B Pharmacy Sem 7: Elective ( Any one of four options)

Subject 5. Elective (Choose any one)

A – Pharmaceutical Regulatory Science
1. Drug Regulatory Affairs: Introduction
2. Regulatory Approval Process in India & Abroad
3. Intellectual Property Rights & Patents
4. Quality Management Systems in Regulatory Compliance
B – Pharmacovigilance
1. Adverse Drug Reactions & Reporting Systems
2. Signal Detection & Risk Management
3. Pharmacovigilance Regulations
4. Methods for Data Mining in Pharmacovigilance
C – Quality Control & Standardization of Herbals
1. Herbal Drug Standardization Parameters
2. WHO & ICH Guidelines for Herbal Products
3. Quality Assurance & GMP in Herbal Industry
4. Pharmacopoeial Standards for Botanicals
D – Computer-Aided Drug Design
1. Introduction to CADD & Molecular Modeling
2. Ligand- and Structure-Based Drug Design
3. Pharmacophore Modeling & QSAR Studies
4. Docking Studies & Virtual Screening Tools

Section A – Pharmaceutical Regulatory Science

Elective A – Pharmaceutical Regulatory Science

Unit 1: Drug Regulatory Affairs – Introduction

This unit provides a foundational overview of Drug Regulatory Affairs (DRA), the discipline that ensures pharmaceutical products meet all statutory and regulatory requirements for quality, safety, and efficacy before and after marketing.

1. Definition & Scope

• Drug Regulatory Affairs:
  A multidisciplinary field encompassing the interpretation, development, and submission of documentation required to obtain and maintain regulatory approval of medicinal products across global markets.

• Scope Includes:

  • Pre‑clinical & Clinical Regulatory Strategy – defining the pathway for IND/CTC filings.

  • Chemistry, Manufacturing & Controls (CMC) – ensuring consistent product quality.

  • Labeling & Packaging – meeting region‑specific requirements for patient information.

  • Pharmacovigilance Interface – post‑marketing safety reporting and risk management.

  • Lifecycle Management – handling changes (formulation, manufacturing site) via variation filings.

2. Historical Evolution

1. Early 20th Century:

   • Pre‑regulation era—no formal oversight; tragedies (e.g., sulfanilamide elixir, 1937) spurred initial laws.

2. Foundational Legislation:

   • United States: Food, Drug, and Cosmetic Act (1938) required safety demonstration.

   • India: Drugs & Cosmetics Act (1940) laid down standards for drugs and cosmetics.

3. Global Harmonization:

   • Formation of International Council for Harmonisation (ICH, 1990) to align technical requirements across US, EU, and Japan.

4. Modern Era:

   • Digital submissions (eCTD), risk‑based approaches (QbD, ICH Q8–Q11), and adaptive pathways for accelerated approvals.

3. Regulatory Framework & Key Guidelines

• Core Regulatory Authorities:

  • India: CDSCO (Schedule Y of Drugs & Cosmetics Rules)

  • USA: FDA (21 CFR Parts 210–212, 314)

  • EU: EMA (EudraLex Volume 4)

• Major ICH Guidelines:

  • Q1 series: Stability testing

  • Q2(R1): Analytical method validation

  • Q3: Impurities

  • M4 (CTD): Dossier format

• Regional Annexes & Guidance:

  • Local pharmacopeias (IP, BP, USP)

  • National variations (e.g., labeling language, patient‑leaflet content)

4. Key Functions of Regulatory Affairs Professionals

1. Regulatory Intelligence:

   • Monitor evolving regulations, guidance documents, and inspection trends.

2. Submission Management:

   • Compile and submit INDs/NDAs/MAAs in eCTD format; respond to deficiency letters.

3. Cross‑Functional Liaison:

   • Coordinate between R&D, manufacturing, quality, and marketing teams to align on regulatory strategies.

4. Labeling & Advertising Compliance:

   • Ensure promotional materials adhere to approved claims and regulatory standards.

5. Post‑Approval Maintenance:

   • Manage variations, renewals, periodic safety update reports (PSURs), and regulatory inspections.

5. Stakeholders & Collaboration

• Internal Stakeholders: R&D scientists, process engineers, quality assurance, marketing, legal.

