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Would your company

survive a surprise
inspection? An FDA
inspection can be a
nightmare that costs
your company money,
time, and reputation.
Proactive managers
understand the logic
behind FDA regulations
and prepare accordingly.
This three-part survival
guide to inspections
(whether from FDA, a
client, an investor, or a
European agency) will
sharpen your vision
of your companys
regulatory compliance




concerns, problems,
and difficulties are
those that FDA
inspectors look out
for. Then we make
sure you know how
to address those
issues properly (see
the Prepare for an
FDA Inspection
Much of an
inspection focuses
on a companys
quality systems. By
definition, a quality
system is a program
that addresses the
needs and elements
of a specific part of a
manufacturing operation. A training
program, for example, is a quality
system a quality
system that defines
in detail how the
Massoud Lavian and Paul W. Allen
company will ensure
or many companies, coping with an
that its employees have the proper knowledge to
FDA inspection can be a nightmare.
carry out their responsibilities.
Workloads increase significantly before,
Pharmaceutical and biotechnology companies
during, and after an inspection, and
typically determine how they are going to
there is always the potential that a major
classify their quality systems. Quality systems
regulatory economic downfall could be
typically include standard operating procedures
part of a companys future if the inspec(SOPs), monitoring programs, change control
tion yields negative or mixed results.
policies, validation programs, training, deviation
This three-part series addresses common
and investigation programs, and consistent docuissues that arise during an FDA inspection and
mentation practices.
provides advice on how to prevent those difficulOur survival guide, therefore, also begins by
ties. Part 1 describes those actions and programs
focusing on quality systems: on determining
that must be part of routine operations, whether
those quality systems needed and in place, on
an inspection is imminent or not. Part 2 focuses
ascertaining how practical particular quality
on inspection day and what to do during that
systems are, and on checking how well those
examination. Part 3 follows the aftermath
quality systems have been implemented and
responding to inspection results, implementing
followed. It is the responsibility of a companys
corrective actions, and learning from the entire
management to ensure that quality systems are in
inspection process.
place, reviewed periodically, upgraded, impleWe dont try to predict all the possible
mented, and followed.
questions and concerns that can come up during
an inspection. Even an FDA inspector couldnt
SOPs are a critical quality system feature, and
do that. Instead, we discuss common deficiencies.
they frequently get inspected their contents,
This survival guide ensures that you know what
the quality of their preparation, and how well
an inspection is, what aspects of company operathey are followed. SOPs are detailed documents
tions (equipment, documents, tests) are likely to
specify operating guidelines and instructions
be inspected, and what the most common
for every procedure within the company.

SOPs two to do. Two types of SOPs are

Monitoring samples. The monitoring program

common. The first type is corporate or global

SOPs (policies and procedures set forth by the
companys highest management level), that describe general company policies. A companys divisions, functions, and groups subject to GMP
requirements (that is, all departments excluding
functions such as finance, marketing, and sales)
are required to comply with global SOPs (13).
Local SOPs document routine tasks and make
provisions for nonroutine tasks for all specific
functions or departments within the company.
These documents detail the tasks that must be
performed at each step in the manufacturing
process. Examples of these tasks include sterilization, equipment operation, emergencies, and
documentation practices. Examples of observations that FDA inspectors make about SOPs are
listed in the SOP Failures sidebar. Remember,
SOPs are the first line of defense during an inspection: They describe how procedures and situations are supposed to be handled, even those situations, such as an emergency or a contaminated
batch, that a company has never faced before.
Monitoring systems. Another quality system that
is closely scrutinized during a typical inspection is
the monitoring program. Typically, a production
site must have a continuous monitoring program of
all critical elements of the manufacturing operation. Critical elements include, for example, building and equipment monitoring, water quality
assessment, environmental monitoring, and
microbial level measurements in aseptic fill areas.

clearly defines what needs to be sampled and

when, how the sample is taken, and how the
sample must be handled and tested. It also
outlines acceptable results supported by validation studies. Monitoring programs must include
provisions for test results outside acceptable
limits, assigning action and alert limits, addressing who needs to be notified, assessing the effect
of the out-of-specification (OOS) result, and
approving and implementing a corrective action.
Responsibility must be assigned to a specific
person who reviews the results in each area and
identifies trends in the data.
OOS results. FDA observations about monitoring programs cite the lack of clear specifications
for when to sample, the location from which to
draw the sample, the number of samples, and
poor handling for OOS or failed test results. It is
inevitable that at some point a test result will fail.
(In fact, an experienced inspector will doubt the
validity of test results that remain acceptable over
long periods of time.) Inspectors want to know
how the failed result was handled, how the effect
of the OOS result was assessed, how the corrective action was agreed upon, who approved the
corrective steps, what the thought processes were
behind the final decision about corrective action,
and how the entire episode was documented.
Therefore, before your company is notified that
an inspection is imminent, review your monitoring programs and make sure they are sound and






