Health Authority Inspection Management. GMP Inspection practices L. Mansolelli, Group Compliance & Auditing June 2012

Transcription

1 Health Authority Inspection Management GMP Inspection practices L. Mansolelli, Group Compliance & Auditing June 2012

2 Abstract As global health authorities align in inspection standards and practices, key systems, metrics, and indicators emerge as critical elements for pharmaceutical companies in assuring quality and compliance overall, in monitoring facilities, and in preparing for Health Authority inspections. Understanding current approaches and areas of focus for Health Authorities in conducting GMP inspections is critical to successful inspection management and assuring sustained compliance.

3 FDA UPDATE Enforcement initiative In August 2009, FDA Commissioner Hamburg made a commitment that FDA will begin swift, aggressive, and effective enforcement of FDA laws and regulations. Initiatives affecting enforcement Set post-inspection deadline Take responsible steps to speed Warning Letter process Work more closely with FDA`s regulatory process Prioritize follow up on Warning Letters and other enforcement actions Be prepared to take immediate action in response to public health risks Develop and implement formal warning letter close-out process

4 FDA UPDATE Enforcement initiative In August 2009, Comissioner Hamburg made a commitment to swift, aggressive, and effective enforcement of FDA laws and regulations. Initiatives affecting enforcement Set post-inspection deadline Improving Enforcement Process Take responsible steps to speed warning letter process Work more closely with FDA`s regulatory process Transparency Prioritize follow up on warning letters and other enforcement actions Be prepared to take immediate action in response to public health risks Develop and implement formal warning letter close-out process

5 FDA consistent expectations Senior management is responsible - Quality risk management (site audits, testing of incoming, traceability up and down the chain, security against tampering and diversion) - Implementation and maintenance of quality systems - Instilling accountability within the ranks - State of Control - Data Integrity (falsification of data) A reportable event to FDA Supplier management The FDA regards all contract facilities as an extension of the marketing authorization holders This is why they are listed in all Applications. Contractor and Contract giver are Liable for Adulterated drug. If a contract lab does not comply with cgmps it is the Contractor who is held responsible.

6 Supply Chain Management Process Performance and Product Quality Monitoring Quality is built into a Finished drug starting with its ingredients and it s packaging components Stages at which ingredient quality can go awry - Upstream supply chain - Manufacturers of APIs, intermediates, excipients - Distribution of ingredients (transportation, warehouse) Drug defects and Supply Chains - Glass containers for injectable drug products shed glass lamellae - Product odor traced to lumber used to fabricate wooden pallets upon which HDPE containers for the products were stored - Recalls can be traced to excipient variability (dissolution failures) - Contamination traced to excipients (chemical, particulate, microbiological)

7 Supply Chain Management Process Performance and Product Quality Monitoring FDA has re-focused to address Supply chain concerns Partner with global regulatory counterparts Communication and guidance - DEG, melanine, TBA, glass lamellae Identify gaps in statute and regulations Outreach and support - Foster monograph modernization FDA strategic plan designed to address globalization Global data info system Build additional capabilities in intelligence gathering

8 MHRA concerns Top five UK GMP deficiencies Quality management Quality system documentation Batch release/qp duties Environmental monitoring Supplier/raw material control Top five third country deficiencies Microbiological contamination potential Quality management Premises design and maintenance Environmental monitoring Supplier/raw material control NOV_PGL0612

9 What are the current hot topics? Falsified medicines directive, 2011/62/EC API GMP assurance Vendor management Quality risk management Updates to EU GMP Part I: Chapters 1 to 8 Part III: Q10 integration/site Master Files Good Distribution Practice Joint inspections

10 Health Authorities consistent expectations Understand product quality attributes Building knowledge Process validation lifecycle Raw materials / in process / finished goods Process map / control points / advanced engineering principles and control technologies / risk assessment Understand the sources of variability Scientific data assessment product and process Process parameters Monitor, analyze and control the process (variability) Operate within an integrated Quality System Diligent oversight is required Continuous improvement

11 FDA UPDATE The top FDA drug GMP citation so far this year from an analysis of all GMP inspections is a lack of adherence to responsibilities and procedures applicable to the quality control unit, according to CDER Division of International Drug Quality. The top FDA GMP citations...

