Comprehensive AAV Gene Therapy CMC Services
SMAT Consultants provides comprehensive, phase-appropriate CMC support for AAV-based gene therapies. Our services span vector design optimization, CMC-driven facility design and equipment strategy, manufacturing and process development (AAV and plasmid), analytical characterization, regulatory and quality strategy, vendor management, and technology transfer.
For investors and strategic partners, we provide technical due diligence, manufacturing feasibility assessment, and COGS analysis for AAV programs.
We combine deep scientific expertise with practical business acumen to accelerate programs from IND enabling through commercial readiness while managing risk, timelines, budgets, and regulatory requirements..
WHY CHOOSE SMAT CONSULTANTS?
Technical Depth
PhD in AAV vector optimization with 25+ years hands-on experience. We don't just provide strategy—we solve actual technical problems.
Proven Track Record
7-fold yield improvements delivered
Multiple successful regulatory submissions
3 patents in AAV manufacturing innovation
80%+ purity improvements achieved
Business Understanding
Former CTO strategic responsibilities. We understand timelines, budgets, and business implications of CMC decisions.
Industry Network
Extensive relationships across CDMOs, CROs, vendors, and service providers. We help you find the right partners.
Regulatory Experience
Extensive experience developing regulatory strategy for FDA and EMA submissions through IND preparation. Close collaboration with regulatory affairs teams and agency interactions. We know what regulators expect.
Flexible Engagement
From hourly consulting to comprehensive program support. We adapt to your needs and budget.
VECTOR DESIGN & OPTIMIZATION
AAV Vector Engineering
Optimize your vector design for both performance and manufacturability — the two don't always align naturally.
Vector Design Services:
Capsid selection and serotype optimization for target tissue
ITR design considerations (single-strand vs. self-complementary)
Terminal resolution site (TRS) modifications for scAAV
D-sequence identification and functionality
Promoter selection and expression cassette optimization
Payload capacity assessment and optimization
Codon optimization strategies
Transgene stability evaluation
Regulatory strategy for novel vector design modifications and comparability assessments
Manufacturability Assessment:
Production efficiency of different capsid variants
Plasmid design for optimal AAV yields
Helper virus considerations (if applicable)
Empty capsid propensity of different constructs
Scale-up considerations
Recent Specialized Work:
ITR modifications for self-complementary AAV production
Analysis of TRS deletion impacts on packaging and transduction
Optimization of expression cassettes for difficult-to-manufacture payloads
Evaluation of novel capsid variants for manufacturing feasibility.
Cell Line Development
Generate stable, high-yielding cell lines as well as producer and packaging cell lines for reproducible AAV manufacturing.
Cell Line Development Services:
Stable producer cell line generation (AAV + transgene)
Packaging cell line development (capsid + Rep)
Multi-plasmid stable integration strategies
Clonal selection and screening protocols
Cell line characterization and genetic stability
Master cell bank (MCB) generation and qualification
Working cell bank (WCB) development
Regulatory documentation for cell banks
Platform Experience:
HEK293-based systems
SF9/baculovirus platforms
Alternative mammalian cell lines
Suspension vs. adherent systems
Regulatory considerations for each platform
Advantages of Stable Cell Lines:
Improved batch-to-batch consistency
Reduced raw material costs (no transfection reagents)
Enhanced scalability for commercial production
Better process control and reduced variability
Typical Timeline:
Cell line generation and screening: 3-6 months
MCB generation and testing: 2-3 months
Process development with new line: 4-6 months
Integrated Vector Development:
Successful AAV vector development requires coordinated optimization of both vector design and production cell systems. Our comprehensive approach ensures that design improvements translate to robust, scalable manufacturing processes, reducing development timelines and accelerating your path to clinical trials.
FACILITY & EQUIPMENT
R&D Laboratory Design
Design R&D laboratory configurations optimized for AAV process development workflows and analytical testing requirements.
