Basic Laboratory Methods in a Regulated Environment · PDF fileBasic Laboratory Methods in a...

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Basic Laboratory Methods in a

Regulated Environment

CLASSROOM ACTIVITY: FRANCES KELSEY AND

THALIDOMIDE IN THE UNITED STATES: A CASE STUDY

RELATING TO PHARMACEUTICAL REGULATIONS

Submitted by Madison Area Technical College

Contact Person: Lisa Seidman, [email protected]

Bio-Link Courses-in-a-Box Basic Lab Methods Classroom Activities

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NOTES TO THE INSTRUCTOR

The regulation of pharmaceutical/medical products raises a number of significant questions.

Should AIDS patients be able to obtain drugs that have not been fully tested for safety or

efficacy? Should herbal/nutritional supplements be regulated by the government? How does

society balance the potential benefit of new pharmaceuticals against their potential risk? What

are the responsibilities of companies to ensure the safety of drugs? This case study explores

some of these topical issues through a discussion of a pivotal episode in the history of drug

regulation in the United States.

In the early 1960s, Dr. Frances Kelsey and her colleagues at the Food and Drug

Administration refused to approve the sedative, thalidomide, for use in the U.S.. Thalidomide

was later found to cause severe birth defects when taken by pregnant women in Germany,

England, and many other countries. This dramatic case captures students’ interest and provides

an effective springboard for discussion of pharmaceutical regulation and related scientific,

societal, and ethical issues.

We have used this case study with beginning technical college students who are preparing for

laboratory careers in biotechnology. We anticipate that this material would be quite appropriate

for high school students as well. It has been effective in our classroom to have the students read

up to Questions 1 and 2, at the end of the section entitled “The Beginning of the Thalidomide

Story.” After discussion, the class votes on whether they would have approved the drug, based

on its use in Germany and its supposed safety record there. The students also list on the

blackboard what scientific studies they think might adequately demonstrate the safety of a drug.

This seems to be an effective way to get the students engaged in the story and discussions of

later questions have been spirited. We use a two hour block of time and do not get to all the

questions, but some are assigned as homework.


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PURPOSE

This dramatic case study tells the story of Dr. Frances Kelsey of the Food and Drug Administration

(FDA) and the drug thalidomide. This incident provides a good introduction to the processes by which

drugs are approved and regulated in the United States, and the reasons for these processes. This is also a

great story showing how the actions of individuals can be important.

BACKGROUND RELATING TO PHARMACEUTICAL REGULATION

When you reach into your medicine cabinet for a bottle of aspirin, you probably assume that the

bottle indeed contains aspirin and that taking a couple of tablets will not lead to your untimely death. We

take for granted that pharmaceuticals are properly manufactured, labeled, and tested for safety. We can

reasonably have this level of confidence in pharmaceuticals because the production of medical products is

stringently regulated and controlled by the federal government. However, this was not always the case;

the quality of drugs and foods was virtually unregulated until the early 1900s (for a glimpse of the drug

industry at its worst, go to

http://www.fda.gov/cder/about/history/Gallery/Gallerypg.htm).

Around that time, a major industry emerged to process foods for urban consumers. This burgeoning food

industry was filthy and badly managed. There were various efforts to regulate food processing, however,

no legislation was passed until 1906. At that time, Upton Sinclair published the novel, “The Jungle,” which

graphically described the alarming practices in the food industry. People were so

outraged by Sinclair’s descriptions that Congress passed a law to help regulate the

production of food and, at the same time, drugs. This law was the original Food Drug

and Cosmetic Act (FDCA). In 1927 a separate law enforcement agency, eventually

named the Food and Drug Administration (FDA), was formed to enforce food and

drug laws.

The 1906 FDCA authorized regulations ensuring that manufacturers did not

adulterate or mislabel products, but did not deal with the safety or effectiveness of

drugs. An attempt to license drug manufacturers was introduced into Congress in the early 1930s, but

the pharmaceutical industry vigorously combated its passage, and legislation to strengthen drug regulation

languished.

It finally took a tragic incident to convince the country of the need for new drug safety legislation.

