Best Practice
Survival Guide to FDA Inspections
Preparation – Conduct – Follow up
April 2012
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Survival Guide to FDA Inspections
Contents
1. Introduction ............................................................................. 5
2. Laws – Regulations – Guidelines .......................................... 7
Laws ...................................................................................................8
Regulations ........................................................................................9
Guidance Documents ......................................................................10
Inspection Guides ............................................................................12
Compliance Policy Guides ...............................................................13
Industry Guidance ............................................................................13
3. FDA Inspections .................................................................... 14
Traditional vs. Risk-based system Inspections ................................15
Focusing Inspections on Highest Risks ...........................................17
4. Consequences of Non-compliance...................................... 18
483 Inspectional Observations.........................................................19
Establishment Inspection Report (EIR) ............................................20
Warning Letter .................................................................................21
Product Recall..................................................................................22
Seizure .............................................................................................24
Consent Decree ...............................................................................25
Import Alerts and Denials.................................................................26
Debarment .......................................................................................27
5. Studying FDA Inspection Reports ....................................... 28
Most Frequent Citations ...................................................................28
Examples of Citations ......................................................................29
6. Efficient Quality Systems to Prevent Non-compliance ...... 49
Comply with Common Requirements for all Regulations ................51
Inspection Findings from Previous Inspections ...............................53
Look at Specific Details as Required by Individual Regulations ......53
Quality Systems ...............................................................................54
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Facilities and Equipment ..................................................................55
Materials Systems ............................................................................56
Production Systems .........................................................................57
Packaging and Labeling Systems ....................................................58
Laboratory Control Systems ............................................................59
7. Preparing for and Conducting FDA Inspections ................. 61
Preparing your Organization for FDA Inspections ...........................61
Internal Audits ..................................................................................66
Prepare Required Documentation ...................................................69
Conducting the Inspection ...............................................................71
After the Inspection ..........................................................................73
8. Responding to 483’s and Warning Letters .......................... 74
Responding During the Inspection ...................................................74
Response to 483 Inspectional Observations ...................................75
Response to Warning Letters ..........................................................76
Preparing for the Next Inspection ....................................................77
Appendix A: Glossary ............................................................... 77
Appendix B: References ........................................................... 84
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Survival Guide to FDA Inspections
Survival Guide to FDA Inspections
1. Introduction
The United States Food and Drug Administration’s (FDA) mission
is to protect consumers' health and safety under the Federal Food,
Drug, and Cosmetic Act (FD&C) (1) and other laws. To do this the
FDA has developed two basic strategies:

Monitoring the quality of products through surveillance
activities such as sampling and analyzing products in
distribution.

Evaluating through factory inspections, including the collection
and analysis of associated samples, the conditions under
which products are developed, manufactured, tested, packed,
labeled and held. An FDA inspection can be a nightmare that
costs your company money, time and reputation, or it can be
an opportunity to improve your quality system and to make a
long-lasting good impression on the FDA
During inspections the FDA verifies that a company’s procedures
and processes are in compliance with FDA GxP regulations such
as Good Laboratory Practices, Good Clinical Practices and Good
Manufacturing Practices. If the FDA inspections identify deviations
from the regulations, they will issue inspectional observations
using a special form containing the number 483. These reports are
usually called 483’s or 483 inspectional observations. Depending
on the severity of the deviations the company may get a warning
letter later on.
Over the last couple of years many companies have received FDA
483 inspection observations and warning letters because they
failed to comply with FDA’s GxP regulations. Some of these
companies are well-established and well-known with global
presence. Warning letters have not only been issued to companies
in the United States but also in Europe, Asia and Australia.
Receiving a warning letter can mean a financial disaster for a
company because new product approval may be delayed,
manufacturing of drugs can be stopped or import and marketing of
finished drugs, active pharmaceutical ingredients, bulk material or
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medical devices into the United States can be denied. In some
cases warning letters can also cause personal problems for
individual employees if they are held accountable for noncompliance. The FDA publishes the warning letters on the Internet
and so makes consumers, competitors and business partners
aware of a company’s non-compliance, which is obviously bad for
the image of a company.
The risk of receiving 483’s and warning letters can be minimized
by following a couple of recommendations:
1. Know regulations and guidelines. As well as knowing the text
you also need to understand the intent and the meaning. This
includes GxP’s as well as 21 CFR Part 11 on Electronic
Records and Signatures.
2. Inform yourself on the consequences of deviations of noncompliance. Make your management aware of these
consequences.
3. Learn about mistakes others have made through studying
inspectional observations (483s) and warning letters.
4. Build up a quality system in line with industry standards and
regulations and guidelines.
5. Develop procedures and practices on how to make the best
out of FDA Inspections. To do this take learning experience
from FDA inspectional practices, inspectional observations and
warning letters.
6. Minimize the damage of 483 inspectional observations and
warning letters by effective response.
It is far out of the scope of this paper to teach readers in detail
about the necessary regulations and guidelines. There is a lot of
literature available, for example a 120-page primer on GLP and
GMP (2) and a series of audio seminars with guidance on
understanding and implementing FDA and other regulations and
guidelines,(3). Reference 4 includes a list of FDA regulations or
so-called predicate rules.
This primer will focus on steps two to six. There are individual
chapters on building a quality system, understanding the FDA’s
inspection and enforcement practices, preparing your organization
for FDA inspections and responding to FDA inspection
observations and warning letters. After the introduction section we
will continue with a brief chapter on FDA regulations and
guidelines followed by a chapter on FDA actions in case of
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deviations. The next chapter lists typical and most frequently cited
deviations. For this we studied several hundred GxP related
warning letters and inspection reports. Readers can use this
information to educate themselves on the current thinking of FDA
inspectors as well as learning from past mistakes and how to avoid
them.
For this paper we made extensive use of the Internet. Most
literature and reference material cited in this paper are available
online. Links can be found in Appendix B of this primer.
2. Laws – Regulations – Guidelines
In preparation for FDA inspections companies are advised to study
laws, regulations and guidance documents related to their
business. In this chapter we describe the official documents that
are important and how they relate to each other. The relationship
between different documents is shown in figure 1. The starting
point is laws, which are the highest-level documents followed by
regulations and various guidance documents.
Law
Regulation/Rule
Guidance
Inspection report
Passed Congress
• Federal Food, Drug, and
Cosmetic Act
Promulgated by FDA
• cGMP, GLP, GCP
• E-records/signatures
Issued by FDA
• Compliance policy
• Inspection, Industry guidance
Issued by FDA
• 483’s, EIR’s
• Warning letters
Figure 1. Hierarchy and Meaning of Laws, Regulations and
Guidance Documents
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Laws
Laws are passed by the U.S. Congress, and therefore derive from
the highest authority. Laws are created by and can only be
changed by this Congress. An example is the Federal Food, Drug,
and Cosmetic Act (FD&C) (1). It is the single most important law
for the pharmaceutical, biopharmaceutical and medical device
industry and therefore a good reason to discuss it a little bit more
in detail.
The first Act was passed by the Congress as early as 1906. In
1937, a public health disaster tragically drove home the need for a
stronger federal law. Sulfanilamide, the first ‘wonder drug’ and a
popular and effective treatment for diseases like strep throat and
gonorrhea, was formulated into an Elixir of Sulfanilamide and
marketed for use on children. But the liquid formulation contained
a poison, the same chemical used in antifreeze, and it killed 107
people, most of them children. The earlier law did not require the
drug manufacturers to test the formulation for safety before it was
sold.
Congress corrected this weakness in the law the next year when it
passed the Federal Food, Drug, and Cosmetic Act (FD&C). This
law, for the first time, required companies to prove the safety of
new drugs before putting them on the market. The new Act
became effective in 1938 and also added the regulation of
cosmetics and therapeutic devices, and generally updated the law
to improve consumer protection.
This Act from 1938 is intended to reassure the consumer that:

Foods are pure and wholesome, safe to eat and produced
under sanitary conditions.

Drugs and medical devices are safe and effective for their
intended uses. This includes drugs used in medicated feeds
for animals.

Cosmetics are safe and properly labeled.

Packaging and labeling of these products is truthful and
informative.
The FD&C Act has been amended several times since 1938.
Amendments in1962 required that all drugs be proven effective as
well as safe and gave the FDA the authority to regulate
prescription drug advertising. The Medical Device Amendment of
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1976 gave the FDA authority to ensure the safety and
effectiveness of medical devices, including diagnostic products.
Laws are quite general and usually don’t state how they should be
implemented.
Regulations
The Food and Drug Administration’s (FDA) mission is to enforce
the Federal Food, Drug, and Cosmetic Act (FD&C) and other laws
that are designed to protect consumers' health and safety. The
FDA’s responsibilities are specified by the scope of the laws. Laws
with impact on the FDA can be downloaded from Reference 5.
These laws equally apply to domestic and imported products.
For enforcement of laws Federal Agencies such as the FDA
promulgate rules or regulations. These are published as the Code
of Federal Regulation (CFR) in the Federal Register and inform
the public and industry how the laws are implemented. For
example, the Federal Food, Drug, and Cosmetic Act (FD&C)
generally states that no food labeling may be “false or misleading
in any particular” and that “the name and address of a
manufacturer shall appear on the label”. The FDA “Labeling”
regulation 21 CFR 201 specifies exactly what should appear on
the label as well as its size and location and the regulation
includes many examples of different labels. Unlike laws, which can
only be changed by the Congress, regulations can be changed by
the FDA. It takes time and the FDA would have to publish a Notice
of Proposed Rule Making and accept comment - but it is possible.
The most well-known FDA regulations are the GLP, GCP and
GMP regulations. GMP stands for Good Manufacturing Practice,
GCP for Good Clinical Practice and GLP for Good Laboratory
Practice. Sometimes these regulations are also called “predicate
rules”. The most important FDA regulations can be downloaded
from Reference 4. They refer to the regulations that the FDA has
promulgated under the Federal Food, Drug, and Cosmetic Act
(FD&C) and other laws to ensure that products are developed,
manufactured and held in a state of control, thereby contributing to
their safety, effectiveness and purity. Regulations assist all
company employees in knowing what is necessary to help ensure
company compliance by setting quality standards. It is therefore
very important for everyone to be familiar with the regulations.
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Survival Guide to FDA Inspections
Guidance Documents
In many cases regulations are not detailed enough for inspectors
and for the industry. In this case the FDA develops guidance
documents. They provide assistance to the regulated industry by
clarifying requirements imposed by Congress or issued in
regulations by the FDA and by explaining how industry may
comply with these statutory and regulatory requirements. They
also provide specific review and enforcement approaches to help
ensure that the FDA's employees implement the agency's
mandate in an effective, fair and consistent manner.
These documents describe the FDA’s interpretation or policy on a
regulatory issue and represent the agency’s current thinking on a
particular subject. Guidance documents include documents that
relate to the design, production, labeling, promotion,
manufacturing and testing of regulated products; the processing,
content and evaluation or approval of submissions and inspection
and enforcement policies. They are not legally binding for either
the pharmaceutical industry or the FDA. Therefore guidance
documents must not include mandatory language such as “shall”,
“must”, “required” or “requirement”, unless the FDA uses these
words to describe a statutory or regulatory requirement. An
alternative approach can be used if such approach satisfies the
requirements of the applicable statute, regulations or both.
However, if alternative approaches are used, they should be
justified and correctly documented. FDA inspectors are advised
not to cite guidance documents in inspectional observations or
warning letters.
Development of FDA guidance documents is regulated by 21 CFR
10.115, called Good Guidance Practices (GGP) (6). The regulation
describes two levels of guidance documents:
 Level 1 guidance documents set forth initial interpretations of
statutory or regulatory requirements and changes in
interpretation or policy that are of more than a minor nature.
They may cover complex scientific issues or highly
controversial issues.
 Level 2 guidance documents are guidance documents that set
forth existing practices or minor changes in interpretation or
policy.
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The regulation also states that an agency may not use other
documents or other means of communication to informally
communicate new or different regulatory expectations to a broad
public audience for the first time. Good Guidance Practices must
be followed whenever regulatory expectations that are not readily
apparent from the statute or regulations are first communicated to
a broad public audience.
According to 21 CFR 10.115 the industry has a variety of options
to influence the type and content of guidance documents:
 Suggest areas for guidance document development.
Suggestions should address why a guidance document is
necessary.
Provide input on guidance documents that the FDA is
developing.
 Submit drafts of proposed guidance documents for the FDA to
consider.
 At any time, suggest that the FDA revise or withdraw an
already existing guidance document. The suggestion should
address why the guidance document should be revised or
withdrawn and, if applicable, how it should be revised.
 Once a year the FDA will publish, both in the Federal Register
and on the Internet, a list of possible topics for future guidance
document development or revision during the next year.
Industry can comment on this list (e.g., by suggesting
alternatives or making recommendations on the topics that the
FDA are considering).
 If the FDA agrees to draft or revise a guidance document,
industry can participate in the development of that guidance.
 Give inputs to draft guidances within 60 days.
The regulation also describes the procedures for developing and
issuing guidance documents:
 Before the FDA prepares a draft of a Level 1 guidance
document they can seek or accept early input from individuals
or groups outside the agency. For example, the FDA can do
this by participating in or holding public meetings and
workshops.
 After the FDA prepares a draft of a Level 1 guidance document
they will publish a notice in the Federal Register announcing
that the draft guidance document is available and post the draft
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guidance document on the Internet as well as making it
available on hard copy.
 Industry is invited to comment on the draft guidance document.
After providing an opportunity for public comment on a Level 1
guidance document, the FDA will review any comments
received and prepare the final version of the guidance
document that incorporates suggested changes, when
appropriate.
 The FDA publishes a notice in the Federal Register
announcing that the guidance document is available.
Within each center and office there must be written procedures
that detail the approval of guidance documents. The procedures
must ensure that appropriate senior officials review and approve
the issuing of guidance documents.
Examples of guidance documents are:
 Inspection Guides
 Compliance Policy Guides
 Industry Guidance
 Technical Inspection Guides
Inspection Guides
Inspection guides are used by field investigators to assist in
performing inspections of specific products or processes.
Inspection guides were previously known as the Inspector’s
Technical Guide (ITG). Both are meant to provide investigators
with additional technical information when they encounter highly
technical issues during inspections. The Office of Regulatory
Affairs (ORA) issues the inspection guides.
Examples are:
 Guide to Inspections of Pharmaceutical Quality Control
Laboratories (7).
 Guide to Inspections of Foreign Pharmaceutical Manufacturers
(8).
 Guide to Inspections of Quality Systems (23)
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Survival Guide to FDA Inspections
Compliance Policy Guides
A Compliance Policy Guide (CPG) explains the FDA’s policy on
regulatory issues related to the FDA regulations. These include
Current Good Manufacturing Practice (CGMP) regulations and
application commitments. They advise the field inspection and
compliance staff on how the agency's standards and procedures
should be applied when determining industry compliance.
Compliance Policy Guides may derive from a request for an
advisory opinion, from a petition from outside the agency, or from
a perceived need for a policy clarification by FDA personnel. The
purpose of the CPG is to provide a convenient and organized
system for statements of FDA compliance policy, including those
statements that contain regulatory action guidance information.
Examples are:


Drug Manufacturing Inspections Program (9)
Computerized Drug Processing, Input/Output Checking (10)
Industry Guidance
Industry guidances are targeted to the pharmaceutical and medical
device industry and represent the Food and Drug Administration’s
(FDA) current thinking on specific topics. It does not create or
confer any rights for or on any person and does not operate to
bind the FDA or the public. An alternative approach may be used if
such an approach satisfies the requirements of applicable statutes
and regulations.
Examples are:

General Principles of Software Validation, Final Guidance for
Industry and FDA Staff (11)

Good Clinical Practice, Consolidated Guidance (12)

Guidance for Industry Part 11, Electronic Records; Electronic
Signatures Scope and Applications (24)

Quality Systems for Drug CGMPs (28)
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3. FDA Inspections
A primary mission of the Food and Drug Administration is to
conduct comprehensive regulatory coverage of all aspects of
production and distribution of drugs and drug products to assure
that such products meet the 501(a)(2)(B) requirements of the
Food, Drug, and Cosmetic Act (FD&C) (1). To ensure the safety of
marketed products, FDA staff inspect domestic and foreign
manufacturers, check shipments of imported products and collect
and test product samples for signs of contamination.
For drugs the FDA has developed two basic strategies:

Evaluating through factory inspections, including the collection
and analysis of associated samples, the conditions and
practices under which drugs and drug products are
manufactured, packed, tested and held, and;

Monitoring the quality of drugs and drug products through
surveillance activities such as sampling and analyzing products
in distribution.
Factory inspections should to be done every two years. These are
called routine inspections. In addition the FDA can initiate “for
cause” inspections if they have any reason for it. A reason for a
“for cause” inspection can be poor quality of drugs found during
routine monitoring or if they are initiated as a result of other
serious health risks that were brought to the FDA’s attention.
Before a product is released into the market the FDA makes a preapproval inspection and after it has been introduced a postapproval inspection. In addition whenever a company makes a
significant change to its process, the FDA has to be notified. The
FDA may decide to come and inspect the new process for
compliance.
A primary source of information regarding agency policy and
procedures for field investigators and inspectors is the
Investigations Operations Manual (IOM) (13).
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Survival Guide to FDA Inspections
Traditional vs. Risk-based system Inspections
It is very important to understand how the FDA conducts
inspections. There was a change from traditional inspections of
profile classes towards risk-based system inspections.
Traditional FDA Inspections
At traditional inspections FDA inspectors checked compliance of a
specific product across departments and systems. The inspectors
may have gone from production areas to storage rooms.
Emphasis was on profile classes and there was no connection
between a system and infrastructure. The focus was on products
(see figure 2). If deviations were found no conclusion could be
made as to whether this was a specific site or department problem
or if it was a company-wide process problem.
Preparation
• Company
compliance
history
• File review
• Submission
review
• FDA Guidances
• IOM
Tour
•Facilities
•Personnel
•Processes
•Procedures
•Equipment
•Storage areas
•Laboratories
•Cleaning
practices
Documentation
Review
• Procedures
• Org charts
• Laboratory
controls
• Validation
• Training
• Raw data
• E-records
• OOS
Observations
• Inadequate
procedures
• Procedures not
followed
• Inadequate
computer
validation
• Missing raw
data
Figure 2. Flow of Product Inspections
System Based cGMP Inspections
Nowadays however, the FDA promotes the system-based
inspections approach for cGMP inspections. The FDA has defined
six systems including the quality systems. The systems are
illustrated in figure 3.
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Figure 3: System based inspections
1.
2.
Quality Systems: They assure overall compliance with cGMP
and internal procedures. The quality assurance unit is part of
this system.
Facilities and Equipment: They include the measures and
activities that provide an appropriate physical environment and
resources.
3.
Materials Systems: Include measures and activities to control
finished products.
4.
Production Systems: Include measures and activities to
control the manufacture of drugs and drug products.
5.
Packaging and Labeling Systems: Include measures and
activities that control the packaging and labeling of drugs.
6.
Laboratory Control Systems: Include measures and activities
related to laboratory procedures and processes like testing.
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The quality system is always inspected plus one additional system
for abbreviated inspections and three more systems for full
inspections. Management controls are always reviewed and most
likely the Corrective Action and Preventive Action (CAPA)
procedure and systems, people qualification, change control and
validation will be inspected at each inspection. With this approach
the FDA takes a broader look at a firm’s operations. If the FDA
finds a problem with any single drug it can then extrapolate it to all
drugs within that profile and assume there could also be problems
with any of the other drugs.
Focusing Inspections on Highest Risks
Because of limited resources the FDA cannot inspect all the
required pharmaceutical sites, and within a site they cannot
inspect all systems. As part of the FDA’s 21 CGMP initiative it
announced that it would be focusing on those aspects that pose
the greatest potential risk to the public.
The FDA has identified some priorities for inspections:
 Sterile manufacturing operations
 Prescription drug manufacturers
 New registrants not previously inspected
Other factors include the company’s compliance history and type
of drugs that are manufactured at a specific site, e.g., typical
extent of patient exposure. One likely result could also be more
frequent inspections of plants producing injectable therapies as
opposed to conventional drugs.
With many biotech therapies clearly in the high-risk category, the
agency will be increasingly emphasizing a risk-based control
point’s analysis in its scientific approach to cGMPs.
A good source of information for the FDA’s risk-based approach is
its Quality System Regulation (QSR) for medical device
manufacturers (29), which came into effect in 1997. Like device
manufacturers, drug manufacturers are also advised to estimate
and document the risk involved in a drug. The standard document
for risk management in pharmaceutical industry is the ICH Guide
Q9: Quality Risk Management (30). This guideline provides
principles and examples of tools for quality risk management that
can be applied to different aspects of pharmaceutical quality.
These aspects include development, manufacturing, distribution,
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and the inspection and submission/review processes throughout
the lifecycle of drug substances, drug (medicinal) products,
biological and biotechnological products.
The process to estimate and document risks has been described
and extensively documented by L. Huber (31). The drug and its
manufacturing process is identified and all types of anticipated
risks documented. Next the severity and probability of occurrence
are estimated and the levels defined as high, medium or low. From
this the overall risk is calculated and defined as high, medium or
low risk. The rationale behind your risk assessment should be welldocumented.
However, the ultimate objective is not only to assess risks, but also
to mitigate them to the extent necessary and possible. This
requires a program for cost effective mitigation and ongoing
monitoring and control. Reference 30 describes the process and
includes templates for risk assessment, mitigation and ongoing
control.
4. Consequences of Non-compliance
Deviations from GxP regulations can have several consequences.
The type of consequence will depend on the severity of the
deviation and even more importantly on a company’s compliance
history. Most critical for a company is if deviations from previous
multiple inspections have not been corrected, especially if the
deviation can have a severe negative impact on public health.
Typical outcomes of non-compliance can be:








483 form inspectional observation, written by inspectors during
the inspections and handed over at the end
Deviations cited in the Establishment Inspection Report (EIR)
Warning letter
Product recall
Import Alert for foreign companies with possible denial for
importing the product into the U.S.
Civil money penalties
Product seizure
Consent decree
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Survival Guide to FDA Inspections
483 Inspectional Observations
When an inspector finds non-compliance he/she will write an
inspectional observation during the inspection. Inspectors use a
special form, the so-called FD 483 form. A 483 is actually an
inspectional observations form that the FDA uses to convey to a
company the issues they have observed during their audit or
inspection. The information can be handwritten or typed using a
typewriter or a computer and is handed over to the company at the
conclusion of the inspection.
483 forms include the statement: The observations noted in this
Form FDA-483 are not an exhaustive listing of objectionable
conditions under the law. Your Firm is responsible for conducting
internal self audits to identify and correct any and all violations of
the quality system requirements.
This is to inform companies that the observation did not cover all
aspects of the quality system. The advantage of 483’s is that firms
get a direct response on deviations immediately after the
inspection so that prompt corrective action can be initiated. The
problem is that they only give the inspector’s or inspection team’s
viewpoint and are not approved by FDA management with
consequent inconsistencies. It may also happen that certain
citations may never be approved because they may not be in line
with the FDA’s current way of thinking.
However they can also have consequences, for example
withholding of product approvals, and because they can be made
available to business partners and competitors they can have a
negative impact on the company’s reputation.
An example of a typical 483 can be downloaded from Reference
15. 483’s are inspectional observations, and do not represent a
final agency determination regarding a company’s compliance. If a
company has an objection to an observation, have implemented,
or plan to implement corrective action in response to an
observation, they may discuss the objection or action with the FDA
representative(s) during the inspection or during the exit meeting.
Most companies take advantage of this option to make an initial
verbal response during the exit discussion and send a written
response afterwards.
In theory 483’s are available to the public right after they have
been handed over to the company. However, in practice they are
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difficult to obtain. In general they are not published on the Internet
but selected 483’s are available through service providers for a
fee. For example, selected representative examples are available
through www.fdawarningletter.com. Visitors can see excerpts for
free and download the full observation for an annual fee. They are
also available from the Freedom of Information (FOI) but one
would have to know that this exists, it takes may take several
years to get them and they are also not free of charge.
Also, parts will be blackened out that are proprietary in nature so
when you receive a copy of a 483 from the FDA through FOI don't
be surprised to see parts missing.
Establishment Inspection Report (EIR)
After the inspection an Establishment Inspection Report (EIR) is
written by the agency when the inspector is back in the district
office. The observations are classified as “No Action Indicated
(NAI)”, “Voluntary Action Indicated (VAI)” or “Official Action
Indicated (OAI)”. The OAI is typically a warning letter but can also
have other consequences like an Import Alert for foreign
companies, withheld approvals, product recalls, seizure, civil
money penalties or consent decrees combined with fines of
millions.
The EIR is reviewed, e.g., by the regional headquarter office and if
the deviations and conditions are serious enough, a warning letter
may follow.
EIR’s are more helpful in preparation for FDA inspections than
483’s or warning letters. They report all inspection findings and
give a good overview on inspection practices, especially on the
type of questions asked. Typically they include paragraphs on:








Persons interviewed
Individual responsibility
History of business
Facility and design
SOP Review
Laboratory review (or other systems)
Training
Stability
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Manufacturing batch record review
Complaints review
Annual reports review
Closing meeting
Objectionable conditions
Attachments
An example of a typical 483 can be downloaded from Reference
16. Unfortunately EIR’s are also not easy to get hold of. There are
a couple of commercial service providers offering selected EIR’s,
e.g., some excerpts can be viewed at www.fdawarningletter.com
and downloaded for a member fee.
Warning Letter
Depending on the severity of the deviations and possible negative
impact on public health the FDA may send a warning letter to the
company. Warning letters are described in FDA/ORA’s Regulatory
Procedure Manual (17) as: A Warning Letter is a written
communication from FDA notifying an individual or firm that the
agency considers one or more products, practices, processes, or
other activities to be in violation of the Federal FD&C Act, or other
acts, and that failure of the responsible party to take appropriate
and prompt action to correct and prevent any future repeat of the
violation, may result in administrative and/or regulatory
enforcement action without further notice.
An example can be downloaded from Reference 18. The warning
letters frequently make references to the 483 inspection
observations and sometimes also to the company’s response to
the 483.
Warning letters are reviewed by higher-level FDA officials and
since March 1st, 2003, by FDA centers. This should help provide a
more consistent approach for warning letters as well as help
identify possible program inconsistencies and resolve them before
warning letters are issued and to analyze deviations. Regular
analysis of these data aids the centers in identifying trends used to
further develop a risk-based strategy towards cGMP enforcement
practices. The FDA can also use this knowledge to enhance
policy, provide guidance and establish training for the FDA field
staff and regulated industry.
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A warning letter indicates that the FDA believes that a serious
regulatory violation exists. Companies are expected to respond
within 15 days. If there is no response or if the response is
inadequate the FDA will take further actions which may cause
delay of new product approvals, Import Alerts and denials, product
recalls, seizure or consent decree or the company may also lose
any governmental contracts. Generally, a follow-up inspection is
scheduled so that the company has time to fix the problem. But we
should not forget, any company that gets a warning letter is on the
FDA’s radar screen and this will go into its records under the
“company’s compliance history”. FDA’s assumption is that if there
are serious quality problems at one site, they also may exist at
other sites.
The FDA publishes warning letters on two websites:
 Letters that are supplied by the CDER Freedom of Information
Office (FOI). This page only covers letters issued by the
Division of Drug Marketing, Advertising, and Communications
and by Headquarters (33).