Laboratory Planning:
Process development lab design
Analytical lab configuration
BSL-2 containment requirements
Small-scale manufacturing capabilities
Cold storage and sample management
Equipment Selection & Budgeting:
Capital equipment prioritization
Vendor evaluation
Cost-effective alternatives
Lease vs. purchase analysis
Shared resource strategies
Workflow Optimization:
Laboratory layout for efficiency
Sample flow and logistics
Equipment utilization planning
Staffing requirements
Safety & Compliance:
Biosafety cabinet placement
Chemical storage and handling
Waste management systems
Emergency procedures
Lab Infrastructure & Utilities:
Laboratory benches and workstation design
Fume hood placement and specifications
Electrical requirements for equipment
Compressed gas distribution systems
Vacuum systems and waste management
Data infrastructure (LIMS, network connectivity)
Temperature and humidity control requirements
Regulatory Compliance for R&D Labs:
Electronic lab notebook (ELN) strategy
Method transfer readiness
Tech transfer documentation preparation
GMP Manufacturing Facility Design
Design manufacturing facilities from a CMC and process perspective, optimizing equipment selection, cleanroom layout, material flow, and utility requirements for AAV production efficiency, scalability and GMP compliance..
Facility Design Services:
Manufacturing suite layout optimized for AAV workflowsCleanroom classification strategy (production and fill/finish operations)Equipment placement for process efficiency and GMP compliancePersonnel and material flow design (dirty/clean transitions, gowning areas)Differential pressure cascade designContamination control and cross-contamination preventionBiosafety cabinet and isolator placement considerationsAccess control and airlocks design
Equipment Selection:
Bioreactor specification and selection
Chromatography systems (process-scale)
TFF/UF systems
Filtration equipment
Automated liquid handling
Analytical instrumentation
Fill-finish equipment (semi-automated BSC/isolator vs. fully automated)
Vendor evaluation and comparison
Utility Requirements & Specifications:
Water for injection (WFI) systems
Clean steam
Clean compressed gases
HVAC and environmental controls
Monitoring and alarm systems
Power requirements assessment and electrical distribution
Cooling water systems and capacity planning
Gas supply systems (nitrogen, CO2, O2, compressed air)
Emergency backup and redundancy systems
AAV-Specific Considerations:
Specialized facility design requirements for AAV manufacturing that address unique material compatibility, contamination control, and biosafety needs.
Material compatibility with oxidizing disinfection agents
Contamination control strategy for viral vector production
Cleanroom classification requirements (ISO 5/7/8) for drug substance and drug product operations
Equipment selection for cell culture, purification, and fill-finish
Scale-appropriate equipment sizing (bench to commercial)
Biosafety containment design (BSL-2 requirements)
Documentation & Validation Strategy:
Comprehensive documentation frameworks supporting facility qualification, cleaning validation, and GMP compliance.
User requirement specifications for manufacturing equipment
Cleaning validation strategy and protocol design
Cross-contamination risk assessment
Facility qualification planning (DQ/IQ/OQ)
Environmental monitoring program design
SOP Strategy & GMP Operations:
Comprehensive SOP framework development for compliant manufacturing operations across equipment, cleaning, environmental monitoring, and quality procedures.
Standard operating procedure framework for manufacturing operations
Standard operation and maintenance procedures
Cleaning and sanitization protocols (routine and campaign-based)
Environmental monitoring procedures
Batch record review and release procedures
Deviation and CAPA investigation protocols
Change control procedures
Personnel training and qualification programs
Gowning and facility access procedures
Compliance & Risk Assessment:
Proactive evaluation of facility design against GMP requirements with risk-based approaches to contamination control and environmental monitoring.
GMP compliance evaluation for facility design
Cleaning validation strategy
Cross-contamination risk assessment
Environmental monitoring program design
Facility qualification roadmap
Regulatory Considerations:
Strategic alignment of facility design with FDA expectations and regulatory requirements for viral vector manufacturing.
