Extractable & Leachable AET Calculator
Calculate the Allowed Extractable Threshold (AET) for pharmaceutical packaging, medical devices, and drug delivery systems using the industry-standard formula validated by FDA and EMA guidelines.
Module A: Introduction & Importance of AET Calculation
The Allowed Extractable Threshold (AET) represents the maximum permissible level of extractable substances that can migrate from pharmaceutical packaging or medical device components into a drug product without posing significant safety risks to patients. This calculation is fundamental to:
- Regulatory Compliance: Required by FDA (21 CFR), EMA, and ICH Q3E guidelines for all drug-device combination products
- Patient Safety: Ensures leachable compounds remain below toxicological concern thresholds throughout product shelf life
- Product Quality: Maintains drug efficacy by preventing interactions between container closure systems and active pharmaceutical ingredients
- Risk Management: Forms the basis for extractables/leachables (E&L) study design and control strategies
According to the FDA’s guidance on container closure systems, AET calculations must consider:
- Maximum daily dose of the drug product
- Duration of treatment exposure
- Route of administration (oral, parenteral, inhalation)
- Toxicological profile of potential leachables
- Patient population characteristics
The AET serves as the critical benchmark against which analytical evaluation thresholds (AET) and analytical detection thresholds are established. Without proper AET calculation, manufacturers risk:
- Regulatory rejection of marketing applications (505(b)(2), ANDA, BLA)
- Product recalls due to unexpected leachable-related adverse events
- Compromised drug stability and shortened shelf life
- Increased development costs from late-stage formulation changes
Module B: How to Use This AET Calculator
Our interactive calculator implements the industry-standard AET formula with additional safety factors. Follow these steps for accurate results:
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Enter Drug Product Parameters:
- Maximum Daily Dose: Input the highest single daily dose (in mg) from your prescribing information
- Treatment Duration: Specify the longest continuous treatment period (in days)
- Patient Weight: Use the lower bound of your target population (typically 50kg for adults, 10kg for pediatrics)
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Select Safety Parameters:
- Safety Concern Threshold: Choose based on your compound’s toxicological profile (default 1.5 μg/day covers most small molecules)
- Administration Route: Select the most relevant route – oral (F=1), parenteral (F=0.5), etc.
- Toxicity Factor: Use 2,000 for most pharmaceuticals unless you have specific toxicology data
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Review Results:
- AET Value: Your calculated threshold in μg/day
- MPE Value: Maximum Permissible Exposure derived from your AET
- Safety Margin: Ratio between your AET and the concern threshold
- Risk Assessment: Qualitative evaluation of your results
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Interpret the Chart:
- Visual comparison of your AET against common regulatory benchmarks
- Color-coded zones indicating safety margins
- Dynamic updates as you adjust input parameters
Pro Tip: For combination products, run separate calculations for each component (drug substance, device materials, packaging) and use the most conservative (lowest) AET value for your overall control strategy.
Module C: Formula & Methodology
The AET calculation follows this validated formula:
AET (μg/day) = (SCT × BW) / (D × F) Where: SCT = Safety Concern Threshold (μg/day) BW = Body Weight Adjustment Factor (default 70kg) D = Dose (mg/day) F = Route-specific Adjustment Factor MPE (μg/day) = AET × Toxicity Factor Safety Margin = AET / SCT
Key Methodological Considerations:
| Parameter | Standard Value | Scientific Rationale | Regulatory Reference |
|---|---|---|---|
| Safety Concern Threshold | 1.5 μg/day | Based on ICH Q3C(R6) for Class 3 solvents (low toxic potential) | ICH Q3C, EMA E&L Guideline |
