Forced degradation studies comparison between ICH, EMA

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Forced degradation studies comparison between ICH, EMA

Transcript Of Forced degradation studies comparison between ICH, EMA

Forced degradation studies – comparison between ICH, EMA, FDA and WHO guidelines and ANVISA’s resolution RDC 53/2015
Wissenschaftliche Prüfungsarbeit zur Erlangung des Titels
„Master of Drug Regulatory Affairs“
der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms -Universität Bonn
vorgelegt von Helene Janzen aus Susanowo
Bonn 2016

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Betreuer und 1. Referent: Prof. Dr. Usfeya Muazzam 2. Referent: Dr. Christin Selent-Stier

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Table of Contents
List of Figures ......................................................................................................................... IV
List of Abbreviations............................................................................................................... V
1. Introduction and scope ..................................................................................................... 1
2. Forced degradation studies .............................................................................................. 2 2.1 Terms for forced degradation........................................................................................... 2 2.2 Purpose of forced degradation testing.............................................................................. 2
3. Regulatory overview ......................................................................................................... 4 3.1 ICH guidelines - regulatory overview.............................................................................. 4 3.1.1 ICH Q1A – Stability Testing of New Drug Substances and Products ......................... 5 3.1.2 ICH Q1B – Photostability Testing of New Drug Substances and Drug Products........ 6 3.2 ICH Q2B – Validation of Analytical Procedures: Methodology..................................... 7 3.2.1 ICH Q3A Impurities in New Drug Substances/ ICH Q3B Impurities in New
Products ........................................................................................................................ 8 3.2.2 M4Q(R1) – The Common Technical Document for the Registration of
Pharmaceuticals for Human Use: Module 3: Quality................................................... 8 3.3 EMA guidelines - regulatory overview............................................................................ 9 3.4 FDA guidelines - regulatory overview .......................................................................... 10 3.5 Pharmacopoeia requirements- regulatory overview ...................................................... 12 3.5.1 USP Pharmacopoeia ................................................................................................... 12 3.5.2 JP Pharmacopoeia....................................................................................................... 12 3.1 World Health Organization............................................................................................ 12 3.2 Typical stress test conditions for forced degradation studies ........................................ 15 3.2.1 Thermal stress tests - dry heat and wet heat ............................................................... 16 3.2.1 Photolytic degradation ................................................................................................ 16 3.2.1 Hydrolytic degradation ............................................................................................... 17 3.2.1 Oxidation degradation ................................................................................................ 17 3.2.2 Current view on limits for forced degradation ........................................................... 18 3.2.3 Analytical methods for identification of degradation products .................................. 18 3.2.4 Time point for performing forced degradation studies............................................... 20 3.3 ANVISA – regulatory overview .................................................................................... 21 3.3.1 Background and history on the ANVISA legal requirements regarding stability and
forced degradation ...................................................................................................... 21 3.3.2 General remarks to applicability and timelines of ANVISA’s resolution RDC
53/2015 ....................................................................................................................... 23 3.3.3 Comparison between resolution RDC 53/2015 and ICH guidelines and critical
assessment .................................................................................................................. 24
4. Discussion ......................................................................................................................... 35
5. Outlook............................................................................................................................. 36 5.1 Degradation profile protocol.......................................................................................... 37 5.1.1 Purpose of degradation study ..................................................................................... 37 5.1.2 Information on the structural formula ........................................................................ 38 5.1.3 Analytical procedure................................................................................................... 38 5.1.4 Overview of the performed Studies............................................................................ 38 5.1.5 Results of the studies .................................................................................................. 39 5.1.6 Evaluation and conclusion of the degradation studies................................................ 40
6. Conclusions ...................................................................................................................... 42

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7. Summary .......................................................................................................................... 43 References ............................................................................................................................... 45

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List of Tables
Table 1: Definitions for forced degradation testing and confirmatory studies........................... 6 Table 2: Typical stress conditions in pre-formulation stability studies [30]............................ 14 Table 3: Adopted RDC 53/2015 versus ICH definitions [1, 5, 7, 15, 16, 58].......................... 25 Table 4: Thresholds for degradation products according to resolution RDC 53/ 2015 .......... 33 Table 5: Thresholds for degradation products according to ICH Q3B .................................... 34 Table 6: Structural and molecular formula, chemical name of drug substance/ characterized
impurities ............................................................................................................... 38 Table 7: Stress conditions ........................................................................................................ 39 Table 8: Assay and degradation profile at 70°C in Fe2+ and Cu2+ solution ............................. 40
List of Figures
Figure 1: Importance of forced degradation in pharmaceuticals................................................ 4 Figure 2: General stress conditions used for drug substances and drug products for
degradation studies [32] ........................................................................................ 15 Figure 3: Timing for performing forced degradation studies................................................... 21 Figure 4: Development on ANVISA’S forced degradation legislative.................................... 22

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List of Abbreviations

ANVISA

National Health Surveillance Agency (in Portuguese Agência Nacional de Vigilância Sanitária)

Art.

