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Post-Approval

Readiness

Best Practices

Presented by

Pepe Rodriguez-Perez, PhD

Business Excellence Consulting Inc / BEC Spain SL

www.calidadpr.com email [email protected]

http://www.calidadpr.com/

mailto:[email protected]

2

Agenda

US FDA: Structure and Authority

Regulatory Background: cGMPs, Labeling, Field Alert

Report, Recalls

Types of Inspection

Inspection results: Form 483 and the Establishment

Inspection Report (EIR)

The cost of Non-Compliance: Untitled/Warning Letters,

Injunctions and Seizures

FDA Online Tools: Recalls/Warning Letters/ FOI Pages

FDA Enforcement Story: Current Trends

FDA Inspector Preparation: Data Integrity Finders

3

Agenda (cont.)

How to be Ready for FDA Inspections

– The FDA Inspection Process

– FDA Domestic vs. Foreign Inspections

– Pre-Inspection Activities: the Value of a Mock Audit

Inspection: Do & Don’ts

Interaction with FDA Inspectors:

– Interviews with Employees

– Body Language and Other Signs

– Knowing your Inspector(s)

Post-Inspection Activities - How to Respond to an FDA

483: Do & Don’ts

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Objectives

Understand the regulatory requirements and current practices of cGMP inspections for Drug Manufacturers

Have a basic perception of FDA and current regulatory issues and strategies

Discuss the prime target for FDA inspections

Examine the best practices before, during, and after the inspection

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FDA Overview US Department of Health & Human Services

US Food and Drug Administration Centers for:

– Food Safety and Nutrition (CFSAN)

– Drug Evaluation and Research (CDER)

– Biologics Evaluation and Research (CBER)

– Devices and Radiological Health (CDRH)

– Center for Veterinary Medicine (CVM)

– Center for Tobacco Products (CTP)

– Office of Regulatory Affairs (ORA HQ)

– Field Regions (SER, SWR, PAR, NER, CER) » District Offices

San Juan District Office (SJN-DO)

– SJN, MRP, PON, USVI

14,000

http://www.psych.lancs.ac.uk/people/images/staff2004.jpeg

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FDA Mission: To ensure that

– Foods are safe, wholesome, and sanitary

– Human and veterinary drugs, biological products,

and medical devices are safe and effective

– Cosmetics are safe

– Electronic products that emit radiation are safe

Authority for Inspections

United States of America

– Federal Food, Drugs &

Cosmetic Act

– The FDA is responsible for

protecting the public health by

assuring the safety, efficacy, and

security of human and veterinary

drugs, biological products,

medical devices, our nation’s

food supply, cosmetics, and

products that emit radiation 7

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FDA Laws Overview

1906 – Congress enacted Food and Drug Act

1938- Federal Food, Drug, and Cosmetic Act

– To ensure that food are safe and produced under sanitary conditions

– Drugs and device are safe and effectives for their intended use

– Cosmetics are safe and made from appropriate ingredients

– Labeling and packaging is truthful

1963 - Fist version of GMP for Drugs

1978 cGMP for Drugs 21 CFR 211

1987 Guideline on General Principles of Process Validation

1997 – FDA Modernization Act (FDAMA): Fine-tuning FDA laws

1997- Electronic Records (21 CFR Part 11)

2013 – Combination Products

Why does FDA inspect

drug/biotech manufacturers?

To minimize consumers exposure to adulterated drug products.

To determine whether inspected firms are operating in

compliance with applicable CGMP requirements, and if not, to

provide the evidence for actions to prevent adulterated

products from entering the market and as appropriate to

remove adulterated products from the market, and to take

action against persons responsible as appropriate.

To provide cGMP assessment which may be used in efficient

determination of acceptability of the firm in the pre-approval

review of a facility for new drug applications.

To provide input to firms during inspections to improve their

compliance with regulations

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Field Alerts

To quickly identify distributed drug products

that pose potential safety threats.

Under 21 CFR 314.81(b)(1), manufacturers

of products approved under a NDA/ANDA

must submit a FAR within 3 working days of

identifying any significant problems with an

approved drug.

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Field Alerts

A FAR for any distributed drug product must alert

the FDA of:

Any incident that causes the drug product or its

labeling to be mistaken for or applied to another article,

Bacterial contamination,

Significant chemical, physical, or other change,

Deterioration of the distributed drug product, and

Failure of one or more distributed batches of the drug

product to meet the specifications established in its

application.

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Recalls Recalls are classified into one of three classes, according to the

level of hazard involved:

Class I: Dangerous or defective products that predictably could

cause serious health problems or even death.

