Consequences of Failing to Comply with
CGMPs –
An FDA Perspective
Steven Lynn, MS, CMQ/OE
Director
Office of Manufacturing and Product Quality
Office of Compliance
CDER/FDA
FDLI
July 2013
TOPICS
• Our Common Goal: To avoid unnecessary risks to
the Patient
– achieved via a Strong, Robust Quality System
• What Can Happen?
• Indicators
• Inspectional Trends
• Go on an Inspection with Me
2
21st Century: Industry Evolution
• An industrial paradigm shift is in progress:
– Scientific risk management throughout
lifecycle, with better process understanding and
continual improvement
– Quality Systems approach, e.g.
• Senior management responsibility
• Robust quality monitoring programs
– Proactive quality culture detects problems
promptly
3
FDA and Industry Have a Common
Interest in…
• Assuring consistently safe and effective
drugs are available to the public
• Building quality in throughout the lifecycle
and supply chain to prevent risks
• Finding science-based solutions and using
contemporary technologies/approaches to
address problems
• Adapting to globalization
4
The Patient is the Customer
• Quality should be patient-focused
– Emphasis on minimizing consumer risk to assure patients receive safe
and effective medicines (see ICH Q9)
• Quality is achieved through a robust Quality System
– Starts with senior management Commitment to Quality, and is
underpinned by Quality Risk Management (QRM) & Knowledge
Management (KM)
– Quality is better assured when management recognizes and leads with
the understanding that upstream control and prevention make good
business sense
– Sustainable compliance is readily realized when a Quality Assurance
(proactive) culture replaces the antiquated Quality Control (reactive)
paradigm
– QRM and KM are used to identify potential failure modes, and address
variability in facilities, processes, and materials throughout the lifecycle
5
What Can Happen?
The consequences of
non-compliance
6
Why Follow CGMPS?
– It’s the law – Food Drug and Cosmetic Act (FD&C):
• 501(a)(2)(b): requires conformity w/ CGMP
– “A drug... shall be deemed to be adulterated if... the methods used in, or the
facilities or controls used for, its manufacture, processing, packing, or holding do
not conform to or are not operated or administered in conformity with current
good manufacturing practice...”
– “to assure that such drug meets the requirements of this Act as to safety and has
the identity and strength, and meets the quality and purity characteristics,
which it purports or is represented to possess.”
• Codified in 21 CFR 210 & 211
– Not following CGMP regulations constitutes adulteration under the Act
– Scope of CGMPs
• Ingredients
• Finished dosage forms
– OTC, Rx products
– Biologics, veterinary drugs
– Drugs undergoing study (IND, e.g.)
• Manufacturers, test laboratories, packagers (including pharmacies)
7
Consequences of Non-Compliance – con’t
• FDA’s Compliance Policy Guides (CPG)
• Explains FDA policy on regulatory issues related to the FDA laws
or regulations.
• http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyG
uidanceManual/ucm116271.htm
• FDA’s Compliance Program Guidance Manual (CPGM)
• Provide instructions to FDA personnel for conducting activities to
evaluate industry compliance with the Federal Food, Drug, and
Cosmetic Act and other laws administered by FDA.
• http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgra
mManual/default.htm
Note: Neither the CPGs or CPGMs create or confer any rights for or on any
person and does not operate to bind FDA or the public.
•
An alternative approach may be used as long as the approach satisfies the requirements
of the applicable statutes and regulations.
8
Consequences of Non-Compliance – con’t
• FDA’s Regulatory Procedures Manual (RPM)
• http://www.fda.gov/ICECI/ComplianceManuals/Re
gulatoryProceduresManual/ucm176446.htm
• Outline for all of FDA’s Actions
– A reference manual for FDA personnel.
– Provides FDA personnel with information on internal
procedures to be used in processing domestic and import
regulatory and enforcement matters.
Note: It does not create or confer any rights for or on any
person and does not operate to bind FDA or the public.
9
Consequences of Non-Compliance – con’t
– Who is Responsible for Adulterated Products?
• Everybody in a firm and across the ENTIRE SUPPLY CHAIN
• Top executives of the company, operations managers, and
quality managers are examples of individuals who have
fundamental roles in preventing these violations
– Commitment to Quality
• Cannot settle on meeting perceived “regulator’s minimum
standard”
• Must meet YOUR standards to reliably produce high quality
products
• What Dr. Woodcock said….