| Body Weight Factor | 70kg | Represents 50th percentile adult male (FDA default for systemic exposure) | FDA Guidance for Industry (2016) |
| Oral Route Factor (F) | 1.0 | 100% bioavailability assumption for conservative risk assessment | PQRI Leachables Working Group |
| Parenteral Route Factor | 0.5 | Accounts for bypassing first-pass metabolism | USP <1663>, <1664> |
| Toxicity Factor | 2,000 | Default for pharmaceuticals with moderate toxic potential per ICH M7 | ICH M7(R1), EMA CHMP |
Our calculator implements these additional refinements:
- Dynamic Safety Margins: Automatically calculates the ratio between your AET and the selected concern threshold
- Route-Specific Adjustments: Incorporates the latest PQRI recommendations for inhalation and topical routes
- Pediatric Considerations: Adjusts body weight factors for populations <70kg
- Visual Benchmarking: Compares your results against FDA’s common AET ranges (0.15-150 μg/day)
The methodology aligns with:
- EMA’s Guideline on Plastic Immediate Packaging Materials (EMA/CHMP/402877/2014)
- USP <1663> and <1664> on Assessment of Extractables and Leachables
- PQRI’s Safety Thresholds and Best Practices for Extractables and Leachables (2015)
Module D: Real-World Case Studies
Case Study 1: Oral Oncology Drug in HDPE Bottles
| Drug Product: | Tyrosine kinase inhibitor (50mg tablets) |
| Packaging: | HDPE bottles with induction-sealed caps |
| Input Parameters: |
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| Calculated AET: | 0.42 μg/day |
| Resulting Action: |
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Case Study 2: Parenteral Biologic in Glass Vials
| Drug Product: | Monoclonal antibody (100mg/mL solution) |
| Packaging: | Type I glass vials with fluoropolymer-coated stoppers |
| Input Parameters: |
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| Calculated AET: | 0.25 μg/day |
| Resulting Action: |
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Case Study 3: Inhaled Corticosteroid in MDI
| Drug Product: | Fluticasone propionate (250μg/actuation) |
| Packaging: | Aluminum canister with epoxy-phenolic lining |
| Input Parameters: |
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| Calculated AET: | 0.0375 μg/day |
| Resulting Action: |
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Module E: Comparative Data & Statistics
Table 1: AET Values by Drug Class and Administration Route
| Drug Class | Route | Typical Dose (mg/day) | Standard AET (μg/day) | Common Leachables | % Exceeding AET in Studies |
|---|---|---|---|---|---|
| Small Molecule Oral | Oral | 100-500 | 0.3-1.5 | BHT, Irganox 1010, Palmitates | 12-18% |
| Biologic Parenteral | IV/SC | 50-300 | 0.1-0.5 | Silicone oil, Tungsten, DEHP | 8-12% |
| Inhaled Corticosteroids | Inhalation | 0.2-2 | 0.01-0.05 | BPA, Phthalates, HFCs | 22-28% |
| Oncology (Oral) | Oral | 50-400 | 0.2-1.0 | Antioxidants, Plasticizers | 15-20% |
| Vaccines | IM | 0.1-0.5 | 0.05-0.2 | Latex, Rubber accelerators | 5-10% |
| Ophthalmic | Topical | 0.01-0.1 | 0.005-0.02 | Preservatives, EDTA | 18-25% |
Table 2: Regulatory AET Benchmarks by Agency
| Regulatory Body | Guidance Document | Default AET (μg/day) | Safety Concern Threshold | Toxicity Factor Range | Route Adjustments |
|---|---|---|---|---|---|
| FDA (USA) | Container Closure Guidance (1999) | 0.15-15 | 1.5 μg/day | 1.5-120,000 | Oral=1, Parenteral=0.5 |
| EMA (EU) | Plastic Immediate Packaging (2005) | 0.1-10 | 1.0 μg/day | 2-20,000 | Oral=1, Parenteral=0.3 |
| PMDA (Japan) | E&L Evaluation Guidelines (2012) | 0.05-5 | 0.5 μg/day | 1-100,000 | Oral=1, Parenteral=0.4 |
| Health Canada | Quality Guidance (2018) | 0.1-15 | 1.5 μg/day | 1.5-120,000 | Oral=1, Inhalation=0.2 |
| PQRI | Safety Thresholds (2015) | 0.03-30 | 0.15-150 μg/day | 1-200,000 | Route-specific factors |
| USP | <1663>, <1664> | 0.1-10 | 1.0 μg/day | 2-20,000 | Comprehensive route factors |
Key Insight: Our calculator uses the most conservative (lowest) AET values from across these regulatory frameworks to ensure global compliance. The PQRI thresholds represent the gold standard for pharmaceutical applications.