• External Stakeholders: Regulatory agency reviewers, contract research organizations (CROs), contract manufacturing organizations (CMOs), notified bodies (in EU), and patient advocacy groups.

6. Importance & Impact

• Patient Safety: Guarantees that only products meeting rigorous safety and efficacy standards reach the market.

• Business Continuity: Timely approvals accelerate time‑to‑market, protecting competitive advantage.

• Global Access: Harmonized submissions facilitate simultaneous multi‑region launches.

• Regulatory Compliance: Reduces risk of product recalls, warning letters, and import bans.

7. Key Exam Tips

• Define Drug Regulatory Affairs and list its five core functions.

• Outline the major ICH guidelines relevant to CMC and clinical submissions.

• Discuss one historical legislation (e.g., Food, Drug, and Cosmetic Act) and its influence on modern DRA.

• Sketch the submission lifecycle from IND to NDA/MAA and post‑approval variations.

Unit 2: Regulatory Approval Process in India & Abroad

This unit examines the stepwise procedures, key milestones, and region‑specific requirements for obtaining marketing authorization of new drugs in India (CDSCO) and major international markets (US FDA, EMA).

1. India – CDSCO Approval Pathway

1.1 Governing Legislation & Guidelines

• Drugs & Cosmetics Act, 1940 and Rules, 1945 (particularly Schedule Y)

• Guidance Documents: CDSCO procedural guidelines for clinical trials and new drug approvals

1.2 Approval Steps

1. Pre‑Submission Consultation

   • Optional meeting with CDSCO to discuss development plans, clinical trial design, and CMC requirements.

2. Clinical Trial Permission (CTP)

   • Submit Form CT‑04 (application for permission to conduct clinical trials) along with pre‑clinical data, protocol, and investigator’s brochure.

3. Conduct of Clinical Trials

   • Phase I–III trials per ICH–GCP, safety reporting under Rule 122DAE.

4. New Drug Application (NDA)

   • File Form 44 and fee in Form CCS‑3.

   • Provide Module 1 (administrative), Module 2 (summaries), Module 3 (CMC), Module 4 (non‑clinical), and Module 5 (clinical) as per CTD format.

5. Regulatory Review & Queries

   • CDSCO reviews dossier, may issue Refusal to File if incomplete or Query Letter seeking clarifications.

6. GCT and Technical Committee Evaluation

   • Expert committees evaluate scientific data, safety, and efficacy.

7. Final Grant of Marketing Authorization

   • CDSCO issues Form 25 (manufacturing license for new drug) and Form 28 (sales license).

8. Post‑Approval Commitments

   • Submit Periodic Safety Update Reports (PSURs) and lifecycle management filings for changes.

2. United States – FDA Approval Pathway

2.1 Governing Legislation & Guidelines

• Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR Parts 312 (IND) & 314 (NDA)

• FDA Guidance: Various “Guidance for Industry” documents on CMC, clinical trials, and eCTD submissions.

2.2 Approval Steps

1. Pre‑IND Meeting

   • Engage FDA to discuss preclinical data, clinical trial protocols, and regulatory expectations.

2. Investigational New Drug (IND) Application

   • Submit IND with pre‑clinical toxicology, manufacturing information, and Phase I protocol.

   • 30‑day safety review period before trials can commence.

3. Clinical Development

   • Phase I–III trials under IND; safety reporting per 21 CFR 312.32 and GCP.

4. New Drug Application (NDA)

   • Submit eCTD with all modules, including clinical study reports, labeling proposals, and CMC data.

   • Include User Fee payment under PDUFA.

5. FDA Review

   • Filing Review: Check for completeness (60 days).

   • Substantive Review: Evaluate safety, efficacy, and CMC (PDUFA goal date typically 10 months for standard review, 6 months for priority).

6. Advisory Committee

   • External experts review data, provide non‑binding recommendations.

7. Action Letter

   • Approval Letter or Complete Response Letter detailing deficiencies requiring resubmission.

8. Post‑Marketing Requirements

   • Phase IV studies, Risk Evaluation and Mitigation Strategies (REMS), and Annual Reports.

3. European Union – EMA Approval Pathways

3.1 Centralized Procedure

• Applicable: Innovative medicines, orphan drugs, biotech products.

