Module 10 · Chapters 12, 13, 14 and 15
Quality Management, the Regulator, Adult Vaccination and New Vaccines
NQAS for AEFI surveillance, CDSCO/CDL/PvPI roles and PSUR rules, AEFI surveillance for adults and pregnancy, and active surveillance for new vaccine introductions.
Chapter 12 · Quality Management System for AEFI surveillance
Setting standards against benchmarks is the first step of a QMS — robust standards make processes transparent, fix responsibility and accountability, and improve efficiency and safety; regular assessment identifies gaps to close. A key strategy is a QMS within AEFI surveillance, including third-party certification.
- Under the NHM quality assurance programme: institutionalisation, quality teams at all levels, continuous assessment using the National Quality Assurance Standards (NQAS), capacity building and NQAS certification of facilities. NQAS is internationally accredited by ISQua (International Society for Quality in Healthcare).
- State and District Quality Assurance Committees (SQAC, DQAC) are supported by trained quality teams.
- NQAS for AEFI surveillance developed in 2016; the national AEFI Secretariat has been NQAS-AEFI certified since 2016. QMS was piloted in two districts each in two states, then finalised for national rollout.
12.1 Overview of NQAS for AEFI surveillance
Aligned with these guidelines. Areas of concern:
- Four checklists — one per level: national, state, district and PHC/session site; each divided into areas of concern → standards → measurable elements (ME) → score card (Figure 12.1).
- Assessment methods: observation, staff interview, beneficiary interview, record review.
- Three types of assessment — internal, peer, external — using the same checklist for a level. Scores per ME; checklist-, area- and standard-wise scorecards. External assessments by qualified assessors lead to certification (if other conditions are met).
- Details in the NQAS for AEFI surveillance guidebook (2016); tools revised whenever operational guidelines change.
12.2 Implementation
Applies at all levels from session sites to national. Key activities:
- Orientation of state/district quality assurance managers and immunization programme managers.
- State implementation plan.
- Budget based on selected districts, projected in state PIPs under the appropriate FMR code.
- Notification including state/district QA unit members in AEFI committees.
- State finalises SOP templates; quality policy and objectives; disseminate SOPs, checklists; clarify roles.
- Operationalise in states — orientation, SOPs, quality policy/objectives, internal assessment, gap closure, peer and external assessment, certification of state and session sites.
- Operationalise in districts — train district staff and PHC MOs, customise SOPs, internal audits, gap closure, peer assessments.
- Operationalise in PHCs and session sites — orientation, SOPs, internal assessment, gap closure, peer assessment.
Quality experts are members/special invitees of state and district AEFI committees. States implement with support from the AEFI Secretariat, NHSRC and the state QA committee/unit; all districts and municipal corporations should start.
Chapter 12 summary
- QMS is a key strategy for better AEFI surveillance, applicable from session sites to national level.
- Implemented jointly by immunization managers and QA experts.
- NQAS-AEFI contains indicators, benchmarks and tools for session site/PHC, district, state and national levels.
- Internal, peer and external assessments by areas of concern, standards and measurable elements.
- Certification is for an entire state/UT.
Chapter 13 · National Regulatory Authority for vaccines
13.1.1 CDSCO
- The Central Drugs Standard Control Organization, under the DGHS in MoHFW, is India’s NRA.
- All vaccines are “New Drugs”, regulated under the New Drugs & Clinical Trials Rules 2019, the Drugs & Cosmetics Act 1940 and the Drugs & Cosmetics Rules 1945 (also Medical Devices Rules 2017 for devices).
- HQ New Delhi; 8 zonal offices, 6 sub-zonal offices, 13 port offices and 7 laboratories.
- Each state/UT has its own drugs control department monitoring manufacture, sale and distribution; manufacturing and sale licences are granted by the state Drugs Control Department.
