Compliance Environment June 2012 - americanconference.com · Legal Context and Examples of Enforcement ... Effective Management Oversight U.S. Congress, and the Budget Battle Do More

ACI

Creating a “Quality Culture”

Of GMP Compliance

January 23, 2014

Discussion Topics

Creating the Culture

Challenging Industry and Regulatory Environments

Continues … and Evolving Expectations

Quality Culture Elements

Legal Context and Examples of Enforcement

Corporate and Individual Accountability

Discussion Q&A

2 Lachman Consultant Services Inc.

Focus

Global Supply Chain Initiatives

Information Sharing by International Regulators Rapid Alert Notifications

Joint API and DP Inspection Programs

Recent FDA/MHRA “For Cause” Inspection initiative

PICS Membership

Parallel CMC QbD reviews

Harmonizing Standards

OUS FDA Offices (Inspection; Training; Cooperation;

Calibration)

Proliferation-“Import Alerts” Based on Appearance Std

3

Lachman Consultant Services Inc.

Challenging Environment Continues

Global competition and Un-level

Playing Fields?

Pricing Pressures to Worsen

Product Life Cycles are Shorter

Pipeline and Profitability Concerns

Increasing Customer Demands

Regulatory Pressures to Strengthen

Corporate Governance and Oversight

Constant stream of new and revised

regulatory “guidance” and evolving

expectations … GXP; worldwide

Increasing Regulatory Intolerance

Internal/External Demands for

Effective Management Oversight

U.S. Congress, and the Budget Battle

Do More with Less

Heightened Sense for FDA to ACT

Natural instinct to be more aggressive

to protect patient

Congressional pressure

Extraordinary number and nature of

enforcement actions

FDA Search of Cost-Effective

Synergies - International Counterparts

Lachman Consultant Services Inc. 4

Regulators’ Enforcement Priorities

Contamination Prevention –

micro, chemical, intrinsic,

extrinsic, particulates

Data Integrity

Investigations Program

Complaints

OOS/Rejections

CAPA Programs

Quality Systems/Quality

Culture

OTC Drug Quality

High Risk Compounded Drugs

Internet Health Fraud

Unapproved Drugs

Adverse Event Reporting

Supply Chain

Security, CMOs, Quality

Agreements

Field Alert/Rapid Notification

Reporting

Prevention or Prompt

Mitigation of Drug Shortages

5

US Congress Steps In FDA Safety and Innovation Act 2012 (FDASIA)

Complex law, providing many new significant

authorities to strengthen FDA capabilities. Key areas:

Collect and Analyze Data to Allow Risk-Informed Decision-

making

Risk-Based Approach to Facility Evaluation –

oversight/enforcement

Partnering with counterpart regulatory authorities – information

sharing and mutual recognition of foreign inspections

Tools to help FDA better drive and regulate product quality and

safety throughout the global supply chain

NOTE: Track and Trace dropped from the law at the last minute

due to disagreements on approaches and timing


FDASIA Collect and Analyze Data

Mandatory Registration of Foreign and Domestic

Manufacturers and Commercial Importers

Unique Facility Identification # - self disclosed, to

identify all sites and locations

Drug Manufacturers must provide UFI’s for Excipients

Burden of Proof Shifts to Importers to Demonstrate

Compliance of Imports

Requires drug manufacturers, importers and

distributors to notify FDA when drugs threaten

serious industry/death, are lost, stolen or counterfeit


FDASIA Risk Based Approach to Facility Evaluation

Objectives are better use of resources, strengthened

assurance of safety and quality, and parity between

approaches used for US and Foreign facilities

Eliminates 2 yr. minimum frequency for inspection of

domestic drug manufacturers

Requires risk-based approach to inspection frequency

for domestic and foreign drug manufacturers … based

on information collected, history and risk assessment

Authority to Request Records For Evaluation (outside

of inspection context)

8


FDASIA Partner with Foreign Regulatory Authorities

Allows the exchange of certain information

Foreign government inspection results can be

used for risk-based inspection decisions

(frequency; scope)

Allows for the recognition of foreign

government inspections


FDASIA Additional Tools

Significant consequences where a facility refuses, delays

or limits inspection

Authorization to destroy goods refused for importation

Administrative detention authority for drugs, similar to

existing medical device and food authorities

Requires manufacturers to adopt quality management

systems as part of CGMPs

Increased penalties-counterfeits, intentional adulteration

Provides for Extraterritorial Jurisdiction to enforce the

USFDC Act outside the US, where appropriate


What is a GMP Violation?