• Single Application: Submit through the European Medicines Agency (EMA); results in an EU‑wide Marketing Authorization (MA).

3.2 Mutual Recognition & Decentralized Procedures

• Mutual Recognition: For products already authorized in one Member State to gain approval in others.

• Decentralized: Simultaneous submission to multiple Member States for products without prior national approval.

3.3 Approval Steps (Centralized)

1. Scientific Advice

   • EMA Committee for Medicinal Products for Human Use (CHMP) provides guidance pre‑submission.

2. Submission of MA Application

   • eCTD format; includes modules 1–5 per CTD.

3. Validation & Assessment

   • EMA validates application (15 days); CHMP conducts assessment (~210 days excluding clock stops for queries).

4. Opinion & EC Decision

   • CHMP issues positive Opinion; European Commission grants MA (30 days).

5. Post‑Authorization Activities

   • Periodic Safety Update Reports (PSURs), Variations, and Pharmacovigilance Risk Assessment Committee (PRAC) oversight.

4. Comparative Highlights

5. Key Exam Tips

• Map the IND → NDA in the US and CT‑04 → Form 25/28 in India, highlighting key form numbers.

• Compare review timelines and fee structures across regions.

• Discuss centralized vs. decentralized vs. mutual recognition in the EU.

• Explain the role of advisory committees in FDA and EMA processes.

Unit 3: Intellectual Property Rights & Patents

This unit covers the framework that protects pharmaceutical innovations—patents, data exclusivity, and related IP mechanisms—ensuring inventors can commercialize new drugs while balancing public access.

1. Definitions & Purpose

• Intellectual Property (IP):
  Legal rights granted to creators over their inventions or works, providing exclusive exploitation for a limited period.

• Purpose in Pharma:

  • Encourage investment in costly R&D by granting a temporary monopoly.

  • Facilitate technology transfer through licensing agreements.

  • Balance innovation with public health by eventually allowing generics.

2. Types of IP Relevant to Pharmaceuticals

3. Pharmaceutical Patents

3.1 Patentable Subject Matter

• Chemical Entities: New active molecules or salts.

• Formulations: Novel controlled‑release matrices, co‑crystals.

• Polymorphs & Isomers: Distinct crystalline forms or stereoisomers with improved properties.

• Methods of Use: New therapeutic applications for known compounds.

• Manufacturing Processes: Innovative synthetic routes or purification methods.

3.2 Patent Requirements

1. Novelty:

   • Not disclosed anywhere before the filing date (absolute novelty in most countries).

2. Inventive Step (Non‑Obviousness):

   • Not obvious to a person skilled in the art, considering prior publications and patents.

3. Industrial Applicability (Utility):

   • Must have a specific, substantial, and credible utility (therapeutic benefit).

3.3 Patent Application Process

1. Priority Filing:

   • File initial application; establishes priority date.

2. International Phase (PCT):

   • Optional PCT application extends decision time by 30 or 31 months.

3. National Phase Entry:

   • Enter national filings in desired jurisdictions before priority deadline.

4. Examination & Grant:

   • Patent office examines novelty, inventive step, and utility; issues grant if criteria are met.

5. Maintenance:

   • Pay annual renewal fees to keep patent in force.

4. Supplemental Protection Certificates (SPCs) & Extensions

• SPC (EU):

  • Extends protection beyond 20 years to compensate for regulatory approval delays (max 5 years).

• Patent Term Extension (US):

  • Up to 5 years to restore effective patent life lost during FDA review (not exceeding 14 years post‑approval).

5. Compulsory Licensing & Patent Challenges

• Compulsory License:

  • Government‑granted permission to manufacture a patented drug without patent holder consent under specified conditions (e.g., public health emergencies in India under Section 84 of the Patents Act).

• Patent Opposition & Litigation:

  • Pre‑grant Opposition: Third parties challenge patents before grant.

  • Post‑grant Opposition: Challenges after grant (up to 1 year in India).

  • Litigation: Courts resolve infringement disputes, validity challenges.

6. Balancing Innovation & Access

• Evergreening:

  • Filing follow‑on patents (e.g., polymorphs, salts) to extend exclusivity—controversial, subject to stricter patentability standards (India’s Section 3(d)).

