Note: If the available dose is expressed per kg body
weight, a body weight of 60 kg is assumed, and the
dose is calculated accordingly before insertion
into the above equation.
UFc = Composite uncertainty Factor(s)
- UFH = Inter-individual variability and
seriousness of effect
- UFA = nterspecies differences; extrapolation from
other animal to human.
- UFS = For extrapolating from short study
duration to long study duration
- UFL = Dose to Presumed No Effect Level (PNEL)
- UFD = Database Completeness
MF = Modifying Factor(s)
α = Bioavailability Factor
AF = Accumulation Factor
V = Volume of air breathed in 8 hr. period ( 10 m3 per day for mod-
erate work load)
III. ADE Setting
As with the setting of an OEL, the purpose of a hazard evaluation
in setting the ADE is to identify all possible hazards associated with
a pharmaceutical product and to rank hazards according to their severity. When combined with a dose-response assessment, the critical
effect can be defined. This is typically the first clinically significant
adverse effect that is observed as the dose increases.
The ADE is used to derive swab or rinse limits for cleaning validation purposes. In order to apply ADEs to specific subpopulations,
further adjustments may be required to address a variety of uncertainties, as well as differences in bioavailability when extrapolating
between different routes of exposure. Normally, the ADE is based on
the data for the route that it will be applied to in the evaluation. If
route-to-route extrapolation is necessary, a sound scientific rationale
is required to support application to a different route.
An example ADE calculation (expressed in milligrams or micro-
grams per cubic per day) is shown as:
ADE (mg/day)= NOAEL mg/kg/day ; BW (kg)
UFc ; MF ; PKF
Where: NOAEL = No Observable Adverse Effect Level. If a NOAEL or
NOEL is not available other values are used such as:
• LOAEL = Lowest Observed Adverse Effect Level
• LOEL = Lowest Observed Effect Level
• Lowest Therapeutic Dose (LTD)
BW = Body Weight
UFc = Composite Uncertainty Factor(s)
- UFH = Inter-individual variability or seriousness of effect
- UFA = Interspecies differences; extrapolation from other animal to
- UFS = For extrapolating from short study duration to long study
- UFL = LOAEL to presumed NOAEL extrapolation. Where a LOAEL
is not available the lowest dose may be extrapolated to a PNEL
using a larger factor as appropriate.
- UFD = Database Completeness
MF = Modifying Factor(s)
PKF = Pharmacokinetic Factor
IV. Hazard Bands
Based on the hazard characterization and devel-
opment of an OEL, APIs can be placed into hazard
or control bands depending on their potency and
toxicological effects. This is the first step in the identifi-
cation of the hazard potential of the New Chemical Entity
(NCE) or API and the associated exposure controls to ensure
personal protection and minimize product cross contamination
when handling potent and highly potent APIs. Each hazard/control
band should be associated with safe handling guidelines that outline
the appropriate facility, equipment, and administrative controls to
ensure exposure is maintained below the OEL for the NCE/API. In
general, a potent API is defined as one with an occupational exposure
limit (OEL) at or below 10 µg/m3 and a highly potent API as having an
OEL below 1 µg/m3. Good industrial hygiene practice dictates that the
primary means to control personal exposure be engineering controls.
Containment equipment such as isolators, contained transfer sys-
tems, and other contained chemical and pharmaceutical process equip-
ment are examples of these types of engineering controls in use today.
Containment systems and equipment with integrated containment sys-
tems are being designed and used by bio(pharmaceutical) manufacturing
facilities for all operations and for all dosage forms including solid, paren-
teral, and others, including inhalation and dermal, to control personal ex-
posure and minimize cross contamination within a multi-product facility.
The process of selecting containment equipment and systems
1) Perform a process review of the process steps, unit operations,
and tasks (including charging/discharging, in-process manipulations, sampling, and cleaning).
2) Identify the APIs, intermediates, and finished products to be
handled and processed, including their associated OELs and/or
3) Set a containment performance target (CPT) for the process.
4) Specify and select the containment equipment and devices based
on the task list and the CPT.
5) Verify containment performance by performing a factory acceptance test (FAT) and site acceptance test (SAT).
6) Evaluate containment performance and occupational exposure to
workers during actual operations processing the NCE or API.
With the demand for these High Potency Active Pharmaceutical
Ingredients continuing to increase, having an understanding of the regulatory landscape and utilizing a risk based approach to manufacturing these
products is critical for pharma and CMOs interested in expanding or adding high-potency API capacity. Expanded use of these types of ingredients
will continue to challenge manufacturing, quality and design professionals. Having a multi-disciplined team consisting of process technologists, industrial hygienists, regulatory compliance and cleaning validation personal
assess the risks will result in a successful outcome for your project. ■
1 Roots Analysis Private Ltd, HPAPIs and Cytotoxic Drugs
Manufacturing Market, 2014-2024, August 2014