Qualification // Validation Qualification Validation

Quality Risk Assessment in the Quality Risk Assessment in the Pharmaceutical Industry Pharmaceutical Industry -- Challenges and Opportunities -Challenges and Opportunities

Andreas Brutsche Novartis Switzerland

GMP Conference, 11.06.04, Istanbul

GMP-Conference / 10.-11. June 2004 / Istanbul

Qualification, Validation, Calibration Qualification, Validation, Calibration

Validation/Qualification Iceberg
Visible Process Unvalidated Process New System

GMP-Conference / 10.-11. June 2004 / Istanbul

Validation / Qualification Approach

User Requirement Specifications

related to

Performance Qualification

Functional Specifications

related to

Operational Qualificaton

Design Specifications

Installation Qualification

System Build

GMP-Conference / 10.-11. June 2004 / Istanbul

Quality Risk Assessment in the Quality Risk Assessment in the Pharmaceutical Industry Pharmaceutical Industry
Risk Assessment has become a key concept in the decision making process of todays pharmaceutical industry. Its impact affects many disciplines including:
Engineering Manufacturing Project Management Quality Safety Environmental

GMP-Conference / 10.-11. June 2004 / Istanbul

Quality Risk Assessment Quality Risk Assessment

People Associated Systems Utilities Analytical Testing

Validation

Equipment Manufacturing Process

Validation Validation of the analytical method Qualification Computer Training

Product Quality

Equipment Qualification Qualification / Validation Part 11 Water / Air / Process gases

GMP-Conference / 10.-11. June 2004 / Istanbul

Risk Assessment: Risk Assessment:

Each step in a process is assessed on its influence on product quality. Critical steps have to be validated/qualified Uncritical steps no activities are required

GMP-Conference / 10.-11. June 2004 / Istanbul

Equipment Qualification Equipment Qualification

User Requirement Specifications (URS) Design Qualification
Conceptual Design Basic Design Detail Design

Installation Qualification

GMP-Conference / 10.-11. June 2004 / Istanbul

Equipment Qualification Equipment Qualification

Operational Qualification Performance Qualification Calibration and Maintenance Programs Retrospective Qualification

GMP-Conference / 10.-11. June 2004 / Istanbul

Equipment Qualification Equipment Qualification

Design Qualification

Defining the quality parameters required of the equipment and manufacturer

GMP-Conference / 10.-11. June 2004 / Istanbul

Equipment Qualification Equipment Qualification

Installation Qualification

Assurance that the intended equipment is received as designed and specified.

GMP-Conference / 10.-11. June 2004 / Istanbul

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Equipment Qualification Equipment Qualification

Operational Qualification

Confirmation that the equipment functions as specified and operates correctly.

GMP-Conference / 10.-11. June 2004 / Istanbul

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Equipment Qualification Equipment Qualification

Performance Qualification

Confirmation that the equipment consistently continues to perform as required.

GMP-Conference / 10.-11. June 2004 / Istanbul

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Validation
To prove that a process works is, in a nutshell, what we mean by the verb to validate.

E. Frey, FDA

GMP-Conference / 10.-11. June 2004 / Istanbul

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Validation
Process Validation Cleaning Validation Computer system Validation Validation of Analytical Methods Part 11 Compliance Risk based approach is key !!! Focus on Product, not only on technology
GMP-Conference / 10.-11. June 2004 / Istanbul
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Link between Validation/ Qualification

Product

Risk Analysis Equipment Qualification

Risk Analysis Process Validation

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Quality Risk Analysis Quality Risk Analysis

Flow Chart for a Solid Dosage Form Process Flow Chart for a Solid Dosage Form Process
Weigh Active Agents Weigh Excipients Add Binder Water / Solvent Weigh Excipients Dry Mix Wet Mix / Granulate Dry Dry Granulate Weigh Lubricant Add Lubricant Blend Compress Solution Preparation Coat (optional)
GMP-Conference / 10.-11. June 2004 / Istanbul
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Quality Risk Analysis Quality Risk Analysis

Key Parameters Key Parameters
Process Stage Parameter Worst Case Values Min-Max values Target +/- xC Min-Max used in Pilot Scale Normal time +/- x minutes Upper-lower in process spec Upper-lower in process spec Normal production range (e.g. 100000/hr-150000/hr) Min-Max Target + / - x target rate + / - x
17 ___________________________________________________________________________________________________________________________________________ __________________