District Office warning letters (34).
The only problem is that there are thousands of them and they
mostly relate to marketing and labeling so it is difficult to find the
ones that are of interest, for examples ones related to GxP issues.
Excerpts are available on www.fdawarningletter.com, they are
searchable by keywords and full text can be downloaded for an
annual member fee.
Product Recall
A recall is a firm’s removal or correction of a marketed product that
the FDA considers to be in violation of the laws it administers.
Recalls are described in FDA/ORA’s Regulatory Procedure
Manual (6) as: Recalls are an appropriate alternative method for
removing or correcting marketed consumer products, including
their labeling and/or promotional literature, that violate the laws
administered by the Food and Drug Administration (FDA). Recalls
may be undertaken at any time on the initiative of manufacturers
and distributors to carry out their responsibility to protect the public
health and well-being, or in response to a formal request by FDA.
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Product recall is required when distributed products do not comply
with regulations or are not in specifications. An example of a
product recall announcement can be downloaded from Reference
14. A product recall can also be initiated if the analytical
equipment used to measure impurities in the finished drug was not
calibrated or qualified and there exists a high risk that the
analytical test result as the criterion for product release was
incorrect.. Another example would be if the person who authorized
the release of a batch was not qualified to do so.
U.S. product recalls are divided into three categories, depending
on the time delay (6):

Class I: A situation in which there is a reasonable probability
that the use of, or exposure to, a violative product will cause a
serious adverse health consequence or death.
 Class II: A situation in which the use of, or exposure to, a
violative product may temporary or reversible adverse health
consequences or where the probability of serious health
consequences is remote.
 Class III: A situation in which the use of, or exposure to, a
violative product is not likely to cause adverse health
consequences (6).
Companies should have an SOP for product recall. This should
include sections on responsibilities, the reason for the recall and
classification according to the categories above and detailed steps
for the recall. Recalls should be managed by the QA department.
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Figure 4. Example of a Drug Class II Product Recall
The first step is to form a team with representatives from
manufacturing, laboratories, compliance and regulatory affairs and
the legal department. QA should notify the regulatory agency
about cause, classification, planned steps and time schedule.
Notification should also include a corrective action plan and a
preventive action plan that demonstrates how to avoid similar
occurrences in the future.
U.S. product recalls are published on the Internet in the FDA
Enforcement Report (14). Recalls are sorted by month and year
and within each month by drugs, biologics and devices. An
example is shown in Figure 4.
Seizure
Seizure and the steps taken by the FDA and its consequences are
described in FDA/ORA’s Regulatory Procedure Manual (17).
Seizure is an action taken to remove a product from the market
because it is in violation of the law. In serious compliance or
quality cases, original documents, including batch records and
laboratory data, hard disk drives, or downloads of e-mail
messages may also be seized as evidence.
The seizure of a product that violates the Federal Food, Drug, and
Cosmetic Act is an action taken against the product, not against
the owner. Its purpose is to prevent consumption or use of the
seized product. When by inspection and laboratory analysis, the
FDA discovers that a product does not conform to the law, the
Agency requests the U.S. Department of Justice to file a “libel”
with the proper federal court.
Acting on a warrant issued by the court a U.S. marshal (usually
accompanied by an FDA official) then seizes the articles. The
owner is notified, and given an opportunity to appear in court to
contest the government's charges if he/she believes them to be in
error.
Sometimes the FDA publishes a press release about a specific
seizure (32).
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Consent Decree
According to the FDA/ORA’s Regulatory Procedure Manual (17)
an injunction is a civil process to stop or prevent violation of a law,
and to correct the conditions that caused the violation to occur. In
serious violations companies may decide to consent to a decree of
preliminary or permanent injunction before the issue goes to trial.
Typically a consent decree is a long-term process where at the
end the company under consent decree voluntarily enters into the
agreement. Frequently, the consent decree is the last step before
criminal prosecution and usually there are multiple 483
inspectional observations, EIR’s, warning letters and other
documented communications between the FDA and senior
management. At the end the company agrees to pay a one-time
charge and to initiate corrective action plans, frequently with the
help of outside consultants.
Probably most well-known are the consent decrees with Abbott
and Schering Plough. Abbott’s consent decree resulted in a onetime charge of $168 million in 1999. This was not the only financial
loss. The decree included:

