VALIDATION  BOOT  CAMP  #4  

LIFECYCLE  APPROACH  TO  PHARMACEUTICAL  VALIDATION  –    

PRINCIPLES,  IMPLEMENTATION,  AND  PRACTICE

EQUIPMENT QUALIFICATION –

LIFECYCLE APPROACH

Paul L. Pluta, PhD

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OUTLINE

I.  Equipment Qualification – Lifecycle Approach •  Qualification approaches •  Documentation hierarchy •  Document outlines

II.  Documentation problems

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EQUIPMENT QUALIFICATION – LIFECYCLE APPROACH KEY POINTS SUMMARY

1. Equipment qualification is a vital part of validation. 2. New FDA process validation guidelines has changed expectations

for equipment qualification. 3. Approach equipment qualification by lifecycle approach stages

•  Stage 1. Design / understand •  Stage 2. Demonstrate •  Stage 3. Monitor / maintain.

4. Equipment qualification must not be considered a one-time event. 5. Key validation principles identified -- Confirmation, risk analysis,

documentation, others. 6. Qualification options: IO/OQ/PQ or ASTM E2500. 7. Model documents recommended. 8. Documentation is vital: Consistency, content, good documentation

practices, and document retrieval.

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INTRODUCTION -- VALIDATION AND QUALIFICATION PROCESS VALIDATION – PROCESS QUALIFICATION

PROCESS PERFORMANCE QUALIFICATION Qualification Qualification Equipment #1 HVAC

Utilities Equipment #2 Facilities

Computers Equipment #3

Analytical methods validation Cleaning process validation Packaging process validation

PROCESS IS VALIDATED

ALL SUPPORTING EQUIPMENT, FACILITIES, UTILITIES, CONTROL SYSTEMS, ANALYTICAL, ETC. MUST BE QUALIFIED.

Unit    Opera.on  

#1      #2      #3            

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FDA PROCESS VALIDATION GUIDANCE 2011

Validation History •  1978 – GMP includes Validation •  1987 – First Validation Guidance

o  Equipment IQ

•  2000 à New approaches / documents / presentations •  2008 – New Process Validation draft guidance

o  Equipment and analytical included

•  2011 – New Process Validation Guidance issued

FDA EXPECTATIONS FOR VALIDATION / QUALIFICATION

CONSIDER POTENTIAL APPLICATION TO EQUIPMENT SAME AUDITORS – PHARMA, DEVICES, PROCESSES, EQUIPMENT

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Definition FDA – 2011 Definition: Collection and evaluation of data, from the

process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.

Three stages of activities: •  Stage 1 – Process Design – Development and scale-up activities •  Stage 2 – Process Qualification – Reproducible manufacturing •  Stage 3 – Continued Process Verification – Routine production

1987 VALIDATION -- FOCUS IS PRIMARILY STAGE 2. 2011 VALIDATION -- LIFECYCLE APPROACH

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Medical Device Validation

Comparison to Pharma

•  Device IQ = Pharma IQ / OQ / PQ •  Device OQ = Product R&D (Stage 1 development) •  Device PQ = Pharma PV

Reference: Device GHTF

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VALIDATION / QUALIFICATION PRINCIPLES •  Validation is confirmation •  Risk analysis determines everything •  Science and technical basis for design and development •  Lifecycle approach

–  Understand, demonstrate, monitor and maintain

•  Sampling and testing -- rationale and justification •  Pre-approved acceptance criteria •  Data-based judgments •  Documentation of above •  Document retrieval •  Maintain validation continuously •  Change control

APPLICATION TO EQUIPMENT QUALIFICATION

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VALIDATION IS CONFIRMATION

Successful validation is expected. Do not initiate validation unless success is

expected. Validation is not the final step in development,

installation, optimization, fine-tuning, or other development activities.

Amendments, mistakes, failures scope changes, etc. all have negative implications.