Sulfanilamide, an antibiotic, was introduced in the 1930s (Young 1983). Sulfanilamide has the disadvantage

of being relatively insoluble and therefore was only available in a pill form making it difficult to administer

to children. To obtain a soluble form of the drug, in1937, a chemist at the S.E. Massengill Company

dissolved sulfanilamide in the toxic industrial solvent, diethylene glycol. Many children were treated with

the toxic preparation resulting in at least 358 poisonings and 107 deaths. Under the drug laws at that


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time, a company had no obligation to prove that their drug was safe; therefore Massengill was not held

responsible for the deaths. (The company was, however, fined $500 for labeling the drug an “elixir”

when it did not contain alcohol.) In response to this tragic incident, drug reform became popular and a

revised FDCA was passed in 1938. This law contained the critical provision requiring that manufacturers

prove the safety of new drugs with animal and clinical studies.

Since the passage of the revised FDCA in 1938, a lengthy, complex process for safety-testing new

drugs has evolved, along with a requirement that new drugs be safe and effective. The idea for a drug

product is first researched in the laboratory. If the substance shows promise, tests are performed in

animals to determine how the drug is handled in the body and whether the substance appears safe for

human testing. In 1975, FDA inspections of animal testing laboratories revealed poorly conceived and

carelessly executed experiments and badly run animal facilities. These deficiencies led the FDA to

institute the Good Laboratory Practice regulations to control studies of drugs in animals.

If a drug appears safe and efficacious in animal studies, investigators prepare a plan to investigate the

product in human volunteers. They submit their plan to the FDA in the form of an Investigational New

Drug Application (IND). If FDA reviewers decide the IND is acceptable the company can move into

human testing.

Good Clinical Practices are regulations that govern trials of drug safety and efficacy in humans. Clinical

trials are conducted in stages. Phase I trials are the first introduction of the proposed drug into humans,

whereby the safety of the drug is evaluated in healthy volunteers. If a drug meets the safety requirements

at this phase, then it enters Phase II trials involving a small number of diseased patients. If the drug meets

safety requirements and demonstrates efficacy at Phase II, it progresses to a broader Phase III clinical

trial.

If a drug passes all three phases of testing, the company may submit an application, called a

New Drug Application (NDA), to the FDA documenting their evidence that the drug is safe and

effective. If the FDA reviewers decide the evidence is sufficiently favorable, the new product is

approved and can be manufactured for sale.

THE BEGINNING OF THE THALIDOMIDE STORY

Thalidomide was first synthesized in 1953 by a West German Company (McFadyen 1976;

Hoffmann 1997). Early tests in animals and humans indicated that the drug had little toxicity and

that in humans it promoted sleep, although it did not have any sedative effect on animals. By

1957 the drug was introduced to the West German market and soon became a popular sleeping

pill, taken by both adults and children. Thalidomide could be ingested in large quantities without

apparent harm and was thought to be so safe that it did not require a prescription. Moreover,

the drug prevented nausea due to pregnancy and was frequently used for this purpose.

Eventually the German manufacturer began to license the distribution of thalidomide in other


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countries. The American pharmaceutical firm, William S. Merrell Company,

wanted to distribute thalidomide in the lucrative U.S. market. On September

12, 1960 the FDA received an NDA from Merrell requesting approval for

thalidomide. The NDA contained glowing claims for the drug and reports of

animal and human tests indicating the drug’s therapeutic dosage and its

presumed safety. Since thalidomide was already widely used, the NDA was

thought to be routine and was assigned to the agency’s newest medical officer,

Dr. Frances Oldham Kelsey. Kelsey later explained that "They gave it [the NDA

for thalidomide] to me because they thought it would be an easy one to start

on. As it turned out, it wasn't all that easy". (Burkholz 1997)

Frances Kelsey was born in Canada and later became a naturalized American citizen. She

attained a Ph.D. degree in pharmacology at the University of Chicago where, as a graduate

student, she played a small role in the investigations to determine why

Massengill’s sulfanilamide elixir was harmful. Dr. E.M.K. Geiling and his

colleagues at the University of Chicago performed pharmacologic and

pathologic studies of animals treated with the Massengill product. It was

these animal studies that revealed that diethylene glycol was the drug’s

toxic component. As Kelsey later reported, “All graduate students were required to watch the

progress of all these studies and to lend their assistance, wherever possible...”(Kelsey 1993). In a

speech prepared for the Medical Alumni Association of the University of Chicago, Kelsey said:

“The urgency of the situation, the intensive round-the-clock toxicological studies and the

subsequent changes in the law relative to the control of drugs could not and did not fail to make

a deep impression on a graduate student such as myself in the University’s Department of

Pharmacology.” (Kelsey 1963)

In 1950 Dr. Kelsey completed her medical degree and after graduation worked as an editorial

associate for the American Medical Association (AMA) Journal. As she reported, “I soon

learned...that good scientists are almost invariably good writers and that poor writing is often a

sign of poor science ... when I came to the Food and Drug Administration..., I found that many of

the studies in support of safety of the new drugs were done by investigators whose work had

not been accepted for publication in the Journal [of the AMA]” (Kelsey 1993).

