CGMPs and Drug Quality Assurance
Richard L. Friedman, M.S.
Associate Director
Office of Manufacturing and Product Quality
Office of Compliance
FDLI “Understanding CGMPs” Conference
July 10, 2013
• CGMP and the Consumer
• Quality Systems
– Oversight of State of Control is basic requirement
of GMP
– Examples
• Pharmaceutical Quality in the 21st Century
– Paradigm shift
CGMP and the Consumer
CGMP Objective:
Assure Quality of Every Batch, Every Day
“We rely upon the manufacturing controls and
standards to ensure that time and time again, lot
after lot, year after year the same clinical profile will
be delivered because the product will be the same in
its quality… We have to think of the primary
customers as people consuming that medicine and
we have to think of the statute and what we are
guaranteeing in there, that the drug will continue to
be safe and effective and perform as described in the
- Janet Woodcock, M.D.
Potential for Tension between Commercial and Public
Health Interests
• “The probability alpha, also known as the
producer's risk, is the risk that adequate product is
rejected. The probability beta is known as the
consumer's risk because defective product is
• The associated risk probabilities will depend on
“inspecting and scrapping good product” or “the
[later] costs of shipping bad product.”
[Jim Colton, Quality Digest, Dec., 2011 “Statistical Tools for Pharmaceutical Manufacturing”]
Sources of Variability
Major factors that can affect manufacturing output and
adversely impact drug quality:
Materials (APIs, Excipients, etc.)
Procedures (SOPs, master batch records, etc.)
Measurement Systems
CGMP: Framework for Industrial Quality
A drug manufacturer is responsible for implementing
dependable daily operations that assure consistent
drug quality. Management’s daily decisions on
myriad issues involving equipment, materials,
maintenance, staff qualifications, supervision,
process control, and investigations will ultimately
determine the quality of the drugs that are shipped
from a given facility.
[Woodcock, J and M. Wosinska, Clinical Pharmacology & Therapeutics,
“Economic and Technological Drivers of Generic Sterile Injectable Drug Shortage,” Jan 2013]
Key Ingredient: Top management support for
major quality improvements
• Survey of 400 executives (many industries) found that
most companies are willing to sacrifice long term
economic value in order to deliver short term earnings.
• Quality-oriented leaders establish systems that detect
problems (new or emerging risks)
– Monitor for OOT instead of waiting for OOS
– Early warning system that enables effective
management review (QA instead of reliance on QC)
Mauboussion, M. “The True Measures of Success,” Harvard Business Review, Oct, 2012
Quality Systems
Reliable Manufacturing
• …Clearly the responsibility for maintaining quality rests
squarely with the manufacturers themselves...the widespread
and successful adoption of six sigma and related quality
management techniques in other manufacturing sectors
would imply that reliable, high-quality manufacturing is also
attainable in the pharmaceutical sector.
• We must ask ourselves, in an area where the stakes are so
high, why is this not being achieved?
Dr. Janet Woodcock
Commentary in May-June 2012 edition of PDA Journal
Importance of an Effective Pharmaceutical
Quality System
The pharmaceutical quality system “assures
that the desired product quality is routinely met,
suitable process performance is achieved, the
set of controls are appropriate, improvement
opportunities are identified and evaluated, and
the body of knowledge is continually
ICH Q10, Section 3.1.3 Commercial Manufacturing
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 (not only“plan-do”)
GMP-Compliant Quality System:
Effective Management Oversight & Controls Over Manufacturing
FDASIA Revision to FD&AC Act
THE DRUG SUPPLY. Section 501 (21 U.S.C.
351) is amended by adding:
“For purposes of paragraph (a)(2)(B), the
term ‘current good manufacturing
practice’ includes the implementation of
oversight and controls over the
manufacture of drugs to ensure quality,
including managing the risk of and
establishing the safety of raw materials,
materials used in the manufacturing of
drugs, and finished drug products.’
Leadership and the Corporate Quality Culture
Daily Decisions ...
Strong Corporate Quality Culture
& Manufacturing Consistency
Unreliable Systems &
Manufacturing Problems
… influence your direction
Defects, Regulatory
Actions, Business Failures
Adapted from Richard Davis (2004)
How mature is your quality system?