–
–
–
–
proactively identify & promptly correct issues
design/qualify robust operations
maintain equipment and facilities
Implement robust quality systems
10
Consequences of Non-Compliance
–
–
–
–
–
–
–
–
–
–
Form 483 Citations
Regulatory Meetings
Untitled Letters
Warning Letters
Withholds for Pending Applications
Recalls
Market Withdrawals
Consent Decrees
Seizures
Site Shutdowns due to inability to consistently produce
a quality product(s)
– Firm shuts itself down – no longer in business
– Criminal Investigations
11
Indicators:
Field Alert Reports (FARS)
12
Field Alert Reports (FARs) = Quality Defects
21 CFR and FD&C Act basis for requirement
– 21 CFR 314.81 Other Postmarketing Reports
– 21 CFR 314.98 (c) Postmarketing reports
– FD&C Act, Sec. 505(k)
• NDA and ANDA holders are responsible for filing FARs.
• Foreign application holders are required to have a US agent registered
in the US per 21 CFR 314.50(a)(5). The US agent will report FARs.
13
What is Reported?
• Application holders are required to report to the FDA any incident
that causes the distributed drug product or its labeling to be
mistaken for, or applied to, another article – in other words,
instances of adulteration or misbranding.
• In addition, they must also report any:
•
•
•
•
Bacteriological contamination
Significant chemical, physical or other change
Product deterioration
Out-of-specification result
• If firm cannot invalidate problem within 3 days, Field Alert must be
reported
• Quality defects serve as an early signal of problems with product
quality
14
FARs continued….
 The number of FARs received from a company/sponsor is
usually is a good indicator of general CGMP compliance
 Quality defects can take many forms (products with missing labels,
sub-potent products, etc.)
 However, just the number of quality defects by itself may
be misleading
 large firms with a larger portfolio of drugs, as opposed to smaller
firms with smaller portfolios
 complexity of the dosage forms, for example:
 transdermals vs. capsules
 sterile dosage forms vs. non-sterile dosage forms
15
Indicators:
Recall Trends
16
Recall Classifications:
OTC and Rx
Total OTC Products Recalled by Year and Classification
1600
1471
1431
1400
1200
1000
Class I
787
800
Class II
Class III
600
409
400
322
262270
213
200
15
55 77
71
24
107
52
141129
57
25
21
61
26
154
97
36
100
27
38
86
22
5 23 15
9
57 31
0
OTC
Rx
2008
OTC
Rx
2009
OTC
Rx
2010
OTC
Rx
2011
OTC
Rx
2012
OTC
Rx
2013
17
2011 Top Recall Failures
18
18
2012 Top Recall Failures
19
19
Indicators–
Inspection Trends
20
Top 10 Drug Observations Used in Turbo EIR
between 01 Jan 2012 and 31 Dec 2012 (as of 24 Jan 2013)
211.22d: Lack of written
procedures describing
roles/responsibilities of
the QCU
211.192: Lack of
investigations into batches that
fail to meet specifications and
review of all affected batches
211.100(a): Lack of process
validation to assure that the drug
products has the identity,
strength, quality, and purity that it
is purported to possess
21
Turbo Cite and related 21 CFR 211 Reference for
2012
22
Turbo Cite and related 21 CFR 211 Reference
23
Summary of Top 10 Cites – 01 Jan to 31 Dec 2012
1.
2.
3.
4.
211.22d: Lack of written procedures describing roles/responsibilities
of the QCU
211.192: Lack of investigations into batches that fail to meet
specifications and review of all affected batches
211.100(a): Lack of process validation to assure that the drug
products has the identity, strength, quality, and purity that it is
purported to possess (e.g., the production process is not validated for
it’s intended use throughout the life cycle of the product)
211.160(b): Lack of scientifically sound laboratory controls, such as
specifications, standards, test methods, sampling plans, to assure that
components, containers/closures, in-process materials, labeling, and
drug products conform to standards of identity, purity, quality and
strength
24
Summary of Top 10 Cites – 01 Jan to 31 Dec 2012
5.
6.
7.
8.
9.
10.
(cont’d.)