12 FDA UPDATE Failure to thoroughly review any unexplained discrepancy or batch failure or failure of any of its components to meet its specifications No adequate training program for employees Written production and process control procedures are not established to monitor the output of manufacturing processes or followed No written procedures for equipment cleaning and maintenance and equipment and utensils are not cleaned or maintained at appropriate intervals Testing and release procedures do not include laboratory confirmation that product meets specifications Laboratory controls do not include scientifically sound and appropriate specifications, standards, or sampling plans No written production and process control procedures designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to posses

13 FDA UPDATE Failure to thoroughly review any unexplained discrepancy or batch failure or failure of any of its components to meet its specifications No adequate training program for employees Written production and process control procedures are not established to monitor the output of manufacturing processes or followed No written procedures for equipment cleaning and maintenance and equipment and utensils are not cleaned or maintained at appropriate intervals Testing and release procedures do not include laboratory confirmation that product meets specifications Laboratory controls do not include scientifically sound and appropriate specifications, standards, or sampling plans No written production and process control procedures designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to posses

14 FDA UPDATE No adequate training program for employees Failure to thoroughly review any unexplained discrepancy or batch failure or failure of any of its components to meet its specifications Written production and process control procedures are not established to monitor the output of manufacturing processes or followed No written procedures for equipment cleaning and maintenance and equipment and utensils are not cleaned or maintained at appropriate intervals Testing and release procedures do not include laboratory confirmation that product meets specifications Laboratory controls do not include scientifically sound and appropriate specifications, standards, or sampling plans No written production and process control procedures designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to posses

15 FDA UPDATE No adequate training program for employees Failure to thoroughly review any unexplained discrepancy or batch failure or failure of any of its components to meet its specifications Written production and process control procedures are not established to monitor the output of manufacturing processes or followed No written procedures for equipment cleaning and maintenance and equipment and utensils are not cleaned or maintained at appropriate intervals Testing and release procedures do not include laboratory confirmation that product meets specifications Laboratory controls do not include scientifically sound and appropriate specifications, standards, or sampling plans No written production and process control procedures designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to posses

16 FDA UPDATE Failure to thoroughly review any unexplained discrepancy or batch failure or failure of any of its components to meet its specifications No adequate training program for employees Written production and process control procedures are not established to monitor the output of manufacturing processes or followed No written procedures for equipment cleaning and maintenance and equipment and utensils are not cleaned or maintained at appropriate intervals Testing and release procedures do not include laboratory confirmation that product meets specifications Laboratory controls do not include scientifically sound and appropriate specifications, standards, or sampling plans No written production and process control procedures designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to posses

17 FDA UPDATE Failure to thoroughly review any unexplained discrepancy or batch failure or failure of any of its components to meet its specifications No adequate training program for employees Written production and process control procedures are not established to monitor the output of manufacturing processes or followed No written procedures for equipment cleaning and maintenance and equipment and utensils are not cleaned or maintained at appropriate intervals Laboratory controls do not include scientifically sound and appropriate specifications, standards, or sampling plans Testing and release procedures do not include laboratory confirmation that product meets specifications No written production and process control procedures designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to posses

18 FDA UPDATE Failure to thoroughly review any unexplained discrepancy or batch failure or failure of any of its components to meet its specifications No adequate training program for employees Written production and process control procedures are not established to monitor the output of manufacturing processes or followed No written procedures for equipment cleaning and maintenance and equipment and utensils are not cleaned or maintained at appropriate intervals Laboratory controls do not include scientifically sound and appropriate specifications, standards, or sampling plans Testing and release procedures do not include laboratory confirmation that product meets specifications No written production and process control procedures designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to posses

19 FDA UPDATE Failure to thoroughly review any unexplained discrepancy or batch failure or failure of any of its components to meet its specifications No adequate training program for employees No written procedures for equipment cleaning and maintenance and equipment and utensils are not cleaned or maintained at appropriate intervals Written production and process control procedures are not established to monitor the output of manufacturing processes or followed Testing and release procedures do not include laboratory confirmation that product meets specifications Laboratory controls do not include scientifically sound and appropriate specifications, standards, or sampling plans No written production and process control procedures designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to posses

