Ex ,e cu t iv e Responsibility 'i 1n
Lesson Title:Phar'm aceut ica l Manufacturing
Keywords:
Learning Objectives:
• Define Executive Management
• Describe the purpose and function of FDA
• Explain FDA 483s, Warning1 Letters and Consent
Decrees
□
• Describe the personal implications of non-compliance
• Explain the term,s Quality Policy and Quality System1
• Explain the purpose of the Quality System
• Describe FDA's approach to inspecting the Quality
System
• Compliance
• Food Drugi and
Cosmetic Act
• Consent Decree
• FIDA 483
• Criminal Prosecution
, • GMIP
• Debarment
• Personal Responsibility
• Executive Mlanagement • Quality Policy
"The person who is responsib le for the failure to comply, shall
be subject to regulatory action".
This quote is taken from the section of the U.S. Code of Federal
Reg1 ulations (CFRs) that governs the U.S,. drug manufacturing
industry,. As an executive manager
in a pharm1 ac
eutical facility,
you are the respons ible person.
In this Lesson we will look at the respons ibilities of executive
m1 an
agement, key industry regulations and how they are
enforced and the consequences of non-comiplia noe. We will
also look at how compliance is achieved throug1 h a properly
functioning1 Quality System.
Ex e,cutiv e IManage1m
Y ou
Ar e Respons'ib l e
e n t
Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
The Food, Drug, and Cosmetic Act
The CFIRs are derived from the most important piece of U.S.
legislation affect ing the pharmaceutical industry - the Food,
Drug, and Cosmetic Act (FD&C Act).
□□
The FD&C Act is the basic food and drug1 law of the United
States. It was passed by congress in 1938 and has been
amended several times since then. Its introduction marked the
first time that companies in the U.S. were required to prove the
safety of new drugs before selling them. J □
The law was prompted by a number of serious drug incidents.
In 1937 an antibiotic medicine called Sulfanilamide Elixir killed
11 07 people in the U.S. The medicine had not been tested for
Acts, Regulations and Codes
safety and contained the poisonous solvent diethylene
glycol.
Sulfanilamide, E:lixir
The federal regulations covering pharmaceutical products are
called 21 CFIR IP art 2110 and 211 CFR Part 211.
□
The regulations describe current Good !M anufacturing Practices
(cGMPs) for drug products and are com1 m o n ly
referred to as
cGMP regulations,. G1 M I P is part of quality assurance. Its purpose
is to ensure that drug products are consistenUy
m1 a nuf
actured to required quaUty standards.
I
cGMP regulations are the means by which the FD&C Act is
enforced on a practical basis. Under th1 e F , D& C Act, executive
m1 a nage
m e nt
ca n
be held criminally responsible for not
complying with the Act and, reg
ulations . Enforcement is the
riesponsibility of a U.S. fe, de ra l agency called the Food and Drugi
Administration or FDA.
I
GIM P'
FDA
.
Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
FDA
FDA is a public health agency. Its duty is to promote and protect
public health by approving products such as drugs and m1 e dical
devices for sale in the United States and monitoring these
products for continued safety after they are in use.
FDA's responsibilities also include food, cosm1 e tics and blood
products.
The section of the FDA that deals with drug products
is called the Center for Drug Evaluation and Research or
GOER.
Companies that m1 anufactu re drug1 products for sale in the U.S.
are monitored fo, r G M P compliance with the FD&C Act to ensure
that their products are safe and effective.
IFDA Respons'i b i li t i e s
Safe and Effective
This is done through on-site FDA inspections of manufacturing
facilities.
_xecutive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
FDA Inspections
FDA inspection activities are categorized as premarket and
postmarket.
Premarket - If your company wants approval to manufacture a
new drug product, FDA will perform a preapproval iinspectio n
of the manufacturing facility. The inspection will determine if the
facility complies with cGMIP regulations and if the information
given in the New Drug Applicat ion (NOA) is authentic and
accurate. Ultimately, FDA wants proof that the drug will be
safe and effective if manufactured at the facility.
If the new drug product is approved, FDA will carry out a
postapproval iinspection. The main focus here is the
validation studies for the product. Validation involves providing
documented proof that the drug product can be manufactured in
a consistent way, batch after batch.
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Cii
Preapproval Inspection
Postapproval Inspection
FDA Inspections Ctd.
Once products are on the market (postmarket) FDA continues
to monitor how they are manufactured by performing
postmarket surveillance inspections. These inspections can be
either Full or Abbreviated.
A Full inspection is used when FDA has no previous knowledge
of your company s GMP status.
