Delivery Platform Selection Risk Assessment: LNP vs. GalNAc Conjugate

Document type	Risk Assessment
Topic area	Drug Product
Level	Advanced
Updated	September 2026

This is a ready-to-use risk assessment for choosing between lipid nanoparticle (LNP) delivery and GalNAc-conjugate delivery for an oligonucleotide program, scored against the actual mechanism each platform depends on rather than assumed on habit or precedent from a prior program. Replace every <<FILL: ...>> placeholder with your own specifics. A worked filled specimen follows. Verify each cited reference against the current source before you rely on it.

Document control header

Field	Entry
Document title	Delivery Platform Selection Risk Assessment for `<<FILL: program>>`
Document number	`<<FILL: e.g. DPR-2026-02>>`
Version	`<<FILL>>`
Payload	`<<FILL: siRNA / ASO / other oligonucleotide chemistry>>`
Target tissue	`<<FILL>>`
Assessment owner	`<<FILL>>`

1. Purpose

This assessment scores the risks associated with each candidate delivery platform, LNP or GalNAc conjugate, for <<FILL: program>>, so the platform decision rests on the target tissue’s actual accessibility and each platform’s real CMC and clinical-handling burden, not on which platform the last program used.

2. Scope

Dimension	Decision
Program / payload in scope	`<<FILL>>`
Development stage	`<<FILL: e.g. candidate selection / formulation lock>>`
Out of scope	`<<FILL: e.g. drug substance synthesis route selection, covered separately>>`

3. Methodology and scoring scales

Score each risk factor on severity (impact on program feasibility, timeline, or patient-relevant performance if the risk materializes) and likelihood (probability the risk factor actually limits the platform for this specific target and payload). Risk priority is severity multiplied by likelihood; a score of 12 or higher, on a 1 to 5 scale for each factor, requires a documented mitigation or a platform decision that avoids the risk, not just a note for later.

Score	Severity meaning	Likelihood meaning
5	Platform is not viable for this target; program-ending if not caught before lock	Confirmed or near-certain for this target/payload combination
4	Major feasibility or timeline impact, likely requires platform switch	Likely based on available target-biology or precedent data
3	Moderate impact, added characterization or development burden but not platform-ending	Possible, needs confirmatory data before ruling in or out
2	Minor impact, manageable within normal development scope	Unlikely based on available data
1	Negligible impact	Rare, no supporting signal for this target

4. Platform risk assessment

Risk factor	Platform	Severity	Likelihood	Risk priority	Mitigation
Target tissue not accessible via ASGPR-mediated hepatocyte uptake	GalNAc conjugate	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL: e.g. confirm receptor expression and uptake data before committing; switch to LNP or another platform if not hepatocyte-restricted>>`
Payload not amenable to direct conjugation chemistry (e.g. size, structure)	GalNAc conjugate	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`
Unconjugated species / ligand-degradation impurities uncharacterized	GalNAc conjugate	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL: e.g. dedicated stability-indicating method for unconjugated species>>`
Cold chain infeasible at intended distribution model	LNP	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL: e.g. confirm frozen distribution feasibility early; budget for it in the network process-step map>>`
Particle CQA panel (size, PDI, encapsulation efficiency, zeta potential) not yet qualified for this lipid composition	LNP	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL: e.g. LNP CPP qualification protocol executed before formulation lock>>`
PEG-lipid immunogenicity (anti-PEG antibody response) affecting repeat dosing	LNP	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL: e.g. immunogenicity monitoring plan, alternative surface chemistry evaluated>>`
Manufacturing process complexity and site capability mismatch	LNP	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL: e.g. CDMO technical assessment scoped specifically to microfluidic mixing and TFF capability>>`
Biodistribution outside the intended target tissue (off-target exposure)	LNP	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`
`<<FILL: any program-specific risk not listed above>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`

5. Residual risk

For every risk priority scored 12 or higher, state the residual risk after mitigation and who accepted it.

Risk factor	Risk priority before mitigation	Mitigation applied	Risk priority after mitigation	Residual risk accepted by
`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`	`<<FILL>>`

6. Platform decision

Field	Entry
Selected platform	`<<FILL>>`
Basis for selection	`<<FILL: tie explicitly to the highest risk-priority factors above>>`
Decision made by	`<<FILL>>`
Date	`<<FILL>>`

7. Approval

Role	Name	Signature	Date
Assessment author	`<<FILL>>`
Formulation Development	`<<FILL>>`
Quality Assurance	`<<FILL>>`

8. References

ICH Q9(R1), Quality Risk Management. ICH Q8(R2), Pharmaceutical Development.

Confirm the current version of each reference before issue.

9. Revision history

Version	Date	Author	Summary of change
`<<FILL: 1.0>>`	`<<FILL>>`	`<<FILL>>`	Initial issue.

Filled specimen

Extract from a platform selection risk assessment for Acme Therapeutics’ ATX-siR2, an siRNA candidate against a hepatocyte-expressed target.

Risk factor	Platform	Severity	Likelihood	Risk priority	Mitigation
Target tissue not accessible via ASGPR-mediated hepatocyte uptake	GalNAc conjugate	5	1	5	Target confirmed hepatocyte-restricted by expression data; risk retired, not a limiting factor for this program
Cold chain infeasible at intended distribution model	LNP	4	2	8	Not selected; noted for reference only
Manufacturing process complexity and site capability mismatch	LNP	4	2	8	Not selected; noted for reference only
Unconjugated species / ligand-degradation impurities uncharacterized	GalNAc conjugate	4	4	16	Dedicated ion-pair HPLC method developed and validated to resolve unconjugated species from the conjugated drug substance before formulation lock

Decision: GalNAc conjugate selected. Target is confirmed hepatocyte-restricted, and the conjugate’s lighter CMC and cold-chain burden is the deciding factor once the one real risk specific to that platform, unconjugated species characterization, carried a documented mitigation. The LNP-specific risks were scored for completeness but did not drive the decision, since the platform was not selected.

Common inspection findings this assessment prevents

A delivery platform selected with no documented confirmation that the target tissue is actually accessible through the mechanism the platform depends on.
A risk assessment that scores only the selected platform, with no record of why the alternative was not chosen.
A high risk-priority factor with no documented mitigation, or a mitigation with no connection to a specific method, study, or protocol.
A platform decision made with no named decision-maker or date, discovered only when the decision is questioned later in development.

How to adapt this assessment

Set your document number, payload, and target tissue in the header.
In section 4, score every risk factor for both candidate platforms, even the platform you expect not to select, so the decision in section 6 has a documented basis for ruling out the alternative.
Trace every mitigation for a risk priority of 12 or higher to a specific study, protocol, or design change.
Tie the platform decision in section 6 explicitly to the highest-scoring factors, not to precedent or convenience.
Confirm every reference in section 8 against the current published version before issue.