Pharmaceutical Development and Technology

ISSN: 1083-7450 (Print) 1097-9867 (Online) Journal homepage: http://www.tandfonline.com/loi/iphd20

Determination and Application of the Permitted

Daily Exposure (PDE) for Topical Ocular Drugs in
Multipurpose Manufacturing Facilities

Ester Lovsin Barle, Jean-Claude Bizec, Milica Glogovac, Kamila Gromek &
Gian Christian Winkler

To cite this article: Ester Lovsin Barle, Jean-Claude Bizec, Milica Glogovac, Kamila Gromek &
Gian Christian Winkler (2017): Determination and Application of the Permitted Daily Exposure
(PDE) for Topical Ocular Drugs in Multipurpose Manufacturing Facilities, Pharmaceutical
Development and Technology, DOI: 10.1080/10837450.2017.1312442

To link to this article: http://dx.doi.org/10.1080/10837450.2017.1312442

Accepted author version posted online: 31

Mar 2017.

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Determination and Application of the Permitted Daily Exposure (PDE)
for Topical Ocular Drugs in Multipurpose Manufacturing Facilities

Ester Lovsin Barlea*, Jean-Claude Bizecb, Milica Glogovaca, Kamila

Gromeka, Gian Christian Winklerb

a
Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland

b
Novartis Pharma AG NIBR, Postfach, CH-4002 Basel, Switzerland

*Corresponding author:

Ester Lovsin Barle, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland,
[email protected]; Tel: +41613246256

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Co-Authors:

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Jean-Claude Bizec, Novartis Pharma AG NIBR, Postfach, CH-4002 Basel, Switzerland,
[email protected], Tel: +41798743462
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Milica Glogovac, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland,
[email protected]; Tel: +41616966851
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Kamila Gromek, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland

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[email protected]; Tel: +41616969193

Gian Christian Winkler, Novartis Pharma AG NIBR, Postfach, CH-4002 Basel,

Switzerland, [email protected]; Tel: +41613241432
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Determination and Application of the Permitted Daily Exposure (PDE)
for Topical Ocular Drugs in Multipurpose Manufacturing Facilities

Limits for the carryover of product residues should be based on toxicological

evaluation such as described in the ‘Guideline on setting health based exposure
limits for use in risk identification in the manufacture of different medicinal
products in shared facilities’ (EMA, 2014). The toxicological evaluation should
be performed also for locally administered drugs to ensure patient safety.
Currently, there is no guidance on setting PDE for ocular drug substances in
particular. The purpose of this investigation was to identify and describe a
method for calculating a PDE value for topical ocular drugs (PDEocular). As an
alternative method, extrapolation of a PDE for systemically administered drugs to
a PDEocular is presented. These methods may be applied in cross-contamination

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risk assessments for manufacturing of topical ocular drugs. Similarly, the
methods apply to systemically administered drugs, if their production precedes

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manufacturing of a topical ocular drug. We have examined pharmacokinetic (PK)
properties of topical ocular drugs and compared them to the PK parameters of
systemically administered drugs. Furthermore, we examined possible adverse
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effects of the carry-over in topical ocular drugs at therapeutic doses.
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Keywords: Ocular drug, Risk assessment, Permitted Daily Exposure (PDE),

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Cleaning Validation, Multipurpose Manufacturing Facility

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Introduction
A recently introduced EU GMP Guideline for Medicinal Products for Human

and Veterinary Use ANNEX 15 (PIC/S, 2015) describes the principles of qualification

and validation applicable to the facilities, equipment, utilities and processes used for

manufacturing of medicinal products. Section 9.5 states that the "limits for the carry-

over of product residues should be based on a toxicological evaluation to determine the

product specific permitted daily exposure (PDE) value“ and should be documented in a

risk assessment. The PDE represents a dose that is likely to be without an appreciable

risk of deleterious effects to the potential patient population, by any route, during an

average lifetime. This limit should be calculated in accordance with the revised GMP

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guideline and EMA’s "Guideline on setting health based exposure limits for use in risk

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identification in the manufacture of different medicinal products in shared facilities"

(EMA 2014). The concept of the PDE is similar to limits developed by other regulatory
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or authoritative bodies (as well as individual manufacturers) to define “tolerable” or

“acceptable” daily intake limits (TDI, ADI).

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Currently available guidance on setting PDE limits are focused on systemic

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effects mainly after oral, intravenous (IV) or inhalation exposure. To ensure patients

safety, the toxicological evaluation should have been performed also for locally
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administrated drugs, such as topical ocular drugs.