- AEFI cells at CDSCO HQ and all zonal offices with focal persons; the AEFI Division of CDSCO (HQ) coordinates with IPC, the Immunization Division and zonal cells.
| Figure 13.1 · Under the Drugs Controller General (India) | Functions |
|---|---|
| Headquarters | New drugs; biologicals incl. vaccines; GMS; enforcement; PSUR; pharmacovigilance; cosmetics; AYUSH; import & registration; export; medical devices & IVD; blood centres; large-volume parenterals; ethics committees; veterinary drugs; global CT; legal cell |
| Zonal offices (8) · sub-zonal (6) | GMP/GCP/GLP inspection; enforcement; sampling of drugs; coordination with states |
| Port offices (13) | Import, export |
| Laboratories (7) | Testing and lot release of vaccines — CDL Kasauli |
13.1.2 Central Drugs Laboratory, Kasauli · CDL Kolkata
CDL Kasauli is the National Control Laboratory for immunobiologicals (vaccines and antisera) — indigenous, imported, for UIP and export. NABL-accredited since 2008 (biological and chemical testing). CDL Kolkata is the national statutory lab for implicated AD/reconstitution syringes and vitamin A (sterility and physical parameters).
13.1.3 Pharmacovigilance Programme of India (PvPI), IPC Ghaziabad
The Indian Pharmacopoeia Commission — autonomous under MoHFW — is the National Coordination Centre for PvPI and for the Materiovigilance Programme of India (MvPI) (devices and diagnostics). It publishes the Indian Pharmacopoeia and National Formulary of India and supplies IP Reference Substances (IPRS). PvPI was operationalised in July 2010 to reduce risks of medicines in India.
13.1.4 National AEFI Secretariat, ITSU-MoHFW
With four zonal AEFI consultants; supports the NAC and its four sub-committees (causality, investigation, laboratory, media) and the Immunization Division; besides causality it runs signal management as part of the regulatory process.
13.2.1 Roles of CDSCO (D&C Act 1940 and Rules)
- Approve new drugs, clinical trials, BA/BE studies and centres.
- Import registration and licensing.
- License blood banks, large-volume parenterals, vaccines, antisera, r-DNA products, veterinary products, medical devices.
- Lay down standards and control quality of imported drugs — ensuring safety, efficacy and quality of all vaccines.
- Coordinate state drug control organisations for uniform enforcement.
- Regulatory decisions based on PvPI (NCC at IPC) and the AEFI surveillance programme of the Immunization Division.
- Ensure every importer/manufacturer of a “new drug” (incl. vaccines) has a pharmacovigilance system to collect, process and forward ADR reports to CDSCO (Fifth Schedule, NDCT Rules 2019).
- Regulatory decisions from analysis of PMS, PSUR and AEFI data per expert committee recommendations.
Fifth Schedule, New Drugs and Clinical Trials Rules 2019 — post-marketing assessment
- At approval, safety/efficacy data come from limited, controlled trials that often exclude high-risk patients and those on other drugs, with limited long-term data and close monitoring.
- Real-world use is broader and less monitored; rare events appear → post-marketing benefit–risk assessment is required.
- Any importer/manufacturer of a new drug must have a pharmacovigilance system forwarding ADR reports to the Central Licensing Authority.
- Managed by qualified, trained personnel; the officer in charge must be a medical officer or a pharmacist trained in ADR collection and analysis.
- Post-marketing assessment methods below.
Phase IV (post-marketing) trial
Additional interaction, dose-response or safety studies under approved indications (e.g. mortality/morbidity), with an approved protocol; ethics, compensation for trial-related injury or death and GCP apply; study drug usually free of cost unless justified to the CLA and ethics committee.
PMS / observational / non-interventional study (active surveillance)
Under approved conditions with a CLA-approved protocol; inclusion per prescribing information; drug is part of treatment chosen by the prescriber; clinical-trial rules do not apply (drug already approved).
PSURs
Report new information; relate data to patient exposure; summarise worldwide authorisation status and safety variations; indicate needed product-information changes. One PSUR covers all dosage forms, formulations and indications (separate presentations within). Interval data only.
