Download h) Implementation of a Quality Systems Model for Use in

A REGULATORY WRITING PRIMER FOR PREPARING AND
SUBMITTING DOCUMENTS FOR THE UNITED STATED
BIOMEDICAL INDUSTRY
by Joseph F. Tarsio, M.B.A., Ph.D.
July 17, 2013
I.
Introduction
This Regulatory Primer is designed to benefit innovative thinkers who want to develop their
understanding of the medical technology regulatory process in the United States. Readers may
include those interested in learning about US regulations concerning Medical Devices,
Pharmaceuticals, Biologics, and other biotechnology-related products. Whether you are a
student, engineer or a doctor, or other professional interested in increasing your knowledge in
this area, you will benefit greatly from this course.
This Regulatory Primer will be a self-study course targeted towards professional interested in
starting a career in regulatory writing for the United States Pharmaceuticals, Medical Device,
and Biotechnology Products Industry. Within the coursework, students will be provided the
opportunity to take multiple-choice tests. At the end of this document the correct answers to the
questions for each test will be supplied so that students may gauge their understanding of this
subject matter. If they finish a test with a score of less than 75% of the correct answers, it is
recommended that the subject matter pertaining to that test be reviewed again by the student. A
correct score of 75% or above is considered acceptable mastering of the subject matter.
II.
How are Medical Products Classified: Distinction Amongst Pharmaceutical Drugs,
Biologics, Medical Devices, or Combination Products - Distinctions
a) Medical technology involves the application of various methods and systems to derive new
medical products such as pharmaceutical drugs which can be chemically synthesized; naturallyderived compounds such as proteins, glycoproteins or lipids (collectively called “biologics”); or
medical devices; to diagnose, prevent, or treat human disease.
b) Drugs are developed to prevent the occurrence of disease or to treat a prevailing disease in
humans. Drugs may be comprised of “small molecule” compounds synthesized or purified from
a natural source. An example of a small molecule drug is benzylpenicillin, commonly known as
penicillin G, a β-lactam antibiotics discovered by Sir Alexander Fleming in 1928, which is
produced and purification from the Penicillium mold. In 1942, U.S.-made penicillin G produced
by Merck & Company was used for the first time in human patients to treat streptococcal
septicemia. Since then many different chemically modified derivatives of penicillin G have been
produced and approved for use in the United States by the Food and Drug and Drug
Administration (FDA). Another example of a small molecule drug is sildenafil, a compound that
was synthesized by a group of pharmaceutical chemists working at Pfizer and the active
component in Viagra which was patented in 1996 and approved for use in males for erectile
dysfunction by the FDA on March 27, 1998.
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c) Drugs that don’t exists in plentiful supply from a natural source may also be developed from
"new" biotechnology techniques that enable scientists to modify the genetic material in cells,
tissue or whole organisms at the cellular or molecular level. These latter compounds are called
“biopharmaceuticals,” “biologic compounds,” or just “biologics.” For example bacteria and
mammalian cells may be used to produce a protein that can be administered as a drug targeted to
correct medical disorders in human patients. An example would be the insertion of the human
insulin gene into a bacteria and the production of human insulin through fermentation. The
human insulin produced would next be purified to a high degree and formulated into a drug that
can be repeatedly administered to human patients. This corrects disorders in glucose production
in human diabetics who have insufficient levels of insulin or a defect in the ability of their own
body’s insulin to properly regulate glucose metabolism. This would be the use of a genetically
engineered molecular drug to treat a chronic disorder in human patients. Another example would
be the acute administration of a “clot-buster” drug comprised of genetically engineered and
manufactured tissue plasminogen activator (TPA) to decrease a severe blockage in the blood
vessels that supply the human heart with nourishment. The latter would be a biologic produced to
treat a life-treating acute disorder.
d) Besides pharmaceutical and biopharmaceutical drugs to treat or prevent disease, medical
devices need to enter a regulatory process in order to be approved for use in the United States.
Medical devices range from simple tongue depressors and bedpans to complex programmable
pacemakers with micro-chip technology and laser surgical devices. In addition, medical devices
include in vitro diagnostic products, such as general purpose laboratory equipment, reagents, and
test kits, which may include monoclonal antibody technology. Certain electronic radiation
emitting products with medical application and claims meet the definition of medical device.
Examples include diagnostic ultrasound products, x-ray machines and medical lasers.
One description (www.isomedix.com/TechTeam/Resources/TechTip14.html) of a medical
device provided by a medical device development company is:
“Any instrument, apparatus, appliance, material, or other article, whether used alone or in
combination, including the software necessary for its proper application intended by the
manufacturer to be used for human beings for the purpose of:
 diagnosis, prevention, monitoring, treatment, or alleviation of
disease;
 diagnosis, monitoring, treatment, alleviation of, or
compensation for an injury or handicap;
 investigation, replacement, or modification of the anatomy or
of a physiological process;
 control of conception; and which does not achieve its principal
intended action in or on the human body by pharmacological,
immunological, or metabolic means, but which may be
assisted in its function by such means.”
According to the FDA, if a product is labeled, promoted or used in a manner that meets the
following definition in section 201(h) of the Federal Food Drug & Cosmetic (FD&C) Act, it
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will be regulated by the FDA as a medical device and is subject to premarketing and
postmarketing regulatory controls. A medical device is:
"an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or
other similar or related article, including a component part, or accessory which is:
 recognized in the official National Formulary, or the United States
Pharmacopoeia, or any supplement to them,
 intended for use in the diagnosis of disease or other conditions, or in the cure,
mitigation, treatment, or prevention of disease, in man or other animals, or
 intended to affect the structure or any function of the body of man or other
animals, and which does not achieve any of it's primary intended purposes
through chemical action within or on the body of man or other animals and which
is not dependent upon being metabolized for the achievement of any of its
primary intended purposes."
This definition provides a clear distinction between a medical device and other FDA
regulated products such as drugs. If the primary intended use of the product is achieved
through chemical action or by being metabolized by the body, the product is usually a drug.
See http://www.fda.gov/CDRH/DEVADVICE/312.html
e) When the intended use of a product is achieved by combining any of two or more of the
above diagnostic or treatment types it is classified as a combination device.
As defined in 21 CFR § 3.2(e), the term combination product includes:
“(1) A product comprised of two or more regulated components, i.e., drug/device,
biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or
otherwise combined or mixed and produced as a single entity;
(2) Two or more separate products packaged together in a single package or as a unit and
comprised of drug and device products, device and biological products, or biological and
drug products;
(3) A drug, device, or biological product packaged separately that according to its
investigational plan or proposed labeling is intended for use only with an approved
individually specified drug, device, or biological product where both are required to achieve
the intended use, indication, or effect and where upon approval of the proposed product the
labeling of the approved product would need to be changed, e.g., to reflect a change in
intended use, dosage form, strength, route of administration, or significant change in dose; or
(4) Any investigational drug, device, or biological product packaged separately that
according to its proposed labeling is for use only with another individually specified
investigational drug, device, or biological product where both are required to achieve the
intended use, indication, or effect.” See: http://www.fda.gov/oc/combination/definition.html.
Combination products (i.e., drug-device, drug-biologic, and device-biologic products) are
increasingly incorporating cutting edge, novel technologies that hold great promise for
advancing patient care. For example, innovative drug delivery devices have the potential to
make treatments safer or more effective, or more convenient or acceptable to patients. Drug4
eluting cardiovascular stents have the potential to reduce the need for surgery by preventing
the restenosis that sometimes occurs following stent implantation. Drugs and biologics can
be used in combination to potentially enhance the safety and/or effectiveness of either
product used alone. Biologics are being incorporated into novel orthopedic implants to help
facilitate the regeneration of bone required to permanently stabilize the implants.
Stakeholders report that FDA can expect to receive significantly more combination products
for review as technological advances continue to merge therapeutic products and blur the
historical lines of separation between the various medical product regulated by the FDA.
Therefore combinations products are regulated by more than one regulatory division of the
FDA (http://www.fda.gov/oc/combination/overview.html). This most likely will be
combined regulation by FDA's new Office of Combination Products (OCP) and by one of
three product centers -- the Center for Drug Evaluation and Research, the Center for
Biologics Evaluation and Research, or the Center for Devices and Radiological Health – the
latter division assigned to the combination product by the OCP (see Section III below).
Examples of recently approved FDA combination products include 1) the incorporation of
Neupro (the drug-rotigotine) into a transdermal skin patch to treat symptoms of early
Parkinson's disease (a device containing a drug), 2) dental bone grafting material with a
growth factor (a device plus a biologic), and 3) a system that integrates a glucose meter and
an insulin pump with a dose calculator into one device as a fully automated glucose
monitoring and insulin delivery system to be used by human diabetic (contains multiple
devices, software, and a drug). See: http://www.fda.gov/oc/combination/approvals.html.
III.
FDA’s Regulatory Divisions
The FDA`s Center for Devices and Radiological Health (CDRH) is responsible for regulating
firms who manufacture, repackage, relabel, and/or import medical devices sold in the United
States. In addition, CDRH regulates radiation-emitting electronic products (medical and nonmedical) such as lasers, x-ray systems, ultrasound equipment, microwave ovens and color
televisions (http://www.devicewatch.org/reg/overview.shtml).
Manufacturer assistance regarding medical devices can be obtained from the Division of
Small Manufacturers, International and Consumer Assistance (DSMICA) or by writing to
FDA/CDRH/OCER/DSMICA (HFZ-220)
1350 Piccard Drive
Rockville, MD 20850-4307 U.S.A.
See: http://www.fda.gov/cdrh/contacts.html
If your product is not a medical device but regulated by another Center in the FDA, each
component of the FDA has an office to assist with questions about the products they regulate.
In cases where it is not clear whether a product is a medical device there are procedures in
place to use the DSMICA Staff Directory to assist you in making a determination. See
http://www.fda.gov/CDRH/DEVADVICE/312.html
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Human pharmaceutical drugs are regulated by FDA's Center for Drug Evaluation and
Research (CDER).
Biological products which include blood and blood products, and blood banking equipment
were originally solely regulated by FDA's Center for Biologics Evaluation and Research
(CBER). However, on October 1, 2003, FDA transferred certain product oversight
responsibilities from the Center for Biologics Evaluation and Research (CBER) to the Center
for Drug Evaluation and Research (CDER) (http://www.fda.gov/cder/biologics/default.htm).
See also http://www.fda.gov/oc/combination/transfer.html.
FDA's Center for Veterinary Medicine (CVM) regulates products used with animals.
Therefore, the FDA is organized into various components which each have separate
responsibilities. Each component of FDA has an office to provide technical assistance to
manufacturers. This includes assistance to manufacturers of human drugs, animal drugs and
devices, biological products, food products and cosmetics. Besides the CDHR listed above,
the following offices can also be contacted for technical assistance for products regulated by
the FDA (see http://www.fda.gov/CDRH/DEVADVICE/3123.html) :
Human Drug Products:
Center for Drug Evaluation and Research (CDER)
Office of Training and Communication
Division of Drug Information (HFD-240)
5600 Fishers Lane, Room 12B-05
Rockville, MD 20857 U.S.A.
Telephone Number: 301-827-4573
Fax Number: 301-827-4577
CDER Home Page: http://www.fda.gov/cder
Email Address: [email protected]
Biological Products:
Center for Biologics Evaluation and Research (CBER)
Office of Communication, Training and
Manufacturers Assistance (HFM-43)
1401 Rockville Pike, Room 200N
Rockville, MD 20852-1448 U.S.A.
Telephone Number: 301-827-2000 or 800-835-4709
Fax Number: 301-827-3843
Fax-On-Demand: 888-223-7329 or 301-827-3844
CBER Home Page: http://www.fda.gov/cber
Email Address:
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Manufacturers Assistance and Technical Training Team: [email protected]
Consumer & Health Professional Assistance:. [email protected]
Animal Drugs and Devices:
Center for Veterinary Medicine (CVM)
Communications Staff
7519 Standish Place, HFV-12
Rockville, Maryland 20855
Telephone Number: 301-827-3800
Fax Number: 301-827-4065
CVM Home Page: http://www.fda.gov/cvm
Email Address: [email protected]
Food Products and Cosmetics:
Center for Food Safety and Applied Nutrition (CFSAN)
Outreach and Information Center
5100 Paint Branch Parkway, HFS-555
College Park, MD 20740-3835
Telephone Number: 1-888-SAFEFOOD (1-888-723-3366)
Telephone Number: 301-436-2600
Fax Number: 301-436-2618
CFSAN Home Page: http://www.cfsan.fda.gov/
Email Address: [email protected]
Combination Products:
The medical products industry expects the FDA to receive significantly more combination
products for review as technological advances continue to merge therapeutic products and
blur the historical lines of separation between FDA's medical product Centers.
Since combination products involve components that would normally be regulated under
different types of regulatory authorities, and frequently by different FDA Centers, they also
raise challenging regulatory, policy, and review management issues.
To address these concerns, FDA's Office of Combination Products (OCP) was established on
Dec. 24, 2002, as required by the Medical Device User Fee and Modernization Act of 2002
(MDUFMA). The law gives the Office broad responsibilities covering the regulatory life
cycle of drug-device, drug-biologic, and device-biologic combination products. However, the
primary regulatory responsibilities for, and oversight of, specific combination products will
remain in one of three product centers -- the Center for Drug Evaluation and Research, the
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Center for Biologics Evaluation and Research, or the Center for Devices and Radiological
Health -- to which they are assigned.
OCP duties include:

assigning an FDA Center to have primary jurisdiction for review of a combination
product

ensuring timely and effective premarket review of combination products by
overseeing reviews involving more than one agency center

ensuring consistency and appropriateness of postmarket regulation of combination
products

resolving disputes regarding the timeliness of premarket review of combination
products

updating agreements, guidance documents or practices specific to the assignment of
combination products

submitting annual reports to Congress on the Office's activities and impact.
The Office also has assumed the functions of the Combination Products Program begun in
2002 within the FDA Office of the Ombudsman. Among these functions:

working with FDA Centers to develop guidance or regulations to clarify the agency
regulation of combination products

serving as a focal point for combination products issues for internal and external
stakeholders.
See: http://www.fda.gov/oc/combination/overview.html.
IV.
Details Regarding Regulatory Planning, Documents Preparation, and FDA
Submissions to Gain Market Approval of Drugs in the US
A. The Drug Regulatory Process
A description of the Drug Development Process is given in Figure 1. It is a general
description of a successful scheme from the identification of a drug candidate and the
movement of a pharmaceutical compound through the drug development pipeline that
includes preclinical and clinical development, FDA approval, and post-approval monitoring.
The development program for each specific drug candidate will vary somewhat from this
generally described process. In addition, there can be no assurance that a drug candidates will
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successfully complete the entire process, since the drug process for any specific candidate
may end prematurely before US market approval is gained.
The Drug Development Process is comprised of the following:
1. Preclinical Testing
Laboratory tests and animal studies are conducted. These studies show biological activity of
the compound in relation to animal models of the targeted human disease or condition. Along
with these results, the compound is evaluated for toxicology.
2. Investigational New Drug Application (IND)
An Investigational New Drug Application (IND) is filed with the U.S. Food and Drug
Administration (FDA) after completion of preclinical testing. This allows testing of the drug
in humans to begin.
3. Phase I Clinical Trials
Small numbers of healthy volunteers are tested with the drug to determine its duration in the
bloodstream and the drug’s initial safety profile. This study also provides information about
how the drug is absorbed, distributed, metabolized, and excreted in humans.
4. Phase II Clinical Trials
Approximately 100-500 volunteer patients with the disease or condition are tested with the
drug to assess its effectiveness.
5. Phase III Clinical Trials
A large number of patients (usually at least 1,000-5,000 subjects) in clinics and hospitals are
tested and monitored closely by physicians to confirm efficacy and to identify any adverse
effects.
6. New Drug Application (NDA)
7. If the drug is determined to be safe and effective, an New Drug Application (NDA)
is filed with the FDA at completion of the clinical trials.
8. Drug Approval
Once the FDA approves the NDA, physicians may prescribe the drug to patients.
9. Phase IV
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If adverse effects are reported by patients taking the drug, the FDA may require Phase IV
trials to evaluate long-term effects of the drug.
Figure 1. The Drug Development Process
Discovery Research
Clinical Trials
FDA Review Process
Preclinical Testing
Identification of a drug candidate
from discovery research,
laboratory studies, in vitro
studies, animal studies
evaluate toxicology,
show biological activity at
disease targets,
develop formulations
IND
Phase I
20-100
healthy
volunteers
Phase II
100-500
patient
volunteers
Phase III
1000-5000
patient
volunteers
NDA
Phase IV
assess
safety and
dosage
observe
for
effectiveness and
side
effects
confirm
effectivene
ss, further
monitor for
adverse
reactions
review
process
and
approval
additional
testing if
required by
the FDA
Years
B. Details Regarding Preclinical Research
The preclinical phase of drug product development involves the development of lead
therapeutic molecules. This is done using laboratory tests and animal models relevant for a
specific targeted disease or condition.
During the early 20th Century many scientist relied on serendipity and happenstance and
stumbled upon drug candidates in unexpected ways. This gave way beginning in the 1980s to
the screening of large libraries of random compounds in order to find drug candidates. This
became more manageable in the 1990s using automated equipment for the industrial-scale
analysis of compounds and is called “high-throughput screening.” A more sophisticated and
current approach favors “targeted discovery.” This type of “rational drug discovery,”
involves the utilization of knowledge about intracellular pathways, genes, and proteins that
influence disease states and lend themselves to modulation by drugs. An example of the more
rational approach to drug discovery involved structural genomics and proteomics to identify
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molecules that react with key targets involved in a biological process (“biomarkers”) affected
in humans disease. The candidate molecules are then tested in animal and human cells grown
in tissue culture outside of their host (“in vitro” bioassays), and in animals (“in vivo” tests).
a) Structural Genomics
Currently, many of the initial laboratory tests used to develop lead compounds involves
structural genomics of a particular protein or its receptor. In general, in this process a
protein’s gene coding sequence is determined, the protein is expressed in high levels of
sufficiently purity, the protein is crystallized, characterized by NMR or X-ray measurements,
and inferences made about its structure.
The steps in the process involve:
(1)
(2)
(3)
(4)
PCR amplification of the coding sequence from genomic or cDNA,
cloning the coding sequence into an appropriate expression vector,
expressing the protein at a sufficiently high level,
sequencing the cloned gene to verify that the coding sequence was correctly
amplified,
(5) confirming the identity of the expressed protein and characterizing it as a prelude
to NMR or crystallographic studies,
(6) obtaining the protein in sufficient amounts and purity for either approach,
(7) defining suitable crystallization or NMR solution conditions,
(8) conducting NMR or X-ray measurement,
(9) determining and refining the experimental structure,
(10) calculating comparative protein structure models using this new template,
making inferences from the structure concerning how the protein normally
functions and how this may be altered in human disease.
An example of the above process applied to drug discovery would if the protein being
investigated is a biological effector molecule, the newly characterized protein may represent
a pharmaceuticals in its own right. On the other hand, if the protein being characterized is a
biological receptor, a database of comparative protein structure models could be used for “in
silico” docking with compound libraries of small organic molecules. The resulting database
of docked structures could permit identification of putative therapeutic lead compounds.
b) Animal Models of Human Disease
The ability to rapidly screen drug candidates has developed dramatically over the past 50
years. A good example of this has been in the cancer field. The National Cancer Institute
(NCI; Bethesda, MD) began formal screening efforts in 1955 to find new anticancer
compounds. This was initially done in mouse models of leukemia, sarcomas, and carcinomas.
After twenty years of experimentation, NCI researchers found that they had developed agents
that cured cancer in mice but were largely ineffective in humans. In the mid-1970s onward,
NCI researchers refocused their testing strategy using xenograft mouse models. In this
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approach, human tumors are transplanted into immunosuppressed mice and compounds are
advanced that show the ability to limit or kill these tumors.
c) Cell-Based Bioassays
Looking again at cancer drug discovery it was soon appreciated that not all human diseases
can be sufficiently model using animals. A major limitation of the predictive value of NCI’s
approach was that many of the key events related to cancer, such as metastasis, did not occur
in the xenograft mouse model.
A further step to deal with the limitations of the xenograft mouse model next was the
development and testing of human cancer cell lines. As a result of this work the NCI
currently has developed over 60 human tumor lines which it uses to test lead compounds.
NCI's screening based on human cell lines has produced about 5,000 agents with antitumor
activity and 1,200 have been selected for further testing. Similar cell-based approaches are
used in cancer drug screening in the pharmaceutical and biotechnology industry.
d) Drug Candidate Screening Using Cell-Free Molecular Response Cascades
Another development in drug screening has been the use of automated one-to-one binding
assays. In this approach, a target of interest, such as a receptor known to be involved in a
disease, is exposed to potential inhibitors. However a rational drug approach implies that
multiple receptors or enzyme-linked cascades are involved in the development of disease.
Therefore currently high-throughput lead-validation is based on combinations of automated
assays using cell culture and cell-free molecular drug response cascades. The choice of which
cascades to use have been based on the study of signal transduction utilizing proteomics.
e) Proteomics
Proteomics involves characterizing proteins and their interaction in molecular pathways and
cascades within cells. There are many important protein pathways that have been shown to
be involved in disease such as signal transduction, cell proliferation, necrosis, apoptosis
(programmed cell death), for example. Important protein molecules are being discovered on a
daily basis. Compounds discovered through structural genomics need to be functionally
characterized and this can be done through proteomics using cell-free systems comprised of
molecular pathways and cascades.
f) Product Safety and Good Laboratory Practices (GLP)
Nonclinical laboratory studies in support of FDA-regulated products must be conducted
according to scientifically sound protocols and with meticulous attention to quality. The
United Public Health Service Acts requires that sponsors of FDA-regulated products submit
evidence of their product’s safety in research and/or marketing applications. These products
include food and color additives, animal drugs, human drugs and biological products, human
medical devices, diagnostic products, and electronic products. If the product is a drug the
submission is called an Investigative New Drug Application or IND.
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In the 1970s, FDA inspections of nonclinical laboratories revealed that some studies
submitted in support of the safety of regulated products had not been conducted in accord
with acceptable practice, and that data from such studies was not always of the quality and
integrity to assure product safety. As a result of these findings, the FDA promulgated the
Good Laboratory Practice (GLP) Regulations, 21 CFR Part 58, on December 22, 1978 (43
FR 59986). The regulations became effective June 1979. The regulations establish standards
for the conduct and reporting of nonclinical laboratory studies and are intended to assure the
quality and integrity of safety data submitted to the FDA.
The FDA relies on documented adherence to GLP requirements by nonclinical laboratories in
judging the acceptability of safety data submitted in support of research and/or marketing
permits. The FDA uses these data to answer questions regarding:
1.
2.
3.
4.
5.
The toxicity profile of the article (i.e., molecule or compound).
The observed “no adverse effect” dose level in the test system.
The risks associated with clinical studies involving humans or animals.
The potential teratogenic, carcinogenic, or other adverse effects of the article.
The level of use that can be approved.
Besides reviewing documents provided by sponsors of FDA-regulated products, the FDA
also has implemented a program of regular inspections and data audits to monitor laboratory
compliance with the GLP requirements. Documentation review and inspections therefore
allow the FDA to fulfill its objectives regarding non-clinical testing before allowing a
sponsor to perform clinical investigations in humans. FDA objectives in this program are:
1. To verify the quality and integrity of data submitted in a research or marketing
application.
2. To inspect (approximately every two years) nonclinical laboratories conducting
safety studies that are intended to support applications for research or marketing
of regulated products.
3. To audit safety studies and determine the degree of compliance with GLP
regulations.
The FDA Centers or ORA headquarters initiated all nonclinical laboratory inspections. The
types of Inspections are:
1. Surveillance Inspections:
Surveillance inspections are periodic, routine determinations of a laboratory's
compliance with GLP regulations. These inspections include a facility inspection
and audits of on-going and/or recently completed studies.
2. Directed Inspections:
Directed inspections are assigned to achieve a specific purpose, such as:
a. Verifying the reliability, integrity, and compliance of critical safety studies
being reviewed in support of pending applications.
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Investigating issues involving potentially unreliable safety data and/or
violative conditions brought to FDA's attention.
c. Re-inspecting of laboratories previously classified OAI usually within 6
months after the firm responds to a Warning Letter. (QAI refers to
“Official Action Indicated.” This refers to previous regulatory and
administrative actions recommended by the FDA as opposed to NAI or
“No Action Indicated.” NAI is no objectionable conditions or practices
were found during the inspection or the objectionable conditions found do
not justify further regulatory action).
d. Verifying the results from third party audits or sponsor audits submitted to
FDA for consideration in determining whether to accept or reject
questionable or suspect studies.
b.
FDA investigators therefore will determine the current state of GLP compliance by
evaluating the laboratory facilities, operations, and nonclinal study performance. A sponsor
submitting an FDA-regulated product therefore must be familiar with the following reference
documents that can be found at http://www.FDA.gov.:
1. 21 CFR 58.1 - 58.219 Good Laboratory Practice Regulations effective June 1979,
and amended effective October 1987
2. Good Laboratory Practice Regulations, Management Briefings, Post Conference
Report, August 1979
3. Good Laboratory Practice Regulations, Questions and Answers, June 1981
4. "Toxicological Principles for the Safety Assessment of Direct Food Additives and
Color Additives used in Food," FDA, Bureau of Foods
5. Guide for the Care and Use of Laboratory Animals, DHHS Publication No. (NIH)
96-23
6. The Animal Welfare Act, 9 CFR Parts 1, 2, 3
7. 21 CFR 11 - Electronic Records. Electronic Signatures Regulation effective
August 1997.
8. "Guide to Inspection of Computerized Systems in Drug Processing," February
1983
9. "Software Development Activities, Technical Report" July 1987
10. "Guide For Detecting Fraud in Bioresearch Monitoring Inspections," April 1993.
In regards to GLP, FDAs regulatory guidance regarding specific topics can be outlined as
compiled in the following table (from
http://www.access.gpo.gov/nara/cfr/waisidx_07/21cfr58_07.html):
Title 21--Food and Drugs
CHAPTER I--FOOD AND DRUG ADMINISTRATION,
DEPARTMENT OF HEALTH AND HUMAN SERVICES
14
PART 58--GOOD LABORATORY PRACTICE FOR
NONCLINICAL LABORATORY STUDIES
58.1
Scope.
58.3
Definitions.
58.10
58.15
Applicability to studies performed under grants and
contracts.
Inspection of a testing facility.
58.29
Personnel.
58.31
Testing facility management.
58.33
Study director.
58.35
Quality assurance unit.
58.41
General.
58.43
Animal care facilities.
58.45
Animal supply facilities.
58.47
Facilities for handling test and control articles.
58.49
Laboratory operation areas.
58.51
Specimen and data storage facilities.
58.61
Equipment design.
58.63
Maintenance and calibration of equipment.
58.81
Standard operating procedures.
58.83
Reagents and solutions.
58.90
Animal care.
58.105
Test and control article characterization.
58.107
Test and control article handling.
58.113
Mixtures of articles with carriers.
58.120
Protocol.
58.130
Conduct of a nonclinical laboratory study.
58.185
Reporting of nonclinical laboratory study results.
58.190
Storage and retrieval of records and data.
58.195
Retention of records.
15
58.200
Purpose.
58.202
Grounds for disqualification.
58.204
58.206
Notice of and opportunity for hearing on proposed
disqualification.
Final order on disqualification.
58.210
Actions upon disqualification.
58.213
Public disclosure of information regarding
disqualification.
Alternative or additional actions to disqualification.
58.215
58.217
58.219
Suspension or termination of a testing facility by a
sponsor.
Reinstatement of a disqualified testing facility.
Professionals that will be involved in submitting drug application, particularly INDs, to the
CDER Division of the FDA should open the text or pdf links on the topics outlined above and be
extremely knowledgeable in their content and insure that the prelinical studies conducted in
support of all INDs that they submit to the FDA adhere to all of the above 21 CFR Part 58
recommendations.
In addition to the above, the FDA has provided copies of many of the common answers that have
been addresses to them regarding GLP and these questions and the FDA’s response can be found
at http://www.fda.gov/ora/compliance_ref/bimo/GLP/81GLP-qanda.pdf. Since copies of these
GLP Q&A documents are often reviewed by field investigators prior to making GLP inspections
and by headquarters personnel involved in the GLP program, all regulatory personnel involved in
GLP whether inside or outside of the FDA should be familiar with these issues.
C. Details Regarding INDs
a) Introduction
Current Federal law requires that a drug be the subject of an approved marketing application
before it is transported or distributed across state lines. Because a sponsor will probably want to
ship the investigational drug to clinical investigators in many states, it must seek an exemption
from that legal requirement. The IND is the means through which the sponsor technically obtains
this exemption from the FDA.
During a new drug's early preclinical development, the sponsor's primary goal is to determine if
the product is reasonably safe for initial use in humans, and if the compound exhibits
pharmacological activity that justifies commercial development. When a product is identified as
a viable candidate for further development, the sponsor then focuses on collecting the data and
information necessary to establish that the product will not expose humans to unreasonable risks
when used in limited, early-stage clinical studies.
16
FDA's role in the development of a new drug begins when the drug's sponsor (usually the
manufacturer or potential marketer) having screened the new molecule for pharmacological
activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic
potential in humans. At that point, the molecule changes in legal status under the Federal Food,
Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug
regulatory system.
b) Types and Categories of INDs
There are three IND types:

An Investigator IND is submitted by a physician who both initiates and conducts an
investigation, and under whose immediate direction the investigational drug is
administered or dispensed. A physician might submit a research IND to propose studying
an unapproved drug, or an approved product for a new indication or in a new patient
population.

