A 121 Avoid Warning Letters (2)

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How to Avoid FDA Warning Letters

Revision 1.02

February 2005

Published by

www.labcompliance.comGlobal on-line resource for validation and compliance

Author: Ludwig Huber

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1. Introduction

The United States Food and Drug Administrations (FDA) mission is to

protect consumers' health and safety under the Federal Food, Drug, and

Cosmetic (FD&C) Act (1) and other laws. To do this the FDA hasdeveloped 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, packed, tested and held.

During inspections the FDA verifies that companies 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 with

number 483. These reports are usually called 483sor 483 inspectional

observations. Depending on the severity of deviation the companies may

get a warning letter later on.

In the last couple of years many companies have received FDA 483

inspection observations and warning letters because they failed to comply

with FDAs GxP regulations. Amongst those are well established and

well known companies with global presence. Warning letters have been

issued for companies in the United States but also in Europe, Asia and

Australia. Getting a warning letter can be a financial disaster for the

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 medical devices into the

United States can be denied. In some cases warning letters can also be a

personal problem for individual employees if they are hold accountable


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for non-compliance. The FDA publishes the warning letters on the

internet and makes consumers, competitors and business partners aware

about a companies non-compliance which is bad for the image of acompany.

The risk to get 483s and warning letters can be minimized by following a

couple of advices:

1. Know regulations and guidelines, both the text as well as understand

the intent and the spirit. This includes GxPs as well as 21 CFR Part

11 on electronic records and signatures.

2. Learn about mistakes others made through studying inspection

observations (483s) and warning letters

3. Build up a quality system in line with regulations and guidelines.

Take learning experience from FDA inspectional practices,inspectional observations and warning letters for this.

4. Develop procedures and practice on how to make the best out of FDA

Inspections.

5. Minimize the damage of inspection observations and warning letters

by effective response.

It is far out of the scope of this paper to teach readers on regulations and

guidelines. There is lots of literature out, for example a 120 page primer

on GLP and GMP (2) and a series of publication on understanding and

implementing 21 CFR Part 11 (3). Reference 4 includes a list of FDA

regulations, so-called predicate rules. Building a quality system is also

not in the scope of this paper but an in depth understanding of regulationscan also be used to build such a system

This article will focus on steps number two, four and five. Other steps are

covered very much in detail in the book FDA Inspections (5).

For this paper we make extensive use of the Internet. Most literature and

reference material cited in this paper are available online. Links can be

found in the reference section at the end of this paper.

.


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Studying Inspectional Observations and

Warning Letters Learning from OthersMistakes

FDA regulations usually stay for a long time. On the other hand they are

not specific leave a lot room for interpretation and inspection practices

can depend on the expertise and opinion of individual inspectors. Thats

why the FDA has developed guidance documents for the industry to

document FDAs interpretations on critical topics and for inspectors to

ensure harmonization across all FDA inspections. Unfortunately guidance

documents are still not specific enough to teach the industry on all details

and many times they include general statements like enforcement

depends on the risk on product quality or the extent of validationdepends on the system complexity. Again this leaves a lot of room for

interpretation that may change over time. The real current thinking of the

FDA and their inspectors can be judged from FDA inspectional

observations and warning letters.

When inspector finds non-compliance he/she will write an inspectional

observation during the inspections. Inspectors use a special form, so-

called 483 form. The information can be handwritten or typed using

typewriter or computers and is handed over to the company at the

conclusion of the inspection. The advantage of 483s 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 showthe inspectors view and are not approved by FDA management with

consequent inconsistencies. It also may happen that certain citations may

never be approved because they may not be in line with FDAs current

thinking. On the other hand they can 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 companies reputation. An example of a typical 483 can be

downloaded from reference 6

Depending on the severity of deviations and possible negative impact on

public health the FDA may send a warning letter to the company. An

example can be downloaded from reference 7. The warning lettersfrequently make references to the 483 inspection observations and

sometimes also to the companies response.


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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 takefurther actions which may cause delay of new product approvals, import

alerts and denials, product recalls, seizure or consent degree and the

company may loose any governmental contract it has. Generally, a

follow-up inspection is scheduled such that the company has time to fix

the problem. But we should not forget, that any company that gets a

warning letter is on FDAs radar screen and will go into FDAs records

for the companys compliance history. Sometimes the assumption is that

if there are serious quality problem at one site, they also may exist at

other sites.

Warning letters are more representative because they have to be approved

by a higher level. To some extent they can be viewed as FDAs mostcurrent and most specific thinking on how to interpret regulations.

Warning letters can be downloaded from the fda website www.fda.gov .

The website www.fdawarninglter.com list excerpts of more than 100

warning letters related to GxP and validation.

In this chapter summarizes most cited deviations. They are not sorted in a

specific order. They are all important there fore we dont give some kind

of hit list.