Article

API

Active Pharmaceutical Ingredient

ATD

Average Daily Dosage

CGMP

Current Good Manufacturing Practices

CP

Public Consultation (in Portuguese Consulta Pública)

CTD

Common Technical Document

DMF

Drug Master File

EMA

European Medicines Agency

FDA

Food and Drug Administration, USA

FDC

Fixed-Dose Combination

FPP

Finished Pharmaceutical Product

HPLC

High Performance Liquid Chromatography

ICH

International Conference on Harmonization

IND

Investigational New Drug Application

JP

Japanese Pharmacopoeia

LoD

Limit of Detection

LoQ

Limit of Quantification

PDA

Photodiode Detector Array

QOS-PD

Quality Overall Summary - Product Dossiers

RDC

Board Resolution Collegiate (in Portuguese Resolução de Diretoria Colegiada)

RRF

Relative Response Factor

RRT

Relative Retention Time

RH

Relative Humidity

RT

Room Temperature

USP

US Pharmacopoeia

UV

Ultraviolet

WHO

World Health Organization

EPAR

European Public Assessment Report

WHOPAR

World Health Organization Public Assessment Report

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1. Introduction and scope
Forced degradation is an exposure of the drug substance or drug product to different stress conditions (more severe than accelerated conditions) [1] which results in relevant degradation products. Purposefully used forced degradation is a useful tool in predicting drug stability. The drug stability is a critical parameter and has an impact on purity, potency, and safety of the drug product. For instance, changes in drug stability can result in lower doses or toxic degradation products. Therefore it is fundamental to know the behavior and the purity profile of a drug under various conditions [2].
Currently several guidelines provide recommendations and guidance on forced degradation studies, but none of the guidelines gives detailed, complete and clear instructions or definitions regarding the individual aspects e.g. exact conditions or exposure times. This leads to uncertainty and disagreement between the pharmaceutical companies resulting in different approaches when conducting forced degradation studies.
In the past years one of the national regulatory agencies - the Brazilian National Health Surveillance Agency (ANVISA) - has dedicated themselves to deal with the topic “forced degradation”. ANVISA has taken over a pioneering task in establishing further requirements and guidance in comparison to what is currently available.
In 2013 ANVISA published resolution RDC 58/2013 and introduced new standards for reporting, identification and qualification of degradation products in drug products [3]. To enable the companies to comply with the new requirements ANVISA additionally issued a degradation products guide, the revised document CP 68 [4]. The guide is intended to promote the views of ANVISA regarding the degradation profile and the testing procedures for the identification and qualification of degradation products.
According to the deadline for the Collegiate Board Resolution (RDC), the resolution RDC 58/2013 was expected to come into force end of December 2015. But on December 4th 2015 ANVISA revoked RDC 58/2013 and published instead an updated version of this resolution: Resolution RDC 53/2015 [5]. Resolution RDC 53/2015 includes updated standards on different aspects and topics of forced degradation to which the pharmaceutical companies have to comply. For all new concentration or new dosage form inclusions the new resolution became valid on December 23, 2015. For medicines which are already registered in Brazil the resolution RDC 53/2015 includes different timeliness for the implementation.

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The aim of this master thesis is:  To provide a general overview on the topic forced degradation and on the current available regulatory guidance (ICH including EMA, FDA and WHO)  To give an overview on the requirements of resolution RDC 53/2015 and provide a comparison between the new standards laid down in ANVISA’s resolution RDC 53/2015 and the currently available regulatory standards  To start a discussion on the differences and similarities as well as the challenges and critical points for the pharmaceutical companies to meet the new requirements  To discuss the content of a protocol describing the degradation profile for products, which is requested by ANVISA to be provided by the pharmaceutical companies in the content of this resolution

2. Forced degradation studies

2.1

Terms for forced degradation

Internationally different terms are used for the description of forced degradation. Even within the ICH guidelines more than one term for the description of forced degradation is used e.g. ICH Q1A [1] uses the term ‘stress testing’, while ICH Q1B [7] uses the term ‘forced decomposition’.

2.2

Purpose of forced degradation testing

According to the ICH guideline Q1A, section 2.1.2 the purpose of stress testing for the new drug substances is as follows [1]:

“Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved”.

In summary, from the regulatory perspective, forced degradations studies are performed [1]:

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 To identify possible degradation products  To establish degradation pathways and intrinsic stability of the drug molecule  To validate stability-indicating analytical procedures
When looking beyond ICH guidelines and looking into the literature and the current trends for forced degradation studies, the initial purpose of forced degradation studies is to understand drug molecule chemistry [8], to investigate stability-related properties of an API and to develop an understanding of the degradation products and pathways [9]. In following a selection of purposes for performing forced degradation studies is listed [2, 8, 9, 10, 11, 12]:
 “to elucidate the structure of the degradation products”  “to develop and validate a stability-indicating analytical method”  “to identify impurities related to drug substances or excipients”  “to generate more stable formulations”  “to distinguish degradation products in formulations that are related to drug
substances from those that are related to non-drug substances (e.g., excipients)”  “to solve stability-related problems (e.g., mass balance)”  “to generate a degradation profile that mimics what would be observed in a formal
stability study under ICH conditions”  “to facilitate improvements in the manufacturing process and formulations in
parallel with accelerated pharmaceutical studies”  “to choose the correct storage conditions, appropriate packaging and better
understanding of the potential liabilities of the drug molecule chemistry”  “to facilitate improvements in the manufacturing process and formulations in
parallel with accelerated pharmaceutical studies” Figure 1 shows the importance of forced degradation studies with respect to current pharmaceutical scenarios [13].

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Figure 1: Importance of forced degradation in pharmaceuticals

3. Regulatory overview

3.1

ICH guidelines - regulatory overview

Until today ICH (The International Committee for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) [6] has achieved harmonization in many areas of quality e.g. in conducting of stability studies or in providing definition of relevant thresholds for impurity testing. ICH has published several guidelines which have been discussed, agreed upon and adopted by the regulatory authorities of the ICH regions United States, Europa and Japan [6]. When it comes to the topic “forced degradation” the most ICH guidelines emphasize the importance of conducting forced degradation studies, but provide only very general and limited information on the experimental stress conditions and only general guidance on how to conduct forced degradations studies. For example, the guidelines do not provide specific information and recommendations on the stress conditions e.g. pH, temperature ranges, specific oxidizing agents, or conditions to use.
DegradationDegradation ProductsDegradation StudiesDrug SubstancesGuidelines