Defining Quality In A Sponsor-Owned QTPP Before The CDMO Even Starts

By Devanshi Doshi and Sagi Nahum, CellVira

Most cell and gene therapy (CGT) sponsors working on CAR-T and other gene-modified products outsource lentiviral vector manufacturing to a CDMO. Developing in-house viral vector capacity requires significant capital investment, and a capable CDMO offers process expertise and infrastructure that many sponsors find hard to justify building themselves. However, this partnership is effective only if the sponsor has a clear written definition of what "quality" means for that particular product.

In practice, that question goes unanswered more often than it should. Sponsors adopt a CDMO's default testing panel without independently defining their own requirements. The CDMO, as the party running the process, fills that gap with its own internal standards. Neither side is acting improperly. It is simply what happens when nobody puts pen to paper first, and the consequences surface at the worst possible time: during batch release, at a pre-IND meeting, or when a regulator asks why the acceptance criteria were set as they were.

The tool that closes this gap is a sponsor-authored, version-controlled quality target product profile (QTPP): a prospective definition of quality, established before manufacturing begins and maintained as a living document throughout the program's development life cycle.

No Single Governing Guideline

The continued shift toward decentralized manufacturing has made establishing consistent quality expectations for lentiviral vector (LVV) products increasingly complex. When the same product is manufactured across multiple development and manufacturing sites, differences in CDMOs, manufacturing platforms, analytical methods, and local quality systems can lead to variability in how product quality is defined, controlled, and assessed. Each manufacturing site could present its own unique challenges for a sponsor that doesn't have a defined QTPP.

Recent work on quality management systems for decentralized CGT manufacturing has made clear that a centralized quality framework, including a master specification document that all sites are bound to follow, is a prerequisite for maintaining product comparability and regulatory alignment across a distributed network.^1,2 That framework must be built around the sponsor-owned QTPP.

What complicates QTPP development for LVV programs is that no single unified regulatory guideline provides a comprehensive template for developing an LVV-specific QTPP. The FDA and EMA approach the question from different frameworks; both apply to sponsors developing products for global registration, and the two are not fully aligned.

Under the FDA, the primary applicable reference is guidance on Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications,³ which organizes quality expectations through the Common Technical Document (CTD) Module 3 structure and defines what characterization is expected for an LVV drug substance at each clinical phase. It does not, however, mandate a QTPP as a discrete stand-alone document. The QTPP framework derived from ICH Q8(R2)⁴ defines it as "a prospective summary of the quality characteristics a drug product should possess in order to ensure the desired safety and efficacy."

ICH Q9(R1)⁵ supplies the risk management methodology for translating quality characteristics into critical quality attributes (CQAs) requiring active control, while ICH Q10⁶ governs the pharmaceutical quality system, including outsourced manufacturing relationships, and provides the accountability structure within which the QTPP and the CDMO relationship sit. Collectively, these documents provide a structured framework for developing and maintaining product quality throughout development, although none provides an LVV-specific QTPP template.

The EMA's approach is more prescriptive on structure and is grounded in an advanced therapy medicinal product (ATMP) specific regulatory classification. The Guideline on the Quality, Non-clinical and Clinical Aspects of Gene Therapy Medicinal Products (EMA/CAT/80183/2014)⁷ specifies quality requirements for gene therapy medicinal products (GTMPs), including vector characterization, drug substance specification structure, and the expectation that quality attributes are justified by development data.

More recently, the Guideline on Quality, Non-clinical and Clinical Requirements for Investigational ATMPs in Clinical Trials (EMA/CAT/22473/2025)⁸ applies the same framework to the investigational setting and reflects updated expectations for phase-appropriate quality documentation. EMA's approach links quality documentation obligations explicitly to the marketing authorization holder, placing ownership of the quality framework squarely on the sponsor.

Neither the FDA nor EMA specifies the right acceptance criterion for attributes such as infectious titer or how many logs of RCL (replication-competent lentivirus) sensitivity an assay must demonstrate. Those are product- and process-specific determinations. What both frameworks agree on is that someone must make those determinations, document the scientific rationale, and own the decisions. If the sponsor does not do that before the CDMO relationship begins, the CDMO will apply its own standards. The sponsor then inherits a specification it never independently evaluated, which may not fully reflect the sponsor’s intended product profile or future regulatory strategy.

For sponsors working across both regulatory jurisdictions, the QTPP cannot be built to satisfy one framework and treated as adequate for the other. It must be structured on the ICH Q8/Q9/Q10 foundation that both the FDA and EMA recognize, populated with characterization data and CQA determinations that meet both agencies' evidentiary expectations, and explicit about where the two frameworks diverge so those divergences are addressed proactively rather than discovered during parallel regulatory review.