20 Regulatory Inspection Readiness Program Points to be covered A systematic approach towards successfully Regulatory Agency Inspections Objective and Rational Background to proposed Inspection Readiness approach Regulatory Inspection Readiness Process Support Tools Conclusions & Key Points

21 Objective & Rational To achieve Regulatory Inspection Readiness on a continuous basis Avoid a tarnished image e.g. 483 s/ Warning Letters become public To successfully pass any upcoming FDA/Regulatory Inspection No Critical / Major Observations Avoid contract difficulties with customer, government or suppliers Avoid adverse impact on Marketed Products or New Product Introductions

22 Background of Inspection Readiness Inspection readiness is Ensuring that Regulatory Agency Inspection results do not have an adverse impact on Marketed Products or New Product Introductions A Team Approach with well defined and co-ordinated responsibilities from multiple areas of expertise within the company, including the Site, Global Quality, Global Audit & Compliance, Tech Ops, Regulatory Affairs, etc. All play a key role in ensuring a successful Inspection Ensuring Sites are continuously ready for Regulatory Agency Inspections without extensive last minute preparation The use of multiple Regulatory Inspection Readiness Tools and processes to ensure that the proper systems are in place and that the Inspection Risks are effectively identified and addressed

23 Background of Regulatory Inspection Readiness The 3 pillars of Inspection Readiness Build up Awareness Check Compliance Ensure Effective Inspection Performance Regulatory Agency Inspection Readiness, through Teamwork

24 Background of Inspection Readiness Approach involves a 3 Phased Process Target time-frame is usually 1-2 years Routine Preparedness Activities Move activities back in time!! Risk Assessment and / or Event Specific Preparation Inspection Phase 1 Phase 2 Phase 3

25 Regulatory Inspection Readiness Process Inspection Readiness Program: A combination of several processes Activity Regulatory Inspections and Internal Audits are not necessarily identifying every issue, highlighting the importance of a multi-layered and Team approach A well defined process, which clearly details specific responsibilities, timelines and approach Phase 1: Routine Preparedness Activities Phase 2: Specific Preparation Activities Phase 3: Regulatory Inspection Months/Years Time Weeks/ Months Days

26 Systematic Inspection Readiness: Phase 1: Routine Preparation Activities Phase 1: Site Activities Inspection Preparation Program Site Level Self inspection Site Risk Assessment Tool Readiness Support Tools Site Quality plan Site SOPs/Ways of Working Quality KPI s Gap Analysis 483s / Warning letters ID Repeated issues Review CAPAs/gaps identified and corrected Training Others partnership Phase 1: Other Activities Regular GMP compliance audits Target 1 or 2 years Provide Readiness Support Tools Follow up corrective actions by Global Quality (oversight) On-going Site & Compliance support Focus on key risk areas Annual Site Quality reviews Warning Letters, 483 commitments company wide Training Others 26 SQLC monthly update November 7, 2011

27 Regulatory Inspection Readiness Process Inspection Readiness Program: A combination of several processes Activity Regulatory Inspections and Internal Audits are not necessarily identifying every issue, highlighting the importance of a multi-layered and Team approach A well defined process, which clearly details specific responsibilities, timelines and approach Phase 1: Routine Preparedness Activities Phase 2: Specific Preparation Activities Phase 3: Regulatory Inspection Months/Years Time Weeks/ Months Days

28 Systematic Inspection Readiness: Phase 2: Specific Preparation Activities Phase 2: Site Activities More frequent self inspection Site Risk Assessment Tool Thorough CAPA review Identify remaining risks Identification of potential Backlogs Continued Gap Analysis WLs/483s and commitments Prepare position papers Root causes Actions performed Actions planned Others partnership Phase 2: Other Activities Mock inspection Based upon known risks Should be the final confirmation of Site Readiness 6 to 12 months in advance Follow-up Mock Inspections if needed 3-months prior to agency Inspection Regulatory agency commitments Etc. Inspection management training Review remaining risks Thorough review of CAPAs Review position papers Others