The primary aim of this publication is to develop a method for calculating a

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PDE value (PDEocular) specifically for active pharmaceutical ingredients (APIs), applied

via the topical ocular route (as drops or gels/creams). Drugs applied intravitreally and

high molecular weight APIs (>40kD) are not in scope of this manuscript. Additionally,

we propose a strategy for determination of the PDEocular followed by manufacturing of a

drug for systemic administration. Alternatively, a PDE conversion formula for

systemically administered drugs is provided, which is applicable as PDEocular for the

systemic drug, for topical ocular drugs produced on the same manufacturing equipment

after the production of drugs for systemic administration. Selection of adequate PDEs

for different production scenarios are examined and explained in detail.

Methodology/Background

PDE calculation
In a first step, the calculation of a PDE involves the hazard identification

(reviewing all relevant preclinical and clinical data), identification of critical health

effects (effects most likely to be relevant for the target population and target route of

exposure) and selection of the point-of-departure (PoD). Next, a reliable and robust no-

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effect level in humans has to be extrapolated by applying Composite Adjustment

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Factors (CAF) to the most relevant PoD. CAF is a result of multiplication of several

adjustment factors (AFs), covering various uncertainties as described in Table 1.

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PoD (mg/kg/day) * Body Weight (BW) (kg)
PDE (µg/day) = (1)
Composite Adjustment Factor (CAF)
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[TABLE 1]

An overview of the essential factors in ocular pharmacokinetics and their

impact on AFs selection
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Many clinically used topical ocular drugs are small molecules and fairly

lipophilic. The limiting molecular weight for conjunctival penetration is between 20 and
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40 kDa. After topical ocular administration, they are absorbed rapidly (within a few

minutes) to the systemic circulation (Boddu et al. 2014, Järvinen et al. 1995, Urtti

2006). This process may take place directly from the conjunctival sac via local blood

capillaries or the nasal cavity, which is extensively vascularized and thin. Only a few

studies investigating systemic absorption in humans can be found in the literature, e.g.
for timolol (almost 100% ocular absorption) or pilocarpine (up to 80%) (Urtti and

Salminen 1993). As the most conservative general approach, it is assumed that around

90% of a drug applied topically to the eye will end up in the circulation (Kim et al.

2014, Zafar et al. 2016). Systemic effects after topical ocular administration must be

identified and characterized in the comprehensive health hazard assessment for each

topical ocular drug.

Generally, the total amount of the applied drug is so small, that the level in the

blood is below detection limit or such data are not available (Kompella et al. 2010).

However, some exceptions have been described for molecules acting on receptors

which are not unique to the eye e.g. beta-blockers (e.g. timolol) or muscarinic

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antagonists (e.g. atropine, scopolamine) (Princelle et al. 2013, Izazola-Conde et al.

2011). TE
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Some topical ocular drugs are metabolized during or after absorption e.g.

pilocarpine, levobunolol and epinephrine (Nakano et al. 2014, Järvinen et al. 1995,
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Salminen 1990). Metabolism may reduce unwanted systemic drug effects.

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Ocular absorption of a drug may be limited also by some protective

mechanisms, which ensure proper functioning of the eye and by other concomitant

factors. For example drainage of the instilled solutions, lacrimation and tear turnover,
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and binding by the lacrimal proteins may impact ocular absorption.

Based on published literature intra-ocular bioavailability of topical ocular drugs

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is less than 5% (Kim et al. 2014, Petal et al. 2013, Kompella et al. 2010, Cholkar et al.

2014) and depends on drop volume as well (Keister et al. 1991). Some publications

state that only 1% or less of a topically applied drug will be absorbed across the cornea

and thus reach the anterior segment of the eye (Saettone 2002). From the aqueous

humor the drug has easy access to the iris and ciliary body, where the drug may bind to
melanin. Melanin bound drugs may form a reservoir that is released gradually to the

surrounding cells, thereby potentially lowering the activity (Cmax), but possibly

prolonging the drug activity (no changes in AUC) (Agrahari et al. 2016). There is a

clear intraspecies variability considering melanin distribution in the human population.

Individuals with deep brown irides may have up to four times more ocular melanin than

individuals with light blue eyes. This may impact therapy by the ocular route (Abelson

and McLaughlin 2014, Siegfried et al. 2011). Many classes of ocular drugs, including

alpha- and beta-adrenergics, antibiotics and corticosteroids, have been shown to bind to

melanin-containing tissues with high affinity (Abelson and McLaughlin 2014). In

general, due to the disposition in the anterior chamber and short biological half-life, the

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risk of bioaccumulation is low, even for individuals with high melanin level.