Data integrity requirements (21 CFR Part 11)
Equipment calibration and maintenance programs
FDA facility expectations
Environmental monitoring programs
Cleaning validation strategy
Computer system validation (CSV)
AAV & Plasmid Expertise
Plasmid DNA
Plasmid Design:
Plasmid redesign and optimization for improved AAV production yields
Regulatory strategy for plasmid system selection
Antibiotic resistance marker selection
Plasmid stability assessment and improvement
Vendor coordination for plasmid production implementation
GMP Manufacturing:
Bacterial strain selection and recommendations (advanced strains for improved performance)
Fermentation process optimization and technology evaluation
Purification method review and improvement recommendations
Endotoxin and RNA removal strategy optimization
Regulatory-grade documentation guidance
Plasmid Banking:
Master cell bank generation strategy and coordination
Working cell bank qualification protocols
Stability and quality testing program design
Regulatory documentation requirements
Plasmid Quality & Analytics:
Identity testing strategy (restriction mapping, sequencing)
Purity assessment protocols (endotoxin, RNA, chromosomal DNA)
Structural integrity analysis methods
Stability testing program design
Release testing specifications
Adeno-Associated Viruses (AAV)
Natural Serotypes:
AAV1-9 with serotype-specific process knowledge
Understanding of serotype differences in manufacturing and purification
Experience with both easy (i.e. AAV2, AAV8) and challenging (i.e. AAV5, AAV7, AAV9) serotypes
Serotype selection strategy for target tissue and clinical application
Manufacturability assessment for serotype-specific process development
Engineered Variants:
Rationally designed capsids
Directed evolution-derived variants
Hybrid capsids
Manufacturability assessment of novel capsids
Genome Configurations:
Single-strand AAV (ssAAV)
Self-complementary AAV (scAAV) with ITR optimization
Understanding of impacts on manufacturing and analytics
Genome size optimization for packaging efficiency
Regulatory elements selection and positioning strategy
Production Platforms:
Transient transfection (HEK293, other mammalian cells)
Baculovirus/Sf9 systems
Herpes simplex virus (HSV) helper systems
Stable producer cell lines
Platform selection guidance
Our Expertise:
Deep understanding of plasmid DNA production systems and AAV manufacturing across multiple serotypes and platforms, with hands-on experience optimizing vector designs, manufacturing processes, and analytical methods for improved performance and regulatory compliance
Investment Due Diligence & Technical Assessment
For Investors & Partners
Make informed investment and business develop-ment decisions with comprehensive technical evaluation of AAV manufacturing programs. We provide objective, expert analysis to help you under-stand opportunities, identify risks, and benchmark against industry best practices.
Our Due Diligence Services:
Pre-acquisition technical assessment of AAV drug candidates and programs
Manufacturing feasibility and scalability analysis
CMC risk identification and mitigation recommendations
Competitive landscape analysis and technology positioning
COGS modeling and manufacturing strategy for commercial scalce
Portfolio company CMC assessment and optimization
Technology platform evaluation (baculovirus, HEK293, stable cells, purification strategy)
Regulatory pathway assessment and timeline projections
Comparability strategy evaluation for process changes
Supply chain risk analysis and mitigation strategies
Value to Investors:
Identify technical red flags before they become expensive problems
Understand realistic manufacturing costs and scalability challenges
Benchmark against industry standards and best practices
Receive actionable recommendations for portfolio company improvements
Typical Deliverables:
Comprehensive technical assessment reports
Risk matrices with prioritized mitigation strategies
Comparative COGS analysis vs. industry benchmarks
Manufacturing timeline and capital requirement projections
For Biotech Companies
We also provide strategic CMC planning and cost optimization services to help you make informed decisions about manufacturing strategy, CDMO selection, and resource allocation.
Cost Optimization Services:
Detailed process economics modeling
CDMO cost benchmarking across multiple vendors
Manufacturing yield optimization strategies
Unit operation cost analysis (upstream, downstream, fill-finish)
Scale-up planning and capital requirements
Raw material cost reduction initiatives
Technology selection for cost-effective production
Typical Cost Reduction Opportunities:
30-50% through process optimization and yield improvement
20-40% through strategic CDMO selection
15-30% through fill-finish strategy optimization
10-25% through improved analytical testing strategy
Analysis Includes:
Cost per batch at different scales
Cost per dose based on dose requirements
Sensitivity analysis (yield, purity, titer impacts)
Comparison of production platforms
Capital vs. operating expense trade-offs
When You Need This:
Preparing Series fundraising with manufacturing projections
Commercial planning and pricing strategy
Evaluating manufacturing strategy alternatives
Portfolio prioritization decisions
Pre-partnering cost disclosure
Integrated Approach:
Effective CMC strategy requires both proactive planning and responsive implementation support. Our approach combines strategic roadmap development with hands-on guidance during execution, ensuring your program maintains regulatory compliance while meeting aggressive timelines. Whether you need comprehensive program oversight or targeted support for specific challenges, we provide the expertise to keep your AAV gene therapy development on track.
