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The FDA cGMP Inspection is Coming: Make the Best of It

,
,
Abhishek Patel Darshit S. Patel, Ph.D.
Narendra Patel Jan 29, 2016 8:00 am PST
By

Figure 1: Drug approval process &

cGMP inspection.
ABSTRACT
This article discusses some facts that may be helpful in understanding how current good manufacturing practices (cGMPs)
establish the foundation for drug product quality. It discusses points to consider before, during, and after a statutory US Food
and Drug Administration inspection to be in the best possible regulatory compliance position. This article will present critical
information regarding FDA inspections and also demonstrate how an FDA inspection readiness assessment can maximize the
probability of a drug manufacturing firm passing said inspection. The level of preparation within an organization will make a
significant difference in its level of success.
INTRODUCTION
Current good manufacturing practices (cGMPs) for human pharmaceuticals affect every American. Consumers expect that
each batch of medicines that they take will meet quality standards to ensure safety. Most people, however, are not aware of
cGMPs, or how US Food and Drug Administration assures that drug manufacturing processes meet these basic objectives.
Recently, FDA has announced a number of regulatory actions taken against drug manufacturers based on the lack of cGMPs
(1).
cGMPs
cGMP refers to the current good manufacturing practice regulations enforced by FDA. cGMPs provide for systems that assure
proper design, monitoring, and control of manufacturing processes and facilities. Adherence to the cGMP regulations assures
the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control
manufacturing operations. This includes establishing strong quality management systems, obtaining appropriate quality raw
materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining
reliable testing laboratories. This formal system of controls at a pharmaceutical company, if adequately put into practice, helps
to prevent instances of contamination, mix-ups, deviations, failures, and errors. This assures that drug products meet their
quality standards.
The cGMP requirements were established to be flexible to allow each individual manufacturer to decide how to best implement
the necessary controls by using scientifically sound design, processing methods, and testing procedures. The flexibility in

these regulations allows companies to use modern technologies and innovative approaches to achieve higher quality through
continual improvement. Accordingly, the c in cGMP stands for current requiring companies to use technologies and
systems that are up-to-date in order to comply with regulations.
It is important to note that cGMPs are minimum requirements. Many pharmaceutical manufacturers are already implementing
comprehensive, modern quality systems and risk management approaches that exceed these minimum standards (1).
Why are cGMPs so important?
A consumer usually cannot detect (through smell, touch, or sight) that a drug product is safe or if it will work. While cGMPs
require testing, testing alone is not adequate to ensure quality. In most instances testing is done on a small sample of a batch
(for example, a drug manufacturer may test 100 tablets from a batch that contains two million tablets), so that most of the
batch can be used for patients rather than destroyed by testing. Therefore, it is important that drugs are manufactured under
conditions and practices required by the cGMP regulations to assure that quality is built into every step of the design and
manufacturing process. Some examples of how cGMP requirements help to assure the safety and efficacy of drug products
are facilities that are in good condition, equipment that is properly maintained and calibrated, employees who are qualified and
fully trained, and processes that are reliable and reproducible (1).
How does FDA determine if a company is complying with cGMP regulations?
FDA inspects pharmaceutical manufacturing facilities worldwide using scientifically and cGMP-trained individuals whose job is
to evaluate whether the company is following cGMP regulations. FDA also relies upon reports of potentially defective drug
products from the public and the industry. FDA will often use these reports to identify sites for which an inspection or
investigation is needed. Most companies that are inspected are found to be fully compliant with the cGMP regulations (1).
If a manufacturer is not following cGMPs, are drug products safe for use?
If a company is not complying with cGMP regulations, any drug it makes is considered adulterated under the law. This kind
of adulteration means that the drug was not manufactured under conditions that comply with cGMP. It does not mean that
there is necessarily something wrong with the drug. The importance and relationship of methods, facilities and controls to
product quality is underscored in these often-cited sections of the Federal Food, Drug, and Cosmetic Act (FFDCA):
A drug or device shall be deemed to be adulterated if it is a drug and the methods used in, or the facilities or controls used
for, its manufacture, processing, packaging, or holding do not conform to or are not operated or administered in conformity
with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has
the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.
FFDCA, Section 501(a)(2)(B)(2)
For consumers currently taking medicines from a company that was not following cGMPs, FDA usually advises these
consumers not to interrupt their drug therapy, which could have serious implications for their health. Consumers should seek
advice from their healthcare professionals before stopping or changing medications. Regulatory actions against companies
with poor cGMPs are taken as a preventive measure because the manufacturing processes do not meet FDAs regulatory
standards. By focusing on the procedures and processes used to make these drugs, FDA is working to ensure that drugs
meet their quality standards and are safe and effective. The impact of cGMP violations depends on the nature of the
transgressions and on the specific drugs involved. A drug manufactured in violation of cGMP may still meet its labeled
specifications, and the risk that the drug is unsafe or ineffective could be minimal. Thus, FDAs advice will be specific to the
circumstances, and healthcare professionals are the most able to balance risks and benefits and make the right decision for
their patients (1).
What can FDA do to protect the public when there are cGMP violations?
If the failure to meet cGMPs results in the distribution of a defective drug, the company may subsequently recall that product.
Removing these drugs from the market protects the public. While FDA cannot force a company to recall a drug, companies will
usually recall voluntarily or at FDAs request. If a company refuses to recall a drug, FDA can warn the public and may seize
the drugs that are on the market.
Even if the drugs are not defective, FDA can bring a seizure or injunction case to court to address cGMP violations. When
FDA brings a seizure case, they ask the court for an order that allows federal officials to take possession of adulterated
drugs and destroy them. This enables FDA to immediately prevent a company from distributing those drugs to consumers.