In 1952, Dr. Kelsey and her family moved to South Dakota where she taught pharmacology

and worked as a temporary doctor in small communities. In 1960 she was hired by the FDA to

review applications for drug approval.

http://www.fda.gov/cder/about/history/


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QUESTIONS

1a. Outline the steps that the Merrell Company needed to go through to have thalidomide

approved in the U.S.

b. If you were Dr. Kelsey, what sort of scientific studies would you be looking for in the

thalidomide NDA?

2. Thalidomide had been tested previously in West Germany and, compared to other sedatives,

was safe at high doses. It was widely used in Europe with apparently few, if any, problems. The

Merrell company was anxious to have the drug marketed. If you were Dr. Kelsey, would you

approve the drug for distribution in the U.S.?

Stop. Do not read further until the class has discussed these questions.


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THE STORY CONTINUES

Dr. Kelsey reviewed the NDA from Merrell Company in collaboration with an FDA chemist

and a pharmacologist. The pharmacologist and chemist both noted omissions in the NDA. For

example, the chronic toxicity data were incomplete, meaning that no evaluation could be made

of the safety of the drug when used for prolonged periods of time. The chemist found numerous

deficiencies relating to details of the manufacturing processes and the methods used to

determine the identity, strength, and purity of the new drug substance. The reviewers were

concerned that thalidomide did not put animals to sleep because this suggested that there are

differences in the way humans and animals absorb or metabolize the drug (Kelsey 1963). Such

differences made the animal safety studies suspect.

According to the laws at that time, Merrell would have been able to market thalidomide if the

company had not heard back from the FDA within 60 days of submitting their NDA. Therefore,

if Dr. Kelsey had done nothing at this point the drug would have been marketed. Indeed, Merrell

was poised to begin distribution in the U.S., having brought in at least 5 tons of thalidomide to its

warehouses (McFadyen 1976). Instead, on November 10, Dr. Kelsey sent a letter to Merrell

outlining the deficiencies noted by the reviewers and asking for more testing.

The Merrell company was anxious to get the drug approved and began a campaign to push

the application through the FDA approval process. Dr. Joseph Murray of the Merrell Company

repeatedly called and visited FDA. However, Dr. Kelsey resisted approving the drug because of

concerns about the adequacy of the safety data in the NDA.

Five months after the NDA was submitted, Dr. Kelsey learned about the occurrence of

peripheral neuritis (deterioration of the nerves in the hands and feet) in patients who had used

thalidomide over a long term. Merrell Company investigators reported that the incidence of

peripheral neuritis was low and the condition was rapidly reversible. Merrell suggested that a

caution about this side effect be put onto the drug label and that it then be approved. However,

by this time Kelsey and other reviewers were even more concerned about the drug and refused

to approve it.

While this concern about peripheral neuritis was simmering, FDA reviewers voiced another

issue. Thalidomide was used by pregnant women and the reviewers considered the possibility

that a fetus might be harmed by the drug. Kelsey had been involved in studies of the antimalarial

drug, quinine, performed at the University of Chicago. She knew that a rabbit fetus lacked the

ability to metabolize quinine; the required enzyme appeared only after birth. Subsequent studies

showed that many drug-metabolizing enzymes are absent in the fetus. As Kelsey (1993) later


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explained "... at this time there was growing concern regarding the exposure of the fetus to

drugs and other substances to which the mother was exposed during pregnancy.” Dr. Kelsey

brought up her concerns regarding possible harm to a fetus to Dr. Murray. Merrell responded

by showing studies indicating that the drug was safe in the third trimester of pregnancy, but FDA

asked for evidence that it was safe throughout gestation. Merrell then suggested releasing the

drug with a warning on the label that the safety of the drug during pregnancy was not

established, but Kelsey did not accept this suggestion (Kelsey 1993).

The pressure on Dr. Kelsey and the FDA intensified during the spring and summer of 1961.