Level 1: Small problems ultimately
snowball into larger ones, and
management becomes aware only
when there is a crisis.
Level 2: Nearly always reactive, but
there is some willingness to change.
Patchwork corrections are the norm.
Level 3: More proactive. Increasingly
surfaces major issues and makes
lasting systemic improvements.
Level 4: Routinely acts preventively,
and institutionalizes (rewards)
meaningful process and system
Good Decisionmaking Through
Sound Quality Risk Management (QRM)
• The output/results of the risk management process should be
reviewed to take into account new knowledge and experience.
• Once a quality risk management process has been initiated,
that process should continue to be utilized for events that
might impact the original quality risk management
decision, whether these events are planned (e.g., results of
product review, inspections, audits, change control) or
unplanned (e.g., root cause from failure
investigations, recall).
• The frequency of any review should be based upon the level of
risk. Risk review might include reconsideration of risk
acceptance decisions (section IV.D.4).
[ICH Q9]
Risk Management: Some Information That
May Trigger Risk Review or CAPA
 Nonconformances, discrepancies, deviations, failures, recalls
 Product Quality Data
 Process monitoring results
 e.g., trend analyses from process performance and product quality
 Equipment or Facility issues
 Raw Material Issues
 Regulatory Findings (local or at another site)
 Audits and self-inspections
 Complaints/Returns
 Stability Testing results
• “After establishing and confirming the
process, manufacturers must maintain
the process in a state of control over the
life of the process, even as materials,
equipment, production environment,
personnel, and manufacturing
procedures change.” (FDA PV Guidance)
• State of Control: A condition in which the
set of controls consistently provides
assurance of continued process
performance and product quality. (ICH
• FDA’s CGMP inspection program began
evaluating state of control using the
quality systems approach in 2002.
Effective monitoring & control systems
• FDA’s 2011 Process Validation Guidance:
– An ongoing program to collect and analyze product and process
data that relate to product quality must be established. The data
collected should include relevant process trends and quality of
incoming materials or components, in-process material, and
finished products. The data should be statistically trended and
reviewed by trained personnel. The information collected should
verify that the quality attributes are being appropriately
controlled throughout the process.
– Scrutiny of intra-batch as well as inter-batch variation is part of
a comprehensive continued process verification program (lifecycle
stage 3).
FDA Warning Letter
• When preparing your SOPs, please note that a
CGMP-compliant quality system supports a
sustainable state of control. This includes but is not
limited to systems to ensure proper raw materials,
vigilant quality monitoring, and appropriate
corrective and preventive actions. FDA expects your
firm to perform a comprehensive assessment of
manufacturing operations to ensure that drug
products conform to FDA requirements.
Contracting Risks and Complexity
“Not only are buyers unable to observe manufacturing quality,
but firms that contract out manufacturing of their product
often do not have the same level of insight into or oversight of
the contract manufacturer’s quality systems as they would have
into their own. Over-commitment on manufacturing capacity
by a contract manufacturer can lead to an unsustainably high
number of products on each line and substandard oversight of
the process.”
[Woodcock, J and M. Wosinsksa, Clinical Pharmacology & Therapeutics,
“Economic and Technological Drivers of Generic Sterile Injectable Drug Shortage,” Jan 2013]
Warning Letter
LVP Contract Manufacturer
Your firm failed to thoroughly investigate several non-sterility
complaints. For several weeks spanning April-May, your firm received
complaints from multiple customers (sponsors) informing you that USP
IV bags were contaminated with a swirling mass in LVP bags, and
provided the identity of fungi and bacterial contaminants. Your firm
did not adequately investigate the root causes of the problem, or
address other lots that were impacted by the problem. You ultimately
found that sharp edges on stereos used in your LVP bag labeling
operation caused a recurring problem with pinhole punctures in bags.
This loss of container closure integrity led to the contamination.
However, your firm originally failed to address other impacted lots
beyond those with specific complainants… Your firm also submitted
late Field Alerts regarding these serious nonsterility issues.
“OOS results may indicate a flaw in product or process design.
For example, a lack of robustness in product formulation,
inadequate raw material characterization or control, substantial
variation introduced by one or more unit operations of the
manufacturing process, or a combination of these factors can be
the cause of inconsistent product quality. In such cases, it is
essential that redesign of the product or process be undertaken
to ensure reproducible product quality.”