When FDA brings in an injunction case, they ask the court to order a company to stop violating cGMPs. Both seizure and
injunction cases often lead to court orders that require companies to take many steps to correct cGMP violations, such as
hiring outside experts, writing new procedures, and conducting extensive training of their employees. FDA can also bring
criminal cases to court because of cGMP violations, seeking fines and jail time (1).
UNITED STATES FEDERAL REGULATIONS
The Code of Federal Regulations (CFR) is divided into 50 titles that represent broad areas subject to Federal regulations.
Section 21 of the CFR contains most regulations pertaining to food and drugs. Drug manufacturers are required to comply with
the following cGMP code of federal regulations:
21 Code of Federal Regulations Part 210 (21 CFR 210): Current Good Manufacturing Practice in Manufacturing
Processing, packing, or Holding of Drugs
21 Code of Federal Regulations Part 211 (21 CFR 211): Current Good Manufacturing Practice for Finished
Pharmaceuticals (3)
Figure 1: Drug approval process & cGMP inspection.

DRUG APPLICATIONS AND cGMP REGULATIONS

FDA ensures the quality of drug products by carefully monitoring drug manufacturers compliance with its cGMP regulations.
The cGMP regulations for drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing,
processing, and packaging of a drug product. The regulations make sure that a product is safe for use, and has the

ingredients and strength it claims to have.

The approval process for drug marketing applications (Figure 1) includes a review of the manufacturers compliance with the
cGMP. FDA inspectors (or FDA investigators) determine whether the firm has the necessary facilities, equipment, and skills to
manufacture the new drug for which it has applied for approval. Decisions regarding compliance with cGMP regulations are
based upon inspection of the facilities, sample analyses, and compliance history of the firm. This information is summarized in
reports that represent several years of the firms history.
FDA can issue a warning letter or initiate other regulatory actions against a company that fails to comply with cGMP. Failure to
comply can also lead to a decision from FDA not to approve an application to market a drug (3).
TYPES OF FDA AUDIT/INSPECTION
According to FDAs compliance programs, FDA conducts the following inspections for drug manufacturing:
Pre-approval inspections
Post-approval audit inspections
Drug manufacturing inspections (routine cGMP [Surveillance] Inspection) (4)
Pre-Approval Inspections
The FFDCA provides that FDA may approve a new drug application (NDA), an abbreviated new drug application (ANDA), and
a biologic licensing application (BLA) if, among other requirements, the methods used in, and the facilities and controls used
for, the manufacture, processing, packing, and testing of the drug are found adequate as well as ensure and preserve its
identity, strength, quality, and purity.
A pre-approval inspection (PAI) is performed to contribute to FDAs assurance that a manufacturing establishment named in a
drug application is capable of manufacturing a drug, and that submitted data are accurate and complete. This program directs
the Office of Regulatory Affairs (ORA) district office or the Division of Manufacturing and Product Quality (DMPQ) in the
evaluation of establishments by on-site inspections and/or it directs the file review of the establishment when the firm is named
in the Chemistry, Manufacturing, and Controls (CMC) section of a NDA, ANDA or BLA. This includes original submissions,
CMC amendments to pending original submissions, and CMC supplements to approved drug applications. There are two
types of PAI: priority and discretionary.
Priority PAI: DMPQ strongly recommends that a pre-approval inspection be performed because one or more priority PAI
criteria was met. If one or more of the following apply, the establishment meets the priority criteria and an inspection is to be
performed:
Establishment is named in an application to FDA for the first time, including establishments that have never been
inspected or have been inspected only for non-application drugs
Applicant filed first application (for coverage of finished dosage manufacturing and testing)
First ANDA filed for an approved drug (for coverage of finished dosage manufacturing and testing)
Finished product contains a new molecular entity (NME) (does not apply to supplements)
Finished product content assay has a narrow range (e.g., 95-105% labeled strength for narrow therapeutic index
drugs) or drug is expected to require titrated dosing (does not apply to supplements)
Finished product or active pharmaceutical ingredient (API) is manufactured by a substantially different manufacturing
process or dosage form than previously covered at the establishment
API derivation is high risk (e.g., API is derived from animal tissues) or the intended use has significantly changed (e.g.,
API previously used in non-sterile product is now intended for a sterile drug product)
Numerous application submissions or certain site/process/product changes that are expected to pose significant
challenge to the state of control of the facility or process
Profile class status of application product or API is unacceptable or not updated via a site inspection within the past
two years (three years for control laboratories and four years for packaging and labeling), for original applications or
significant pre-approval CMC supplements

Discretionary PAI: DMPQ recommends that no pre-approval inspection be performed because the priority PAI criteria were not
applicable to the site or product. Certain situations that may justify performance of a discretionary inspection include the
following:
Multiple applications filed in short period of time involving a single establishment for manufacture of the finished product
Significant deficiencies were found during the last pre-approval inspection or the firm has a history of non-compliant
pre-approval inspections
Additional potentially adverse information regarding the compliance status of an establishment not yet known to Center
for Drug Evaluation and Research (CDER), such as an expected enforcement action recommendation during an ongoing inspection, multiple recalls, or new firm management
So, if based on the above criteria, a company has been designated for either a priority or discretionary PAI, the following
discusses what one can expect regarding scheduling and composition of the inspection team.
There are three primary inspectional objectives of PAI. These objectives are:
Objective 1: Readiness for commercial manufacturing
Objective 2: Conformance to application
Objective 3: Data integrity audit
If ones company has been designated for a PAI, at least one of these objectives will be addressed during the inspection.
Summary of Objectives
Readiness for commercial manufacturing is the first objective. The overarching objective in this area is to demonstrate that
one has a quality system in place designed to achieve sufficient control over the facility and commercial manufacturing
operations. Key elements of control include:
Manufacturing and laboratory changes, deviations, and trends relating to the development of new drug substance as
well as product manufacturing have been adequately evaluated.
A sound and appropriate program for sampling, testing, and evaluation of components, in-process materials, finished
products, and containers and closures for the purpose of releasing materials or products has been established. This
includes a robust supplier qualification program.
The establishment has sufficient facility and equipment controls in place to prevent contamination of and from the
application product (or API).
Adequate procedures exist for batch release, change control, investigating failures, deviations, complaints, and
adverse events; and for reporting this information to FDA, such as field alert reporting.
The feasibility of the proposed commercial process and manufacturing batch record, including instructions, processing
parameters and process control measures, are scientifically and objectively justified. This objective links to the firms
process validation program.
Objective 2 is conforming to application. Verify that the formulation, manufacturing or processing methods, and analytical or
examination methods are consistent with descriptions contained in the CMC section of the application for the biobatch and
other pivotal clinical batches (when applicable), the proposed commercial scale batch, and the API(s).
Objective 3 is auditing the data integrity. Audit the raw data, hardcopy or electronic, to authenticate the data submitted in the
CMC section of the application. Verify that all relevant data (e.g., stability, biobatch data) were submitted in the CMC section
such that CDER product reviewers can rely on the submitted data as complete and accurate (5)
Post-Approval Audit Inspections
Post-approval audit inspections program is designed to audit for changes in the production and control practices that occur
after approval and to confirm that the approved applications have been appropriately supplemented to reflect those changes.
The main objectives of this continuing compliance program are twofold: 1) to assure that any changes in manufacturing and
process control are in compliance with cGMP regulations; and 2) to assure that all changes 21 CFR 314.70 requires are
documented in supplemental applications or annual reports. Appropriate regulatory action will be taken against those
establishments not meeting these requirements. Additionally, through the use of related compliance programs, a secondary
objective of this program is to confirm that NDA/ANDA requirements concerning adverse reaction reports, NDA field alerts,

