Challenges in the use of Permitted Daily Exposure for

cleaning risk management

Carsten Baun SenholtPrinciple Scientist, Novo Nordisk A/S

Challenges in the use of Permitted Daily Exposure for cleaning risk management 20 April 2016, ISPE Copenhagen - Carsten B. Senholt

Content

• What is risk• What is exposure • What are health based exposure limits• Why use animals data?• Translation of non-clinical data• PDE model as defined in the ICH guidelines • Relationship with other impurity guidelines such as the

ICH M7 for mutagenic impurities• Case studies for biological products

Key messages

• Carry-over constitute a patient risk that can be managed but never eliminated

• Human data takes precedence to animal data but not all effects can be covered

• Permitted Daily Exposures can be calculated using broadly established translation factors

• The threshold of toxicological concern in ICH M7 can be useful when limited toxicity data is available

• Biologicals may not require considerations for carry-over of active substance

Challenges in the use of Permitted Daily Exposure for cleaning risk management 20 April 2016, ISPE Copenhagen - Carsten B. Senholt

Risk carry-over and the challenge to manage it

PDEs for cleaning rationale in multipurpose manufacture plants Jan 2014 4

0.5-1M

NaOH

40-60°

1 hour

How low should verification

assays be able detect ?

What is risk management?

• planning and carry out identification, estimation, prioritation and control of risks according to previously specified risk acceptance (safety) policy

• where risk is a product of severity and propability of harm

• zero risk cannot be obtained

Many steps involved in exposure

Potencyand affinity

Patient exposure

Cell

Toxic effects

Absorption

Distribution

Metabolism

Excretion

Periferal binding

Blood plasmaSite ofadministration

Target organ

20 April 2016, ISPE Copenhagen - Carsten B. Senholt Challenges in the use of Permitted Daily Exposure for cleaning risk management

Why use animal data?

• Clinical data is based on a human response and there preferred to animal data

• Some safety hazards (eg. immunogenicity) can only be addressed by human data

• Some effects observed in animals have no human relevance

• BUT a lot of important endpoints (eg. mortality and histopathology) cannot be observed in clinical trials

• Developmental and reproduction toxicity cannot be studied in the clinical without substantial bias

• Most cancers takes too long to develop in humans

”Dose makes the poison”Paracelsius (1493-1541) each of ten years

”You too can be a toxicologist in two easy lessonsArnold Lehman 1955-

Two fathers of toxicology

20 April 2016, ISPE Copenhagen - Carsten B. Senholt

Health base exposure limits

Dose-response

Dose makes the poison

Paracelsius

Dose

Critical effect(s)

Acceptable risk

Hazard identification

Acceptable exposure

Uncertainty assessment(Safety margin)

Mechanism(s) Relevance to man

Challenges in the use of Permitted Daily Exposure for cleaning risk management 20 April 2016, ISPE Copenhagen - Carsten B. Senholt

Translation (1)Animal versus man

• Sufficient evidence for mechanism with no human relevance

• Sensitivity between species

Challenges in the use of Permitted Daily Exposure for cleaning risk management 20 April 2016, ISPE Copenhagen - Carsten B. Senholt

Translation (2)Human population

articleStory

Translation (3)Other sources of variability

• Duration studies • Nature (severity) of findings• Quality of the dose-response established• Route of administration

Challenges in the use of Permitted Daily Exposure for cleaning risk management 20 April 2016, ISPE Copenhagen - Carsten B. Senholt

Permitted Daily Exposure (PDE) is a well-established acceptance criteria

WHO EHC 170ICH Q3C Appendix 3

F2 = 10 for variation between individual humans

F3 = Short duration animal studies to chronical human exposure

F4 = 10 for teratogencity, neurotoxicity and non-genotoxic carc

F5 = 10 for using LOAEL

F1 = 2-12 for variation between species

An example: Di(2-ethylhexyl)phthalateCas no 117-81-7

Study Route NOAEL(mg/kg/day)

LOAEL(mg/kg/day)

Effect(s)

Jacobson et al. (1977) IV 0.021 Histopathological changes in liver, altered BSP clearance kinetics

Rubin and Chang(1978)

IV 7.7 to 13 Pulmonary effects

Rutter (1973) IV 21.4 Hepatomegaly, increased liver enzyme levels, increased lung weight

Rubin and Chang(1976)

IV 40 Reduced blood pressure

Petersen et al. (1975) IV 5.0 Reduced fertility

Sjoberg et al. (1985a) IV 25 250 Altered Sertoli cells, degeneration of primaryspermatocytes

AdvaMed (2001) IV 60 300 Testicular atrophy, decrease in diameter ofseminiferous tubules and depletion of

germinal cells in testes, hepatomegaly

Ref:: Safety Assessment of Di(2-ethylhexyl)phthalate (DEHP); Center for Devices and Radiological Health; U.S. Food and Drug Administration.

20 April 2016, ISPE Copenhagen - Carsten B. Senholt Challenges in the use of Permitted Daily Exposure for cleaning risk management

Di(2-ethylhexyl)phthalateCas no 117-81-7

PDE (mg/kg/day) =

NOAEL

5 x 10 x 10=

25 mg/kg/day

500

= 0.05 mg/kg/day

Relationship to ICH M7

• Explicit TTC values derived for different duration of exposure

• Applies to clinical trial products

• Only mutagenicity is considered

• Does not apply to peptide and proteins

Challenges in the use of Permitted Daily Exposure for cleaning risk management 20 April 2016, ISPE Copenhagen - Carsten B. Senholt

Questions