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RISK MANAGEMENT

Risk defines everything. Test only critical equipment parameters in

validation. Risk level determines level of testing. Test non-critical equipment parameters during

commissioning. Document risk assessment.

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EQUIPMENT QUALIFICATION APPLICATIONS Lifecycle approach Risk analysis Science and technical basis for design and development Validation confirms equipment design and development Sampling and testing -- rationale and justification – based on risk Pre-approved acceptance criteria Data-based judgments Document everything – Retrieve documents Maintain validation continuously throughout lifecycle -- based on risk •  Preventive maintenance •  Calibration •  Change control

DOES THIS MAKE SENSE?

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EQUIPMENT QUALIFICATION Qualification approaches •  DQ / IQ / OQ / PQ (IQ for medical devices) •  ASTM E2500

Documentation hierarchy

Document outlines •  Model documents

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QUALIFICATION APPROACHES DQ / IQ / OQ / PQ

Traditional qualification DQ – Multiple functions and applications

•  Purchasing document •  Equipment design document

Documents may be combined •  IQ, OQ, PQ •  IOQ, PQ •  IOQ

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DQ / IQ / OQ / PQ CONTENT DQ – Design Qualification •  Equipment description •  Equipment design requirements •  Purchase / design specific requirements

IQ – Installation Qualification •  Components •  Drawings •  Operating manuals •  Product-contact material composition •  Surface area calculations (product contact equipment) •  Calibration •  Preventive maintenance •  Equivalence to other equipment •  Most difficult to clean locations •  Other

OQ – Operation Qualification •  Worst case / range parameter operation

PQ – Performance Qualification •  Integrated parameter operation with representative materials

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ISPE EQUIPMENT VALIDATION User Requirements PQ Specification Functional Specification OQ Design Specifications IQ

System Build

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EQUIPMENT QUALIFICATION LIFECYCLE 1.  Capital request with design (DQ) 2.  Equipment build 3.  Factory Acceptance Test (FAT) 4.  Site Acceptance Test (SAT) 5.  Commissioning 6.  IQ 7.  OQ 8.  PQ 9.  Preventive Maintenance and Calibration 10.  Change control 11.  Decommissioning

CONSISTENT WITH STAGE APPROACH DOCUMENTATION ON ALL

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EQUIPMENT QUALIFICATION

Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) Test and document critical items only. FAT, SAT, and Commissioning Test and document non-critical items.

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ASTM E2500. Standard Guide for Specifications, Design, and Verification of Pharmaceutical and Biopharmaceutical

Manufacturing Systems and Equipment

•  Design Input •  Design Review •  Risk Mitigation •  Critical Control Parameters Define •  Acceptance Criteria •  Verification Testing •  Performance Testing •  GEP scope and QA scope have clear boundary •  Process, Product Quality and Patient Safety •  Quality by Design, Design Space and Continuous Improvement

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ASTM E2500

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ASTM E2500

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TRADITIONAL QUALIFICATION VS. E2500 Focused objective Comprehensive approach Includes risk analysis Critical parameters Less paperwork

•  Same content

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DOCUMENTATION HIERARCHY Company policy Validation Master Plan DQ Design and development SAT / FAC Commissioning Validation / Qualification Request / Plan IQ /OQ /PQ Protocol / Results / Report Post Validation Monitoring / Maintenance Change control Associated technical document (e.g., manuals, etc.) Associated documents (e.g., training, HR) Management Review

CONSISTENT LIFECYCLE APPROACH

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DOCUMENT OUTLINES

Validation Initiation Validation Plan IQ – Protocol and Results OQ – Protocol and Results PQ – Protocol and Results IQ/OQ/PQ Report

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VALIDATION REQUEST OUTLINE

Objective of validation Why needed? Impact of validation

•  Risk analysis

Why acceptable? •  Compliance to internal requirements, policies, engineering standards, etc. •  Regulatory impact (Prior approval, CBE, CBE30, etc.) •  Other systems or product impacted •  Procedure changes or other document changes •  Notifications to affected groups (internal, external, labs)