Vendor audit

Source code


Routine audits


Unit test

Stress test

Back-ups and archive

Vendor RFP


Change control
Traceability matrix

Disaster recovery plan

Validation master plan

SOP development

Configuration design

SOP validation

System test user


Validation summary

Program design

SOP system use

21 CFR Part 11
Security plan
Data migration plan
Tool description

Change control
Audit trail

Problem report

Figure 1. Validation protocols for a typical software

life cycle

Hardware description
Acceptance criteria




At your next staff meeting, ask your coworkers,
Does our company have a comprehensive
validation program in place? Be prepared for
several interesting responses.
Validation programs are arguably what inspectors are most interested in when they visit your
company. During validation, critical parameters
and acceptable ranges are established for
processes and equipment. The quality of the validation program indicates how tests are performed
and documented, how deviations are handled, and
how conclusions are reached. How a validation
To Prepare for an FDA Inspection
This list of five To Do or Not to Do items will help you prepare for an
FDA inspection.
Dont procrastinate. Never wait until the last minute to prepare for a scheduled

inspection. At a minimum, examine your quality systems, your training program,

how well your SOPs are being followed, your documentation, and your
correction processes at departmental levels on a regular basis. This will ensure
that you are current with any changes in your systems and are properly
documenting them.
Correct issues that FDA has already cited. Make sure that all corrective actions have
been taken and thoroughly documented. Simply knowing that a problem exists
is not a defense. Be proactive, and review public records on actions the agency
has taken against other companies.
Assign responsibilities. Assign specific responsibilities to departments. Allow the

department leader to assign the responsibility to a specific individual or job role,

making both the department leader and the individual accountable. Build the
responsibilities directly into job descriptions, and make them part of an
employees annual review. There is no substitute for accountability.
Document everything. FDAs unwritten rule is that if something is not documented,

it either does not exist or never took place. Follow good documentation
procedures (GDP). Technology makes it easy to follow established formats and
Work with QA, not against it. The QA department is responsible for overseeing

quality system implementation and approves final decisions. Ultimately, the

responsibility of producing drugs and devices rests with QA (actually theres not a
lot of resting involved). So work collaboratively with them instead of against them.

process is carried out is the best example of how

work is planned, executed, and documented on a
daily basis. Therefore, the quality of a companys
validation program shows an inspector the level
of detail and technical knowledge that the
company applies to day-to-day operations. Even
if an inspection does not start with validation, it
almost always raises issues that can be traced
back to the original validation work.
A comprehensive validation program starts
with policies that establish guidelines and responsibilities for validation processes. Those policies
typically cover procedures for preparing, reviewing, approving, executing, and completing the
validation plan.
In separate documents, the validation requirements for individual areas, such as laboratory
equipment and processes, computers, cleaning,
and utilities, among others, must be clearly
defined. This set of documents establishes a companys commitment to its validation efforts. The
documents also establish a requalification
program at timely, preestablished intervals to
verify the results of the original validation effort.
A validation master plan (VMP) is also essential
because it establishes a companys validation
plans for the near future. It should include a list
of validation activities that the company plans to
complete within a reasonable time frame. Once a
VMP is approved, periodic reviews will ensure
that validation plans are on schedule assuring inspectors that the company is committed to
completing its validation tasks. VMPs do not,
however, replace completed validation efforts.
Validation protocols are the most critical element
of a validation program. Figure 1 shows the validation processes in a typical software life cycle.
Creating validation protocols is an extremely
detailed process, but as a general rule, companies
should ask the questions in the Before an

Before an Inspection
A proactive manager asks questions
about the companys validation
protocols well before an inspection is
anticipated. Questions such as the
following will shine a light on any fog in
your companys regulatory compliance
Is our validation approach sound? That
is, are we testing what we should be
testing? Is our validation approach in line
with current industry practices and with
the latest guidelines?




Are our validation protocols clear and

detailed enough that they can be followed
easily without further explanations?
Are all equipment, computer systems,
processes, utilities, and lab equipment
validated? Has the final report for those
validation activities been reviewed and
Does our validation effort establish
operation limits? Are those limits
incorporated into our daily operation? Are
instructions in place on what to do when
those limits are exceeded?

Are all instructions in our general

protocol followed? If not, why?
Are all results supported by data and
Is our companys requalification program
on track and on time?
Are all our validation documents
assembled, reviewed, and included?
What is the quality of our companys
Are all GMPs included and followed in
our validation efforts?

Inspection sidebar about the companys validation programs.

