B Pharmacy Sem 6: Quality Assurance

Implement TQM, QbD, ISO, ICH, GLP, and GMP principles, plus calibration, validation, warehousing, and complaint management in Quality Assurance

Subject 6: Quality Assurance

Unit 1 – QMS Concepts (TQM, QbD, ISO 9000/14000, ICH, NABL)

Unit 2 – Organization, Facilities & Raw Material Management

Unit 3 – Quality Control & GLP

Unit 4 – Complaint Handling & Documentation

Unit 5 – Calibration, Validation & Warehousing

Unit 1: Quality Management System (QMS) Concepts

This unit introduces the frameworks and standards that ensure consistent product quality in pharmaceutical manufacturing, focusing on Total Quality Management (TQM), Quality by Design (QbD), ISO 9000/14000, ICH guidelines, and NABL accreditation—all with concise, exam‑focused definitions.

6.1 Total Quality Management (TQM)

• Definition: An organization‑wide approach emphasizing continuous improvement, customer focus, and process optimization.

• Key Principles:

  • Customer Orientation: Quality defined by end-user needs.

  • Process Approach: Manage activities as interrelated processes.

  • Continuous Improvement (Kaizen): Incremental enhancements to processes.

  • Employee Involvement: Cross‑functional teams, empowerment.

6.2 Quality by Design (QbD)

• Definition: A systematic development approach where quality is built in from the outset by understanding process and product variability.

• Core Elements:

  • Quality Target Product Profile (QTPP): Desired product characteristics (e.g., release profile).

  • Critical Quality Attributes (CQAs): Physical, chemical, biological properties that must be controlled.

  • Design Space: Range of input variables and process parameters proven to deliver CQAs.

  • Control Strategy: Real-time monitoring and setpoints to maintain product quality.

6.3 ISO 9000 & ISO 14000 Series

• ISO 9000 Family:

  • Scope: International standards for quality management systems (QMS).

  • Key Standard: ISO 9001: Specifies requirements for a QMS—process documentation, management review, corrective actions.

• ISO 14000 Family:

  • Scope: Standards for environmental management systems (EMS).

  • Key Standard: ISO 14001: Framework to manage environmental responsibilities—pollution prevention, resource efficiency.

6.4 ICH Guidelines

• Definition: Harmonized guidelines by the International Council for Harmonisation (regulatory authorities & industry) to ensure quality, safety, and efficacy of pharmaceuticals.

• Key Quality Guidelines:

  • Q8 (Pharmaceutical Development): Incorporates QbD principles.

  • Q9 (Quality Risk Management): Systematic risk assessment for quality.

  • Q10 (Pharmaceutical Quality System): Lifecycle approach to QMS integrating TQM and QbD.

  • Q11 (Drug Substance): Development and manufacture of active substance.

6.5 NABL Accreditation

• Definition: National Accreditation Board for Testing and Calibration Laboratories—accredits labs for technical competence and compliance with ISO/IEC 17025.

• Importance in Pharma:

  • Ensures reliability and traceability of analytical test results for raw materials, in‑process checks, and finished products.

  • Promotes robust method validation, equipment calibration, and staff competency.

Key Exam Tips

• TQM vs. QbD: TQM is organization‑wide improvement; QbD builds quality into product design.

• ISO Series: ISO 9001 for QMS; ISO 14001 for environmental management.

• ICH Q‑Guidelines: Q8–Q10 form a lifecycle: development (Q8), risk (Q9), system (Q10).

• NABL (ISO 17025): Accreditation for analytical labs—vital for QA testing.

Unit 2: Organization, Facilities & Raw Material Management

This unit outlines the structural framework, facility requirements, and raw material controls essential for maintaining product quality and compliance in pharmaceutical manufacturing.

6.2.1 Organizational Structure

• Quality Unit

  • Quality Assurance (QA): Defines and oversees the QMS, reviews and approves procedures, deviations, and change controls.

  • Quality Control (QC): Conducts testing of raw materials, in‑process samples, and finished products; ensures methods are validated.

• Cross‑Functional Teams

  • Production, Engineering, QA/QC, Regulatory: Collaborate on process design, validation, and continuous improvement.

• Roles & Responsibilities

  • Head of QA: Final authority on product release.

  • Qualified Person (QP): Legal responsibility for batch certification (in EU/WHO contexts).

  • Batch Release Officers: Ensure each batch meets specifications before distribution.

6.2.2 Facility Design & Layout

• Zoning & Flow

  • Unidirectional Flow: Raw materials → processing → packaging to prevent cross‑contamination.

  • Grade Levels: Defined cleanroom classifications (e.g., Grade A/B for sterile, C/D for non-sterile).

