Approach to Simplifying Aseptic Contract Manufacturing – Part 2: Documentation

Eric SmartIndustry, Innovation, Manufacturing

Aseptic manufacturing at Singota

In the first installment of this series, we discussed the overall approach of using robotic, isolator-based filling technology to streamline the manufacturing of aseptic drug products. We focused on the advantages of a fully integrated filler/isolator system with built-in decontamination technology, such as the Vanrx SA25 Aseptic Filling Workcell used by Singota, and explored the ways this technology simplifies aseptic fill/finish operations.

In this article, we will focus on the impacts of the SA25’s operating principles, which combine to radically reduce and simplify manufacturing documentation.

Aseptic manufacturing at Singota As we all know, the documentation requirements for cGMP manufacturing are extensive. Regulatory guidelines require detailed records of every aspect of the manufacturing process. Preparing a complete and accurate set of batch documentation can, in some ways, be as challenging as the actual act of manufacturing a batch of finished, sterile drug product. Traditionally, much of this documentation has taken the form of paper records that are filled out by hand by operators, laboratory technicians, and others in a manufacturing organization. Despite advances in automation and digital technology, the pharma industry has continued to rely heavily on legacy paper-based systems lagging behind high tech industries that have embraced more modern, automated manufacturing techniques and associated record keeping.

An important consideration in Singota’s selection of its robotic aseptic manufacturing equipment was a desire to simplify and streamline the generation of GMP documentation. Not only did they want to cut down on the labor and time involved in generating, reviewing, and approving documents, Singota also wanted to make it easier for their clients to review and keep track of batch documentation.

Singota’s choice of the Vanrx SA25 was in part based on the way this system facilitates both the simplification and reduction in volume of batch documentation. Two key factors make the SA25 superior to many other systems in this regard: Automated record keeping and process simplification. Let’s take a detailed look at each:

Automation in Record Keeping:
Unlike many other aseptic manufacturing systems, the SA25 fully integrates Grade A isolator technology with automated robotic fill/finish technology. The system is controlled by a single, integrated operating system that controls all manufacturing operations downstream of the compounding/sterile filtration process. Functions controlled by the SA25 include:

  • Decontamination of isolators by Vapor Phase Hydrogen Peroxide
  • Aeration of decontaminated isolators
  • Differential pressurization of isolators
  • Environmental monitoring
  • Calibration of dispensing pump
  • Container filling (vials, syringes, or cartridges)
    • Product non-destructive or destructive weight checks
    • Fill counts (acceptable vs reject)
  • Container sealing with or without inert gas overlay

Each activity is digitally monitored and recorded within the control system of the SA25. The only human input required is entering the required batch parameters (e.g. container size, fill weight, fill tolerance, and batch size) into the human/machine interface (HMI), and loading the staging isolator with pre-sterilized, ready-to-use components pre-nested in tubs. At the end of robotic manufacturing, the sterile units in tubs are removed. Indeed, the gloveless nature of the isolator precludes human interaction with the product while the aseptic filling operation is underway.

An excellent example of batch record streamlining is the way product weight checks are carried out and documented. The SA25 is programmed to conduct weight checks frequently or infrequently, as determined by the client and Singota’s manufacturing team. The weight check process is also fully automated and most often done as non-destructive. Without human intervention, the system can take a container, fill it, weigh the filled unit, and calculate the net weight of the product. This data is captured and stored digitally by the control system. The system will alert operators in the event of an out-of-trend or out-of-tolerance result and recommend appropriate corrective action (i.e. pump adjustment). Any such adjustments are made via the SA25’s HMI. Following completion of production, all weight checks, pump adjustments, calibrations, and other digitally recorded data are downloaded, printed, and incorporated into the completed batch record.