Emergency Use IND allows the FDA to authorize use of an experimental drug in an
emergency situation that does not allow time for submission of an IND in accordance
with 21CFR , Sec. 312.23 or Sec. 312.34. It is also used for patients who do not meet
the criteria of an existing study protocol, or if an approved study protocol does not exist.

Treatment IND is submitted for experimental drugs showing promise in clinical testing
for serious or immediately life-threatening conditions while the final clinical work is
conducted and the FDA review takes place.
There are two IND categories:

Commercial

Research (non-commercial)
c) Content of the IND
The IND application must contain information in three broad areas:

Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment
as to whether the product is reasonably safe for initial testing in humans. Also included
are any previous experience with the drug in humans (often foreign use).

Manufacturing Information - Information pertaining to the composition, manufacturer,
stability, and controls used for manufacturing the drug substance and the drug product.
This information is assessed to ensure that the company can adequately produce and
supply consistent batches of the drug.

Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical
studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.
Also, information on the qualifications of clinical investigators--professionals (generally
physicians) who oversee the administration of the experimental compound--to assess
17
whether they are qualified to fulfill their clinical trial duties. Finally, commitments to
obtain informed consent from the research subjects, to obtain review of the study by an
institutional review board (IRB), and to adhere to the investigational new drug
regulations.
The chart on the next page summarizes the IND process, including how CDER determines if the
product is suitable for use in clinical trials (for subsection details click on the corresponding
specific portion of the FDA website’s interactive chart).
18
19
d) FDA Guidance Documents on Preparing INDs
Regulatory Professionals should consult the FDA guidance documents listed below to help in the
preparation of INDs. Guidance documents represent the Agency's current thinking on a
particular subject. These documents are prepared for FDA review staff and applicants/sponsors
to provide guidelines to the processing, content, and evaluation/approval of applications and also
to the design, production, manufacturing, and testing of regulated products. They also establish
policies intended to achieve consistency in the Agency's regulatory approach and establish
inspection and enforcement procedures. Because guidances are not regulations or laws, they are
not enforceable, either through administrative actions or through the courts. Therefore an
alternative approach may be used if such approach satisfies the requirements of the applicable
statute, regulations, or both.
FDA Guidance Documents on the Preparation of INDs

Guidance for Industry: INDs--Approaches to Complying with CGMP's for Phase 1 Drugs (Draft) [HTML]
or [PDF] (1/12/2006)

Guidance for Industry: Exploratory IND Studies [HTML] or [PDF] (1/12/2006)

Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs
Including Well Characterized, Therapeutic, Biotechnology-Derived Products.
Provides description of
required sections of an application.

Q & A - Content and Format of INDs for Phase 1 Studies of Drugs, Including Well-Characterized,
Therapeutic, Biotechnology-Derived Products. Optional Format: PDF. This guidance is intended to clarify
when sponsors should submit final, quality-assured toxicology reports and/or update the Agency on any
changes in findings since submission of non-quality-assured reports or reports based on non-qualityassured data. (Issued 10/00).

Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General
Considerations. Optional Format: PDF (Issued 10/2000, Posted 10/27/2000). This guidance should be
useful for applicants planning to conduct bioavailability (BA) and bioequivalence (BE) studies during the
IND period for an NDA, BE studies intended for submission in an ANDA, and BE studies conducted in the
postapproval period for certain changes in both NDAs and ANDAs.

IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of
Cancer. (1/2004)

Drug Master Files. A Drug Master File (DMF) is a submission to the Food and Drug Administration
(FDA) that may be used to provide confidential detailed information about facilities, processes, or articles
used in the manufacturing, processing, packaging, and storing of one or more human drugs.

Required Specifications for FDA's IND, NDA, and ANDA Drug Master File Binders.

Immunotoxicology Evaluation of Investigational New Drugs [PDF] (Issued 10/2002, Posted 10/31/2002).
This guidance makes recommendations to sponsors of investigational new drugs (INDs) on (1) the
parameters that should be routinely assessed in toxicology studies to determine effects of a drug on immune
function, (2) when additional immunotoxicity studies should be conducted, and (3) when additional
mechanistic information could help characterize the significance of a given drug’s effect on the immune
system.
20
e) FDA Code of Regulation regarding INDs
Distinct from FDA guidelines which are recommendation, the FDA does enforce laws enacted
by the U.S. Congress and regulations established by the Agency to protect the consumer's health,
safety, and pocketbook. The Federal Food, Drug, and Cosmetic Act is the basic food and drug
law of the U.S. With numerous amendments it is the most extensive law of its kind in the world.
The law is intended to assure consumers that foods are pure and wholesome, safe to eat, and
produced under sanitary conditions; that drugs and devices are safe and effective for their
intended uses; that cosmetics are safe and made from appropriate ingredients; and that all
labeling and packaging is truthful, informative, and not deceptive.
Final FDA regulations are published in the Federal Register (daily published record of proposed
rules, final rules, meeting notices, etc.) are collected in the Code Of Federal Regulations (CFR).
The CFR is divided into 50 titles that represent broad areas subject to Federal regulations. The
FDA's portion of the CFR interprets the Federal Food, Drug and Cosmetic Act and related
statutes. Section 21 of the CFR contains most regulations pertaining to food and drugs. The
regulations document all actions of all drug sponsors that are required under Federal law. That
being said, the following regulations apply to the IND application process:
FDA Regulations Regarding the IND Process
21CFR Part 312
Investigational New Drug Application
INDA and NDA Applications for FDA Approval to Market a New
Drug (New Drug Approval)
Orphan Drugs
Good Lab Practice for Nonclinical Laboratory [Animal] Studies
Protection of Human Subjects
Institutional Review Boards
Drug Labeling
Financial Disclosure by Clinical Investigators
21CFR Part 314
21CFR Part 316
21CFR Part 58
21CFR Part 50
21CFR Part 56
21CFR Part 201
21CFR Part 54
f) IND Forms and Instructions
After reviewing FDA guidance and regulations regarding the IND process, the Regulatory
Professional fills in and submits the following forms to the FDA.
Forms for Use in Submitting INDs:

FDA 1571

FDA 1572

Instructions for completing FDA forms 1571 and 1572

FDA Form Distributions Page includes links to:
Certification: Financial Interest and Arrangements of Clinical Investigators
Investigational New Drug Application
Statement of Investigator
21
Disclosure: Financial Interest and Arrangements of Clinical Investigators
MedWatch: FDA Medical Product Reporting Program - Voluntary
MedWatch: FDA Medical Products Reporting Program - Mandatory

The FDA also allows electronic form submissions, see ERSR
Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical
trials. During this time, FDA has an opportunity to review the IND for safety to assure that
research subjects will not be subjected to unreasonable risk ( see
http://www.fda.gov/cder/Regulatory/applications/ind_page_1.htm#Introduction).
D.
Conducting Human Clinical Trials
a) Moving from Discovery to Clinical Development
As stated above (see Section B), in the pre-clinical discovery stage, literally thousands of
molecules are applied to targets developed to simulate various disease groups. Once an active
molecule is discovered, various permutations of the structure of the molecule are tested to see if
the activity can be enhanced. The most active molecule from these structure-activity
relationships is tested for toxicological results in rats or mice following FDA GLP guidelines. If
no particular worrisome toxic endpoints are observed, the molecule is promoted to the status of
lead molecule and becomes a candidate for clinical development.
After an Investigational New Drug Application (IND) is accepted by the FDA, the process of
manufacturing the drug must be developed and materials made available for Human Clinical
Trials. During clinical development there is usually an exponential increase in the amount of
money and resources needed to test behavior of the lead candidate initially in healthy volunteers,
and later, in large scale studies of patients having the disorder or disease. Concomitant with the
human population studies, process research and formulations work is conducted to both supply
the drug for testing purposes as well as to design and construct a commercial plant if the product
is launched. Also since the drug must be administered to human subjects at an appropriate dose
that is effective with few side effects, pharmacological and toxicological animal studies often are
continued in parallel with the human studies to predict human dosage levels.
b) Process Development and Scale-up of the Drug
This usually involves moving from a bench-scale process used to produce small amounts of the
drug for the molecular characterizations, bioactivity and animal toxicology studies conducted
during pre-clinical research (see Section B above) to the production of sufficient high-quality
drug product to sustain Phase I through Phase III Human Clinical Trials. The scaled-up process
must be shown to be a repeatable, reliable, and robust process. When this is achieved it is often
referred to as making “fixed processed material.” Concomitant with this goal is that of ensuring
that the fixed processes that are developed are in alignment with the FDA’s “Current Good
Manufacturing Practices” or “CGMPs.” Drug product made under the latter conditions is often
22
referred to as the “CGMP-manufactured drug product” or drug “manufactured under CGMP
conditions.”
c) Introduction to the FDAs Guidelines for Pharmaceuticals CGMP
The drug manufactured “under CGMP” is done so throughout the clinical development phase of
testing in human subjects and likewise during manufacturing after the drug has achieved
approval to enter the market commercially.
The most recent revision of the FDA’s pharmaceuticals CGMP was announced in August of
2002 and is called “Pharmaceutical CGMPs for the 21st Century Initiative.” See
http://www.fda.gov/cder/guidance/7260fnl.htm.
In that announcement, the FDA explained the Agency’s intent to integrate quality systems and
risk management approaches into its existing programs with the goal of encouraging industry to
adopt modern and innovative manufacturing technologies. The CGMP initiative was spurred by
the fact that since 1978, when the last major revision of the CGMP regulations was published,
there have been many advances in manufacturing science and in our understanding of quality
systems. In addition, many pharmaceutical manufacturers are already implementing
comprehensive, modern quality systems and risk management approaches. This guidance is
intended to help manufacturers implementing modern quality systems and risk management
approaches to meet the requirements of the Agency's CGMP regulations. The Agency also saw a
need to harmonize the CGMPs with other non-U.S. pharmaceutical regulatory systems and with
FDA’s own medical device quality systems regulations. This guidance supports these goals. It
also supports the objectives of the Critical Path Initiative, which intends to make the
development of innovative medical products more efficient so that safe and effective therapies
can reach patients sooner.
The CGMPs for the 21st Century Initiative steering committee created a Quality System
Guidance Development working group (QS working group) to compare the current CGMP
regulations, which call for some specific quality management elements, to other existing quality
management systems. The QS working group mapped the relationship between CGMP
regulations (parts 210 and 211 and the 1978 Preamble to the CGMP regulations 2 ) and various
quality system models, such as the Drug Manufacturing Inspections Program (i.e., systems-based
inspectional program),3 the Environmental Protection Agency's Guidance for Developing Quality
Systems for Environmental Programs, ISO Quality Standards, other quality publications, and
experience from regulatory cases. The QS working group determined that, although the CGMP
regulations do provide great flexibility, they do not incorporate explicitly all of the elements that
today constitute most quality management systems.
The CGMP regulations and other quality management systems differ somewhat in organization
and in certain constituent elements; however, they are very similar and share underlying
principles. For example, the CGMP regulations stress quality control. More recently developed
quality systems stress quality management, quality assurance, and the use of risk management
tools, in addition to quality control. The QS working group decided that it would be very useful
to examine exactly how the CGMP regulations and the elements of a modern, comprehensive
23
quality system fit together in today's manufacturing world. This guidance is the result of that
examination.
d) Glossary of Terms Related to Pharmaceuticals CGMP
To gain a common understanding of a quality systems approach, the following terms are used
throughout the FDA’s CGMP guidance and should become the lexicon of any regulatory
professional involved in CGMP:
Annual Review – An evaluation, conducted at least annually, that assesses the quality standards
of each drug product to determine the need for changes in drug product specifications or
manufacturing or control procedures
CAPA – Corrective and preventive action: A systematic approach that includes actions needed
to correct (“correction”), prevent recurrence (“corrective action”), and eliminate the cause of
potential nonconforming product and other quality problems (preventive action) (21CFR
820.100)
Continual Improvement – Ongoing activities to evaluate and positively change products,
processes, and the quality system to increase effectiveness
Correction – Repair, rework, or adjustment relating to the disposition of an existing discrepancy
Corrective Action – Action taken to eliminate the causes of an existing discrepancy or other
undesirable situation to prevent recurrence
Customer – A person or organization (internal or external) that receives a product or service
anywhere along the product’s life cycle
Discrepancy – Datum or result outside of the expected range; an unfulfilled requirement; may be
called non-conformity, defect, deviation, out-of-specification, out-of-limit, out-of-trend
Harm – Damage to health, including the damage that can occur from the loss of product quality
or availability
Non-conformity – A deficiency in a characteristic, product specification, process parameter,
record, or procedure that renders the quality of a product unacceptable, indeterminate, or not
according to specified requirements
Preventive Action – Action taken to eliminate the cause of a potential discrepancy or other
undesirable situation to prevent such an occurrence
Product/Service – The intended results of activities or processes; products/services can be
tangible or intangible
Quality – A measure of a product’s or service’s ability to satisfy the customer’s stated or implied
needs
Quality Assurance – Proactive and retrospective activities that provide confidence that
requirements are fulfilled
Quality Control – The steps taken during the generation of a product or service to ensure that it
meets requirements and that the product or service is reproducible
Quality Management – Accountability for the successful implementation of the quality system
Quality Objectives – Specific measurable activities or processes to meet the intentions and
directions as defined in the quality policy
Quality Plan – The documented result of quality planning that is disseminated to all relevant
levels of the organization
24
Quality Planning – A management activity that sets quality objectives and defines the
operational and/or quality system processes and the resources needed to fulfill the objectives
Quality Policy – A statement of intentions and direction issued by the highest level of the
organization related to satisfying customer needs. It is similar to a strategic direction that
communicates quality expectations that the organization is striving to achieve.
Quality System – Formalized business practices that define management responsibilities for
organizational structure, processes, procedures, and resources needed to fulfill product/service
requirements, customer satisfaction, and continual improvement
Quality Unit – A group organized within an organization to promote quality in general practice
Risk – The combination of the probability of occurrence of harm and the severity of that harm
Risk Assessment – A systematic process for organizing information to support a risk decision
that is made within a risk management process. The process consists of the identification of
hazards and the analysis and evaluation of risks associated with exposure to those hazards.
Risk Management – The systematic application of quality management policies, procedures,
and practices to the tasks of assessing, controlling, communicating, and reviewing risk
Senior Management – Top management officials in a firm who have the authority and
responsibility to mobilize resources
Stakeholder – An individual or organization having an ownership or interest in the delivery,
results, and metrics of the quality system framework or business process improvements
Verification – Confirmation, through the provision of objective evidence, that specified
requirements have been fulfilled. (Reference: The ASQ Auditing Handbook, 3rd edition, ASQ
Quality Audit Division, J.P. Russell, Editor)
Validation – Confirmation, through the provision of objective evidence, that the requirements
for a specific intended use or application have been fulfilled. (Reference: The ASQ Auditing
Handbook, 3rd edition, ASQ Quality Audit Division, J.P. Russell, Editor)
e) Goal of the CGMP Guidance
FDAs CGMP guidance describes a comprehensive quality systems model, which, if
implemented, will allow manufacturers to support and sustain robust, modern quality systems
that are consistent with CGMP regulations. The guidance demonstrates how and where the
elements of this comprehensive model can fit within the requirements of the CGMP regulations.
The inherent flexibility of the CGMP regulations should enable manufacturers to implement a
quality system in a form that is appropriate for their specific operations.
The overarching philosophy articulated in both the CGMP regulations and in robust modern
quality systems is:
Quality should be built into the product, and testing alone cannot be relied on to ensure
product quality.
This guidance is intended to serve as a bridge between the 1978 regulations and our current
understanding of quality systems. In addition to being part of the FDA's CGMP initiative, this
guidance is being issued for a number of reasons:
25