• Environmental Controls

  • Air Handling: HEPA‑filtered supply and exhaust; positive/negative pressure differentials as required.

  • HVAC Systems: Maintain temperature, humidity, and air changes per hour.

• Utilities

  • Water Systems: Purified water (PW) and water for injection (WFI) with periodic microbial and endotoxin monitoring.

  • Clean Steam & Compressed Air: Must meet USP/Ph. Eur. standards; regularly validated.

6.2.3 Raw Material Management

• Vendor Qualification

  • Assessment: Audit supplier’s GMP compliance, quality systems, and reliability.

  • Approval: List of approved vendors based on audit results and performance.

• Receiving & Sampling

  • Quarantine: All incoming lots placed in quarantine until QA release.

  • Sampling Plans: Defined procedures for representative sampling (e.g., stratified sampling for granules).

• Testing & Release

  • Specification Review: Identity, purity, assay, microbial limits, and residual solvents.

  • Certificate of Analysis (CoA): Supplier’s CoA verified against in‑house testing.

• Storage & Handling

  • Conditions: Labelled storage areas with controlled temperature, humidity, and segregation of hazardous materials.

  • Inventory Control: First‑in, first‑out (FIFO) for lot traceability; periodic stock reconciliation.

Key Exam Tips

• Organizational Roles: Distinguish QA vs. QC responsibilities; know the QP’s legal role.

• Facility Zoning: Unidirectional flow and cleanroom grades prevent contamination.

• Raw Material Lifecycle: Quarantine → sampling → testing → QA release → controlled storage.

Unit 3: Quality Control (QC) & Good Laboratory Practices (GLP)

This unit covers the activities and standards that ensure laboratories produce reliable and reproducible data for pharmaceutical quality control, focusing on analytical testing and GLP compliance.

6.3.1 Quality Control (QC)

• Role & Scope

  • Ensures that raw materials, in-process samples, and finished products meet predefined specifications.

  • Provides data for QA decisions on batch disposition.

• Analytical Method Validation

  • Specificity: Ability to assess the analyte in presence of impurities, degradants, matrix components.

  • Accuracy & Precision:

    • Accuracy: Closeness of measured value to true value (% recovery).

    • Precision: Repeatability (intra-day) and intermediate precision (inter-day, different analysts).

  • Linearity & Range: Demonstrates proportional response over concentration range.

  • Limit of Detection (LOD) & Limit of Quantitation (LOQ): Smallest amount that can be reliably detected/quantified.

  • Robustness & Ruggedness: Method’s resilience to small deliberate variations (pH, temperature).

• Routine QC Tests

  • Identity: IR, UV, TLC

  • Assay: HPLC, titration

  • Dissolution: Tablet release profile

  • Microbial Limits: Total aerobic count, specified pathogens

  • Impurity Profiling: Related substances by HPLC/GC

6.3.2 Good Laboratory Practices (GLP)

• Definition: A quality system of management controls for studies conducted to ensure the safety of chemicals and pharmaceuticals, as per OECD Principles of GLP.

• Key Elements:

  • Study Planning:

    • Study Plan/Protocol: Clear objectives, methods, acceptance criteria.

    • Standard Operating Procedures (SOPs): Detailed instructions for all laboratory activities.

  • Study Conduct:

    • Documentation: Raw data, notebooks, electronic records with traceability.

    • Personnel:* Defined roles—Study Director, Principal Investigator, Quality Assurance Unit.

  • Equipment & Materials:

    • Calibration & Maintenance: Scheduled and documented for all instruments.

    • Reagents & Standards: Traceability to certified reference materials.

  • Quality Assurance Unit (QAU):

    • Independent Monitoring: Audits study conduct, facilities, records, and reports.

    • Audit Reports: Document any deviations and corrective actions.

  • Study Reporting & Archiving:

    • Final Report: Comprehensive results, methods, deviations, conclusions.

    • Archive: Secure storage of records (raw data, SOPs, reports) for retention period.

Key Exam Tips

• QC vs. QA: QC tests product quality; QA oversees the entire system.

• Validation Parameters: Memorize specificity, accuracy, precision, LOD/LOQ, robustness.

• GLP Roles: Study Director directs study; QAU audits independently.

• Documentation: “If it’s not documented, it didn’t happen”—critical for both QC and GLP.

Unit 4: Complaint Handling & Documentation

This unit addresses the systematic management of customer complaints, product deviations, and the critical documentation practices that ensure traceability, regulatory compliance, and continuous improvement.

6.4.1 Complaint Handling

• Definition: The formal process of receiving, investigating, and resolving complaints regarding product quality or performance.

