# What is No Observed Adverse Effect Level – NOAEL and LD50

## No Observed Adverse Effect Level – NOAEL versus LD50

Understanding what is No Observed Adverse Effect Level NOAEL and LD50 is very important during cleaning validation.

No Observed Adverse Effect Level NOAEL is defined as the greatest concentration or amount of a substance found by experiment or observation which causes no detectable adverse alteration of morphology, functional capacity, growth, development, or life span of the target organism under defined conditions of exposure.

This term is used commonly in cleaning validation to denote the level of exposure of a person or animal, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effects of the tested protocol.

Do not confuse the No Observed Adverse Effect Level NOAEL with the LD50.

## What is LD50?

The LD50 is a standard measurement of acute toxicity that is stated in milligrams (mg) of pesticide per kilogram (kg) of body weight. An LD50 represents the individual dose required to kill 50 percent of a population of test animals (e.g., rats, fish, mice, cockroaches). Because LD50 values are standard measurements, it is possible to compare relative toxicities among pesticides. The lower the LD50 dose, the more toxic the pesticide.

## How to determine the maximum exposure based on the NOAEL or LD50?

Assumes that all of the (organic and inorganic) residues are comprised of the most toxic agent.

Maximum Exposure = Tolerance Intake = NOAEL,

LOAEL x Body Weight / Uncertainty Factors =

or LD50 x Body Weight / Uncertainty Factors.

Generally, the NOAEL limit will be greater than the limit calculated from LD50.

This reflects the lack of certainty when using data that is less directly derived.

The limit to be used is the NOAEL limit, if NOAEL data is not available then use LD50 derived limit.

Assure a Body weight 70kg (See note 1 below)

Tolerance Intake = (LD50) / Uncertainty Factors

Uncertainty Factors:

UF1 = Inter-individual variation among humans variability (range 1-10) default 10

UF2 = Extrapolation from a species that is not human (range 1-10) default 10

UF3 = Quality relevance of experimental data (range 1-100) default 10 – LD50

= Source of data (reputation), implantation vs oral, arbitrary end-point (LD50)

Oral: devices (transient exposure):implant = 1:3:10

WHO = 1 Random independent Source = 10

50% endpoint = 10.

NOAEL = 1

So, UF3 = 30 for devices, 100 for implant if using LD50 from WHO.

Multi-device factor default 10 (assumes -10 devices/exposure – i.e. max exposure is shared between multiple devices) (M)

Note 1: Bodyweight – default maximum of 70 kg for general patient population – use lower e.g. for pediatric products application.

Note 2: During organic residue evaluation, you will use the most toxic component as “worst case” – no need to quantify ALL components of residue. In-organic – need to test/quantify for each component of residue individually.

Acceptable residue per device = Max Exposure = Tolerance Intake x Body Weight

Tolerance Intake = NOAEL or LOAEL / Uncertainty Factors or

LD50 / Uncertainty Factors.

Samples were taken in the final package (vs immediately at the exit from cleaning)

Refer to the current version of USP Chapter <232> for the requirement for the following (4) four inorganic elements:

## FDA Definition of No Observed Adverse Effect Level NOAEL

In other words, the No Observed Adverse Effect Level – NOAEL “is the highest dose level that does not produce a significant increase in adverse effects in comparison to the control group.”

### STATUTORY AND REGULATORY REQUIREMENTS

More details on specific FDA expectations can be found in the guidance document below.

httpss://www.iso.org/standard/53394.html

For a preview, refer to httpss://www.iso.org/obp/ui/#iso:std:iso:14644:-1:ed-2:v1:en

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## References

PIC/S Guideline to Validation – PI -006-3 (2007)

ICH Guideline Q7 “GMP for APIs

Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide

httpss://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=225.1

httpss://www.fda.gov/validation-cleaning-processes-793

httpss://www.gmp-compliance.org/gmp-news/what-does-the-fda-expect-from-cleaning-validation-today

httpss://gmpnews.net/2019/06/fda-requirements-for-cleaning-validation/

httpss://www.pda.org/docs/default-source/website-document-library/chapters/presentations/australia/contamination-control-cleaning-validation.pdf?sfvrsn=4

## Related topics and resources:

Validation Plan, Installation Qualification, Operational Qualification, Performance Qualifications, Component Qualification, Traceability Matrix, Ppk, Control Charts, Cpk, User Requirements, Functional Requirement Specifications, GAMP5, risk assessment

## Ramon Cayuela, MS, BS, Chemical Engineering

CIQA President and CEO.
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