Automated data recording offers several benefits:

  • More compact batch record (e.g. no weight check tables (only printed upon batch completion))
  • Greater legibility (fewer hand-written entries)
  • Precise and complete recording of system parameters (e.g. filled/rejected units, start/stop times, etc.)
    • No need for manual calculations of weight checks
  • Reduced burden on operators (no missed entries)

While the actual batch record remains a paper document, batch records for Singota’s clients contain only a fraction of the number of pages of a conventional record (see details under “Simplification” below). The compounding section is similar to any other batch production record since each compounding process is unique and requires a tailor-made process. Downstream of compounding, however, is where the SA25’s automation allows the record to be dramatically less complicated and much less voluminous than a conventional batch record.

Process Simplification:
As we discussed in the previous installment of this series, the SA25 relies on the use of pre-sterilized product components including vials/syringes/cartridges and closures (stoppers/plungers/seals). The sterilization and packaging of these items is conducted by Singota’s suppliers using fully validated, commercial processes, eliminating several equipment systems from Singota’s site that would ordinarily be found in an aseptic manufacturing facility. These include autoclaves, depyrogenation systems (tunnel or oven), water for injection system, a clean steam generator, and a purified water system. Each of these units requires their own sets of documentation including records covering installation, qualification, calibration, maintenance, and use. Consequently, there is no need for Singota to generate the GMP documents associated with these activities, which dramatically reduces the size of a completed batch record. The required documentation included in the executed batch record consists solely of the certificates of compliance from the component manufacturers. Singota estimates that elimination of the component preparation sections of the manufacturing record reduces the overall size of the executed record in a typical manufacturing run by more than fifty percent compared to a conventional operation.
Because of this significant reduction in overall batch record size, the amount of time and effort required to review and finalize a record once it is generated is greatly reduced. This results in time savings that can be passed onto the client.

A final advantage associated with the use of ready-to-use components is the reduction in risk that comes with the fact that unlike traditional systems where components are sterilized at the time of use, ready to use components have been processed and fully released well in advance of their use in a fill/finish process. This avoids the potential that a manufacturing defect (for example a failed autoclave cycle) could impact the finished drug product. In a scenario where autoclave and depyrogenation cycles are conducted as part of the overall manufacturing process of a batch of drug product, there is usually little or no time available to review equipment/process performance before components are introduced to the fill/finish process. In the case of pre-processed vials, stoppers, seals, and other sterile components, these materials will arrive at the fill/finish site after having undergone a rigorous release process. Thus, essentially eliminating the risk that a finished product batch could be subject to a failure related to the sterility of production components.

Conclusion:
The SA25 system represents a significant improvement over traditional manufacturing technology relative to generating concise and accurate batch documentation. The system relieves operators of much of the burden of routine data recording and allows personnel to focus on proper execution. Singota’s experience has confirmed that automation greatly reduces human error. Additionally, the implementation of ready-to-use components greatly reduces the volume of documentation that must be generated, simplifying and speeding up the review/approval of executed batch records. In the end, clients benefit from smaller batch records, automation, and ready-to-use components by using a CMO that values a streamlined manufacturing system that fulfills the goal of saving the client time and helping to get products downstream to the patient faster.
 
 

About the Author
Eric Smart

Eric Smart

Eric Smart is the Senior Advisor, Aseptic Manufacturing at Singota Solutions and President of Fountainhead Pharmaceutical Consulting. Prior to his current roles, he was President of Piramal Pharma Solutions’ aseptic manufacturing business based in Lexington, Kentucky. Eric earned his BS in Chemistry from Vanderbilt University and an MBA from the University of Maryland. After serving eight years as an officer in the United States Navy, he began a career that has spanned 24 years in the pharmaceutical contract manufacturing industry. Eric’s experience includes leadership roles in sales and marketing, operations, laboratory services and executive management at a number of contract development/manufacturing companies including roles at Albemarle, AlliedSignal/Honeywell, Organichem, AMRI and Coldstream Laboratories/Piramal Pharma Solution. Eric established Fountainhead Pharmaceutical Consulting which provides services to a wide variety of pharmaceutical, biotechnology and CMO companies in the areas of manufacturing operations, project management, vendor selection, and due diligence. Eric began working with Singota Solutions as an advisor when they installed and qualified a state-of-the-art automated sterile fill operation.