“They came to Washington, it seemed, in droves. They wrote letters and they telephoned - as

often as three times a week. They telephoned my superiors and they came to see them

too...Most of the things they called me, you wouldn’t print”, recalled Dr. Kelsey (Mulliken

1962). Despite the intense pressure, Dr. Kelsey continued to ask for more proof of the drug’s

safety.

QUESTIONS

3. If you were an FDA reviewer, what would you have done at this point?

4. Dr. Kelsey was under tremendous pressure to approve thalidomide. Why do you suppose

she resisted the pressure?

Stop. Do not read further until the class has discussed these questions.


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THE STORY CONTINUES

In late November, 1961, more than a year after the drug application was submitted to FDA,

Dr. Murray called Dr. Kelsey and told her that thalidomide was being withdrawn from the

German market because of reports of congenital abnormalities in children born to mothers who

had used it. By 1962 it was clear that the drug caused crippling malformations of the arms and

legs. Children had been born with hands and feet protruding directly from their torsos. Others

had limbless trunks with toes extending from their hips; others were born with just a head and a

torso; still others had cardiac problems. It is estimated that anywhere from 8,000 to 80,000

thalidomide-deformed babies were born in Europe. Because of the stubborn skepticism of Dr.

Kelsey and others in the FDA, this tragedy was largely averted in the U.S. For her efforts, Kelsey

received the President's Distinguished Federal Civilian Service Award in 1962, the highest civilian

honor available to government employees.

INVESTIGATION

During the time the NDA was being reviewed, Merrell had distributed thalidomide to more

than 1000 physicians, supposedly for “investigational use.” This distribution of a drug for

research purposes was not illegal at that time, although FDA had thought only 35-60 physicians

were “investigating” the drug.

On July 20, 1962 the executive vice president of Merrell told the FDA commissioner that a

recall of thalidomide distributed to U.S. doctors was complete. However, an FDA inspector

visiting the Merrell offices found employees still in the process of contacting the many physicians

who were thought to have received the drug. The FDA subsequently discovered that many

http://www.fda.gov/cder/about/history/Page31.htm


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doctors who had distributed thalidomide had made no effort to contact patients to whom they

had given it and, indeed, often had no records of those whom they had given the pills. An FDA

survey showed that more than 2,500,000 tablets had been distributed to over 20,000 patients.

Eventually 10 well-documented cases were found in the U.S. of women who had received

thalidomide during pregnancy and delivered seriously deformed babies (McFadyen 1976).

There was ample evidence that the Merrell company’s distribution of thalidomide supposedly

for research purposes was, in fact, part of a marketing campaign. It was eventually decided,

however, that there was not sufficient evidence to prove that they had withheld knowledge of

the drug’s adverse effects. The justice department declined to press criminal charges against

Merrell although there were at least ten civil lawsuits against Merrell that resulted in settlements

to families with disabled children.

POLITICS

Dr. Helen Taussig, a physician, visited Europe shortly after the effects of thalidomide were

discovered. When Taussig returned to the U.S. she wrote articles and speeches reporting on the

effects of thalidomide in Europe and the narrowly averted tragedy in the U.S. Despite her efforts

to bring this story to the attention of the American people, she received little press. Meanwhile,

Senator Estes Kefauver of Tennessee had been involved for several years in an in-depth

investigation of the drug industry. He was primarily interested in reducing drug prices, but he

also had unsuccessfully introduced a bill to tighten drug safety regulations. In the summer of

1962, one of Kefhauver’s staff read about Dr. Taussig’s speeches. Senator Kefauver and his staff

decided to promote the story to help the passage of their proposed legislation. Kefauver

convinced a reporter from the prestigious Washington Post newspaper to interview Dr. Kelsey.

The Washington Post printed the story on page one and it was followed by a media blitz with

numerous follow-up stories around the country.

As had occurred in response to the sulfanilamide tragedy, the thalidomide incident mobilized

public demands for stronger drug regulations. Senator Kefauver’s previously unsuccessful bill was

resurrected and passed in 1962 as the Kefauver-Harris Drug Amendments to the FDCA. These

amendments strengthened the regulation of drugs and tightened the rules governing the conduct

of drug testing in humans so that physicians could not casually distribute investigational drugs (as

had occurred with thalidomide).


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QUESTIONS

5. What records would a company need to maintain in order to be able to effectively recall a

drug that had been widely distributed? What would it be like to work in a company maintaining

these records?

