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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5855_Библиотеки_им_академика_М_И_Перельмана.pdf
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Chapter 4
WHO Listed Authority and Other
International Reliance and
Harmonization Initiatives
4.1. Introduction
n 1 June 2018, the Pharmaceutical Inspection Co-operation Scheme (PIC/S) published a Guidance on Good
Manufacturing Practice (GMP) Inspection Reliance
O
global supply chains, the demand for inspecting pharmaceutical manufacturing facilities far exceeds what any one National Competent Authority
can accomplish and a framework is required to assist regulators in managing product quality risks posed by the increasingly complex pharmaceuticals
global supply chain.” This PIC/S GMP Inspection Reliance is contin-
gent upon PIC/S Participating Authorities being guided by the following operating principles:
with the following introduction. “With the complexity of
WHO Listed Authority and Other International Reliance and Harmonization Initiatives
— recognition of the GMP compliance status of a manufacturing
facility located within the territory of a PIC/S Participating
Authority; or
— having a mutual recognition agreement (MRA) on GMP Inspec-
tion in place; or
— in the absence of a MRA, or not being a PIC/S Participating
Authority, the recognition of the inspection outcome of a hosting inspectorate which has been assessed under a robust framework, e.g., the European Economic Area Joint Audit Program.
This is a program which aims to ensure consistency of GMP
standards and a harmonized approach throughout Europe.
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In addition to the 2018 PIC/S GMP Inspection Reliance, the Worl d
Health Organization (WHO) has also published a Policy Docu-
ment entitled: Evaluating and Publicly Designating Regulatory
Authorities as WHO Listed Authorities in 2021. This WHO docu-
ment covers a broader set of reliance activities across the entire sets
of regulatory functions, beyond GMP inspection, to also include
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
the overall national regulatory system, registration and marketing
authorization, clinical trials oversight, other regulatory inspections
such as GDP and GCP inspections, licensing of establishments, vigilance, market surveillance and control, laboratory testing, and
national regulatory authorities (NRAs) lot release. In this document, key terminologies such as WHO Listed Authority and Reliance have been defined as reproduced below:
WHO Listed Authority
A WHO Listed Authority (WLA) is defined as a NRA or a regional
regulatory system (RRS) which has been documented to comply
with all the relevant indicators and requirements specified by WHO
for the requested scope of listing based on an established benchmarking and performance evaluation process.
Reliance
Reliance is defined as an act whereby the regulatory authority in
one jurisdiction may take into account and give significant weight
to assessments performed by another regulatory authority or
trusted institution, or to any other authoritative information, in
reaching its own decision. The relying authority remains independent, responsible and accountable for decisions taken, even when it
relies on the decisions, assessments and information of others. It is
pertinent to point out that reliance does not represent a less stringent form of regulation or an outsourcing of regulatory mandate.
On the contrary, mutual reliance is the hallmark of modern and
ecient regulatory authority and smart regulation!
A practical approach has been advocated for NRAs to adopt a stepwise process in the implementation of regulatory reliance. NRAs
can begin by building trust and improving eciency through
WHO Listed Authority and Other International Reliance and Harmonization Initiatives
work-sharing, implementing abridged pathways using reliance,
adopting regional reliance mechanisms and, ultimately, the use of
unilateral or mutual recognition.
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Source: World Health Organization TRS 1033, Annex 10
4.2. Historical Context to WHO Reliance Initiative
In 2014, the World Health Assembly Resolution 67.20 (WHA 67.20)
on Regulatory System Strengthening (RSS) for medical products
recognizes that eective regulatory systems are an essential component of health system strengthening. RSS is also necessary for
the implementation of universal health coverage, contributing ultimately to better health outcomes. Resolution WHA 67.20 also recognizes that inecient regulatory systems can be a barrier to access
to safe, eective and quality medical products. In essence, Resolution WHA 67.20 calls upon WHO to:
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
a) apply evaluation tools to generate and analyze evidence of regu-
latory system performance;
b) facilitate the formulation and implementation of institutional
development plans; and
c) provide technical support to NRAs and governments.
WHO will provide the necessary support to Member States in
strengthening regulatory systems as a means of promoting equitable access to, and availability of, quality-assured medical products.
In fact, WHO has already implemented a RSS program to assist
countries in reaching and sustaining a level of medical product
regulatory oversight that is eective, ecient and transparent. The
objectives of the RSS program are to promote regulatory cooperation, convergence and transparency through networking, worksharing and reliance; and to build regulatory capacity in Member
States consistent with good regulatory practices. In order to reach
these objectives, WHO has established a framework to assess regulatory systems and establish Maturity Levels by applying the Global
Benchmarking Tool (GBT) and to evaluate regulatory performance
in order to designate authorities as WLAs. Under WHO GBT, a regulatory authority may be designated as one of four Maturity Levels,
characterized as follows:
• ML1: some elements of regulatory systems exist;
• ML2: evolving national regulatory systems that partially
perform essential regulatory functions;
• ML3: stable, well-functioning and integrated regulatory
systems; and
• ML4: regulatory systems operating at advanced level of
performance and continuous improvement.