• Generic Entry:

  • Paragraph IV certification (US): Generic applicants challenge patents to enter market before expiry; can trigger 30‑month stay.

• Access Programs:

  • Voluntary licensing, tiered pricing, and patent pools (e.g., Medicines Patent Pool) to enhance availability in low‑income countries.

7. Key Exam Tips

• Define novelty, inventive step, and utility in context of pharmaceutical patents.

• Outline the PCT filing timeline and its strategic benefits.

• Compare patent term extensions in US vs. SPCs in EU vs. data exclusivity in India.

• Discuss Section 3(d) of the Indian Patents Act and its impact on evergreening.

• Explain compulsory licensing provisions with an example (e.g., generic HIV drugs).

Unit 4: Quality Management Systems in Regulatory Compliance

This unit examines the frameworks, tools, and processes that ensure consistent product quality and regulatory compliance through an integrated Quality Management System (QMS) in pharmaceutical operations.

1. Definitions & Objectives

• Quality Management System (QMS):
  A structured set of policies, processes, and procedures required for planning and execution (production, development, and service) in the core business area of an organization, ensuring products meet predetermined quality criteria.

• Objectives:

  1. Assure Product Quality: Consistently produce safe, effective medicines.

  2. Regulatory Compliance: Fulfill requirements of GMP, GLP, GDP, and other standards.

  3. Continuous Improvement: Identify and implement enhancements to processes and systems.

  4. Risk Management: Proactively identify, assess, and mitigate potential quality risks.

2. Core Components of a Pharmaceutical QMS

1. Good Manufacturing Practices (GMP):

   • Scope: Covers facility design, equipment qualification, personnel training, sanitation, and production controls (ICH Q7, EU GMP Volume 4, FDA 21 CFR Part 210/211).

   • Key Elements:

     • Documentation & Records: SOPs, batch records, deviation logs.

     • Facility & Equipment: Cleanroom classification, maintenance, calibration.

     • Personnel: Training programs, hygiene, gowning procedures.

     • Materials Management: Supplier qualification, incoming QC, traceability.

     • Process Controls: In‑process testing, change control, CAPA.

2. Good Laboratory Practices (GLP):

   • Scope: Ensures reliability and integrity of non‑clinical safety data (OECD Principles).

   • Key Elements: Study protocols, raw data handling, report archiving, equipment calibration, and personnel qualification.

3. Good Distribution Practices (GDP):

   • Scope: Manages storage and transportation to maintain product integrity (WHO GDP 2019).

   • Key Elements: Warehouse controls (temperature, security), transport validation, traceability, and recalls.

4. Quality Assurance (QA) & Quality Control (QC):

   • QA: System‑wide oversight ensuring processes are followed (audits, change control, management review).

   • QC: Operational activities—analytical testing, release testing, environmental monitoring—to verify product quality.

3. QMS Process Framework

1. Document Control:

   • Lifecycle management of SOPs, specifications, and records; versioning, approval workflows, and archival.

2. Change Control:

   • Formal process to evaluate and authorize changes (materials, processes, equipment) with risk assessment, impact analysis, and implementation tracking.

3. Deviation Management & CAPA:

   • Deviation: Unplanned events that may affect product quality.

   • CAPA (Corrective and Preventive Actions): Investigate root causes, implement corrections, and preventive measures to avoid recurrence.

4. Internal & External Audits:

   • Internal Audits: Scheduled evaluations of QMS compliance across departments.

   • Supplier Audits: Assess critical raw-material vendors for GMP/GDP adherence.

   • Regulatory Inspections: Prepare for and manage FDA, EMA, CDSCO audits.

5. Management Review:

   • Periodic senior‑management review of QMS performance metrics, audit results, CAPA effectiveness, and resource needs.

6. Training & Competency:

   • Continuous training programs; skill matrix, periodic evaluations, and documentation of competency assessments.

7. Risk Management:

   • Apply ICH Q9 principles to identify, analyze, evaluate, and control quality risks throughout the product lifecycle.

4. Tools & Metrics

• Key Performance Indicators (KPIs):

  • Batch‑release cycle time, out‑of‑specification (OOS) rate, deviation counts, audit findings closure rate.