and annual reports are being met.

The program provides for inspections on both routine surveillance and directed/for cause basis.
Routine Surveillance
Products that have received approvals within the previous one to three years undergo FDA scheduled coverage through
routine surveillance. Coverage of these inspections should include at least some products where approval was not based on a
specific pre-approval inspection. Particular emphasis should be directed at assuring that product reviews, NDA and ANDA
annual reports, and other requirements are being met.
Directed and for Cause
These are priority inspections that are likely to be application/product specific. They can be referred from review divisions,
forensic testing laboratories (based upon analysis of previously collected forensic samples), or results from CDER market
surveillance or district surveillance, etc.
Post-Approval Audit Inspections
These inspections confirm that a firms commitments made at the time the application was approved have been completed or
are underway in accordance with those commitments.
The FDA recommends appropriate regulatory and/or administrative action when there are significant deviations from cGMP
regulations or from application commitments. Actions that may be considered are application integrity policy, application
withdrawal, FDA-requested recall, warning letter, seizure, injunction, and prosecution. Center concurrence is required for
warning letters based on unapproved changes or a pattern or practice of unreliable data (6).
Drug Manufacturing Inspections (Routine cGMP [Surveillance] Inspection)
The goal of this inspections activities is to minimize consumers exposure to adulterated drug products. Under this program,
inspections and investigations, sample collections and analyses, and regulatory or administrative follow-up are made to 1)
determine whether inspected firms are operating in compliance with applicable cGMP requirements, and if not, to provide the
appropriate evidence for actions to prevent adulterated products from entering the market, potentially remove adulterated
products from the market, and to take action against persons responsible as appropriate; 2) to provide cGMP assessment that
may be used in efficient determination of acceptability of the firm in the pre-approval review of a facility for drug applications;
3) to provide input to firms during inspections to improve their compliance with regulations; and, 4) to continue FDAs unique
expertise in drug manufacturing in determining the adequacy of cGMP. Sites selected by CDER and district office under this
inspection program receive biennial inspections. This inspection provides two surveillance inspectional possibilities, full
inspection option and abbreviated inspection option.
The Full Inspection Option
This is a surveillance or compliance inspection meant to provide a broad and deep evaluation of the firms cGMP. This occur
when little or no information is known about a firms cGMP compliance; or for firms where there is doubt about the cGMP
compliance in the firm; or follow up to previous regulatory actions. Follow up to a warning letter or other significant regulatory
actions should require a full inspection option. The full inspection option will satisfy the biennial inspection requirement.
The Abbreviated Inspection Option
This is a surveillance or compliance inspection that is meant to provide an efficient updated evaluation of a firms cGMP. The
abbreviated inspection will provide documentation for a firm continuing in a satisfactory cGMP compliance status. Generally
this will be done when a firm has a record of satisfactory cGMP compliance, with no significant recall, or product defect or alert
incidents, or with little shift in the manufacturing profiles of the firm within the previous two years (7).
FDA SYSTEMS INSPECTION
The FDAs Drug Manufacturing Inspection Compliance Program, which contains instructions to FDA personnel for conducting
inspections, is a systems-based approach for cGMP inspection. FDA general scheme of systems for auditing the manufacture
of APIs, drugs, and drug products consists of the following six systems.

Quality System
This system assures overall compliance with cGMPs, 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,
validation protocols, and reports, etc.). It includes all product defect evaluations and evaluation of returned and salvaged drug
products (see the cGMP regulation, 21 CFR 211 Subparts B, E, F, G, I, J, and K).
Facilities and Equipment System
This system includes the measures and activities that provide an appropriate physical environment and resources used in the
production of the drugs or drug products. It includes buildings and facilities along with maintenance; equipment qualifications
(installation and operation); equipment calibration and preventative maintenance; and cleaning and validation of cleaning
processes as appropriate. Process performance qualification will be evaluated as part of the inspection of the overall process
validation, which is done within the system where the process is employed and utilities that are not intended to be incorporated
into the product such as heating, ventilation, and air conditioning (HVAC), compressed gases, steam, and water systems (see
the cGMP regulation, 21 CFR 211 Subparts B, C, D, and J).
Materials System
This system includes measures and activities to control finished products, components, including water or gases, which are
incorporated into the product, and containers and closures. It includes validation of computerized inventory control processes,
drug storage, distribution controls, and records (see the cGMP regulation, 21 CFR 211 Subparts B, E, H, and J).
Production System
This system includes measures and activities to control the manufacture of drugs and drug products including batch
compounding, dosage form production, in-process sampling and testing, and process validation. It also includes establishing,
following, and documenting the performance of approved manufacturing procedures (see the cGMP regulation, 21 CFR 211
Subparts B, F, and J).
Packaging and Labeling System
This system includes measures and activities that control the packaging and labeling of drugs and drug products. It includes
written procedures, label examination and usage, label storage and issuance, packaging and labeling operations controls, and
validation of these operations (see the cGMP regulation, 21 CFR 211 Subparts B, G, and J).
Laboratory Control System
This system includes measures and activities related to laboratory procedures, testing, analytical methods development and
validation or verification, and the stability program (see the cGMP regulation, 21 CFR 211 Subparts B, I, J, and K) (7).
FDA INSPECTION CLASSIFICATION
At the end of an inspection, observations made during an inspection are shared with the most responsible party at the firm in
FDA Form 483, Report of Observations. The determination of whether any condition or practice is violative is FDA decision,
made considering all inspectional and compliance input. An inspection classification is reflected in the FDA Inspections
Database (see Figure 2). The following are the FDA inspection classifications.
Figure 2: Example of FDA Inspections Database (8).