What The QTPP Must Do

Given this dual framework reality, a sponsor-authored LVV QTPP needs to accomplish four things that a CDMO default testing panel cannot.

1. State a regulatory classification position explicitly

The classification of an LVV intended as CAR-T starting material, whether as an ancillary material, an intermediate, or a starting material under applicable FDA and EMA frameworks, carries different GMP obligations and characterization requirements. A QTPP that never addresses its own regulatory classification leaves that question to be answered implicitly by whichever draft of the submission is written first. The QTPP preamble should state the sponsor's classification position, the applicable regulatory basis, and what that classification implies for the GMP framework and required characterization scope.

2. Convert CQA determination into a documented, attribute-by attribute-exercise

Each candidate attribute, including appearance, pH, infectious titer, physical particle titer, p24 antigen, residual host cell DNA, residual plasmid DNA, host cell protein, RCL, sterility, mycoplasma, and endotoxin, should carry an explicit CQA designation, a stated scientific rationale, and citations to the guidance or methodology that supports the call. The specification framework for biological products is provided in ICH Q6B,⁹ which covers test procedures, acceptance criteria, reference standards, and analytical considerations.

For viral safety attributes including RCL, the governing documents are the FDA's Guidance for Retroviral Vector Based Gene Therapy Products¹⁰ and ICH Q5A(R2) on Viral Safety Evaluation from Cell Lines of Human or Animal Origin.¹¹ For potency, Guidance for Cellular and Gene Therapy Products¹² provides the framework for phase-appropriate approaches, including the use of surrogate endpoints when a validated quantitative potency assay does not yet exist. Published characterization data for clinical-scale LVV manufacturing provides useful context for calibrating initial attribute ranges where sponsor-specific data is limited.¹³

This level of documented specificity is what separates a QTPP that serves as a quality anchor from one that is merely a formality. A CDMO presented with clearly defined CQAs, supporting scientific rationale, and documented quality expectations is better positioned to understand where established platform knowledge is applicable and where product-specific development considerations require additional evaluation.

3. Handle uncertainty with discipline rather than avoidance

There is no universal LVV specification template, and industry roundtables have confirmed this specifically for cell and gene therapies.^14,15 Phase-appropriate practice means that safety-critical attributes, including RCL, sterility, and endotoxin, carry numerical limits from day one of clinical manufacturing. Others, such as osmolality and certain purity metrics, legitimately ride as "report result" items at early phases and receive specified limits as development evidence accumulates. The discipline ensures that every open item has a named owner and a target date for resolution.

4. Establish a reference standard strategy alongside the CQA table

Potency, identity, and certain purity attributes routinely reference "comparison to reference material" in a QTPP, but the document rarely addresses how that reference material is qualified, its requalification schedule, or the strategy for the first lot after it is exhausted. An LVV program runs for years through clinical development, and reference standard depletion mid-program creates an analytical continuity risk that is difficult to resolve retroactively. The WHO’s International Lentiviral Vector Reference Material¹⁶ provides an internationally recognized comparator for qualifying in-house standards, but that qualification exercise must be planned, resourced, and documented separately. Identifying potency as a CQA does not answer the question of what the sponsor is measuring potency against.

What The QTPP Does Not Cover

A completed QTPP is not a complete CMC package and should not be treated as one. Three gaps appear consistently even in well-constructed QTPPs, and each requires a separate document or exercise to close.

Upstream process parameters, including plasmid ratio, transfection conditions, and harvest timing, are not QTPP attributes. They are process inputs that produce the quality attributes described in the QTPP. Their characterization belongs in a parallel process of development and risk assessment. A sponsor that treats the QTPP as the full specification artifact has not addressed process characterization.

Similarly, integration site analysis, relevant to insertional oncogenesis risk, sits outside the scope of a vector-level QTPP entirely. It is assessed on the final gene modified cell product, not the vector lot, and requires its own drug product level documentation.

Likewise, stability program design requires more than a headline shelf-life claim. Defined testing intervals, stability-indicating methods, and a forced degradation strategy are each required to support a shelf-life statement and belong in dedicated stability documentation.

What Comes Next

A sponsor-owned QTPP built on the ICH Q8/Q9 framework, annotated to both FDA and EMA requirements, and populated with attribute-by-attribute CQA determinations carrying documented rationale transforms a CDMO relationship from a default acceptance risk into a structured technical collaboration. It establishes a common technical foundation for both sponsors and CDMOs.