PROCESS DEVELOPMENT AND MANUFACTURING
Upstream Process Development
Maximize viral vector productivity through systematic optimization of cell culture and production conditions.
Transfection Optimization:
Method comparison (PEI, calcium phosphate, lipid-based)
Transfection reagent screening and optimization
DNA-reagent complex formation protocols
Plasmid ratio optimization
Timing and feeding strategies
Scale-up from small scale to manufacturing
Cell Culture Optimization:
Cell density at transfection
Media selection and optimization
Feed strategies (batch, fed-batch, perfusion)
Harvest timing based on productivity and quality
Viral vector aggregation prevention
Production Platform Selection:
Transient transfection systems (HEK293)
Baculovirus/SF9 systems
Stable producer cell lines
HSV helper systems
Platform comparison for your specific vector
Media optimization and raw material sourcing strategies
Productivity Enhancement:
Yield optimization (strategies achieving 5-10 fold improve-ments)
Process parameter screening (DoE approaches)
Critical process parameter (CPP) identification
Process monitoring and control strategies
Scale-Up Support:
Ambr15 and Ambr 250 systems
Shake flask to stirred tank bioreactor
Small scale (1-10L) to pilot scale (50-200L) to commercial scale (>500L)
Equipment selection and specification
Technology transfer protocols
Downstream Purification & Empty Capsid Separation
Develop robust, scalable purification methods that meet regulatory specifications for full capsid content.
Clarification:
Depth filtration optimization
Flocculation pretreatment
Filter sizing and selection
Fouling mitigation strategies
Benzonase treatment optimization
Centrifugation alternatives
Primary Purification:
Affinity chromatography (POROS CaptureSelect, AVB Sepharose)
Monolith chromatography evaluation
Heparin chromatography
Platform method development for multiple serotypes
Empty/Partial/Full Capsid Separation:
Ion exchange chromatography (Capto Q, Capto Q ImpRes, other AEX resins)
Ion exchange gradient optimization
Ultracentrifugation (CsCl, iodixanol alternatives)
Combination strategies for challenging serotypes or high purity requirements
Analytical method development for monitoring (AUC, AEX-HPLC)
Polishing & Concentration:
Tangential flow filtration (TFF) / ultrafiltration
Size exclusion chromatography
Buffer exchange optimization
Concentration factor optimization
Aggregate removal
Viral Clearance:
Evaluation of clearance by individual purification steps
Nanofiltration evaluation
Clearance study design
Platform Advantages:
Identified scalable methods applicable to multiple serotypes
Experience with regulatory expectations (FDA and EMA)
Cost optimization without compromising quality
Tech transfer-ready protocols
Formulation & Fill-Finish
Ensure your final drug product is stable, safe, and suitable for administration.
Formulation Development:
Excipient selection and optimization
pH and ionic strength optimization
Surfactant evaluation (Pluronic F68, polysorbate 20/80)
Cryoprotectant screening
Stability enhancement strategies
Freeze-thaw study design
Long-term and accelerated stability programs
Buffer system selection and optimization
Osmolality and tonicity adjustments for administration route
Container/Closure & Device Compatibility:
Syringe compatibility studies
Vial material evaluation (glass types, plastic)
Stopper and seal compatibility
Extractables/leachables studies
Administration device compatibility
Storage container optimization
Fill-Finish Process Development:
Aseptic filling process development
Fill volume and overfill optimization
Sterile filtration (0.2 µm) strategies
In-process and release testing
Visual inspection criteria
Container closure integrity testing
Disinfection strategy development (routine and post-spill protocols for aseptic operations)
Cold Chain & Distribution:
Shipping validation studies
Temperature excursion studies
Packaging design
Global distribution planning
Stability-indicating method development
Regulatory Expertise:
Deep understanding of evolving regulatory requirements and analytical method expectations including:
Empty and partial capsid quantification requirements
Transition from traditional to advanced analytical methods (qPCR to ddPCR, SDS-PAGE to CE-SDS, etc.)
NGS for identity and sequence verification, as well as for heterogeneity assessment
FDA and EMA expectations for method validation and specifications
Emerging guidances on vector quality attributes
ANALYTICAL DEVELOPMENT & CHARACTERIZATION
Vector Characterization Methods
Design robust, regulatory-compliant analytical methods for comprehensive AAV characterization.
