standards for collecting, processing and storing, as well as the socio-economic standards for biobank management.
 AIM: The aim of this Thesis is to analyse and to present the methods for projection of spaces for good manufacturing practice.
 METHODS: The European Union has adopted guidelines for good manufacturing practice which define the requirements for manufacturing of sterile products. In the following text we will describe the details for determining microbiological cleanliness and cleanliness of the particles in the air, on the surfaces, etc.
 RESULTS: The length of time between the collecting of blood or tissues could affect the final result. The preparation of sterile products requires special conditions, in order the risk of microbiological contamination and certain pyrogenic contaminations to be minimized. We make difference between four levels of guidelines for good manufacturing practice, which in this Paper are taken from the practice of the European Union. Level A is local zone with high-risk procedures, e.g. filling, closing of bottles, opening of ampoules and bottles and making septic connections. Level B is aseptic preparation and filling of the samples. Level C and D are the clean spaces for less critical procedures for preparation of sterile products.
 CONCLUSION: Technical standards, medical standards, socio-economic standards for biobank management, informatics practices for biobanks, economic recommendations for biobanks have been established, as well as a quality of biobanks has been provided.

Form Fill Seal Technology: A Brief Review

Form fill seal (FFS) technology is an automated computer operated technology, to prepare sterile products. Mostly it is applicable for I.V. infusion bottles. In this process all steps such as formation of container, filling of container with content and sealing of container are performed sequentially, consistently and automatically in a closed sterile chamber of machine. This technology reduces the contamination rate below 0.1%. The reason behind FFS technology is to reduce the contamination during production in a closed sterile chamber of a machine. Thus there should be no personnel intervention to reduce the chances of contamination during the manufacturing of sterile products. Again it gives more production in very low operational cost with high assurance of sterility.

Confirmation of the Sterilization Effect Using a High Concentration of Ozone Gas for the Bio-Clean room

A high-level aseptic environment must be maintained in bio-cleanrooms used for the manufacture of sterile products. In the past, formaldehyde gas was most commonly used to sterilize bio-cleanrooms, but due to strict residual limitations there has been a need to develop a less toxic alternative choice. The authors have developed a revolutionary new sterilization system using a high concentration of ozone gas and used this system to sterilize an actual bio-cleanroom. This system integrates the ozone gas generator with the air conditioning system by proper control. The design specifications for the system included an ozone gas concentration of 200 ppm or more, relative humidity of 80% or more, and a sterilizing time of 120 min. Blow vents and suction ports were placed to ensure a uniform airflow which would extend through the entire room during ozone gas sterilization. Tests regarding long-term material exposure to ozone gas were conducted when the system was introduced to distinguish usable and unusable materials. In an actually constructed cleanroom, simulations were used to predict the evenness of the diffusion of ozone gas concentration and relative humidity during ozone gas sterilization, and measurements of the actual indoor ozone gas concentration, temperature and relative humidity during sterilization revealed that the ozone concentration and relative humidity needed for sterilization had been achieved generally throughout the entire environment. In addition, the CT value (mg/m(3) (=ppm) × min) , derived by multiplying the ozone gas concentration during ozone gas sterilization by the sterilization time, was equal to or greater than the target value of 24 × 10(3) (ppm·min) . When the results of sterilization in a cleanroom were confirmed using a biological indicator (BI) , negative results were obtained at all measurement points, demonstrating that sterilization was being performed effectively in the actual factory at which the ozone gas sterilization system had been introduced.

Media Fill Test for validation of autologous leukocytes separation and labelling by 99mTc-HmPAO

Manufacturing of sterile products must be carried out in order to minimize risks of microbiological contamination. White blood cells (WBC) labelled with (99m)Tc-exametazime ((99m)Tc-hexamethylpropyleneamine oxime; (99m)Tc-HMPAO) are being successfully applied in the field of infection/inflammation scintigraphy for many years. In our radiopharmacy lab, separation and labelling of autologous leukocytes with (99m)Tc-HMPAO were performed in a laminar flow cabinet not classified and placed in a controlled area, whereas (99m)Tc-HMPAO radiolabelling procedure was carried out in a hot cell with manipulator gloves. This study was conducted to validate this process using a Media Fill simulation test. The study was performed using sterile Tryptic Soy Broth (TSB) in place of active product, reproducing as closely as possible the routine aseptic production process with all the critical steps, as described in the our internal standard operative procedures (SOP). The final vials containing the media of each processed step were then incubated for 14 days and examined for the evidence of microbial growth. No evidence of turbidity was observed in all the steps assayed by the Media Fill. In the separation and labelling of autologous leukocytes with (99m)Tc-HmPAO, Media-Fill test represents a reliable tool to validate the aseptic process.

Attainment of Sterility and Satisfactory Material Functional Compatibility to Devices in the Clean Room

Copyright: © 2012 Shintani H. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. A high-level aseptic environment must be maintained in biocleanrooms used for the manufacture of sterile products. Formaldehyde gas exposure was conventionally used to sterilize within biocleanrooms (ISO 14644-1), but Ministry of Health, Labor and Welfare Japan requires quite strict residual limitation of formaldehyde at less than 0.08 ppm because formaldehyde causes one of sick-house disease, so there was a need to seek for a less toxic alternative sterilants. These sterilants are ozone, hydrogen peroxide, peracetic acid and chlorine dioxide gases.

Report of the Seminar on the Manufacturing of Sterile Products by Aseptic Processing According to the ISO Standard

Report of the Seminar on the Manufacturing of Sterile Products by Aseptic Processing According to the ISO Standard