211.110(a): Lack of in-process monitoring of CPPs that validate the
performance of manufacturing processes that cause variability of the
in-process materials or drug product
211.67(b): Lack of written procedures for cleaning and maintenance
equipment used in the manufacturing, process, packing or holding of a
drug product
211.67(a): Equipment and utensils not cleaned, maintained, or
sanitized at appropriate intervals to prevent contamination or
malfunctions, which would alter the safety, identity, quality, purity
and strength of a drug product
211.25(a): Lack of CGMP training and written procedures
211.68(a): Routine calibration of equipment not performed
according to a written procedure designed to assure proper
performance
211.165(a): Lack of testing drug products to assure products meet
final specs and identity/strength of active ingredients
25 prior to release
25
Top 10 Drug Observations Used in Turbo EIR
between 01 Jan 2011 and 31 Dec 2011 (as of 24 Jan 2013)
211.22d: Lack of written
procedures describing
roles/responsibilities of
the QCU
211.160(b): Lack of
scientifically sound
laboratory controls,
211.100(a): Lack of process validation to
assure that the drug products has the
identity, strength, quality, and purity that
it is purported to possess
26
26
Turbo Cite and related 21 CFR 211 Reference for
2011
27
Turbo Cite and related 21 CFR 211 Reference for
2011
28
Summary of Top 10 Cites – 01 Jan to 31 Dec 2011
1.
2.
3.
4.
5.
211.22d: Lack of written procedures describing roles/responsibilities
of the QCU
211.160(b): Lack of scientifically sound laboratory controls, such as
specifications, standards, test methods, sampling plans, to assure that
components, containers/closures, in-process materials, labeling, and
drug products conform to standards of identity, purity, quality and
strength
211.100(a): Lack of process validation to assure that the drug
products has the identity, strength, quality, and purity that it is
purported to possess (e.g., the production process is not validated for
it’s intended use throughout the life cycle of the product)
211.192: Lack of investigations into batches that fail to meet
specifications and review of all affected batches
211.100(b): Written production procedures not followed and/or
documented at the time of performance
29
Summary of Top 10 Cites – 01 Jan to 31 Dec 2011
6.
7.
8.
9.
10.
(cont’d.)
211.25(a): Lack of CGMP training and written procedures
211.67(b): Lack of written procedures for cleaning and
maintenance equipment used in the manufacturing, process,
packing or holding of a drug product
211.67(a): Equipment and utensils not cleaned, maintained, or
sanitized at appropriate intervals to prevent contamination or
malfunctions, which would alter the safety, identity, quality,
purity and strength of a drug product
211.110(a): Lack of in-process monitoring of CPPs that validate
the performance of manufacturing processes that cause
variability of the in-process materials or drug product
211.165(a): Lack of testing drug products to assure products
meet final specs and identity/strength of active ingredients
prior to release
30
Trends for Top 10 Turbo Citations
2011 – 2012










211.22(d)
211.100(a)
211.160(b)
211.192
211.110(a)
211.67(b)
211.67(a)
211.25(a)
211.100(b)
211.165(a)
2008 – 2010










211.22(d)
211.192
211.160(b)
211.100(b)
211.110(a)
211.100(a)
211.67(a)
211.67(b)
211.25(a)
211.188
2004 - 2007










211.22(d)
211.110(a)
211.100(b)
211.160(b)
211.192
211.100(a)
211.165(a)
211.25(a)
211.188
211.67(b)
There are MULTIPLE Repeat Citations!!!
