On February 20, 2020 the Directorate for Health and Food Safety of the European Commission published a further draft for the revision of Annex 1 of the EU GMP Guide to Good Manufacturing Practice. In this revision, the scope of sterile drugs is expanded to sterile products, emphasizing the comprehensive application of Quality Risk Management (QRM) and Contamination Control Strategy (CCS). It also contains detailed information about some technical applications, such as restricted access barrier systems (RABS), isolators, rapid detection and monitoring systems for microorganisms and sterilization technologies, etc.
From the requirement of current version Annex 1 and the trend of pharmaceutical industry, freeze-dried drugs are the essential dosage forms of sterile preparations. Examples of freeze-dried products are antibiotics, bacteria, sera, diagnostic medications, protein-containing and biotechnological products (mAb, vaccines, recombinant proteins, etc.), cells and tissues. There are very high sterility requirements and market demand for freeze-dried products. It believes that “Automation, Isolation, System Integration and Continuous Processing” are becoming main stream for aseptic processing of sterile injectables.
Thinking of the CCS in Freeze Drying System Design
With over 500 integrated Freeze Drying Systems and 8,000 key equipment for lyophilized injectables applications, Tofflon has accumulated wide knowledge and experience. Tofflon Freeze Drying System is composed of Auto Solution Preparation Systems, Aseptic Filling Line, Freeze Dryer, Auto Loading Systems, Barrier Systems, Intelligent Vision Systems and Leak Detection Systems.
Tofflon has developed CCS (Contamination Control Strategy) at different stages of Freeze Drying System to meet cGMP compliance. CCS is not a new concept. It can be simply understood as all contamination control strategy in the entire product life cycle, and these measures shall be continuously updated to ensure continuous improvement of production and control methods. CCS is an essential embodiment of the QRM principle applied in the aseptic process.
CCS is a part of the quality management system which should be considered at the initial stage of the facility design and production line .It requires the establishment of CCS files, adopting risk management methods to determine the key control points, all control measures and monitoring measures in the production process, performing verification and evaluating effectiveness, updating CCS and continuously improving the production process and control methods.
CCS development requires comprehensive technical capabilities and process expertise. In addition, “plant and process design, plant and equipment, personnel, utility systems, raw and auxiliary materials control, product containers and seals, supplier approval, outsourcing services, process risk assessment, process verification, preventive maintenance, cleaning and disinfection, daily monitoring, corrective and preventive actions (CAPA)” and comprehensive continuous improvement should be fully considered.
Application of Auto Loading Systems
In the “Aseptic preparation and processing”, Chapter 8 “ Production and Specific Technologies”, EU GMP Annex 1 “Manufacturing of Sterile Medicinal Products” (draft for comment), Article 8.10 mentions that “Robotics and automation of processes can also be considered to eliminate direct human critical interventions (e.g. dry heat tunnel, automated lyophilizer loading, sterilization in place)” and “Lyophilizers that are manually loaded or unloaded should be sterilized before each load. For lyophilizers loaded by automated closed systems or located within systems that exclude operator intervention, the frequency of sterilization should be justified and documented as part of the CCS”.
Since personnel is the main source of contamination for sterile products, more than 80% of contamination in clean rooms are caused by personnel, from the perspective of regulations, it is recommended that automated equipment should be used to reduce the risk of personnel contamination and prevent personnel error. Manual operations bring many uncertain factors, causing a high risk of contamination, and the corresponding contamination control strategy is required. Hence, the auto loading systems play an increasingly significant role in the Freeze Drying System and will be widely used in the freeze-dried formulation manufacturing. Equipped with a more advanced isolation system (Close RABS/Isolator), it not only avoids cross-contamination to products due to personnel intervention but also protects safety of operators.
Application of Isolator Technology
In the “Aseptic preparation and processing”, Chapter 8 “Production and Specific Technologies”, EU GMP Annex 1 “Manufacturing of sterile medicinal products” (draft for comment), Article 8.10 mentions that “Where possible, the use of equipment such as RABS, isolators or other systems, should be considered to reduce the need for critical interventions into the Grade A zone and to minimize the risk of contamination”.
RABS is an barrier system added between products and personnel to isolate the personnel from the products. For sterile products, it can avoid contamination caused by personnel. For highly active or potent drugs, it is necessary to protect the safety of personnel while ensuring the sterility of drugs. Hence, isolation offers sterility and safety protection between personnel and drugs.
With the years of experience and practice in Freeze Drying System projects by Tofflon and analysis of market trends ,it is predicted that the existing aseptic production still face more challenges:
Increasingly high requirements of regulatory agencies for aseptic processes
More drugs with highly added value
Higher drug costs
Growing demand for small batch and multi-product production lines
More highly potent oncology drugs
Increasing requirements for temperature and humidity control
To responde the challenges and trends mentioned above, the isolation technology has been fully applied in the sterility assurance level (SAL), highly active, highly potent, multi-product production line, etc. and it will undoubtedly be applied in more projects.
Given the changes in regulatory policies for the pharmaceutical industry, Tofflon combines existing resources to analyze the impact of policy changes comprehensively from multiple perspectives through regulation benchmarking. Tofflon is continuously improving its technology with rapid development at the same time, keeping up with the market trends based on the cGMP requirements, committed to create “Automation, Isolation, System Integration and Continuous Processing” Freeze Drying System Solution.