Oral Bioavailability: A Practical Guide to Enhancement Strategies

The Solubility Wall

Oral bioavailability depends on two things: how much drug dissolves in the gastrointestinal tract and how much of the dissolved drug crosses the intestinal wall into the bloodstream.

For BCS Class I drugs, both happen efficiently and bioavailability is high. For BCS Class II drugs, the drug dissolves poorly and absorption is limited by how fast and how much drug enters solution. For BCS Class III, the drug dissolves readily but crosses the intestinal membrane slowly. For Class IV, both are problems.

The majority of pharmaceutical development programmes now involve BCS Class II or IV molecules. That is not a coincidence. Simple, soluble molecules were developed first. The pipeline that remains is disproportionately full of hard problems.

Matching the Strategy to the Molecule

There is no universal bioavailability enhancement approach. The right strategy depends on the answer to a specific set of questions about the molecule.

Is poor solubility the rate-limiting step, or is permeability also limiting?
What is the dose? A molecule dosed at 1 mg faces a different solubility challenge than one dosed at 500 mg.
Is the molecule thermally stable? That determines whether hot melt extrusion is an option.
Is it ionisable? That opens the door to salt and co-crystal strategies.
What is the log P? That informs whether lipid-based formulation is feasible.
What is the target patient population and their ability to swallow different dosage forms?

Answering these questions rigorously in pre-formulation, before any formulation strategy is committed to, is how good programmes avoid expensive strategy changes halfway through development.

The Enhancement Strategy Landscape

Strategy	Mechanism	Best Suited For	Key Limitation
Micronisation (jet milling)	Increases surface area; faster dissolution rate	Moderate solubility gap; crystalline API; doses above 50 mg	Cannot reliably produce particles below 1 micrometre; no solubility improvement
Nanosuspension (wet milling)	Marked surface area increase; modest Ostwald-Freundlich solubility improvement	BCS Class II with moderate solubility gap; API that is compatible with aqueous milling	Downstream processing needed; recrystallisation risk if poorly stabilised
Salt or co-crystal formation	Improved intrinsic solubility of salt/co-crystal form; faster dissolution	Ionisable APIs; moderate to severe solubility limitation	Disproportionation risk in GI tract; not applicable to non-ionisable molecules
Amorphous solid dispersion (ASD)	Converts crystalline API to amorphous; supersaturation in GI fluid	Severe solubility limitation; BCS Class II/IV; permeability not limiting	Physical stability risk; development and manufacturing complexity
Lipid-based formulation (SEDDS/SMEDDS)	Self-emulsification in GI tract; drug presented in dissolved form in lipid droplets	Highly lipophilic APIs (log P above 3); dose flexibility; fill-in-capsule acceptable	High lipid content; fill weight limits dose; not suitable for hydrophilic drugs
Cyclodextrin complexation	Inclusion complex improves apparent solubility; solid complex for oral delivery	Moderate log P range; fit of molecule in cyclodextrin cavity required	High cyclodextrin to drug ratio increases tablet size at higher doses
Prodrug approach	Chemical modification improves solubility or permeability; converted to active form in vivo	When other physical approaches are insufficient; hydrolysable ester prodrugs most common	Regulatory classification as new molecular entity; full development programme required

The Dose-Solubility Ratio: A Practical Triage Tool

The dose number (D0 = dose / (solubility x volume)), introduced in the BCS classification framework, is a quick way to estimate whether solubility is likely to limit absorption in a typical patient. A dose number above 1 suggests that the drug cannot fully dissolve in the available GI fluid volume at the intended dose, even at maximum solubility, and that bioavailability enhancement is likely to be needed. This calculation, using even a rough solubility estimate, often provides enough information to rule in or rule out certain strategies before any formulation work begins.

Why Enhancement Strategy Selection Belongs in Pre-Formulation

Every enhancement strategy involves trade-offs. ASDs are powerful but introduce physical stability risk. Lipid formulations are effective for lipophilic drugs but are not manufacturable for highly potent APIs without specialised containment. Nanosuspensions require controlled downstream processing. Salt strategies do not work for non-ionisable molecules.

Understanding these trade-offs before the formulation programme starts, not after the first strategy fails, is the difference between a programme that reaches GMP on schedule and one that does not.

Ardena’s Multi-Site Bioavailability Enhancement Capabilities

Ardena’s formulation expertise spans the full enhancement landscape. Salt and co-crystal screening at Ghent, ASD development by spray drying and HME at Somerset and Pamplona, nanosuspension at Oss, and lipid-based formulation across the network. The pre-formulation team recommends the most appropriate strategy based on the molecule’s properties and the programme’s goals, with no bias towards a particular technology platform.

Oncology Drug Development: Why the Therapeutic Area Demands a Specialist CDMO

The Hardest Drugs to Make

Oncology is consistently the largest therapeutic area in pharmaceutical development pipelines, and it is consistently the most technically demanding. The molecules tend to be highly potent. The patient populations are often defined by specific biomarkers, requiring precise clinical supply and diagnostic coordination. The tolerability window is narrow, making dose accuracy and product consistency critically important. And the speed imperative is real: patients with advanced cancers cannot afford the delays that are merely inconvenient in other therapeutic areas.

A CDMO that works well for a standard oral solid in cardiovascular disease may not be equipped for an oncology programme. The containment requirements, the analytical sensitivity demands, the clinical supply complexity, and the regulatory scrutiny are all substantially higher.