No/inadequate procedures or procedures not followed

No management review

The responsibility of quality control unit not defined or the qualitycontrol unit did not follow the procedures

No internal audits

No/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/inadequate stability testing

Incomplete validation of computer systems

Rawdata not maintained

No or inadequate security procedures

No procedures of handling out of specification situations or

procedures not followed

No procedures for corrective and preventive actions to avoid

occurrence of similar problems


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Best Practices for FDA Inspections

A good quality system and compliance with regulations does not mean a

company can not get in trouble with the FDA. It is also important that

your people know what the FDA inspector feels to be important and to

make documentation readily available. A good preparation of your people

and documentation is a prerequisite for surviving FDA audits without

trouble. In this chapter we give advice on how to prepare your

organization for an FDA inspection and how to look best during the

inspection.

Preparing your organization for FDA inspections

FDA inspections are important for your department, for your company

and for your people. Failing and inspection can have tremendous

consequences and therefore your department should be well prepared.

Recommended steps in preparation for an FDA inspection are:

1. Learn about inspection practices and

2. Develop and implement an internal audit program

3. Develop standard operating procedures for FDA inspections4. Identify an FDA inspection response team

5. Identify who gets noticed if an inspection is coming

6. Prepare company personnel for FDA inspections

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 and/or regulations or customer requirements.

Internal audits are an ideal to tool in to prepare an organization forexternal inspections, for example FDA inspections

Internal audits should be well planned and follow a certain structure.

Needless to say not all systems can be audited for all items at one go,


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however this is not practical. A better recommendation is to set up a

schedule such that different systems are audited at different times and

over a certain period of time all items should have been checked in allsystems. Priorities of the audits should be based on risk assessment: high

risk systems should be audited first.

Internal audits are divided in three phases:

Preparation

Conduct

Conclusion, report and follow up.

In the following bulleted lists recommendations for all steps for the audit

of a laboratory control system are summarized.

Preparation

1. Establish audit team and lead auditor.

2. Review results of previous audits.

3. List areas to be evaluated.

4. Contact the laboratory.

5. Prepare an agenda.

6. Review agenda with the department and get consensus.

Conduct

1. Review selected documents, e.g. procedures for handling out of

specification situations and procedures for operator training.

2. Interview management and ask for organizational structure andresponsibilities of management, QA/QC and other functions.

3. Ask for a risk management procedure to categorize laboratory in

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 and software have been validated.9. Ask if tests have been made under high load.

10. Check system security. Try to access the system.

11. Examine test procedures and ask for results from a certain time

period.


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12. Trace the result back to methods for analysis and data evaluation,

operators and raw data. Review raw data.

13. Check data integrity. Specifically check if operators could manipulateelectronic records interactively on the computer and if so check if the

changes have been recorded by the system though an electronic audit

trail.

14. Ask which application software and which version has been used at

that time.

15. Ask what the difference was to the previous software version and

how users did make sure, that the new version worked as intended.

16. Verify if operators have been trained and successful completion of

the training has been documented.

17. Give immediate advice if any non-compliance with FDA regulations

or company standards has been found.

Conclusion, report and follow up

1. Have a closing meeting with all auditors and the laboratory

management.

2. The (chief) auditor/inspector summarizes all findings, assigns level of

concerns to each finding and listens to the labs response. Any

misunderstandings should be resolved at this point.

3. 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 sends the report to the

laboratory management. This also includes a time frame when the

response, e.g., 30 days, is needed.

4. The laboratory makes a plan to resolve the problem and writes anofficial statement to the auditor.

5. If the statement is accepted by the audit team, the file is closed.

SOP for FDA inspections

FDA inspections are so important that there should be a standard

operating procedure. The procedure should include information on:

Areas and documents that are subject to FDA inspections and that are

not. Prepare a list with examples.

Responsibilities (by department and function) Who should be informed when the inspection is announced and 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

Audit response team

Prior to the audit and audit response team should be established with

members from:

Quality assurance (owners, host)

Quality control Regulatory affairs

IT department

Manufacturing/laboratories

Validation group

People training

Employees should be prepared for FDA inspections. Typically they are

nervous to answer questions to the inspector, especially if it is the first

FDA inspection. Internal audits will help in the preparation but

employees should also be trained and get information on:

why are inspections necessary

inspection items, 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, what if they ask to take software for

evaluation of specific data

what typical questions that go beyond the daily work, e.g, about the

companies quality policy

company policies for visitors, e.g., safety and if visitors are not

allowed to take photos. How to apply policies to FDA inspectors, for

example what to say if they try to get into areas that only can be

entered with specific qualification requirements

how to provide documents, electronic vs. paper


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how to report inspection findings to management to make sure

management is aware of any problems.