6. a. What is the role of Congress in ensuring drug safety?

b. What is the role of the FDA in ensuring drug safety?

c. What is the role of a pharmaceutical company in ensuring drug safety?

d. What is the role of the consumer in ensuring drug safety?

7. Suppose you are hired as a representative of the pharmaceutical industry. Prepare a position

paper for the industry on regulation. What principles would you advocate? What would be your

position on government regulation of your industry? Prepare arguments to support your

position.

8. AIDS patients have expressed frustration at the slow rate at which drugs are developed to

treat their illness. Drug companies attribute the slowness to stringent drug testing requirements.

Patients argue that they are dying while safety studies are conducted. Therefore, FDA has

provided avenues by which AIDS patients can obtain drugs that have not been fully tested. What

do you think about this “fast-tracking” of AIDS drugs? What do you think of allowing patients

with less serious conditions access to drugs that are not well-tested and might pose unknown

risks?

9. Currently, herbal preparations (such as Saint John’s Wort that is popularly used for

depression) are not required to meet the requirements enforced by FDA. Therefore, there is

limited oversight to ensure that herbal preparations have been tested for safety, or that they are

processed properly. Some people think that herbal preparations should be FDA-regulated to

protect consumers. Others fear that government oversight of these products will cause them to

become more expensive and less available. What do you think?

10. How do public opinion and politics influence drug regulation?


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POSTSCRIPT

Thalidomide is now known to have complex, multiple effects on the body. One effect is that

it inhibits new blood vessel growth (angiogenesis). This is detrimental to a fetus because

angiogenesis provides a "road map" for the growth of limbs and organs during development. The

way that thalidomide acts in the body is still being deciphered. You can read about it at:

http://www.nytimes.com/2010/03/16/science/16limb.html.

Interestingly, it has been found that thalidomide, despite its terrible effects on a developing

fetus, may be useful in treating some diseases. For example, thalidomide is being investigated as

a treatment for breast, prostate, and brain cancer by inhibiting angiogenesis.

In the 1960s, an Israeli physician gave thalidomide to leprosy patients to help them sleep in

spite of painful, disfiguring lesions caused by their disease. Surprisingly, thalidomide not only

sedated the patients, it also helped to heal the lesions (Kling 2000).

In 1998, FDA approved thalidomide for the treatment of leprosy and in 2006 for treatment of

multiple myeloma. The dispensing of the drug is tightly controlled in an effort to keep it from

being used by pregnant women. You can read about this at:

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001053/

QUESTION

10. What do you think about the use of this drug for treating varied disorders? Is it acceptable to

distribute a drug that is known to cause severe birth defects, since once a drug is distributed it

might find its way into pregnant women?

REFERENCES

Burkholz, H. (September-October 1997). Giving Thalidomide a Second Chance. FDA Consumer

Magazine http://www.fda.gov/fdac/features/1997/697_thal.html

Food and Drug Administration. The FDA homepage is http://www.fda.gov . The information on

this website changes frequently. Search for thalidomide for the most current articles.

Hoffmann, R. (1997) The Same and Not the Same, New York, NY; Columbia University Press.


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Kelsey, F.O. (June 6, 1963) Chicago and New Drug Legislation. Speech presented to the Medical

Alumni Association, University of Chicago.

Kelsey, F.O. (December 9,1993). Denial of Approval for Thalidomide in the United States.

Speech presented at the National Library of Medicine, Bethesda, MD.

Kling, J. (June, 2000) Redeeming Thalidomide. Modern Drug Discovery (a publication of the

American Chemical Society), 35-39.

McFadyen, R.E. (1976). Thalidomide in America: A Brush With Tragedy. Clio Medica, 11, (2), 79-

93.

Mulliken, J. (August 10, 1962). A Woman Doctor Who Would Not be Hurried. Life Magazine, 53,

28-9.

Young, J.H. (1983). Sulfanilamide and Diethylene Glycol. In J. Parascandola and J.C. Whorton

(Eds.), Chemistry and Modern Society: Historical Essays in Honor of Aaron J. Ihde (pp. 105 -125).

Washington D.C.: American Chemical Society.


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THE U.S. CODE OF FEDERAL REGULATIONS:

ORGANIZATION AND ACCESS


Modified from a document written by Noreen Warren



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This document explains how the United States Code of Federal Regulations is organized and how to

access it through the internet.

The Code of Federal Regulations (CFR) is a codification of the general and permanent rules of the

Federal Government 1. The CFR contains the complete and official text of the regulations that are

enforced by federal agencies. The CFR is organized as follows:

• The CFR is divided into 50 titles that represent broad areas subject to Federal regulations.