No Action Indicated (NAI)

No objectionable conditions or practices were found during the inspection (or the significance of the documented objectionable
conditions found does not justify further action).
Voluntary Action Indicated (VAI)
Objectionable conditions were found and documented but the district and/or center is not prepared to take or recommend any
of the regulatory (advisory, administrative, or judicial) actions, since the objectionable conditions do not meet the threshold for
regulatory action. A VAI classification should be made only if FDA-483 has been issued.
Official Action Indicated (OAI)
Objectionable conditions were found and one of the regulatory actions should be recommended. Typically, an OAI
classification should be made only if FDA-483 has been issued and the documented evidence supports the action
recommended (8).
REGULATORY ACTIONS
If a firm is in apparent noncompliance with FDA regulations, FDA can move forward with the following administrative actions
for noncompliance:
Warning letter
Application action (e.g., recommendation for Denial of Pending Application [NDA, ANDA] Recommendation for
Revocation of Approved Application [NDA, ANDA])
Recall
Import Alert
Implementation of the Application Integrity Policy
Furthermore, if a firm is in apparent noncompliance with FDA regulations, the FDA can move forward with the following
civil/criminal actions:
Seizure
Injunction
Civil Penalty
Prosecution under the FFDCA (8)
GUIDELINES FOR AN FDA INSPECTION
Upon Notification of an Inspection from FDA
FDA inspections can occur with or without prior notice. Both the length and the frequency of inspections are at the discretion of
FDA. However, FDA will usually contact a company to set up a routine inspection if a companys last inspection was nonviolative. FDA will also generally contact a company before conducting a preapproval inspection for approval application. FDA
will not contact a firm to preannounce an inspection when the firm has had a prior violative inspection, such as one resulting in
a warning letter or other action.
When FDA contacts a company to notify it of an upcoming visit, understand that the start time of the inspection is not a
negotiation point. However, a company should let FDA know whether there is some extraordinary event about to occur, such

as an all-day meeting that will have the entire management team off-site, a festival holiday, or any other regulatory agency
audit. FDA might then decide to change its plans, but be aware that it might not.
Upon notification from FDA that an inspection will be initiated, obtain the following information:
Starting date and expected duration
FDA inspector name and contact information
Who and what is being inspected
Reason for the inspection
Requests for specific documents/information
Before the Site FDA Inspection
The best possible position to be in before an inspection is to already be aware of problems and to be countering them. The
worst possible position to be in is having the FDA investigator (or FDA inspector) get the impression that he or she had to call
the problem to a companys attention.
Establish and maintain systems that ensure sustained compliance with applicable laws and regulations. No amount of
inspection-specific preparation or training will ensure success if the elements the investigator assesses do not comply with
laws and regulations. Companies need to understand and abide by applicable regulations, and put in place systems for
internal audit and periodic management review to ensure those systems perform as intended. A key reference for senior
managers to use to understand current regulatory expectations of management teams is International Conference on
Harmonization Guideline Q10, the Pharmaceutical Quality System. This document contains detailed and valuable guidance for
senior executive teams in the pharmaceutical industry. Regular, thorough internal compliance audits are a key need to ensure
a sustainable state of compliance.
Understand the rules that govern inspection. Much confusion, anxiety, and some procedural missteps can be avoided if
company personnel understand what FDA has the right to see, which things can lawfully be denied, and which things may be
provided on a discretionary basis, but do not have to be provided. This takes some time and effort, and there are many details,
but the following summarizes the essentials:
FDA may enter and conduct an inspection any time regulated activities are taking place. This may or may not coincide with
normal business hours. It is what is happening at the facility that determines the legitimacy of the timing of the inspection, not
the clock and not the calendar. Refusing FDA access to anything the agency is lawfully entitled to see is a criminal violation of
the FFDCA, and may trigger other adverse consequences such as forcing FDA to seek an administrative inspection warrant
from the Federal court. All of this is preventable with good planning and management.
The FDA personnel must appropriately identify themselves by showing their credentials (identification) and issuing a Notice of
Inspection to a senior company official. This is for the companys protection to assure that only duly authorized FDA personnel
are present for the inspection.
FDA has the right to review, copy, and verify records required to be kept by FDA regulations, including procedures and
documents that show how activities were conducted, and the raw data (source documents) that support the creations of batch
records, investigation reports, validation reports, and so on.
FDA may elect to collect samples of products or extraneous matter observed during an inspection, although this is not always
done.
Ordinarily FDA will conduct daily debriefings and discuss the days findings, but they are not obligated by law to do this until
the end of the inspection. At the conclusion of the inspection, a full list of observations of potential violations will be provided in
the FDA-483 form.
INITIATIVES TO PREPARE FOR AN FDA -INSPECTION
Commission a Quality System Self-Study
Invest in a comprehensive, self-assessment of ones system by third-party experts who can identify cGMP compliance gaps in
ones established procedures and practices. Make an in-depth, system-by-system analysis in order to reveal as much as
possible, and disclose all the findings to executive management. Develop a broad project plan that identifies priority targets for