A quality system addresses the public and private sectors’ mutual goal of providing a high-quality drug
product to patients and prescribers. A well-built quality system should reduce the number of (or prevent)
recalls, returned or salvaged products, and defective products entering the marketplace.

It is important that the CGMP regulations are harmonized to the extent possible with other widely used
quality management systems, including ISO 9000, non-U.S. pharmaceutical quality management
requirements, and FDA’s own medical device quality system regulations. This guidance serves as a first
step to highlight common elements between the CGMP regulations and Quality Management Systems.
With the globalization of pharmaceutical manufacturing and the increasing prevalence of drug- and
biologic-device combination products, the convergence of quality management principles across different
regions and among various product types is very desirable.

The FDA has concluded that modern quality systems, when coupled with manufacturing process and
product knowledge and the use of effective risk management practices, can handle many types of changes
to facilities, equipment, and processes without the need for prior approval regulatory submissions.
Manufacturers with a robust quality system and appropriate process knowledge can implement many types
of improvements. In addition, an effective quality system, by lowering the risk of manufacturing
problems, may result in shorter and fewer FDA inspections.

A quality system can provide the necessary framework for implementing quality by design 4. (building in
quality from the development phase and throughout a product’s life cycle), continual improvement, and
risk management in the drug manufacturing process. A quality system adopted by a manufacturer can be
tailored to fit the specific environment, taking into account factors such as scope of operations, complexity
of processes, and appropriate use of finite resources.
f) Scope and Organization of the FDAs Quality Systems Model for CGMPs
This FDA guidance applies to manufacturers of drug products (finished pharmaceuticals),
including products regulated by the Center for Biologics Evaluation and Research (CBER), the
Center for Drug Evaluation and Research (CDER), and the Center for Veterinary Medicine
(CVM). It may also be useful to manufacturers of components (including active pharmaceutical
ingredients) used in the manufacture of these products.
To provide a reference familiar to industry, the quality systems model described in section IV of
this guidance is organized — in its major sections — according to the structure of international
quality standards. Major sections of the model include the following:

Management Responsibilities

Resources

Manufacturing Operations

Evaluation Activities
Under each of these sections the key elements found in modern quality systems are discussed.
When an element correlates with a CGMP regulatory requirement, that correlation is noted. In
some cases, a specific CGMP regulation is discussed in more detail as it relates to a quality
system element. At the end of each section, a table is included listing the quality system
elements of that section and the specific CGMP regulations with which they correlate. A
glossary is included at the end of the document.
26
g) CGMPS and the concepts of modern Quality Systems
Several key concepts are critical for any discussion of modern quality systems and the FDA
applies these concepts throughout their CGMP guidance as they relate to the manufacture of
pharmaceutical products:
1. Quality
Every pharmaceutical product has established identity, strength, purity, and other quality
characteristics designed to ensure the required levels of safety and effectiveness. For the
purposes of the guidance document, the phrase achieving quality means achieving these
characteristics for a product.
2. Quality by Design and Product Development
Quality by design means designing and developing a product and associated manufacturing
processes that will be used during product development to ensure that the product consistently
attains a predefined quality at the end of the manufacturing process. 5. Quality by design, in
conjunction with a quality system, provides a sound framework for the transfer of product
knowledge and process understanding from drug development to the commercial manufacturing
processes and for post-development changes and optimization. The CGMP regulations, when
viewed in their entirety, incorporate the concept of quality by design. This guidance describes
how these elements fit together.
3. Quality Risk Management
Quality risk management is a valuable component of an effective quality systems framework. 6.
Quality risk management can, for example, help guide the setting of specifications and process
parameters for drug manufacturing, assess and mitigate the risk of changing a process or
specification, and determine the extent of discrepancy investigations and corrective actions.
4. CAPA (Corrective and Preventive Action)
CAPA is a well-known CGMP regulatory concept that focuses on investigating, understanding,
and correcting discrepancies while attempting to prevent their recurrence. Quality system
models discuss CAPA as three separate concepts, all of which are used in this guidance.

Remedial corrections of an identified problem

Root cause analysis with corrective action to help understand the cause of the deviation and potentially
prevent recurrence of a similar problem

Preventive action to avert recurrence of a similar potential problem
5. Change Control
27
Change control is another well-known CGMP concept that focuses on managing change to
prevent unintended consequences. The CGMP regulations provide for change control primarily
through the assigned responsibilities of the quality control unit. Certain major manufacturing
changes (e.g., changes that alter specifications, a critical product attribute or bioavailability)
require regulatory filings and prior regulatory approval (21 CFR 314.70, 514.8, and 601.12).
Effective change control activities (e.g., quality planning and control of revisions to
specifications, process parameters, procedures) are key components of any quality system. In
this guidance, change is discussed in terms of creating a regulatory environment that encourages
change towards continual improvement. This means a manufacturer is empowered to make
changes subject to the regulations based on the variability of materials used in manufacturing and
process improvements resulting from knowledge gained during a product’s lifecycle.
6. The Quality Unit
Many of the modern quality system concepts described here correlate very closely with the
CGMP regulations (refer to the charts later in the document). Current industry practice generally
divides the responsibilities of the quality control unit (QCU), as defined in the CGMP
regulations, between quality control (QC) and quality assurance (QA) functions.

QC usually involves (1) assessing the suitability of incoming components, containers, closures, labeling, inprocess materials, and the finished products; (2) evaluating the performance of the manufacturing process
to ensure adherence to proper specifications and limits; and (3) determining the acceptability of each batch
for release.

QA primarily involves (1) review and approval of all procedures related to production and maintenance, (2)
review of associated records, and (3) auditing and performing/evaluating trend analyses.
This guidance uses the term quality unit 7. (QU) to reflect modern practice while remaining
consistent with the CGMP definition in § 210.3(b)(15). The concept of a quality unit is also
consistent with modern quality systems in ensuring that the various operations associated with all
systems are appropriately planned, approved, conducted, and monitored.
The CGMP regulations specifically assign the QU the authority to create, monitor, and
implement a quality system. Such activities do not substitute for, or preclude, the daily
responsibility of manufacturing personnel to build quality into the product. The QU should not
take on the responsibilities of other units of a manufacturer’s organization, such as the
responsibilities handled by manufacturing personnel, engineers, and development scientists. 8.
Manufacturing personnel and the QU are both critical in fulfilling the manufacturer’s
responsibility to produce quality products.
Other CGMP assigned responsibilities of the QU are consistent with modern quality system
approaches (§ 211.22):

Ensuring that controls are implemented and completed satisfactorily during manufacturing operations

Ensuring that developed procedures and specifications are appropriate and followed, including those used
by a firm under contract to the manufacturer
28

Approving or
rejecting incoming
materials, inprocess materials,
and drug products

Reviewing
production records
and investigating
any unexplained
discrepancies
Under a quality
system, it is normally
expected that the
product and process
development units, the
manufacturing units,
and the QU will
remain independent.
In very limited
circumstances, a single
individual can perform
both production and
quality functions.
That person is still
accountable for
implementing all the controls and reviewing the results of manufacture to ensure that product
quality standards have been met. Under such circumstances, it is recommended that another
qualified individual, not involved in the production operation, conduct an additional, periodic
review of QU activities.
7. The Six-system Inspection Model
The FDA's Drug Manufacturing Inspection Compliance Program, which contains instructions to
FDA personnel for conducting inspections, is a systems-based approach to inspection and is very
consistent with the robust quality system model presented in this guidance.9. The diagram
below shows the relationship among the six systems: the quality system and the five
manufacturing systems. The quality system provides the foundation for the manufacturing
systems that are linked and function within it. The quality system model described in this
guidance does not consider the five manufacturing systems as discrete entities, but instead
integrates them into appropriate sections of the model. Those familiar with the six-system
inspection approach will see organizational differences in this guidance; however, the interrelationship should be readily apparent. One of the important themes of the systems based
inspection compliance program is that you have the ability to assess whether each of the systems
is in a state of control. The quality system model presented in this guidance will also serve to
help firms achieve this state of control.
29
h) Implementation of a Quality Systems Model for Use in Pharmaceuticals Manufacturing
It should be noted that implementing an effective quality system in a manufacturing organization
will require a significant investment of time and resources. However, the FDA feels strongly
that that the long-term benefits of implementing a quality system will outweigh the costs. 10.
This section describes a robust quality systems model that, if properly implemented, can provide
the controls to consistently produce a product of acceptable quality. Where applicable, the
relationship between elements of this model and CGMP regulations is noted. At the end of each
section, a table shows how the specific CGMP regulations correlate to the elements in the quality
systems model. As already explained, many of the quality systems elements correlate closely
with the CGMP regulations. It is important to emphasize that this guidance is not recommending
new regulatory requirements. The guidance is intended to provide recommendations to
manufacturers who are implementing, or plan to implement, a quality systems model to help
them comply with CGMP regulations. FDA regulatory and inspectional coverage will remain
focused on the specific CGMP regulations.
The model is described according to four major factors:

Management Responsibilities

Resources

Manufacturing Operations

Evaluation Activities
In each of the sections that follow, the specific elements of a robust modern quality systems
model are described. When elements of the quality systems model correlate with specific CGMP
regulations, this correlation is noted.
1. Management Responsibilities
Modern robust quality systems models call for management to play a key role in the design,
implementation, and management of the quality system. For example, management is
responsible for establishing the quality system structure appropriate for the specific organization.
Management has ultimate responsibility to provide the leadership needed for the successful
functioning of a quality system. This section describes management's role in developing,
implementing, and managing a robust quality system. There is some overlap with the CGMP
regulations in this section (see the table at the end of the section).
i. Provide Leadership
In a robust, modern quality system, senior management should demonstrate commitment to
developing and maintaining their quality system. Quality system plans should be aligned with a
manufacturer’s strategic plans to ensure that the system is part of the manufacturer’s mission and
quality strategies. For example, quality systems departments normally have equal standing with
other departments within an organization. Quality systems staff are effectively integrated into
manufacturing activities and are involved in activities such as nonconformance investigations.
30
Senior managers set implementation priorities and develop action plans. All levels of
management can provide support of the quality system by:

Actively participating in system design, implementation, and monitoring, including system review (see
IV.A.5.)

