Health Authority Inspection Management€¦ · Health Authority Inspection Management GMP Inspection practices ... and practices, key systems, metrics, and indicators emerge as critical

Health Authority Inspection Management

GMP Inspection practices

L. Mansolelli, Group Compliance & Auditing

June 2012

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.

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

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

• 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

Improving Enforcement Process

Transparency

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.

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)

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

MHRA concerns

NOV_PGL0612

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

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

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

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....

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

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

Laboratory controls do not include scientifically sound and appropriate

specifications, standards, or sampling plans

No written procedures for equipment cleaning and

maintenance and equipment and utensils are not cleaned or

maintained at appropriate intervals

No adequate training program for employees

FDA UPDATE

FDA UPDATE



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







FDA UPDATE 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











FDA UPDATE



specifications Written production and process control

procedures are not established to monitor

the output of manufacturing

processes or followed











FDA UPDATE



specifications













FDA UPDATE



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







FDA UPDATE



specifications







Laboratory controls do not include scientifically sound

and appropriate specifications, standards, or

sampling plans





FDA UPDATE



specifications










maintenance and equipment and utensils

are not cleaned or maintained at appropriate

intervals


Regulatory Inspection Readiness Program Points to be covered

Objective and Rational

Background to proposed Inspection Readiness approach

Regulatory Inspection Readiness Process

Support Tools

Conclusions & Key Points

A systematic approach towards successfully Regulatory Agency Inspections

Objective & Rational

To achieve Regulatory Inspection Readiness on a continuous basis

To successfully pass any upcoming

FDA/Regulatory Inspection

No “Critical”/”Major” Observations

Avoid adverse impact on Marketed Products

or New Product Introductions

Avoid contract difficulties – with

customer, government or suppliers

Avoid a tarnished image – e.g. 483’s/

Warning Letters become public

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

Background of Regulatory Inspection Readiness

Build up Awareness

Check Compliance

Ensure Effective

Inspection Performance

“Regulatory Agency Inspection Readiness, through Teamwork”

The 3 pillars of Inspection Readiness

Background of Inspection Readiness

Approach involves a 3 Phased Process

Target time-frame is usually 1-2 years

!

Routine

Preparedness

Activities

Risk Assessment

and / or Event

Specific

Preparation Inspection

Phase 1 Phase 2 Phase 3

Move activities back in time!


Inspection Readiness Program: A combination of several processes

• 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

Time

Activ

ity

Phase 1: Routine Preparedness Activities

Phase 2

: Specific

Pre

para

tion A

ctiv

ities

Phase 3

: Regula

tory

Inspectio

n

Weeks/

Months Days

Months/Years

26 | SQLC monthly update | November 7, 2011

Systematic Inspection Readiness: Phase 1: Routine Preparation Activities

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

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





Time

Activ

ity


Phase 2

: Specific

Pre

para

tion A

ctiv

ities

Phase 3

: Regula

tory

Inspectio

n

Weeks/

Months Days

Months/Years

Systematic Inspection Readiness: Phase 2: Specific Preparation Activities

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

Phase 2: Site Activities

• More frequent self inspection


• 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





Time

Activ

ity


Phase 2

: Specific

Pre

para

tion A

ctiv

ities

Phase 3

: Regula

tory

Inspectio

n

Weeks/

Months Days

Months/Years

Systematic Inspection Readiness: Phase 3: Regulatory Inspection

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

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

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

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


• 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

“Rapid Alert” Process deployed to address timely notification of issues and findings

Collection and compilation of

data

• 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 and designing of

questionnaire

• 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.

Rollout and tracking

• 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.

Evaluation of data and

feedback from the divisions

• 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.

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”!

Coordination is key

Health Authority Inspection Management€¦ · Health Authority Inspection Management GMP Inspection practices ... and practices, key systems, metrics, and indicators emerge as critical

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