GLP & GMP – Comprehensive Study Notes

Introduction

• Previously: Unit on evaluation & quality control emphasised pharmacopoeias/formularies for ingredients, strength, dosage-forms, QC.
• Current unit: explores integrated Quality Assurance across R&D → manufacturing → clinical use.
• Core quality families
  • Good Laboratory Practice (GLP) – non-clinical data integrity.
  • Good Manufacturing Practice (GMP) – production & in-process control.
  • Good Clinical Practice (GCP) – ethical/ scientific conduct of human studies (to be covered in later pages).
• Relevance: assuring safety/efficacy, supporting global trade, avoiding duplication, legal compliance.

Stated Objectives

• Explain principles of $GLP, GMP, GCP$.
• Understand Quality-Assurance responsibility chain.
• Detail structure & role of GLP authority + inspectors.
• Identify GMP facility/aseptic-area features & personnel roles.
• Outline importance & phases of GCP, Declaration of Helsinki, Schedule-Y, IRB/IEC (announced; content not yet in transcript).

GOOD LABORATORY PRACTICE (GLP)

1. Historical Context

• 1976 US-FDA issued first non-clinical GLP rule → basis for OECD work.
• 1978 OECD expert group drafts global principles; adopted by OECD Council $1981$.
• 1995–96: major revision → current harmonised text.
• India: Department of Science & Technology (DST) sets up National GLP Compliance Monitoring Authority $2002$; status = OECD “provisional member/observer”.

2. Indian Apex Body (high-level governance)

• Chaired by Secretary, DST (Govt of India).
• Members: Secretaries of Chemicals & Petrochemicals, Agriculture, Health, Commerce, Environment, Fertilisers, Consumer Affairs; DCGI; DG-CSIR; Head–National GLP Programme.
• Mandate: ensure programme aligns with OECD norms.

3. Definition & Scope

• GLP = formal management system for planning, performing, monitoring, recording, reporting & archiving non-clinical safety studies.
• Applicable products: pharmaceuticals, agrochemicals, cosmetics, veterinary drugs, food/feed additives, industrial chemicals, biocides.
• Test items: synthetic, natural, biological or living organisms.
• Goal: data integrity + mutual international acceptance → eliminates retesting, $\Downarrow$ costs/time; removes technical barriers to trade; protects human health & environment.
• Environments: laboratory, greenhouse, field.

4. Powers & Functions of GLP Authority (India)

• Monitor implementation progress.
• Operate national GLP compliance system.
• Grant, suspend, withdraw GLP certification (valid $3\text{ years}$).
• Notify foreign GLP authorities on major non-compliance.
• Set up technical committees/working groups; approve internal rules.
• Maintain OECD compatibility; conduct scheduled & surprise inspections.

5. Nature of Certification Programme

• Voluntary; open to any facility performing relevant studies.
• Ongoing surveillance visits (announced or unannounced).
• Cooperation with foreign regulators for joint study audits.
• Sanctions: suspension if serious deviations threaten data validity.

6. GLP Inspectors

• Drawn from Government labs; trained by National GLP Office/OECD.
• Core duties
  • Pre-inspection dossier review.
  • On-site opening/closing meetings.
  • Evaluate competence vs OECD Principles/Test Guidelines.
  • Draft confidential reports → Technical Committee only.
• Rights/limits
  • Access to data; must preserve confidentiality.
  • Prefer consented entry; but unscheduled visits allowed if public health/ environment at risk (refusal ⇒ certificate suspension).