Titer & Concentration Methods:
Digital droplet PCR (ddPCR) for absolute quantification
Capsid ELISA (total capsid concentration)
Optical density (A260/A280) methods
Method comparison and correlation studies
Empty/Full Capsid Ratio:
Analytical ultracentrifugation (AUC)
AEX-HPLC (analytical ion exchange)
Charge detection mass spectrometry (CDMS)
Transmission electron microscopy (TEM)
Capsid Protein Analysis:
LC-MS/MS for VP ratio (VP1:VP2:VP3)
Post-translational modification characterization
Capillary Western Blot (Capsid protein identity confirmation and correct ratio)
Vector Purity Analysis:
Empty/partial/full capsid evaluation
Aggregate analysis (SEC-HPLC, DLS)
Potency & Infectivity Assays
Establish meaningful potency assay strategies that correlate with clinical efficacy.
Potency Assay Development:
In vitro transduction assays (cell-based)
qPCR-based transgene expression quantification
Functional protein assays (if applicable)
Reporter gene systems
Dose-response curve generation
Method qualification and validation
Infectivity Assessment:
Infectious titer determination
Cell-based infectivity assays
Comparison to physical titer (full-to-infectious ratio)
Impact of empty capsids on infectivity measurements
Method Validation:
ICH Q2 validation parameters
Specificity, linearity, accuracy, precision
Range and robustness
Stability-indicating capability
Method transfer to CROs
Regulatory Alignment:
Ensuring potency assays meet regulatory expectations and provide meaningful characterization of your product.
Impurity & Safety Testing Strategy
Comprehensive testing strategy to ensure product safety and regulatory compliance.
Process-Related Impurities:
Plasmid and host cell DNA quatification
Residual transfection reagent detection (PEI, calcium phosphate)
Serum components (if applicable)
Benzonase and other enzymes
Aggregation and particle analysis strategies
Safety Testing:
Sterility
Endotoxin (LAL/recombinant Factor C)
Mycoplasma
Adventitious agents testing approaches
Replication-competent AAV (rcAAV)
Residual helper virus (if applicable)
Advanced Characterization:
Next-generation sequencing (NGS) for genomic integrity
Packaged DNA analysis
ITR integrity assessment
Genome truncations and deletions
Critical quality attribute (CQA) identification and testing strategy
Comprehensive Analytical Strategy:
Robust analytical development requires integrated characterization, potency assessment, and impurity testing strategies that support both process development and regulatory submissions. Our approach ensures analytical methods are fit for purpose across development stages, from early characterization through commercial release testing, while meeting evolving regulatory expectations for AAV products.
REGULATORY & QUALITY STRATEGY
IND & BLA CMC Support
Expert guidance and documentation support for successful regulatory submissions.
IND Preparation (Module 3 - Quality):
Drug substance manufacturing description
Drug product manufacturing and controls
Control of materials and reagents
Analytical methods and validation summaries
Stability data and strategy
Nonclinical and clinical material CMC documentation strategy
Container closure systems
Manufacturing facility information
Quality control testing strategy
BLA/MAA Support:
Expanded manufacturing description
Process validation documentation
Commercial manufacturing strategy
Comprehensive analytical validation
Stability commitment fulfillment
Comparability protocols and studies
Regulatory Strategy:
Phase-appropriate development planning
Risk-based approach to testing and controls
Comparability strategy across process changes
Specification setting rationale
Stability testing program design
Prior knowledge and platform technology documentation strategies
FDA/EMA Interactions:
Pre-IND meeting preparation
Type B and C meeting support
Response to regulatory queries and information requests
CMC deficiency response
Manufacturing change notifications
Quality Systems & GMP Compliance
Design robust quality systems strategies that ensure consistent product quality and regulatory compliance.