Advocating continual improvement of operations of the quality system

Committing necessary resources
In a robust quality systems environment, all managers should demonstrate strong and visible
support for the quality system and ensure its implementation throughout the organization (e.g.,
across multiple sites).
All managers should encourage internal communication on quality issues at all levels in the
organization. Communication should be ongoing among research and development, regulatory
affairs, manufacturing, and QU personnel on issues that affect quality, with management
included whenever appropriate.
ii. Structure the Organization
When designing a robust quality system, management has the responsibility to structure the
organization and ensure that assigned authorities and responsibilities support the production,
quality, and management activities needed to produce quality products. Senior managers have
the responsibility to ensure that the organization’s structure is documented.
All managers have the responsibility to communicate employee roles, responsibilities, and
authorities within the system and ensure that interactions are defined and understood.
An organization also has the responsibility to give the individual who is appointed to manage the
quality system the authority to detect problems and implement solutions. Usually, a senior
manager administers the quality system and can, thus, ensure that the organization receives
prompt feedback on quality issues.
iii. Build Your Quality System to Meet Requirements
Implementing a robust quality system can help ensure compliance with CGMP regulations
related to drug safety, identity, strength, quality, and purity. Under the quality systems model,
the Agency recommends that senior managers ensure that the quality system that is designed and
implemented provides clear organizational guidance and facilitates systematic evaluation of
issues. For example, according to the model, when documenting the implementation of a quality
system, the following should be addressed:

The scope of the quality system, including any outsourcing (see IV.B.4.)

The quality standard that will be followed

The manufacturer’s policies to implement the quality systems criteria and the supporting objectives (see
IV.A.4.)
31

The procedures needed to establish and maintain the quality system
It is recommended under a modern quality systems approach that a formal process be established
to change procedures in a controlled manner. It is also recommended that, when operating under
a quality system, manufacturers develop and document control procedures to complete, secure,
protect, and archive records, including data, which provide evidence of operational and quality
system activities. This approach is consistent with the CGMP regulations, which require
manufacturers to establish and follow scientifically sound and appropriate written controls for
specifications, plans, and procedures that direct operational and quality system activities and to
ensure that these directives are accurate, appropriately reviewed and approved, and available for
use (see the CGMPs at § 211.22 (c) and (d)).
iv. Establish Policies, Objectives, and Plans
Policies, objectives, and plans under a modern quality system provide the means by which senior
managers articulate their vision of and commitment to quality to all levels of the organization.
Under a quality system, senior management should incorporate a strong commitment to quality
into the organizational mission. Senior managers should develop an organizational quality
policy that aligns with this mission; commit to meeting requirements and improving the quality
system; and propose objectives to fulfill the quality policy. Under a quality system, to make the
policy relevant, it must be communicated to, and understood by, personnel and contractors (if
applicable) and revised, as needed.
Managers operating within a quality system should define the quality objectives identified for
implementing the quality policy. Senior management should ensure that the quality objectives
are created at the top level of the organization (and other levels as needed) through a formal
quality planning process. Objectives are typically aligned with the manufacturer’s strategic
plans. A quality system seeks to ensure that managers support the objectives with necessary
resources and have measurable goals that are monitored regularly.
Under a quality systems approach, managers would use quality planning to identify and allocate
resources and define methods to achieve the quality objectives. Quality system plans should be
documented and communicated to personnel to ensure awareness of how their operational
activities are aligned with strategic and quality goals.
v. Review the System
System review is a key component in any robust quality system to ensure its continuing
suitability, adequacy, and effectiveness. Under a quality system, senior managers should
conduct reviews of the quality system’s performance according to a planned schedule. Such a
review typically includes assessments of the process, product, and customer needs (in this
section, customer is defined as the recipient of the product and the product is the goods or
services provided). Under a quality systems approach, a review should consider at least the
following:

The appropriateness of the quality policy and objectives

The results of audits and other assessments
32

Customer feedback, including complaints

The analysis of data trending results

The status of actions to prevent a potential problem or a recurrence

Any follow-up actions from previous management reviews

Any changes in business practices or environment that may affect the quality system (such as the volume or
type of operations)

Product characteristics meeting the customer’s needs
When developing and implementing new quality systems, reviews should take place more
frequently than when the system has matured. Outside of scheduled reviews, the quality system
should typically be included as a standing agenda item in general management meetings. In
addition, a periodic review performed by a qualified source, external to the organization, may
also be useful in assessing the suitability and effectiveness of the system.
Review outcomes typically include

Improvements to the quality system and related quality processes

Improvements to manufacturing processes and products

Realignment of resources
Under a quality system, the results of a management review would typically be recorded.
Planned actions should be implemented using effective corrective and preventive action and
change control procedures.
The following table shows how the CGMP regulations correlate to specific elements in the
quality systems model for this section. Manufacturers should always refer to the specific
regulations to make sure they are in compliance.
21 CFR CGMP Regulations Related to Management Responsibilities
Quality System Element
Regulatory Citations
1. Leadership
—
2. Structure
Establish quality function: § 211.22 (a)
(see definition
§ 210.3(b)(15))
Notification: § 211.180(f)
3. Build QS
QU procedures: § 211.22(d)
QU procedures, specifications: §
211.22(c), with reinforcement in: §§
211.100(a), 211.160(a)
QU control steps: § 211.22(a), with
reinforcement in §§ 211.42(c), 211.84(a),
33
4. Establish Policies,
Objectives and Plans
5. System Review
211.87, 211.101(c)(1), 211.110(c),
211.115(b), 211.142, 211.165(d), 211.192
QU quality assurance; review/investigate:
§§ 211.22(a), 211.100(a-b) 211.180(f),
211.192, 211.198(a)
Record control: §§ 211.180(a-d),
211.180(c), 211.180(d), 211.180(e),
211.186, 211.192, 211.194, 211.198(b)
Procedures: §§ 211.22(c-d), 211.100(a)
Record review: §§ 211.100, 211.180(e),
211.192, 211.198(b)(2)
2. Resources
Appropriate allocation of resources is key to creating a robust quality system and complying with
the CGMP regulations. This section discusses the role of resources in developing, implementing,
and managing a robust quality system that complies with the CGMP regulations.
i. General Arrangements
Under a robust quality system, sufficient resources should be allocated for quality system and
operational activities. Under the model, senior management, or a designee, should be
responsible for providing adequate resources for the following:

To supply and maintain the appropriate facilities and equipment to consistently manufacture a quality
product

To acquire and receive materials that are suitable for their intended purpose

For processing the materials to produce the finished drug product

For laboratory analysis of the finished drug product, including collection, storage, and examination of inprocess, stability, and reserve samples
ii. Personnel Development
Under a quality system, senior management should support a problem-solving and
communicative organizational culture. Managers should encourage communication by creating
an environment that values employee suggestions and acts on suggestions for improvement.
Management should also develop cross-functional groups to share ideas to improve procedures
and processes.
In a quality system, personnel should be qualified to do the operations that are assigned to them
in accordance with the nature of, and potential risk of, their operational activities. Under a
quality system, managers should define appropriate qualifications for each position to help
34
ensure that individuals are assigned appropriate responsibilities. Personnel should also
understand the effect of their activities on the product and the customer. Although QU personnel
should not take on the responsibilities of other units of the organization, these personnel should
be selected based on their scientific and technical understanding, product knowledge, process
knowledge and/or risk assessment abilities to appropriately execute certain quality functions (this
quality systems feature is also found in the CGMP regulations, which identify specific
qualifications, such as education, training, and experience or any combination thereof (see §
211.25(a) and (b)).
Under a quality system, continued training is critical to ensure that the employees remain
proficient in their operational functions and in their understanding of CGMP regulations.
Typical quality systems training should address the policies, processes, procedures, and written
instructions related to operational activities, the product/service, the quality system, and the
desired work culture (e.g., team building, communication, change, behavior). Under a quality
system (and the CGMP regulations), training should focus on both the employees’ specific job
functions and the related CGMP regulatory requirements.
Under a quality system, managers are expected to establish training programs that include the
following:

Evaluation of training needs

Provision of training to satisfy these needs

Evaluation of effectiveness of training

Documentation of training and/or re-training
When operating in a robust quality system environment, it is important that managers verify that
skills gained from training are implemented in day-to-day performance.
iii. Facilities and Equipment

Under a quality system, the technical experts (e.g., engineers, development scientists), who have an
understanding of pharmaceutical science, risk factors, and manufacturing processes related to the product,
are responsible for defining specific facility and equipment requirements.

Under the CGMP regulations, the quality unit (QU) has the responsibility of reviewing and approving all
initial design criteria and procedures pertaining to facilities and equipment and any subsequent changes (§
211.22(c)).

Under the CGMP regulations, equipment must be qualified, calibrated, cleaned, and maintained to prevent
contamination and mix-ups (§§ 211.63, 211.67, 211.68). Note that the CGMP regulations require a higher
standard for calibration and maintenance than most non-pharmaceutical quality system models. The
CGMP regulations place as much emphasis on process equipment as on testing equipment (§§ 211.160,
211.63, 211.67, and 211.68) while most quality systems focus only on testing equipment. 11.
35
iv. Control Outsourced Operations
Outsourcing involves hiring a second party under a contract to perform the operational processes
that are part of a manufacturer’s inherent responsibilities. For example, a manufacturer may hire
another firm to package and label or perform CGMP regulatory training. Quality systems call
for contracts (quality agreements) that clearly describe the materials or service, quality
specification responsibilities, and communication mechanisms.
Under a quality system, the manufacturer should ensure that a contract firm is qualified before
signing a contract with that firm. The contract firm’s personnel should be adequately trained and
monitored for performance according to their quality system, and the contract firm's and
contracting manufacturer’s quality standards should not conflict. It is critical in a quality system
to ensure that the management of the contractor be familiar with the specific requirements of the
contract. However, under the CGMP requirements, the manufacturer’s QU is responsible for
approving or rejecting products or services provided under a contract (§ 211.22(a)).
As the following table illustrates, the CGMP regulations are consistent with the elements of a
quality system in many areas in this section. However, manufacturers should always refer to the
specific regulations to ensure that they are complying with all regulations.
21 CFR CGMP Regulations Related to Resources
Quality System Element
Regulatory Citation
1. General Arrangements
—
2. Develop Personnel
Qualifications: § 211.25(a)
Staff number: § 211.25(c)
Staff training: § 211.25(a-b)
3. Facilities and Equipment
Buildings and facilities: §§ 211.22(b),
211.28(c),
211.42 – 211.58, 211.173
Equipment: §§ 211.63 – 211.72,
211.105, 211.160(b)(4), 211.182
Lab facilities: § 211.22(b)
4. Control Outsourced Operations Consultants: § 211.34
Outsourcing: § 211.22(a)
3.. Manufacturing
Significant overlap exists between the elements of a quality system and the CGMP regulation
requirements for manufacturing operations. It is important to emphasize again that FDA’s
enforcement programs and inspectional coverage remain based on the CGMP regulations. When
quality system elements in this section do not correlate to the CGMP regulations, the guidance
makes recommendations to help facilitate compliance with the CGMP regulations. The language
in this section has been tailored to the pharmaceutical manufacturing environment.
36
i. Design, Develop, and Document Product and Processes
In a modern quality systems manufacturing environment, the significant characteristics of the
product being manufactured should be defined from design to delivery, and control should be
exercised over all changes. In addition, quality and manufacturing processes and procedures —
and changes to them — must be defined, approved, and controlled (§ 211.100). It is important to
establish responsibility for designing or changing products. Documenting processes, associated
controls, and changes to these processes will help ensure that sources of variability are identified.
Documentation includes:

Resources and facilities used

Procedures to carry out the process

Identification of the process owner who will maintain and update the process as needed

Identification and control of important variables

Quality control measures, necessary data collection, monitoring, and appropriate controls for the product
and process