31
GMP Issues Found on International Inspections FY 2012
UNVALIDATED LAB TEST METHODS
2%
CONTROL COMPONENTS,
INTERMEDIATES, RAW MATERIALS
6%
SYSTEM QUALIFICATION (IQ/OQ) BUILDINGS/FACILITIES COMPUTER VALIDATION
1%
2%
2%
CONTAMINATION
CONTROL OF WATER SYSTEMS
STABILITY PROGRAM
REPROCESSING/REWORKS
1%
DEFICIENCIES2%
IN MEDIA FILL
4%
0%
1%
QA SYSTEMS
9%
PRODUCTION/PROCESS CONTROLS
5%
PACKAGING/LABELING
1%
DEFICIENCIES IN RECORDS/REPORTS
8%
DEVIATION FROM DMF/NDA/ANDA
DEVIATION FROM0%
ANTIBIOTIC
REQUIREMENTS
0%
DEVIATION FROM MONOGRAPH
0%
EQUIPMENT
CLEANING/MAINTENANCE, CLEANING
VALIDATION
9%
EQUIPMENT DESIGN, SIZE, LOCATION
NONE (NO FD-483 ISSUED)
1% HOLDING/DISTRIBUTION CONTROLS
11%
0%
INADEQUATE COMPLAINT
INVESTIGATIONS
NO PROCESS VALIDATION PROTOCOL
4%
1%
INADEQUATE ENVIRONMENTAL
LACK OF/INADEQUATE SOPS
CONTROLS
INADEQUATE LAB CONTROLS
6%
*Data derived from DIDQ compliance officer reviews of inspection
INADEQUATE VALIDATION PROTOCOL
4%
12%
information,
INADEQUATE PROCESS VALIDATION
1%
for inspections occurring in FY2010-2012. Data pulled Febuary 19th,
3%
ORGANIZATION/PERSONNAL
1%
2013 from CMS. FY 2012 may not be complete.
32
GMP Issues Found on International Inspections FY 2011
BUILDINGS/FACILITIES
3%
CONTAMINATION
1%
STABILITY PROGRAM COMPUTER VAL1%
REPROCESSING/REWORKS
CONTROL COMPONENTS,
3% 0%
1%
QA SYSTEMS
INTERMEDIATES, RAW MATERIALS
CONTROL OF WATER SYSTEMS
10%
5%
2% DEFICIENCIES IN MEDIA FILLS
PRODUCTION/PROCESS
DEVIATION FR ANTIBIOTIC REQ
1%
DEFICIENCIES IN
CONTROLS
0%
RECORDS/REPORTS
DEVIATION FROM
5%
9%
PACKAGING/LABELING
DMF/NDA/ANDA
ORGANIZATION/PERSONNAL
2%
1%
DEVIATION FROM MONOGRAPH
1%
0%
EQ.CLEAN/MAINT-CLEAN VAL9%
NONE (NO FD-483 ISSUED)
10%
EQ DESIGN-SIZE-LOC.1%
NO PROCESS VAL PROTOCOL
1%
LACK OF/INADEQUATE SOPS
7%
INADEQUATE VALIDATION
PROTOCO
1%
INADEQUATE PROCESS
VALIDATION
4%
HOLDING/DIST.CONTROLS
1%
INADEQUATE COMP INV.3%
INADEQUATE ENV. CONT 4%
INADEQUATE LAB CONTROLS
13%
33
*Data derived from DIDQ compl
FY2010-2012. Data pulled Febu
Inspections
34
The Quality System:
Foundation for Assuring an Ongoing State of Control
•
•
•
•
•
•
FDA Inspection Program
Includes:
Materials System
Equipment & Facilities
Production
Laboratory
Packaging & Labeling
Quality System
Investigations Operations Manual (IOM):
http://www.fda.gov/ICECI/Inspections/IOM/default.htm
35
What Investigators do
• Evaluate the firm’s Quality Control Unit
(QCU)
• Evaluate production and control systems
• Evaluate avenues of potential adulteration
• Evaluate any potential misbranding
• Evaluate SOPs and if firm follows SOPs
36
36
What Investigators look for?
•
•
•
•
•
•
•
•
•
•
Marketed products that do not meet USP specifications
Products or processes not validated
Changes made outside validation processes/parameters
Process validated throughout the life cycle of the product?
Product list – high risk products, products manufactured
infrequently
How a firm handles OOSs
How firm conducts investigations and follow-up. Did firm
determine the “root cause”. Are other affected lots
eliminated and/or not evaluated as part of the
investigation?
Complaints - only looking at each batch or looking at batch
to batch variations/trends?
Recalls
Overall - Systems which allow inferior product to the
market!
37
What do Investigators look at/review?
•
•
•
•
•
•
•
•
Validation protocols and reports
Product Development Reports& Summary
Annual Product Reports
Annual Product Reviews
Field Alert Reports (FARs)
Change Controls
Deviations, non-conformances, incidents
CAPAs
38
38
What do Investigators look at?
