�WHO Support for Regulatory System Strengthening in India �

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Dr. Madhur Gupta; MD, DM

Technical Officer- Pharmaceuticals

WHO India Country Office

New Delhi, India

guptamadh@who.int

WHO Advanced In-Country Workshop on Good Manufacturing Practices (GMP) Regulatory Inspection using Risk Based Approach

11-15 March 2024, Pune, India

To continue to support Member States upon their request in the area of regulatory system strengthening, including, as appropriate, by continuing to:

WHA Resolution 67.20:

What WHO should do

Pre IDP

Observed Audit

Vigilance field visit

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IDP implementation (Monitoring + Capacity building activities)

WHO NRA Benchmarking Policy�Benchmarking Methodology

Rapid Benchmarking

India’s NRA Assessment 2012

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The WHO assessment (benchmarking) of the Indian vaccine regulatory system was conducted in 2012 by an international team of experts. During the aforementioned assessment, an institutional development plan (IDP) and the road map for strengthening the NRA of India were developed to address the identified gaps

��India’s NRA Assessment 2017�

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NRA Re-benchmarking in India

2017�

Regulatory Inspection Function��

Objective and expected outcomes

Objective:

1. Re-benchmark the status of the India vaccine regulatory system against the WHO NRA Global Benchmarking Tool (GBT) and measuring the maturity of the system.
2. Update the Institutional Development Plan (IDP) developed by WHO and CDSCO and other involved affiliated institutions to address existing and/or potential gaps and build upon the strengths of the existing vaccine regulatory system.

Expected Outcome:

1. Assess and document the status of the India vaccine regulatory system and its maturity level,
2. Identify gaps and strengths of the vaccine regulatory system, and
3. Agree on an IDP to build upon identified strengths and addressing areas for improvement.

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NRA Benchmarking Team

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Observer

ICT

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Maturity level

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WHO Observed Audit �of India FDA GMP Regulatory Inspection

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Haffkine Bio-Pharmaceutical Corporation Limited

Biological E Limited

Bharat Biotech International Limited

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WHO Team

• Alireza Khadem, Scientist, WHO/HQ/RSS/CRS Group Leader a.i (Team Leader)
• Mohamed Refaat, Consultant, WHO/HQ/RSS
• Madhur Gupta, WHO/CO India
• Henning Willads Petersen, DKMA, Denmark
• Kasra Ghasemi, DKMA, Denmark
• Achiraya Praisuwan, TFDA, Thailand

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HIS| EMP| RSS| Country Regulatory Strengthening Group

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Manufacturing Site

• M/s Biological E Limited. �Plot No.1, S.P. Biotechnology Park, Phase –II, Kolthur(V), Shameerpet (M) , Ranga Reddy (Dist.), Telangana, India-500078

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Haffkine

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Common Strengths

• Proper and professional preparation of the regulatory inspection
• Effective conduction and performance of the inspection process.
• Proper reporting to the manufacturer
• Inspection teams are technically competent and maintains positive atmosphere for the inspection through their attitude and values

HIS/EMP | Communications Planning

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Strengths

• Inspectors' Technical Competency
• Experience in the inspection methodology was evident (the search of root causes of non-compliances and the identification of supporting evidence for the findings) and adequate depth in the inspection areas
• Application of GMP knowledge was well demonstrate by both lead inspector and inspectors

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Common Areas for Improvement

Inspection Management

• Time management
• Team management including splitting (when applicable), team building and leadership.
• Inspection information management (e.g. data collection, recording and archiving.

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Areas for Improvement

• Inspection Conduction
• Obviously rationale for the inspection team split or merge
• Systemic use of inspection facilitation aids such as Aide Memoires/checklists and inspection note taking templates.
• Inspectors' Attitude
• Time management

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• Budgetary provisions made for expansion of man power & Infrastructure
• Actual manpower & Infrastructure is increased and strengthened
• E-Governance started
• IDP is developed and implemented for last many years
• Drugs and Cosmetics Act& Rules has been amended mandating all manufacturers and importers of Vaccine for setting up of the Pharmacovigilance system managed by qualified and trained personnel within their company; Risk Management plan is established
• QMS is established in CDSCO (regulatory authority), Pharmacovigilance Programme of India, Adverse Event following Immunization division, central laboratories

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Achievements of

National Regulatory System after 2012 NRA assessment

Achievements in the past years subsequent to benchmarkings- high political will…

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Sustaining the Momentum through IDP Implementation …

• India has made significant progress in strengthening the regulatory system for medical products
• Outcome of rebenchmarking of vaccines program
• Introduction of Medical Devices Rule
• Establishment of PVPI as a WHO CC
• Full member of WHO NCL Network for Biologicals
• Information-sharing platform, etc.
• Reflects importance GoI has placed on access to quality-assured medical products needed by the population

