News & Insights
As the cell therapy sector continues to mature, regulatory expectations are rising. Deviation and change control management are now table stakes, and failed pre-approval inspection (PAI) findings at third-party manufacturing sites have resulted in time-intensive and costly delays in reaching the market. Given the stakes, PAI readiness can’t be last-minute paperwork or a war room exercise; it has to be embedded in the way a cell therapy manufacturing organization operates. To better understand the common causes of PAI setbacks and how to build an organization-wide culture that avoids them, we spent some time with Melodie Bryce, Vice President and Global Head of Quality at Kincell Bio.
Top Approval Delaying PAI Challenges
Roughly three-quarters of Complete Response Letters (CLRs) issued from 2020 to 2024 are attributed to quality or manufacturing deficiencies, process control gaps, thin stability packages, unvalidated methods, or findings from GMP inspections. “However, the good news is that these issues are avoidable within cell therapy manufacturing organizations that deeply embed PAI readiness into their organization’s culture,” shared Bryce.
The following are the most common drivers of cell therapy PAI setbacks, but with a proactive approach, these issues can be addressed before they become problems, putting programs in a much greater state of control.
Potency strategy not aligned to the mechanism of action
Cell therapies rarely have a single, definitive measure of potency. The FDA expects an evidence-based potency assurance strategy that reflects the mechanism of action (MoA), uses qualified/validated methods, and includes clear lot release criteria.
Insufficient comparability data after process, site, or scale changes
Because cell therapy programs, platforms, and suppliers tend to evolve rapidly, the FDA now places strong emphasis on comparability, including thoroughly defining critical quality attributes (CQAs), justifying analytical methods and specifications, and presenting bridging data when changes are made to equipment, raw materials, process unit operations, scale, or facilities.
Aseptic processing and contamination control gaps
Cell therapies are aseptically produced, so inspectors examine media fills, environmental monitoring, sterilization practices, and the robustness of closed systems. Inadequate contamination control strategies or poorly executed aseptic procedures routinely trigger observations. The FDA aseptic processing guidance and the EU’s Annex 1 revision set clear expectations for risk-based contamination control strategies.
Chain of identity (CoI), chain of custody (CoC), and data integrity
End-to-end traceability, from donor/patient through collection, manufacturing, testing, storage, and clinical administration, must be well constructed. Inspectors often focus on documentation that proves the right product reaches the right patient, as well as controls that ensure records are complete and accurate.
Starting material and raw material control
Programs stumble when donor eligibility, cell bank characterization, or qualification of critical or ancillary materials is incomplete, single-sourced without mitigation, or poorly documented. FDA details expectations for donor screening, cell-bank testing, and material qualification; USP <1043> complements this with best practices for ancillary materials used in cell and gene therapy manufacturing.
Insufficient method readiness and validation planning
Phase-appropriate doesn’t mean insufficient. By BLA filing, the FDA expects validated methods for release, stability, and in-process controls, as well as evidence of system suitability and robustness.
Needed Flexibility Doesn’t Negate Commitment to Quality
Unlike conventional biologics, cell therapies are living products with inherent variability. Batch health can shift substantially depending on donor biology, cell-specific attributes, and the manner of bedside handling. This means that the more concrete playbooks from more uniform processes, such as monoclonal antibody (mAb) manufacturing, don’t always directly apply to cell therapy manufacturing.
According to Bryce, “Teams must plan for ambiguity, write explicit ‘call points’ into batch records, and define decision trees that direct what to do when a given quality characteristic, like viability, is below the established threshold. You have to be able to live in the gray compliantly without letting the gray become an excuse.”
Phase-appropriate does not mean flimsy
Early-phase studies do allow for flexibility. For example, methods may be qualified rather than validated, and limits may be set based on fit-for-intended-use data; however, “phase-appropriate” can never mean undocumented, ad hoc, or non-reproducible. Kincell adopts a phase-appropriate approach, ensuring the necessary flexibility for early-phase programs while preparing for success as a program matures. If a given approach won’t hold up to inspection or help a sponsor defend CMC decisions in later filings, it isn’t good enough in the early phases. This mindset helps avoid the pitfalls of speed today and the expense of time-consuming, costly comparability work later.
