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HBEL

Calculate Health Based Exposure Limit for Cleaning Validation.

Summary

The method and theory for this caculartor are based on WHO TRS 1033 - Annex 2: Points to consider when including Health-Based Exposure Limits (HBELs) in cleaning validation.

Health-based exposure limits (HBELs) are substance-specific exposure limits established using toxicological and pharmacological data to define a level of exposure at or below which no appreciable risk to human health is anticipated. HBELs are applied in the context of pharmaceutical manufacturing to support a science- and risk-based approach to the prevention of cross-contamination, particularly in facilities and equipment used for the manufacture of more than one product.

HBELs are derived through a structured assessment of available non-clinical and clinical data, including information on pharmacology, toxicology, and, where available, clinical experience. The assessment identifies the critical effect and an appropriate point of departure, such as a no-observed-adverse- effect level (NOAEL) or, where necessary, a lowest-observed- adverse-effect level (LOAEL). Adjustment factors are applied to address uncertainties related to interspecies extrapolation, inter-individual variability, study duration, severity of effect, and limitations in the available data.

For the purposes of cleaning validation and cross-contamination control, the HBEL is typically expressed as a permitted daily exposure (PDE). The PDE represents the maximum acceptable daily intake of a substance that is considered to be without appreciable health risk, even if exposure were to occur on a daily basis over a lifetime.

HBELs should be established for all pharmaceutical substances manufactured in shared facilities, irrespective of their perceived toxicity or therapeutic class. The use of fixed or empirical limits that are not supported by scientific risk assessment is not considered acceptable as a general approach. HBELs provide a consistent and harmonized basis for the determination of acceptable residue limits, ensuring that patient safety remains the primary consideration.

HBELs should be route-specific, where relevant, and should take into account the intended route of administration of the subsequently manufactured product. Separate HBELs may be required where multiple routes of administration are applicable.

The establishment and maintenance of HBELs should be governed by written procedures and supported by appropriately qualified experts. The assessment, rationale, and conclusions should be documented in a manner that is transparent, traceable, and suitable for regulatory review. HBELs should be reviewed and updated when new or additional data become available, or when changes occur that may impact the original risk assessment.

In cleaning validation, the HBEL (expressed as a PDE) serves as the basis for the calculation of maximum safe carryover and maximum safe surface residue limits. These derived limits are used to design, justify, and verify cleaning procedures to ensure that residues remaining on shared equipment do not present a risk to patients exposed to the next product manufactured.

Step-by-step: Derive an HBEL (PDE) for a substance

  1. Set up governance and scope for HBELs
    • Establish and document a company-wide policy for HBEL setting for shared facilities.
    • Define when you'll generate/review HBELs (e.g., existing products and new products introduced via change control).
    • Define how scientific/toxicological data will be obtained, assessed, and how HBELs will be established (written procedure).
  2. Collect the full scientific/toxicological data package

    WHO expects the HBEL report to include (as applicable) items such as:

    • substance identification, chemical structure
    • indication, mode of action
    • route(s) of administration (separate HBELs if more than one route)
    • nonclinical toxicity (repeat dose, geno, carc, repro/dev, immunotox/sensitization)
    • clinical data, PK/PD
    • critical effect(s), point of departure, adjustment factors, and rationale
  3. Ensure qualified expert assessment (and peer review)
    • Data should be critically evaluated by a qualified expert (toxicology/pharmacology or related), and the report should be peer-reviewed by another qualified expert.
    • If outsourced, WHO expects controls like vendor qualification and agreements to ensure reliability.
    • If different assessors produce different HBELs for the same substance, the difference should be investigated/clarified.
  4. Identify the critical effect and pick a Point of Departure (PoD)
    • Determine the critical effect(s) and select a Point of Departure for the HBEL calculation.
    • WHO notes PoD can be based on a NOAEL/NOEL, or if unavailable, LOAEL/LOEL (or other acceptable PoD approaches).
  5. Choose route-specific HBEL(s)
    • If there is more than one route of administration, WHO expects separate HBELs for each route.
  6. Calculate PDE (this is the HBEL in this WHO document)

    WHO provides this structure for calculating PDE:

    PDE =NOAEL * weight adjustmentF1 * F2 * F3 * F4 * F5

    Key points from WHO:

    • F factors are adjustment factors; each selected value should be justified and ideally compound-specific; defaults are used only if compound-specific data are not available.
    • WHO describes what each uncertainty factor addresses:
    • F1 (2-12): interspecies extrapolation
    • F2 (10): inter-individual variability
    • F3 (10): short duration repeat-dose studies (<4 weeks)
    • F4 (1-10): severe toxicity considerations (e.g., non-genotoxic carcinogenicity, neurotoxicity, teratogenicity)
    • F5 (up to 10): when no NOAEL exists (e.g., using LOEL/LOAEL depending on severity)
    • If no NOAEL is obtained, WHO states LOAEL may be used.
    • WHO also allows additional modifying factors to address residual uncertainties if well supported and well discussed.

    Output of this step: a PDE in dose/day units (WHO presents PDE in the appendix context used later as ug/day).

    Regulators expect PDEs to come from a documented, expert-driven toxicological risk assessment or an appropriately justified authoritative source --not from historical rules of thumb.

Step-by-step: Convert HBEL (PDE) into cleaning limits (MSC to MSSR)

WHO's Appendix 1 gives an explicit, practical workflow to turn PDE into cleaning validation risk metrics.

  1. Calculate Maximum Safe Carryover (MSC)

    WHO Step 1 equation:

    MSC a (g) =PDE a (ug) * Batch size b (kg)Maximum Daily Dose b (mg)

    Where:

    • a = preceding product (the residue source)
    • b = subsequent product (next manufactured product)

    Practical interpretation:

    This gives the maximum amount of a allowed to carry over into b without appreciable patient risk (WHO glossary calls this MSC).

    Identify the product manufactured before the next product on this equipment (product a).

    Health-based exposure limit for product a. PDE is a substance- specific dose unlikely to cause adverse effects with lifelong daily exposure.

    Maximum daily dose (MDD) for the subsequent product (product b) used in the MSC denominator.

    Batch size for the subsequent product used to calculate maximum safe carryover (MSC).

  2. Enter inputs to see MSC results here.

    Tabulate your facility/product data

    WHO Step 2 instructs to tabulate at least:

    • API / PDE (ug/day)
    • MDD (mg/day) for subsequent product
    • Batch size (kg) for subsequent product
    • Shared equipment surface area (m2)
  3. Calculate Maximum Safe Surface Residue (MSSR)

    WHO Step 3 equation:

    MSSR (mg/m2) =MSC a (g) * 1000Shared surface for b (m2)

    WHO glossary also defines MSSR as MSC divided by total shared product contact surface area, i.e., MSC/Total Product Contact Surface Area. Use the product contact surface area calculator to confirm shared surface values.

    Total shared contact surface area used to convert MSC to a surface residue limit (MSSR).

    Enter inputs to see MSSR results here.

    Calculate swab limit
    Swab limit (mg/swab) =MSSR (mg/cm^2)Swab area (cm^2)

    Surface area represented by one swab sample for swab limits.

    Percent of residue recovered by swab sampling to adjust swab limits.

    Provide swab area to calculate swab limits.

    Calculate rinse limit
    Rinse limit (mg/L) =MSC (mg)Rinse volume (L)

    Total rinse volume collected for rinse-based limits.

    Percent of residue recovered by rinse sampling to adjust rinse limits.

    Provide rinse volume to calculate rinse limits.

  4. Build the product-to-product risk matrix and identify risks

    WHO Step 4 says to tabulate MSSR and identify where there is risk based on MSSR not being met when considering:

    • cleanability of the procedure, or
    • visual residue limit of the compound/product

What you should keep as documented outputs (per WHO expectations)

At minimum, your HBEL/PDE package should result in:

  • An HBEL report with the required scientific elements and rationale (critical effect, PoD, factors, route-specific values).
  • Evidence of qualified expert assessment and peer review.
  • A documented dataset and calculations for MSC and MSSR, plus the matrix of preceding vs following products to support cleaning validation risk decisions.

Batch calculation for multiple compounds

Download the template, fill one compound per row, then upload to receive a results file.

Regulatory references

Read-only guidance aligned with major regulatory bodies.

FDAEMAICHUSPISPEPDA