After January 10th, Abbott removed 80 diagnostic kits from the
market.
 180 kits were deemed to be medically necessary so they could
still be sold. Abbott had one year to bring their manufacturing
systems into compliance. If the FDA did not certify
manufacturing for compliance, Abbott was required to pay the
U.S. Treasury 16% of the gross revenue generated by these
products.
 Abbott was required to submit a compliance master plan and a
validation plan with a time frame on how to fix the problem. If
the deadlines could not be met, Abbott had to pay $15,000 per
business day per process.
Schering Plough was charged $500 million in 2002, which was the
highest charge at that time (19, 20). Figure 5 shows excerpts of a
press release. Typically lost sales revenues and costs for
upgrading systems are higher than the charges.
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Figure 5. Example of Consequence of Non-Compliance
Import Alerts and Denials
With the exception of most meat and poultry, all food, drugs,
biologics, cosmetics, medical devices, and electronic products that
emit radiation, as defined in the FD&C and related Acts, are
subject to examination by the FDA when they are being imported
or offered for import into the United States. Most meat and poultry
products are regulated by the U.S. Department of Agriculture.
All imported products are required to meet the same standards as
domestic goods. Imported foods must be pure, wholesome, safe to
eat and produced under sanitary conditions; drugs and devices
must be safe and effective; cosmetics must be safe and made
from approved ingredients; radiation-emitting devices must meet
established standards; and all products must contain informative
and truthful labeling in English.
Import Alerts were developed to communicate guidance to FDA
Field Offices. The purpose of an Import Alert is to identify and
disseminate import information (problems, violated trends, etc.) to
the FDA personnel thus providing for more uniform and effective
import coverage. Import Alerts identify problem commodities
and/or shippers and provide guidance for import coverage.
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If serious manufacturing problems exist at a specific site the FDA
can recommend withholding approval of any new product
application or companies are not allowed to import products into
the United States when the product was manufactured at that
particular site. Products can be finished drug products, Active
Pharmaceutical Ingredients (API) or bulk material. It is not unusual
that losses resulting from an Import Alert are as high as $100
k/day.
An example of a warning letter with an announcement for Import
Alert until successful re-inspection is available from Reference 36:
Until FDA has re-inspected this facility and confirms compliance
with CGMPS and correction of these deficiencies, this office will
recommend withholding approval of any new drug applications
listing this facility as the manufacturer of active pharmaceutical
ingredients (APIs). Failure to promptly correct these deficiencies
will result in the refusal to permit entry of these products into the
United States (www.fdawarningletter.com W-097)
Debarment
In 1992 the Generic Drug Enforcement Act became effective. The
act enables the FDA to debar companies and individual employees
from providing services or participating in drug applications.
Individuals are not allowed to work for companies producing drug
products. Individuals can be fined up to $250,000, companies up
to $1 million. Debarment can be temporary or permanent. The
names of individuals and companies who have been debarred are
posted on the FDA website (35).
It is interesting to note that while in the past the list was populated
mostly by companies, more recently it only includes names of
individuals.
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5. Studying FDA Inspection Reports
FDA regulations are usually valid for a long time period but they
are not specific. They still leave a lot of room for interpretation and
inspection practices can also depend on the expertise and opinion
of individual inspectors. That’s why the FDA has developed
guidance documents for the industry to document FDA’s
interpretations on critical topics and for inspectors to ensure
harmonization across all FDA inspections. Unfortunately guidance
documents are still not specific enough to educate the industry on
all details and many times they include very general statements
such as “enforcement depends on the risk on product quality” or
“the extent of validation depends on the system complexity”. This
leaves a lot of room for interpretation by inspectors and
interpretations may also change over time. The real current
thinking of the FDA and their inspectors can be judged from 483
inspectional observations and warning letters. 483’s are written
during or right after inspections by inspection teams or individual
inspectors and give the inspector’s point of view. Warning letters
are more representative because they have to be approved at a
higher level. To some extent they can be seen as the FDA’s most
current and most specific thinking on how to interpret regulations.
This is the reason why one chapter of this primer is dedicated to
warning letters and 483’s. The chapter includes two parts. Part
one lists most frequently cited deviations while part two cites
specific warning letters. We also include examples of 483
observations in situations, which in our opinion are generic enough
not only to show the viewpoint of an individual inspector.
The citations are categorized into various topics and with correct
understanding can be viewed as recommendations on how such
citations can be avoided. For each citation we also give
references as to where the full text of the FDA document can be
downloaded. This is important as a lot of the time excerpts of
warning letters only make sense in the context of the full text that
typically also describes the application.
Most Frequent Citations
In this section we list most frequent citations. They are not sorted
in any specific order. They are all important and therefore it is not
necessary to put them in ranking order.
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No or inadequate procedures
Procedures not followed.
No management review of procedures.
The responsibility of quality control unit not defined or the
quality control unit did not follow the procedures.
No internal audits.
No or inadequate employee training.
Manufacturing process not validated.
Inadequate laboratory controls.
No or inadequate equipment maintenance and cleaning.
Inadequate environmental monitoring.
Inadequate validation of analytical methods.
No or inadequate stability testing.
Incomplete validation of computer systems.
Raw data not maintained.
No or inadequate security procedures.
No procedures for handling Out-Of-Specification situations or
procedures not followed.
No procedures for corrective and preventive actions to avoid
occurrence of similar problems.
Examples of Citations
In this section we give some citation examples. They are
considered to be representative within their categories. Originals
with complete text are available from Reference 21. W-xxx
references in the text below correspond to the numbers in
Reference 21.
Procedures
 Written standard operating procedures covering .... were
inaccurate, incomplete, and contained no documentation of
origin, review or approval (W-051).
 Failure to follow written production and process control
procedures as required by 21CFR 211.100 (W-051).
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There are no cGMP training SOPs in place and at least one
employee denied knowledge of cGMP regulations (W-051).
Failure to establish and to follow written control procedures
designed to assure batch uniformity and the integrity of drug
products
(W-066).
Failure to follow the Standard Operating Procedure (W-053).
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Written procedures are not followed for the maintenance of
equipment used in manufacture, processing, packing or
holding (W-217)
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Failure to establish and maintain procedures to control the
design of the device in order to ensure specified design
requirements are met (W-218)
Management Controls/Reviews
 Appropriate management representatives do not review audit
reports (W-038).
 Failure to establish management review procedures and failure
to document the dates and results of these management
reviews (W-048).
 Failure to conduct management reviews as required by 21
CFR 820, 2O(c) and as called for in your procedure QOO1
“Quality System”, to assure that your firm is in compliance with
the regulations (W-050).
 Failure to appoint and document such an appointment of a
member of management who irrespective of other
responsibilities shall have established authority over and
responsibility for ensuring that quality system requirements are
effectively maintained and to report on the performance of the
quality system to management with executive responsibility
(W-092).
 Management has not ensured that quality system requirements
have been effectively established and maintained (W-134)
 Failure of management with executive responsibility to ensure
that the established quality policy is understood, implemented,
and maintained at all levels of the organization (W-195)
 Failure of the management with executive responsibility to
ensure that an adequate and effective quality system has been
fully implemented and maintained at all levels of the
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organization, as required by 21 C.F.R. § 820.20. For example,
your firm's management has not effectively implemented
adequate and global corrective actions in a timely manner to
correct quality issues across your analyzer product lines (W196)
Failure to have management with executive responsibility to
ensure the quality policy has been fully implemented and
maintained [21 CFR 820.20(a)]. Admittedly, you lack a Quality
Plan and a management representative and have continued to
operate since 2004 (W-205)
Quality Control Unit/Quality Assurance Programs
 Failure to have a document, which delineates the
responsibilities and procedures applicable to the quality control
unit (W-044).
 Failure to establish and operate an effective quality control unit
in conformity with requirements of 21 CFR 211.22 (W-051).
 There are no written procedures concerning individual
responsibility for quality control operations (W-051).
 Your firm does not have a quality assurance program in place
to: a) qualify analytical equipment prior to their use, and b)
calibrate and maintain analytical equipment according to
manufacturers’ specifications (W-058).
 There is no documentation of the Batch Production Records
being reviewed and approved by the quality control unit since
January 1, 2001 (W-054).
 Failure to have an adequate quality control unit to perform its
functions and responsibilities. Failure to have an adequate
quality control unit is demonstrated by the number and types of
inspectional observations made during this inspection (W-065).
 Failure to have an adequate quality control unit to perform its
functions and responsibilities, as required by 21 CFR 211.22.
Failure to have an adequate quality control unit is
demonstrated by the number and types of inspectional
observations made during this inspection (W-066).
 Failure to maintain written procedures that describe the
responsibilities and procedures applicable to the quality control
unit (W-173)
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Document Control/ Documentation
 Failure to promptly remove obsolete documents from all points
of use (W-173)
 Your firm failed to establish and maintain adequate
procedures to control documents and ensure all obsolete
documents are promptly removed from use or otherwise
prevented from unintended use (W-212)
 The response states that retrospective validation studies have
been completed for all APIs and that protocols and final
validation reports are attached. Only the Chinese versions
were attached. We are unable to evaluate these studies at this
time (W-090).
 During the inspection, our investigator requested to see
investigations of process deviations and Out-Of-Specification
laboratory results. She was informed that these investigations
are conducted but not documented (W-102).
(Internal) Quality Audits
 Failure to document the dates and results of quality audits (W048).
 Failure to conduct quality audits required by 21 CFR 820.22,
and in your procedure QO02, “Audits” to assure your firm is
operating in compliance with the regulations (W-050).
 Quality audits are inadequate to assure that the quality system
is in compliance with the established quality system
requirements and to determine the effectiveness of the quality
system (W-064).
 We are requesting that you submit to this office on the
schedule below, certification by an outside expert consultant
that he/she has conducted an audit of your establishment’s
manufacturing and quality assurance systems (W-074).
Personnel
 There are no cGMP training SOPs in place and at least one
employee denied knowledge of cGMP regulations (W-051).
 Failure to ensure that each person engaged in such activities
has the education, training and experience, or any combination
thereof, to enable them to perform their assigned functions, as
required by 21 CFR 211.25. Your failure to have staff adequate
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to perform their assigned functions is the number and type of
inspectional during this inspection (W-065).
Your formalized training program is inadequate in that it does
not address current Good Manufacturing Practices (W-091).
Your firm fails to have sufficient personnel with the necessary
training to assure that all activities required by ... are correctly
performed (W-100).
Employee training on the use of the new [redacted] computer
system, which is used in donor screening and product
processing, was not complete (W-103).
The center director had not received any training on this
computer system even though he retains a high security level
for data entered on this computer system (W-103).
There are no records to document that the Information
Technology (IT) service provider staff personnel have received
training that include current Good Manufacturing Practice
regulations and written procedures referred by the regulations
(W-101).
No one on the organizational chart, including supervisors in QA
and QC, are identified as having academic or other suitable
training in chemistry or microbiology (W-135)
A supervisor and QC manager could not explain how the
calculation was done for the xxx assay determination (W-135)
Individuals responsible for supervising the manufacture,
processing, packing, holding of a drug product lack the
education, training, experience to perform their assigned
functions (W-219)
Our review of your firm's training program disclosed that there
was no requirement for on-going CGMP training of employees.
The firm only had an initial CGMP training and did not provide
regular CGMP training to all employees involved in the
manufacture of drug products. There is no reference to CGMP
training of supervisors or directors. (W-219)
Specifically employees who manage, perform, and assess
work affecting quality have not been adequately trained as
members of your firm’s quality unit. Quality Assurance
employees have not performed effectively in conducting
complaint investigations, corrective/preventive action activities,
design activities, internal audits, risk analysis and/or document
reviews (W-211)
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Building and Facilities / Environmental Conditions
 Failure to maintain adequate control over air handling and
exhaust systems (W-065).
 Failure to have adequate building design and construction
used in manufacture, processing, packing, or holding of drug
products to facilitate cleaning, maintenance, and proper
operations (W-181)
 Failure to establish and maintain adequate procedures to
control environmental conditions (W-200)
Complaint Procedures
 There was no documentation describing any evaluations of the
returned goods or their quality problems as they were related
to your customer complaints (W-062).
 Complaints are not handled in a uniform and timely manner as
specified by your procedures. Specifically, there are instances
where the assignee of a complaint did not notify the complaint
coordinator and indicated an expected date of investigation
completion after the 60 day due date which is specified by the
complaint handling procedures (W-212)
Material / Supplies
 The reliability of the supplier's certificate of analysis (COA) was
not established in that a complete analysis was not performed
with the COA at the appropriate intervals. (W-149)
 Procedures for solvent recovery have not been established to
ensure that solvents are controlled and monitored (W-149)
 Incoming labels received from the vendor are not proofed
against the master label (W-149)
 Failure to establish and maintain purchasing control
procedures (W-205)
 There are no data to support extension of expiration for xxx
Reference Standard (W-217)
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Your firm has not established procedures for purchasing
controls which include the evaluation and selection of raw
material suppliers and the establishment of specified
purchasing data requirements for purchased or otherwise
received product (W-218)
Failure to establish and maintain procedures for acceptance
activities including inspections, tests, or other verification
activities. (W-218).
Manufacturing Process
 Products were manufactured and shipped in interstate
commerce before process validation was successfully
completed (W-063).
 Revalidation protocols do not cover the largest batch size or
the most complex manufacturing process (W-085).
 There is no manufacturing process validation in place for drug
products (W-099).
 No change control SOP for documentation and manufacturing
processes (W-094).
 Failure to validate a process whose results cannot be fully
verified by subsequent inspection and test (W-200)
Cleaning Validation
 Failure to clean and maintain equipment … at appropriate
intervals (W-086).
 Cleaning procedures for non-dedicated reaction vessels,
holding vessels, re-crystallizers, centrifuges, and dryers used
to produce APIs and intermediates have not been validated
(W-096).
 The cleaning validation documents did not include a sampling,
test method for analyzing samples, and specification limits.(W124)
Vendor/Supplier/Service Provider Qualification
 Failure to establish and maintain the requirements, including
quality requirements that must be met by suppliers. For
example, your firm has not specified quality requirements for
suppliers, maintained lists of approved suppliers and
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developed written procedures describing how suppliers are
evaluated for quality acceptance requirements (W-048).
The firm has no SOP for the qualification of vendors and
contract laboratories, nor has such documented qualification
been conducted (W-094).
The firm has been using the service of .... for the testing of
Purified Water, however there has been no audit conducted at
this contract laboratory (W-094).
Subcontractors / Contract Laboratories
 Failure to conduct audits of contract laboratories that perform
testing-of-incoming API. Your SOPs indicate that these audits
are to be conducted every two years (W-173)
 The firm does not receive and review all raw data from contract
testing laboratories (W-187)
 Your firm did not qualify the contract laboratories used for the
testing (W-219).
 It is FDA's expectation that your firm have a quality agreement
with the contract laboratories in place. We recommend that this
agreement be signed by all parties involved and that it include,
as a minimum, specific details delineating the roles and
responsibilities of each party. A description of the materials,
services, communication, and all testing expected to be
performed by each party should also be included. Your firm
should ensure that the contract laboratory facility is compelled
to produce accurate analytical results for the tested material,
conduct adequate laboratory investigations of out-ofspecification results, and report to the client such investigations
or any changes (219).
Equipment
 Failure to adequately clean, maintain, and sanitize equipment
and utensils at appropriate intervals to prevent malfunctions or
contamination that would alter the safety, identity, strength,
quality or purity of the drug product and failure to follow written
procedures for cleaning and maintenance of equipment,
including utensils, used in the manufacture, processing,
packing, or holding of a drug product as required by 21 CFR
211.67(a) & (b). (W-214)
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Written procedures are not followed for the maintenance of
equipment used in manufacture, processing, packing or
holding (W-218)
You indicated that the Installation Qualification and Operation
Qualification have been completed and that the Performance
Qualification of your ... system is expected to be completed by
the end of 2009. You stated that a preliminary study and
periodic monitoring of the system has to be done. However, no
details of protocol, short term or long term action plan with
supportive documentation were included in your response - In
addition, there is no assurance that the ... used in the
preparation of your ... meets the USP requirements for ...
because your facility has not completed the requalification of
the ... system (W-219).
Computer/Software
 Failure to have an adequate validation procedure for
computerized spreadsheets used for in-process and finished
product analytical calculations. SOP 644.00, QA/QC
Spreadsheet Validation, is deficient in that only a small range
of values are being used to challenge computerized
spreadsheet mathematical calculations. (W-063)
 Validation of the system did not include critical system tests
such as volume, stress, performance, boundary and
compatibility (W-067).
 Failure to validate computer software used as part of the
quality system for its intended use according to an established
protocol as required by 21 CFR 820.70(i). For example:
Software such as Excel, Access, and Word used to create and
maintain databases (rejects, complaints, and concessions) and
electronic documents, is not validated (W-073).
 Firm lacks to validate computer data integrity acquisition for
the use of the xxx. Also stress of the computer has not been
tested proven that the system can run in parallel at the same
time. (W-132)
 The validation and installation records for the [redacted]
computer system were incomplete (W-103).
 Complete software structural design descriptions have not
been maintained or updated from original design specifications
(W-101).
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Complete diagrams and text descriptions identifying all other
network program interfaces with XXX, and which specify the
data being exchanged between the XXX and other programs
have not been maintained or updated from original design
specifications (W-101).
Wide Area Network diagrams (WAN) with appropriate
definition documentation identifying corporate sites on the
network that use XXX have not been included in any XXX
validation documents (W-101).
No procedures are established to validate for its intended
purpose the Microsoft Word or Microsoft Excel software used
in creating and maintaining nonconformance records, product
return records, internal audit corrective records, or corrective
action records (W-189)
During the inspection, I asked if the computer software has
been validation to assure that it performs for it's intended use. I
was told that the software was validated by the manufacturer.
The managing director provided me a copy of the letter the
received from (the vendor). The letter indicated that the
software was validated. She also the gave me a copy of
validation information that was obtained from (the vendor)
during the inspection. - I told the managing director I still need
to see what they have done to validate the system since the
computer was making a decision to accept or reject potential
donors (W-191)
There was inadequate software version control (W-099).
Software used as part of the production quality system was not
validated for its intended use according to an established
protocol [21 C.F.R. 820.70(i)]. Specifically, (a) Spreadsheets
intended to check for outliers and calculate mean, SC, % CV,
value assignments for finished devices.(b) Complaint handling
software (c) Quantrol database program (W-201)
Computer Numerical Control (CNC) Machine #C-4 had out of
specification results during operational qualification conducted
during validation. These out of specification results were not
investigated or addressed in the validation report (W-207)
Laboratory Controls
 Your firm has no system for the receipt and storage of
standards and analytical chemicals (W-058).
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Expired standards were used in the calibration of equipment.
Working solutions were not properly labeled or documented in
laboratory notebooks or other records in that the data did not
bear complete information, including the analyst or preparer’s
identity, solution designation, strength and expiry dates (W058).
Failure to perform laboratory testing on each batch of drug
product prior to release, to determine satisfactory conformance
to final specifications for the drug product, including the identity
and strength of each active ingredient (W-086).
Extraneous HPLC peaks continuously explained to be auto
injector contamination, no further investigation (W-014).
The firm needed to upgrade several pieces of their equipment.
Principally, the old HPLC being used still was using the
equivalent of a strip chart recorder. (W-133)
Failure to establish and maintain procedures to ensure that
sampling methods are adequate for their intended use, to
ensure, that when changes occur the sampling plans are
reviewed, and that sampling plans are written based on a valid
statistical rationale (W-206)
Failure to establish and implement sampling plans based on a
valid statistical rationale. You did not have a rationale for the
number of packages which are visually inspected every
[redacted] hours on the [redacted] packaging machines (W211)
Laboratory Equipment Qualification
 The calibration procedure for HPLC systems is inadequate in
that it did not include integrator and detector’s linearity,
injector’s reproducibility, and accuracy of temperature settings
for column heater and detector (W-097).
 Calibration records show many instances where examination of
the pipettes found them Out-Of-Specification. There is no way
to determine when the (pipettes) units in question have been in
use for analytical purposes while Out-Of-Specification (W-089).
 Failure to ensure that all inspection, measuring and test
equipment is suitable for its intended purposes and is capable
of producing valid results (W-092).
 Analytical balances are used outside specified range (W-089).
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You continued to utilize this revised QC Lab data acquisition
system without ensuring that the system would perform as
intended (W-130).
The balance used to weigh more than 20 mg did not comply
with the USP 0.1% requirement for balance measurement
uncertainty (W-161)
The firm does not have a written procedure that includes
requirements for the performance verification of HPLC and GC
systems. They do not have specific directions (W-161)
During the inspection, the firm did not provide an SOP for the
performance verification of the HPLC and GC systems.
Actually, they are contracting services for the verification of
those systems, and then they are adopting contractor's SOP.
Each of them has different SOPs, which includes different
types of tests that does not compare. The firm should establish
a procedure to assure uniformity providing specific directions
and requirements for all GC Systems. Also, it will apply to
HPLC systems. (W-161)
Methods
 Linearity and limits of detection were determined above the
limit of the test (W-017).
 Laboratory tests for assay, impurities and … were not
performed according to established procedures described in
the individual Drug Master Files (DMF) that specify the USP
methods (W-090).
 Laboratory controls have not established that the test method
for assay of xxxx content of xxxx “is scientifically sound to
assure that this product conforms to specifications of strength,
quality and purity” (examples: insufficient separation, no
verification of method suitability under actual conditions
etc) (W-024).
 Your firm uses USP methods to analyze your products, but
changes have been made to the USP methods and no
validation has been performed. For example, for Migrazone
Capsules, the USP uses three different wavelengths to analyze
the three active ingredients. Your firm changed the method to
use [redacted] of or all three actives and no validation of the
new procedure was performed (W-182)
 Failure to establish and document the accuracy, sensitivity and
reproducibility of test methods employed. for example,
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methods that were validated at one facility and transferred to
xxx site are being used without method transfer or revalidation
protocol (W-184)
The test methods performed for heparin sodium USP have not
been verified to ensure suitability under actual conditions of
use. Specifically, you have failed to conduct adequate
verification of USP compendial test methods as applied to the
production of your firm's API. You assert that USP <1226>,
Verification of Compendia1 Procedures, states that verification
is not required for basic compendial test procedures that are
routinely performed unless there is an indication that the
compendial procedure is not appropriate for the article under
test. We disagree with your assertions that verification is not
required for those USP test methods used by your firm (W213)
Microbial / Microbiological Testing
 No microbial limits testing (W-016).
 No written procedures for any microbiological tests performed
(W-016).
 A total of ...microbial tests were conducted for this product, yet
there was no documented investigation into these
discrepancies nor was there any conclusion or follow-up (W098).
 The microbiological laboratory fails to document the lot number
and expiry date of xx (W-149)
 Your firm has not established appropriate written procedures
designed to prevent microbiological contamination of drug
products purporting to be sterile, including procedures for
validation of any sterilization process (W-219).
Active Pharmaceutical Ingredients (API)
 There were inadequate laboratory procedures and records to
assure that APIs have the appropriate quality and purity. The
inspection reported deficiencies regarding the following
laboratory procedures and records: Analytical methods
validation, systems suitability testing, incomplete laboratory
records, inaccurate laboratory calculations and inadequate
calibration of laboratory equipment (W-042).
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This letter concerns FDA inspections of your active
pharmaceutical ingredient manufacturing facilities located in ....
During both inspections, our investigators documented
significant deviations from current Good Manufacturing
Practices (cGMPs) in the manufacture of active pharmaceutical
ingredients (API’s) (W-096).
Failure to test each batch of API to determine conformance to
specifications (W-164)
The laboratory did not have an adequate impurity profile that
identifies organic, inorganic and solvent impurities to monitor
unidentified and apparent impurities in the API (W-149)
Aseptic Processes
 The aseptic powder fill process simulation (media fills) did not
adequately address several critical issues such as the lengths
of campaign and the length of time critical equipment is issued
without re-sterilization (W-095).
 Qualification of procedures for sanitizing equipment surfaces
not adequate to ensure an aseptic processing environment (W095).
Stability Testing
 Failure to implement a written testing program designed to
assess the stability characteristics of drug products, using
reliable meaningful and specific test methods (W-086).
 One internal standard was four months old with no data on its
stability over that period, in-process testing inadequately
performed (W-090).
 Failure to follow your firm's written stability testing program as
required by 21 CFR 211.166(a) in that your firm has no
validation data to demonstrate that the method used to analyze
products for stability is capable of detecting degradation of the
products (W-182)
 Failure to establish a stability testing program which includes
reliable, meaningful, and specific test methods' (W-203)
Out-Of-Specification / Out of-Trend / Failure Investigation
 Laboratory controls are deficient in that the firm established a
written procedure, which allowed for the averaging of Out-Of-
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Specification and within-specification analytical test data results
(W-056).
There are no documented investigations of process deviations
or Out-Of-Specification (OOS) laboratory results (W-102).
The chromatographic test data reflecting the out-ofspecification test results were not recorded in laboratory
notebooks. Instead, a new sample preparation was injected
within the same chromatographic run without supervisory
approval, as required by your firm's SOP (W-180)
Any OOS result obtained should be investigated and
documented according to a procedure. This procedure should
include analysis of the data, assessment of the extent and
cause of the problem, allocation of the tasks for corrective
actions, and conclusions. (W-209)
Any re-sampling or retesting after OOS results should be
performed according to a documented procedure. (W-209)
- Written procedures should be established and followed for
investigating deviations or the failure of a batch of intermediate
or API to meet specifications. The investigation should extend
to other batches that may have been associated with the
specific failure or deviation. (W-209)
Although results above your alert limits may be an indication
of an ongoing uncorrected problem, no investigation was
conducted to identify a potential root cause of the problem (W219)
Comment by Labcompliance: this is an example for OOT (outof-Trend) deviation
Your firm invalidated failing microbial test results of ... obtained
from your contract testing laboratory and retested four of the
five samples without conducting an investigation or providing
scientific justification. Your firm's retests were used to
inappropriately replace four of five failing samples with the
following result (W-219)
Corrective and Preventive Actions (CAPA)
 Failure to verify or validate corrective and preventive action to
ensure that such action is effective and does not adversely
affect the finished device (W-071).
 Failure to maintain adequate procedures for implementing
Corrective and Preventive Actions (CAPA) such as analyzing
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data to identify existing and potential causes of non-conforming
product or other quality problems (W-084).
The response does not document that all other laboratory
procedures have been reviewed for similar deficiencies (W090).
Failure to establish procedures for implementing corrective and
preventive action addressing the analysis of sources of quality
data to identify existing and potential causes of non-conforming
product or other quality problems (W-092).
Your firm failed to analyze, identify and document existing and
potential causes of non-conforming product and other quality
problems (W-100).
Your firm failed to establish and maintain adequate procedures
for implementing corrective and preventive action (CAPA) to
ensure the analyzing of sources of quality data to identify
existing and potential causes of nonconforming product, or
other quality problems and employ appropriate statistical
methodology, where necessary, to detect recurring quality
problems (W-212)
Trend Analysis
 Your firm also lacked a trend analysis of your ... sample results
and failed to monitor the ... level prior to or after the .... (W219).
Raw Data
 Laboratory records do not always include raw data for all the
laboratory testing performed (W-085).
 Laboratory procedures are inadequate in that raw data was not
always recorded (W-090).
 During the inspection of your facility, you were unable to
present records of raw data pertaining to the subject stability
batches submitted (W-097).
 Operating parameters were maintained with the relevant xxx.
However, electronic raw data was not saved (W-176)
 The firm routinely assigned method validation chemists, lead
chemist, and laboratory supervisors system administrator
status with the ability to modify and delete raw data files in the
HPLC data acquisition system (W-187)
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During discussions and lab demonstrations, it was determined
that neither system prevents analysts from overwriting original
raw data. A review of the software validation showed initial
failures for modules demonstrating the ability to delete or
overwrite data. Documentation in the validation report stated
that this capability could not be changed. During the laboratory
demonstration, I observed the statement, "Data will be
overwritten" with the option to ignore this.(W-192)
Records
 Failure to retain all production, control, or laboratory records to
assure that drug products adhere to established specifications
(W-018).
 Failure to maintain records of changes to documents (W-071).
 Failure to include in laboratory records complete records of the
periodic calibration of laboratory instruments and there are no
calibration records available for the FTIR Spectroscope and the
HPLC laboratory instruments (W-086).
 Failure to maintain records of calibration checks and
inspections of automatic, mechanical, or electronic equipment
(W-098).
Electronic Records
 In addition to the above listed violations, our investigator noted
that the laboratory is using an electronic record system for
processing and storage of data from the atomic absorption and
HPLC instruments that is not set up to control the security and
data integrity in that the system is not password controlled,
there is no systematic back-up provision, and there is no audit
trail of the system capabilities. The system does not appear to
be designed and controlled in compliance with the
requirements of 21 CFR Part 11, Electronic Records (W-081).
 Data files are automatically deleted after a hard copy is
generated (W-087).
 Review of your electronic complaint files reveals they have not
been properly validated, there is no ability to generate accurate
and complete copies of records in human readable and
electronic form, there is no protection of records to enable their
accurate and ready retrieval, access to your system has not
been limited, as well as other significant deficiencies. (W-068)
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We strongly encourage you to perform a thorough and
complete evaluation of all your electronic records in
accordance with 21 CFR Part 11 as well as any guidance
generated by FDA to assure conformance to our
requirements.(W-068)
You failed to encrypt and/ or physically secure your data backup system to comply with the requirements to prevent
deterioration or deletion of the analyzer data (W-185)
The audit trail generated within xxx does not truly reflect the
identity of the responsible individuals. Individuals have been
able to log on to the system under an other individuals account
and make changes which then show up on the audit trail to the
first individual (W-187)
The firm's review of laboratory data does not include the audit
trail/revision history to determine if unapproved changes have
been made. (W-187)
Electronic records generated during manufacture of APIs were
not reviewed prior to release of validation lots or for any lots
manufactured thereafter to include the most recently released
API lot (W-190)
Furthermore, your system does not have an audit trail to
document changes (W-203)
Failure to establish adequate controls and procedures to
assure the authenticity, integrity, and security of all electronic
records including data generated in the laboratory (W-203)
System administrator privileges were to be assigned to
validation chemists, lead chemists, and laboratory supervisors
only. These privileges include the ability to modify and delete
raw data files and to lock/unlock projects for reprocessing in
the chromatographic data acquisitions system which is used in
the laboratory for finished product release testing, stability
testing, and method validation studies (W-203)
Our investigators documented many instances with extensive
manipulation of data with no explanation regarding why the
manipulation was conducted. This manipulation would include
changing integration parameters or re-labeling peaks such that
previously resolved peaks would not be integrated and
included in the calculation for impurities (W-203)
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System Security
 Password protection can be bypassed in the system (W-087).
 Failure to establish and implement adequate computer security
and data integrity in that during this inspection it was observed
that an employee was found to have utilized another person's
computer access into the..... computerized record system (W040).
 Insufficient security controls to prevent analysts from
submitting modified data (W-029).
 The xxx system computers in the lab do not time-out. If an
employee fails to log off a computer and walks away other
individuals can easily access the computer under the first
employees account. (W-187)
 Validation of the (brand name) laboratory software used to
control instruments, generate data, perform calculations, and
store data from raw material and finished product testing failed
to demonstrate adequate security. Analysts have the ability to
overwrite original data, and are not required to utilize the
protection of individual passwords (W-192)
Good Laboratory Practice Regulation
 You failed to maintain a copy of a master schedule of all nonclinical
laboratory studies (W-088).
 You failed to assure QAU oversight during the preparation of
histology slides for all GLP studies (W-088).
 You failed to assure that protocol deviations and QAU
inspection reports for study #323 were evaluated by a
replacement study director (W-083).
 Failure of the study director to assure that all experimental data
were accurately recorded and verified and document the
reason for any change in the entries (W-194)
 For study xxx your study director failed to assure that dosing
were accurately recorded to confirm that study animals
received protocol-specified doses of the vehicle. (W-194)
 Failure of QAU to assure that reported results in the final study
report accurately reflected the raw data (W-194)
 Failure of QAU to maintain written and properly signed records
of each periodic inspection (W-194)
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Failure to identify the test and control articles with appropriate
characteristics in the final report (W-194)
Clinical Investigations / Trials
 Failure to ensure adequate monitoring of the investigation (W183)
 Data were missing and inaccurate data was corrected for
Subject [redacted] (W-183)
 Failure to secure the investigator's compliance with the signed
investigator agreement, the investigational plan, applicable
FDA regulations, and any other conditions of approval imposed
by the reviewing IRB or FDA (W-183)
 There are repeated deviations from the investigational plan,
spanning several years, with no apparent steps taken to bring
the clinical investigators into compliance, which indicates
failure to ensure investigator compliance (W-183)
 Review of the inspection report indicates that the IRB failed to
follow written procedures for conducting initial and continuing
review of research (W-184)
 The IRB's written procedures state that "the IRB shall consist
of thirteen (13) members." Since October 12, 2005, the IRB
membership roster has listed only 12 members (W-184)
 The IRB's written procedures state that "meetings will be held
on an as-needed basis, but no less than quarterly." However,
the IRB records indicate that the IRB has met at intervals
greater than three months on four occasions since August
2004. (W-184)
 Failure to use expedited review procedures only for certain
kinds of research involving no more than minimal risk or for
minor changes in approved research [21 CFR 56.110] (W-184)
 Failure to ensure that the IRB reviewed proposed research at
convened meetings at which a majority of the members of the
(W-184).
FDA Notification
 Failed prompt reporting to … the FDA of any unanticipated
problems involving risks to human subjects or others, any
issues of serious or continuing non-compliance with these
regulations (W-093).
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Risk Analysis/Critical Steps
 Failure to conduct a thorough risk analysis to identify and
document any possible hazards associated with the design of
the devices in both normal and fault conditions (W-113)
 The protocol did not identify critical process steps, critical
process parameters, in-process tests or specifications (W102).
 Your firm failed to conduct and document adequate risk
analyses that discuss the safe use of your devices with/without
their accessories (W-202)
 Risk analysis is incomplete. The risk analysis for the hazard of
linking PET/CT scans to the incorrect patient was performed
after a June 2006 incident. The risk analysis has not been reassessed/updated for increased probability given the three
subsequent incidents. Your firm's Standard Operating
Procedure directs risk analysis be reviewed and updated upon
receipt of safety-related complaints. However, no risk analysis
was performed for complaints related to incorrect normalization
values in [redacted] PET/CT scanners ( W-212)
6. Efficient Quality Systems to Prevent
Non-compliance
In this chapter we will give recommendations on what companies
should do to be able to demonstrate that they are in compliance
with FDA regulations. Recommendations are based on FDA
regulations, FDA inspection and compliance policy guides, 483
inspection reports, EIR’s and warning letters, industry guidances
and ISO standards as well as the author’s personal experience
with inspections and audits.
Some good sources of information include the many FDA
publications related to risk-based inspection approaches for
medical devices and drug manufacturers. Another good source of
information is the FDA’s Compliance Policy Guide for Inspection of
Medical Device Manufacturers (22). This program provides
guidance to FDA field and center staff for the inspections and
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administrative/enforcement activities related to the Quality
Systems and Good Manufacturing Practices.
The Guide to Inspections of Quality Systems (23) was designed to
inspect quality systems of medical device manufacturers but the
concept of system-based inspections is very much in line with the
FDA’s 21st century GMP initiative and therefore also worthwhile
having a look at.
In September 2004 the FDA released an Industry Guidance
dealing with quality systems for drug cGMPs: Quality Systems
Approach to Pharmaceutical Current Good Manufacturing Practice
Regulations (28). This guidance describes a comprehensive
quality system (QS) model for manufacturing human and
veterinary drugs, including biological drug products. It is intended
to help implementing modern quality systems and risk
management approaches and at the same time to meet cGMP
requirements. It is positioned as part of FDA's pharmaceutical
CGMP initiative for the 21st century where the FDA explained the
agency's intent to integrate quality systems and risk management
approaches into existing programs with the goal of encouraging
the adoption of modern and innovative manufacturing
technologies.
Other documents include the Inspection Guide for Quality Control
Laboratories (7) and the Foreign Inspection Guide (8). Probably
the most useful document to find out what inspectors are advised
to look at for pharmaceutical drug manufacturers is the FDA’s
Compliance Program Manual for Drug Manufacturing Inspections
(9). The document provides a lot of details and most concepts of
this program are very much in line with the FDA’s new approach to
risk-based system inspections.
Besides FDA documents, reference books of private authors are
also very good resources for selected topics, for example
reference books on validation (25, 26).
This chapter has three basic recommendations as preventive
actions to avoid non-compliance findings:
1.
Look at and comply with high-level requirements that are
typically common to all regulations and quality systems.
2.
Correct deficiencies from previous inspections.
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3.
Look at specific detailed requirements of the target regulation.
As an example we recommend looking at the FDA’s
Compliance Program Manual as described in Reference 9.
Comply with Common Requirements for all Regulations
Despite the fact that different regulations have different
requirements there are a couple of things that are common to all
regulations. These are listed at the beginning of this section with a
strong recommendation to look at them first. Typically these are
also higher-level requirements and should be part of any quality
system. They are typical primary targets of FDA inspections as
deficiencies at higher levels also indicate non-compliance at
detailed levels.
Based on these requirements the recommendations to achieve
compliance are:

Develop a corporate compliance master plan or quality plan
that describes the companies policies and intent towards
quality and compliance

Develop an organizational structure as required by the
regulation.

Define and document roles and responsibilities of the
management, of the quality control and quality assurance unit
and of other functions that are important for compliance.

Develop corporate or global standard procedures that describe
general company processes and procedures to implement the
company policies.

Develop step by step standard operating or working
procedures (SOPs) to document routine tasks.

Develop and implement procedures to develop, review,
distribute, update and archive documentation.

Implement procedures for internal audits.

Implement procedures for people qualification. The program
should specify who needs to be trained on what and how
frequently refresher training will be required. Training should
include regulations, and training activities should be
documented.
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Implement procedures to assess and qualify suppliers, service
providers and subcontractors.

Implement procedures to validate processes, e.g.,
manufacturing processes and analytical processes.

Implement procedures to validate equipment. Development
and periodic review of an equipment Validation Master Plan
(VMP) is strongly recommended. This should include
information on which systems should be validated, how tests
are performed, how acceptance criteria are defined and how
deviations from acceptance criteria are handled. The VMP
should also include recommendations and criteria for
revalidation.

Implement procedures to validate computer systems.

Implement and periodically review procedures to ensure
system security and data integrity of electronic records.

Implement procedures to define, archive and retrieve electronic
records generated by computer systems. Archiving media and
the time frame for processing of records should be based on
documented risk assessment.

Develop and implement procedures on how to test and accept
incoming material, e.g., raw materials, active pharmaceutical
ingredients and reference standards. Test results should be
documented. If such tests are performed by an outside test
laboratory, the lab should be audited and qualified.

Develop procedures to document production records, test data
and raw material. Test data should include information on
equipment used, analytical procedures, environmental
conditions and personnel operating the equipment.