remediation. Extend the initiative across sites to ensure that findings are shared and global action occurs.
Design Quality Systems to Measure Performance
Ensure that quality systems are not only designed to be compliant, but that they are also designed to enable the system to be
managed as well. Each system should be designed to provide performance metrics that explain how well the system is being
managed, as well as what quality issues and trends the system reveals. For example, an aging report on open complaint
investigations describes how well the system is being managed, while a trend report on type of complaint by product helps to
identify the quality issues.
Conduct Active and Decision-Oriented Management Reviews
Establish a management review process that gets the metrics in front of management at the level commensurate with the risk
being reported as well as the level that has the authority to assign resources and approve the spending necessary for the
solution. Decision-making and accountability for measurable results must formalize and characterize the review process.
Tremendous business benefits can result from a cultural tone set at these review meetings of intolerance for repeated root
causes of nonconformities and unfavorable quality trends.
Manage Projects to a Verifiable Conclusion
Once projects are initiated to address product, process, quality trend, and system issues oversee the project to completion.
This requires taking an active part to ensure that the project has a plan and is being managed accordingly. Furthermore,
management should actively supports the plan by ensuring organizational alignment and removal of obstacles that impede
progress toward success. A successful conclusion must be determined by means of verifiable evidence that the corrective and
preventive action (CAPA) truly addressed the root cause and that the solution is both in place, in use and has achieved the
desired result. Given the risk being managed, there is a benefit to objective third-party verification in addition to ones own.
Train Employees to Manage FDA Inspections
Understanding the process and the reasons why inspections unfold as they do will help to alleviate anxiety. Practicing
responses to typical interview questions will assure a smoother inspection process and help employees answer confidently
and truthfully, without going overboard in the amount of information they provide.
This procedure should address everything from the contact by the receptionist on the first day to the inspection closeout
meeting on the last. It should outline personnel roles and responsibilities, call down lists, and define the company position on
such controversial subjects such as FDA requests to take pictures. Know in advance the subject matter experts who have
necessary skills to interface with an FDA investigator. Take special effort to train these individuals on appropriate demeanor
and how to respond to investigator questions. Help them to understand that it is okay to say, I dont know, to a question
rather than to guess, ramble on about hypotheses, or to lie and mislead.
Employee preparation is essential. Each and every employee does not need to know the details of the execution and goings
on within the audit, but they do have to be prepared and know the role they play within the audit. Employees should be
prepared to answer key questions such as:
What is the quality policy?
Ensure each employee understands and can speak to what the policy means to them
Use the quality policy training
How do you know whats required of you in your job?
Employees must know what is defined by their job description
Make sure employees know to follow approved procedures and work instructions
Make sure employees know how to access procedures and work instructions
Have employees bring up errors in procedures and instructions now
Is your training current?
Ensure the training is current
If there are gaps, complete the training now and maintain it!

What if one doesnt know the answer?

The correct answer for employees is I am not sure but I will get the information for you.
Conduct Mock Inspections to Rehearse Systems and Assess Employee Readiness
These exercises can be very useful both to identify compliance issues that need to be addressed before an inspection takes
place as well as familiarize employees with the process and how best to respond to questions that may be addressed to them.
It should be noted that FDA inspections differ from internal audits performed by company personnel in several important ways.
FDA personnel are not as familiar with internal company practices as company auditors, and furthermore, FDA personnel are
charged with documenting their observations and asking questions designed to determine responsibility for compliance
lapses. Therefore, during internal audits, the mock FDA investigator should know how to play the role effectively in order for
the preparation to be fully useful.
Establish Systems to Manage the FDAs Presence On-Site
Key things to address in the system include:
Who to notify when FDA arrives at the site.
Where to take the FDA employee upon arrival.
Who will accept the Notice of Inspection on behalf of the company.
Who will be in charge of the inspection for the company.
Who will escort the FDA personnel while they are on-site.
Where will the FDA personnel be housed (conference room, etc.) while on-site.
How will the company assure prompt access to needed people and documents.
Who will take notes for the company as the inspection progresses, and/or what e-systems, if any, will be employed
(such as real time network communication via instant messaging or chat room format).
Who will discuss daily audit summaries.
Who will participate in the exit discussion, what the strategy for that discussion will be, and who will speak for the
company.
What is the company policy regarding FDA taking photographs or asking that affidavits be signed by company officials.
Assign Roles and Responsibilities
There are far more roles and responsibilities during an inspection than are first imagined. They may be thought of as roles that
are technical and may be called upon to answer investigator questions, and administrators who are responsible for logistics
and communication. Knowing who will fill these roles, defining their responsibilities in advance, and having them well trained
are quite important to a smooth inspection. Important roles include: inspection coordinator, functional or technical
spokesperson, inspector escorts, daily scribe, corporate communicator, document retriever, document logger, messengers,
investigator request logger, and potential issue list maintainer.
The FDA coordinator is the company personnel assigned to accompany the FDA investigator/inspector during the FDA
inspection. The FDA coordinator is responsible for ensuring that the company policies are adhered to and followed, and for
ensuring that comprehensive and accurate notes are taken during the FDA inspection.
The FDA escort is the company personnel assigned to accompany the FDA investigator/inspector during the FDA inspection,
in the event that there is more than one FDA investigator/inspector. The role of FDA escort is to act as hall monitor or
chaperon, to ensure that the FDA investigator is not left unattended while on company property and to direct all company
related questions that the FDA inspector may have to the FDA coordinator. In the immediate absence of the FDA coordinator,
the FDA escort is responsible for taking comprehensive and accurate notes as necessary.
Commonly Requested Information
Anticipate what the FDA investigator will request to see. The following is commonly requested information one must have
ready for FDA inspection:
The relationship and responsibilities of the firm being inspected to other sites in the organization
Organizational charts with full name and title of corporate officers, plant officers and managers, and key plant
personnel to the supervisory level

