Mariah Ultramari, PhD – Specialist in Degradation Products

2018 Pharmaceutical Industry and Regulators Symposium

▪ Background

▪ Cases

▪ Concluding Remarks

2005

RE n.1

Stability Guideline

2008

IT n.1

Degradation Product

1999

ANVISA creation

2012

CP n.11

2013

RDC n.58

2015

RDC n.53

Guideline n.4

2017

RDC n.171

Post marketed deadlines reviewed

2016

ANVISA became

member of ICH

2006

ICH Q3B (R2)

(1996)

2015

ICH M7

2017

RDC n.200

Compatibility Studies

2014

RDC n.60

Compatibility Studies

Adapted from Lhasa presentation, Sindusfarma, april2018

✓ Hydrolysis H+/OH-

✓ Oxidation

✓ Heat

✓ Light

✓ NaOH 1M/60°C/10days 12%

✓ HCl 1M/RT/10days 10%

✓ Oxidation 3%H2O2/24h 10%

✓ Heat 60°C/10days 7%

✓ Light 1 cycle 7%

Experiment Design 1Before Zeneth and Forced Degradation Studies

✓ Diluent

✓ Pigments

✓ Antioxidant

✓ Lubricant

API

15 days

15 days

Experiment Design 2After Zeneth and Forced Degradation Studies

✓ Diluent

✓ Pigments

✓ Antioxidant

✓ Lubricant

100% API

EUREKA!

Adapted from Lhasa presentation, Sindusfarma, april2018

Hydrolysis

HCl 6M/24h/60°C 87%

API

NaOH 0.05M/10min/RT 90%

API

Adapted from Lhasa presentation, Sindusfarma, april2018

Hydrolysis

* Allmendinger, T., et al - Reaction of the API with Lactose

Lactose adduct

Unknown impurity

Experiment Design

✓ Lactose

✓ Lubricant15 days + Unknown Impurity

Development of Stability Indicating Method

Internally or by partners

STEP

01

Impurities acquisition:

✓ Pharmacopoeias

✓ DMF

✓ Suppliers

Adapted from Lhasa presentation, Sindusfarma, april2018

API Oxidation

API N-oxide

STEP

02Method Validation

Internally

STEP

03

STEP

04

STEP

05

Stability Study

For new drugs and post marketed

Identification assays

Internally or by partners

Qualification assays

In silico, in vitro, in vivo

Development of Stability Indicating Method

Internally or by partners

STEP

01

Long Term Stability Study2 Degradation Products above

specification

(unknown)

STEP

04Identification assays

Internally or by partners

R

R

R

R

R

R

Zeneth has been routinely and successfully applied tosolve Aché’s demands from the very beginning of theprojects until the end;

Nice tool to design compatibility studies, stresstesting and also identification of degradationproducts;

In silico prediction can help us to choose theimpurities for acquisition, saving money and time;