Kincell Bio Builds PAI Readiness by Design
Kincell operationalizes PAI readiness as an integrated, end-to-end system, built by the entire organization from hands-on operators to members of the executive leadership team. The approach is intentional, systematic, and lived every day. Rather than relying on last-minute preparation, Kincell embeds regulatory alignment, operational discipline, and cultural accountability into every process, creating an organization where inspection-grade performance is the standard for how all work is conducted.
The following are some of the central elements that enable Kincell’s PAI ready everyday operational approach.
1) Mapping quality
Kincell maintains a live regulatory matrix that links each applicable requirement to a clear policy and an executable standard operating procedure. This approach forces the entire team to identify gaps within procedures and policies. When a gap is identified, it is noted, ranked by risk, and assigned to and addressed by accountable team members.
2) Quality procedures that account for variability
Policies and procedures are written with predefined gates and call points, allowing operators to pause, escalate, or proceed confidently when real-world variability arises. This prevents avoidable deviations and turns nebulous situations into controlled ones.
3) Account for open manipulations
Closed processing is utilized wherever possible. However, open manipulations are sometimes essential, so controls must be well-defined, operators well-trained, and regular internal auditing must be conducted.
4) Every day is audit day
From top to bottom, the Kincell Bio team conducts itself as if an audit will happen on any given day. In other words, operational behavior remains the same on audit days and non-audit days.
“Being audit-ready every day means living quality, not just documenting it. We continually measure ourselves against regulations from the FDA and leading global regulators to ensure that every policy and procedure meets the standards required for inspection. It’s not a scramble for PAI; it’s a mindset of accountability, transparency, and doing the right thing even when no one’s watching,” shared Bryce.
5) Investigate with the knowledge that patients’ lives are on the line
Deviations trigger root cause investigations led by the people closest to the work and coached by highly experienced quality assurance executives within the Kincell organization. When deviations do occur, our team well understands that patients’ health and well-being are at stake. This knowledge and culture foster the openness necessary to quickly identify, understand, and address problems when they arise.
6) Quality excellence comes from within
Kincell’s PAI readiness work is primarily conducted by full-time team members, many of whom are closely involved in day-to-day operations. We support our teams with external experts when necessary, but our internal team members are the primary architects of all our policies and procedures. This builds ownership and makes new ways of working durable.
“It isn’t a top-down paper exercise or approaches developed by external consultants,” Bryce notes. “The people who do the work help develop how the work is done, building a culture of ownership and accountability.”
7) Servant leadership
Quality issues across the cell therapy sector often stem from leadership turnover, limited experience in cell therapy, and weak accountability. Kincell addresses this head-on with a culture of servant leadership and well-defined standards. Managers roll up sleeves, assess strengths and gaps, and coach to outcomes.
PAI Readiness Is Who We Are
Because we are driven by assuring the success of our clients’ cell therapy products in the market, PAI readiness isn’t a project milestone for Kincell Bio; it’s the foundation of how we operate every day. Every regulation is directly mapped to a documented policy and procedure, creating a transparent and auditable chain that sponsors can trust. Batch records include clear call points that guide real-time decision-making, reducing deviations and strengthening consistency across variable cell therapies. Our manufacturing strategy prioritizes closed systems and disciplined aseptic technique, while data integrity and change control are embedded from day one.
Featured SME
Melodie Bryce
VP, Global Head of Quality
With nearly three decades in the biopharmaceutical industry, Melodie Bryce brings deep, hands-on expertise in quality, manufacturing, and supply chain leadership. Before joining Kincell Bio as the Global Head of Quality, she directed quality operations for both cell therapy and monoclonal antibody programs at KBI Biopharma. Earlier roles at Bayer, Talecris, and Grifols laid the foundation for her work in large-scale biologics manufacturing, while her roles at Matica Biotechnology and Cognate Biotherapeutics demonstrated her ability to implement robust quality systems and prepare facilities for regulatory inspection readiness. Melodie earned her B.S. from North Carolina Wesleyan University.
