Integrating an HTST Skid to Prevent Biopharma Cell Culture Contamination
One of the most critical challenges of biopharmaceutical manufacturing is cell culture contamination prevention. Contamination of nutrients used to grow cells means scrapping the whole product and starting over, potentially costing the manufacturer millions of dollars.
Here’s how Matrix Technologies recently helped one of the world’s largest biopharmaceutical companies integrate a High Temperature Short Time (HTST) virus inactivation skid into existing cell culture operations for thermal treatment of media to reduce the possibility of contamination.
The Manufacturer’s Goal: Use an HTST Skid to Pasteurize Media
Media is a solution containing amino acids, vitamins, inorganic salts, glucose, and other vital ingredients essential for cell growth and protein formation. The media is transferred into the bioreactors where it is consumed by the cells.
Contaminated media causes cells to grow and behave abnormally, which ruins the product. Contamination usually happens before the media reaches the manufacturer’s plant.
A leading biopharmaceutical manufacturing company wanted to use an HTST skid for media pasteurization, to inactivate any viruses in the media that might cause contamination but without harming the media itself.
The manufacturer turned to the engineers of Matrix Technologies for the skid integration project. Matrix is a long-time system integration resource for this manufacturer, with in-depth knowledge of the manufacturer’s programming standards, systems, and documentation requirements from prior successful projects. Matrix also has extensive experience in all phases of biopharmaceutical manufacturing, including validation and HTST skid integration.
How an HTST Skid Works
An HTST skid has two heat exchangers. One heat exchanger heats anything flowing through it to a high temperature; the second heat exchanger cools it down. The media is heated up for a short time and then cooled.
Flow rate and temperatures are critical to the process. To prepare a skid for the manufacturing process, operators run water through the skid to condition it to achieve the desired flowrate and temperatures for heating and cooling the water. Once the skid is conditioned and the flow rate is right, operators switch from running water through the skid to media.
The process also involves hot water for injection (WFI) to flush the system and condition the skid and Clean in Place (CIP) and Steam in Place (SIP) cleaning capabilities.
Project Requirements & Challenges
For this project, this manufacturer’s system requirements included:
- Maintaining a flow rate of 80 LPM
- Heating the media from 40°C to 102°C in a single pass
- Maintaining temperature for a minimum time
- And cooling the media back to 40°C
This manufacturer has an established process that governs the planning and execution of system integration projects. Matrix engineers know the process, having worked with the customer for many years. Among the customer’s requirements are:
- Having Matrix engineers write the Functional Requirement Specifications (FRS) first and get the customer’s approval. This establishes the desired functionality and makes the subsequent programming phase much easier
- Using the customer’s development site. Matrix puts all code on the development site so the customer can do validation testing to make sure the system is running the way it should be
- Using the manufacturer’s existing Add-On Instructions (AOIs) and phase templates
A Crucial Component of Biopharmaceutical Manufacturing: Validation & Change Control
Validation is vital to biopharmaceutical manufacturing. Compliance with CFR 21 Part 11, a federal regulation that governs the process, requires far more documentation and testing than in other industries.
Integrators like Matrix that work closely with biopharmaceutical companies must have expert-level organization, validation, and documentation skills, plus extensive experience with the standards for Good Documentation Practices (GDP) and Good Manufacturing Practices (GMP). Pharmaceutical firms must be GMP-certified to meet federal production requirements.
Documentation is key: The FDA wants to be sure the drug manufacturing process matches the documentation. The manufacturer and integrator must document and test every change and provide explanations why changes are being made. FRS and Detailed Design Specifications (DDS) are gospel.
The Steps of Integration
Though project design was 90% complete at the project start, the HTST skid design was not finalized. Without complete skid design, automation and controls cannot be properly defined. Matrix collaborated with the skid supplier and the customer to finalize the skid design to meet the customer’s system requirements.
In addition to assisting with skid design, Matrix also planned the design of the controls, programmed the controls, developed the documentation and specifications for validation and testing, and went on site to the plant to help commission the skid and bring it up live.
Among the specific services Matrix provided were :
- Electrical design, including a new HTST power panel, new HTST PLC panel, updating existing system drawings, and coordinating with the skid vendor in their design and implementation of the HTST skid I/O panel, VFD panel, and pneumatic panel
- Control system, documentation, programming, testing, and implementation. Design included a new 1756-L72 ControlLogix PLC, a remote Ethernet I/O ring, and modifying the existing PCS
Project deliverables included:
- User Requirements Specification (URS)
- New HTST DDS
- New HTST SDS
- Updates to the manufacturer’s existing Upstream and Utilities FRS and DDS
- I/O List
- Loop Check Forms
- Trace Matrix
- Software FAT Documentation
- RSLogix 5000
- FactoryTalk View SE
- FactoryTalk Batch
- MiMic Simulation
- FactoryTalk Historian
Tips for Success
System integration projects for biopharmaceutical manufacturing, including using an HTST skid for cell culture contamination prevention, come with unique challenges. Here are some tips for success:
- Find an integrator with proven pharmaceutical experience who is proficient in all aspects of the manufacturing process. The integrator must be able to provide a variety of services from start to finish, from planning and panel design to installation. The integrator’s ability to organize and manage the complex validation and documentation needed for compliance with CFR 21 Part 11 is especially important
- Establish close collaboration between the integrator and manufacturer and do the documentation in phases, making sure the customer reviews and signs off at each step, especially on functional specifications
- If installing an HTST skid, get the integrator involved before skid design is complete to enable the integrator to properly develop controls.
- Select an integrator who knows and uses Good Documentation Practices (GDP)
Matrix Technologies is one of the largest independent process design, industrial automation engineering, and manufacturing operations management companies in North America, with decades of experience serving pharmaceutical manufacturers. To learn more about our systems integration expertise and services for biopharmaceutical manufacturing, contact Greg Pfleghaar, Senior Manager, Industrial Systems Division.
© Matrix Technologies, Inc.
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