The Technical Demands of Oncology Drug Development

High-Potency Handling

Most small molecule oncology drugs are cytotoxic or have high pharmacological potency. Occupational exposure limits in the nanogram per cubic metre range require engineering controls, dedicated manufacturing suites, and validated decontamination procedures that are a significant capital and operational investment. Not all CDMOs have them.

Bioavailability Challenges

Many kinase inhibitors, PARP inhibitors, and other targeted oncology agents are BCS Class II or IV molecules with poor aqueous solubility. Getting adequate bioavailability to support efficacious plasma exposures often requires amorphous solid dispersion technology, nanosuspension, or lipid-based formulation. The CDMO must have these capabilities in-house, and they must be compatible with HPAPI handling if the API requires it.

Bioanalytical Complexity

Oncology clinical trials require sophisticated bioanalytical programmes. PK characterisation across a wide dose range. Pharmacodynamic biomarkers that demonstrate target engagement. Immunogenicity testing for biologic oncology agents. Cell-based assays for cell therapy programmes. A CDMO with integrated bioanalysis can manage all of these as a coherent programme; a CDMO without bioanalysis capability requires the sponsor to manage a separate vendor relationship.

What Oncology Programmes Need from a CDMO Partner

Requirement	Why It Matters in Oncology	Ardena Capability
HPAPI manufacturing at OEB 4-5	Cytotoxic small molecules and ADC payloads require strict containment	Pamplona: OEB 3-5 containment; isolators; validated decontamination
ASD formulation for BCS Class II/IV	Many targeted oncology agents have poor oral bioavailability	Somerset and Pamplona: spray drying and HME
Aseptic fill-finish for cytotoxic injectables	IV oncology formulations require sterile manufacturing with HPAPI controls	Ghent: aseptic fill-finish; HPAPI-compatible sterile suite
ADC bioanalysis (total Ab, conjugated Ab, free payload)	ADCs require multi-analyte PK characterisation	Assen: LBA and LC-MS/MS for full ADC PK panel
Biomarker and flow cytometry assays	Companion diagnostics and PD biomarkers are central to oncology trial design	Assen: MSD multiplex; multi-parametric flow cytometry
CMC regulatory expertise for oncology	Oncology programmes often use accelerated pathways with higher CMC scrutiny	Multi-site regulatory team; experience with Breakthrough Therapy and PRIME designations
Small-batch GMP for rare tumour subtypes	Patient populations in oncology trials can be very small	All sites: clinical batch capability without minimum batch size constraints that force waste

Speed Without Shortcuts

Oncology drug development operates under genuine time pressure. Patients with limited treatment options are waiting. But the speed imperative does not justify cutting corners that create problems later. A poorly characterised solid form that requires reformulation at Phase II. A stability programme that does not cover the clinical trial duration. A CMC package that triggers a regulatory hold.

The fastest programmes are not the ones that skip steps. They are the ones that identify the critical path clearly, run parallel workstreams where the science allows, and avoid the rework that comes from doing development in the wrong order. That requires a partner with enough experience in oncology to know which steps can be accelerated and which cannot.

How Ardena Serves Oncology Programmes

Ardena’s network covers the full oncology development and manufacturing chain. HPAPI capability at Pamplona, ASD formulation at Somerset and Pamplona, sterile manufacturing at Ghent, and integrated bioanalysis at Assen give oncology sponsors a single partner across the technical domains their programmes require. The project management model, with a single project manager coordinating work across sites, means the sponsor is not left to manage four separate CDMO relationships.

The Virtual Biotech Model: How to Build a Drug Programme Without a Lab

The Model That Changed Biotech

Twenty years ago, a credible pharmaceutical development programme needed laboratories, equipment, and scientists on the payroll. The idea that a five-person team could advance a drug candidate from lead optimisation to Phase II without owning a single centrifuge would have seemed implausible.

Today it is routine. The virtual biotech model, built on outsourcing relationships with CDMOs, CROs, and specialist consultants, has become one of the dominant organisational forms in early-stage pharmaceutical development. It allows small teams to access world-class scientific and manufacturing capabilities without the capital overhead, and it lets investors fund science rather than infrastructure.

It also fails regularly, for predictable reasons that have nothing to do with the science.

What Goes Wrong in Virtual Biotech Programmes

Too Many Vendors, Not Enough Oversight

The instinct of many virtual biotech teams is to find the best vendor for each individual piece of work. Best formulation house for development, best CRO for animal studies, best CMO for manufacturing. The result is a programme spread across five or six organisations with no single point of accountability and a coordination overhead that consumes the management team.

No Internal CMC Expertise

A virtual biotech can outsource the execution of CMC work. It cannot outsource the judgement about what CMC work is needed. Without someone on the team who understands what a regulator will expect to see in Module 3, the programme can spend months generating data that does not answer the right questions.

The Tech Transfer That Should Not Have Existed

Many virtual biotechs develop a molecule with one vendor, then transfer it to a different GMP manufacturing partner because the first vendor does not have GMP capability. Every tech transfer is a risk event. Data is interpreted by new people, processes are reproduced on different equipment, and unexpected results emerge. The transfer that could have been avoided by choosing an integrated partner from the start costs months and money to resolve.

