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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]
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
4
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
5
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
6
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
8
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
9
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.
10
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.
11
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.
12
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
14
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
16
17
18
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.
19
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
20
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
23
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)
24
FDA ONLINE Resources http://www.fda.gov
25
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)
27
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)
29
http://www.fda.gov/ICECI/CriminalInvestigations/default.htm
30
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
31
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
32
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)
33
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
34
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?
36
37
38
FDA Quality Systems Guidance
for Finished Pharmaceuticals
39 Inspection Readiness BEC
Inspection Readiness BEC 40
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.
Inspection Readiness BEC 41
“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
Inspection Readiness BEC 42
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
Inspection Readiness BEC 44
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
Inspection Readiness BEC 45
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
Inspection Readiness BEC 46
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
Change control system
Investigation of Discrepancies.
Inspection Readiness BEC 47
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
Inspection Readiness BEC 48
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
Inspection Readiness BEC 49
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
Change control system
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)
50
Before the Inspection
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
Before the Inspection
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
52
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
53
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
54
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
55
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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
Inspection Readiness BEC 59
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
Inspection Readiness BEC 60
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.
Inspection Readiness BEC 61
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.
Inspection Readiness BEC 62
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
Inspection Readiness BEC 63
After the Inspection:
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
Inspection Readiness BEC 64
After the Inspection:
The Effective 483 Response
Include a commitment/statement from senior
leadership
Address each observation separately
Note whether you agree or disagree with the
observation
Inspection Readiness BEC 65
After the Inspection:
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?)
Inspection Readiness BEC 66
After the Inspection:
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
Inspection Readiness BEC 68
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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