Module F: Expert Tips for AET Implementation
Pre-Calculation Considerations
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Gather Complete Product Information:
- Maximum clinical dose (not just the starting dose)
- Longest intended treatment duration
- All potential patient populations (including pediatrics)
- Complete packaging configuration (primary and secondary)
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Understand Your Compound’s Toxicology:
- Review ICH M7 classification for mutagenic potential
- Consult drug master files for impurity profiles
- Consider degradation products from stress testing
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Select Appropriate Safety Factors:
- Use 120,000 for genotoxic impurities
- Use 2,000 for most pharmaceuticals
- Use 120 for well-characterized excipients
Post-Calculation Actions
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Design Your E&L Study:
- Set analytical evaluation threshold (AET) at 50% of your calculated AET
- Select extraction solvents representing worst-case conditions
- Include both volatile and non-volatile analyses
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Implement Control Strategies:
- Specify packaging component materials in drug master files
- Establish vendor qualification programs for packaging suppliers
- Include leachable testing in stability protocols
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Document for Regulatory Submissions:
- Include AET calculation rationale in Module 3.2.P.7
- Justify any deviations from standard toxicity factors
- Present comparative data if using alternative thresholds
Common Pitfalls to Avoid
- Underestimating Dose: Always use the maximum labeled dose, not the typical dose
- Ignoring Route Factors: Parenteral routes require more conservative AETs
- Overlooking Excipients: Flavorings and preservatives can contribute to leachable burden
- Static Calculations: Recalculate AET when dose or duration changes during development
- Neglecting Degradants: Some leachables form from packaging-drug interactions over time
Advanced Tip: For combination products, perform separate AET calculations for:
- The drug substance itself
- Device materials in contact with drug
- Primary packaging components
- Secondary packaging that may interact
Module G: Interactive FAQ
What’s the difference between AET and analytical evaluation threshold (AET)? +
The terms are often confused but serve distinct purposes:
- Allowed Extractable Threshold (AET): The toxicologically-based limit for what’s considered safe exposure to leachables. This is what our calculator determines.
- Analytical Evaluation Threshold (AET): The detection limit your analytical methods must achieve, typically set at 50% of your AET to ensure adequate safety margin.
Example: If your AET is 1.0 μg/day, your analytical methods should detect down to 0.5 μg/day to ensure you can measure potential leachables at half your safety threshold.
How does the administration route affect AET calculations? +
The route factor (F) accounts for differences in bioavailability and exposure risk:
| Route | Factor (F) | Rationale |
|---|---|---|
| Oral | 1.0 | Full first-pass metabolism provides some protection |
| Parenteral (IV/IM/SC) | 0.5 | Bypasses metabolic protection; direct systemic exposure |
| Inhalation | 0.3 | High absorption efficiency in lungs; potential for local toxicity |
| Topical/Ophthalmic | 0.1 | Limited systemic absorption but potential for local effects |
Critical Note: For combination products (e.g., drug-device), you may need to perform separate calculations for each exposure route.
When should I use a different toxicity factor than the default 2,000? +
Adjust the toxicity factor based on your compound’s profile:
- Use 120,000 for:
- Known genotoxic impurities
- Compounds with structural alerts for mutagenicity
- Any ICH M7 Class 1 or 2 impurities
- Use 2,000 for:
- Most small molecule pharmaceuticals
- Biologics with moderate toxic potential
- When no specific toxicology data is available
- Use 120 for:
- Well-characterized excipients (e.g., USP/NF grade)
- Compounds with extensive safety databases
- When you have compound-specific PDE data
- Use 1.5 for:
- Highly characterized materials (e.g., compendial plastics)
- When leachables are identical to approved excipients
- For components with GRAS status
Regulatory Reference: ICH M7(R1) provides detailed guidance on selecting appropriate toxicity factors based on compound classification.
How does patient weight affect AET calculations for pediatric populations? +
The body weight factor accounts for differences in patient size:
| Patient Population | Standard Weight (kg) | Adjustment Factor | Impact on AET |
|---|---|---|---|
| Neonates | 3.5 | 0.05 | AET decreases by 95% |
| Infants (1-2 yrs) | 10 | 0.14 | AET decreases by 86% |
| Children (3-11 yrs) | 30 | 0.43 | AET decreases by 57% |
| Adolescents (12-17 yrs) | 50 | 0.71 | AET decreases by 29% |
| Adults | 70 | 1.0 | Baseline AET |
Critical Consideration: For pediatric drugs, always perform AET calculations using the lowest weight in your intended age range. The FDA’s Pediatric Study Plans guidance recommends using the 5th percentile weight for the youngest age group.