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Reforms in Drug Regulation

Paper based Application & Licensing Process

Paperless Online Licensing System

Pharma sector business analysis

Analysis of Health requirements

Analytics on Performance

Transforming India

Through ICT

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Strengths in India being scaled up

• Existence of high level policy/strategy:

National Vaccine Policy, CDSCO IDP, Road map for strengthening of India regulatory land scape, Quality Risk Management and the development of the regulatory system as part of twelfth, five years development plan

• Full implementation of the IDP
• Managerial commitment to develop and establish QMS
• Financial flexibility
• Increased transparency and availability of information on public domain
• E-governance and online registration(SUGAM)
• Strengthening of CDSCO manpower by creating additional new posts, including experts and additional personnel for new laboratories, mobile drug testing labs, E-governance, training academy

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Moving forward on regulation

• Strengthening of state regulators a key priority for the Government of India, recognizing role states play as an integral part of the regulatory system
• Vision and proposed plan for achieving status of internationally recognized regulatory system for vaccines and medicines
• A catalyst to convening meeting of states regulators is the annual platform- Annual Regulators Conclave for national and state regulatory authorities in India which deliberates on the various facets of regulatory strengthening
• 1^st International Conclave on Best Practices in Regulation�Bhopal, India 21-22 August 2017;
• 2^nd Annual Regulators Conclave for Central and State Regulatory Authorities in India, 2018, Kasauli, Himachal Pradesh
• 2^nd Annual Regulators Conclave for Central and State Regulatory Authorities in India, August 2019, Goa

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NRA Strengthening Institutional Development Plan being implemented and monitored in India

• Basic GMP workshops for regulators from central and state levels 1-5 October 2018
• Advanced GMP workshops for regulators from central and state levels 2-6 December 2018
• Basic GMP workshops for regulators from central and state levels June 2019
• Advanced GMP workshops for regulators from central and state levels July 2019
• Deficiency Classification Workshop for Regulators, 11-13 September 2019
• Approx 130 regulatory personnel from CDSCO and Zonal offices trained in the above workshops.

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Pharmacovigilance Inspections in India

CDSCO-WHO-EU In-Country Workshop for “Pharmacovigilance Inspections for Central & State Regulators and other Stakeholders In India”

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India Initiative for fostering Local Production�2020-2022

WHA74.6: Strengthening local production of medicines and other health technologies to improve access, 31 May 2021

• Member States’ commitment to achieve the Sustainable Development Goals including those that relate to local production of medicines and other health technologies (Goals 3, 8 and 9)
• Innovative options to enhance the global effort towards the production and equitable distribution of COVID-19 medicines and other health technologies through local production
• Need to improve access to quality, safe, effective and affordable medicines and other health technologies, inter alia, through building capacity for local production, technology transfer on voluntary and mutually agreed terms, cooperation with, support to and development of voluntary patent pools and other voluntary initiatives, such as the WHO COVID-19 Technology Access Pool (C-TAP) and the Medicines Patent Pool, and promoting generic competition
• Inter-agency statement on promoting local production signed by six organizations (the Global Fund to Fight AIDS, Tuberculosis and Malaria, UNAIDS, UNCTAD, UNICEF, UNIDO and WHO) calls for a holistic approach, close partnership, interministerial and relevant stakeholder cooperation, and global synergy in promoting quality and sustainable local production of safe, effective, quality and affordable medicines and other health technologies;
• Work of the Interagency Pharmaceutical Coordination Group hosted by WHO and the role of Unitaid and the Medicines Patent Pool to help countries to enhance their access to medicines particularly for HIV/AIDS, tuberculosis and malaria;

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Specific Objectives

1. Engage through workshop and mentorship for Current Good Manufacturing Practices (cGMP) with pharmaceutical units manufacturing formulations to promote availability and access to medicines
2. Provide WHO cGMP and regulatory updates for manufacturers and introduce ‘best in class’ systems
3. Develop Workshop material on cGMP regulatory requirements for Pharmaceutical units in line with International Standards such as WHO, EU, US
4. Enable wide adoption of WHO cGMP standards by Pharmaceutical units and enable WHO Pre-Qualification (PQ) as suppliers for quality medical products.