Name and title of key officials on-site and description of responsibilities

Name and address of the individual to whom regulatory correspondence should be addressed
Regulatory agent (US Agent): name, address, phone, fax, and e-mail
List of US product with (drug master file [DMF] number, NDA/ANDA number and status)
List of post-approval supplement (NDA/ANDA number and status) since the last inspection
List of customers for US product (name, address, contact name)
List of all lots shipped to US (product, lot number, quantity, customer)
Manufacturing flow chart for each product manufactured at the site
Floor diagrams of facilities with details on production and filling areas
Production and laboratory work schedule
Diagram of water purification systems and changes implemented since the previous inspection
List of process and critical equipment and its changes since the last inspection
Annual reports and product reviews for all products since the last inspection
Lots rejected, reworked, or reprocessed including the reason and disposition
Procedure for reprocessing and reworking
Procedure and list of the following (include the open date, closed date, description of event, lot number and outcome):
Deviation reports
Change controls
CAPA
Complaints
Laboratory out-of-specification reports (including finished products, in-process products, raw materials, stability
tests, bioburden, and sterility tests)
Summarized environmental monitoring data for all controlled (aseptic) areas since the previous inspection
Summarized water systems monitoring data since the previous inspection
Stability data for all products (include list of all lots currently on stability and a summary)
Recalls
Filed alerts
Validation master plan and timetable
Labels, inserts and marketing materials
Current year facility drug registration
Copy of FDA assigned labeler code
Site master file
DURING THE SITE FDA INSPECTION
The best possible position to be in during an inspection is to have well-placed confidence in the readiness of the management
team to flawlessly shepherd the inspection process with professionalism and grace.
Arrival of FDA inspector
Escort the inspector to an appropriate meeting room. This room shall serve to minimize disruption to normal business
activities. The FDA coordinator, FDA escort, vice president (VP)/quality assurance (QA) director/regulatory affairs (RA)
director/production director should be available when the inspector first arrives. Receptionist/FDA coordinator must notify each
of company department managers that FDA inspector/investigator is on-site/company premises. This will ensure that all
appropriate personnel are available for consultation during the inspection. FDA coordinator must use the FDA inspection
recording form (Figure 3). Print out sufficient quantities of form (usually, quantity one of page one and quantity 10-20 of page
two per FDA inspector). For multi-day inspection, use a different colored paper for each day.

Initial Meeting with FDA Inspector

The FDA coordinator, FDA escort, and VP/director-QA/RA/production meet and introduce themselves to the FDA investigator.
Request and record the following information from the FDA investigator:
The name(s) of the investigator(s)
The credentials of the investigator(s)
The purpose of the visit
If the purpose of the visit is for facility inspection, the investigator(s) should issue a Notice of Inspection (FDA Form
482)
As appropriate, introduce the FDA investigator(s) to the FDA escort(s), and explain the role of the FDA escort. Request that
the FDA investigator(s) direct all company-related questions to the FDA coordinator.
Have the FDA coordinator/ FDA escort inform the FDA investigator that it is company policy that the use of cameras, tape
recorders, and other recording equipment are not permitted within the facility. Exceptions to policy may be made on a perincident basis, but only after consultation with company executive management. During FDA inspections, only company
copying equipment shall be used to duplicate documents and files.
Have the chief executive officer or director of regulatory affairs and director of quality assurance make a short presentation
regarding the nature of the company business. Provide a brief tour of the company facility to the FDA investigator(s).
FDA Coordinator, FDA Escort(s)
The principal responsibility of the FDA coordinator and the FDA escort(s) is to create and maintain an atmosphere of
professional and congenial cooperation. The FDA coordinator shall seek to resolve difficult matters as quickly as possible, so
as to preserve a good working relationship with the FDA investigator. The FDA coordinator shall be present during all
conversations between the FDA investigator(s) and other company personnel.
The FDA coordinator should attempt to directly answer the FDA investigator(s) questions. The FDA coordinator may allow
department managers or other personnel to answer questions but only upon a determination that a particular employee is
appropriate to respond. The FDA coordinator shall be present during all interactions between the FDA investigator(s) and the
department managers.
Decide whether or not other company personnel are required to participate in the FDA inspection. Avoid allowing non-

essential personnel to be drawn into conversations, unless specifically requested.

In general, do not leave the FDA investigator(s) alone at any time. The FDA investigator(s) may be left alone to review
documents that they have collected, although the FDA coordinator should remain conveniently available to the FDA
investigator(s) during the review in order to answer any questions that may arise.
The FDA investigator(s) may physically observe any area, equipment, or process related to manufacture. The FDA coordinator
and department managers should be careful to recognize that the FDA investigators questions may not be completely
consistent with company operations or jargon, therefore employees who have been authorized to participate in responding
may misunderstand the questions.
The FDA coordinator and department managers should ensure that all persons responding to questions by the FDA
investigator understand the questions. If the FDA coordinator or department manager believe that a question is argumentative
or inappropriate, the escort should ask the FDA investigator to clarify or rephrase the question, or, if necessary, instruct the
employee not to answer the question until their objections to the question are resolved.
During the course of an inspection, the FDA investigator(s) may identify a condition that merits correction. If proper correction
can be promptly made, then remedial action should be taken immediately during the inspection. Even so, this remedial action
may not prevent the mention of the condition on the FDAs list of inspectional observations (FDA Form 483). However, the
remedial action should be implemented and documented. The FDA investigator(s) should be asked to note the correction of
the condition on the Establishment Inspection Report (EIR), if not on the FDA Form 483.
A FDA affidavit (FDA Form 463) is generally used to establish Interstate Commerce. Unless the company sells only within
state, and unless all raw materials used by the company for its products are obtained in-state, Interstate Commerce can be
readily established. Only company executive management shall have responsibility to read, sign or initial, acknowledge, or
ratify such FDA affidavit.
Note-Taking
FDA coordinator, escort(s), department managers (or designees), must take detailed notes during the FDA visit. All notes shall
be recorded on form, and shall be factual, accurate, and without opinion.
FDA coordinator, escort(s), must record all documents and files that are reviewed by the FDA investigator(s). The FDA
investigator(s) should be given adequate time to review these documents and files. Identify all items that require follow-up
during the investigation.
The FDA investigator(s) will be taking notes during the inspection. The FDA coordinator, FDA escort(s), and department
managers should be alert for any issues that attract the attention of the FDA investigator(s), and should take note of these
issues. Unusual questions or FDA investigator volunteered comments will often indicate such issues.
Operate a Front and Back Room
Not all conversations or activities are appropriate in front of FDA investigator(s). The primary conference room or front room
is more formal and is the location where interviews with FDA investigators take place and where investigators review
requested documents. This is the primary location where the official business occurs, as well as other parts of the facility the
investigator may wish to see. The front room will be the location from which the FDA investigators, inspection coordinator, and
scribe will primarily reside. The back room is the nerve center of the inspection process. It is the location where document
requests are taken, delivered, and reviewed before taken to the front room. The back room is also where spokespersons are
on standby for interviews, document requests logged, copies of documents are made, and messengers are continuously
running documents. These two rooms need to be convenient to each other, as there is the need for the inspection coordinator
to move between them.
Keep Documents Flowing Expeditiously
Only documents specifically requested by the inspector should be provided for review. Some FDA investigators have the
reputation of getting quite impatient if it takes longer than a few minutes to retrieve a requested document. A company must
always know where a document normally resides, and where it lives if one happens to be checked out for a legitimate
purpose. It is far more important to use time to become familiar with the requested document in the back room than it is to use
the time tracking down the location of a missing document. The expeditious flow of documents exhibits control and confidence,