Is this Product Perfect?

What deems a drug adulterated? • Distinguish from the facts of a drug – not

just meeting specifications

• “Most prosecuted cases turn on proof of failure to follow GMP practices – NOT the final quality of the drug”

• Park Doctrine


FDA Remains Concerned About Product Recalls

FDA considers an indicator of the failure of the regulatory system and

industry to prevent problems

Continued concern about lack of assurance of sterility based on poorly

designed and/or executed aseptic processes

Increasing focus on particulates in small volume parenteral products

Intolerance of physical defects and foreign/non-descript matter in solids,

often without apparent safety concern

FDA Concern … Is Product Quality worse now than in the past?

Inspection approach better targets potential problem areas

FDA more assertive pressuring firms about plans for addressing distributed

product

Enforcement environment + focus on corporate/ individual accountability +

threat of criminal sanctions sometimes drives conservative decisions

Many recalls now based on GMP “lack of assurance” versus actual/probable

defects.

1


Continuing Concern About Drug Shortages

Number and duration of shortages worrisome

Finger-pointing regarding primary causes

The need for enforcement discretion erodes

meaningfulness of GMP and Product Quality

standards … FDA concern about “abuse”

Enforcement discretion places the Regulator and

the Industry at risk

Shipments of products under enforcement

discretion are the sole responsibility of the

company

Watch the “Shifting Winds” 1


FDA Wants Problem Products Remediated

QbD concepts and regulatory review processes for

new products essentially in place

FDA concerned about existing commercial

products that were not adequately developed

where there are repeated batch failures and

product recalls.

FDA pressuring companies to permanently “fix”

problem products. Recent FDA communication to

a large global company …

“Your quality systems are now robust … many of

your products are not … time to fix them!”

1


Examples of Recent GMP Enforcement

Firm Action Date

Numerous QSR Warnings to Medical

Device Manufacturers

Numerous GMP Warnings to Dietary

Supplement Manufacturers

Numerous GCP Warning to Institutional

Review Boards and Clinical Investigators

RANBAY DECREE EXTENSION

Warning Letters Last 12

months

Wolkhardt Ltd., Aurangabad, India Warning Letter – sterile products; serious concerns

about the integrity, reliability and accuracy of GMP

records; 75 BRs found in trash with information

different from “official” records; inspection

delays/limitations, etc. IMPORT ALERT

July 2013

Fresnius Kabi Oncology, West Bengal,

India

Warning Letter – APIs; lab data integrity concerns;

inspection refusal/delays; blending lots to pass; etc.

July 2013

Cispharma, Cranbury, NJ Warning Letter – inadequate complaint investigations;

Tab defects follow-up; inadequate understanding of

process and validation; test methods not validated

July 2013 (15 months

post – insp)

Ebewe Pharma Ges.m.b.H NFG, A-

4866,Unterach am Attersee, Austria

Addressed to Novartis CEO

Warning Letter – unapproved change from semi-

automatic to automatic inspection for non-viable

particulates in injectable products, and concern about

recurring instances of not detecting particulates until

after release/distribution.

May 2013

15 Lachman Consultants

Recent Examples of GMP Enforcement

Firm Action Date

Baxter Healthcare Corp, Marion, NC

and Jayuya, PR

Warning Letter – aseptic processing GMP deviations; inadequate

maintenance; mold; inadequate justification for EM sampling

plan and traceability of results to locations sampled; terminal

sterilization is insufficient rationale for downplaying risk of

contamination impacts; concerns about findings on parametric

release program. T

May 2013

RPG Life Sciences Ltd, Gujarat,

India

(2 sites … MS-Ankleshwar and MS-

Navi Mumbai)

Warning Letter – inadequate OOS investigation and related

questionable practices, disregard of failing stability results,

discarding OOS documentation, failure to retain documentation

of certain sample weights/preps/dilutions, electronic lab data

issues and controls, backdating, inadequate retrospective

review of lab data, etc. IMPORT ALERT

May 2013

Hospira Healthcare India Pvt., Ltd.,

Sriperumburdur, India

Addressed to CEO M. Ball

Warning Letter – aseptic processing GMP deviations;

• Concern that violations are similar to those found at

Rocky Mount, NC plant.