It may also be used if FDA
has doubts about your company s GMP compliance status or to
follow up on previous regulatory action.
The Abbreviated inspection option is normally used if FDA is
already familiar with your facility processes and products. It
can also be used to re-examine specific areas highlighted
Full Inspection
during an initial Full inspection.
Abbreviated Inspectior
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Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
Systems
FDA's approach to surveillance inspect ions is systems-based.
Activities in drug manufacturi ng facilities can be organized into
some or all of the following systems: c
• Quality System1
• Facilities and Equipment System
• Materials System
• Production System
• Packaging and Labeling System
• Laboratory Control Sy,stem
Each system1 has a different function and requ ires differen t
procedures, personnel, and reco rded informatio n to fulfill the
requiremen ts of GMP. Control of these systems helps ensure
that a facility produces drugs that are safe, effective and of the
required quality.
I ll
t ii
Systems
Quality System
•
Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03 -
Control of Systems
During an inspection, your company's Quality System is always
examined. It is here that FDA looks for assurance that your
company is in overall compliance with GMIP regulations and
your own internal procedures and specifications. □□
FDA will determine whether your company has all its systems
under control. If any of the systems is found to be out of control,
in other words, it is found that GMP has not been followed, then
FDA will consider your company to be out of control and in
breach of GMIP regulations. It may also consider your products
to be adulterated.
In such circumstances there are a number of different actions
FDA can take.. The action chosen depends on a number of
factors including the severity of the problem and your
company 's record in GMP compliance.
111
Clil
Inspecting Your Procedures
Adulterated
Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-5,00-03
FDA 483 Reports
FDA initially presents adverse inspection findings to executive
management by complet ing an FDA 483 report at the end of the
inspection. This report lists perceived GMP violatio ns.
Although you are not required by law to provide a written
respo nse to an FDA 483 report, it is normal industry practice to
dlo so.
It is essential ior executive manage ment to be involved in
respo nding to FDA 483s. Correcting alleged violations can be
expensive. Less senior members of management may promise
too much too soon, leading1 t o further problems when FDA
makes a return visit.
It is important to address each FDA 483 item individually,
identify the root causes of the violation and its proposed
solution and provide a reasonable timeframe for implementing1
the solution.
Cii
IFDA 483
·
•
Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
Warning Letters
An FDA 483 report is included in an inspector's Establishment
Inspection Report (E.I R). The ElR is reviewed by high level
FDA officials who will decide if regulatory action is needed.
The first step towards regulatory action is a Warning Letter. A
warning letter does not commit FDA to taking regulatory action
against you and your company but it does indicate that such
action is likely if you fail to take corrective action.
You m1u st repliy to a warning letter setting out in detail how you
will correct the perceived GMP violat ions. Your response should
be careful and well thought out. A hasty reply may trigger further
r,egulatory action.
EIR Review
Warning Letter
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Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
Further Actions
If after receiving1 a warning1 l etter, you fail to take corrective
action or FDA is dissatisfied with the actions taken, it can take
regulatory action without further notice. These actions include,
but are not limited to, seizure of product, I consent decree
injunctions , civil money penalties, or criminal prosecution. FDA
may also reject a Nlew Drug Application resulting in millions of
dollars in lost revenue and neg1ative corporate publicity.□
A consent decree injunction is a court order that enforces an
agreement made between FDA and a non-compliant company.
The company must agree to correct its deficiencies and
thereafter maintain regulatory compl iance . Failure to honor a
consent decree can result in an FDA-initiated lawsuit against
named members of executive management within a company.
Product Seizure
Monetary Penalties
Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-5'00-03
Criminal Prosecution
The m1 ost severe consequence of violating GMP is criminal
prosecution. As we have seen, under th1 e FD&C Act execu tive
manageme nt can be held criminally responsible for non­
compliance. You can be prosecuted if FDA can prove that
because of your position of responsibility, you had the authority
to prevent or correct violations but failed to do so.
This has been upheld by the U.S. Supreme Court in several
cases including United States versus Dotterweic h. In the
Dotterweich case, the company purchased drugs from a
different manufacturer and repacked and sold the drugs under
its own label. The Dotterweich company, its president and the
general manager were found guilty of shipping1 misbranded
drugs in interstate com1 merce and of ship ping an adulterated
drug..
Criminal Prosecution
Dotterweich
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Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
Debarment
If you are convicted of a felony related to violation of the FD&C
Act, you can be barred for life from working in the
pharmaceutical industry. This action is known as "debarment"
from the word "debar" meaning to exclude or prohibit. I
If you are debarred, FDA wi'II notify the public by publishing your
name in the federal register. our name will also be added to a
debarment list available for public viewing on FDA's website. I
A company illegally employing a debarred individual can be
heavily fined as can the debarred individual concerned.