Without a clearly defined QTPP, a quality agreement stating that "the sponsor retains oversight" is an aspiration. With it, oversight becomes a defined set of attributes, acceptance criteria, and CQA calls that both parties have reviewed and agreed to before the first batch runs. The second article in this series explores the next step: how a decision rights matrix translates the sponsor-defined QTPP into a practical governance framework that clearly assigns decision ownership, change authority, and quality responsibilities across the sponsor-CDMO relationship.

References:

1. Nahum S, Doshi D, Kosnik C, Jeffries E, Nishida K, Caplan V, von der Leyen H. From production to bedside: A tiered QC framework for regulatory alignment and analytical comparability in decentralized CGT. Regenerative Therapy. 2026;32. https://www.sciencedirect.com/science/article/pii/S2352320426000532
2. von der Leyen H, Delgado J, Mazouz C, Schmitt M, Caplan V. Implementation of a quality management system for decentralized manufacturing of cell and gene therapy products: technical and regulatory considerations. Frontiers in Medicine. 2025;12:1591751. https://doi.org/10.3389/fmed.2025.1591751
3. FDA. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). Guidance for Industry. January 2020. https://www.fda.gov/media/113760/download
4. ICH. Pharmaceutical Development Q8(R2). August 2009. https://www.fda.gov/media/71535/download
5. ICH. Quality Risk Management Q9(R1). January 2023. https://www.fda.gov/media/167721/download
6. ICH. Pharmaceutical Quality System Q10. June 2008. https://www.ema.europa.eu/en/ich q10 pharmaceutical quality system scientific guideline
7. EMA/CAT/80183/2014. Guideline on the Quality, Non clinical and Clinical Aspects of Gene Therapy Medicinal Products. March 2018. https://www.ema.europa.eu/en/quality preclinical clinical aspects gene therapy medicinal products scientific guideline
8. EMA/CAT/22473/2025. Guideline on Quality, Non clinical and Clinical Requirements for Investigational Advanced Therapy Medicinal Products in Clinical Trials. January 2025.  https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy-medicinal-products-clinical-trials_en.pdf
9. ICH. Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products Q6B. September 1999. https://www.ema.europa.eu/en/ich q6b specifications test procedures acceptance criteria biotechnological biological products scientific guideline
10. FDA. Testing of Retroviral Vector Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow up. Guidance for Industry. January 2020. https://www.fda.gov/media/113790/download
11. ICH. Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin Q5A(R2). January 2024. https://www.fda.gov/media/163115/download
12. FDA. Potency Tests for Cellular and Gene Therapy Products. Guidance for Industry. January 2011. https://www.fda.gov/media/79856/download
13. Perry C, Rayat ACME. Lentiviral Vector Bioprocessing. Viruses. 2021;13(2):268. https://doi.org/10.3390/v13020268
14. CASSS. Roundtable Discussion: CQA Risk Assessments for Cell and Gene Therapies. 2023. https://www.casss.org/docs/default source/cgtp/2023 roundtable notes/cqa risk assessments for cell and gene therapies.pdf
15. CASSS/WCBP. Setting Specifications on Limited Data, Clinically Relevant Specs, Next Generation Control Strategies. 2025. https://www.casss.org/docs/default source/wcbp/2025 roundtable notes/setting specifications on limited data clinically relevant specs next generation control strategies looking ahead to revision of ich q6b.pdf
16. WHO/NIBSC. Development of the First World Health Organization International Reference Preparation for Lentiviral Vectors. https://pmc.ncbi.nlm.nih.gov/articles/PMC5628571/

About The Authors:

Devanshi Doshi is a GMP Quality Control Manager at CellVira specializing in cell and gene therapy manufacturing, analytical development, and regulatory compliance. She has extensive experience in assay qualification, technology transfer, QC data review, and eQMS implementation within cGMP environments. Through her work across biotech organizations, she has helped establish robust QC frameworks, improve operational efficiency, and strengthen regulatory readiness for advanced therapies. She holds an M.S. in Biological Sciences from the Florida Institute of Technology and is dedicated to advancing scalable and compliant approaches for next-generation cell therapies.

Sagi Nahum, PhD, leads Global Analytical Sciences and CMC activities at CellVira, where he focuses on analytical solutions for cell and gene therapies in point-of-care settings, as well as the decentralized manufacturing of advanced cell and gene therapy products. Prior to joining CellVira, he led the Innovation Lab at Cognate BioServices, where he developed and validated high-throughput assays. He has been a member of ISO Technical Committee 276 (Biotechnology) and has authored or co-authored several publications in the fields of plant and human genetics, as well as biological assay development and technology transfer.

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