Five Best Practices to Adapt and Improve Quality Control Programs for CGTs

To launch a successful GMP program for biologics, a robust quality control (QC) release testing protocol is essential. QC testing, which is mandated by global regulatory authorities, helps ensure that a product meets scientific specifications and reaches patients safely. Though each program will have unique parameters, QC testing should gather data to answer the following questions:

  • Identity: Have you produced the correct product? 
  • Purity: What manufacturing and product byproducts are present? 
  • Strength: What is the potency and quantity of your product? 
  • Safety: Is your product safe and free of unwanted adventitious agents, e.g. Virus, bacteria, and mycoplasma? 
  • Product Quality Attributes: Have you demonstrated that product specific attributes are present? 

As biologics continue to diversify beyond monoclonal antibodies (mAbs) and recombinant proteins to include cell and gene therapies (CGTs), QC programs are shifting to accommodate the unique challenges associated with these advanced and novel therapeutics.

Recognizing Important Shifts

CGTs require adaptive and advanced assays for characterization and safety assessments; in many instances, the assays historically used for biologics do not fit the needs of these novel therapies. For example, mycoplasma has long been an area of key testing concern due to its ability to pass through standard sterilization filters. The standard mycoplasma culture-based assay takes 28 days to complete. This cycle is incompatible with the short shelf life of CGT products; as a result, the industry has pivoted to PCR testing for mycoplasma in CGTs, which can be completed in just a few days.

Empty/full ratios for viral vectors are another critical quality characteristic that has been challenging to characterize in the GMP setting thus far. To date, Analytical ultracentrifugation (AUC) has served as the best assessment of empty, full, and partial populations on the market, and as the identification of these ratios grows increasingly vital, AUC will continue to be an important implement for QC programs.

Several other considerations, including defining the critical quality attributes of raw materials and navigating evolving regulatory guidance, have left CGT developers and manufacturers looking for greater insight into how best to design their QC approach.

Identifying Five Best Practices for QC Programs

As you strive to design a strategic QC program, assess how you can leverage the following five best practices in your approach:

  1. Align to Your Risk Assessment:To mitigate risk, begin with a GMP mindset from the start, including sourcing well-characterized cell lines and raw materials while accounting for scale in your processes.
  2. Take a Quality by Design (QbD) Approach: Implementing QbD processes entails several deliberate choices, including ensuring you have the inventory necessary for your product lifecycle, creating a reference standard, and tracking trends as you set specifications.
  3. Leverage Templates and Platforms: Utilizing a templated or platformed approach helps you minimize variation in your process and establish streamlined validations, defined assay parameters, and a thorough understanding of each step.
  4. Gain Proximity to the Manufacturing Floor: The closer the QC lab’s proximity to the manufacturing floor, the better. The goal is to implement real-time, continuous testing in parallel with your manufacturing process.
  5. Participate in Knowledge Sharing: Disseminating key findings between stakeholders across the industry ― particularly around data, technology, and regulatory interactions ― yields major benefits for everyone, including patients.


Where Can I Learn More?

If you’d like more insight into improving your QC program, Dr. Audrey Chang, Executive Director at WuXi Advanced Therapies, recently hosted a webinar in which she highlighted the difficulties of developing QC programs for CGTs and her recommendations for how to improve them. You can watch the full webinar here or contact us to schedule a time to speak with her directly.


 [CD1]Link to be added once webinar summary is live.

6 Key Questions to Cover When Selecting Your Cell Banking Manufacturing Partner

The purpose of cell banking is to provide cells of a specific genetic and phenotypic profile for use in the production of disease therapies in adequate quantities for the lifespan of the therapeutic. Cell banks and cell lines used for pharmaceutical products are governed by regulatory agencies worldwide. 

Cell banks can be research cell banks (RCB), master cell banks (MCB), working cell banks (WCB), and end of production cell banks (EOPCB). Research cell banks are the result of extensive modification and selection processes that provide the seed stock for the MCB.

Expanding from RCB to MCB, and ultimately, to WCB involves a significant transition of growing cells under research conditions to growing cells using GMP-compliant processes. A large part of what changes during this transition is the extensive testing required to ensure genetic and phenotypic consistency, safety, purity, and functionality. In addition, when creating MCB and WCB especially, there needs to be proper documentation produced for support of regulatory requirements.

Choosing the right cell banking service provider is critical to the speed and success of the production of the therapeutic. Whether you are a small academic medical center provider or a large therapy developer or CDMO, here are six key questions you should be asking to help understand how well your needs will be addressed.