What Successful Virtual Biotechs Do Differently

Success Factor	What It Looks Like in Practice
Choose an integrated partner early	Select a CDMO with development and GMP manufacturing capability at the start; avoid planned tech transfers between development and manufacturing
Keep CMC expertise internal	Hire or retain a Head of CMC or CMC consultant with regulatory filing experience; do not rely on the CDMO to own regulatory strategy
Define deliverables, not activities	Contract for outcomes (Phase I CMC package) rather than activities (12 months of stability work); gives the CDMO flexibility to design the most efficient programme
Build in formal decision gates	Schedule quarterly scientific reviews where the programme strategy is assessed against the data, not just the timeline
Use project management tools the CDMO actually supports	Do not assume the CDMO will use your project management system; agree on reporting format and frequency before work starts
Plan for the unexpected	Build contingency time and budget into the plan; virtual programmes with no slack are brittle when something goes wrong

The Integrated CDMO as a Virtual Biotech’s Scientific Department

For a five-person virtual biotech, the CDMO is not just a service provider. It is, functionally, the scientific organisation. The quality of the science that goes into the programme, the data generated, the decisions made, the regulatory strategy pursued, is largely determined by the quality and engagement of the CDMO team.

This is why the consultative tone that characterises good CDMO partnerships matters more for virtual biotechs than for large pharma. A CDMO that executes instructions without pushing back when the science suggests a different approach is not providing the partnership a virtual biotech needs. A CDMO that raises the question about polymorph stability before the first GMP batch is planned, that flags the dissolution method issue before the IND is filed, is providing something genuinely valuable.

How Ardena Supports Virtual Biotech Programmes

Ardena’s model is particularly well suited to virtual biotech programmes. The integrated multi-site network covers solid state research, formulation development, analytical services, GMP manufacturing, bioanalysis, and regulatory support under a single project management framework. For a virtual biotech that does not have scientific departments of its own, Ardena provides the depth of capability that would otherwise require five separate vendor relationships.

GMP Deviations: How to Investigate, Resolve, and Prevent Them

Deviations Are Not the Problem. The Response Is.

In any GMP manufacturing environment, deviations will happen. A process parameter drifts outside its validated range. A raw material fails an incoming test. A batch record is completed incorrectly. These events are not evidence of a dysfunctional organisation. They are the normal noise of complex manufacturing.

What matters is what happens next. A deviation that is investigated thoroughly, attributed to a genuine root cause, and closed with a corrective action that actually prevents recurrence is a system working as it should. A deviation that is closed with a vague root cause and a CAPA that amounts to retrain the operator is a system generating paperwork, not quality.

Regulators know the difference. So do sponsors reviewing their CDMO’s quality metrics.

The Deviation Life Cycle

Stage	What Happens	Common Failure Mode
Detection	Operator or automated system identifies an event outside expected parameters	Detection delayed because monitoring is inadequate or parameters are not well defined
Immediate containment	Affected material quarantined; process halted if necessary; batch placed on hold	Production continues before the scope of the deviation is understood
Initial assessment	Quality unit classifies severity; determines whether batch can continue	Severity underestimated; critical deviation treated as minor to avoid disruption
Root cause investigation	5-Why analysis, fishbone diagram, or fault tree analysis identifies the underlying cause	Root cause attributed to human error without investigating why the error occurred
Impact assessment	All potentially affected material and batches are reviewed	Impact assessment limited to the single batch; historical batches not reviewed
CAPA development	Corrective action addresses root cause; preventive action reduces recurrence risk	CAPA is procedural (update the SOP) rather than systemic (fix the system that allowed the deviation)
Effectiveness check	CAPA is verified to have worked after implementation	Effectiveness check not scheduled; CAPA closed before evidence of effectiveness gathered

Root Cause Analysis: Beyond Human Error

The most common root cause in pharmaceutical deviation investigations is human error. It is also the least useful root cause attribution there is.

Attributing a deviation to human error tells you nothing about why that error occurred or how to prevent it. It closes the investigation without answering the real question. Was the procedure unclear? Was the operator undertrained? Was the workstation poorly designed? Was there time pressure that encouraged shortcuts? Was the check system inadequate?

A genuinely useful root cause investigation works backwards from the event through the contributing factors to the system-level condition that made the error possible. That is the condition that needs to be fixed.

Out-of-Specification (OOS) Results: A Special Category

An out-of-specification analytical result requires a specific investigation process governed by the FDA’s guidance on OOS results and EU GMP Chapter 6 on quality control. The process has two phases: a laboratory investigation to determine whether the OOS result is a genuine product failure or a laboratory error, followed by a full-scale investigation if the laboratory phase cannot identify an assignable cause.

The distinction matters because the two scenarios have different consequences. A laboratory error that is identified and confirmed allows the original sample to be retested (with restrictions). A genuine OOS result triggers a full investigation including review of the manufacturing record, assessment of related batches, and a decision about batch disposition.

Invalidating an OOS result without a confirmed, documented, and justified assignable laboratory cause is a major regulatory finding. Inspectors specifically look for OOS investigations where the outcome was invalidation without adequate justification.

CAPA: The System That Should Drive Improvement

Corrective and preventive action (CAPA) is the mechanism by which deviations feed back into the quality system and generate genuine improvement. A well-managed CAPA system tracks the status of all open actions, links CAPAs to their originating deviations, and monitors whether closed CAPAs have actually achieved their intended effect.

