The Role of Process Simulation

Aseptic Process simulation, sometimes known as a media fill, is a tool that is used to assess the capability of an aseptic process to deliver a drug product that is sterile and free from microbiological contamination. Aseptic process simulation is achieved by running a batch of sterile microbiological nutrient growth medium, usually Tryptic Soy Broth, through a manufacturing process using the same process parameters, equipment, components and procedures as would be used for the manufacture of a batch of drug product.

The purpose of the Aseptic Process Simulation is to challenge the aseptic manufacturing process against potential microbiological contamination vulnerabilities and in doing so assesses the ability of the process, personnel and manufacturing environment involved in the process to remove and prevent microbiological contamination of the finished drug product.

Aseptic process simulations are performed at several different stages in the lifecycle of a manufacturing process and start with qualification media fills that demonstrate that a new process has been designed appropriately and can deliver a safe product free from microbiological contamination. Aseptic process simulations are performed twice per year for each validated process following initial qualification and after any significant change to the manufacturing environment, the manufacturing process or equipment and after organisational changes such as the introduction of 24/7 shift patterns.

An appropriately designed and well thought out Aseptic Process Simulation is the key to ensuring that all elements of the aseptic manufacturing process from the initial sterilisation of components to the final sealing of the drug product unit are challenged concurrently with other critical factors such as operator aseptic technique, the manufacturing environment and the processing equipment.

Many drug product manufacturers today have multiple aseptic process designs for multiple different products, all using the same processing equipment. Therefore, the best aseptic process simulation design will utilise several approaches such as bracketing of vial sizes, an equipment family approach and multiple line speeds to ensure that critical aspects of each process are fully challenged in a manner that provides robust challenge to the process, is fully compliant with cGMP and does not negatively affect productivity.

cGMP guidelines relating to Aseptic Process Simulations in all jurisdictions provide clear guidelines regarding the minimum number of units that must be filled during an aseptic process simulation and the acceptance criteria that must be met for an aseptic process simulation to be considered successful. However, the future of aseptic process simulations will see a further tightening and removal of ambiguity around acceptance criteria with the introduction of the new draft Annex 1 guidance that is expected in 2019. With this in mind it is a good time for companies to review their current aseptic process simulation design, policies and procedures and assess them for suitability as we head into a new future for sterile drug product manufacturing.

This review should incorporate assessment of common media fill deficiencies reported by regulatory inspection agencies such as:

• All elements of the manufacturing process were not simulated
• Worst case scenarios were not simulated
• Maximum bulk hold times were not used
• Inadequate control of interventions by operators
• Processed media was discarded

Interventions by manufacturing operators into an aseptic process poses the highest risk for the introduction of microbial contamination into the process and ultimately into the finished product. Therefore, an important element of aseptic process simulation design relates to how the aseptic process simulation will be challenged with all inherent and corrective interventions required for the process. How this will be achieved needs to be balanced with the requirement for qualification of the operators in the performance of these interventions during the aseptic process simulation.

Risk Assessment using the principles of ICH Q9 Quality Risk Management is an essential tool to determine, identify and prioritise aseptic process interventions in terms of their criticality to the quality and safety of the finished product. The outcome of this risk assessment can then inform the aseptic process simulation design in terms of how many times interventions will be performed and by whom.

Ultimately, successful Aseptic Process Simulation requires a cross functional approach with the cooperation of many departments such as Manufacturing, Validation, Microbiology and Quality Assurance to build a robust, challenging and cGMP compliant media fill design that combines multiple different elements.

The Parenteral Drug Association (PDA) Revision to their “Points to Consider for Aseptic Processing (Part 2) published in May 2016 lists five guiding and linked principles for aseptic process improvement and efficiencies as follows:

Science- and risk-based approaches should be used to obtain information needed to make decisions related to the evaluation, design, qualification, operation, and monitoring of sterile product manufacturing processes.

2. Technology should be considered to mitigate or reduce the risk to product quality identified in sterile product manufacturing processes and operations.
3. Traditional testing and monitoring methods as control strategies should be challenged to ensure they are the best means for aseptic processes.
4. New products, therapies, and technologies will present challenges to traditional and existing methods for development, manufacture, validation, and testing of sterile products.
5. Global health authority technical and regulatory guidance and requirements should be harmonized with regard to technical language and definitions.

https://store.pda.org/TableOfContents/43527_TOC.pdf

Further guidance on the validation of aseptic processes can be found on the PIC/S website at the following link:

https://picscheme.org/layout/document.php?id=153

The PharmaLex team can also provide you with support and guidance on the establishment, implementation or improvement of your Aseptic Process Simulations. If you would like further information or wish to discuss how we can tailor our services to assist you, please connect with us to discuss +353 1 846 4742 or contactirl@pharmalex.com