WHO Listed Authority and Other International Reliance and Harmonization Initiatives
4.3. The First NRAs to Achieve ML4 and WLA Status
In February 2022, the Singapore Health Sciences Authority (HSA)
and the Korea Ministry of Food and Drug Safety (MFDS) became the
first two NRAs in the world to be designated by the WHO as having
attained ML4 — the highest of the four maturity levels. This means
that these two NRAs are operating at an advanced level of performance and continuous improvement for medical products, including
vaccines. And in October 2023, both Singapore HSA and Korea MFDS
together with the Swiss Agency for Therapeutic Products (Swissmedic)
became the first three pioneer WLAs, following a performance evaluation of their respective regulatory systems. The US Food and Drug
Administration (FDA) and the European Medicines Regulatory Network followed suit as WLAs in May 2024. These successful achievements of Singapore HSA are attributed to the exemplary leadership
of its Group Director, Assoc. Prof. Chan Cheng Leng, together with a
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Co-author (Sia Chong Hock), Dr Alireza (WHO), Prof. Chan Cheng Leng (HSA),
seated 1st, 2nd and 3rd from left, together with key HSA sta — March 2020
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Core Team which included the co-author (Sia Chong Hock) and the
functional unit Directors. Displayed on the previous page is a photograph showing a visit by Dr Alireza of WHO to Singapore in March
2020 to explain the mechanism of the WHO GBT evaluation process
to key HSA sta. Also shown are two social media reports put up by
the Singapore Minister for Health (Ong Ye Kung), highlighting the
WHO Listed Authority and Other International Reliance and Harmonization Initiatives
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achievements of Singapore HSA as a pioneer ML4 NRA and a WLA in
2022 and 2023 respectively, following the WHO evaluations.
4.4. Purpose and Benefits of WHO Reliance Initiative
The principle of reliance is a pivotal approach of WHO to RSS and
eective regulation, regardless of the size and maturity level of
the authority. According to WHO, “reliance and regulatory cooperation are built on trust and confidence which are dependent on
knowledge and transparency of the regulatory systems and the performance of the regulatory authority upon which others may rely.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
The introduction of a framework for designating and publicly listing a regulatory authority as a WLA provides a transparent and
evidence-based pathway for regulatory authorities to be globally
recognized as meeting and applying WHO and other internationally recognized standards and guidelines, as well as good regulatory
practices.”
“A key purpose of introducing WLA designation is to replace the
concept of a Stringent Regulatory Authority (SRA) which was
developed initially to guide global procurement of medicines.” This
has been declared by WHO in its Policy Document on Evaluating
and Publicly Designating Regulatory Authorities as WHO Listed
Authorities. The SRA concept had been used by the WHO Secretariat and the Global Fund to guide medicine procurement decisions
and had subsequently become widely recognized by the international regulatory and procurement community. The definition of
an SRA, first published by the Global Fund in 2008, was based on
membership in the International Council for Harmonization (ICH)
prior to 23 October 2015.
According to WHO, “whilst GBT remains the foundation for assessing the maturity levels of regulatory systems, the WLA framework
strives to provide a comprehensive and detailed picture of how a
regulatory system operates via a performance evaluation process.”
This regulatory performance evaluation of NRAs with at least
ML3 status examines key regulatory outputs and consistency with
respect to compliance with international standards as well as good
regulatory practices. The designation of a regulatory authority as a
WLA is intended to promote access and supply of safe, eective and
quality medical products through the use of reliance based on the
decisions of trusted regulatory authorities and other international
organizations. This in turn facilitates the procurement decisions of
WHO Listed Authority and Other International Reliance and Harmonization Initiatives
the United Nations and other agencies to reduce redundancy and
waste of limited regulatory and financial resources. “The concept
of WLA is also intended to expand the pool of regulatory authorities beyond SRAs upon which other NRAs and the WHO Prequalification Program can rely on, as well as to create an enabling
environment for regulatory innovation through implementation
of reliance approaches.”
In summary, the WHO GBT forms the basis for evaluating the
maturity levels of regulatory authorities whilst the WLA performance evaluation assesses the consistent performance of the regulatory authority, including adherence to international standards
and good regulatory practices. NRAs or RRSs must have at least
attained an overall ML3 as established by the GBT to be eligible for
consideration as a WLA. An NRA or RRS can be listed as a WLA
for one or more product categories and/or for one or more regulatory functions. In order to avoid duplication of work and to ensure
optimal use of limited resources for performance evaluation, previous benchmarking or audit exercises undertaken by WHO or
other relevant organizations such as the PIC/S, Benchmarking
of European Medicines Agencies or the International Organization for Standardization will be taken into consideration when
determining compliance with the requirements for WLA designation. A WLA listing will initially be valid for a period of five years
unless extended. A risk-based process will be used to renew the
initial listing. Once renewed, the listing will no longer be subject
to a validity period but to a continuous monitoring based on risk
management principles to ensure that requirements for the listing
continue to be met. Changes or events that could cause sucient
concern that the requirements for the listing are no longer met
will trigger a re-evaluation of the WLA. Re-evaluation will be riskbased and will focus on the issues of concern.
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