Pharmaceutical Validation Overview

Pharmaceutical Validation

• Pharmaceutical validation is a broad process, encompassing every aspect of pharmaceutical processing.
• A documented program, established in 1987, assures a specific process consistently produces a product meeting pre-determined specifications and quality attributes.
• The program emphasizes quality assurance and Good Manufacturing Practices (GMPs).

Scope of Validation

• Validation covers various aspects of pharmaceutical operations:
  • Buildings and Facilities
  • Equipment
  • Analytical Test Methods
  • Manufacturing processes (Process validation)
  • Cleaning
  • Instrument Calibration
  • Process Utility services
  • Raw materials
  • Packaging materials
  • Product Design
  • Operators

Importance of Validation

• Assurance of Quality: End-product testing alone is insufficient; validated processes are crucial for consistent quality.
• Reduction of Quality Costs: Validation minimizes internal failures (e.g., rejects, retesting) and external failures (e.g., recalls, complaints).
• Increased Operational Safety: Calibration of instruments (e.g., gauges) ensures reliability and safe operation.

Organization for Validation

• Validation is not the responsibility of a single department.
• A homogeneous team, drawn from multiple departments (R&D, Quality, Production, Engineering), is crucial.

Validation of Buildings and Facilities

• Validation of buildings and facilities ensures they consistently produce the specified environmental conditions within pre-defined limits.
• Similar to equipment validation, this involves five documents:
  • User Requirement Specification (URS)
  • Design Qualification (DQ)
  • Installation Qualification (IQ)
  • Operational Qualification (OQ)
  • Performance Qualification (PQ)

URS for Buildings and Facilities

• URS details user expectations/requirements for manufacturing formulations in specific buildings and facilities.
• The URS documents:
  • Manufacturing processes, like tablet coating or capsule filling
  • Volumes and quantities of various formulations
  • Product types (e.g., tablets, parenterals)
  • Warehousing, QC/R&D lab, pilot plants, utilities block, car parking, and other facilities.

Design Qualification (DQ)

• DQ specifies total building and facility characteristics, including design, specifications, and details of location, size, HVAC systems, and grouping of areas.
• Critically examines environmental conditions like air, temperature, humidity, sound level, storage.
• Detailed drawings, dimensional layouts of rooms, material/equipment placement are part of the document.

Installation Qualification (IQ)

• IQ verifies installation of facilities and equipment according to the DQ.
• This includes verification of room size, surface finishes, HVAC systems, and environmental air systems.
• Completeness and proper installation of equipment like cleaning, sanitation, maintenance, plumbing, and waste disposal systems.

Operational Qualification (OQ)

• OQ confirms the specified operational parameters are correct.
• This involves confirmation of airflow patterns, lighting, noise levels, staff and material movement, sewage/waste management, sanitation, and maintenance of the entire facilities.

Performance Qualification (PQ)

• PQ evaluates the total operational performance of equipped and operational premises.
• It ensures the quality specifications of the output during operation, including various sounds, production of dust, exhaust system functionality, heat generation, and choked filters.
• It examines how people are working, and handling of various materials during operation.

Validation of Equipment

• Equipment validation is essential for pharmaceutical processing.
• It involves these distinct steps:
  • Customer Requirements (URS)
  • Design Qualification (DQ)
  • Installation Qualification (IQ)
  • Operational Qualification (OQ)
  • Performance Qualification (PQ)

Customer Requirements (URS)

• URS incorporates user expectations regarding equipment and parameters.
• Parameters often include details like equipment size, speed, ease of operation, cleaning, and maintenance, material of construction.

Preparation of Design Qualification (DQ)

• Detailed DQ document is essential for fabrication of equipment per specifications outlined in URS.
• This is agreed upon by both purchaser and manufacturer to ensure conformity with specifications.
• Factory Acceptance Test (FAT) is performed at the manufacturer's facilities.

Installation Qualification (IQ)

• IQ is the verification that the installation conforms to the manufacturer's recommendations and ensures codes and approved DQ.

Operational Qualification (OQ)

• OQ is the process of verifying the system or subsystem functions within the established operating limits.

Performance Qualification (PQ)

• PQ assesses operational and performance functions of the equipment under full-operational parameters.

Process Validation

• Process Validation (PV) details the documented program guaranteeing the consistent production of a product that meets its specifications and quality standards.
• Validation of process starts after the qualification program is complete (DQ, IQ, OQ, PQ).
• The process can be categorized as:
  • Prospective validation
  • Concurrent validation
  • Revalidation
  • Retrospective validation

Prospective Validation

• Prospective validation is performed during product development and design stages.
• Input resources, material specifications, equipment parameters, and operating conditions are defined and recorded.
• Output parameters are evaluated and verified experimentally to ensure consistent results. .

Concurrent Validation

• Concurrent validation is conducted during the production phase.

Revalidation

• Revalidation is necessary when major changes occur in formula, equipment, procedures, or raw materials.

Retrospective Validation

• Retrospective validation examines historic data and information about existing and running production processes to evaluate the quality or results of the processes.
• It is useful when there is insufficient pre-production validation.

Validation of Analytical Methods

• Analytical method validation establishes the accuracy, precision, specificity, limit of detection (LOD), and limit of quantitation (LOQ) for the intended analytical application, by laboratory studies.

Accuracy

• Accuracy refers to the closeness of test results obtained by a method to the true value.

Precision

• Precision is the degree of agreement among individual test results from multiple sampling of the homogenous sample.

Specificity

• Specificity assesses unequivocal presence of an analyte in the presence of interfering components like impurities, degradation products, and matrix components.

Limit of Detection (LOD)

• LOD is the lowest analyte amount that can be detected, but not necessarily quantitated, under the stated experimental conditions.

Limit of Quantitation (LOQ)

• LOQ is the lowest analyte amount that can be determined with acceptable accuracy and precision.

Linearity

• Linearity refers to the capacity of an analytical method to generate test results that are directly proportional to the analyte concentration within a given range using linear or well-defined mathematical models.

Range

• Range is the interval between the upper and lower levels of the analyte that has been practically demonstrated. It is ideally measured in the same units as the test result (e.g., percentage, parts per million).

Ruggedness

• Ruggedness assesses the reproducibility of test results under different operational conditions (different laboratories, and analysts).

Robustness

• Robustness measures how an analytical method remains unaffected by small but deliberate variations.

Cleaning Validation

• Cleaning and decontamination are critical in pharmaceutical operations.
• Cleaning protocols are crucial for ensuring product purity and safety by determining what equipment, surfaces, cleaning agents, and concentration are required.
• CFR 211.67 mandates cleaning and sanitization at appropriate intervals to avoid malfunctions and contamination.
• Cleaning validation protocols detail the procedures, equipment, and materials.
• Cleaning validation emphasizes the consistent attainment of required cleaning levels.