Implement procedures to investigate non-compliance and OutOf- Specification situations, for Corrective and Preventive
Actions (CAPA) to avoid occurrence of the same or similar
problems.

Implement procedures to assess the risk that a process,
equipment, or products can have on public health. Categorize
the systems and processes into high, medium or low risk
systems.

Implement formal change control procedures that should
assess the need for revalidation for process and equipment
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changes. Changes should be justified, approved and
documented.

Implement procedures for management reviews and on-going
improvements
All procedures should be documented, well communicated to
employees, understood by employees, and readily available at
workplaces and to inspectors. Internal audits should confirm that
procedures are followed.
Inspection Findings from Previous Inspections
The most important recommendation is to look at previous
inspection reports, if any exist. Look at each deviation and your
response. Check if all actions described in your response were
followed up in time and corrected. Also check if the root cause of
the problem was identified and if a program was initiated and
documented to prevent occurrence of similar problems in other
areas.
Look at Specific Details as Required by Individual
Regulations
Looking at all details of regulations is probably the most timeconsuming step and requires an in-depth knowledge of the
regulation and frequently a common sense interpretation and
science-based implementation.
A good tip is to look at interpretations and recommendations for
inspections made by the FDA. An excellent document to look at is
the FDA’s GMP Compliance Program as defined in Reference 9.
The program refers to system-based inspections and defines six
systems:
1. Quality Systems
2. Facilities and Equipment
3. Material Systems
4. Production Systems
5. Packaging and Labeling Systems
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6. Laboratory Control Systems
The program recommends always inspecting the quality system
and three of the other five systems for full inspections and one of
five for abbreviated inspections.
Quality Systems
It is expected that a company’s quality system is always the first
step evaluated during each inspection. The assumption is that
without a well functioning and well-documented quality system a
company cannot ensure GMP compliance at lower levels.
Therefore a well-documented quality system and procedure should
be in place.
The system should ensure overall compliance with cGMP and
internal procedures and specifications. The system includes the
quality control unit and all of its review and approval duties (e.g.,
change control, reprocessing, batch release, annual record review,
people qualification, validation protocols and reports). It also
includes all product defect evaluations and evaluation of returned
and salvaged drug products.
The system should also define roles and responsibilities of
management. Procedures should be in place to review all
processes as defined by the quality system.
According to Reference 9, procedures should be available for:

Product Reviews: at least annually; they should include
information from areas listed below as appropriate; batches
reviewed, for each product, are representative of all batches
manufactured; trends are identified.

Complaint Reviews (Quality and Medical): documented;
evaluated; investigated in a timely manner; includes corrective
action where appropriate.

Discrepancy and Failure Investigations Related to
Manufacturing and Testing: documented; evaluated;
investigated in a timely manner; includes corrective action
where appropriate.

Change Control: documented; evaluated; approved; need for
revalidation assessed.
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Product Improvement Projects: for marketed products.

Reprocess/Rework: evaluation, review and approval; impact on
validation and stability.

Returns/Salvages: assessment; investigation expanded where
warranted; disposition.

Rejects: investigation expanded where warranted; corrective
action where appropriate.

Stability Failures: investigation expanded where warranted;
need for field alerts evaluated; disposition.

Quarantine Products.

Validation: status of required validation/revalidation (e.g.,
computer, manufacturing process, laboratory methods).

Training/Qualification of employees in quality control unit
functions.
Facilities and Equipment
According to Reference 9, procedures should be available for:
Facilities

Cleaning and maintenance.

Facility layout and air handling systems for prevention of crosscontamination (e.g. penicillin, beta-lactams, steroids,
hormones, cytotoxics, etc.).

Specifically designed areas for the manufacturing operations
performed by the firm to prevent contamination or mix-ups.

General air handling systems.

Control system for implementing changes in the building.

Lighting, potable water, washing and toilet facilities, sewage
and refuse disposal.

Sanitation of the building, use of rodenticides, fungicides,
insecticides, cleaning and sanitizing agents.
Equipment

Adequacy of equipment design, size and location.
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
Equipment installation and operational qualification where
appropriate.

Equipment surfaces should not be reactive, additive or
absorptive.

Appropriate use of equipment operations
(lubricants,
coolants,
refrigerants,
etc.)
products/containers etc.

Cleaning procedures and cleaning validation.

Controls to prevent contamination, particularly with any
pesticides or any other toxic materials, or other drug or nondrug chemicals.


Qualification, calibration and maintenance of storage
equipment, such as refrigerators and freezers for ensuring that
standards, raw materials, reagents etc. are stored at correct
temperatures.
Equipment qualification, calibration and maintenance, including
computer qualification/validation and security.
Control system for implementing changes in the equipment.
Equipment identification practices (where appropriate).

Documented investigation into any unexpected discrepancy.


substances,
contacting
Materials Systems
According to Reference 9, procedures should be available for:

Training/qualification of personnel.

Identification of components, containers and closures.

Inventory of components, containers, closures and storage
conditions.

Storage under quarantine until tested or examined and
released.

Representative samples collected, tested or examined using
appropriate means.

At least one specific identity test is conducted on each lot of
each component.
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
A visual identification is conducted on each lot of containers
and closures.

Testing or validation of supplier's test results for components,
containers and closures.

Rejection of any component or container or closure not
meeting acceptance requirements. Investigate fully the firm's
procedures for verification of the source of components.

Appropriate retesting/reexamination of components, containers
and closures.

First in-First out use of components, containers and closures.

Quarantine of rejected materials.

Water and process gas supply, design, maintenance,
validation and operation.

Containers and closures should not be additive, reactive, or
absorptive to the drug product.

Control system for implementing changes in the materials
handling operations.

Qualification/validation and security of computerized or
automated data handling system.

Finished product distribution records by lot.

Documented investigation into any unexpected discrepancy.
Production Systems
According to Reference 9, procedures should be available for:

Training/qualification of personnel.

Control system for implementing changes in processes.

Adequate procedure and practice for charge-in of components.

Identification of equipment with contents, and where
appropriate phase of manufacturing and/or status.

Validation and verification of
cleaning/sterilization/depyrogenation of containers and
closures.
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
Calculation and documentation of actual yields and percentage
of theoretical yields.

Contemporaneous and complete batch production
documentation.

Established time limits for completion of phases of production.

Implementation and documentation of in-process controls,
tests, and examinations (e.g., pH, adequacy of mix, weight
variation and clarity).

Justification and consistency of in-process specifications and
drug product final specifications.

Prevention of objectionable microorganisms in non-sterile drug
products.

Adherence to preprocessing procedures (e.g., set-up and line
clearance etc.).

Equipment cleaning and use of logs.

Master production and control records.

Batch production and control records.

Process validation, including validation and security of
computerized or automated data handling system.

Change control; the need for revalidation evaluated.

Documented investigation into any unexpected discrepancy.
Packaging and Labeling Systems
According to Reference 9, procedures should be available for:

Training/qualification of personnel.

Acceptance operations for packaging and labeling materials.

Control system for implementing changes in packaging and
labeling operations.

Adequate storage for labels and labeling, both approved and
returned after issued.

Control of labels which are similar in size, shape and color for
different products.
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
Finished product cut labels for immediate containers which are
similar in appearance without some type of 100 percent
electronic or visual verification system or the use of dedicated
lines.

Gang printing of labels. This is not done unless differentiated
by size, shape or color.

Control of filled unlabeled containers that are later labeled
under multiple private labels.

Adequate packaging records that will include specimens of all
labels used.

Control of issuance of labeling, examination of issued labels
and reconciliation of used labels.

Examination of the labeled finished product.

Adequate inspection (proofing) of incoming labeling.

Use of lot numbers, destruction of excess labeling bearing
lot/control numbers.

Physical/spatial separation between different labeling and
packaging lines.

Monitoring of printing devices associated with manufacturing
lines.

Line clearance, inspection and documentation.

Adequate expiration dates on the label.

Conformance to Tamper-Evident Packaging (TEP)
requirements (see 21CFR 211.132 and Compliance Policy
Guide, 7132a.17).

Validation of packaging and labeling operations including
validation and security of computerized or automated data
handling system.

Documented investigation into any unexpected discrepancy.
Laboratory Control Systems
According to Reference 9, procedures should be available for:

Training/qualification of personnel.
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
Adequacy of staffing for laboratory operations.

Adequacy of equipment and facility for intended use.

Calibration and maintenance programs for analytical
instruments and equipment.

Validation and security of computerized or automated data
handling system.

Reference standards; source, purity and assay, and tests to
establish equivalency to current official reference standards as
appropriate.

System suitability checks on chromatographic systems (e.g.,
GC or HPLC).

Specifications, standards and representative sampling plans.

Adherence to the written methods of analysis.

Validation/verification of analytical methods.

Control system for implementing changes in laboratory
operations.

Required testing is performed on the correct samples.

Documented investigation into any unexpected discrepancy.

Complete analytical records from all tests and summaries of
results.

Quality and retention of raw data (e.g., chromatograms and
spectra).

Correlation of result summaries to raw data; presence of
unused data.

Adherence to an adequate Out-Of-Specification (OOS)
procedure which includes timely completion of the
investigation.

Adequate reserve samples; documentation of reserve sample
examination.

Stability testing program, including demonstration of stability
indicating capability of the test methods.
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7. Preparing for and Conducting FDA
Inspections
At this stage you have now done your very best to bring your
department, site or organization into compliance with FDA
regulations. But you can still make many mistakes prior to and
during the inspection and your excellent preparation can be a
waste of time if you are not careful. In this chapter we give advice
on how to prepare your organization and personnel for an FDA
inspection and how to make a good impression during the
inspection.
Preparing your Organization for FDA Inspections
FDA inspections are important for your department, your company
and your people. Failing an inspection can have tremendous
consequences and therefore your department should be well
prepared.
Recommended steps in preparation for an FDA inspection are:
1. Develop a Standard Operating Procedure for FDA inspections.
2. Develop checklist
3. Train management and staff
4. Conduct ‘FDA inspection’ like internal audits
5. Establish an FDA inspection response team.
6. Review previous inspections and corrective actions
7. Reserve and prepare meeting rooms.
Review Previous Inspections
If you have already experienced inspections the first step is to take
a close look at the inspection report (EIR) and deviations, if any.
There are two reasons for this:
1. This is how the inspectors will prepare themselves. They will
look at your company compliance history, at the latest
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inspection reports and deviations. They will follow-up on these
with questions to see if deviations have been taken care of and
corrective actions have been completed.
2. Failing the same deviations twice is very bad. This brings your
company into the FDA’s radar screen and you will have the
reputation that you are either not able or willing to bring your
system into compliance.
Don’t only look at inspections that took place at your department or
site, but also at your entire organization. Determine what
commitments your company has previously made and whether or
not these commitments were properly addressed and if everything
was documented. If previous commitments were not addressed,
identify why and find out if there is still a plan in place to address
them in the near future.
1. The (chief) auditor/inspector writes a report (the detailed report
should not contain any surprises that were not mentioned in
the summary under 1). The (chief) auditor/inspector sends the
report to the laboratory management. This also includes a time
frame as to when the response, e.g., 30 days, is needed.
2. The laboratory makes a plan to resolve the problem and writes
an official statement to the auditor.
3. If the statement is accepted by the audit team, the file is
closed.
Develop Standard Guide or SOP for FDA Inspections
FDA inspections are so important that there should be a standard
inspection guide or operating procedure. The procedure should
include information on:






Areas and documents that are subject to FDA inspections as
well as those that are not. Prepare a list with examples.
Responsibilities (by department and function) and internal
contacts for the audit.
Who should be informed and how when the inspection is
announced.
Who should be informed and how when the inspector arrives.
How inspections are prepared.
How inspections are to be conducted.
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





How inspectors are to be handled.
How to answer questions.
How to treat company confidential information.
How documentation is provided to inspectors.
How to follow-up on inspections.
How to distribute inspection reports.
Establish the Inspection Response Team
Prior to the inspection a response team should be established with
members from:

Quality assurance (owners, host)
 Quality control
 Regulatory affairs
 IT department
 Manufacturing/Laboratories
 Validation group
Members should be knowledgeable in particular business areas or
about particular projects. For each team member a back-up should
be identified mitigating the risk of unavailability of core members.
A list should be created and maintained with contact information of
core members and back-ups (Figure 6).
Team members should be asked to reserve time prior to, during
and after the inspection. They should form sub-teams to address
specific inspection issues, e.g., preparing appropriate
documentation. For example, if a new LIM System has been
implemented, the responsible “validation” contact forms a LIMS
sub-team to make sure all validation documents are available and
there are no open issues that have not been documented. If you
subcontract major work to a 3rd party organization, a
representative of that organization should also be on the list.
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Function
Name
Office
Phone
Cell
Phone
E-mail
Quality
Assurance
Back-up
Quality Control
Back-up
Regulatory
Affairs
Back-up
IT
Back-up
Manufacturing
Back-up
QC-Lab
Back-up
Figure 5: Members of the Audit Response Team
People Assignment
Prior to the inspection people should be assigned for:




The role of the host, who will be the company’s direct interface
with the inspector, prior to, during and after the inspection.
Keeping notes to document what happens during the audit, for
example which documents have been given to the inspector.
The role of the escort, who picks up the inspector at the front
desk, accompanies the inspector during the inspection and
makes sure that the inspector is never left alone.
Bringing/removing documents requested by the inspector.
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People Training
Employees should also be prepared for FDA inspections.
Obviously they will be nervous in answering questions asked by
the inspector, especially if it is the first FDA inspection. Internal
audits will help in the preparation but employees should also be
trained and receive information on:

Why the inspections are necessary.

Inspection items and also areas that are not subject to
inspections.

Content and meaning of the inspection SOP.

How to react to questions.

What to give the inspector to take back to the office, e.g., how
to deal with proprietary information or what to do if they ask to
take software for evaluation of specific data.

What are typical questions that go beyond the daily work, e.g.,
about the company’s quality policy.

Company policies for visitors, e.g., safety and whether visitors
are allowed to take photos or not. How to apply policies to FDA
inspectors, for example what to say if they try to get into areas
that can only be entered with specific qualification
requirements.

How to provide documents, electronic vs. paper.