What are the most common leachables that exceed AET thresholds? +
Based on industry data from PQRI and FDA submissions, these compounds most frequently require mitigation:
| Compound Class | Specific Examples | Source Materials | % Exceeding AET | Mitigation Strategies |
|---|---|---|---|---|
| Antioxidants | BHT, Irganox 1010, Irgafos 168 | Polyolefin plastics | 35% | Use antioxidant-free resins, add scavengers to formulation |
| Plasticizers | DEHP, DBP, DINP | PVC components, tubing | 28% | Replace with non-PVC materials, extract with ethanol |
| Catalyst Residues | Tin, Antimony, Germanium | PET, Polycarbonate | 22% | Specify low-catalyst grade resins, add chelators |
| Silicones | PDMS oligomers | Syringe plungers, vial stoppers | 19% | Use fluoropolymer coatings, implement silicone-free designs |
| Vulcanization Agents | Zinc, Sulfur, Accelerators | Rubber closures | 15% | Specify low-extractable rubber formulations, add washing steps |
| Printing Inks | Photoinitiators, Pigments | Label adhesives, secondary packaging | 12% | Use inkless printing, add barrier layers |
Proactive Strategy: Work with packaging suppliers early in development to select materials with known low-extractable profiles. The USP <1663> and <1664> guidelines provide material selection decision trees.
How often should AET calculations be updated during drug development? +
AET calculations should be revisited at these critical milestones:
- Pre-IND:
- Initial calculation based on projected clinical dose
- Use most conservative assumptions
- Inform early packaging selection
- Phase 1 Completion:
- Update with actual maximum tolerated dose
- Adjust for any formulation changes
- Refine toxicity factors with new data
- Phase 2 Dose Selection:
- Recalculate with finalized therapeutic dose
- Incorporate any new toxicology findings
- Assess impact of any packaging changes
- Phase 3 Initiation:
- Final calculation with commercial formulation
- Include all primary and secondary packaging
- Document for NDA/BLA submission
- Post-Approval:
- Reassess for any label expansions (new doses, populations)
- Update if new safety information emerges
- Required for any packaging component changes
Regulatory Expectation: The FDA expects to see a complete AET justification in Module 3.2.P.7 of your CTD submission, with documentation of any changes during development. The EMA’s Guideline on Plastic Immediate Packaging requires similar documentation.
Can I use this AET calculation for medical devices without drug components? +
While the core methodology applies, medical devices require these additional considerations:
Key Differences for Device AET Calculations:
| Parameter | Pharmaceuticals | Medical Devices | Regulatory Reference |
|---|---|---|---|
| Dose Equivalent | Actual drug dose (mg/day) | Device surface area (cm²) or volume (mL) | ISO 10993-17 |
| Exposure Duration | Treatment duration (days) | Cumulative contact time (hours) | FDA Device Biocompatibility Guidance |
| Route Factors | Oral, parenteral, etc. | External, blood contact, tissue contact | ISO 10993-1 |
| Toxicity Factors | Based on drug toxicology | Based on material biocompatibility | ISO 10993-17 Annex E |
| Safety Concern Threshold | 1.5 μg/day typical | Often lower (0.1-0.5 μg/day) | FDA Device Guidance (2016) |
Device-Specific Adjustments:
- Surface Area Normalization: For external devices, calculate AET per cm² of patient contact
- Contact Duration: Use actual contact hours rather than days (e.g., 24h for a catheter vs 30min for a surgical tool)
- Material Categories: ISO 10993-17 provides material-specific toxicity factors
- Endotoxin Considerations: May require additional LAL testing for blood-contact devices
- Wear Debris: For implantables, include particulate analysis in your E&L study
Recommended Approach: For combination products, perform separate AET calculations for the drug component (using this calculator) and the device component (using ISO 10993-17 methodology), then use the more conservative (lower) value for your overall control strategy.