• Storage/manufacturing practices that may result
in potential contamination
• Poor employee practices, esp. in aseptic areas
• Rejected/reworked/reprocessed batches
• Equipment in disrepair or improperly designed
• Material and equipment identification system
• Potential products for product/label mix-ups
• Utilities with inappropriate plumbing connections
39
39
What do Investigators look at?
•
•
•
•
•
Maintenance records
Equipment usage logs
Cleaning status records
Observed practices vs. validated practices
Personnel observed vs. expected behavior (may
interview employees, but not interfere with their
duties)
• Batch records in-process
40
40
What do Investigators look for?
•
•
•
•
•
SOPs present in areas
Calibration stickers on gauges and devices
Proper identification of materials in laboratories
Inappropriate or non-validated analytical methods
Multiple sets of data
41
41
Systems Inspection Evaluation
• The basic principle of QA:- a drug should be
produced so that it is fit for “its intended use”.
• A firm is considered out of control if any one system
is out of control.
• A system is out of control if the quality, identity,
strength and purity of the products resulting from
that system(s) cannot be assured adequately.
• Effective process validation contributes significantly
to assuring drug product quality.
42
42
Benefits of an Effective Quality System
• Support and Ownership of Quality Goes Beyond the
Quality/Compliance Units
• Scientific Risk Management Throughout the process
Lifecycle Yields Many Benefits:
– Enhanced Process Stability Drives Productivity and
Performance.
– Prevention Reduces Compliance Risks and Costs.
– Fewer Significant Complaints and Investigations and
Therefore More Efficient QA Release of Batches.
– Protection of Your Client’s Brand
– Etc., Etc., Etc.
43
Potential Risks from a Product (or
Ingredient) Problem
• Patient/consumer Risk
– Lessened, excessive or
Poor Quality
inconsistent therapeutic
Interruption in
effect.
manufacturing or supply.
– Side effects and transient
Disqualification of
supplier and need to
adverse events.
qualify new supplier.
– Permanent adverse effects.
Customer complaints and
– Loss of confidence in safety
returned goods.
and quality of drug(s).
Loss of reputation, profits,
– Needed drug is unavailable.
market share – hurt the
brand.
Decline in stock value.
• Corporate/business Risk
–
–
–
–
–
–
44
Comparative Cost of (Poor) Quality
$
Most
Costly
1000x
$
Less
Costly
100x
Defect found after
it’s delivered to
customer
Defect found at
company before
being shipped
External Failure
Cost
Internal Failure
Cost
Source: Principles of Quality Costs, 3rd Edition, Campanella, Pg. 8
Least
$
Costly
1x
No Defect! The Firm’s QMS is
designed, planned and
organized for defect
prevention and continual
improvement
Prevention Cost
A Quality System Creates REAL Fixes
• A robust quality system is:
–
–
–
–
–
–
Science and risk-based
At the core of Good Manufacturing Practice
Vigilant and Proactive
Culture-focused
Able to identify issues while they are still small
Responsible for assuring any contracted site is qualified to do the
function, and performed it satisfactorily
– Supportive of business needs because it creates dependability and
sustainability, as well as efficiency and effectiveness!
• It should not be:
– Reactive or defensive (issues should be surfaced)
– Solely a procedural approach (only “plan-do”)
46
Conclusion
•
A strong and vigilant QS is the offense to counteract a firm
from traveling down the cascading trail of enforcement.
•
Maintaining a strong and vigilant quality system
throughout the product lifecycle will enable an ongoing
state of control.
•
An effective quality system allows distributors and
manufacturers to assure that consistently high quality
drugs are provided to consumers (quality throughout the
supply chain)
•
The intensity of FDA oversight is related to a firm’s ability
to manage risk(s) associated with product quality.
47
Acknowledgments
• Rick Friedman,
FDA/CDER/OC
• Arun Shakya,
FDA/CDER/OC
• Monica Caphart,
FDA/ORA/OO/OMPTO
• Sharon Thoma,
FDA/ORA/OO/OMPTO
• Kevin Starry,
FDA/ORA/OO/OEIO
48
Steven Lynn, MS, CQM/OE
US FDA
Steven.lynn@fda.hhs.gov
49