rather than an image of disarray or possible alteration of documents. Very quickly the front room can be filled with documents.
Be sure that they do not get mixed-up or comingled as a result of a flurry of requested documents. Develop a means to stay
organized, such as each requested document or set of documents living in a folder or pouch that the logged request identifies.
Consider what will be done with the documents in the front room at the end of the day that ensures both security and the
ability to pick up quickly the next day where the process left off.
Release only single copies of documents to the FDA investigator(s). A copy of each document released to the FDA
investigator(s) should be made prior to release (it is very important to keep a copy of every record/document that is provided to
the inspector during the inspection). A file shall be maintained that contains a complete copy of all documents released.
Communicate Effectively
Develop effective means of communication during the inspection between company personnel involved in the inspection and
the FDA investigators, as well as communication within the company. FDA investigators are open to a debriefing session at
the end of the day, particularly after the first few days of an inspection. Take the opportunity to ask if they have identified any
issues. It gives one an opportunity to address issues during the inspection and possibly avert an observation. Inquire after the
effectiveness of the administration of the inspection and if service can be improved in any areas. Also discuss on a daily basis
among the company inspection team on how the process can be improved and how to best prepare for the next day of the
inspection. Use this time to develop a collective sense of how well the inspection is proceeding and whether to initiate midcourse corrections.
Whether or not one considers an inspection eminent, a well-exercised drill plan will help company to be prepared for an
inspection and help build confidence that company inspection team will be an asset, not a hindrance, to the inspection process.
Inspection Conclusion
At the conclusion of the inspection, if the FDA investigator has not offered to have an exit discussion (exit interview or closeout), the FDA coordinator should insist that such a session be held. The exit discussion shall be scheduled such that the
following relevant management personnel are in attendance:
Chief executive officer
Director of regulatory affairs and director of quality assurance
Head/managers from all inspected departments
During this meeting, if serious deficiencies have been found during the inspection, an Inspectional Observations Form FDA 483
will be issued, which lists the deficiencies. Every item is to be read carefully and understood. If a comment is not understood,
an explanation or basis of the comment or observation shall be requested of the FDA investigator(s).
Do not argue with the FDA investigator(s). If there is a misunderstanding, or if the investigator is in factual error, an
explanation shall be made as to why he/she/they is/are in error. The FDA investigator(s) is unlikely to delete an item from the
FDA Form 483, but may cross out and initial an item.
The FDA investigator(s) may discuss in more detail some observations on the FDA Form 483 than actually appears on the
form, and will often suggest what should be done to make corrections, but will usually avoid specifying how to make
corrections. It is appropriate to discuss documents or other information that the FDA investigator may or may not have been
taken into account during the inspection, and that are relevant to issues on the FDA Form 483.
If a condition that merits correction was identified in the course of the investigation, and was properly corrected, it should be
verified that the FDA Form 483 form notes that the condition has been corrected. When timeframes for action are stated,
ensure that the timeframes can be met.
If FDA Form 483 is presented, it is sufficient at the closing meeting of the inspection to advise the FDA investigator, orally, of
the companys intention (or likelihood) to submit a written response to the FDA Form 483. If FDA Form 483 is not presented, it
is appropriate to request a copy of the Establishment Inspection Report (EIR).
ACTIONS TO BE TAKEN AFTER AN FDA INSPECTION
Inspection Summary Report
Within five business days, the FDA coordinator shall prepare an executive summary of the FDA inspection to company senior