• Key Steps:

  1. Receipt & Logging: Record complaint details in a Complaint Log—product name, batch number, complainant information, nature of complaint.

  2. Triage & Categorization: Assess severity (e.g., potential safety issue vs. minor inconvenience) and assign a priority level.

  3. Investigation:

     • Sample Collection: Obtain retained samples or representative product units.

     • Root Cause Analysis: Use tools like Ishikawa (fishbone) diagrams and 5 Whys to identify underlying causes.

     • Impact Assessment: Determine if other batches or products are affected.

  4. Corrective & Preventive Actions (CAPA):

     • Corrective Action: Immediate measures to address the specific event (e.g., product recall, replacement).

     • Preventive Action: Process changes to prevent recurrence (e.g., updated SOP, training).

  5. Closure & Feedback: Document findings, actions taken, and communicate resolution to the complainant.

• Regulatory Requirements:

  • Timely reporting of serious adverse events to health authorities.

  • Maintenance of complaint records for specified retention periods (e.g., 5–10 years).

6.4.2 Documentation Practices

• Good Documentation Practices (GDP): A set of standards ensuring all records are accurate, legible, contemporaneous, original, and attributable (ALCOA).

• Key Elements:

  • SOPs & Work Instructions: Clear, version‑controlled, approved by QA before use.

  • Batch Manufacturing Records (BMR): Detailed, step‑by‑step records of production activities for each batch.

  • Batch Packaging Records (BPCR): Documentation of labeling, packing, and release activities.

  • Change Control Records: Formal review and approval of any changes to processes, equipment, or documents.

  • Deviation & Non‑Conformance Reports: Recorded when processes or specifications are not met; must include investigation and CAPA.

  • Training Records: Documentation of staff training on SOPs, safety, and quality policies.

  • Audit & Inspection Reports: Findings from internal/external audits with follow‑up actions.

• Electronic vs. Paper Records:

  • 21 CFR Part 11 Compliance: For computerized systems—ensures electronic signatures, audit trails, and data integrity.

  • Record Retention: Aligns with regulatory guidelines (e.g., WHO, FDA)—typically several years post–product expiry.

Key Exam Tips

• Complaint lifecycle: Logging → investigation → CAPA → closure.

• GDP acronym ALCOA: Attributable, Legible, Contemporaneous, Original, Accurate.

• Essential documents: SOPs, BMR/BPCR, change control, deviation reports.

• e‑Records compliance: Know basics of 21 CFR Part 11 for electronic documentation.

Unit 5: Calibration, Validation & Warehousing

This unit focuses on ensuring equipment accuracy, process reliability, and proper storage of materials and products, with precise definitions for exam-ready recall.

6.5.1 Calibration

• Definition: Comparison of an instrument’s performance against a standard to detect and correct deviations.

• Key Aspects:

  • Standards & Traceability: Use certified reference materials traceable to national/international standards (e.g., NIST).

  • Frequency: Defined in calibration schedules—initial, periodic, and after major repairs.

  • Documentation: Calibration certificates detailing instrument ID, date, standard used, results, and next due date.

6.5.2 Validation

• Definition: Establishing documented evidence that a process, method, or system consistently produces a result meeting predetermined specifications and quality attributes.

• Types of Validation:

  • Process Validation: Demonstrates consistent manufacturing—includes Installation Qualification (IQ), Operational Qualification (OQ), Performance Qualification (PQ).

  • Analytical Method Validation: See Unit 3; ensures test methods are suitable for intended purpose.

  • Cleaning Validation: Confirms cleaning procedures remove residues to acceptable levels—determines worst-case scenario, sampling, and acceptance criteria.

  • Computer System Validation: Ensures software and computerized systems perform as intended (21 CFR Part 11).

6.5.3 Warehousing

• Definition: Controlled storage of raw materials, intermediates, and finished products to preserve quality and traceability.

• Key Elements:

  • Storage Conditions: Temperature, humidity, light control as per product requirements (e.g., 2–8 °C cold chain, < 25 °C for dry goods).

  • Inventory Management:

    • First‑In, First‑Out (FIFO): Prevents expiry of older stock.

    • Batch Traceability: Clear labeling with batch, expiry, and storage instructions.

  • Security & Access Control: Restricted access to authorized personnel; logs for entry/exit.

  • Quarantine & Release: Separate areas for quarantine, sampling, testing, and QA release before use or dispatch.

Key Exam Tips

• Calibration vs. Validation: Calibration ensures equipment accuracy; validation ensures process reliability.

• Validation Phases: IQ (installation), OQ (operation), PQ (performance under real conditions).

• Warehousing priorities: Maintain required conditions, FIFO, and strict access control.