– Examples include: contaminated food, food with undeclared allergens, a

label mix-up on a lifesaving drug, or a defective pacemaker.

Class II: Products that might cause a temporary health problem,

or pose only a slight threat of a serious nature.

– Example: a drug that is under-strength but that is not used to treat life-

threatening situations.

Class III: Products that are unlikely to cause any adverse health

reaction, but that violate FDA labeling or manufacturing laws.

– Examples include: a minor container defect or incorrect lot number

printed on label.

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13

Adulteration Regulations

To ensure that marketed products conform to FDA

quality requirements

Potentially unclean, unsafe, ineffective

– Distributed nonconforming products are considered

adulterated

Cover manufacturing and post-market conditions

All devices are registered (exempts, pre-market

notification (510K) and pre-market approval (PMA)

Class III devices has premarket approval

requirements (PMA)

– Need an application for PMA

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Examples of Misbranding

Examples of false labeling include:

incorrect, inadequate or incomplete identification;

unsubstantiated claims of therapeutic value;

inaccuracies concerning condition, state, treatment, size, shape or style; and

Examples of misleading labeling include:

ambiguity, half-truths, and trade puffery;

expressions of opinion or subjective statements; and

Examples of other objectionable labeling practices include:

deceptive pictorial matter;

misleading testimonials;

misleading list of parts or components; and

use of brand or trade names instead of "established names."

Types of Inspection and

Results

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FDA Inspection

Reasonableness of the Inspection – At reasonable times and within reasonable limits and in

a reasonable manner..

Frequency – At least every two year

Consent unnecessary – A refusal to permit an inspection is a prohibited act

Warrant Unnecessary – When an entrepreneur embarks on such a business, he

has chosen to subject himself to a full arsenal of governmental regulations.

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FDA Inspections

Present Credentials: form 482

Scope of Inspection: the authority under the FDA Act does not extend to

– financial data

– sales data (other than shipment data)

– personnel data (other then qualifications)

– Research data (R&D)

Establishment Inspection Report (EIR)

– Available under Freedom of Information [FOA] Act

Form 483 Inspectional Observations

In-plant photographs

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How does FDA classify

inspection reports?

NAI – No action indicated

VAI – Voluntary action indicated – some

deficiencies identified but not serious

OAI – Official action indicated –

serious deficiencies identified,

and FDA must take action to

assure correction

Form 483

Form 483 is issued to the firm management at the

conclusion of an inspection when investigator(s)

discovered conditions that in their judgment may

constitute violations of the FD&C Act and related Acts.

Form 483 notifies the company’s management of

objectionable conditions

If no enforcement action is contemplated, or after

enforcement action is concluded, FDA provides

inspected establishments with the final inspection report

(EIR), 21

Form 483

Inspection Readiness BEC 22

Enforcement Actions

Warning Letters are addressed to the President and CEO of a

company

Consent Decrees and Criminal Prosecutions typically name

individuals in addition to the corporation

The FDA Investigator’s job includes development of evidence

as to whom to charge in any regulatory action that results from

the inspection

“The identification of those responsible for violations is a critical part of the

inspection, and as important as determining and documenting the violations

themselves. Responsibility must be determined to identify those persons to hold

accountable for violations, and with whom the agency must deal to seek lasting

corrections.”

--FDA Investigations Operations Manual, Section 5.3.6

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Disgorgements

due to cGMP

Abbott Labs, Consent Decree of Permanent

Injunction filed 11/2/1999 (payment of $100 million)

Wyeth-Ayerst Labs., Consent Decree of

Condemnation and Permanent Injunction filed

10/4/2000 ($30 million)

Schering-Plough Corp., Consent Decree of

Permanent Injunction filed 5/20/2002 ($500 million)

Genzyme Corp., Consent Decree of Permanent

Injunction filed 5/24/2010 ($175 million)

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FDA ONLINE Resources http://www.fda.gov

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FDA Top Observations Drug Inspections

(FY 2008-2013)

Sec. 21

CFR 211

FY

2008

FY

2009

FY

2010

FY

2011

FY

2012

FY

2013

211.22 155 236 268 300 261 237 211.25 104 116 192 203 177 134 211.67 150 195 220 243 199 192 211.84 84 134 147 163 163 147 211.100 152 228 283 296 257 218 211.110 109 123 129 119 137 98 211.160 201 248 275 313 293 245 211.165 128 133 171 188 171 179 211.166 107 115 125 145 145 153 211.192 153 194 212 239 193 211 211.198 115 115 136 155 142 112 26