Validation plan -- Approach to accomplish validation

Above applicable to equipment and other qualification

HAVE MODEL DOCUMENTS AVAILABLE

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QUALIFCATION PLAN OUTLINE Introduction Technical information Qualification strategy and testing Qualification documentation

•  List of required protocols, reports, procedures, etc. •  Administrative benefit

References •  List of reports and scientific references (including Stage 1

reports)

HAVE MODEL DOCUMENTS AVAILABLE

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PROTOCOL OUTLINE Introduction Equipment Testing with justification Sampling with justification Sampling and data pages Data treatment Acceptance criteria with justification

HAVE MODEL DOCUMENTS AVAILABLE

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RESULTS OUTLINE Introduction Data sheets compiled Data treatment Results Deviations, Non-conformances, etc. Discussion •  “Results pass” is not sufficient.

Validation statement: “Results indicate that ___ is validated / qualified.” Post-validation plan

WRITE DISCUSSION SECTION FIRST – MOST IMPORTANT SECTION

HAVE MODEL DOCUMENTS AVAILABLE

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QUALIFICATION REPORT

Combined IQ / OQ / PQ results Helpful in audit – total summary “Cut and paste” results and conclusions sections Consistency and completeness important

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REPORT FORMAT •  Introduction •  Key information from Validation Plan •  Supporting information •  Protocol #1 results – “Cut and paste” •  Protocol #2 results – “Cut and paste” •  Protocol #3 results – “Cut and paste” •  Protocol #n results – “Cut and paste” •  Write transitional narrative •  Project conclusions •  Validation statement

–  “Results indicate that ______ is validated / qualified.”

HAVE MODEL DOCUMENTS AVAILABLE

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TEMPLATES vs. MODEL DOCUMENTS

Recommendation: 1. Prepare “perfect” document – make available as

needed 2. Assemble multiple documents from different

applications 3. Upgrade as needed 4. Documents available to technical writers 5. Validation Review Board maintain standards.

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DOCUMENTATION PROBLEMS

•  Qualification statement: “________ is qualfied.” •  Documentation content

o  Scientific and technical o  Compliance with policies/procedures/regulations

•  Errors, mistakes, and omissions o  Sampling and data pages o  Equipment not ready to be qualified

•  Original data consistency o  Documentation practices – original data o  Missing results o  Retrieval

•  Documentation rules •  Others

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DOCUMENTATION – THREE SIMPLE RULES

1.  Clear, complete, concise, consistent 2.  “Stand-alone” documents – written for the

reader 3.  Short sentences and simple words

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SUMMARY

1. Equipment qualification is a vital part of validation. 2. New FDA process validation guidelines has changed expectations for

equipment qualification. 3. Approach equipment qualification by lifecycle approach stages

•  Stage 1. Design / understand •  Stage 2. Demonstrate •  Stage 3. Monitor / maintain.

4. Equipment qualification must not be considered a one-time event. 5. Key validation principles identified -- Confirmation, risk analysis,

documentation, others. 6. Qualification options: IO/OQ/PQ or ASTM E2500 . 7. Documentation is vital: Consistency, content, good documentation

practices, and document retrieval. 8.  Implementation strategies: Management support and document content. 9.  Lifecycle change = Reorientation – Not a significant change.

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     PAUL  L.  PLUTA,  PhD    

Editor-­‐in-­‐Chief  Journal  of  Valida-on  Technology  Journal  of  GXP  Compliance  Advanstar  Communica.ons  

   

Adjunct  Associate  Professor  University  of  Illinois  at  Chicago  (UIC)  College  of  Pharmacy  Chicago,  IL,  USA  

   

PharmaceuJcal  industry  experience      

Contact:    paul.pluta@comcast.net    

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