The most common CAPA failure mode is the procedural fix. The batch record instruction was unclear, so the CAPA is to update the batch record instruction. This may be necessary, but it is rarely sufficient. If an operator did not follow a clear instruction, the question is why. If the instruction was genuinely unclear, the deeper question is why it was unclear and how other instructions in the same system should be reviewed.

How Ardena Manages Deviations Across Its Network

Ardena’s quality management system applies consistent deviation investigation and CAPA standards across all sites, with centralised oversight of quality metrics and trend analysis. Sponsors receive timely notification of deviations affecting their programmes and have visibility into the investigation timeline and closure status through the programme’s quality governance structure.

Preparing for a Regulatory GMP Inspection: What Sponsors Need to Know

Why Your CDMO’s Inspection Record Is Your Problem Too

When a regulatory agency inspects a contract manufacturing organisation, it is not just inspecting the CDMO. It is inspecting the GMP compliance of every product made at that site, including yours.

A Form 483 observation or a warning letter to your CDMO does not automatically stop your programme, but it can. Regulators may place a clinical hold, request additional manufacturing information, or delay the approval of a marketing authorisation application if there are unresolved GMP concerns at a manufacturing site named in the submission. Understanding how inspections work, and what questions to ask your CDMO before one happens, is basic programme risk management.

How Inspections Are Triggered

Routine Surveillance Inspections

The FDA inspects domestic manufacturing sites roughly every two years and foreign sites less frequently, prioritising those associated with products marketed in the US. EU national competent authorities inspect licensed sites on a risk-based schedule, typically every three to five years. These routine inspections are not triggered by any specific concern and are a normal part of operating a GMP facility.

Application-Based Inspections

When a new drug application, biologics licence application, or marketing authorisation application names a manufacturing site, regulators may conduct a pre-approval inspection (PAI) to verify that the site is capable of manufacturing the product as described in the application. A PAI finding that identifies significant GMP deficiencies can delay approval or require a complete response.

For-Cause Inspections

A for-cause inspection is triggered by a specific concern, such as a product recall, a serious adverse event with a potential manufacturing cause, a whistleblower complaint, or unsatisfactory results from a prior inspection. These inspections are more intensive than routine surveillance and carry higher risk of serious regulatory action.

What Inspectors Look For

Inspection Focus Area	What the Inspector Is Assessing	Common Finding
Data integrity	Are records accurate, complete, and attributable? Can the inspector trace every action to a person and a time?	Electronic records without adequate audit trails; backdated entries; deletions without justification
Change control	Are manufacturing changes properly assessed, approved, and reflected in regulated documents?	Changes implemented without formal change control; regulatory filings not updated
Out-of-specification investigations	Are OOS results properly investigated? Are invalidated results justified?	OOS investigations closed prematurely; root cause attributed to human error without adequate evidence
Contamination control	Are cleaning validation, environmental monitoring, and personnel practices adequate?	Environmental monitoring exceedances not investigated; cleaning validation data gaps
Batch record review	Are batch records complete and do they reflect the actual manufacturing process?	Unexplained corrections; missing critical in-process data; batch records not reflecting deviations
CAPA effectiveness	Are corrective actions actually preventing recurrence?	Repeat deviations for the same root cause; CAPA closed before effectiveness verified

Questions Sponsors Should Ask Their CDMO

You have a right to understand the inspection history of any facility manufacturing your product. The following questions are reasonable and professional to ask before engaging a CDMO and at regular intervals during a manufacturing relationship.

When was the facility last inspected and by which authority?
Were there any findings (Form 483 observations or Warning Letters from the FDA; critical or major findings from EU inspectors)?
How were those findings resolved? Can you share the response?
Is any ongoing regulatory correspondence active relating to GMP compliance at this site?
How are inspection preparation activities managed, and can the sponsor attend a mock inspection?

How a Well-Prepared CDMO Handles an Inspection

A GMP-mature CDMO treats inspection readiness as a continuous state, not a sprint that happens when an inspection notice arrives. Documentation is current, deviations are closed or actively progressed, and the quality team can answer questions about any product or process without scrambling for information.

When an inspection begins, the CDMO’s quality leadership manages the interaction professionally, provides accurate and complete information, and does not make commitments on behalf of sponsors without appropriate coordination. Sponsors are notified promptly when their product or process is discussed during an inspection.

Ardena’s Inspection Track Record

Ardena’s manufacturing sites are subject to regular inspection by national competent authorities in Belgium, the Netherlands, and Spain, as well as by the US FDA for sites that supply products to the US market. The quality teams at each site maintain inspection-readiness as a core operational discipline, with regular internal audits and a proactive approach to managing open findings.

Formulating Oligonucleotide Therapies: siRNA, ASO, and Beyond

A Pipeline That Has Finally Arrived

Oligonucleotide therapies have been in development for decades. The science was compelling from the start: target any gene in the human genome with exquisite specificity by designing a short nucleotide sequence that binds the corresponding mRNA. Switch off disease-causing genes. Restore lost protein expression. Correct splicing errors.

The delivery problem kept most of it on the bench. Oligonucleotides are large, negatively charged, enzymatically unstable molecules that do not cross cell membranes easily. They are rapidly degraded by serum nucleases and cleared by the kidney before they reach their target.