- FDA Guidance on Investigating Out-of-Specification Test Results for Pharmaceutical Production (2006)
Top 10 Drug Observation in Turbo EIR (since 2000)
C ount
C F R N o.
C itatio n T e xt
21 C F R 211.22(d)
T he resp onsib ilities a nd proc edures a pplica ble to the qu a lity c ontrol unit a re not [in w riting] [fu lly
follow ed]. S pec ifica lly, ***
21 C F R 211.100(b)
W ritten produ ction a nd proc ess control proc edures a re not [follow ed in the ex ecution of produ ction a nd
proc ess control functions] [docu m ented a t the tim e of p erfor m a nc e]. S pec ifica lly, ***
21 C F R 211.160(b)
L a boratory controls do not inc lu de the esta blis hm ent of scientifica lly sou nd a nd a ppropriate
[specifica tions] [sta nda rds] [sa m p ling pla ns] [test procedures ] des igned to a ssure tha t [com p onents ] [drug
product c onta iners] [c losures] [in -proc ess m a teria ls] [la beling] [dru g products] c onfor m to a ppropria te
sta nda rds of identity, strength, qua lity a nd purity. S pecifica lly, ***
21 C F R 211.192
T her e is a fa ilure to thorou ghly review [a ny u nexp la ined discr epa nc y] [the fa ilure of a ba tch or a ny of its
com p onents to m eet a ny of its spec ifica tions] w hether or not the ba tch ha s been a lrea dy distributed.
S pec ifica lly, ***
21 C F R 211.100(a )
T her e a re no w ritten proc edures for production a nd proc ess controls des igned to a ssure tha t the drug
products ha ve the identity, strength, qua lity, a nd purity they purport or are repres ented to poss ess.
S pec ifica lly, ***
21 C F R 211.110(a )
C ontrol proc edur es a re not esta blis hed w hich [m onitor the output] [va lida te the p erfor m a nc e] of thos e
m a nufa cturing proc ess es tha t m a y b e respons ible for ca using va ria bility in the c ha ra cteristics of in -proc ess
m a teria l a nd the drug product. S pec ifica lly, ***
21 C F R 211.165(a )
T esting a nd relea s e of drug produ ct for distribution do not inc lu de a ppropria te la bora tory deter m ina tion of
sa tisfa ctory confor m a nc e to the [fina l sp ec ifica tions] [identity a nd strength of ea c h a ctive ingredient] prior
to relea s e. S pec ifica lly, ***
21 C F R 211.25(a )
E m ployees a re not given tra ining in [the pa rticula r opera tions they p erfor m a s part of their function]
[current good m a nu fa cturing pra ctices] [w ritten proc edures requ ir ed b y current good m a nu fa cturing
pra ctice regu la tions]. S pec ifica lly, ***
21 C F R 211.67(b)
W ritten proc edur es a re not [esta blis hed] [follow ed] for the c lea ning a nd m a intena nc e of equip m ent,
inc lu ding utens ils, used in the m a nu fa cture, process ing, pa cking or holding of a drug product. S pec ifica lly,
21 C F R 211.188
B a tch produ ction a nd control rec ords [a re not prepa red for ea c h ba tch of drug product produc ed] [do not
inc lu de c om p lete inform a tion rela ting to the productio n a nd control of ea c h ba tch]. S pec ifica lly, ***
Pharmaceutical Quality
in the 21st Century
Pharmaceutical Quality in the 21st Century
• Regulatory paradigm shift to:
– Performance and Management-Based
• Establish performance standards (e.g., metrics)
– Lifecycle focus
• Evaluate capability of firm’s quality system to consistently
meet performance standards, including determining:
– whether state of control is maintained throughout
– determining how effectively the facility manages risks
• Allow flexibility for technological advancement and
continual improvement
Pharmaceutical Quality in the 21st Century
• Industrial paradigm shift to:
– Quality Systems approach, with strong process
performance and quality monitoring programs, and
a proactive quality culture
– Engaged Senior Managers who create and reinforce
the quality culture, through both policies and
– Scientific risk management throughout lifecycle,
with CAPA and continual improvements made
based on knowledge gained

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