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The selection of AFs for LOAEL (Lowest Observed Adverse Effect Level) to
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NOAEL (No Observed Adverse Effect Level) for extrapolation and duration of

exposure may not be different for the calculation of the PDEocular and the calculation of
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the PDE for systemically administered drugs. The severity of effect AF must consider
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local as well as systemic critical health effects based on the whole dataset.

If preclinical studies are used as a basis for calculation, an appropriate

interspecies adjustment factor has to be applied. For ocular drugs, the most relevant
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species will be rabbit or monkey (Eskes et al. 2014). The relevance of the PK

parameters in the eye is compared between topical ocular drugs and systemically
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administered drugs in Table 2.

[TABLE 2]

Operational scenario considerations for manufacturing of ocular topical drugs

There are three possible operational scenarios for the manufacturing process of

topical ocular drugs (see Figure 1):

 First scenario: Manufacturing of topical ocular drug followed by manufacturing

of another topical ocular drug. In this case the PDEocular must be selected for the

Maximum Safe Carry-over (MSC) calculation.

Second scenario: Manufacturing of topical ocular drug followed by

manufacturing of a drug intended for systemic administration (e.g. IV, oral, inhalation).

In this case the correct PDE (e.g. PDEintravenous, PDEoral, PDEinhalation) must be selected

which reflects the route of systemic administration of the next drug produced in the

shared equipment.

Third scenario: Manufacturing of a drug intended for systemic administration

(e.g. IV, oral, inhalation) followed by manufacturing of a topical ocular drug. In this

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case the PDEocular must be selected for the MSC calculation.

[FIGURE 1]
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First scenario: Manufacturing of topical ocular drug followed by manufacturing
of another topical ocular drug
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This scenario results in much less uncertainty for PDE calculation than the other
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two scenarios, because both drugs have known safety profiles, posology and the same

route of administration. Human data are the most reliable for any PDE calculation.
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Therefore, the minimal topical ocular therapeutic dose (MinDD) or the lowest

pharmacologically effective dose (expressed in mg/eye/day) should be used as a PoD.

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This dose is considered as a LOAEL or NOAEL, depending on the significance of

effects observed (Bercu et al. 2016). Critical adverse effects must be recognized and

included into considerations. Key is the considerations of an identified adverse effect

potential and its dose level for local or systemic effects of topically applied drugs. With

the application of adequate AFs, the calculated PDEocular will provide sufficient
protection from critical adverse effects in the eye (even when applied to both eyes), as

well as from adverse systemic effects.

Equation 2, 3: Example of the calculation of the PDE and MSC in the

manufacturing scenario of a topical ocular drug (A) followed by manufacturing of a

second topical ocular drug (B). The assumption is that the drug load in the second drug

product is 100%.

MinDD ocular A
PDEocular [µg/eye/day] = (2)
CAF

PDE ocular A [µg/eye/day]* Batch size (product B)[kg]

MSC [g] = (3)
Max DD ocular (product B)

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Where:

CAF: Composite Adjustment Factor

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MinDD: Minimal ocular daily human therapeutic dose (mg/eye/day)
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MaxDD: Maximum ocular daily human therapeutic dose (mg/eye/day)

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MSC: Maximum Safe Carry-Over

Second scenario: Manufacturing of topical ocular drug followed by

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manufacturing of a drug intended for systemic administration (e.g. IV, oral,

inhalation)
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In general, the most relevant PoD for PDE calculation is the MinDD in the most

sensitive subpopulation, relevant for the intended route of exposure (Bercu et al. 2016).

For some topical ocular drugs, it is a challenge to select the adequate PoD and predict

critical effects after systemic exposure, if the systemic route of administration has not

been examined as well. Should the available dataset not cover all endpoints, such as

fertility or reproductive toxicity, the most sensible approach is comparison with other
drugs of the same class. Pharmacokinetics of some drugs administered to the eye may

resemble the intravenous route rather than the oral or enteral route of administration, but

usually the amount of the applied drug is below detection limit. Therefore, ocular

therapeutic doses will be over conservative, if used as a PoD for systemic PDE

calculation. Alternatively, the lowest ocular therapeutic dose may be used as a NOAEL

and no additional AF is applied. Frequently, systemic data are available e.g. for steroids,

antibiotics and analgesics. In this case the systemic NO(A)ELs are used as a PoD as

described in the section Methodology/Background of this manuscript.