• Quality Dashboards:

  • Real‑time visualization of metrics for proactive decision‑making.

• Statistical Process Control (SPC):

  • Control charts to monitor critical process parameters and detect trends or shifts.

• Root Cause Analysis (RCA):

  • Fishbone diagrams, 5‑Why analyses to systematically identify underlying issues.

5. Benefits & Challenges

• Benefits:

  • Regulatory Confidence: Fewer inspection findings, faster approvals.

  • Operational Excellence: Reduced waste, lower rework, and improved efficiency.

  • Product Consistency: Higher batch uniformity and reduced variability.

• Challenges:

  • Cultural Change: Embedding quality mindset across all levels.

  • Resource Investment: Dedicated QMS software, training, and audit personnel.

  • Complexity Management: Coordinating cross‑functional processes and global standards harmonization.

6. Key Exam Tips

• Define each of GMP, GLP, and GDP and list two critical elements of each.

• Outline the change‑control process steps and its importance in QMS.

• List at least three CAPA activities following a major deviation.

• Explain how ICH Q9 risk management integrates with CAPA and change control.

Elective B – Pharmacovigilance

Unit 1: Adverse Drug Reactions & Reporting Systems

This unit introduces the principles of identifying, classifying, and reporting Adverse Drug Reactions (ADRs), the cornerstone of pharmacovigilance aimed at safeguarding patient safety post‑marketing.

1. Definition & Scope

• Adverse Drug Reaction (ADR):
  A noxious and unintended response to a medicinal product, at doses normally used for prophylaxis, diagnosis, or therapy.

• Scope of Pharmacovigilance:

  • Detection: Identify new or changing ADR patterns.

  • Assessment: Evaluate causality and severity.

  • Prevention: Implement measures to minimize risk.

  • Communication: Share findings with regulators, healthcare professionals, and the public.

2. Classification of ADRs

1. Type A (Augmented):

   • Dose‑related and predictable from the known pharmacology of the drug (e.g., hypoglycemia with insulin).

2. Type B (Bizarre):

   • Non‑dose‑related, unpredictable (e.g., anaphylaxis with penicillin).

3. Type C (Chronic):

   • Associated with long‑term therapy (e.g., adrenal suppression with corticosteroids).

4. Type D (Delayed):

   • Occurring some time after use (e.g., teratogenic effects of thalidomide).

5. Type E (End of use):

   • Related to withdrawal (e.g., opioid withdrawal syndrome).

6. Type F (Failure):

   • Unexpected failure of therapy (e.g., antibiotic resistance).

3. Severity & Seriousness

• Severity:
  Clinical intensity of the ADR (mild, moderate, severe).

• Seriousness:
  Regulatory definition—results in death, life‑threatening event, hospitalization, disability, congenital anomaly, or requires intervention to prevent permanent damage.

4. Causality Assessment

• WHO‑UMC Scale:
  Categories: Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, Unassessable/Unclassifiable.

• Naranjo Algorithm:
  A questionnaire‑based numeric scale (0–13+) to standardize causality assignment.

5. Reporting Systems

1. Spontaneous (Voluntary) Reporting:

   • Healthcare professionals and patients submit reports (e.g., FDA MedWatch, EudraVigilance, India’s PvPI).

   • Advantages: Broad coverage, cost‑effective.

   • Limitations: Under‑reporting, reporting bias.

2. Stimulated Reporting:

   • Encouraging specific groups (e.g., specialists) to report ADRs for targeted drugs or events.

3. Mandatory Reporting:

   • Marketing Authorization Holders (MAHs) required to report all serious ADRs within defined timelines (e.g., 15 days serious in EU, 7 days fatal/ life‑threatening in US).

4. Cohort Event Monitoring (CEM):

   • Prospective follow‑up of a patient cohort using a new drug to systematically record all adverse events.

5. Targeted Spontaneous Reporting (TSR):

   • Focused on high‑risk drugs or populations to improve signal detection.

6. Key Reporting Metrics

• Reporting Rate: Number of ADR reports per million patient‑days or per defined period.

• Proportional Reporting Ratio (PRR): A measure of disproportionate reporting for a specific drug‑event pair compared to all others in the database.