Two decades of formulation innovation have changed that. Lipid nanoparticles, GalNAc conjugation, and chemical modification strategies have collectively unlocked systemic and local delivery of oligonucleotides to a growing range of tissues. The pipeline has followed.

The Three Main Classes and Their Delivery Needs

Class	Mechanism	Primary Delivery Challenge	Current Delivery Solutions
siRNA (small interfering RNA)	Triggers RISC-mediated degradation of complementary mRNA; gene silencing	Negative charge; nuclease degradation; endosomal escape; off-target effects	LNP (ionisable lipid); GalNAc conjugation for hepatic delivery; chemical modifications (2-OMe, PS backbone)
Antisense oligonucleotide (ASO)	Binds pre-mRNA or mRNA; blocks translation or triggers RNase H cleavage	Nuclease degradation; tissue distribution; nuclear access for splice-switching ASOs	Naked delivery with chemical modifications (PS backbone; LNA/BNA); GalNAc for liver; local delivery to CNS or lung
Aptamer	Folds into 3D structure that binds target protein; blocks or modulates protein function	Rapid renal clearance; short half-life; large-scale synthesis	PEGylation; conjugation to larger carriers; chemical modifications
saRNA (self-amplifying RNA)	Encodes an RNA polymerase that amplifies the therapeutic RNA in the cell	Larger molecule than mRNA; requires same endosomal escape strategy; immunogenicity	LNP; same platform as mRNA but larger payload size requires formulation optimisation
miRNA mimic or inhibitor	Modulates endogenous miRNA activity; broad gene regulatory effect	Same as siRNA/ASO depending on class; off-target effects from broad miRNA activity	LNP; conjugate delivery; chemical modifications

GalNAc Conjugation: The Hepatic Delivery Revolution

For oligonucleotides targeting the liver, GalNAc (N-acetylgalactosamine) conjugation has transformed the field. GalNAc is a sugar that binds with high affinity and specificity to the asialoglycoprotein receptor (ASGPR) expressed at high levels on hepatocytes. Conjugating a GalNAc moiety to an ASO or siRNA drives receptor-mediated uptake specifically into liver cells, achieving therapeutic silencing at doses that would be ineffective for the naked oligonucleotide.

GalNAc-conjugated siRNAs (GalNAc-siRNA) are administered as subcutaneous injections, often once monthly or less frequently, with no nanoparticle carrier required. The simplicity of the delivery system relative to LNPs, no lipid formulation, no cold chain, simple subcutaneous administration, has made GalNAc the dominant delivery platform for hepatic oligonucleotide therapies.

The limitation is obvious: it only works for liver targets. For any other tissue, GalNAc does not help.

Chemical Modifications: Stability Before Delivery

Before any delivery system can work, the oligonucleotide must survive long enough to reach the target. Naked, unmodified RNA is degraded by serum nucleases within seconds. Chemical modifications slow that degradation and, in many cases, improve the potency and duration of action of the drug.

The phosphorothioate (PS) backbone modification, where a non-bridging oxygen in the phosphodiester linkage is replaced by sulphur, was the first widely used modification and remains standard in most clinical ASOs. It significantly improves nuclease resistance and increases protein binding in plasma, which extends circulation half-life but also contributes to off-target effects at high doses.

Locked nucleic acid (LNA) modifications constrain the ribose ring in a fixed conformation that increases binding affinity and nuclease resistance. 2-O-methyl and 2-O-methoxyethyl modifications are also widely used. Modern clinical oligonucleotides typically carry a combination of several modification types, optimised for the specific target and delivery context.

Formulation Development for Oligonucleotides

For LNP-delivered siRNAs, the formulation development process is closely analogous to mRNA LNP development: ionisable lipid selection, N:P ratio optimisation, microfluidics manufacture, and physicochemical characterisation of particle size, PDI, encapsulation efficiency, and zeta potential. The key difference is that siRNA is significantly smaller than mRNA, which affects the optimal lipid composition and the encapsulation efficiency assay (Ribogreen versus strand-specific hybridisation assays for siRNA quantification).

For subcutaneous GalNAc-conjugate delivery, the formulation is simpler: the conjugate is dissolved in a compatible aqueous buffer at the target concentration, filtered, and filled into prefilled syringes or vials. The formulation challenges are primarily related to concentration (high concentration formulations can form gels) and stability of the conjugate bond under storage conditions.

Ardena’s Oligonucleotide Platform at Oss

Ardena’s nanomedicine team at Oss has formulation development and GMP manufacturing capability for LNP-delivered oligonucleotides, including siRNA and saRNA payloads. The site’s encapsulation efficiency assays have been adapted for siRNA quantification, and the team has experience optimising LNP formulations for small nucleic acid payloads where the optimal composition differs from mRNA LNP formulations.

Quality Agreements in Pharmaceutical Outsourcing: What They Must Cover

The Document Nobody Reads Until Something Goes Wrong

Quality agreements are one of those documents that get negotiated carefully, signed by the right people, filed away, and never looked at again. Until something goes wrong.

When a GMP deviation occurs, when a batch fails, when a regulatory inspection raises a question about oversight, the quality agreement is the document that defines who was responsible for what. If it is vague, incomplete, or has not been reviewed since the programme started, the consequences are predictable.

A good quality agreement is not just a legal formality. It is a genuine operational tool that prevents disputes, clarifies accountability, and ensures that GMP responsibilities are distributed logically between the sponsor and the CDMO.