Third scenario: Manufacturing of a drug intended for systemic administration

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(e.g. IV, oral, inhalation) followed by manufacturing of a topical ocular drug

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Especially, if a topical ocular drug is manufactured by a contract manufacturing

organization (CMO), it is possible that the preceding drug produced has been one
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intended only for systemic administration. For such a drug, a standard health hazard

assessment will not include a PDEocular. Only adverse health effects to the eye after
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systemic administration will be described. However, it is unlikely, that these adverse

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eye effects will be apparent after ocular administration due to its low ocular

bioavailability. For topical ocular drugs, it is known that they do not reach the posterior

segment drug targets (retina, vitreous, choroid). These targets may be treated by high
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drug doses administered intravenously or by intravitreal administration (Kim et al.

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2014, Kompella et al. 2010). Therefore, adverse effects which appear after systemic

administration need separate health hazard considerations, regarding their possible

relevance after topical ocular administration.

Alternative PDE calculation approach: how to convert the systemic PDE into a
PDEocular
The anatomy and physiology of the eye make it well suited for localized,

compartmental drug therapy (Urtti 2006). The human eye (in adults) is an

approximately globular structure with a diameter of 24 mm, and a mass of about 7.5

grams. The eyes occupy less than 0.05% of the total body weight (Kim et al. 2014),

which represents a factor of approx. 3000 when compared to the weight of the whole

body (assuming: 7.5 g per eye = 15 g weight of both eyes; the body weight of the

patient: 50 kg, therefore the conversion factor would be: 50 kg/15 g = 3333, rounded to

3000).

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If we apply the same criteria as for clinically used ocular topical drugs, it is

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expected that drugs intended for systemic administration will have a bioavailability in

the eye of 5% or less due to the presence of natural barriers (Reshma et al. 2015, Petal
EP
et al. 2013,). Additionally, drug absorption into the systemic circulation decreases the

drug concentration in lacrimal fluid extensively, resulting in a very short biological half-
C

life in the anterior chamber. Low bioavailability and short biological half-life reduce the
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potential for adverse effects in the eye.

Based on arguments regarding the low ocular bioavailability and the weight of
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the eyes, the systemic PDEiv may be modified for topical ocular administration

(PDEocular) by using a factor of 150 as seen in equation 6. PDEiv is already calculated as

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the safe dose for lifetime exposure considering 100% bioavailability. Consequently, if

the drug would be systemically absorbed with the dose of the PDEiv, no adverse

systemic effect would be expected. However, since 1-5% of the drug reaches the eye,

bioavailability may be adjusted to extrapolate the PDEiv to the safe dose for ocular

administration. In addition, the relation factor of eye to body weight is used as

correction formula. In this calculation example, the more conservative approach of 5%

topical ocular bioavailability is used.

% systemic bioavailability (route of exposure)

Bioavailability factor (BF) = (4)
% system bioavailability (route of administration at the PoD)

5 % (topical)
Bioavailability factor (BF) = (5)
100 % (iv)

PDEiv [µg/day] PDEiv [µg/day]

PDEocular [µg/eye/day] = = (6)
3000*0.05 150

Eq. 4-6: The use of bioavailability and PDEiv [µg/day] as an alternative formula to

calculate a PDEocular for systemically applied drugs

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Conclusions
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The topical ocular route is the most common route of ocular drug administration
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to the eyes. Eye-drops are convenient dosage forms, which account for 90% of currently

accessible ophthalmic formulations (Petal et al. 2013). The unique anatomy and
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physiology of the eye make it a highly protected and sensitive organ. Pharmacokinetic
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parameters are different for topical ocular drugs as compared to pharmacokinetics of

systemically administered drugs. In this paper, we have discussed the essential factors

in ocular pharmacokinetics and their impact on PDEocular calculation, as well as possible

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side effects (systemic and local). PDEocular should be always ≥ PDEiv, considering the

almost complete absorption to the circulation.

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The purpose of this investigation was to identify and describe a method for

calculating a PDE value for topical ocular drugs (PDEocular) and present appropriate

adjustment factors. Additionally, we propose a simple formula of calculating PDEocular

for MCS calculation in different settings of manufacturing in shared facilities. If a drug

intended for systemic administration is produced before a topical ocular drug, the factor
of 150 can be used to extrapolate a PDEocular from the PDEiv. This extrapolated PDEocular

is then used as the safe dose in the cleaning validation process for of the ocular drug.

Selection criteria for appropriate PDE values in cleaning validation risk assessments are

presented in table 3:

[TABLE 3]

Acknowledgements
The authors would like to thank Ronald Newton, Maarten Prause and Mark

Milton for their valuable contribution.

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Declaration of Interest
The authors report no declarations of interest.