  1. Do they have experience with your cell type?

 It’s vital to choose a manufacturing partner that has demonstrated experience with your cell type and the growth and production targets you need to meet to support your program. Only a provider with prior experience will be able to knowledgeably assess their ability to deliver.

Common cell types used in cell banking include:

Human

Embryonic Retina (PER-C6)

Spleen

Kidney (MRC-5)

Neuroblastoma cells

Embryonic Kidney (HEK 293)

Umbilical cord

Murine

Hybridoma

Hybridoma Sp2/0

Myeloma (NSO)

Monkey

Africa Green Monkey (VERO)

Rhesus Monkey (LLC MK2)

Insect

Drosophila S2

Fall armyworm Sf9

Hamster

Ovary (CHO)

Canine

Kidney (MDCK)

Chicken

Embryo

2. What is the anticipated timeline and approach?  

Even the most robust cells and cell expansion protocols are subject to unknown pitfalls when transferring from provider to a manufacturing partner. Putting emphasis on the technical transfer of the cell bank expansion characteristics from the start will help avoid issues.

Make sure there is a clear and well documented understanding of the expected growth characteristics and a plan to test those before proceeding to the actual manufacturing runs. Minimally, the provider should be proposing that test runs be conducted for at least several passages, with cell counts and viability recorded at each passage.

The timeline for the pre-bank verification can vary, but it’s typically completed in approximately three weeks. Following that, MCB or WCB GMP production is typically three weeks. Two to six additional weeks are needed for testing and two to four weeks for document production should also be included in the timeline.

3. How will the partner manage in-process and release testing?

Understanding how your manufacturing partner will manage the testing of your cell bank during and after the production run is critical to ensure successful project execution. The timeline required for post-bank testing should be established early in the discussion with the provider.

Special attention should be given to the in-process testing as it’s vital to gauge the progress and health of the cells at each passage. The results may indicate a need to adjust expansion plan parameters.  At harvest and vialing there may be a need for quick turnaround of test results (STAT testing) to facilitate conditional release. Make sure your provider can perform STAT testing when needed.

Examples of the types of tests used for cell banking include:

  • Pre-Bank Sterility and Mycoplasma
  • Adventitious Viral Screening
  • Animal-derived Raw Material vVruses
  • Specific Virus Screening (Sf-rhabdovirus, Calicivirus, retroviruses, etc.)
  • Cell Morphology
  • Post-Bank Viability and Usability
  • Post-Bank Sterility and Mycoplasma
  • Cell Line Identification
  • Stability Testing

4. Is the testing done in-house or outsourced?

Find out if your provider will outsource the testing or if they have integrated testing capabilities. In-house testing alleviates the need to ship samples to a secondary site.  This will significantly impact the turnaround time for results and can also influence the number of vials needed for testing.

Your provider should be willing and able to advise you on the appropriate release tests for MCBs, WCBs, EOBCs, and genetic testing for stability studies. Their testing services need to include STAT testing, conditional release, pre- and post-bank testing, all within a proven and robust quality system.  

5. What is the provider’s approach to materials management?

An often-overlooked aspect of cell banking projects is materials management.

Finding a manufacturing partner who can quickly develop the Bill of Materials (BOM) and source the media, media additives, specific culture containers, and culture systems will help avoid delays.  

You may have to consider alternative materials, so choose a cell banking partner that can help suggest, source, and test the new components. It’s important to be sure that your provider has extensive experience in materials management for all types of cell banking and be willing to collaborate with you to quickly obtain and test alternative components.

6. Can the provider analyze for phenotypic / genetic drift?

Phenotypic and genetic drift is a potential risk in cell banking and ensuring that this has not happened should be part of the process. Make sure your provider has knowledge of the appropriate methods to access morphological and genetic changes. These can include microscopic evaluation, short tandem repeat profiling, growth curve comparisons, and testing for mycoplasma presence.

In conclusion, careful consideration of your cell banking service provider is critical to the success and speed of your journey from discovery to commercial manufacturing.  The ideal cell banking service provider has experience with the cell types, systems, and testing needed for your project. Importantly, those services and capabilities should also be part of an integrated development, GMP production, and testing workflow.

WuXi Advanced Therapies has been providing cell banking services, testing, and regulatory support for over 20 years. We can support your cell banking needs at any point in the journey from discovery to commercial production. Our teams also have extensive capabilities and experience in gene therapy and cell therapy processes, furthering our understanding of cell bank use. We conduct all manufacturing and testing from our state-of-the art facilities in Philadelphia, PA. Get in touch today to discuss your cell banking requirements.  

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