Raw materials Particle size Active agent Surface area Wet mixing Binder temperature Binder volume Mixing time Drying Granule moisture Blending Granule particle size Compression Compressor speed Pre-compression pressure Inlet air temperature Spray rate

Coating
GMP-Conference / 10.-11. June 2004 / Istanbul

Quality Risk Analysis Quality Risk Analysis

Critical Process Parameter Critical Process Parameter
Parameters: Colette gral mixer Agitator - Speed 2 Chopper - off Mixing time - 5 minutes After mixing take 12 samples from the mixing bowl using a sample thief. Samples to be taken 4 top, 4 middle, 4 bottom. Sample to be 300 mg approx. Analyse each sample for active agent content

Sampling Regimen: Testing: Acceptance

All individual values to be within + 7 - 10 % of the group Crite mean RSD to be less than 6 %. The mean to be within + 7 - 5 % of the theoretical value ________________________________________________________________ ______ Solid dosage form
GMP-Conference / 10.-11. June 2004 / Istanbul
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Tool box Tool box

Risk Assessment Risk Assessment
FMEA (= Failure Mode and Effect Analysis) HACCP (= Hazard Analysis Critical Control Points) FTA (= Failure Tree Analysis) System Kepner-Tregoe

Analysis of the situation Analysis of the problem Analysis of the decisions Analysis of potential problems

GMP-Conference / 10.-11. June 2004 / Istanbul

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Tool box Tool box

Risk Assessment Risk Assessment
FMEA (Failure Mode and Effect Analysis) Define the Risk Priority number ( - RPN)
Example: Steam sterilisation Process - Steampressure / Temperature in the autoclave - Sterilisation Time - Measures to avoid air in the autoclave - Treatment of the product before and after the process
decreasing Risk

GMP-Conference / 10.-11. June 2004 / Istanbul

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FTA (Failure Tree Analysis) FTA (Failure Tree Analysis)

Basic Concept:

Undesired Incident

Basic Incident 1

Basic Incident 2

Basic Incident 3

Basic Incident 4
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GMP-Conference / 10.-11. June 2004 / Istanbul

Risk Assessment Risk Assessment

Key Success Factor: Training and Skills of people
Scientific skills Broad - Experience in pharmaceutical Industry Leadership, Responsibilities

GMP-Conference / 10.-11. June 2004 / Istanbul

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Change // Deviation Change Deviation

Change usually refers to a planned alteration which is documented and considered before implementation. Normally, changes are either permanent or have a fixed period of validity. Deviation represents a change which may occur for a variety of reasons during operations, or may be observed to have happened after the operation. Normally, deviations are not permanent and represent single events
Planned Deviations ??

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Documentation
Validation Master Plan Qualification Master Plan GMP Risk Analysis Validation Protocol Test protocol (including specification) Validation Report Summary of Deviations / Issues

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Change Management Change Management

Who made the change Why was the change necessary When was the change implemented What international consequences arise:
- Risk / benefit assessments - Cost / benefit assessments - Regulatory impact

Who gave approvals

_____________________________________________________________________________________________________________________________________ _____________

Changes are necessary - Uncontrolled changes are dangerous

GMP-Conference / 10.-11. June 2004 / Istanbul
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Computer Simulations in Conventional Clean Rooms (Sterile Manuf.)

To be in compliance with all microbiological and particulate requirements, the design of the sterile facilities plays the most important role. Computer simulation studies of air flows should be used to analyse the most critical areas. Detailed analysis was made with regard to conflicting areas of class 10`000 and critical class 100 areas in order to prevent any possible contamination of the product. Detailed qualification of the balance is a prerequisite for a successful implementation of these design concepts.

GMP-Conference / 10.-11. June 2004 / Istanbul

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Initial Air Handling Design

Picture shows air inlets (units) and air exhaust systems

Laminar flow units Exhaust Unformatting table Filling station Formatting table Loading buffer Unloading buffer Freeze dryer 2 Freeze dryer 1

Transfer cart with horizontal laminar flow

GMP-Conference / 10.-11. June 2004 / Istanbul

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Improved Air Handling Design

Picture shows new and modified air inlets (LF units) and air exhaust systems
New exhaust

Additional laminar flow units New inlets (background area)

Modified exhaust

New exhaust

New exhaust

New exhaust

Modified inlet on cart New exhaust

GMP-Conference / 10.-11. June 2004 / Istanbul

New exhausts on cart New exhaust

Modified exhaust
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