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Table 1. Adjustment factors (AFs) typically used to account for uncertainties in the

derivation of the PDE for systemically administered drugs (Sussman et al. 2016).

Adjustment Value Purpose of the AF References

factor (AF) range

Interspecies 1-12 Differences between species: EMA 2014,

variability uncertainties associated with U.S. FDA

estimating a human equivalent dose 2005;

from animal studies Naumann and

As a default value: AF= 1 (when Weiderman

human dose is used) 1995.

D
Intraspecies Default Differences between individuals: EFSA

variability value: TE
physiological, biochemical or social Scientific
EP
AF=10 or aspects Committee

Calculated there is a possibility to derive CSAF 2012, EMA

C

value on case-by-case basis, when 2014, U.S.

AC

(CSAF) appropriate data is available: CSAF= EPA 2002,

HKAF x HDAF WHO 2001,

As a default value: AF=10 Naumann and

ST

Weiderman

1995.
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LOAEL to 1-10 In order to extrapolate to a BAuA 2014,

NOAEL NOAEL: ECETOC

from LOEL: AF= up to 10; or 2010, ECHA

LOAEL: AF= 3 2012, ISPE

As a default value: AF= 1 (when 2010,

 NOAEL, NOEL is defined) Sussman et al.

2016,

Naumann and

Weiderman

1995

Duration of 1-10 To extrapolate from the short or EMA 1998,

exposure sub-chronic exposure to the daily ICH S4 1998,

Default exposure BAuA 2014,

value (study shorter than the duration of 4- ECETOC

AF= 1 week is generally considered as 2010, ECHA

D
insufficient for PDE calculation) 2012, EFSA

TE
As a default: AF= 1 (a lifetime daily Scientific
EP
exposure, human therapy) Committee

2012,
C

Sussman et al.
AC

2016.

Database 1-10 Judgment on the quantity and ISPE 2010,

completeness quality of data (available studies, EMA 2014.

ST

gaps in the package)

As a default value: AF= 1 (no gaps

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identified)

Severity of effect 1-10 In order to provide an additional ISPE 2010,

margin of safety: severe or EMA 2014,

irreversible toxicity observed, e.g. Sussman et al.

embryo fetal developmental effects, 2016.

 necrotic degenerative organ lesions

As a default value: AF= 1 (no severe

effects were reported)

Bioaccumulation Calculated An adjustment may be needed if a Reichard et al.

value potential for bioaccumulation is 2016.

identified

Accumulation ratio= (1.44 x half-life)

/ Dosing interval

As a default value: AF= 1 (when

half-time is ≤24 hrs, or daily dose is

D
used as a PoD)

Bioavailability Calculated Differences in TE

route-specific Reichard et al.
EP
value bioavailability 2016.

As a default value: AF= 1 (when the

C

relevant route of administration is

AC

used)

a default value to extrapolate from i.v.

to oral: 50% for oral BA is assumed

ST

Composite Multiplication of all the above factors

adjustment
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factor (CAF)

*NOAEL: No Observed Adverse Effect Level, **LOAEL: Lowest Observed Adverse

Effect Level, ***LOEL: Lowest Observed Effect Level

Table 2. The relevance of the absorption, distribution, metabolism and elimination

(ADME) parameters in the eye as compared to systemically administered drugs. Since

topical ocular drugs do not reach the posterior segment drug targets (retina, vitreous,

choroid). Treatment may be accomplished by high drug doses given intravenously or

by intravitreal administration.

Parameter Ocular administration Systemic administration

Administration 1-5% bioavailability to the eye, Default 100% IV and inhalatory

the rest is systemic absorption bioavailability
Default 50% oral bioavailability

D
Distribution The volumes of distribution are Generally information is available
difficult to determine due to the for evaluation and assessment
slow equilibration of drug in the
ocular tissues
TE
case-by case
EP
Metabolism There are significant levels of Orally applied drugs can be a
various esterases, peptidases, subject of extensive first-pass
C

proteases and other enzymes in metabolism.

the ocular tissues. Presystemic
AC

hepatic first-pass metabolism is

avoided
ST

Elimination Half-lives of drugs in the Is assessed case-by case; some

anterior chamber are typically drugs have prolonged half-life,
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short, about an hour leading to the potential for

bioaccumulation
Table 3. Selection of PDE for the cleaning validation purpose.

To → Ocular DS Systemic DS

↓From

Ocular DS Use PDEocular based on ocular Use PDE for appropriate

PoD systemic administration of the

next DS

Systemic DS Use PDEocular based on Not in scope of this document

PDEIV/150

D
TE
EP
C
AC
ST
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