• Request for a current global corrective action plan.

Threat of Import Alert

May 2013

Contract Pharmaceutical Services,

North Ryde, Australia

Warning Letter – solid dose form packaging facility; inadequate

environmental controls to protect product during packaging and

storage; absence of time limits; inadequate investigations;

threat of import alert

May 2013


Key FDA/DOJ Expectation

ACCOUNTABILITY

Corporation

Corporate Management

Site Management and Personnel

1


Key Draft Guidance - May 2013

Contract Manufacturing for Drugs: Quality Agreements

No Major Surprises

Owner is responsible for assuring that contractors produce and test drug products, in accord with cGMPs and conditions of approval

Contractor is responsible for complying with cGMP and other requirements of the Quality Agreement

Owner is ultimately responsible for approving or rejecting drug products produced by contractors

Strong Quality Agreement … No “head in the sand” by either party

Key Elements of Agreement

Facilities and Equipment

Materials Management

Detailed Product-Specific Requirements

Laboratory Controls

Documentation

Change Control

Use of Sub-contractors

Knowledge Transfer

Communication and Information Exchange

Oversight and Auditing

Illustrative Scenarios

1


FDA Inspection Program Continues to Evolve

Better Use of Limited Resources in Expanding Universe

Leverage Activities and Information Available From Other

Regulators, where possible (e.g., EMEA; MRA; TGA; HC)

Improve Strategic Programs and Planning based on Risk

Management Criteria (Compliance Profiles; Surveillance Data)

Perform More Effective Inspections / Less Resources per

Inspection

2013 - First Year More GMP Inspection Resources Being

Devoted to Foreign Inspections than Domestic!

19


What is a Quality Culture?

What is your role in establishing, maintaining and

nurturing the Quality Culture for GMP compliance?

How do you know “it’s” in place and working?

Based on Product Quality?

Based on Systems and Controls?

Based on People?

Can your employees define the Quality Culture?

Can Your Senior Executives/Board Members?

What are the building blocks of a Quality Culture?


0

Building Blocks of a Quality Culture?

Knowledge of Laws, Regulations, Guidances, Policies

Knowledge of Regulatory/FDA Processes

Organized to Execute

Standards, SOPs and Enabling Documentation

Right People in Right Positions

Clear Roles, Responsibilities and Accountabilities

Training (GMPs, Ethics, etc.)

Good Documentation

Data/ Record Keeping

Capacity

Infrastructure

Metrics

Evidence (raw data and records)

Follow Up

21


Knowledge by All Personnel of Laws, Regulations,

Guidances, Policies – 21 CFR 210, 211, ICH Q7A, Q9,

Q10, EU Directives, TGA, ANVISA, PMDA, WHO, etc.

Knowledge of Regulatory Processes – i.e. for FDA -

Commissioner, CDER, CBER, OCI, OC, ORA,

Investigators, Guidances, CPGs, CPMGs, etc.

Organized to Execute – Functional not Hierarchical

Standards, SOPs and Enabling Documentation – Global,

Regional, Site? Format and structure (best practices?)



Right People in Right Positions – education, experience and training???? Not Enough – Performance and Culture!!!

Clear Roles, Responsibilities and Accountabilities - are employees trained and are there adequate job descriptions? How do they know what to do hourly, daily, weekly, monthly, quarterly???

Training (GMPs, Ethics, Skills, Leadership, Budgeting, etc.)

Good Documentation, Data/ Record Keeping Key

Capacity – are there enough personnel to execute and provide OVERSIGHT (Making sure personnel are following procedures)???



Infrastructure – enough space, people. software, hardware, computers, automation, etc. – Trackwise, Training Software, etc.

Metrics to drive performance and compliance – measures and diagnostics in all departments and subsystems, first time right.