and executive management. The report should be kept with documents and include:
A summary of questions and discussions between inspector and each employee
List of all product or facilities/departments viewed
List of all records reviewed
Copies of all documents duplicated for the inspector
Note of all samples taken, and receipt for samples (FDA Form 484)
Note of all commitments made (include completion dates if set with FDA)
Inspector comments
Write a Cooperative Response to Form FDA 483
FDA uses the company response as a critical gauge to develop its opinion of a company and its management. It is not only an
opportunity to convey a positive tone and a sense of urgency to resolve the issues, but a quality and compliance philosophy as
well. The FDA investigators and district office personnel will be examining not only the adequacy of response to the specific
observation, but whether the response truly gets at the heart of the matter. The response will need to show that the company
is not just correcting a problem, but that the company has broadly examined the impact of the problem, and the company has
made changes to prevent the problem from recurring. They will examine whether the company has made the same promises
before, and failed, or whether the steps the company is taking will truly address the fundamental issues. Provide commitment
dates for deliverables, and stick to them. Timetables for deliverables must be balanced between showing a sense of urgency
and reasonableness based on the risk that needs to be mitigated. The company may hear from FDA that the timetables for
certain deliverables seem too long. If company indicates this is due to inadequate resources, FDA will politely say that this is
not their problem.
The FDA coordinator, with the cooperation and inputs of all relevant company personnel, shall be responsible for authoring
and preparing all written responses and other related subsequent correspondence to the FDA Form 483.
The written response, directed to the FDA district office, should be submitted within 15 days of receipt of the FDA Form 483.
The response should address the following:
An explanation of any matters the FDA investigator(s) included on the FDA Form 483, but which the company does not
intend to change
A description of changes that have been implemented
A description of changes currently being implemented, with an estimated date of completion
An identification of any unclear or incorrect observations
A request for a copy of the EIR
The written response shall be a point-by-point response to the items identified on the FDA Form 483. The response should
address broad-ranging quality and compliance issues, not just the specific item on the FDA Form 483. The written response
shall be professional, businesslike, nonargumentative in tone, and include extensive exhibits and attachments as appropriate.
Only written correspondence shall be provided in response to the FDA Form 483.
Take Commitment Dates Seriously
Count on the fact that someone within FDA is taking notes on when a company says in response letter, or verbally during an
inspection close-out meeting, that they will correct specific items. Slipped dates are either a sign of mismanagement or truly
underestimating the magnitude of the task. Missed dates are equated with continued exposure of a violation or risk condition.
It is better that FDA finds out about slipped dates from a company directly than to find out for themselves during a follow-up
inspection. CAPA projects can be complex and require significant cross-functional and cross-site coordination. For this reason,
the skills of a professional project manager should be employed that can breakdown the tasks and use professional tools to
develop plans and objectively monitor and report on progress. The plan then becomes the object of playing a scenario in
which obstacles arise and active intervention can occur. This is far better than learning about delays by informal means, or
relying on the unfounded confidence of a biased individual who thinks everything is on track.
Develop a Plan with Verifiable Results
The mistake is often made that the response itself to the FDA Form 483 is the CAPA plan for the inspection observations. The
response is often viewed as the checklist, and management often relies on the good word from the staff that things are on

track or completed. When one considers the potential global impact of a single inspection, a thoughtful plan must be
developed to ensure that the issues are addressed globally and in a manner that sustains results. Such a plan goes leads to
careful examination of root causes and effective global implementation that achieves sustained changes on the shop floor or
anywhere in the organization where the issue applies. Objective evidence must be acquired and examined to verify that
results have been achieved. To accomplish this requires the application of project management discipline, management
direction, and oversight.
Even though a company may have completed a commitment in a response to FDA, they will likely nod graciously and indicate
that they will find out for themselves when they come back on a follow-up inspection. So count on the fact that FDA will verify
the effectiveness of the action the company has taken. This is all the more reason a company should know the effectiveness
for itself and not rely upon the outcome of an inspection to be the source of information. This is accomplished first by defining
what measurable success criteria looks like, and secondly by assembling a file on each observation with the objective
evidence that the success criteria had been met. Conduct a formal review of the file and challenge the evidence to be certain
that it holds up to critical examination. Consider the use of third-party participation to provide an unbiased perspective. Such
an exercise will not only rehearse for a follow-up inspection, but will provide company with the necessary degree of confidence
that the issue has been resolved.
Activities that follow FDA inspection are critical and many important aspects are often overlooked. These activities need to be
characterized by a thorough analysis and disciplined execution to arrive at a confident conclusion (11-15).
CONCLUSION
cGMP FDA inspections are critical business activities that can have lasting impact on a companys profitability, and may result
in serious regulatory consequences if violations are uncovered.
This paper has attempted to provide the basis for being well-prepared for FDA inspection. Practical initiatives were described
to ensure that a firm is in the best possible position from a regulatory compliance perspective before, during, and after FDA
inspection.
While the emphasis here has been on the benefits of such an approach for a successful inspection outcome, it is worth
mentioning that business benefits are derived as well from stable and capable processes, elimination of waste due to cost of
non-conformance, implementation of best practice across global organizations, and cost avoidance of enforcement penalties.
As such, this paper is a call for preparedness to ensure effective, permanent solutions are implemented in areas identified by
an in-depth assessment of quality systems; and also a call for proactive leadership in managing regulatory compliance.
REFERENCES
1. FDA, Facts About Current Good Manufacturing Practices (cGMPs), available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing /ucm169105.htm
2. FDA, Sec. 501, Chapter V: Drugs and Devices, Federal Food, Drug, and Cosmetic Act, available at:
http://www.fda.gov/RegulatoryInformation/Legislation
/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/default.htm
3. FDA, Drug Applications and Current Good Manufacturing Practice (CGMP) Regulations, available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess /Manufacturing /ucm090016.htm
4. FDA, Drug Compliance Programs, available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation
/ucm252671.htm
5. FDA, Pre-Approval Inspections, Program 73456.832, Chapter 46, New Drug Evaluations, FDA Compliance Program
Guidance Manual, 2010.
6. FDA, Post Approval Audit Inspections, Program 7346.843, Chapter 46, New Drug Evaluations, FDA Compliance
Program Guidance Manual.
7. FDA, Drug Manufacturing Inspections, Program 7356.002, FDA Compliance Program Guidance Manual, 2002.
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Regulatory Affairs, Food and Drug Administration, available at:
http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ ucm056246.htm
9. FDA, Inspection Classification Database Search, available at: http://www.accessdata.fda.gov/scripts/inspsearch/
10. How to Prepare for an FDA Inspection, PathWise, available at: http://www.pathwise.com/audit_consulting.php

11. Snyder J.E., Preparing for FDA Inspections: Before, During and After, Journal of GXP Compliance, Vol. 8, No. 2,
2004: pp. 25-32.
12. Armstrong M., How to Manage an FDA Inspection, Regulatory Compliance Newsletter, GMP Labeling, Inc., 2007,
available at: www.gmplabeling.com/news_letters/news0907.pdf
13. Guidelines for an FDA Inspection, Office of Research Compliance, Emory University, available at:
http://www.orc.emory.edu/ORC_documents/FDAInspection-guidelines21511.pdf
14. Chesney D.L., Pharmaceutical Companies Preparing for FDA Inspections, Pharmaceutical Compliance Monitor,
2012, available at: http://www.pharmacompliancemonitor.com/pharmaceutical-companies-preparing-for-fdainspections/
15. Guidance for FDA Inspections, Coastal Consulting Group, Ltd, available at:
www.coastalcg.com/PDFS/GUIDE_1_4.pdf GXP

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