Debarment
Debarment List
•
Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
Sequence of Events
It is crucial to understand that although FDA 483s, warning
letters, and legal enforcement represent increasingly serious
situations, they do not necessarily occur in that order. You can
receive a warning letter without a preceding FDA 483. Legal
action may follow on directly from an FDA 483 without any
warning let ter.
It is also important to appreciate that FDA considers individual
company facilities to be part of a whole. In other words if FDA
uncovers the same violation twice in your organization, it is
considered a repeat observation, even if the observation is
made at two different sites. FDA will be led to conclude that
you have a corporate-wide problem in that area.
Different Sites
QuaIity Policy
As we have seen, FDA places great importance on your
company's Quality System - it is always inspected. As a
miemiber of executive manag1e ment you must be thoroughly
familiar with this system and what FDA expects of it.
A Quality System is built upon a corporate Quality Policy. The
Quality Policy sets out the overall intentions and direction of
your organization with respec t to quality. Establis hing a Quality
Policy is the responsibility of management with executive
respo nsibility. But merely establishing a quality policy will not
ensure compliance. During an inspection, FDA will look for
evidence that the policy is actually understood and implemented
at all levels of your organization.
Quality Polli cy
I mplem1 entation
The Quality System1 is the practical means by which the Quality
Policy is implemented.
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Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-S00-03
Quality System Re,quir,ements
A properly functioning Quality System1 limits you and your
company's exposure to regulatory action. To function properly a
Quality System requires a number of different elem1 e nts. These
include an organizat ional structure , clearly defined
responsib ilities, written procedures , processes and adequate
reso urces ,.
It is the responsibility of executive manag,e, m ent to ensure that
all of these elements are in place. Adequate resources are
particularly important to a Quality System. Resources include
sufficient funding, personnel, facilities and training1 .
FDA investigators can be expected to ask executive
Quality System
m1 a nagement about the adequacy of resources during an
Nl o Excuses
inspection,. Lack of resources will never be accepted by FDA as
an excuse for non-compliance.
•
Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
QuaIity System Inspection
During an inspection of your Quality System , FDA places a lot
of emphasis on documentation. Documentation is essential to a
properly functioning Quality System and its importance cannot
be overstated. Documentation provides objective evidence of
compliance to an inspector.
FDA wants to see that you have adequate written procedures
relat ing to production, quality control and quality assurance
activities. These procedures must be reviewed and approved
by your company's Quality Unit. FDA also requires proof that
these procedures are being followed, in other words, that you
have adequate record keeping1 systems.
Documentation
Procedures
QC App 1r o va I
Records
Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
Quality System Inspection Ctd.
The following are examples of areas within your Quality System
that FDA might examine:
• Dealing with complaints I
• Reviewing and improving products
• lnves tig1 ating manufacturing problems
• Training of employees in Quality Control Unit functions I
An inspector will check that you have written approved
procedures to cover these areas and corresponding records to
show that the procedures are being used.
If an inspector uncovers deficiencies within one of these areas
he or she may widen the inves tigation to examine other major
systems in your facility such as the Production System or
Laboratory Control System..
Complaints
Training
Deficiencies
•Executive ResponsibBity
iin Pharmaceutical M:a nufacturing
Code: RGM-500-03
Maintaining the Quality System
FDA needs to see that not only ii s a Quality System
implemented but that it is periodically monitored and evaluated
for its effectiveness . This can !be achieved through audits,
management review, I and corrective and preventive action.
□
Th1i s review of the Quality System will highlight any problems or
potential prob:l ems in advance of an FDA visit. An inspection is
not the place to first become aware of deficiencies in your
Quality System.
1
Management Review
Quality System Deficiencies
.
Executive Responsibility in Pharmaceutical Manufacturing
Code: RGM-500-03
Conclusion
The FD&C Act may place a heavy compliance burden on
executive management but its ultimate aim is to ensure that
only safe and effective products leave a drug manufacturing1
facility.
oGMP regulations are there to protect consumers from poor
quality and unsafe pharm1 aceutical products . Consumers must
be abl,e to trust the quality of these products and, ultim1 a tely,
trust you as a respo nsible person within the pharmaceutical
industry,.
Your comm itment to current Good Manufacturing Practice and
the maintenance of a proper ly functioning Quality System are
both critical in justify ing this trust.
Consumer Trust