Evidence (raw data and records) - authentic, reliable and retrievable

Follow Up, Follow Up, Follow Up – Notification to Management, Events, Quality Councils, Task Teams


Better Trained FDA

Pharmaceutical Inspectorate (and worldwide cross-fertilization)

Targeting Data Integrity


Global Market Swamped in Product Recalls,

Enforcement and Shortages

Regulatory Agencies assertive with companies about recalls.

Global Regulatory Agencies (Except FDA) have mandatory recall

authority.

Overall enforcement environment , focus on corporate and

individuals, “poster child’ criminal and civil actions - resulting in

company decisions to recall

Many recalls based on GMP “lack of assurance” of quality versus

actual/probable defects.

More aggressive recall classifications (I, II, III) and associated

product removal strategies


Top 10 Drug Warning Letter Concerns –

2012*

Domestic WL Foreign WL

Production Records Review Stability Testing

Stability Testing Laboratory Controls

Quality Control Unit Written Procedures

Written Procedures Laboratory Records

Microbial Contamination Component Testing

Batch Production & Control Records

27

* Phil Campbell – ATL District Compliance Director; University of Georgia GMP Conference

March 2013


GMP Deficiencies at Foreign API Manufacturers FDA/PDA Report Sept 2013 – A. Mozzachio

Most Frequently Cited GMP Deficiencies

Inadequate Lab Controls

Inadequate Equipment Controls

Failure of the Quality Unit (QU) to release/reject APIs

Failure of the QU to review and approve all quality-related documents

Failure to ensure quality-related complaints are investigated

Failure to conduct regular quality reviews of APIs

Failure to evaluate the potential impact of proposed changes on the quality of APIs


GMP Deficiencies at Foreign API Manufacturers FDA/PDA Report Sept 2013

Top Regions Where Inadequate Lab Controls Cited:

China (28%);

India (23%);

Europe (18%)

Most Frequently Cited Lab Concerns: Lack of/inadequate method validation

Failure to have scientifically sound and appropriate

specifications and test procedures

Failure to adequately investigate out-of-specification results

Failure to document lab controls at the time of performance

Failure to have an adequate stability testing program to

assess the stability characteristics



Top Regions Where Inadequate Equipment Controls Cited India (19%);

China (17%);

Europe (13%)

Most Frequently Cited Equipment Control Concerns: Inadequate cleaning procedures

Failure to validate cleaning procedures

Failure to clean, store, sanitize or sterilize (if

applicable) equipment to prevent contamination or

carry-over that would alter the quality of API

Inadequate qualification of critical equipment



WARNING LETTER TRENDS (2012 -2013)

Failure to have batch records for each intermediate/API with

complete information about production & control

Failure to have laboratory records that include complete data

derived from all tests

Failure to investigate all critical deviations

Failure to use dedicated production areas for beta lactam

products

Failure to adequately investigate and document OOS results

Failure to establish/exercise adequate controls over computers to

prevent unauthorized access or changes to electronic data

Failure to contemporaneously record all quality-related activities



OTHER COMMON WL CITATIONS (2012 -2013)

Failure of QU to perform quality activities per written procedures

Failure of QU to review/approve all appropriate quality documents

Failure to maintain/clean manufacturing equipment and facilities

Failure to establish specifications of final API

Failure to validate critical operations impacting quality of API

Failure to have adequate stability program

Failure to set an expiry or retest date for APIs based on data

derived from stability studies

Failure to conduct thorough complaint investigations

Combining OOS API batches with in-specification API batches in

order to meet the final specifications


Examples of Recent GMP Enforcement

Firm Action Date

Numerous QSR Warnings to Medical

Device Manufacturers

Numerous GMP Warnings to Dietary

Supplement Manufacturers

Numerous GCP Warning to Institutional

Review Boards and Clinical Investigators

RANBAY DECREE EXTENSION

Warning Letters Last 12

months

Wockhardt Ltd., Aurangabad, India Warning Letter – sterile products; serious concerns

about the integrity, reliability and accuracy of GMP

records; 75 BRs found in trash with information

different from “official” records; inspection

delays/limitations, etc. IMPORT ALERT

July 2013

Fresenius Kabi Oncology, West Bengal,

India

Warning Letter – APIs; lab data integrity concerns;

inspection refusal/delays; blending lots to pass; etc.