Inspecting Deviations
Following are typical
questions that an
experienced inspector has
in mind when inspecting a
companys deviation
management and
corrective action plans.
Is a formal investigation
program in place to address
Are deviations noticed by
chance, or are they detected
in a timely manner during
systematic evaluation?
How was the effect of the
deviation determined? Who
approved that determination?
Was trend analysis
conducted under a formal
program or SOP? Was there
a global approach to
determining whether a
deviation was an isolated
incident? Was a trend
Was the root cause of a
deviation found and
Who was involved in
determining corrective
action? How was the
corrective action decision
Was the investigation of the
deviation performed and
concluded in a timely
Was corrective action
universal? Was it effective?
What was done to prevent
the deviation from happening
What measures were taken
to assess the corrective
action to ensure that it would
not be the source of future
Were all of the above actions
properly documented?

The biopharmaceutical industry generates

massive batch records (about the size of telephone books) full of comprehensive data that
include each step taken during manufacturing and
a log of the necessary controls, checks, and
balances. These documents are a compilation of
production records, test data for raw materials,
components, and product integrity. Everything is
documented in batch records: the vials used, the
equipment used, and the product temperature
when machines are in operation, among many
other items. Batch records are the ultimate proof
that the batch was prepared using established and
predefined steps.
Batch record violations. Batch records are often
one of the first items that FDA inspectors examine
for deviations, missing information, the quality of
a companys documentation practices, and other
operating weaknesses. Inspectors want to assess
whether the companys records are comprehensive
enough to reflect all production facts, how the
companys quality assurance department reviews
the records, how deviations are detected and responded to, and whether there is any missing data
in such documents. FDA frequently cites companies that fail to properly analyze their batch record
data, that keep inadequate data, that fail to describe
deviations in detail, or that provide insufficient
responses to deviations. If batches are OOS, companies must understand why and demonstrate that
they can correct the problem and prevent recurrence. Such documents can be long and the analysis process tedious, but the process can result in
cost savings if the company can identify ways to
solve ongoing problems.
Batch records as preventive measures. Batch
records can clear a companys name and disprove
suspicions of wrongdoing. In 1982, McNeil
Consumer Products, a division of Johnson &
Johnson ( and the maker of
Tylenol, was faced with product alteration in
which Tylenol was laced with cyanide, causing
several U.S. deaths. McNeils batch records
helped the company defend its procedures and
supported the theory that the problem was not a
production deviation but postproduction tampering. Therefore, a company should pay close
attention to the contents of its batch records, how
those records are filled out during operation, and
how the documents are reviewed.


Another frequent focus during inspections is a
companys deviation management and its corrective actions. Deviations can occur during manufacturing, validating, laboratory testing, or
program monitoring. Deviation management is a
program under which OOS results are reviewed,
analyzed, trended, and corrected. Typical questions that an experienced inspector has in mind
when inspecting a companys deviation management and corrective actions are listed in the
Inspecting Deviations sidebar.
Deviations can take place when manufacturing
equipment breaks down or when operators make
errors. In these circumstances, it is important to
analyze trends in the deviations and to determine
the reason for the failures. If there is a trend, what
is causing it? Is it user error or improper equipment use? If the equipment is being used improperly, was there an SOP on the machine, and was
the SOP being followed? Deviations are red flags
that can portend even bigger problems.

A review of the most recent citations issued to
companies by FDA shows that many of the issues
they cite relate to human error (4). The key to
overcoming human error problems is proper and
frequent training.
Inspectors examine training records when they
reach the conclusion that improper use of the
machinery or human errors are the cause of a
cited issue. The inspector in these cases will naturally ask if proper training was conducted. Therefore, you need to ask the questions first.
When evaluating your companys training
program, be sure to document your responses to
training questions. Does a formal program
mandate training? Does the training program
specify who needs to be trained and on what
equipment or processes? Are training materials
presented properly by a qualified trainer? Do the
training records indicate who was trained and on
BioPharm AUGUST 2002

SOP Failures
Reviewing FDA warning letters (4) to other companies can help ensure
that your company isnt making the same mistakes. The most frequently
cited SOP failures include:
Lack of global or corporate policies (at upper management level) for all major
elements of the companys operation: validation, change control, batch release,
and other functions
Lack of local (departmental or functional) level procedures for every job and
task in all company operations
Lack of clarity or specificity in SOPs, which must not require or allow individual
Lack of proper training (when employees covered by an SOP are not trained on
the contents of that document)
Lack of assigned responsible functions for each specific task (SOPs must
assign specific responsibilities, defining who is responsible for carrying out each
particular task)
Lack of or incomplete document history file (each SOP must have a history file
that includes the entire history of that document, the reasons for any changes,
and approval documentation)
Use of outdated SOPs (an SOP system must be properly set up to archive and
remove outdated SOPs from circulation; audit trails now allow this to happen
automatically, if the information technology (IT) team sets them up properly); a
mechanism must be in place to ensure that the latest version of each SOP is
available and in use at all times
Failure to follow SOPs (all SOP instructions must be followed word for word
without exception); in extreme cases of deviation, documentation on what
happened, why it happened, what the effect was, how it was corrected, and who
approved the corrective action must be provided; SOPs should describe how to
handle deviations, actions that must be taken, and necessary approval levels
A majority of inspection observations relate to SOPs that were not followed and
the lack of appropriate instructions when a deviation occurred.