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UN High-Level Meeting on Universal Health Coverage (UHC), 23 Sep 2019

The story of Current Good Manufacturing Practices (cGMP) Online Workshops for Pharmaceutical Units is published on both

South-East Asia Region and Headquarters websites:

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1. South-East Asia Region (SEAR) https://www.who.int/southeastasia/health-topics/universal-health-coverage

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2.WHO HQ. https://www.who.int/southeastasia/news/detail/10-12-2021-current-good-manufacturing-practices-(cgmp)-online-workshops-for-pharmaceutical-units

WHO International Solidarity Trial for Potential Therapeutics for COVID 19 Implementation of the Trial in India 2020-2022

• "Solidarity” was an international clinical trial to help find an effective treatment for COVID-19, launched by the World Health Organization.
• WHO India provided technical and operational support for the implementation of WHO Global International Solidarity Trial for therapeutics for COVID 19 in India.
• These include provision of oversight, facilitating regulatory approvals, developing training modules, undertaking clinical trial site trainings, facilitating serious adverse event reporting among others. "Solidarity” is an international clinical trial to help find an effective treatment for COVID-19, launched by the World Health Organization.
• The Interim results for the original four drugs was published by WHO in New England Journal of Medicine as the 'Original Article' -": Repurposed Antiviral Drugs for Covid-19 —Interim WHO Solidarity Trial Results".

Location of approved clinical trial sites in India

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Strengthening clinical trials and innovation for emerging technologies with science agencies in India

• Technical support for building course modules for clinical trials sites and organized capacity building of centers / institutions collaboratively with science agencies in India.
• Capacity building undertaken of select science agencies’ clinical trial sites investigators and other clinical trials personnel in teams.
• ‘Good Data and Record Management Practices in Clinical Research’ Programme jointly organized by WHO India, Indian Council of Medical Research, and Translational Health Science and Technology Institute, Government of India, New Delhi on November 29-30, 2023

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Vaccine Safety: Initiatives in India�2019-2024….ongoing

Smart Safety Surveillance Approach

• The Smart Safety Surveillance (Triple S) Programme has been a collaborative effort among regulators, the national immunization programme in India and other key vigilance stakeholders for vaccines, to strengthen pharmacovigilance (PV) capacity.
• World Health Organization (WHO) has promoted the Smart Safety Surveillance (3S) approach to strengthen PV systems in developing countries that are introducing new health products, for the safe and effective use of these products.
• To begin with, Rotavac, an oral rotavirus vaccine developed, tested and licensed in India was selected as the vaccine pathfinder, to introduce and test the 3S approach as a path finder.

White Paper on Safety of Rotavirus Vaccine in India

• Over 1500 cases of intussusception analysed.
• Self Controlled Case Series (SCCS) analysis demonstrated no increased risk of intussusception associated with Rotavac vaccination.
• The synthesis of routine data and systematically designed studies adopting sound methodology in India has brought together all stakeholders in immunization safety to demonstrate that Smart Safety Surveillance can leverage multiple data sources to provide reassurance on the safety of a new vaccine.

Better characterized Safety Profile of the

New Vaccine

Advanced Level of Vigilance System

• Pharmacovigilance Inspections introduced and being conducted
• Concept of Risk Management Plans to be submitted with the application for marketing authorization introduced
• Legal obligation for industry to immediately report new information on quality, efficacy and safety with impact on benefit risk introduced
• Signal Management Process for Vaccines established.

Signal Management for Adverse Event Following Immunization for Vaccines

• A Signal Management Framework for Adverse Event Following Immunization (AEFI) as part of the overall vaccine safety surveillance system for India has been set up by Adverse Events Following Immunization (AEFI) Secretariat, Immunization Technical Support Unit, Immunization Division, Ministry of Health and Family Welfare.
• The Signal Review Panel (SRP) is an independent body at the national level (with experienced professionals in the field of clinical pharmacology, medicine, infectious diseases, paediatrics, dermatology, neurology, cardiology, and representation from the drug regulatory authority) to assess information on potential signals of importance for public health, drug regulation, and science from the databases for AEFIs following Universal Immunization Programme vaccines and COVID-19 vaccines.
• The Panel reports its findings and recommendation to the National AEFI Committee, CDSCO and the Ministry of Health and Family Welfare (MOHFW).

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• A hybrid workshop on Signal Management and Risk Benefits for Vaccines for the members of Working groups and Signal Review Panel held on 21^st and 22^nd March 2022 at New Delhi.
• The workshop was proposed with an objective to gain the knowledge of global signal management process and methods through global experts.

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• The speakers from Uppsala Monitoring Centre, WHO-CC, Sweden, UK MHRA and independent international experts in vaccine safety delivered talks covering in-depth aspects of Signal Detection and Management; followed by discussion on Next Steps for Signal Detection Management in India.�
• Four Signal Review Panel meetings to review the Signals for COVID-19 Vaccines (Covaxin, Covishield, Corbevax) in India, have been held so far in 2022.

Organization of WHO Global Meeting- International Conference of Drug Regulatory Authorities (ICDRA) October 2024 in India

HIS/EMP | Communications Planning

HIS| EMP| RSS| Country Regulatory Strengthening Group

guptamadh@who.int

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