July 2013

Cispharma, Cranbury, NJ Warning Letter – inadequate complaint investigations;

Tab defects follow-up; inadequate understanding of

process and validation; test methods not validated

July 2013 (15 months

post – insp)

Ebewe Pharma Ges.m.b.H NFG, A-

4866,Unterach am Attersee, Austria

Addressed to Novartis CEO

Warning Letter – unapproved change from semi-

automatic to automatic inspection for non-viable

particulates in injectable products, and concern about

recurring instances of not detecting particulates until

after release/distribution.

May 2013

33 Lachman Consultants

Recent Examples of GMP Enforcement

Firm Action Date

Baxter Healthcare Corp, Marion, NC

and Jayuya, PR

Warning Letter – aseptic processing GMP deviations; inadequate

maintenance; mold; inadequate justification for EM sampling

plan and traceability of results to locations sampled; terminal

sterilization is insufficient rationale for downplaying risk of

contamination impacts; concerns about findings on parametric

release program. T

May 2013

RPG Life Sciences Ltd, Gujarat,

India

(2 sites … MS-Ankleshwar and MS-

Navi Mumbai)

Warning Letter – inadequate OOS investigation and related

questionable practices, disregard of failing stability results,

discarding OOS documentation, failure to retain documentation

of certain sample weights/preps/dilutions, electronic lab data

issues and controls, backdating, inadequate retrospective

review of lab data, etc. IMPORT ALERT

May 2013

Hospira Healthcare India Pvt., Ltd.,

Sriperumburdur, India

Addressed to CEO M. Ball

Warning Letter – aseptic processing GMP deviations;

• Concern that violations are similar to those found at

Rocky Mount, NC plant.

• Request for a current global corrective action plan.

Threat of Import Alert

May 2013

Contract Pharmaceutical Services,

North Ryde, Australia

Warning Letter – solid dose form packaging facility; inadequate

environmental controls to protect product during packaging and

storage; absence of time limits; inadequate investigations;

threat of import alert

May 2013


Examples of Many Ongoing Actions

Public

Genzyme Decree

McNeil Decree

TAH Decree

Ranbaxy Decree

Caraco Decree

KV/Nesher Decree

Novartis

Hospira

Not Visible (Yet)

GMP Untitled Letter – Global Company

Similar violations at multiple sites

Repeat particulate and foreign matter contamination

with inadequate investigations and CAPAs

Need for Corporate Lessons Learned Program

Major Product Approval Delay

Errors in Electronic Batch Records; inadequate CSV

and Quality oversight; Global response required

Proliferation of Regulatory Meetings

Significant FDA 483s undergoing

evaluation

Aseptic conditions and processing concerns

Process Performance; Investigations; Lab Data Integrity

35


Spike in Data Integrity Inspection Findings

Ranbaxy AIP/Criminal Pleading

Cetero BA/BE Lab … Bankruptcy Ramifications

Wockhardt, RPG and Fresenius, etc., Warning Letters

Chromatographic data remains a key concern area

Audit trail capabilities non-existent, not configured or

turned off

Use of actual samples during system suitability checks

Inconsistent and selective manual re-integration

Sharing Passwords

Scrap Paper

Unofficial Records


Quality Metrics Initiative

CDER Director Janet Woodcock MD clearly focused and driving

Concept is to calculate and use a facility rating to inform

inspection and enforcement decisions, based on:

Quality Metrics periodically submitted by the industry (FDASIA)

FDA Inspections history

Product Quality Complaints and AERs

NDAs and ANDAs information

Information from international regulators

No current intention to make rating public

CDER recognizes the significant challenges. For example:

What metrics; how to define; how to collect; how to analyze; how to

use; even playing field; assurance of reliability; etc.

Need for significant IT capability

CDER currently meeting with stakeholders and seeking input


Prosecutions for GMP and Product Quality Violations?

FDA and DOJ historically have rarely pursued criminal prosecutions based on GMP and product quality cases without associated deaths or injury: DOJ makes GMP Regulations “Top Area of Focus” for 2013

Current Attitude FDASIA provides additional authorities and stiffer penalties for

violating the law.

Federal Sentencing Guidelines are being updated to provide stiffer sentences especially where there is knowledge and intent to violate the law and adulterate products.