• Each title is divided into chapters that are assigned to various agencies issuing regulations

pertaining to that broad subject area.

• Each chapter is divided into parts covering specific regulatory areas.

• Large parts may be subdivided into subparts.

• Each part or subpart is then divided into sections -- the basic unit of the CFR.

• Sometimes sections are subdivided further into paragraphs or subsections. Citations pertaining to

specific information in the CFR will usually be provided at the section level.

An example of a typical CFR citation is 21 CFR 211.67(a). To interpret this:


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• The number 21 is the CFR title 2. The broad subject area is Food and Drugs.3

• The number 211 is the part. Part 211 is entitled Current Good Manufacturing Practice for Finished

Pharmaceuticals.

• The number .67 refers to a particular section. This section is about Equipment cleaning and

maintenance.

• The (a) is the first paragraph or subsection within the section.

There are various ways to access the portions of the CFR relating to the manufacture of

pharmaceuticals by using the web: 4

The FDA web site includes a copy of 21CFR parts 210 and 211 at this address:

http://www.fda.gov/cder/dmpq/cgmpregs.htm. You will also find links to other useful regulatory

information at this site.

Another site that publishes come of the FDA regulations is a commercial site hosted by The GMP

Institute http://www.gmp1st.com/index.htm. This site includes the following useful items:

• You can purchase inexpensive booklets from the GMP Institute that contain the text of the GMP

regulations.

• You can also go to their web site to link to the cGMP regulation 21 CFR Parts 210 and 211 for the

drug industry.

• They also have links to the regulations for the medical device industry (21 CFR Part 820), the food

industry (21 CFR Part 110) and the blood products industry (21 CFR Part 606).

• This site also has an inclusive list of guidance documents from the FDA.

• The Preamble for the current Good Manufacturing Practices as published in the September 29,

1978 issue of the Federal Register, can also be found on their web site. The Preamble is an

interesting document that contains comments from the public relating to the GMP regulations and

the official response to those comments.

Footnotes: 1 This explanation of the CFR is based largely on information from the National Archives and Records

Administration web site. This government web site explains what the Federal Register is and provides

access to government documents (http://www.archives.gov/). 2 Each of the titles of the CFR is assigned to a specific agency. The following link is a list of Government

agencies and their relevant CFR Titles, Subchapters or Chapters.


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( http://www.access.gpo.gov/nara/cfr/parallel/alphabetical_list.pdf ) 3 Title 21 contains three Chapters that relate to Food and Drugs. Often the Chapter and Subchapter are

not cited, but the citation in the example here is found under Chapter 1. The agency that is responsible

for compliance with Chapter 1 is The Food and Drug Administration (FDA). The other Chapters are

controlled by other federal agencies. Chapter 1 has seven subchapters and 1299 Parts. Subchapter C

covers regulations for General Drugs. Other Subchapters within this Chapter cover regulations for Food,

Food additives, and other products regulated by FDA.

4 Federal regulations are first published in the Federal Register (FR) by the executive departments and

agencies of the Federal Government. The Federal Register is a legal newspaper published every business

day by the National Archives and Records Administration (NARA). It contains Federal agency regulations;

proposed rules and notices; and Executive orders, proclamations and other Presidential documents. The

Federal Register informs citizens of their rights and obligations and provides access to a wide range of

Federal benefits and opportunities for funding. The CFR is kept up-to-date by the daily Federal Register.

For the most up-to-date information, these two publications must be used together to determine the

latest version of any given rule. When a Federal agency publishes a regulation in the Federal Register, that

regulation usually is an amendment to the existing CFR in the form of a change, an addition, or a removal.


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CLASSROOM ACTIVITY:

EXPLORING THE FDA WEBSITE AND THE GOOD

MANUFACTURING PRACTICES REGULATIONS

This computer activity was modified from an activity developed by the professional GMP trainer,

James C. Gerner, Ed.D., M.S., M.T. (ASCP).


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PURPOSE

This is a computer activity where you will look at the federal regulations pertaining to pharmaceutical

manufacturing. As you go through this activity, you will get the “flavor” of these laws and will learn how

to access them on the computer. Remember that the particular regulations that you will read are small

parts of a comprehensive quality system that is intended to protect the quality of pharmaceutical

products.