The Regulatory Requirement

EU GMP Chapter 7 on outsourced activities and the FDA’s guidance on contract manufacturing both require written quality agreements between sponsors and their contract manufacturers. The agreement must define the GMP responsibilities of each party clearly and must be reviewed and approved by the quality units of both organisations. It is not sufficient for a general commercial contract to contain quality provisions; a standalone technical or quality agreement is the regulatory expectation.

What a Strong Quality Agreement Covers

Section	What It Should Define	Common Weakness
Scope of work	Exactly which activities are covered; what is in scope and out of scope for the agreement	Scope defined too broadly; changes in the programme not captured by agreement updates
GMP responsibilities	Which party is responsible for each GMP activity: batch record review, release, deviation investigation, CAPA	Joint responsibilities listed without specifying the primary responsible party
Change control	Which changes require sponsor notification; which require sponsor approval before implementation	CDMO retains right to make process changes without sponsor approval; sponsor not notified in time
Deviations and OOS	Timelines for notification; who investigates; who approves the investigation report	Notification timelines too loose; sponsor does not receive deviation reports until batch review
Regulatory inspections	What each party does when the other is inspected; how the agreement is referenced in submissions	No provision for inspection support; sponsor not informed of CDMO inspection findings
Stability	Who owns the stability programme; who has responsibility for out-of-trend results	Stability ownership split between parties without clear escalation path
Batch release	Authorised person responsibilities; what happens when the sponsor and CDMO disagree on release	Release responsibility assumed but not explicitly assigned; AP not named
Annual product review	Which party leads the APR; what data the CDMO provides; timelines	APR responsibility not assigned; CDMO data not available when sponsor needs it

The Change Control Problem

Change control is the section of quality agreements that generates the most disputes in practice. The question is simple: when the CDMO wants to change something about the manufacturing process, the equipment, the supplier, or the facility, what does it need to tell the sponsor, and when?

From the CDMO’s perspective, the ability to make routine operational improvements without seeking sponsor approval for every change is a reasonable operational requirement. From the sponsor’s perspective, any change to the process that manufactured their clinical batches is a potential CMC filing issue that could trigger a regulatory amendment.

The resolution is a tiered change control classification. Minor changes are notified; significant changes require sponsor review; major changes require sponsor approval before implementation. What counts as minor, significant, or major should be defined explicitly in the agreement, not left to interpretation.

Reviewing and Updating the Agreement

Quality agreements should be reviewed at least annually and updated whenever the scope of work changes materially. A quality agreement written at the start of a Phase I programme will not adequately cover the same programme at Phase III. New manufacturing sites, new dosage forms, and new regulatory filings all need to be reflected in the document.

In practice, quality agreements often lag behind the programme. Amendments are negotiated slowly, and in the meantime the teams operate under informal understandings that have no contractual force. Building a formal review cycle into the programme management plan, with responsibility assigned to a named individual on each side, is the most reliable way to prevent this.

How Ardena Approaches Quality Agreements

Ardena’s quality team produces quality agreements that are specific to each programme rather than generic templates with blanks filled in. The change control classifications, notification timelines, and responsibility assignments in an Ardena quality agreement reflect the actual work being done and the regulatory context of the programme.

Age-Appropriate Formulations: Developing Medicines for Paediatric Patients

The Problem with Crushing Adult Tablets

A remarkable proportion of medicines given to children are unlicensed for paediatric use. Nurses crush adult tablets, pharmacists compound extemporaneous liquids, and parents split scored tablets into fractions. None of these workarounds are ideal. All of them introduce dose uncertainty. Some destroy formulation features, like modified release coatings, that were essential to the drug’s performance.

The push towards age-appropriate paediatric formulations is a regulatory priority. The EMA’s Paediatric Investigation Plan requirement and the FDA’s Paediatric Study Plan mandate that sponsors plan paediatric development early, not as an afterthought once adult registration is secured.

Dose Flexibility: The Core Paediatric Formulation Challenge

Adults generally all receive the same dose. Paediatric patients are dosed by weight, which means the same drug needs to be deliverable across a ten-fold or more dose range. A tablet that comes in two strengths cannot achieve that. The formulation must be inherently flexible.

This is why oral liquids, oral dispersible tablets, and multiparticulate systems (granules, mini-tablets, pellets) dominate paediatric formulation science. Each allows dose adjustment without tablet splitting, compounding, or approximation.

Age-Appropriate Formulation Options by Patient Group

Age Group	Preferred Formulation Types	Key Formulation Considerations
Neonates (0-28 days)	Oral liquids; orodispersible films	Extremely small doses; swallowing reflex not developed; strict excipient restrictions; benzyl alcohol contraindicated
Infants (1-23 months)	Oral liquids; orodispersible granules mixed with food	Palatability critical; volumes below 5 ml preferred; no capsules or standard tablets
Young children (2-5 years)	Chewable tablets; orodispersible tablets; oral liquids	Palatability essential; age-appropriate flavours; tablet size below 6 mm for swallowability
Older children (6-11 years)	Film-coated tablets; mini-tablets; oral liquids	Swallowability improving; tablet size up to 8 mm generally acceptable; can begin to consider capsules
Adolescents (12-17 years)	Adult-equivalent formulations generally acceptable	Consider adult formulation with paediatric dosing; review excipient limits for age

Age-group classifications follow EMA ICH E11(R1) and WHO definitions. Formulation acceptability within each group varies by patient and clinical context.