2013 – DOJ Deputy Assistant Attorney General declares that GMP violations posing unacceptable risk of harm is now a top focus area. In addition to the standard elements of GMP, their investigations will focus on people to determine responsibility. Questions to help stay out of trouble:

- Do you have the right people?

- Do you have the right incentives to see, report and fix problems?

- Are your people satisfied and engaged?

- Do our people and policies work in harmony?

- Does management have visibility into what its people are actually doing?


FDA Sanctions to Address Violations

Statutory/Legal

Automatic Detentions

Import Refusals

Seizures

– production materials

– equipment

– products

Injunction

Prosecution

Investigator Disqualification

Debarment

Administrative

Warnings (titled/untitled ltrs; mtngs)

NDA/IND Actions

- Clinical holds

- Study disqualifications

- Withholding approval; Disapproval

- Withdrawing approval

- Post-approval mktng and safety actions

- Suspension of Scientific Review (AIP)

Orange Book Changes

Leveraging through State and Foreign Authorities

New FDASIA Authorities


39

The Reality … and Future

In addition to its routine focus of GMP compliance based on

inspection of Quality Systems and practices, FDA inspection

trends are focusing on:

Product and process robustness (evidence; basis for

confidence; control strategy; analysis; continuous

improvement)

Management awareness and actions to prevent/correct

problems in a sustainable manner.

The results of relatively brief inspections by FDA and other

regulators must not be viewed as the “barometer” for measuring

compliance and state of control. FDA inspection history is full of

examples of “sudden” changes in compliance status. It is the site

and corporate programs that ensure self-awareness and adequate

response to findings that ensure sustainable compliance.

EMA, MHRA, Health Canada, ANVISA, JMH, etc. are following

FDA’s suit. 40


Global Regulators to Remain Vigilant and Intolerant

Ensure the rigor of corporate and site Management Controls.

Frequent failure modes involve inadequacies in:

Senior management awareness and involvement

Assignment/Enforcement-accountability for compliance & quality

Comprehensiveness, Clarity of corporate standards, and effectiveness of

roll-out processes, verification of implementation

Training Programs

QA Presence on-the-floor in Production … and oversight of Lab

Culture of inappropriate rationalization

Site and Corporate Audit Programs … and implementing culture

Intelligent Metrics… meaningful, reliable, collection, reporting, analysis,

and follow-up

Knowledge Management, Lessons Learned and Global Dissemination

Culture of Blaming the Regulator


Major FDC Act Violations Unchanged

Submitting false and/or misleading

information to the agency

Falsification of GXP records,

regardless of whether submitted to

agency

Distributing a drug product in

violation of investigational or

approved requirements

False/misleading use, promotion or

advertising

Drug safety monitoring and

reporting violations

Adulteration of API or

finished drug product

Commercial or clinical use

Not meeting appropriate,

established specifications

Contamination

Manufactured in violation of

GMP requirements,

regardless of whether

analytical specs met

Unlawful distribution of

clinical materials or physician

samples


Conclusions

Firms must have: a robust quality system and

ethics programs; maintain management oversight

(with support and enforcement); procedures and

clear personnel policies that prevent data integrity

matters; be able to detect them if they do occur; and

deal with them effectively in order to have an

adequate “Quality Culture” for GMP Compliance.

Data integrity – Will be a focus and concern during

any FDA/Regulatory inspection

43

Accountability

All are accountable for integrity and compliance within roles and responsibilities.

Corporations and senior management have ultimate responsibility and, as such, are

being targeted by the regulators and prosecutors when appropriate.

Companies are ultimately responsible for use of materials and services from vendors

and contractors.

Little tolerance for repeat significant GMP inspection observations, or similar/same

observations at other sites.

FDA shifting focus to evaluating rigor and effectiveness of corporate governance

and oversight programs.

Adequacy of global standards, process for roll-out and mechanism for ensuring

that translation at the operating level results in compliant SOPs and execution.

Corporations must closely monitor sites and compliance trends and ensure global

CAPAs.


Conclusions

Protect the Health and Safety of Your Patients

Protect Your Company

Protect Your Site & Colleagues

Protect Yourself!


Documents

Compliance Environment June 2012 - americanconference.com · Legal Context and Examples of Enforcement ... Effective Management Oversight U.S. Congress, and the Budget Battle Do More