PSUR structure: (i) title page; (ii) introduction; (iii) current worldwide marketing authorisation status; (iv) actions taken for safety reasons in the interval; (v) changes to reference safety information; (vi) estimated patient exposure; (vii) individual case histories; (viii) studies — significant safety findings from trials, non-interventional and non-clinical studies, literature; (ix) other information; (x) overall safety evaluation (benefit–risk for approved indication); (xi) conclusion; (xii) appendix.
13.2.2 Responsibilities of CDL Kasauli
- Appellate laboratory in AEFI cases — physical aspects, sterility, abnormal toxicity, biochemical identity; reports to CDSCO and UIP.
- Quality control of immunobiologicals (imported, domestic, export).
- Technical advice to NRA; work with manufacturers on quality, incl. post-approval changes.
- Scrutiny of manufacturers’ Summary Lot Protocols and CMC Module-III.
- Pre- and post-licensing testing for consistency of production.
- Develop, evaluate and implement test procedures.
- Review quality-defect reports; advise on withdrawal of vaccines/sera.
- R&D in quality control of immunobiologicals.
13.2.3 PvPI · 13.2.4 Immunization Division and coordination
- IPC has been the NCC for PvPI since 15 April 2011; has a steering committee, working group, signal review panel, quality review panel and core training panel.
- Network of more than 800 ADR Monitoring Centres (AMCs), expanding; professionals and consumers report to the nearest AMC.
- Designated WHO Collaborating Centre for Pharmacovigilance in Public Health Programmes and Regulatory Services.
- Objectives of NCC-PvPI: nationwide patient-safety system; identify and analyse new signals; analyse benefit–risk of marketed medicines; generate evidence on safety; support regulatory decisions; communicate safety information.
- AMC teams collect serious and non-serious AEFIs and report to the NCC; serious AEFIs are shared immediately with the DIO and SEPIO via the Serious AEFI Case Notification Form. Serious ICSRs reaching NCC go immediately to the AEFI Secretariat and CDSCO’s PV Division; non-serious ICSRs regularly; regulatory advisories/alerts on vaccines go to the AEFI Secretariat.
- PvPI works with the AEFI programme (ITSU), NTEP, NACP-NACO, NVBDCP (NCVBDC), industry and professional bodies.
- Reporting tools: AMCs, toll-free 1800-180-3024, Android app “ADR PvPI”, email pvpi.ipc@gov.in.
13.2.4 Immunization Division / AEFI Secretariat
Districts report and investigate; state and national levels do causality. The national causality sub-committee presents results to the NAC for approval → submitted to MoHFW and shared with CDSCO. A Signal Review Panel with CDSCO and pharmacovigilance partners analyses the database and reports; PSURs are evaluated for signals and benefit–risk; recommendations go to CDSCO. Drug inspectors are deputed by the State Drug Control Department and the CDSCO zonal office as DAC members; they collect implicated vials, concomitant drugs, diluents etc. after the DAC decides (in consultation with the SIO), for testing at CDL Kasauli.
Table 13.1 · Coordination with the immunization programme
| Level | Coordination |
|---|---|
| National | AEFI Secretariat shares CRFs every week; shares causality results for regulatory action; CDSCO representative in special investigation teams; AEFI Secretariat attends PSUR review committee meetings; CDSCO, PvPI and CDL Kasauli are members of the NAC, SRP and the monthly pharmacovigilance partners’ meeting; joint capacity building; NCC-PvPI shares AEFI reports from AMCs; AEFI Secretariat trains AMC pharmacovigilance associates |
| State | Zonal CDSCO office supports the SAC; State Drug Controller is a SAC member; part of special investigation teams; AMC nodal officers/technical associates are SAC members |
| District | Drug inspectors are DAC members, join investigations and support specimen collection; AMC nodal officers/associates are DAC members; AMC reports all serious/severe AEFIs to the DIO |
Figure 13.2: CDSCO HQ (New Delhi), NCC-IPC (Ghaziabad), the National Immunization Programme and CDL Kasauli are interlinked, with CDSCO zonal offices, MAHs in India, ADR Monitoring Centres and professional bodies feeding in.
Chapter 13 summary
- CDSCO is the NRA for drugs incl. vaccines.