Excipients: Not Everything That Is Safe in Adults Is Safe in Children

Paediatric patients metabolise and excrete differently from adults. Enzyme systems are immature in neonates and infants. Renal function is proportionally different. Excipients that are routinely used in adult formulations can be hazardous in young children.

Benzyl alcohol, used as a preservative in many injectable products, has been associated with gasping syndrome and death in premature neonates. Propylene glycol, a common solubiliser, can accumulate in infants with immature metabolic pathways. Sorbitol at high doses causes osmotic diarrhoea and dehydration in young children.

The EMA’s guideline on excipients in the label and package leaflet and the EMA’s reflection paper on the use of excipients in paediatric formulations are required reading for any team developing a paediatric formulation. The acceptable daily intake thresholds for excipients in children are often significantly lower than the amounts present in adult formulations.

Palatability: The Formulation Variable That Determines Adherence

A paediatric formulation that children refuse to take is not a medicine; it is a negotiation. Palatability, covering taste, smell, texture, and mouthfeel, is a genuine development objective, not a cosmetic one.

Taste masking is one of the most technically challenging aspects of paediatric oral formulation. Bitter APIs are the norm in pharmaceutical development. Options include polymer coating of drug particles, complexation with ion exchange resins, microencapsulation, and flavouring. Each approach has limits, and the most effective strategy depends on the API’s physicochemical properties and the target formulation.

Formal paediatric acceptability testing using age-appropriate assessment tools, such as hedonic scales adapted for young children, is increasingly expected as part of the development programme and is recognised in EMA guidance as a component of the pharmaceutical development evidence package.

Ardena’s Paediatric Formulation Experience

Ardena’s formulation teams have experience developing paediatric oral formulations including orodispersible tablets, oral liquids, and multiparticulate systems across its European sites. The team is familiar with the EMA’s paediatric regulatory requirements and with the practical challenges of excipient selection, taste masking, and dose flexibility that make paediatric development distinct from adult work.

Prefilled Syringes and Autoinjectors: Formulation and Compatibility Considerations

Why Patients Want Prefilled Syringes

Ask a patient which they would prefer for a monthly self-injection: a glass vial, a needle, and a syringe they have to assemble themselves, or a prefilled autoinjector they click and hold against their arm. The answer is obvious.

Prefilled syringes and autoinjectors have become the standard delivery format for biologics intended for self-administration. They reduce administration errors, improve patient adherence, and eliminate the multi-step preparation that creates both errors and anxiety. For many biologic drug products, the prefilled syringe is not a convenience upgrade; it is a commercial requirement.

The formulation challenge is that the syringe barrel is not a passive container. It is a component that interacts with the drug product. Getting that transition right takes careful development work.

The Key Compatibility Challenges

Silicone Oil

Glass syringes are siliconised to allow the plunger to slide smoothly during injection. The silicone oil droplets that migrate into the drug solution are a known source of protein aggregation for biologic drug products. High shear at the needle tip during injection can further fragment silicone droplets and increase the surface area available for protein adsorption.

The risk is managed by selecting syringe formats with optimised siliconisation (cross-linked silicone; baked-on silicone coatings) and by demonstrating in formulation development that the drug product is tolerant to the silicone levels expected in the chosen syringe. For highly aggregation-prone proteins, silicone-free syringe options including cyclic olefin polymer (COP) or cyclic olefin copolymer (COC) barrels may be required.

Tungsten Residues

Glass syringes are formed using tungsten pins to create the needle tip geometry. Residual tungsten at low microgram levels can remain in the syringe barrel after manufacture and can interact with some proteins to induce aggregation or precipitation. Tungsten compatibility must be assessed during development by incubating the drug product in the intended syringe format and monitoring for aggregation by DLS or SEC.

Extractables and Leachables

Every component that contacts the drug product, the syringe barrel, the rubber plunger stopper, the tip cap, and the needle, can contribute extractable compounds that migrate into the solution over the shelf life of the product. For prefilled syringes, the longer contact time and the absence of a separate packaging step mean the extractables profile is more complex than for a vial-stopper system.

The PQRI leachables guidance for parenteral and ophthalmic drug products and the ICH Q3E guideline on extractables and leachables provide the framework for extractables and leachables assessment. A complete E&L programme for a prefilled syringe system is a significant analytical undertaking that must be planned well in advance of the registration-stage stability studies.

Formulation Parameters That Affect PFS Performance

Parameter	Effect in PFS Format	Development Consideration
Viscosity	High viscosity formulations require greater injection force; affects autoinjector spring design and patient experience	Target viscosity below 20 cP for standard autoinjectors; reformulate or dilute if above 50 cP
pH and buffer	Plunger stopper rubber contains components that can affect pH; buffer capacity must maintain pH over shelf life	Confirm pH stability in the syringe over proposed shelf life; select low-extractables stoppers
Surfactant type and concentration	Surfactants protect against agitation-induced aggregation; must be compatible with syringe components	Polysorbate 20 or 80 standard; confirm compatibility with silicone and rubber components
Protein concentration	Higher concentrations increase aggregation risk from silicone and tungsten interactions	Assess aggregation at target concentration in the syringe format during compatibility studies
Preservatives	Multi-dose PFS may require preservative; single-dose typically preservative-free	Benzyl alcohol and phenol are common; confirm antimicrobial efficacy and compatibility with drug

Device Development: The Formulation-Device Interface

The autoinjector or pen injector selected for a self-injectable drug product must be compatible with the formulation parameters, particularly viscosity, fill volume, and injection speed. These are not independent design choices. A formulation with a viscosity of 40 cP will require a different spring force than one at 5 cP, which changes the injection duration and the force felt by the patient.