Any validation activities, including operating ranges and acceptance criteria

Effects on related process, functions, or personnel
As discussed under section IV.A., above, the model calls for managers to ensure that product
specifications and process parameters are determined by the appropriate technical experts (e.g.,
engineers, development scientists). In the pharmaceutical environment, experts would have an
understanding of pharmaceutical science, equipment, facilities, and process types and of how
variations in materials and processes can ultimately affect the finished product.
Packaging and labeling controls, critical stages in the pharmaceutical manufacturing process, are
not specifically addressed in quality systems models. However, the Agency recommends that
manufacturers always refer to the packaging and labeling control regulations at § 211 Subpart G.
In addition — and this is consistent with modern quality systems — FDA recommends that, as
part of the design process, before commercial production, the controls for all processes within
the packaging and labeling system be planned and documented in written procedures. The
procedures should outline quality control activities and the responsible positions. Specifications
and controls for the packaging and labeling materials should also be determined before
commercial production. Distinct labels with discriminating features for different products, such
as a product marketed with different strengths, should be included to prevent mislabeling and
resulting recalls.
37
ii. Examine Inputs
In a modern quality systems model, the term input includes any material that goes into a final
product, no matter whether the material is purchased by the manufacturer or produced by the
manufacturer for the purpose of processing. Materials can include items such as components
(e.g., ingredients, process water, and gas), containers, and closures. A robust quality system will
ensure that all inputs to the manufacturing process are reliable because quality controls will have
been established for the receipt, production, storage, and use of all inputs.
The CGMP regulations require either testing or use of a certificate of analysis (COA) plus an
identity analysis (§ 211.84) for the release of materials for manufacturing. In the preamble to the
CGMP regulations, these requirements were explicitly interpreted. 12 The preamble states that
reliability can be validated by conducting tests or examinations and comparing the results to the
supplier’s COA. Sufficient initial tests should be done to establish reliability and to determine a
schedule for periodic reassessment. As an essential element of purchasing controls, it is
recommended that data trends for acceptance and rejection of materials be analyzed for
information on supplier performance. 13
The quality systems approach also calls for periodic auditing of suppliers based on risk
assessment. During the audit, a manufacturer can observe the testing or examinations conducted
by the supplier to help determine the reliability of the supplier’s COA. An audit should also
include a systematic examination of the supplier’s quality system to ensure that reliability is
maintained. It is recommended that a combination approach be used (i.e., verify the suppliers'
COA through analysis and audits of the supplier). Under a quality systems approach, if full
analytical testing is not done, the audit should cover the supplier’s analysis (i.e., a specific
identity test is still required under § 211.84(d)(2).
Under a quality systems approach, procedures should be established to verify that materials are
from qualified sources (for application and licensed products, certain sources are specified in the
submissions). Procedures should also be established to encompass the acceptance, use, or the
rejection and disposition of materials produced by the facility (e.g., purified water). Systems that
produce these in-house materials should be designed, maintained, qualified, and validated where
appropriate to ensure that the materials meet their acceptance criteria.
In addition, it is recommended that changes to materials (e.g., specification, supplier, or
materials handling) be implemented through a change control system (certain changes require
review and approval by the QU (§ 211.100(a)). It is also important to have a system in place to
respond to changes in materials from suppliers so that necessary adjustments to the process can
be made and unintended consequences avoided.
iii. Perform and Monitor Operations
An important purpose of implementing a quality systems approach is to enable a manufacturer to
more efficiently and effectively validate, perform, and monitor operations (§ 211.100(a)) and
ensure that the controls are scientifically sound and appropriate. The goal of establishing,
38
adhering to, measuring, and documenting specifications and process parameters is to objectively
assess whether an operation is meeting its design and product performance objectives. In a
robust quality system, production and process controls should be designed to ensure that the
finished products have the identity, strength, quality, and purity they purport or are represented
to possess (see, e.g., § 211.100(a)).
In a modern quality system, a design concept established during product development typically
matures into a commercial design after process experimentation and progressive modification.
Risk management can help identify areas of process weakness or higher risk and factors that can
influence critical quality attributes that should receive increased scrutiny. The FDA recommends
that scale-up studies be used to help demonstrate that a fundamentally sound design has been
fully realized. A sufficiently robust manufacturing process should be in place prior to
commercial production. With proper design (see IV.C.1.) and reliable mechanisms to transfer
process knowledge from development to commercial production, a manufacturer should be able
to validate the manufacturing process. 14 Conformance batches provide initial proof that the
design of the process produces the intended product quality. Sufficient testing data will provide
essential information on performance of the new process, as well as a mechanism for continual
improvement. Modern equipment with the potential for continual monitoring and control can
further enhance this knowledge base. Although initial commercial batches can provide evidence
to support the validity and consistency of the process, 15 the entire product life cycle should be
addressed by the establishment of continual improvement mechanisms in the quality system. 16
Thus, in accordance with the quality systems approach, process validation is not a one-time
event, but an activity that continues throughout a product’s life.
As experience is gained in commercial production, opportunities for process improvements may
become evident. (CGMP regulations § 211.180 require the review and evaluation of records to
determine the need for any change. These records contain data and information from production
that provide insight into the product’s state of control. Change control systems should provide a
dependable mechanism for prompt implementation of technically sound manufacturing
improvements.)
Under a quality system, written procedures are followed and deviations from them are justified
and documented (CGMP requires this; see § 211.100(b)) to ensure that the manufacturer can
trace the history of the product, as appropriate, concerning personnel, materials, equipment, and
chronology and that processes for product release are complete and recorded.
Both the CGMP regulations (§ 211.110) and quality systems models call for the monitoring of
critical processes that may be responsible for causing variability during production. For example:

Process steps must be verified by a second person (§ 211.188). Process steps can also be performed using a
validated computer system. Batch production records must be prepared contemporaneously with each
phase of production (§ 211.100(b)). Although time limits for production can be established when they are
important to the quality of the finished product (CGMP addresses this; see § 211.111), the manufacturer
should have the ability to establish production controls using in-process parameters that are based on
desired process endpoints measured using real time testing or monitoring apparatus (e.g., blend until mixed
vs. blend for 10 minutes).
39

Procedures must be in place to prevent objectionable microorganisms in finished products not required to
be sterile and to prevent microbial contamination of finished products purported to be sterile. Sterilization
processes must be validated for sterile drugs (§ 211.113(b)). 17
Manufacturing processes must consistently meet their parameters, and in-process materials must
meet acceptance criteria or limits (§ 211.110(b) and (c)) so that, ultimately, finished
pharmaceutical products will meet their acceptance criteria. Under a quality system, selected data
are used to evaluate the quality of a process or product. In addition, data collection can provide a
means to encourage and analyze potential suggestions for improvement. A quality systems
approach calls for the manufacturer to develop procedures that monitor, measure, and analyze
the operations (including analytical methods and/or statistical techniques). Monitoring of the
process is important due to the limitations of testing. Knowledge continues to accumulate from
development through the entire commercial life of a product. Significant unanticipated variables
should be detected by a well-managed quality system and adjustments implemented. Procedures
should be revisited as needed to refine operational design based on new knowledge. Process
understanding increases with experience and helps identify when change will lead to continual
improvement. When implementing data collection procedures, consider the following:

Are data collection methods documented?

When in the product life cycle will the data be collected?

How and to whom will measurement and monitoring activities be assigned?

When should analysis and evaluation (e.g. trending) of laboratory data be performed? (see IV.D.1)

What records should be collected?
A modern quality system approach indicates that change control is warranted when data analysis
or other information reveals an area for improvement. Changes to an established process must
be controlled and documented to ensure that desired attributes for the finished product will be
met (§ 211.100(a)).
Change control with regard to pharmaceuticals is addressed in more detail in the CGMP
regulations. When developing a process change, it is important to keep the process design and
scientific knowledge of the product in mind. If major design issues are encountered through
process experience, a firm may want to revisit the adequacy of the design of the manufacturing
facility (§ 211.42), the design of the manufacturing equipment (§ 211.63), the design of the
production and control procedures (§ 211.100), or the design of laboratory controls (§ 211.160).
When implementing a change, its effect should be determined by monitoring and evaluating
those specific elements that may be affected based on an understanding of the process. This
approach allows the steps taken to implement a change and the effects of the change on the
process to be considered systematically. Application of risk analysis may facilitate evaluating
the potential effect of the change. Evaluating the effects of a change can entail additional tests or
examinations of subsequent batches (e.g., additional in-process testing or additional stability
studies). The quality system elements identified in this guidance, if implemented and maintained,
will help a manufacturer manage change and implement continual improvement in
manufacturing.
40
Under a quality systems approach, procedures should be in place to ensure the accuracy of test
results. Test results that are out of specification may be due to testing problems or manufacturing
problems and should be investigated. Any invalidation of a test result should be scientifically
sound and justified.
To maintain quality, the Agency recommends that prior to completion of manufacturing, the
manufacturer should consider storage and shipment requirements to meet special handling needs
(in the case of pharmaceuticals, one example might be refrigeration).
Under a quality system, trends should be continually identified and evaluated. One way of
accomplishing this is the use of statistical process control. The information from trend analyses
can be used to continually monitor quality, identify potential variances before they become
problems, bolster data already collected for the annual review, and facilitate improvement
throughout the product life cycle. Process capability assessment can serve as a basis for
determining the need for changes that can result in process improvements and efficiency (see
IV.D.1.).
iv. Nonconformities
A key component in any quality system is handling nonconformities and/or deviations. The
investigation, conclusion, and follow-up must be documented (§ 211.192). To ensure that a
product conforms to requirements and expectations, it is important to measure the process and
the product attributes (e.g., specified control parameters, strength) as planned. Discrepancies
may be detected during any stage of the process or during quality control activities. Not all
discrepancies will result in product defects; however, it is important to document and handle
discrepancies appropriately. A discrepancy investigation process is critical when a discrepancy
is found that affects product quality (CGMP also requires this; see § 211.192).
In a quality system, it is important to develop and document procedures that define who is
responsible for halting and resuming operations, recording non-conformities, investigating
discrepancies, and taking remedial action. Under a quality system, if a product or process does
not meet requirements, it is essential to identify and/or segregate the product so that it is not
distributed to the customer. Remedial action can include any of the following:

Correct the non-conformity

With proper authorization, allow the product to proceed with justification of the conclusions regarding the
problem’s impact

Use the product for another application where the deficiency does not affect the products’ quality

Reject the product
The corrected product or process should also be re-examined for conformance and assessed for
the significance of the non-conformity (see, e.g., § 211.115). If the non-conformity is
significant, based on consequences to process control, process efficiency, product quality, safety,
efficacy, and product availability, it is important to evaluate how to prevent recurrence (see
IV.D.4.). If an individual product that does not meet requirements has been released, the product
41
can be recalled. 18 Customer complaints must be reviewed and then investigated if a
discrepancy is identified (§ 211.198).
The following table shows how the CGMP regulations correlate to specific elements in the
quality systems model. Manufacturers should always refer to the specific regulations to ensure
that they are complying with all regulations.
21 CFR CGMP Regulations Related to Manufacturing Operations
Quality System Element
Regulatory Citation
1. Design and Develop Product Production: § 211.100(a)
and Processes
2. Examine Inputs
Materials: §§ 210.3(b), 211.80 – 211.94,
211.101, 211.122, 211.125
3. Perform and Monitor
Production: §§ 211.100, 211.103,
Operations
211.110, 211.111, 211.113
QC criteria: §§ 211.22(a-c), 211.115(b),
211.160(a), 211.165(d), 211.188
QC checkpoints: §§ 211.22 (a),
211.84(a), 211.87, 211.110(c)
4. Address Nonconformities
Discrepancy investigation: §§ 211.22(a),
211.100, 211.115, 211.192, 211.198
Recalls: 21 CFR Part 7
4. Evaluation Activities
As in the previous section, the elements of a quality system in terms of monitoring and
evaluation correlate closely with the requirements in the CGMP regulations.
i. Analyze Data for Trends
Quality systems call for continually monitoring trends and improving systems. This can be
achieved by monitoring data and information, identifying and resolving problems, and
anticipating and preventing problems.
Quality systems procedures involve collecting data from monitoring, measurement, complaint
handling, or other activities, and tracking this data over time, as appropriate. Analysis of data can
provide indications that controls are losing effectiveness. The information generated will be
essential to achieving problem resolution or problem prevention (see IV.D.3.).
Although the CGMP regulations (§ 211.180(e)) require product review on at least an annual
basis, a quality systems approach calls for trending on a more frequent basis as determined by
risk. Trending enables the detection of potential problems as early as possible to plan corrective
and preventive actions. Another important concept of modern quality systems is the use of
42
trending to examine processes as a whole; this is consistent with the annual review approach.
Trending analyses can help focus internal audits (see IV.D.2.).
ii. Conduct Internal Audits
A quality systems approach calls for audits to be conducted at planned intervals to evaluate
effective implementation and maintenance of the quality system and to determine if processes
and products meet established parameters and specifications. As with other procedures, audit
procedures should be developed and documented to ensure that the planned audit schedule takes
into account the relative risks of the various quality system activities, the results of previous
audits and corrective actions, and the need to audit the complete system. Procedures should
describe how auditors are trained in objective evidence gathering, their responsibilities, and
auditing procedures. Procedures should also define auditing activities such as the scope and
methodology of the audit, selection of auditors, and audit conduct (audit plans, opening
meetings, interviews, closing meeting and reports). It is critical to maintain records of audit
findings and assign responsibility for follow-up to prevent problems from recurring (see
IV.D.3.).
The quality systems model calls for managers who are responsible for the areas audited to take
timely action to resolve audit findings and ensure that follow-up actions are completed, verified,
and recorded. (FDA’s policy is to refrain from both reviewing and copying reports or records
that result from internal audits per Compliance Policy Guide 130.300. 19 )
iii. Quality Risk Management
Effective decision-making in a quality systems environment is based on an informed
understanding of quality issues. Elements of risk should be considered relative to intended use of
a product, and in the case of pharmaceuticals, patient safety and ensuring availability of
medically necessary drug products. Management should assign priorities to activities or actions
based on an assessment of the risk including both the probability of occurrence of harm and of
the severity of that harm. It is important to engage appropriate parties in assessing the risk. Such
parties include customers, appropriate manufacturing personnel, and other stakeholders.
Implementation of quality risk management includes assessing the risks, selecting and
implementing risk management controls commensurate with the level of risk, and evaluating the
results of the risk management efforts. Since risk management is an iterative process, it should
be repeated if new information is developed that changes the need for, or nature of, risk
management.
In a manufacturing quality systems environment, risk management is used as a tool in the
development of product specifications and critical process parameters. Used in conjunction with
process understanding, quality risk management helps manage and control change.
iv. Corrective Action
Corrective action is a reactive tool for system improvement to ensure that significant problems
do not recur. Both quality systems and the CGMP regulations emphasize corrective actions.
43
Quality systems approaches call for procedures to be developed and documented to ensure that
the need for action is evaluated relevant to the possible consequences, the root cause of the
problem is investigated, possible actions are determined, a selected action is taken within a
defined timeframe, and the effectiveness of the action taken is evaluated. It is essential to
document corrective actions taken (CGMP also requires this; see § 211.192).
It is essential to determine what actions will reduce the likelihood of a problem recurring.
Examples of sources that can be used to gather such information include the following:

Nonconformance reports and rejections

Returns

Complaints

Internal and external audits

Data and risk assessment related to operations and quality system processes

Management review decisions
v. Preventive Actions
Being proactive is an essential tool in quality systems management. Succession planning,
training, capturing institutional knowledge, and planning for personnel, policy, and process
changes are preventive actions that will help ensure that potential problems and root causes are
identified, possible consequences assessed, and appropriate actions considered.
The selected preventive action should be evaluated and recorded, and the system should be
monitored for the effectiveness of the action. Problems can be anticipated and their occurrence
prevented by reviewing data and analyzing risks associated with operational and quality system
processes, and by keeping abreast of changes in scientific developments and regulatory
requirements.
vi. Promote Improvement
The effectiveness and efficiency of a quality system can be improved through the quality
activities described in this guidance. Management may choose to use other improvement
activities as appropriate. It is critical that senior management be involved in the evaluation of
this improvement process (see IV.D.3.).
The following table shows how the CGMP regulations correlate to specific elements in the
quality systems model for this section. Manufacturers should always refer to the specific
regulations to make sure they are complying with all regulations.
21 CFR CGMP Regulations Related to Evaluation Activities
Quality System Element
Regulatory Citation
1. Analyze Data for Trends
Annual Review: § 211.180(e)
44
2. Conduct Internal Audits
3. Risk Assessment
4. Corrective Action
5. Preventive Action
6. Promote Improvement
--
Discrepancy investigation: §§ 211.22(a),
211.192
—
§ 211.110
i) Concluding remarks on Quality System Management and pharmaceutical CGMPs
Implementation of a comprehensive quality systems model for human and veterinary
pharmaceutical products, including biological products, will facilitate compliance with 21 CFR
parts 210 and 211. The central goal of a quality system is the consistent production of safe and
effective products and ensuring that these activities are sustainable. Quality and regulatory
professionals are aware that good intentions alone will not ensure good products. A robust
quality system will promote process consistency by integrating effective knowledge-building
mechanisms into daily operational decisions. Specifically, successful quality systems share the
following characteristics, each of which has been discussed in detail above:

Science-based approaches

Decisions based on an understanding of the intended use of a product

Proper identification and control of areas of potential process weakness

Responsive deviation and investigation systems that lead to timely remediation

Sound methods for assessing and reducing risk

Well-defined processes and products, starting from development and extending throughout the product life
cycle

Systems for careful analysis of product quality

Supportive management (philosophically and financially)
Both good manufacturing practice and good business practice require a robust quality system.
When fully developed and effectively managed, a quality system will lead to consistent,
predictable processes that ensure that pharmaceuticals are safe, effective, and available for the
consumer.
j) References for the CGMPS discussion giving above:
1.
1978 Preamble to the Good Manufacturing Practice Final Regulations – Federal Register Docket No. 73N0339] http://www.fda.gov/cder/dmpq/preamble.txt
45
2.
CPGM 7356.002 Compliance Program – Drug Manufacturing Inspections
http://www.fda.gov/cder/dmpq/compliance_guide.htm
3.
Quality Planning and Analysis, 3rd Ed. by J.M. Juran, F.M. Gryna (McGraw-Hill, New York, N.Y. 1993)
4.
ANSI/ISO/ASQ Q9000-2000: Quality management systems – Fundamentals and vocabulary, (American
Society for Quality, 2000)
5.
Guideline of General Principles of Process Validation, May 1987 –
http://www.fda.gov/cder/guidance/pv.htm
6.
FDA Compliance Policy Guide 7132c.08 Process Validation Requirements for Drug Products and Active
Pharmaceutical Ingredients Subject to Pre-Market Approval, updated 03-12-2004 –
http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg490-100.html
7.
Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing Current Good
Manufacturing Practice – September 2004. See also the draft guidance on investigating Out-ofSpecification (OOS) Test Results for Pharmaceutical Production.
8.
FDA Compliance Policy Guide Sec. 130.300, FDA Access to Results of Quality Assurance Program Audits
and Inspections, (CPG 7151.02) http://www.fda.gov/ora/compliance_ref/cpg/cpggenl/cpg130-300.html
9.
Criteria for Performance Excellence, Business (Baldrige National Quality Program, NIST 2003)
http://baldrige.nist.gov/PDF_files/2003_Business_Criteria.pdf
10. ANSI/ISO/ASQ Q9001-2000: Quality management systems – Requirements (American Society for Quality,
2000)
11. ANSI/ISO/ASQ Q9004-2000: Quality management systems – Guidelines for performance improvement
(American Society for Quality, 2000)
12. ANSI/ISO 17025-1999: General requirements for the competence of testing and calibration laboratories
(American Society for Quality, 1999
13. CMMI-SE/SW, V1.1: Capability Maturity Model Integration for Systems Engineering and Software
Engineering, Staged Representation (Software Engineering Institute, Carnegie Mellon University, 2002)
http://www.sei.cmu.edu/pub/documents/02.reports/pdf/02tr002.pdf
14. The Balanced Scorecard Institute: http://balancedscorecard.org
15. Guidance for Developing Quality Systems for Environmental Program (EPA QA/G-1, Nov 2002)
http://www.epa.gov/quality/qs-docs/g1-final.pdf
16. Guidance for Industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
(U.S. Department of Health and Human Services/ Food and Drug Administration, August 2001) .
17. Good Manufacturing Practices for Pharmaceutical Products: Main Principles (World Health Organization
Technical Report Series, No. 908, 2003) http://www.who.int/medicines/library/qsm/trs908/trs908-4.pdf
18. Procedures For The Implementation of The Federal Managers’ Financial Integrity Act (FMFIA); (FDA
Staff Manual Guide 2350.1)
19. Managing the Risks from Medical Product Use: Creating a Risk Management Framework (U.S. FDA,
1999) http://www.fda.gov/oc/tfrm/1999report.html
46
20. Framework for Environmental Health Risk Assessment – Final Report, Vol.1 (Presidential/Congressional
Commission on Risk Assessment and Risk Management, 1997)
http://www.riskworld.com/Nreports/1997/risk-rpt/pdf/EPAJAN.PDF
21. Report on FDA Quality System Framework for Pharmaceutical Product Regulation Activities; (Quality
System Framework Subcommittee, December 2003)
22. Tutorials for Continuous Quality Improvement (Clemson University, 1995)
http://deming.eng.clemson.edu/pub/tutorials/
23. Variation Risk Management – Focusing Quality Improvement in Product Development and Products by
Anna C. Thornton (John Wiley and Sons, Inc.; Hoboken, New Jersey, 2004
24. Guidance for Industry for the Submission of Documentation for Sterilization Process Validation in
Applications for Human and Veterinary Drug Products – http://www.fda.gov/cder/guidance/cmc2.pdf
25. Chapter 3,“Quality Management in the American Pharmaceutical Industry,” in Pharmaceutical Quality,
Ed. by R. Prince (DHI Publishing, River Grove, IL, 2004)
E. The FDAs Regulation on Good Clinical Practice (GCP)
In addition to regulating the manufacture of pharmaceutical drugs (see the section on CGMFs
above), the FDA is directly involved in regulation the conduct of clinical trials as it pertains to
testing a drug in human subjects. These regulations are refered to as Good Clinical Practice
(GCP).
A overview of GCP at http://www.fda.gov/oc/gcp/regulations.html lists the various final rules
related to FDA's regulations on good clinical practice and clinical trials. Many of these GCP
rules apply to any type of biomedical product (21 CFR Parts 11, 50, 54 and 56, for example)
while others rules are type-specific such as additional special rules for pharmaceutical drugs (i.e.,
21 CFR Parts 312, 314, 320 and Forms 1571 and 1572), biologics (21 CFR Part 601), or medical
devices (21 CFR Parts 812 and 814).
FDA Regulations Relating to Good Clinical Practice and Clinical Trials
Get e-mail updates when this information changes.
Preambles to GCP Regulations: information about the development of final rules related to FDA's regulations on
good clinical practice and clinical trials.
 Electronic Records; Electronic Signatures (21 CFR Part 11)
 Protection of Human Subjects (Informed Consent) (21 CFR Part 50)
 Financial Disclosure by Clinical Investigators (21 CFR Part 54)
 Institutional Review Boards (21 CFR Part 56)
 Investigational New Drug Application (21 CFR Part 312)
 Foreign Clinical Trials not conducted under an IND (21 CFR Part 312.120)
 Forms 1571 (Investigational New Drug Application) and 1572 (Statement of Investigator)
 Applications for FDA Approval to Market a New Drug (21 CFR Part 314)
 Bioavailability and Bioequivalence Requirements (21 CFR Part 320)
 Applications for FDA Approval of a Biologic License (21 CFR Part 601)
 Investigational Device Exemptions (21 CFR Part 812)
 Premarket Approval of Medical Devices (21 CFR Part 814
47
F. Submitting a New Drug Application (NDA)
In this stage, all information (i.e. efficacy, toxicology, process, drug-drug interactions, side
effects, etc.) are combined and submitted to the FDA as a New Drug Application (NDA). This is
described in detail in FDA 21CFR Part 314 (see
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=314 ).
Since the agency has already been involved in the pre-clinical and clinical trial stages, it is also
necessary in the NDA to included answers to questions posed by the agency at earlier stages of
development.
a) General Format of the Application
Three copies of the application are required: An archival copy, a review copy, and a field copy.
An application for a new chemical entity will generally contain an application form, an index, a
summary, five or six technical sections, case report tabulations of patient data, case report
forms, drug samples, and labeling, including, if applicable, any Medication Guide required
under part 208 of this chapter.
The application is required to contain reports of all investigations of the drug product sponsored
by the applicant, and all other information about the drug pertinent to an evaluation of the
application that is received or otherwise obtained by the applicant from any source.
b) Specific FDA guidance on the format and content of the different sections of the applications
is as follows:
Application form
The applicant shall submit a completed and signed application form that contains the following:
(1) The name and address of the applicant; the date of the application; the application number if
previously issued (for example, if the application is a resubmission, an amendment, or a
supplement); the name of the drug product, including its established, proprietary, code, and
chemical names; the dosage form and strength; the route of administration; the identification
numbers of all investigational new drug applications that are referenced in the application; the
identification numbers of all drug master files and other applications under this part that are
referenced in the application; and the drug product's proposed indications for use.
(2) A statement whether the submission is an original submission, a 505(b)(2) application, a
resubmission, or a supplement to an application under 314.70.
(3) A statement whether the applicant proposes to market the drug product as a prescription or an
over-the-counter product.
48
(4) A check-list identifying what enclosures required under this section the applicant is
submitting.
(5) The applicant, or the applicant's attorney, agent, or other authorized official shall sign the
application. If the person signing the application does not reside or have a place of business
within the United States, the application is required to contain the name and address of, and be
countersigned by, an attorney, agent, or other authorized official who resides or maintains a
place of business within the United States.
Index
The archival copy of the application is required to contain a comprehensive index by volume
number and page number to the summary under paragraph (c) of this section, the technical
sections under paragraph (d) of this section, and the supporting information under paragraph (f)
of this section.
Summary
(1) An application is required to contain a summary of the application in enough detail that the
reader may gain a good general understanding of the data and information in the application,
including an understanding of the quantitative aspects of the data. The summary is not required
for supplements under 314.70. Resubmissions of an application should contain an updated
summary, as appropriate. The summary should discuss all aspects of the application, and
synthesize the information into a well-structured and unified document. The summary should be
written at approximately the level of detail required for publication in, and meet the editorial
standards generally applied by, refereed scientific and medical journals. In addition to the agency
personnel reviewing the summary in the context of their review of the application, FDA may
furnish the summary to FDA advisory committee members and agency officials whose duties
require an understanding of the application. To the extent possible, data in the summary should
be presented in tabular and graphic forms. FDA has prepared a guideline under 10.90(b) that
provides information about how to prepare a summary. The summary required under this
paragraph may be used by FDA or the applicant to prepare the Summary Basis of Approval
document for public disclosure (under 314.430(e)(2)(ii)) when the application is approved.
(2) The summary is required to contain the following information:
(i) The proposed text of the labeling, including, if applicable, any Medication Guide required
under part 208 of this chapter, for the drug, with annotations to the information in the summary
and technical sections of the application that support the inclusion of each statement in the
labeling, and, if the application is for a prescription drug, statements describing the reasons for
omitting a section or subsection of the labeling format in 201.57 of this chapter.
(ii) A statement identifying the pharmacologic class of the drug and a discussion of the scientific
rationale for the drug, its intended use, and the potential clinical benefits of the drug product.
(iii) A brief description of the marketing history, if any, of the drug outside the United States,
including a list of the countries in which the drug has been marketed, a list of any countries in
which the drug has been withdrawn from marketing for any reason related to safety or
49
effectiveness, and a list of countries in which applications for marketing are pending. The
description is required to describe both marketing by the applicant and, if known, the marketing
history of other persons.
(iv) A summary of the chemistry, manufacturing, and controls section of the application.
(v) A summary of the nonclinical pharmacology and toxicology section of the application.
(vi) A summary of the human pharmacokinetics and bioavailability section of the application.
(vii) A summary of the microbiology section of the application (for anti-infective drugs only).
(viii) A summary of the clinical data section of the application, including the results of statistical
analyses of the clinical trials.
(ix) A concluding discussion that presents the benefit and risk considerations related to the drug,
including a discussion of any proposed additional studies or surveillance the applicant intends to
conduct postmarketing.
Technical sections
The application is required to contain the technical sections described below. Each technical
section is required to contain data and information in sufficient detail to permit the agency to
make a knowledgeable judgment about whether to approve the application or whether grounds
exist under section 505(d) of the act to refuse to approve the application. The required technical
sections are as follows:
(1)Chemistry, manufacturing, and controls section A section describing the composition,
manufacture, and specification of the drug substance and the drug product (typically referred to
as “the CMC”), which includes the following:
(i)Drug substance. A full description of the drug substance including its physical and chemical
characteristics and stability; the name and address of its manufacturer; the method of synthesis
(or isolation) and purification of the drug substance; the process controls used during
manufacture and packaging; and the specifications necessary to ensure the identity, strength,
quality, and purity of the drug substance and the bioavailability of the drug products made from
the substance, including, for example, tests, analytical procedures, and acceptance criteria
relating to stability, sterility, particle size, and crystalline form. The application may provide
additionally for the use of alternatives to meet any of these requirements, including alternative
sources, process controls, and analytical procedures. Reference to the current edition of the U.S.
Pharmacopeia and the National Formulary may satisfy relevant requirements in this paragraph.
(ii)(a)Drug product. A list of all components used in the manufacture of the drug product
(regardless of whether they appear in the drug product) and a statement of the composition of the
drug product; the specifications for each component; the name and address of each manufacturer
of the drug product; a description of the manufacturing and packaging procedures and in-process
controls for the drug product; the specifications necessary to ensure the identity, strength,
quality, purity, potency, and bioavailability of the drug product, including, for example, tests,
analytical procedures, and acceptance criteria relating to sterility, dissolution rate, container
closure systems; and stability data with proposed expiration dating. The application may provide
additionally for the use of alternatives to meet any of these requirements, including alternative
components, manufacturing and packaging procedures, in-process controls, and analytical
procedures. Reference to the current edition of the U.S. Pharmacopeia and the National
Formulary may satisfy relevant requirements in this paragraph. (b ) Unless provided by
50
paragraph (d)(1)(ii)(a ) of this section, for each batch of the drug product used to conduct a
bioavailability or bioequivalence study described in 320.38 or 320.63 of this chapter or used to
conduct a primary stability study: The batch production record; the specification for each
component and for the drug product; the names and addresses of the sources of the active and
noncompendial inactive components and of the container and closure system for the drug
product; the name and address of each contract facility involved in the manufacture, processing,
packaging, or testing of the drug product and identification of the operation performed by each
contract facility; and the results of any test performed on the components used in the
manufacture of the drug product as required by 211.84(d) of this chapter and on the drug product
as required by 211.165 of this chapter. (c ) The proposed or actual master production record,
including a description of the equipment, to be used for the manufacture of a commercial lot of
the drug product or a comparably detailed description of the production process for a
representative batch of the drug product.
(iii) Environmental impact. The application is required to contain either a claim for categorical
exclusion under 25.30 or 25.31 of this chapter or an environmental assessment under 25.40 of
this chapter.