ACTIVITIES

Prepare:

1. Prepare for this activity by performing the Kelsey case study activity in class or by reading the case

study.

2. Read the handout “How to Access the Code of Federal Regulations.” Don’t worry about the footnotes’

At the Computer:

1. Your instructor will assign your team one or two subparts and sections of the GMP Regulations. Find

and read the sections you have been assigned.

2. Prepare a brief bullet-point summary of the assigned Subparts and Sections of the GMP Regulations.

Write your summary on a transparency, if your class has an overhead projector, or use a word processing

program, as directed by your instructor. Try to use five to seven bullet points for each subpart.

Remember that your team should not rewrite the regulation, but instead simply summarize the content

in a bullet point outline.

3. Once your bullets are complete for each Subpart and Section, mark each bullet point as follows:

Place a circle next to any bullet where a procedure is required. (A procedure tells workers what they

are going to do and how to do it. If the regulation says “there shall be a procedure for…” then this

task is easy; insert a circle. But a procedure is often required, even when the regulation does not

explicitly say so.)

Place a square next to each bullet point where a record is required. (A record states what a worker

did. Place a square next to a regulation that requires a worker to record some type of information.)

Place both a circle and a square next to each bullet point where both a procedure and record are

required.


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4. Present your group’s bullet point summary to the class. Your task is to explain this regulation to

everyone else.

5. On a separate sheet of paper, summarize in your own words how the GMP regulations together

outline the pieces of a quality system for a laboratory in a pharmaceutical company. Consider all the

groups’ presentations. Use one or two paragraphs for your summary.

SECTIONS TO ASSIGN:

Subpart B 211.22* Subpart G 211.122 (a)(b)(c)

211.25 211.134

211.28 (a)(b) 211.137

211.42 Subpart I entire subpart

Subpart C 211.42 (c)(1)(9) 211.160*

Subpart E 211.80 (a) 211.166*

211.82 (b) Subpart J 211.180 (a)(b)(e)(f)

211.84* 211.184 (a)(b)(d)

211.87* 211.186 (a)(b9)

211.94 (d) 211.188 (5)(10)

Subpart F 211.110 (a)(b)(c)* 211.194*

211.113* 211.198 (a)

* Particularly important sections Subpart K 211.208

Bio-Link Courses-in-a-Box M&M Quality Control Activity

21

Basic Laboratory Methods in a Regulated Environment

CLASSROOM ACTIVITY:

QUALITY CONTROL IN THE M&M FACTORY




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PURPOSE

This is a classroom activity that introduces statistical methods as a way to evaluate the variability in a

system. One of the key goals of any quality system is reducing variability in the product. In this exercise

you will learn some simple statistical procedures and how they are used to evaluate product variability.

You will practice:

1. Calculating standard deviation and interpreting its meaning.

2. Constructing and understanding frequency histograms.

3. Thinking about variability and its importance.

BACKGROUND

A. VARIABILITY

There is always variation in any system or process. When producing a product, such as a biotechnology

product, it is important to reduce that variability as much as possible. For example, if a company is selling

an enzyme that is supposed to have an activity of 200 Units/mg, then they want every lot of that enzyme

to have an activity of 200 Units/mg. They do not want the activity to sometimes be 182 Units/mg, or 222

Units/mg, or any values other than 200 Units/mg.

The first step in reducing the variability in a process is to be able to evaluate it. The field of statistics

provides us with techniques to analyze variability in a set of data. In this laboratory exercise, we will

discuss two simple statistical methods to analyze the variability in a product, standard deviation and

frequency histograms. The product that we will examine is M&Ms and the features of the product that

are of interest to us are the numbers of M&Ms per bag and the colors of the candies. The numbers of

M&Ms per bag and the colors of the candies are variables, that is, values that can vary from one individual

to another.

The standard deviation (SD) is a common mathematical measure of the variability of a set of

numerical data. Refer to your textbook to find out how to calculate SD. We will calculate SD in this

exercise to measure and report the variability in the number of M & Ms in packages.

B. USING HISTOGRAMS TO DISPLAY VARIABILITY

Graphs can be used to illustrate data. A frequency histogram is a type of graph that displays the

distribution of a set of data. For example, a frequency histogram might indicate how many field mice

there are of various sizes in a field or how many students got grades of As, Bs, Cs, and Ds in a course.