CMC Technical Support
CMC technical review support for batch records, investigations, and deviation assessments
CMC subject matter expert support for regulatory meetings and submissions
CMC technical assessment of manufacturing changes and comparability evaluations
GMP Strategy & Framework Design:
Manufacturing quality systems design
Batch record development
Deviation management procedures
CAPA (Corrective and Preventive Action) systems
Change control processes
Training programs
Quality Control:
Release testing strategy
In-process testing program
Stability testing protocols
Out-of-specification (OOS) investigations
Trending and continuous monitoring
Quality Assurance:
Quality agreements (with CDMOs, CROs)
Vendor qualification
Audit program design and CMC technical support for vendor qualification audits
Document control systems
Quality metrics and KPIs
Regulatory Compliance:
GMP compliance assessment
Warning letter and 483 response support
Regulatory filing quality review
Experience:
Prepared CMC sections for multiple successful IND submissions and contributed to BLA preparation strategies. Direct experience supporting responses to FDA queries and navigating regulatory expectations. Extensive quality systems consulting including GMP compliance assessments, CAPA and deviation management framework design, and manufacturing site evaluations for both biotech companies and CDMOs. Supported audit preparation and quality agreement development.
VENDOR MANAGEMENT & TECH TRANSFER
CDMO Selection & Management
Find the right manufacturing partner and ensure successful collaboration.
CDMO Selection:
Capability assessment across multiple CDMOs
Technical and quality audits
Capacity and timeline evaluation
Cost comparison and negotiation support
Technology platform alignment
Quality system assessment
Track record and references
Selection Criteria:
AAV manufacturing experience and track record
Serotype-specific expertise
Scale capability (clinical to commercial)
Analytical capabilities
Regulatory compliance history
Geographic considerations
Financial stability
Contract Negotiation Support:
Technical scope definition
Quality agreement terms
Intellectual property provisions
Technology transfer responsibilities
Cost structure and payment terms
Timeline commitments
Ongoing CDMO Oversight Support:
Project oversight and communication
Technical problem solving
Quality review and trending
Change control coordination
Performance metrics tracking
Value Delivered:
Save time in CDMO selection through systematic evaluation. Avoid costly mistakes from choosing wrong partner.
Technology Transfer
Ensure smooth, efficient transfer of manufacturing processes to CDMOs and internal facilities.
Tech Transfer Strategy:
Transfer protocol development
Critical parameter identification
Acceptance criteria definition
Risk assessment
Timeline and resource planning
Transfer Implementation Guidance:
Knowledge transfer session facilitation
Manufacturing demonstration run support and observation
Troubleshooting guidance and optimization strategies
Documentation review
Training facilitation and qualification support
Analytical Method Transfer:
Method transfer protocol
Side-by-side testing
Method qualification at receiving site
Specification alignment
Ongoing method support
Comparability Studies:
Comparability protocol design
Testing strategy
Data analysis and interpretation
Regulatory documentation
Common Tech Transfer Challenges We Solve:
Process performance differences between sites
Analytical method variability
Equipment differences and adaptation
Raw material and reagent differences
Documentation gaps
Our Approach:
Minimize tech transfer risks through systematic protocol development, thorough documentation, and proactive troubleshooting to prevent clinical supply delays.
CRO/Testing Laboratory Coordination
Manage external testing rela- tionships for efficient, reliable analytical support.
Testing Strategy:
Centralized vs. distributed testing approach
CRO capabilities assessment
Method transfer planning
Sample logistics and cold chain
Cost optimization
CRO Selection:
Analytical capability evaluation
GMP compliance assessment
Turnaround time and capacity
Quality system review
Cost comparison
Method Transfer to CROs:
Transfer protocol development
Method qualification oversight
Specification alignment
Ongoing performance monitoring
Sample Management:
Shipping and cold chain validation
Sample stability considerations
Chain of custody
Result reconciliation
Multi-Site Coordination:
Centralized data review
Cross-site comparisons
OOS investigation coordination
Quality agreement management
Coordination Value:
Effective multi-site testing coordination ensures data quality, prevents specification misalignment, and maintains clinical trial timelines through proactive oversight and communication.
READY TO GET STARTED?
Whether you need comprehensive program support or focused expertise in one area, SMAT Consultants provides the specialized knowledge to accelerate your AAV gene therapy program.
Prepare for Our Discussion:
Download our Consultation Preparation Checklist
Complete the checklist to identify your priority areas and specific challenges
Email the checklist to us at fgerner@smatconsultants.com. This helps us tailor our initial
consultation to your program's most critical needs.
Next Steps:
Schedule a confidential, no-obligation consultation
Discuss your specific challenges and objectives
Receive a detailed proposal tailored to your needs
Contact Information:
Email: fgerner@smatconsultants.com