7. Principles & Detailed Requirements

• Test-Facility Organisation & Personnel
  • Management ensures compliance, adequate staff, documented CV/training.
• Quality Assurance Programme (QAP)
  • Independent QA unit reporting to management; verifies GLP adherence.
• Facilities
  • Size/location minimise disturbance & cross-mixing; separated activities.
• Apparatus, Materials, Reagents
  • Adequate capacity; cleaned, maintained, calibrated; calibration traceable to national/international standards.
• Test Systems
  • Physical/chemical: appropriate design; Biological: controlled housing, quarantine on receipt; cull if morbidity/mortality unusual.
• Test & Reference Items
  • Full chain-of-custody records: characterisation, receipt date, expiry, use; containers labelled with ID, expiry, storage.
• Standard Operating Procedures (SOPs)
  • Written, management-approved; current copies at point of use; literature can supplement.
• Performance of Study (Study Plan)
  • Signed by Study Director; QA verifies; amendments justified & signed; deviations documented.
• Reporting of Results
  • Final report per study; PI sections signed; Study Director signs whole accepting responsibility. Amendments tracked with reasons.
• Storage & Retention
  • All docs, raw data, samples archived for period required by regulators; premature disposal justified.

GOOD MANUFACTURING PRACTICE (GMP)

1. Concept & Rationale

• Global standard for controlling manufacture & QC of foods/pharmaceuticals.
• Emphasises in-process oversight rather than post-production testing.
• Requires exhaustive documentation (“If it isn’t written, it didn’t happen”).
• Equipment qualification & process validation mandatory.
• Dosage-form-specific rules (injections, tablets, capsules, liquids).

2. Location & Surroundings

• Site in clean zone, away from contamination sources (open sewage, drains, public lavatories).
• Building design prevents pest ingress & product mix-ups; smooth, crack-free interiors for easy sanitation.
• Controlled ventilation/temperature/humidity via Air Handling Units (AHU).
• Premises kept free from waste; validated cleaning procedures.

3. Water System

• Validated treatment to convert potable source → Pharmacopoeial Purified Water.
• Purified Water used for all operations except external washing.
• Tanks inert, microbiologically safe; periodic cleaning logged.
• Effluent disposal compliant with Pollution Control Board & Bio-Medical Waste Rules $1996$.

4. Warehousing

• Clean, dry, temperature/ humidity controlled.
• Segregated zones: quarantine, released, rejected, returned, recalled, spares.
• Pest-control programme.
• Dedicated sampling area to avoid cross-contamination.

5. Production Area

• Layout minimises cross-contamination; separate dedicated suites for:
  • Sensitive products (penicillins, biologics with live organisms).
  • Potent/contamination-causing items (β-lactams, hormones, cytotoxics).
• Smooth services (pipes, vents) avoid recesses.
• Competent technical staff supervise operations.

6. Ancillary Areas

• Rest/refreshment rooms isolated; toilets not connected to production/storage.
• Change rooms with cleaning/disinfection SOPs.
• Maintenance workshop separate; tools entering sterile areas disinfected.
• Animal house isolated & compliant with guidelines.

7. Quality Control (QC) Area

• Separate from production; own AHU for bio/micro/radio work.
• Continuous water supply for testing.
• Head of QC independent; tests overseen by qualified full-time staff.

8. Personnel (Hygiene & Training)

• Pre-employment medical & annual check (eyes, TB, skin, communicable diseases).
• Hygiene training; SOPs displayed.
• Report illnesses immediately.
• Change rooms (gender-segregated) with wash facilities; outdoor clothing barred.
• No smoking/eating/drinking in process areas.
• Critical steps performed under direct supervision; vessels labelled with product/batch/status.

9. Raw Materials Handling

• Maintain complete inventory per Schedule $U$.
• Quarantine on receipt; store under conditions enabling FIFO ($first\;in / first\;expiry$ principle).
• Purchase from approved suppliers with valid vouchers; prefer direct from producers.

10. Equipment

• Designed/placed for easy cleaning, minimal error risk.
• Each major item has logbook.
• Balances & instruments calibrated per schedule; records kept.

11. Documentation & Records

• Purpose: define specs; enable batch release decision; provide audit trail.
• Records contemporaneous; retained $\ge 1$ year post-expiry.
• Electronic systems allowed with:
  • SOPs + hard-copy master formulae.
  • Restricted access (passwords), audit trails for edits/deletions.
  • Regular back-ups.