The inspection has been announced

When the inspection is announced by the FDA, company management

should be informed immediately. Ask the FDA about type of inspection,

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

send out an e-mail to employees announcing the audit. Include at list

of most important things including 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 that can include review of

documentation and a walk-through of facility

Documents that should be readily available

Make sure that these documents are readily available

Organization charts with responsibilities

Procedures for internal audits and audit schedules

People job description and training records

Validation master plans

Procedures for change control and change control logs

Risk assessment procedures and list of high/low risk systems

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 as classified to be high risk

List of authorized people who have access to critical computer

systems

The inspector arrives

When the inspector arrives ask the same questions as to any other visitor.

These are for the photo ID card, FDA ID and name, office, address and


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phone number. If the inspector is accompanied by other people, 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 forcause inspection and how long the inspection is expected to last. After

that you can create some kind of an agenda together with the inspector.

During the inspection

There are a couple of things that are important during the inspection

Be cooperative

Try to get the answers to questions and requested documents as

quickly as possible

Avoid to argue with the inspector about observations

Escort the inspector at all times. Try to keep him/her in thedesignated room or areas

Take note on all questions and answers

Make a list of all documents provided to the inspector

Keep a copy of all documents requested by the inspector for

removal

Make sure all questions are clearly understood before they are

answered. Dont guess or assume anything!

Be honest and open to questions

Answer only to questions that have been asked. Stop talking when

the question has been answered and even dont explain your

answer.

Try to avoid to answer open ended questions. Ask back for more

details

If you dont know the answer, make this clear to the inspector,

again, dont guess. You may leave the room and get the answers

from anybody else in the inspection team or you may refer to

people who know the answer in bring them in the room.

If the inspector asks for a document where you are no familiar with,

ask back: what do you mean by this? You may have the document

but call it differently.

Try to fix problems during the inspection whenever possible

After the inspection

When the inspection is finished the inspector will note observed

deviations in the 483-form. Use the time when the inspector writes the


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483 form to review your notes write down any questions you still may

have. The inspector will present the 483 form with inspectional

observations in an exit meeting. The observations should be reviewedwith the inspector. If the observations are not understood or too general

ask for more details and examples. Document all your questions and the

answers. You can discuss and suggest corrective actions but dont make

firm commitments for corrective actions or any other follow up before the

consequences have been discussed with the inspection team.

Follow up

After the inspector has left review the observations with the inspection

team and assess the impact of the observations and summarize the

findings from the inspection. Develop a corrective action plan as a directresponse to the observations but also assess the impact the observations

my have on other areas not covered during the inspection

Responding to 483s and Warning Letters

In case a company gets a 483 inspection observation or warning letter, a

timely and correct response is important to minimize damage.

Response to 483-Form Inspectional Observations

In case there the inspector did find a deviation the 483 form is presented

by the investigation team to the firms representatives in the exit meeting.

The content is discussed. It is extremely important that all points are well

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 to an observation and you

feel it could have been caused by misunderstanding or becauseinsufficient information has been provided to the inspector, tell this

openly. There have been situations where inspectors did make changes to

the forms content. You also can point out corrective actions that you

have taken during the inspection before the exit meeting. You also can


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discuss alternatives for remaining corrective actions but be careful to

make time commitments until you have talked to the inspection team. The

inspectors can document your suggestions in the EIR.

Response to the 483 can be sent in writing, addressed to the district

director with a copy to the inspector. Written response should be sent

within two weeks. 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. Include corrective action plan, owners and a realistic time

schedule to fix the problem. It is very bad if you have to go back one or

more times and explain why you need more time. Also explain your

action plan on how to prevent occurrence of similar problems at your and

at other sites.

Response to warning letters

Recommendations on how to respond to warning letters is not much

different from what was said in the previous section about 483s.

Response must come within two weeks. It is important to make a

statement that you understood that you are in non-compliance but it is

your companys 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 for the problem and 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 the time

is acceptable by the FDA and is it 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 can not fix the problem

on your own.


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7. References

1. Federal Food, Drug, and Cosmetic Act

http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm

2. L. Huber, Good Laboratory Practices and Current Good

Manufacturing Practices, Agilent 5988-6197EN, 2002

www.labcompliance.com/publications/order-literature.htm

3. L. Huber, Implementing 21CFR Part 11 - Electronic Signatures

and Records in Analytical Laboratories Part 1, Biopharm 12 (11),

28-34, 1999

www.labcompliance.com/publications/order-literature.htm

4. L. Huber, FDA regulations (Predicate Rules), 2003

http://www.labcompliance.com/info/links/fda/fda-regulations.htm5. L.Huber, FDA Inspections, Labcompliance 2003

http://www.labcompliance.com/books/inspections

6. FDA 483 Inspectional Observation C.F. 24-36921

1998

www.fdawarningletter.com

7. FDA Warning letter SJN-03-04, www.fda.gov

www.fdawarningletter.com