29 Regulatory Inspection Readiness Process Inspection Readiness Program: A combination of several processes Activity Regulatory Inspections and Internal Audits are not necessarily identifying every issue, highlighting the importance of a multi-layered and Team approach A well defined process, which clearly details specific responsibilities, timelines and approach Phase 1: Routine Preparedness Activities Phase 2: Specific Preparation Activities Phase 3: Regulatory Inspection Months/Years Time Weeks/ Months Days

30 Systematic Inspection Readiness: Phase 3: Regulatory Inspection Phase 3: Site Activities Hosts and Manages Inspection, e.g. - Answers questions - Front and back rooms - Document requests Management - Daily updates - Address potential observations - Next day preparation - 483, etc. response - Inspection Follow-up / CAPA - Others partnership Phase 3: Other Activities Support and Advice, including: - Expertise, e.g. FDA expectations - Logistics - Front/backroom support - Language/translation - Interpretation of requests - Provide Corporate position - Assist in 483, etc. response - Others

31 KPIs Global Governance / Oversight Site Risk Assessment Tool Site CAPA Global Quality Audit Global Quality Audit CAPA Regulatory Inspection Results Regulatory Inspection CAPA Regulatory Inspection Follow-up Green = Low Risk Yellow = Medium Risk Red = High Risk

32 Inspection Readiness Support Tools need to be improved or developed Inspection readiness support tools Quality Manual, GOPs, Ways of Working and Procedures Regulatory Agency Inspection Database Site Risk Assessment Tool Risk of Inspection Analysis Sharing Key Learning's of Regulatory Inspections and Global Audits Determination of potential impact of Regulatory Inspection observations on Documentation Sharing Top 10 Findings of Regulatory Inspections and Audits Trending Sharing emerging Regulatory Trends and Expectations ( Regulatory Intelligence ) Sharing Best Practices Audit and Compliance Newsletter Training Tools Corporate Quality and Technical Support Sandoz QA Intranet Homepage All Existing tools to be assessed and improved Some tools to be newly developed

33 Rapid Alert Process deployed to address timely notification of issues and findings Collection and compilation of data Grouping and designing of questionnaire Rollout and tracking Evaluation of data and feedback from the divisions Notification of all regulatory inspections where global systems will be under review to GC&A Divisions to provide related documentation (Minutes, 483, Deficiency letters, Response) Significant issues/ trends from regulatory intelligence (WLs, etc.) Grouping of observations by linking with Novartis requirements, previous commitments to HAs and Global Quality Plan. Issuance of related questions and evaluation criteria for all questions = assessment questionnaire and or actions (i.e. FAR/BPDR). Questionnaire is approved by CAC. GC&A distributes the questionnaire along with inspection observations to all relevant sites (manufacturing, development, CPOs, etc) or global corrective action. Confirmation of receipt will be mandatory tracked by GC&A. CAC to track responses or actions and compile feedback to GC&A. GC&A to open global CAPAs and/or updates to current standards (QSSC) as needed. Incorporation of actions within local SQRA /Quality Plan Incorporation of the gap elements into audit agenda Implementation of remediation actions will follow the same process as for inspection actions. Monitoring is managed by Divisional QA organizations. Trending, tracking and reporting to NQLT by GC&A.

34 Conclusions and Key Points Inspection Readiness is a Continuous Process and the goal is to be inspection ready well before any inspection. The Mock Inspection is the final confirmation of Readiness and all Key Issues need to be addressed well in advance of this final assessment Needed is a systematic, well defined process, which clearly details responsibilities, timelines and approach ( Who does what and when ) Continuous Inspection Readiness is obtained by a combination of many elements, such as Regulatory Intelligence, Audits, Mock Inspections, Self-inspections, Global Support, Training, effective Support Tools and a continuous evaluation of Sites readiness and CAPAs Systematic and thorough Follow-up by Site and Global Quality Functions of CAPAs, including the results of previous Regulatory Inspections, audits and Self-Inspections, as well as site reviews are essential Root cause of issues and not just the individual observations must be addressed Constant assessment of Key Quality Systems by the Site is a Key to success Get the Basics right! Clear and effective Regulatory Inspection Readiness Support Tools need to be made available to Sites and Global Quality Functions Regulatory Agency Inspection Readiness is a true Team Effort!

35 Coordination is key