FDA Top Observations Drug Inspections

(Cumulative FY 2008-2013)

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CAPA Subsystem

Warning Letter Summary

FY # WLs # with CAPA

cite

%

2013 144 127 88

2012 164 143 87

2011 122 104 85

2010 89 81 91

2009 77 68 88

2008 98 86 88

2007 74 62 84

2006 79 69 87

2005 97 85 88

2004 113 89 79 28

Observations per Inspection

(Drugs + Devices)

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http://www.fda.gov/ICECI/CriminalInvestigations/default.htm

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FDA Inspector Preparation:

Get the Factory Jacket

They will read at least the last 3 EIRs, most

of the time all reports for the last 5-10 years

Read all correspondence between firm and

FDA to learn about firm’s commitment and

CAPA plans

Review complaints and Adverse Event

from FDA’s databases

Check firm’s recall history

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Data integrity, data manipulation and fraud appears to be increasing

It’s occuring in early stages of drug development (i.e., clinical studies), during commercial manufacturing and in various FDA regulated products

The FD&C Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigator’s job is to document individual responsibility for violations noted during inspections

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Data Integrity: Information that is accurate, complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections.

– Data needs to meet ALCOA elements of quality

– Attributable – data are identified with a specific subject and a specific

observer and recorder. (Password, audit trail and e-signature)

– Legible – data are readable and understandable by humans (reports, tables,

and listings)

– Contemporaneous - data are recorded at the time they are generated or

observed. (Time stamps and time-limited entry)

– Original – data are recorded for the first time. (Source data)

– Accurate – data are correct (Calculations, algorithms, analyses)

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Specialized training of investigational staff on uncovering data integrity, data manipulation and fraud

PAIs to focus more on data integrity and fraud

Agency committed to follow-up on leads or information regarding data manipulation and fraud

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What is FDA Doing?

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 35

What Can Industry Do?

FDA Quality Systems Guidance

for Finished Pharmaceuticals

39 Inspection Readiness BEC


Routine Drug Inspections

A firm is out of control if any one system is out of

control.

Systems approach: Four systems (full coverage) or two systems (abbreviated coverage).

Quality systems always must be reviewed.

Other systems: Facilities and Equipment, Materials, Production and Process Controls,

Laboratory Controls, Packaging and Labeling.


“State of Control”

Detailed inspection of a system so that the

findings reflect the state of control in that

system for every product (profile) class

If one of the six systems is out of control,

the firm is considered out of control

A system is considered out of control based

on GMP deficiencies which suggest lack of

assurance of quality


FDA Inspections:

What to expect from FDA?

Systems Inspection Approach

» Quality System (21 CFR 211, Subparts B, E, F, G, I, J, & K)

» Facilities and Equipment (21 CFR 211, Subparts B, C, D

& J)

» Materials (21 CFR 211, Subparts B,E H & J),

» Production (21 CFR 211, Subparts B, F & J)

» Packaging and labeling (21 CFR 211, Subparts B, G & J)

» Laboratory Control (21 CFR 211, Subparts B, I, J & K)

Main Inspection Targets

Recalls and Field Alerts

Lab Investigation - CAPA

Rejects/Reworks

Use as it

Documentation

– Say what you do

– Do what your say

– Record that you have done it Inspection Readiness BEC 43


Quality System:

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

– Approval of and adherence to Procedures and associated recordkeeping systems

– Product Reviews

– Complaint Reviews

– Failure Evaluations

– Change Control

– Product Improvement Projects

– Rejects/Reprocessing/Rework

– Stability

– Validation

– Training


Facilities and Equipment:

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification, calibration and

maintenance

Water, steam, compressed gas, HVAC

Change control system

Investigate discrepancies


Materials:

Inspection Target

Procedures and documentation showing adequate control of finished products, in-process materials, components, containers, closures

Qualification/validation and security of computerized or automated processes


Investigation of Discrepancies.


Production System:

Drug Inspection Target

Training/qualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testing/examination

Change Control System

Investigation of discrepancies


Packaging and Labeling:

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaging/labeling records

Line separation

Line clearance, inspection and documentation

Validation of labeling/packaging operations

Investigation of discrepancies


Laboratory Control:

Inspection Target

Staffing and training

Adequate equipment, calibration and maintenance

Reference standards

Adherence to written procedures

Validation/verification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples


Before the Inspection

Profound Literature Review

– At least your two previous inspection (483s, EIRs,

etc) – other Edwards facilities, (Añasco, etc.)

