the who work in the area of bioequivalence€¦ · valeria gigante | technical officer | mvp | dr...
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Valeria Gigante | Technical Officer | MVP | www.who.int
Dr Valeria Gigante - WHO, Technical Officer MQA
Technical Briefing Seminar Geneva, 8 Nov 2019
The WHO work in the
area of Bioequivalence
WHO Biowaiver Project
Agenda
BIOEQUIVALENCE
Normative work and Standard settings
Tools to facilitate the interchangeability of multisource product
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Normative work and standard settings
WHO has built almost 30 years of experience in the field of Bioequivalence
1990’s 2016 2017 2018 20192006 2015
▪ 1992: 33rd ECSPP recognized the need for global guidelines with
respect to multisource products (WHO TRS No. 834, 1993)
▪ 1994: 34th ECSPP report: Multisource (generic) pharmaceutical
products: guidelines on registration requirements to establish
interchangeability (WHO TRS No. 863, Annex 9, 1996)
▪ 1999: 35th ECSPP report: Guidance on the selection of comparator
pharmaceutical products for equivalence assessment of
interchangeable multisource (generic) product (WHO TRS No. 902,
Annex 11, 2002)
It started in the early 90’s with the development of the WHO basic guideline to establish BE
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The WHO experience in the field of BE
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2016
2017
2018
2019
2006
2015
1990’s
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▪ In 2006 the WHO published:
‒ “Proposal to waive in vivo bioequivalence requirements for WHO
Model List of Essential Medicines immediate-release, solid oral
dosage forms” (WHO TRS No. 937, Annex 8, 2006)
• As part of this guidance, WHO had provided with the assistance
of former WHO Collaborating Centre a provisional list of APIs
eligible for biowaiver mostly based on literature data
▪ In the same year WHO revised the publication from 1996:
‒ “Multisource (generic) pharmaceutical products: guidelines on
registration requirements to establish interchangeability”(WHO TRS
No. 937, Annex 7, 2006)
Two additional documents were released in 2006 including the first BCS-based biowaiver list
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2016
2017
2018
2019
2006
2015
1990’s
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The WHO experience in the field of BE
▪ The criteria to grant biowaiver were revised: BCS Class II APIs
were excluded from a BCS-based biowaiver
▪ The WHO guidelines on registration requirements to establish
interchangeability was thus republished as “Multisource
(generic) pharmaceutical products: guidelines on registration
requirements to establish interchangeability” (WHO TRS No.
992, Annex 7, 2015)
▪ “Guidance on the selection of comparator pharmaceutical
products for equivalence assessment of interchangeable
multisource (generic) products” (revision) (WHO TRS Annex 8
No. 992, 2015)
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The WHO experience in the field of BEThe criteria to establish biowaiver were tightened-up excluding BCS Class II products
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2016
2017
2018
2019
2006
2015
1990’s
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▪ “Guidance for organizations performing in vivo bioequivalence
studies” (revision) (Annex 9, WHO TRS No. 996, 2016)
▪ List of International Comparator products (September 2016)
▪ The Expert Committee on Specifications for Pharmaceutical
Preparations (ECSPP) recommended the WHO Secretariat to
revise the “WHO Biowaiver list” (2006) with robust laboratory data
to promote access to quality multisource (generic) essential
medicines.
The ECSPP recommended to revise the 2006 BCS-based biowaiver list
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The WHO experience in the field of BE
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2016
2017
2018
2019
2006
2015
1990’s
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▪ General and high level recommendations for conducting solubility
experiments were provided. “Equilibrium solubility experiments for
the purpose of classification of active pharmaceutical ingredients
according to the BCS”, as an appendix to the WHO guidelines on
Multisource (generic) pharmaceutical products: guidelines on
registration requirements to establish interchangeability (Annex 6
WHO TRS, No. 1003, 2017)
▪ Following the ECSPP’s 2016 directions, the WHO Secretariat
started a multi-centric global project: the WHO Biowaiver Pilot
Project
The WHO basic document was enriched with a new Appendix & the WHO Biowaiver
Project was launched
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Source: Annex 2 WHO TRS 1003, Annex 6, 2017
The WHO experience in the field of BE
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2016
2017
2018
2019
2006
2015
1990’s
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▪ The WHO Secretariat started the Biowaiver Project that
will run also through 2020
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The WHO experience in the field of BEThe Appendix 2 evolved in a self-standing Protocol and the first set of API was classified
accordingly
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2016
2017
2018
2019
2006
2015
1990’s
2020
WHO BE_V Gigante
WHO Biowaiver Project
Agenda
Normative work and Standard settings
Tools to facilitate the interchangeability of multisource product
BIOEQUIVALENCE
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THE BIOWAIVER PROJECT
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Why? What? How?
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▪ In 2017 the 52nd ECSPP recommended to develop a
new WHO Biowaiver list based on verifiable
laboratories data and using the current criteria
▪ The aim is promoting access to quality medicines by
reducing the number of unnecessary in vivo BE
studies
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THE Biowaiver Project: overview
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Such BCS-based classification of APIs promotes access to essential medicines on multiple levels
Regulators▪ Optimize regulatory procedures
▪ Decrease the regulatory burden, diff. regulat. capacity
▪ Optimize the use of HR, focus on higher-risk products
Patients▪ Quicker access to multisource products
▪ Potential impact on final costs
Manufacturers▪ Reduce time to develop multisource products
▪ Reduce costs to develop multisource products
▪ Support post approval changes
Ethics▪ Reduce human exposure in clinical trials
▪ Lower burden for Ethic Committees
Payers▪ Impact on final cost of multisource products (?)