- State Drug Controller sits on the SAC; drug inspectors sit on DACs and lift samples.
- CDL Kasauli is the National Control Laboratory for vaccines.
- PvPI (IPC) coordinates AMCs in medical colleges and large hospitals.
- Signals assessed by the SRP; regulatory recommendations implemented by CDSCO.
Chapter 14 · Safety surveillance for adult vaccinations
The UIP mainly targets pregnant women (Td) and children (schedule in Annexure 24); there is a push to cover adolescents as VPDs shift to older ages with high child coverage.
14.1 Vaccinations in adults
- Immunity wanes with age; comorbidities predispose to VPDs and complications.
- TT after injuries and before surgery; Td in pregnancy (UIP); many rabies doses after animal bites; yellow fever before travel.
- Influenza, hepatitis B, typhoid and other respiratory vaccines have poor uptake (costly, private sector).
- Adult JE vaccination in some endemic districts.
- After smallpox, COVID-19 vaccines are the most administered adult vaccines in India at scale.
- Adult vaccination will grow → widen AEFI surveillance.
14.2 AEFI surveillance for adults
- Same reporting channels, formats, investigation and causality processes and timelines as for children — even for private-sector vaccines; forms now include adult-relevant information.
- Reporting: sensitise HWs and MOs; expand to tertiary hospitals; sensitise medicine, neurology, cardiology, respiratory medicine, obstetrics & gynaecology; doctors should record vaccination history in adult case records; private providers notify the MO/DIO; district investigates.
- Investigation: consider comorbidities and risk factors; collect full history, previous records incl. OPD visits, family history; strongly encourage post-mortems in all adult AEFI deaths; administer the adult verbal autopsy form (Annexure 11) in every death even with post-mortem; include medical specialists, neurologists, cardiologists, respiratory specialists and gynaecologists in DACs.
- Causality: the same specialists in state and national committees; others invited as needed.
14.3 Some vaccines are recommended for adults at risk (illness, comorbidity, travel) — see Annexure 25.
14.4 Vaccination during pregnancy
- Pregnant women are excluded from trials; evidence comes from women inadvertently vaccinated in early pregnancy.
- If a contraindicated vaccine is given in pregnancy, no intervention (such as MTP) is required — risks are largely theoretical.
- For a planned pregnancy, all recommended vaccines at least one month before.
- Killed vaccines and toxoids are safe. Recommended: Td/Tdap and inactivated influenza vaccine — one influenza dose from 26 weeks (FOGSI 2014). Influenza is not in the UIP (private sector).
- Live vaccines contraindicated: BCG, OPV, measles-containing, JE, varicella, yellow fever, live influenza, others.
- Usually-avoided vaccines may be given when benefit clearly outweighs risk — travel to a yellow fever area or a JE outbreak.
- Rabies post-exposure prophylaxis is not contraindicated in pregnancy (rabies is nearly 100% fatal; NCDC 2015 guidelines).
- Hepatitis A (inactivated), hepatitis B (subunit) and meningococcal vaccines may be given with risk factors/special circumstances.
- National Viral Hepatitis Control Programme 2018: institutional delivery is mandatory for HBsAg-positive women so the baby gets birth-dose hepatitis B vaccine and hepatitis B immunoglobulin.
Chapter 14 summary
- India’s adult experience: Td in pregnancy, JE campaigns, COVID-19; also rabies, hepatitis B, influenza.
- Adult coverage will rise; indications based on risk factors and comorbidities.
- Existing formats, timelines and channels apply to adult AEFIs.
- Widen the reporting network through doctors who treat adults.
Chapter 15 · Strengthening safety surveillance for new vaccine introduction
15.1 Introduction
- New vaccines = introduced for the first time on a mass scale, usually via the UIP — in campaigns (e.g. MR campaign for rubella) or directly into the schedule (e.g. rotavirus, IPV).
- Only after CDSCO licensure, based on trials showing safety and efficacy in the Indian population (ethnicity, genetic variation). CDSCO may require bridging studies even with good international data, and Phase IV, PMS or active surveillance incl. AESIs.