Corresponding author
Massoud Lavian is assistant director
of compliance and Paul W. Allen is
the managing partner responsible for
life sciences at Clarkston Consulting
(a management and IT consulting firm
specializing in FDA and validation
issues), 595 Market Street, Suite 1450,
San Francisco, CA 94105,
310.869.4060 or 888.486.1141,
ext. 4931, fax 415.354.8743,,



what equipment or process? Are the records

available for inspection? Was training effective
in preventing further deviations?
Inspectors can choose to determine the effectiveness of a companys training for themselves. For example, they may observe the
gowning procedures for entering classified
areas when the cause of a contamination problem was determined to be improper gowning
practices. To be proactive and prevent the need
for this type of inspection, companies should set
up comprehensive training programs that
clearly define who needs training, what type of
training they need, and how frequently additional or refresher training will be required.
Training programs attended should be documented and attached to each employees record.


Most companies have standard procedures in
place for accepting raw materials and consumable
commodities. Receivables include not only active
ingredients and excipients but also items such as

glassware, clean gowns, coveralls, and chemicals

or components that are used to manufacture drugs
and medical devices.
A receiving and inspection program needs to
define the expectations about each commodity or
ingredient being received. The SOPs on the
program should state those steps that need to be
taken when ingredients or components are
received to ensure that the material received meets
expected quality attributes. The SOPs may include
a review of vendor certificates of analysis and of
test results, or they may require internal sampling
and testing approved by the quality assurance and
quality control (QA/QC) functions within the
company. When a company conducts sample tests,
it must document the results properly. Companies
concerned about quality standards often consider
third-party organizations that can conduct tests and
confirm the required attributes of the raw materials. If this route is chosen, the outside testing laboratory should be audited and qualified.

Throughout the manufacturing operation and
within all production processes, change is
inevitable. New process steps, changes in equipment, and improvements or corrected inadequacies
all cause change within a companys operations.
A formal program must be in place to handle
changes. Inspectors often focus on this facet of
production during an inspection. Inspectors
reviewing a companys change control programs
will ask if a formal change control program is in
place, who administers the program,
department has ultimate authority over
change control.
They will ask how
the effects of a
change are assessed, what steps
are taken to minimize or prevent additional impacts,
how decisions are
made, the thought
processes behind
change, and who approves them. And, as in all
other production processes reviewed, an inspector
will want to know how the entire change event, the
actions taken in response to the change, and the decisions made regarding the change have been
Continued on page 49

Survival Guide continued from page 24

People in the biopharmaceutical industry often
joke that, In God we trust, everything else must
be documented. That phrase speaks for itself
and for the mountains of documents that regulatory compliance requires.
FDA inspectors insist on reviewing documentation processes. Documents are the only proof
that companies have with which to defend their
practices and operating procedures. Therefore no
amount of effort put into preparing proper documents is in vain. Long before an inspection,
review your companys documents . . . and then
review them again. Find and fill document gaps,
obtain approval signatures, be clear and, most
of all, be factual in your documentation. Always
remember, If you dont have the proper documentation for an action or item, you dont have
that item, or no action was taken.


To biopharmaceutical, pharmaceutical, medical
device, outsourcing, or other health carerelated
companies, an inspection translates to an FDA
inspection. But inspections come from other
sources as well, from your customers as due dili-

gence audits, from European and other national

inspecting agencies, and from potential merger,
acquisition, and investing partners.
Preparation for an inspection is critical.
Responsible individuals within the company must
ask all the questions listed in this article to determine how the companys operations are functioning. Responsibility must be assigned to those who
can ensure success. Rules and regulations can be
cumbersome and time consuming, but they serve
specific purposes. Proactive managers are those
who understand the logic behind the regulations
before they attempt to implement them.

(1) Current Good Manufacturing Practice in
Manufacturing, Processing, Packing, or Holding of
Drugs, Code of Federal Regulations, Food and
Drugs, Title 21, Part 210 (U.S. Government Printing
Office, Washington DC), revised 1 April 2001.
(2) Current Good Manufacturing Practice for Finished
Pharmaceuticals, Code of Federal Regulations,
Food and Drugs, Title 21, Part 211 (U.S.
Government Printing Office, Washington DC),
revised 1 April 2001.
(3) Biological Products, Code of Federal Regulations,
Food and Drugs, Title 21, Part 600 (U.S.
Government Printing Office, Washington DC),
revised 1 April 2001.
(4) FDA Warning Letters. Available at
foi/warning.htm (accessed May 2002). BP