7. Data Elements in an ADR Report

• Patient Information: Age, sex, weight, medical history.

• Suspect Drug Details: Name, dose, route, start/stop dates.

• Reaction Description: Onset date, symptoms, seriousness, outcome.

• Concomitant Medications: Potential interactions.

• Reporter Information: Profession, contact for follow‑up.

8. Key Exam Tips

• Differentiate Type A vs. Type B ADRs with examples.

• List the six WHO‑UMC causality categories.

• Describe one strength and one limitation of spontaneous reporting systems.

• Outline the data elements required in a valid ADR report.

Unit 2: Signal Detection & Risk Management

This unit focuses on identifying safety signals from pharmacovigilance data and developing risk management strategies to mitigate adverse effects associated with medicinal products.

1. Definitions

• Signal: Information that arises from one or multiple sources (including observations and experiments) which suggests a new causal association or a new aspect of a known association between a drug and an adverse event warranting further investigation.

• Risk Management: A systematic process to identify, evaluate, and minimize the risks associated with pharmaceutical products, while maximizing their therapeutic benefits.

2. Signal Detection Methods

1. Spontaneous Reporting Databases Analysis

   • Statistical disproportionality metrics applied to large ADR databases (e.g., VigiBase, FAERS).

   • Proportional Reporting Ratio (PRR):

     $$\text{PRR} = \frac{a/(a+b)}{c/(c+d)}$$

     where

     • a = number of reports of specific drug–event pair

     • b = reports of the drug with other events

     • c = reports of the event with other drugs

     • d = all other reports

   • Reporting Odds Ratio (ROR) and Information Component (IC) are also used.

2. Data Mining & Algorithms

   • Bayesian Confidence Propagation Neural Network (BCPNN): Produces the Information Component (IC) to detect unexpected drug–event associations.

   • Multi-item Gamma Poisson Shrinker (MGPS): Generates Empirical Bayes Geometric Mean (EBGM) values.

3. Targeted Reviews & Literature Monitoring

   • Regular screening of published case reports, clinical trial data, and regulatory communications for emerging risks.

4. Electronic Health Records & Claims Data

   • Real‑world evidence analysis to identify patterns not evident in spontaneous reports, using observational study designs (cohort or case‑control).

3. Signal Validation & Prioritization

• Validation Steps:

  1. Case Evaluation: Assess completeness and plausibility of individual ICSRs (Individual Case Safety Reports).

  2. Aggregate Review: Examine the consistency of findings across sources and geographies.

  3. Temporal Trends: Determine whether reporting rates are increasing over time.

• Prioritization Criteria:

  • Seriousness: Life‑threatening or disabling events.

  • Hazard Potential: Potential to cause widespread harm.

  • Public Health Impact: Number of patients exposed.

  • Preventability: Feasibility of risk minimization.

4. Risk Management Planning

1. Risk Management Plan (RMP) / Risk Evaluation and Mitigation Strategy (REMS)

   • EU RMP: Includes safety specification, pharmacovigilance plan, and risk minimization measures.

   • US REMS: May require Elements to Assure Safe Use (ETASU), medication guides, communication plans.

2. Safety Specification:

   • Summarizes known and potential risks and identifies important missing information.

3. Pharmacovigilance Plan:

   • Details activities to further characterize the safety profile (e.g., post‑authorization safety studies).

4. Risk Minimization Measures:

   • Routine: Labeling changes, educational materials.

   • Additional: Controlled distribution programs, restricted prescriber certification.

5. Implementation & Effectiveness Evaluation

• Risk Minimization Tools:

  • Direct Healthcare Professional Communications (DHPC): “Dear Doctor” letters for urgent safety information.

  • Educational Programs: Workshops, e‑learning modules for prescribers and patients.

• Effectiveness Metrics:

  • Process Indicators: Distribution and receipt of materials, completion of trainings.

  • Outcome Indicators: Changes in prescribing patterns, reduction in incidence of targeted ADRs.

6. Common Challenges & Solutions

7. Key Exam Tips

• Define PRR and outline its calculation parameters.

• Differentiate EU RMP vs. US REMS content and purpose.

• List three criteria for signal prioritization.

• Describe one example of an additional risk minimization measure (ETASU).