How to report inspection findings to management to make sure
management is aware of any problems.
Inspection Announcement
Typically the FDA notifies companies on upcoming inspections
using a form 482. This form also describes the reason for the
inspection. When the FDA announces the inspection, company
management should be immediately informed. Ask the FDA about
the type of inspection, its scope, focus and anticipated length. Next
actions are:
 Agree on a date and exact location.

Arrange for meeting rooms for the inspector and for the
inspection response team.
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
Send out an e-mail to employees announcing the audit. Include
a list of most important things and most frequently asked
questions.

Pull documents from the archive or other locations and review
the documents for completeness.

Have a “dry run” with the inspection team, which can include a
review of documentation and a walk-through of the facility.
Reserving and Preparing Meeting Rooms
Meeting rooms should be reserved in time. It is a good practice to
prepare two rooms: one for meeting with the inspector (inspector’s
room) and one for the inspection and response team (preparation
room). Both rooms should be close to each other and equipped
with office supplies, phones, computers, printers and modem or
LAN connection. The preparation room should also be equipped
with a photocopier. Try to locate the meeting rooms away from
manufacturing and laboratories so that the daily operation is not
interrupted too much.
Internal Audits
Internal audits are a key element of any quality system. Their
objective is to evaluate activities and existing documentation to
check whether these meet predetermined internal regulations
andor customer requirements.
Internal audits are an ideal tool in preparing an organization for
external inspections.
Internal audits should be well-planned and follow a certain
structure. Needless to say not all systems can be audited for all
items in one go. A better recommendation is to set up a schedule
so that different systems are audited at different times and over a
certain period of time all items should have been checked in all
systems. Priorities of the audits should be based on risk
assessment and high-risk systems should be audited first.
Internal audits are divided in three phases:

Preparation
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
Conduct

Conclusion, Report and Follow-up
In the following lists recommendations for all steps of a laboratory
control system audit are summarized:
Preparation
1. Establish audit team and lead auditor.
2. Review results of previous audits, if any.
3. List areas to be evaluated.
4. Contact the department.
5. Prepare an agenda.
6. Review agenda with the department and get consensus.
Conduct
1. Review selected documents, e.g. procedures for handling OutOf- Specification situations and procedures for operator
training.
2. Interview management and ask for organizational structure
and responsibilities of management, QA/QC and other
functions.
3. Ask for a risk management procedure to categorize your
laboratory into high, medium and low risk systems. Ask for a
list with high and low risk systems and discuss the rational
behind it.
4. Walk through the facilities, observe people at work and
interview operators.
5. Select an analytical system with high impact on product quality.
6. Ask for a description of the system, its intended use and
specifications.
7. Ask for topological diagrams if the system is networked with
other systems.
8. Verify if the equipment hardware has been qualified.
9. Verify if software and computer systems have been validated.
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10. Ask if tests were done under high load.
11. Check system security. Try to access the system.
12. Verify that limited access to computer systems and data have
been challenged.
13. Examine test procedures and ask for results from a certain
time period.
14. Trace the result back to methods for analysis and data
evaluation, operators and raw data. Review raw data.
15. Check data integrity. Specifically check if operators could
manipulate electronic records interactively on the computer
and if so check if the changes were recorded by the system
through an electronic audit trail.
16. Ask which application software and which version was used at
that time.
17. Ask what the difference was to the previous software version
and how users made sure that the new version worked as
intended.
18. Verify if operators are trained and successful completion of the
training has been documented.
19. Verify if Out-Of-Specification situations have been handled
adequately. If the situation was caused by a laboratory error,
check if a preventive action plan in addition to a corrective
action plan has been implemented.
20. Give immediate advice if any non-compliance with FDA
regulations or company standards has been found.
Conclusion, Report and Follow-up
4. Have a closing meeting with all auditors and the laboratory
management.
5. The (chief) auditor/inspector summarizes all findings, assigns
levels of concern to each finding and listens to the lab’s
response. Any misunderstandings should be resolved at this
point.
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Prepare Required Documentation
Inspectors will spend quite some time with document review. Key
documents should be available in the meeting room and others
easy to access. The key documents should be checked for
compliance.
Collect Required Documentation
Make sure that documents typically required are readily available.
There are three reasons why it should not take long to find and
deliver a specific document:

It is required by some regulations. For example, subpart 21
CFR 211.180(C) reads: Records that are covered under
Subpart J of 21 CFR 211 should be readily available.

It does not make a good impression if it takes too long to find a
specific document. It indicates to the inspector that you are not
in control of your documents. Inspectors record everything they
asked for and can make a note how long it took to get specific
answers.

Long search times for multiple documents will extend the
length of an inspection.
Typical documents that should be available for all records include:
 Organization charts with responsibilities.

Procedures for internal audits and audit schedules.

Job descriptions and training records.

Validation Master Plans.

Procedures for change control and change control logs.

Risk assessment procedures and list of high/low risk systems.

Corrective Action and Preventive Action procedures and plans
(CAPA).

Procedures to ensure system security and data integrity.

Glossary with terms related to the inspection.

System descriptions, specifications, validation plans and
validation reports for systems classified as “high-risk”.
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
List of authorized people who have access to critical computer
systems.

Analytical laboratory notebooks and logs.

Analytical methodologies and validation reports.

Reports of analysis performed for specific lots, supported by
spectra, chromatograms and charts.

Deviation reports.
For pre-approval inspections additional documents should be
available::
 Production records of batches related to clinical trial materials
used to demonstrate bioavailability or bioequivalence. These
clinical trial batches could have been used in early clinical
studies.
 Batch records that are submitted in the application that
demonstrate that the proposed production process is the
process that was used to manufacture the bioavailability,
bioequivalency or stability batches.
 Development notebooks that contain data on bioavailability,
bioequivalency or stability of a new product.
 Inventory records and/or receiving records of drug substance
purchases.
 Stability data.
Subpart J of 21 CFR 211 specifies documents required by GMP:
 Equipment cleaning and use log.

Component, drug product container, closure and labeling
records.

Master production and control records.

Batch production and control records.

Production record review.

Laboratory records.

Distribution records.

Complaint files.
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Obviously not all these documents will be reviewed during an
inspection. Knowing that maybe only 10% or less will be reviewed
can be quite frustrating to individuals who have devoted their time
and efforts to write, prepare and review all the documentation, but
it seems to be Murphy’s law that the inspectors will always ask for
that one document that has not been prepared.
Check all Documents for Compliance
Documents should be checked if they comply with predicate rules
as well as with internal standards. For example, check if
documents are signed when a signature is required either by a
regulation or by an internal procedure. For example, we are not
aware of any regulation that requires students to sign training
records. Such signatures are frequently required by internal
procedures, so they should exist. And if the training record system
is fully electronic, signatures should be in electronic form.
For US-FDA inspections information should be available in
English. This is a requirement under 21 CFR 312.23(C) that a
sponsor submit an accurate and complete English translation of
each part of the IND. The same requirement is true for NDSs
under 21 CR 314.50(G).
Conducting the Inspection
The Inspector Arrives
When the inspector arrives treat him/her as you would any other
visitor. Ask for his/her photo ID card, FDA ID and name, office,
address and phone number. If other people accompany the
inspector, ask why and what their role will be. Notify the host and
escort the inspector to the designated room. Confirm the type of
inspection, e.g., routine or “for cause” inspection and how long the
inspection is expected to last. After that you can create some kind
of an agenda together with the inspector.
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20 important things to consider during the inspection:
There are a couple of important do’s and don’ts during the
inspection:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Don’t panic. Keep in mind that you know your processes much
better than the inspector. Act professionally and provide the
courtesy that should be offered to any visitor.
Be cooperative. Don’t view the FDA inspector as a threat.
Treat inspectors as human beings instead of enemies.
Working with the inspector rather than against him/her is to
your advantage.
Avoid arguing with the inspector about observations during the
inspections. A better time to do this is during the exit meeting.
Escort the inspector at all times. Try to keep him/her in the
designated room or areas.
Take notes on all questions and answers.
Have SOPs, validation protocols and other documentation
readily available. Pay special attention to deviations, rejected
batch records and failed tests. Information should be complete
and accurate. There should be a good explanation if any
required documentation is missing. Also, remove any
misleading items from the documents, like personal notes or
observations.
Make a list of all documents provided to the inspector.
Make a copy of all documents requested by the inspector for
removal and keep the original.
Make sure all questions are clearly understood before they
are answered. If the inspector’s question is unclear, ask for
clarification. Try to get the answers to questions and
requested documents as quickly as possible.
Don’t guess or assume anything! In case of any doubt, you
may repeat the question for clarification.
Be honest and open to questions. Don’t try to mislead the
inspector.
Be consistent with your answers. Inspectors take notes from
questions and answers. Inspectors become suspicious if they
get different answers to the same question.
Listen carefully to what you are asked and be as specific as
possible when responding to the question.
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15. Only answer questions that are asked. Stop talking when you
have answered the question and don’t even explain your
answer.
16. Try to avoid answering open-ended questions. Ask for more
specific details.
17. If you don’t know the answer, make this clear to the inspector.
It is fine to ask the inspector for more time to get and review
the details surrounding the question. If there are other people
who may know the answer say: “Please give me more time to
contact the right person and I will get back to you on your
request”. You may leave the room and get the answers from
somebody else in the inspection team or you may refer to
other people who know the answer and bring them into the
room. This is why creating a contact list with back-up names
and phone information is so important.
18. Try to answer with your company’s perspective and policies in
mind rather than giving your own opinion. For example, if an
inspector asks, “Why did you not test this or that as part of a
validation study?”, your answer may be: “Do you mean: why
does our validation master plan not recommend to do such
tests?”
19. If the inspector asks for a document that you are not familiar
with, ask: “What do you mean by this?” You may have the
document but under a different name.
20. Try to fix problems during the inspection whenever possible.
After the Inspection
The exit meeting
When the inspection is finished the inspector will note observed
deviations in the 483 form. Use the time when the inspector writes
the 483 form to review your notes and write down any questions
you may still have. The inspector will present the 483 form with
inspection observations in an exit meeting. Your management
team is given the opportunity to defend the deficiencies cited by
inspectors. The observations should be reviewed with the
inspector. If the observations are not understood or too general
ask for more details and examples. For example, you may ask
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what the inspector means by “the procedures are inadequate”.
During the process avoid conflict, and do not become too
emotionally involved. Document all your questions and the
answers. You can discuss and suggest corrective actions but don’t
make firm commitments for corrective actions or any other followup before discussing the consequences with the inspection team.
Follow-up
After the inspector has left your site review the observations with
the inspection team, assess the impact of the observations and
summarize the findings from the inspection. Develop a corrective
action plan as a direct response to the observations but also
assess the impact the observations may have on other areas not
covered during the inspection.
8. Responding to 483’s and Warning
Letters
When inspectors find deviations, there are several ways to
respond and correct problems:

During the inspection before the inspection observation has
been drafted.
 In response to the 483 inspection observations.
 In response to warning letters.
 Through other communications with the FDA.
In this chapter we give recommendations on how to respond most
effectively.
Responding During the Inspection
Sometimes minor deficiencies can be fixed short-term. This is very
effective but unfortunately an exception. Examples have been
documented in EIR’s, for example in Reference 27 an investigator
reports:
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“Dr. xxx informed me that he was responsible for the use of
computer/HPLC units in the laboratory. I asked Dr. xxx if there was
a topology map showing which computers control the HPLC units
and how they are linked to the major system. At that time there
was none available, but the next morning I was provided with a
topology map”.
The deviation was fixed during the inspection and did not show up
as a 483 observation.
Response to 483 Inspectional Observations
Typically the investigation team presents the 483 form to the firm’s
representatives in the exit meeting. The content is then discussed.
It is extremely important that all points are perfectly understood.
The firm should not hesitate to ask questions for clarification.
Terms used in the form should be understood as well as the
meaning of the observations. If the text is too general, the firm
should ask for examples and other details. The firm can also ask
for advice on how the problems could be best solved. If you
disagree with an observation and you feel it could have been
caused by a misunderstanding or because insufficient information
was provided to the inspector, state this openly. There have been
situations where inspectors have made changes to the form’s
content. You can also point out corrective actions that you have
taken during the inspection before the exit meeting. You also can
discuss alternatives for remaining corrective actions but be careful
about making time commitments until you have talked to your
company’s inspection team. The inspectors can document your
suggestions in the EIR.
Response to the final 483 observation can be sent in writing
addressed to the district director with a copy to the inspector. The
FDA will expect a response within 15 working days. Only when the
response arrives within this time frame, the content, for example
planned and/or executed corrective actions will be taken into
consideration for drafting a warning letter. If the observation is
really serious, you should call the district office or headquarter
staff depending on who performed the inspection. What matters is
not the number of observations but the type and severity. Try to
set up a meeting or teleconference and make sure you understand
the observations and that they are confirmed by higher-level FDA
officials before developing a written response.
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In preparation for the written response, form a committee that
includes members of quality assurance, regulatory affairs and
operations. The committee should review and clearly understand
the observations made by the FDA. The committee should also
determine whether the observation is isolated or if it is the result of
a bigger issue or trend. If necessary, subcommittees should be
formed to identify the root cause of the observation.
When you write the response it is very important to first focus on
the most serious observations and to address the root cause of
those. Describe how you plan to fix a problem. Include very
specific corrective action plans, owners and a realistic time
schedule to fix the problem.
It gives a bad impression if you have to go back more than once
and explain why you need more time. Making promises you can’t
keep can lead to unnecessary non-compliance in the future. For
multiple deviations, list each item separately and assign separate
action plans and completion dates for all of them. Besides
corrective actions also explain your action plan on how to prevent
occurrence of similar problems at your and at other sites (CAPA).
Response to Warning Letters
Recommendations on how to respond to warning letters are not
that different from what was said in the previous section about
483’s. Response must come within two weeks. It is important to
make a statement that you understood that you are in noncompliance but it is your company’s policy to comply with
regulations. Address each item of the warning letter point by point
with clear reference to each citation. Make it clear that you
understand the root cause of the problem and that your corrective
and preventive action plan is designed not only to fix the problem
cited in the warning letter but also similar problems in other areas.
Include a realistic time frame for the plan. Realistic means a time
that is acceptable by the FDA and is doable by your company. If
you have already started or finished some of the
corrective/preventive actions, attach supporting documents to the
warning letter. If the deviations are really serious, especially if you
have received a second or third warning letter on similar items,
include the use of external consultants in your correction plan
because the FDA may believe you cannot fix the problem on your
own.
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Preparing for the Next Inspection
The best time to start preparations for the next inspection is during
or shortly after the previous one. Start implementing the action
plan immediately after you have submitted your response to the
FDA. Train your people on how to implement all actions. Define
responsible persons to monitor and document the progress of
each corrective and preventive action. Ask for regular status
reports on the timely progress from each responsible person.
Finally, develop a “best practices” document with all your good and
bad inspection experiences. Distribute the document within and
outside your department to learn how to avoid mistakes at future
inspections, and also to improve your quality system.
Appendix A: Glossary
API
Active Pharmaceutical Ingredient
CDER
FDA Center for Drug Evaluation and Research
CFR
US Code of Federal Regulation. Collection of all regulations issued
by U.S. government agencies. The individual titles making up the
regulations are numbered the same way as the federal laws on the
same topic. For example, the Federal Food, Drug, and Cosmetic
Act is found in Title 21 of United States Code and the companion
regulations implementing the law are found in 21 CFR.
CAPA
Corrective and preventive action plan. Required for FDA
compliance in case of specification situations or other deviations.
Change control
A procedural formality required for validation, defining how and
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when changes may be made and in which situations revalidation is
required
Consent decree
Status imposed by the FDA in serious violation of federal
regulations and related safety and quality standards. A company
must agree to a series of measures aimed at bringing it's
manufacturing standard into compliance with federal regulations.
Until agreed-upon conditions are met, a company may be
forbidden to distribute its products in interstate commerce, except
for those products deemed essential for the public health.
CPG
FDA Compliance Policy Guide
EIR
Establishment Inspection Report. Written after an FDA inspection
by the agency. The observations from 483's are classified as no
action indicated (NAI), voluntary action indicated (VAI) of official
action indicated (OAI).
FD&C
Federal Food, Drug, and Cosmetic Act
Functional specification
A written definition of the function that a system or system
component can perform
GCP
Good Clinical Practice. Term used to describe a collection of
loosely-related regulations that define the responsibilities of those
involved in a clinical trial. The regulations include those that govern
institutional review boards, informed consent, and sponsors and
monitors. Refer to 21 Code of Federal Regulations Parts 50 and 6.
GGP
Good Guidance Practices
GLP
Good Manufacturing Practice. Regulations of the U.S. Food and
Drug Administration and other countries that spell out the
requirements for non clinical (animal or laboratory) studies that will
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be submitted to the regulatory agency to support a marketing
application. U.S. GLPs are found in 21 CFR Part 58.
GMP
Also known as current good manufacturing practices, CGMPs and
GMPS. U.S. regulations in 21 CFR Part 211 contain the minimum
current good manufacturing practices for methods, facilities, and
controls to be used for the manufacture, processing, packing, or
holding of a drug to assure that it meets the requirements of the
Federal Food, Drug, and Cosmetic Act for safely and has the
identity and strength and meets the quality and purity
characteristics that it claims. There are good manufacturing
practices for medical devices found in 21 CFR Part 820 and for
blood and blood products found in 21 CFR 606.
GxP
Good x Practices. X = laboratory (L), clinical (C)
or manufacturing (M)
IND
Investigational New Drug application. An application which a drug
sponsor must submit to FDA before beginning tests of a new drug
on humans. The IND contains the plan for the study and is
supposed to give a complete picture of the drug, including its
structural formula, animal test results, and manufacturing
information. Detailed instructions for the submission of IND's can
be found in 21 CFR 312.
IOM
FDA Investigations Operations Manual
LAN
Local-area network - A group of computers and associated
peripheral devices connected by a communications channel,
capable of sharing files and other resources among several users.
A LAN provides a means of communications between network
nodes. A LAN provides a means of communications between
network nodes.
Life Tests
Live, user-site tests: these tests are performed in the end user's
computing environment under actual operating conditions. Testing
should cover continuous operations for a sufficient time to allow
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the system to encounter a wide spectrum of conditions and events
in an effort to detect any latent faults that are not apparent during
normal activities (Part 11 validation guidance, draft version). Such
tests need to be performed for FDA compliance.
LIMS
Laboratory Information Management System. LIMS need to be
qualified for FDA compliance.
For details see: www.labcompliance.com/books/validation3
Macro
Mini program that performs a specific task - to repeat steps
perfectly and with much greater speed. In Excel Macros are written
in a programming language called Visual Basic for Applications
(VBA). In Excel Macros don't have to be created, they are
recorded as keystrokes and mouse actions. Need to be validated
for FDA compliance. Macros need to be qualified for FDA
compliance.
For details see: www.labcompliance.com/books/macros
MDR
Medical Device Reporting (MDR) regulation became final on
December 13, 1984. As a result of changes mandated by the Safe
Medical Devices Act (SMDA) of 1990, and the Medical Device
Amendments of 1992, the 1984 MDR regulations (21 CFR 803 &
807) were revised and published on 12/11/95. The FDA
Modernization Act of 1997 made additional changes to MDR and a
revised MDR Regulation was proposed in May 1998. The final
MDR regulation was published in the Federal Register on January
26, 2000.
MES
Manufacturing Executing System
MRP
Material Requirements Planning System
MRPII
Manufacturing Resource Planning System
NDA
New Drug Application. New drug application. A New Drug
Application is an application requesting FDA approval to market
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interstate commerce a new drug for human use. The application
must contain among other things, data from clinical studies
needed for FDA review from specific technical viewpoints,
including chemistry, pharmacology, biopharmaceutics, statistics,
and anti-infectives, microbiology. Detailed instructions for the
submission of NDA's can be found in 21 CFR 314.
Network
A group of computers and associated peripheral devices
connected by a communications channel capable of sharing files
and other resources among several users. Networks need to be
qualified for FDA compliance.
OOS
Out of specification situation. Requires failure investigation and
corrective and preventive action plan.
ORA
FDA's Office of Regulatory Affairs
ORO
FDA's Office of Regional Operations
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QA
Quality Assurance. A set of activities, often performed by
employees in a similarly named department, that check that the
characteristics or qualities of a product actually exist at the time
the product is sold. Oversight function that audits operations to
determine that procedures and systems are suitable and
recommends required changes to provide evidence that the quality
function is functioning correctly. QA is involved from product
concept through design, manufacture and distribution until the
ultimate use of the product by the patient.
QC
Quality Control. Day to day control of quality within a company,
responsible for the acceptance or rejection of incoming raw
materials and packaging components, in-process tests, labeling,
and inspection, assurance that systems are being controlled and
monitored, and for the approval or rejection of finished dosage
forms.
Qualification
Action of proving that any equipment works correctly and actually
leads to the expected results. The word validation is sometimes
widened to incorporate the concept of qualification.
Equipment and networks need to be qualified for FDA compliance.
For details see: www.labcompliance.com/books
Raw Data
Any laboratory worksheets, records, memoranda, notes, or exact
copies thereof, that are the result of original observations and
activities of a non clinical laboratory study and are necessary for
the reconstruction and evaluation of the report of that study. It may
include photographs, microfilm or microfiche copies, computer
printouts (not for electronic records systems), magnetic media,
including dictated observations, and recorded data from
automated instruments.
Server
Any computer that makes access to files, printing,
communications, and other services available to users of the
network. In large networks, a dedicated server runs a special
network operating system; in smaller installations, a non-dedicated
server may run a personal computer operating system with peer-
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to-peer networking software running on top. Servers need to be
qualified for FDA compliance.
Substantive rule
A substantive rule is a regulation that carries the force and effect
of law
SOP
Standard Operating Procedure. Documented instructions that
should be followed when operating a process for the process to be
considered valid. Required under GLP regulations. Written
documents that prescribe the detailed methods and action steps to
be followed in order to accomplish a particular task. The U.S. Food
and Drug Administration requires SOPs for virtually every aspect
of production, control and testing of pharmaceutical products. One
of the SOPs should describe the issuance and control of SOPs.
Traceability
The property of a result of a measurement whereby it can be
related to appropriate standards, generally international or national
standards, through an unbroken chain of comparisons all having
stated uncertainties.
Validation
Establishing documented evidence that provides a high degree of
assurance that a specific process will consistently produce a
product meeting its predetermined specifications and quality
attributes. Computer Systems and software need to validated for
FDA compliance.
See: www.labcompliance.com/books/validation3
VMP
Validation master plan. Demonstrates a companies approach for
validation. Improves efficiency and consistency for validation.
See: www.labcompliance.com/books/masterplan
Warning Letter
The purpose of a warning letter is to notify the firm’s senior
management that the company is in violation of the law and that
FDA is ready to take regulatory action if voluntary corrections are
not accomplished. For computer validation, warning letters are
usually issued as a result of a field investigator’s FD-483
observation in which a computer system used to ensure the quality
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of a product is found to be deficient. In most cases, warning letters
are issued by an FDA center compliance office. The letters signify
concurrence by the FDA field and headquarters staff and are
therefore excellent resources for identifying current agency policy
and expectations.
Appendix B: References
1.
Federal Food, Drug, and Cosmetic Act, 2004 update
http://www.fda.gov/RegulatoryInformation/Legislation/Federal
FoodDrugandCosmeticActFDCAct/default.htm
2.
L. Huber, Good Laboratory Practices and Current Good
Manufacturing Practices, Agilent 5988-6197EN, 2002, 130
pages
http://www.labcompliance.com/info/links/ref/inspections.aspx
3.
Labcompliance, Audio Seminars with 10+ Best Practice
Documents, 2009 (update)
http://www.labcompliance.com/seminars/audio/default.aspx
4.
FDA regulations (Predicate Rules), 2009 (update)
http://www.labcompliance.com/info/links/fda/regulations.aspx
5.
Compilation of Laws with Impact on the U.S. Food and Drug
Administration
http://www.fda.gov/RegulatoryInformation/Legislation/ucm153
119.htm
6.
FDA, General Administrative Procedures, Sec. 10.115 Good
Guidance Practices.
http://www.labcompliance.com/info/links/ref/inspections.aspx
7.
FDA, Inspection guide, Guide to Inspections of
Pharmaceutical Quality Control Laboratories, www.fda.gov
http://www.labcompliance.com/info/links/ref/inspections.aspx
8.
FDA, Inspection guide, Guide to Inspections of Foreign
Pharmaceutical Manufacturers
http://www.labcompliance.com/info/links/ref/inspections.aspx
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9.
FDA Compliance Guide: Drug Manufacturing
Inspections Program 7356.002
http://www.labcompliance.com/info/links/ref/inspections.aspx
10. FDA, Compliance Policy Guide, Computerized Drug
Processing; Input/Output Checking (CPG 7132a.07)
http://www.labcompliance.com/info/links/ref/inspections.aspx
11. FDA, General Principles of Software Validation; Final
Guidance for Industry and FDA Staff, www.fda.gov
http://www.labcompliance.com/info/links/ref/inspections.aspx
12. FDA, Guidance for the Industry, Good Clinical Practice,
Consolidated Guidance, www.fda.gov
http://www.labcompliance.com/info/links/ref/inspections.aspx
13. FDA, Investigations Operations Manual
http://www.fda.gov/ICECI/Inspections/IOM/default.htm
14. FDA Enforcement Reports
http://www.fda.gov/Safety/Recalls/EnforcementReports/defaul
t.htm
15. FDA 483 Inspectional Observation, Example, 2007
http://www.labcompliance.com/info/links/ref/inspections.aspx
16. FDA Establishment Inspection Report (EIR), Example 1 2004
http://www.labcompliance.com/info/links/ref/inspections.aspx
17. FDA/ORA Regulatory Procedure Manual, Chapter 6: Judicial
Actions, US FDA, 2009
http://www.fda.gov/downloads/ICECI/ComplianceManuals/Re
gulatoryProceduresManual/UCM074317.pdf
18. FDA, Warning Letter, Example, 2008
http://www.labcompliance.com/info/links/ref/inspections.aspx
19. FDA Consent Decree, Example,
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm0958
73.htm
20. Software Quality Management, Inc. (SQM), Press Release
about Consent Decree
http://www.sqminc.com/merchant/whatsnew.ihtml
21. Excerpts and Downloads of Warning Letters, 483’s and EIR’s.
www.fdawarningletter.com
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22. FDA Compliance Policy Guide 7382.845: Inspection of
Medical Device Manufacturers, October 2000
http://www.labcompliance.com/info/links/ref/inspections.aspx
23. FDA, Guide to Inspections of Quality Systems’
http://www.labcompliance.com/info/links/ref/inspections.aspx
24. FDA Guidance for Industry Part 11, Electronic Records;
Electronic Signatures Scope and Applications, 2003
http://www.labcompliance.com/info/links/ref/inspections.aspx
25. L. Huber, Validation of Computerized Analytical and
Networked Systems, Interpharm (IHS), Englewood, April
2002, www.labcompliance.com/books/validation3
26. L. Huber, Validation and Qualification in Analytical
Laboratories, Interpharm (IHS), Englewood, May 1998
www.labcompliance.com/books/labvalidation/default.aspx
27. FDA, Establishment Inspection Report (EIR), Example 2
http://www.labcompliance.com/info/links/ref/inspections.aspx
28. FDA Guidance for Industry
Quality Systems for Drug CGMPs
http://www.labcompliance.com/info/links/ref/inspections.aspx
29. FDA, 21 CFR Part 820, Quality System Regulation
http://www.labcompliance.com/info/links/ref/inspections.aspx
30. ICH Q9: Quality Risk Management
http://www.ich.org/LOB/media/MEDIA1957.pdf
31. L. Huber, Risk Management Master Plan, Best Practices,
Labcompliance, 2009.
www.labcompliance.com/books/risk
32. FDA Press Release about Seizure
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncem
ents/ucm169093.htm
33. FDA Warning Letters issued by the Division of Drug
Marketing, Advertising, and Communications and by
Headquarters
http://www.labcompliance.com/info/links/ref/inspections.aspx
34. FDA Warning Letters issued by District Offices
http://www.labcompliance.com/info/links/ref/inspections.aspx
35. FDA Debarment List
http://www.labcompliance.com/info/links/ref/inspections.aspx
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36. FDA Warning Letter, Announcement of import alert,
320-01-14 (W-097)
http://www.labcompliance.com/info/links/ref/inspections.aspx
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