– Recent inspections at other company facilities

» Request 483, EIR, etc

– Continuously surf FDA’s webpages for

» Competitor’s warning letter

» Competitor’s 483s (from ORA FOIA)

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SOP for Inspection Readiness

Strong Internal Audit/Assessment function

– Continuous assessment using Risk Management

Criteria

– Not autopilot auditing

– Same auditor…

Perform a full-system audit (Mock) at least one

month prior to inspection

– Be sure any necessary CA-PA has been originated 51


Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept.

Promote the participation on the internal audit

cadre

Certify internal auditors

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Before the Inspection:

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something, why your

internal auditor did not?

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

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During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs, etc

Opening meeting

Daily wrap up

Close-our meeting

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During the Inspection:

Answering Inspector’s Questions

Think before your answer

Answer questions accurately and truthfully

Don’t be intimidated or defensive

Know your work and be confident

Be professional

If you don’t know the answer, it is

acceptable to reply that don’t know, but you

can find out

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Inspectors are looking for …

Implement and Follow Adequate Procedure(s)

Perform and Document Thorough Investigations and Testing Commensurate with Event and Potential Impact

Adhere to Time Limits

Identify Other Possibly Affected Lots

Evaluate Impact on Product

Implement and Evaluate Corrective / Preventive Actions

57

Big troubles…

Lack of Documented Investigation

Incomplete Investigation Factors Not Considered / Documented

Blame everything on employee or laboratory error

Inadequate trending

Associated Lots Not Identified / Evaluated

Root Cause Not Established or Justified

Conclusions Not Supported by Data

Timelines Not Followed, Not Extended

Corrective / Preventive Actions Not Implemented, Tracked or Completed Effectiveness Not Verified

At the end of the Inspection

FDA inspector present 483 observations

Firms should use this opportunity to gain

an understanding of the issues as FDA sees

them

Firms can make commitments about

CAPAs but it should be emphasized that

formal reply and action plans will follow in

writing (no more than two weeks is

recommended) Inspection Readiness BEC 58

At the end of the Inspection

Do not hesitate to challenge (be polite!) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However, FDA may interpret silence as

agreement


FDA Activities following the

Inspection

Investigator prepares the EIR and recommend

classification of the inspection

Supervisory review

Classification of inspection: NAI, VAI, OAI

If OAI, referral to DO Compliance Branch for

further review and action


FDA Expectation (IOM 5.2.3.)

All FDA-483s should adhere to the following general

principles:

Observations which are listed should be significant and

correlate to regulated products or processes being

inspected.

Observations of questionable significance should not be

listed on the FDA-483, but will be discussed with the

firm’s management so that they understand how

uncorrected problems could become a violation. This

discussion will be detailed in the EIR.


FDA Expectation (IOM 5.2.3.)

All FDA-483s should have the following characteristics

to be useful and credible documents: – Each observation should be clear and specific.

– Each should be significant. Length is not necessarily synonymous with

significance.

– Observations should not be repetitious.

– The observations should be ranked in order of significance.

– All copies of the FDA-483 should be legible.

If an observation made during a prior inspection has not

been corrected or is a recurring observation, it is

appropriate to note this on the FDA 483.


After the Inspection:

Reasons for the 483 Response

Could mitigate an FDA compliance decision for

further action

– Untitled letter

– Warning Letter

Demonstrate to the FDA an understanding and

acknowledgment of the observations

Demonstrate to the FDA a commitment to

correct and to voluntarily comply



The 483 Response

Assess each observation using risk management tools

– Focus on specifics

– Focus on system-wide implications

– Focus on global implications

– Consider affected products

– Focus on the regulatory requirement(s) associated with each

observation

Develop action plan to achieve immediate, short-term,

and long-term correction and to avoid recurrence



The Effective 483 Response

Include a commitment/statement from senior

leadership

Address each observation separately

Note whether you agree or disagree with the

observation



The Effective 483 Response

Provide corrective action accomplished and/or

planned; tell FDA the plan

– Be SMART

– Be specific (case by case)

– Be complete

– Be realistic

– Address affected products (are they reeased?)



The INEFECTIVE 483 Response

Jump to root causes of the observations

Setting unattainable goals (miss your due dates)

Too much or too little supporting documentation

Do not verify the numbers (or quantities of

affected products) you are providing to FDA

Minimize the significance of a reported

complaints

Minimizing problems by stating that other do the

same thing Inspection Readiness BEC 67


From Deming

It is not necessary to change. Survival is not mandatory.

You can not inspect quality into the product.

Quality is everyone's responsibility.

Gracias

www.calidadpr.com

www.becspainsl.com

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