Device selection should happen in parallel with formulation development, not after it. The target product profile for the device and the formulation should be established together, with viscosity, fill volume, and container closure system selected as a package.

Ardena’s Injectable Formulation Capabilities

Ardena’s formulation and analytical teams at Ghent support injectable drug product development for both vial and prefilled syringe formats, including compatibility assessment, extractables and leachables planning, and GMP fill-finish of clinical batches. The team has experience with complex biologic formulations and the specific challenges that arise in the transition from vial to PFS.

Dissolution Testing: Choosing the Right Method for Your Drug Product

A Test That Needs to Mean Something

Dissolution testing is one of the most widely performed analyses in pharmaceutical development. It is also one of the most frequently misunderstood.

A dissolution test that cannot distinguish a good batch from a bad one is not a quality control tool. It is a formality. And a test that shows 98% release in 30 minutes in pH 6.8 phosphate buffer, but the drug is barely absorbed in patients, is actively misleading. The goal is a method that reflects what actually happens when the patient swallows the tablet.

Getting that right requires understanding the biology of oral drug absorption, the limitations of the most common test methods, and how to match the method to the molecule and the formulation.

The BCS Framework as Your Starting Point

The Biopharmaceutics Classification System (BCS) divides drugs into four classes based on solubility and permeability. The class tells you which absorption step is rate-limiting, and therefore what your dissolution method needs to capture.

BCS Class	Solubility	Permeability	Rate-Limiting Step	Dissolution Test Priority
Class I	High	High	Gastric emptying	Simple: discriminate fast from slow release; biowaver often available
Class II	Low	High	Dissolution in GI fluid	Critical: method must reflect solubility-limited dissolution; biorelevant media often needed
Class III	High	Low	Permeation across intestinal wall	Less critical for formulation discrimination; API properties dominate
Class IV	Low	Low	Both dissolution and permeation	Most challenging: biorelevant media important; in vitro-in vivo correlation difficult

Standard Buffer vs. Biorelevant Media: When It Matters

Standard Buffer Methods

Standard USP buffer systems at pH 1.2, 4.5, and 6.8 are the default for most regulatory dissolution work. They are simple, reproducible, and well-understood. For BCS Class I drugs and many conventional formulations, they do the job.

For BCS Class II and IV drugs, they often do not. Aqueous buffers lack the surfactant and bile salt content of real gastrointestinal fluid. A poorly soluble API may show 100% release in a standard buffer with a high concentration of solubilising excipients, then fail to achieve adequate exposure in patients because the dissolution medium in the GI tract has very different solubilising power.

Biorelevant Media

Biorelevant media such as FaSSIF (fasted-state simulated intestinal fluid) and FeSSIF (fed-state simulated intestinal fluid) contain bile salts and lecithin at physiologically relevant concentrations. They better mimic the solubilising capacity of the intestinal environment and are far more discriminating for BCS Class II molecules.

They are also more variable to prepare, more expensive, and not required by regulators for routine release testing. The practical approach is to use biorelevant media during development to understand in vivo-predictive performance, then design a simpler validated method for GMP release that is correlated to the biorelevant results.

In Vitro-In Vivo Correlation (IVIVC): The Regulatory Goal

An IVIVC links the in vitro dissolution profile to the in vivo absorption profile, creating a model that allows dissolution data to predict bioavailability. A validated Level A IVIVC, where the in vitro dissolution curve maps point-by-point to the in vivo absorption curve, is the most valuable outcome: it allows dissolution testing to serve as a surrogate for bioavailability studies when the formulation changes. The FDA’s IVIVC guidance for extended release oral dosage forms outlines the requirements for establishing and using an IVIVC in regulatory submissions.

Establishing an IVIVC is not always feasible, particularly for Class II/IV molecules with complex absorption behaviour. But even a partial correlation, or a mechanistic understanding of why in vitro and in vivo profiles differ, is more valuable than a dissolution method selected without considering the biology.

Dissolution Testing for Modified Release Products

Extended release, delayed release, and pulsatile release dosage forms require dissolution methods that capture the full release profile over the intended release duration. A method that tests at a single timepoint, or that uses conditions where the release mechanism does not function correctly, will not discriminate failing from passing formulations.

For enteric-coated products, the dissolution method must include a two-stage test: acid stage exposure at pH 1.2 (to confirm the coating resists gastric conditions) followed by buffer stage at pH 6.8 (to confirm complete release in intestinal conditions). The duration and test conditions of each stage must reflect the gastric residence time expected in the target patient population.

Ardena’s Dissolution Development Expertise

Ardena’s analytical teams at Ghent develop dissolution methods as an integrated part of formulation development programmes, not as a separate analytical exercise. Method design is informed by the molecule’s BCS classification, the intended formulation, and the clinical context, ensuring that the method reflects in vivo performance and supports the regulatory filing.