12. Labels & Printed Materials

• Bright, legible; carry complete product info.
• Status labels colour-coded (e.g., under test, approved).
• Separate storage for different printed items; QC verifies before release.

13. Quality Assurance vs. Quality Control

• QA = organisational umbrella ensuring products are designed/manufactured under GMP/GLP/GCP.
• QC = operational techniques (sampling, testing, release) verifying quality meets specs.
• QC lab tasks: establish/validate methods, calibrate instruments, investigate complaints.

14. Product Containers & Closures

• Must meet pharmacopeial specs; validated cleaning & (where applicable) sterilisation.
• No reuse of second-hand containers.
• Avoid particle-shedding materials in prep areas; controlled de-cartoning.

15. Master Formula Records (MFR)

Includes:
• Product name/code, dosage form, strength, batch size.
• Complete list of starting materials (with potential disappearance noted).
• Expected yields & limits.
• Processing location/equipment.
• Equipment prep methods (cleaning, calibration, sterilisation).
• Detailed stepwise instructions + processing times.
• In-process controls & limits.
• Storage/packaging requirements; specimen labels.
• Special precautions.

16. Packing Records

• Batch packaging record per batch; cross-checked workspace clearance, equipment cleanliness.

17. Product Recalls

• Written SOP; rapid notification down to retail level using print/electronic media.
• Distribution records readily accessible; final reconciliation report mandatory.

18. Complaints & Adverse Reactions

• All quality complaints logged & investigated.
• Serious ADRs reported immediately to licensing authority.

19. Specific Requirement – Sterile Products

• Additional GMP layers for parenterals & ophthalmics:
  • Avoid dampness, dirt, darkness.
  • Service lines located to prevent leakage risk.
  • Segregated zones: support → preparation → change → aseptic.

19.1 Aseptic Areas (Civil & HVAC design)

• Surfaces: impervious, non-shedding, coved, crack-free.
• Ceilings solid; lights & grilles flush.
• No sinks/drains in Grade $A/B$.
• Doors aluminium/steel; open toward higher-pressure zone.
• Windows double-paned; flush.
• Furniture stainless steel, washable.
• Change rooms “Black → Grey → White” cascade; hand-wash in first room; doors inter-locked.

19.2 Garments for Aseptic Work

• Non-shedding, tight weave (synthetics); no cotton.
• One-piece suits with hood; cuffs/ankles secure; no pockets/pleats.
• Plastic zips; damaged garments discarded.
• Fresh sterile suit each session; masks & gloves changed every session.

19.3 Solid-Dosage Dust Control (Tablets/Capsules)

• Enclosed systems & air extraction to control dust/cross-contamination.
• HEPA-filtered exhaust; avoid metal/wood contamination (metal detectors recommended).
• Sieves, punches & dies inspected pre/post use.

Connections & Significance

• GLP → assures non-clinical safety data integrity; foundation before human trials (GCP) & manufacturing (GMP).
• GMP → converts validated non-clinical knowledge into reproducible product.
• Combined, they underpin regulator & patient confidence, facilitate international commerce, and protect public/environmental health.
• India’s alignment with OECD & WHO frameworks enhances export credibility.

Ethical & Regulatory Implications

• GLP/GMP non-compliance can lead to: data rejection, market bans, product recalls, public-health risk, legal penalties.
• Voluntary Indian GLP system reflects trust-but-verify model; yet suspension powers exist for societal protection.

Numerical / Statistical References

• GLP certification validity = $3\;years$.
• Retention of manufacturing records = $\ge 1\;year$ after product expiry.
• Medical check frequency for personnel = $1\;year$ minimum.

Quick Self-Assessment Prompts

• Define GLP and state its overarching purpose.
• List at least five mandatory elements within a GMP Master Formula Record.
• Describe the “Black–Grey–White” change-room concept and its role in asepsis.