The first step in preparing a frequency histogram is to categorize the data into classes or types. For

example, for course grades, there are four classes or types: A, B, C, and D. These classes are then

plotted on the X axis of a graph. The number of individual in each class is plotted on the Y axis in the


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form of bars. The number of individuals in each class determines how high the bar will be, that is, how far

up the bar goes on the Y axis.

In practice, we distinguish between situations where classes are continuous and those where they are

discrete. For example, height and weight are continuous variables. A mouse might be 19 g or 20 g or any

weight in between. In contrast, course grades are discrete. A student may get an A or B, or perhaps an

A- or B+ if the instructor uses these grades, but there are no grades in between. When variables are

continuous, the bars are usually plotted so that they touch one another. When variables are discrete, the

bars are usually plotted so that they do not touch one another. In the case of the M & M data that you

will collect, the values will be discrete. There might be 40 M &Ms in a bag or 41, but (unless some are

broken) there cannot be any value in between. Similarly, the number of colors a candy might be is not

infinite; only certain colors are possible.

It is possible to construct a frequency histogram for any data set consisting of the values for a single

variable. The procedure for doing so is given in the box below followed by an example:

Box 1

CONSTRUCTING A FREQUENCY HISTOGRAM

1. Divide the range of the data into intervals, or classes. It is simplest to make each interval the same width. There is no set rule as to how many intervals should be chosen; this will vary depending on the data. (For example, length data could be divided into intervals of 0-9.9 cm, 10.0-19.9 cm, 20.0-29.9 cm, and so on.)

2. Count the number (frequency) of observations that are in each interval.

3. Prepare a frequency table showing each interval and the frequency with which values fell into that interval.

4. Label a graph with the intervals on the X axis and frequency on the Y axis.

5. Draw in bars where the height of a bar corresponds to the frequency with which a value occurred. Center the bars above the midpoint of the class interval.


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AN EXAMPLE OF PREPARING A HISTOGRAM

Consider these hypothetical values for the grades of 43 students:

A D A A B C A C B B A

C B A D C C B B B A B

C B B A D B B A C B B

B A B B C B A B A C

Step 1: Divide the data into classes. This is easy; there are four classes, A, B, C, and D.

Step 2: Count the number in each class.

Step 3: Arrange the values into a table:

FREQUENCY TABLE

VALUE (Grade) FREQUENCY

A 12

B 19

C 9

D 3

Steps 4 and 5: Prepare the graph. Frequency is on the Y

axis and the grade is on the X axis.

ACTIVITIES

1. Open your bag of M &Ms and pour them onto a paper plate or towel. Count and record:

a. The total number of M & Ms in your bag.

b. The number of M & Ms of each color.

2. Record your data on the blackboard.

3. Based only on your own data, construct a histogram of color versus frequency.

4. Based on the class’s data as a whole, construct a histogram of color versus frequency.

5. Discuss the two histograms.

a. Are the two histograms the same or different? Explain.

Class Grade Distribution

0

2

4

6

8

10

12

14

16

18

20

A B C D

Grade


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b. Based on your own histogram, are the colors of M & Ms evenly distributed? Based

on the entire class's data, are the colors evenly distributed?

c. What do you predict a histogram would look like if you checked hundreds of bags of

M & Ms?

6. Based on the data for the entire class, calculate the mean number of M & Ms per bag, and the standard

deviation of the number of M & Ms per bag.

7. Based on the data for the entire class, construct a frequency histogram for the number of M & Ms per

package.

8. Discuss the mean and the standard deviation.

a. What does the mean tell you?

b. What does the standard deviation tell you?

9. If you were to count the number of M & Ms in hundreds of bags, what do you think the

frequency histogram would look like? Draw your prediction.

10. Where do you think variability in the M & M packages comes from? Does the variability in

M&M color distribution and the number of M&Ms per bag affect the quality of the product?

11. Why is it important to be able to measure variability in a process?

12. In what situations does variability in a product affect its quality? Why is it important to

find methods to reduce variability in a process?


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NOTE TO THE INSTUCTOR:

According to the “M & M hotline” the ratios of colors in the 1990s was:

red 20 %

green 10 %

blue 10 %

yellow 20 %

brown 30 %

orange 10 %

This was based on surveys of consumer preferences for different colors. People thought that chocolate

should be brown. However, this ratio has changed over the years with bright colors becoming more

common as consumer preferences change.

Students sometimes predict that if a great number of bags were checked, the colors would eventually be

evenly distributed and all the bars on a frequency histogram would be the same height. This is not the

case.

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