▪ Optimization of financial resources
Procurement (UN/Gov./NGOs)
▪ Facilitate international procurement
▪ Increase the use of harmonized regulatory tools
▪ Replace the WHO list published in 2006
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THE BIOWAIVER PROJECT
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Why? What? How?
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The WHO Biowaiver Project focus is on the solubility classification of APIs
▪ Comparative BA/BE studies (e.g. multisource)
▪ Pre-approval changes requiring BE studies
▪ Post-approval changes requiring BE studies
3. Dissolution at FPP level
Product specific. Eligibility to be confirmed at the FPP level,
considering:
▪ Excipients (type & content)
▪ Dissolution profile of test and reference
▪ Risk of an incorrect decision
1. API solubility classification
BCS-based classification of
API from the EML
Class II/IV Class I/III
Data from in vivo BE
study required
Biowaiver in principle
possible
Potential application
of the BCS-based biowaiver
Focus of the project
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BCS is based on 3 components
2. API permeability
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THE BIOWAIVER PROJECT
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Why? What? How?
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A strategy for scaling-up the WHO Biowaiver Pilot project was written and presented by the WHO
Secretariat and endorsed by the 53rd ECSPP. Key features are:
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Strategy used in project design:7 keys features
Scientific support to laboratories
Scientific methodology
Network of laboratories
Steering Group
Prioritization exercise
with PQT-assessment &
dedicated criteria
Supporting manufacturers
Endorsement from ESCPP,
WHO management RO/CO
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We are shaping a global network of laboratories to achieve the project goal
Network of laboratories
NIFDC,
China
University of Cincinnati, USA
University of St. Louis
Univ. MH de Elche,
SpainUniversity of Valencia,
Spain
Monash University,
Australia
Ajou University, South Korea
Indian
Pharmacopoeia
Commission,
India
North West
University,
South Africa
F.S. University of Jena,
Germany
University of
Goja, Brazil
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Bfarm, Germany
• WebEx Training
• Q&A document
• Ad-hoc support to labs to
ensure no isolation but balanced
towards an independent
evaluation
• Share of knowledge
(monographs, highest dosage
table, CoA, video record of the
training, protocol, available
literature etc)
• Continuous test-learn-improve
exercise
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Scientific support to laboratories
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2018
Pilot
CYCLE I
3 APIs
The journey from the pilot to the full phases
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Scaling up the Biowaiver Project
2019
Full Phase
CYCLE II
14 APIs
2020
Full Phase
CYCLE III
11 APIs
2017
START
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Scientific support for labs: webinar (recorded) / Protocol/ Q&A
addressing laboratories questions / monographs, certificate of
analysis
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The 2019 project in numbers
11Laboratories
16Manufacturers
14 APIs from EML
studied
44 Samples received
for the cycle II
396Experiments
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Criteria for APIs prioritization
API on EML formulation therapeutic area physical-chemical
properties
1 2 3 4
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List developed with PQ-Team assessment, BP Steering Group & comments from public consultation
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Third set of APIs to be studied in Cycle III_2020
1. Chloroquine
2. Cycloserine
3. Emtricitabine
4. Entecavir
5. Mefloquine
6. Miltefosine
7. Oseltamivir
8. Paracetamol
9. Sofosbuvir
Antimalarial medicines
Antituberculosis medicines (MDR-TB)
Antiretrovirals (HIV)
Medicines for hepatitis B
Antimalarial medicines
Antileishmaniasis medicines
Influenza virus
Anti-inflammatory/anti-migraine
Medicines for hepatitis C
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WHO Biowaiver Project
Agenda
Normative work and Standard settings
Tools to facilitate the interchangeability of multisource product
BIOEQUIVALENCE
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Sources: Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products (WHO
TRS 992, Annex 8, 2015)
Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO TRS No. 992, Annex 7, 2015)
1. WHO Guidance on the selection of comparator pharmaceuticalproducts for equivalence assessment of interchangeablemultisource (generic) products
WHO provides Member States criteria for selection of a comparator product for BE studies
WHO provides NRAs with indication for selection of comparator products in order of
preference:
1. innovator product for which Q,S,E has been established (nationally authorized innovator);
2. national market leader product (with a national MA);
3. WHO-recommended comparator product (in List of International Comparator products) or
by PQ Team;
4. innovator product approved by a stringent regulatory authority;
5. product that was granted approval in an ICH-associated country.
6. In case no innovator or comparator product can be identified, the Applicant has to make
& justify its choice. Most important criteria in order of preference:
• PQ-ed by WHO;
• extensive documented use in CTs reported in peer reviewed scientific journals;
• a long and unproblematic period of post-market surveillance.
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Sources: Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products (WHO
TRS 992, Annex 8, 2015)
Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO TRS No. 992, Annex 7, 2015)
1. WHO Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products II
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Sources: List of International Comparator products (September 2016)
General background notes and list of international comparator pharmaceutical products (Annex 5, WHO Technical Report Series 1003, 2017)
2. WHO LIST OF INTERNATIONAL COMPARATORSLiving document providing tabulated information
SPECIFIC FPP -> COMPARATORS MARKET
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Quality is not an accident, it is the outcome of intelligent efforts.
The quality of pharmaceutical products is essential
to assure the maximum level of patient’s
satisfaction and to reach UHC
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Thank youWHO
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1211 Geneva, Switzerland
Valeria Gigante | Technical Officer | MVP |