- Inclusion depends on disease burden, severity and complications, availability and affordability, safety and suitability for programmes, feasibility and cost-benefit. NTAGI (National Technical Advisory Group on Immunization) studies evidence and recommends; manufacturers must assure regular long-term supply; readiness assessments, cold-chain space, training, format changes precede introduction.
- Campaigns give many doses quickly amid heightened public, worker and media sensitivity to temporally linked events.
- Main challenge: an incomplete safety profile — usually trial data only; stringent Phase IV follow-up needed.
- Examples: Rotasiil/Rotavac — only trial data when first used in India; pneumococcal vaccines had long safety records abroad; Ebola vaccines used in Africa under compassionate use; COVID-19 vaccines under EUA/restricted emergency use with continued long-term trial follow-up; manufacturers directed to have post-marketing assessment per the Fifth Schedule.
15.2 Active safety surveillance
Passive surveillance captures minor, severe and serious events and trends but cannot capture all events. Active surveillance proactively obtains and rapidly analyses information to verify or detect signals.
| Method | Description |
|---|---|
| Cohort event monitoring | Vaccine exposure known from the start in a defined cohort, followed for events; usually for new vaccines; gives actual incidence rates, absolute and relative risk; useful in vulnerable groups (pregnant women, children, adolescents). |
| Electronic health records | Insurance/health databases with ICD-10-coded diagnoses → prevalence, incidence and stratified (age, sex, deprivation, region) and near real-time background rates; used in UK, USA, Australia. |
| Sentinel surveillance | Chosen large hospitals identify targeted events; follow up for case definition, exposure, treatment response, outcome and risks. |
- AESIs: predefined medically significant events potentially causally associated with a vaccine needing monitoring and confirmation. For COVID-19, WHO’s SAGE (SPEAC/CEPI) identified 23 potential AESIs, with a subset for LMICs. ITSU, guided by a Technical Advisory Group, ran a multicentric AESI sentinel study in 16 medical colleges, studying 10 of the 23 AESIs.
- INCLEN’s MAASS (Multicentric Active AEFI Surveillance Study): public and private tertiary hospitals; hospitalised under-2 children; cases and controls for seizures, thrombocytopenia and acute encephalitis syndrome.
15.3 Signal detection and communication
The Signal Management Framework (AEFI Secretariat) and SRP began with COVID-19 vaccines and now cover regular and newer vaccines. Where systems are weak, pool data from several sources.
Timely, transparent signal communication is the linchpin of pharmacovigilance: the community should understand benefits and risks without alarm and make informed choices; decision-makers need it for regulatory and programme decisions; professionals to suspect, manage and report; AEFI committees should be trained (district investigation; state/national causality).
15.4 Preparing for new vaccine introductions
- Event-specific background rates — literature review/meta-analysis; surveillance studies before introduction; EHR access for near real-time rates; compare before vs after.
- Easier reporting of all AEFIs incl. minor — expand SAFE-VAC so any health worker incl. doctors in medical colleges and tertiary hospitals can report; integration of SAFE-VAC with U-WIN is the first step.
- Active AEFI surveillance for routine immunization — trained people and systems ready for AESIs/signals; also a recommendation of the WHO NRA assessment in 2017.
- Stronger signal management — statistical tools for fast, accurate, sensitive and specific signal identification.
- Capacity building, monitoring, supervision, communication — train vaccinators, cold-chain handlers, supervisors and managers before introduction (new storage/administration techniques); follow package inserts; stringent session and storage monitoring with immediate corrective feedback.
Chapter 15 summary
- Strengthen surveillance for new vaccines under routine and EUA conditions.
- Active surveillance supplements passive surveillance.
- Cohort event monitoring and sentinel surveillance for AESIs are key methods.
- More reporting (incl. minor) strengthens signal management.
- Quick event-specific rates are essential for benefit–risk.
- Active systems for routine vaccines ensure readiness for new and EUA vaccines.
- Timely, transparent, non-alarming benefit–risk communication maintains trust.
Quick recall
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Self-test · Chapters 12–15
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