(iv) The applicant may, at its option, submit a complete chemistry, manufacturing, and controls
section 90 to 120 days before the anticipated submission of the remainder of the application.
FDA will review such early submissions as resources permit.
(v) The applicant shall include a statement certifying that the field copy of the application has
been provided to the applicant's home FDA district office.
(2)Nonclinical pharmacology and toxicology section. A section describing, with the aid of
graphs and tables, animal and in vitro studies with drug, including the following:
(i) Studies of the pharmacological actions of the drug in relation to its proposed therapeutic
indication and studies that otherwise define the pharmacologic properties of the drug or are
pertinent to possible adverse effects.
(ii) Studies of the toxicological effects of the drug as they relate to the drug's intended clinical
uses, including, as appropriate, studies assessing the drug's acute, subacute, and chronic toxicity;
carcinogenicity; and studies of toxicities related to the drug's particular mode of administration
or conditions of use.
(iii) Studies, as appropriate, of the effects of the drug on reproduction and on the developing
fetus.
(iv) Any studies of the absorption, distribution, metabolism, and excretion of the drug in animals.
(v) For each nonclinical laboratory study subject to the good laboratory practice regulations
under part 58 a statement that it was conducted in compliance with the good laboratory practice
regulations in part 58, or, if the study was not conducted in compliance with those regulations, a
brief statement of the reason for the noncompliance.
(3)Human pharmacokinetics and bioavailability section. A section describing the human
pharmacokinetic data and human bioavailability data, or information supporting a waiver of the
submission of in vivo bioavailability data under subpart B of part 320, including the following:
(i) A description of each of the bioavailability and pharmacokinetic studies of the drug in
humans performed by or on behalf of the applicant that includes a description of the analytical
procedures and statistical methods used in each study and a statement with respect to each study
that it either was conducted in compliance with the institutional review board regulations in part
51
56, or was not subject to the regulations under 56.104 or 56.105, and that it was conducted in
compliance with the informed consent regulations in part 50.
(ii) If the application describes in the chemistry, manufacturing, and controls section tests,
analytical procedures, and acceptance criteria needed to assure the bioavailability of the drug
product or drug substance, or both, a statement in this section of the rationale for establishing the
tests, analytical procedures, and acceptance criteria, including data and information supporting
the rationale.
(iii) A summarizing discussion and analysis of the pharmacokinetics and metabolism of the
active ingredients and the bioavailability or bioequivalence, or both, of the drug product.
(4)Microbiology section. If the drug is an anti-infective drug, a section describing the
microbiology data, including the following:
(i) A description of the biochemical basis of the drug's action on microbial physiology.
(ii) A description of the antimicrobial spectra of the drug, including results of in vitro preclinical
studies to demonstrate concentrations of the drug required for effective use.
(iii) A description of any known mechanisms of resistance to the drug, including results of any
known epidemiologic studies to demonstrate prevalence of resistance factors.
(iv) A description of clinical microbiology laboratory procedures (for example, in vitro
sensitivity discs) needed for effective use of the drug.
(5)Clinical data section. A section describing the clinical investigations of the drug, including
the following:
(i) A description and analysis of each clinical pharmacology study of the drug, including a brief
comparison of the results of the human studies with the animal pharmacology and toxicology
data.
(ii) A description and analysis of each controlled clinical study pertinent to a proposed use of the
drug, including the protocol and a description of the statistical analyses used to evaluate the
study. If the study report is an interim analysis, this is to be noted and a projected completion
date provided. Controlled clinical studies that have not been analyzed in detail for any reason
(e.g., because they have been discontinued or are incomplete) are to be included in this section,
including a copy of the protocol and a brief description of the results and status of the study.
(iii) A description of each uncontrolled clinical study, a summary of the results, and a brief
statement explaining why the study is classified as uncontrolled.
(iv) A description and analysis of any other data or information relevant to an evaluation of the
safety and effectiveness of the drug product obtained or otherwise received by the applicant from
any source, foreign or domestic, including information derived from clinical investigations,
including controlled and uncontrolled studies of uses of the drug other than those proposed in the
application, commercial marketing experience, reports in the scientific literature, and
unpublished scientific papers.
(v) An integrated summary of the data demonstrating substantial evidence of effectiveness for
the claimed indications. Evidence is also required to support the dosage and administration
section of the labeling, including support for the dosage and dose interval recommended. The
effectiveness data shall be presented by gender, age, and racial subgroups and shall identify any
modifications of dose or dose interval needed for specific subgroups. Effectiveness data from
other subgroups of the population of patients treated, when appropriate, such as patients with
renal failure or patients with different levels of severity of the disease, also shall be presented.
52
(vi) A summary and updates of safety information, as follows:
(a ) The applicant shall submit an integrated summary of all available information about the
safety of the drug product, including pertinent animal data, demonstrated or potential adverse
effects of the drug, clinically significant drug/drug interactions, and other safety considerations,
such as data from epidemiological studies of related drugs. The safety data shall be presented by
gender, age, and racial subgroups. When appropriate, safety data from other subgroups of the
population of patients treated also shall be presented, such as for patients with renal failure or
patients with different levels of severity of the disease. A description of any statistical analyses
performed in analyzing safety data should also be included, unless already included under
paragraph (d)(5)(ii) of this section.
(b ) The applicant shall, under section 505(i) of the act, update periodically its pending
application with new safety information learned about the drug that may reasonably affect the
statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling
and, if applicable, any Medication Guide required under part 208 of this chapter. These "safety
update reports" are required to include the same kinds of information (from clinical studies,
animal studies, and other sources) and are required to be submitted in the same format as the
integrated summary in paragraph (d)(5)(vi)(a ) of this section. In addition, the reports are
required to include the case report forms for each patient who died during a clinical study or who
did not complete the study because of an adverse event (unless this requirement is waived). The
applicant shall submit these reports (1 ) 4 months after the initial submission; (2 ) in a
resubmission following receipt of a complete response letter; and (3 ) at other times as requested
by FDA. Prior to the submission of the first such report, applicants are encouraged to consult
with FDA regarding further details on its form and content.
(vii) If the drug has a potential for abuse, a description and analysis of studies or information
related to abuse of the drug, including a proposal for scheduling under the Controlled Substances
Act. A description of any studies related to overdosage is also required, including information on
dialysis, antidotes, or other treatments, if known.
(viii) An integrated summary of the benefits and risks of the drug, including a discussion of why
the benefits exceed the risks under the conditions stated in the labeling.
(ix) A statement with respect to each clinical study involving human subjects that it either was
conducted in compliance with the institutional review board regulations in part 56, or was not
subject to the regulations under 56.104 or 56.105, and that it was conducted in compliance with
the informed consent regulations in part 50.
(x) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract
research organization, a statement containing the name and address of the contract research
organization, identification of the clinical study, and a listing of the obligations transferred. If all
obligations governing the conduct of the study have been transferred, a general statement of this
transfer--in lieu of a listing of the specific obligations transferred--may be submitted.
(xi) If original subject records were audited or reviewed by the sponsor in the course of
monitoring any clinical study to verify the accuracy of the case reports submitted to the sponsor,
a list identifying each clinical study so audited or reviewed.
(6)Statistical section. A section describing the statistical evaluation of clinical data, including the
following:
53
(i) A copy of the information submitted under paragraph (d)(5)(ii) of this section concerning the
description and analysis of each controlled clinical study, and the documentation and supporting
statistical analyses used in evaluating the controlled clinical studies.
(ii) A copy of the information submitted under paragraph (d)(5)(vi)(a ) of this section concerning
a summary of information about the safety of the drug product, and the documentation and
supporting statistical analyses used in evaluating the safety information.
(7)Pediatric use section. A section describing the investigation of the drug for use in pediatric
populations, including an integrated summary of the information (the clinical pharmacology
studies, controlled clinical studies, or uncontrolled clinical studies, or other data or information)
that is relevant to the safety and effectiveness and benefits and risks of the drug in pediatric
populations for the claimed indications, a reference to the full descriptions of such studies
provided under paragraphs (d)(3) and (d)(5) of this section, and information required to be
submitted under 314.55.
Samples and labeling
(1) Upon request from FDA, the applicant shall submit the samples described below to the places
identified in the agency's request. FDA will generally ask applicants to submit samples directly
to two or more agency laboratories that will perform all necessary tests on the samples and
validate the applicant's analytical procedures.
(i) Four representative samples of the following, each sample in sufficient quantity to permit
FDA to perform three times each test described in the application to determine whether the drug
substance and the drug product meet the specifications given in the application:
(a ) The drug product proposed for marketing;
(b ) The drug substance used in the drug product from which the samples of the drug product
were taken; and
(c ) Reference standards and blanks (except that reference standards recognized in an official
compendium need not be submitted).
(ii) Samples of the finished market package, if requested by FDA.
(2) The applicant shall submit the following in the archival copy of the application:
(i) Three copies of the analytical procedures and related descriptive information contained in the
chemistry, manufacturing, and controls section under paragraph (d)(1) of this section for the drug
substance and the drug product that are necessary for FDA's laboratories to perform all necessary
tests on the samples and to validate the applicant's analytical procedures. The related descriptive
information includes a description of each sample; the proposed regulatory specifications for the
drug; a detailed description of the methods of analysis; supporting data for accuracy, specificity,
precision and ruggedness; and complete results of the applicant's tests on each sample.
(ii) Copies of the label and all labeling for the drug product (including, if applicable, any
Medication Guide required under part 208 of this chapter) for the drug product (4 copies of draft
labeling or 12 copies of final printed labeling).
Case report forms and tabulations
The archival copy of the application is required to contain the following case report tabulations
and case report forms:
54
(1)Case report tabulations. The application is required to contain tabulations of the data from
each adequate and well-controlled study under 314.126 (Phase 2 and Phase 3 studies as
described in 312.21 (b) and (c) of this chapter), tabulations of the data from the earliest clinical
pharmacology studies (Phase 1 studies as described in 312.21(a) of this chapter), and tabulations
of the safety data from other clinical studies. Routine submission of other patient data from
uncontrolled studies is not required. The tabulations are required to include the data on each
patient in each study, except that the applicant may delete those tabulations which the agency
agrees, in advance, are not pertinent to a review of the drug's safety or effectiveness. Upon
request, FDA will discuss with the applicant in a "pre-NDA" conference those tabulations that
may be appropriate for such deletion. Barring unforeseen circumstances, tabulations agreed to be
deleted at such a conference will not be requested during the conduct of FDA's review of the
application. If such unforeseen circumstances do occur, any request for deleted tabulations will
be made by the director of the FDA division responsible for reviewing the application, in
accordance with paragraph (f)(3) of this section.
(2)Case report forms. The application is required to contain copies of individual case report
forms for each patient who died during a clinical study or who did not complete the study
because of an adverse event, whether believed to be drug related or not, including patients
receiving reference drugs or placebo. This requirement may be waived by FDA for specific
studies if the case report forms are unnecessary for a proper review of the study.
(3)Additional data. The applicant shall submit to FDA additional case report forms and
tabulations needed to conduct a proper review of the application, as requested by the director of
the FDA division responsible for reviewing the application. The applicant's failure to submit
information requested by FDA within 30 days after receipt of the request may result in the
agency viewing any eventual submission as a major amendment under 314.60 and extending the
review period as necessary. If desired by the applicant, the FDA division director will verify in
writing any request for additional data that was made orally.
(4) Applicants are invited to meet with FDA before submitting an application to discuss the
presentation and format of supporting information. If the applicant and FDA agree, the applicant
may submit tabulations of patient data and case report forms in a form other than hard copy, for
example, on microfiche or computer tapes.
c) General NDA Submission Guidance
The following general requirements apply to the submission of information within the summary
under paragraph:
(1) The applicant ordinarily is not required to resubmit information previously submitted, but
may incorporate the information by reference. A reference to information submitted previously is
required to identify the file by name, reference number, volume, and page number in the agency's
records where the information can be found. A reference to information submitted to the agency
by a person other than the applicant is required to contain a written statement that authorizes the
reference and that is signed by the person who submitted the information.
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(2) The applicant shall submit an accurate and complete English translation of each part of the
application that is not in English. The applicant shall submit a copy of each original literature
publication for which an English translation is submitted.
d) Various Copies of the Original Application
(1)Archival copy. The applicant must submit a complete archival copy of the application. The
FDA will maintain the archival copy during the review of the application to permit individual
reviewers to refer to information that is not contained in their particular technical sections of the
application, to give other agency personnel access to the application for official business, and to
maintain in one place a complete copy of the application. Applicants may submit the archival
copy on paper or in electronic format provided that electronic submissions are made in
accordance with CFR 21 Part 11. The archival copy must also contain the content of labeling
(commonly referred to as the package insert or professional labeling) including all text, tables,
and figures.
(2)Review copy. The applicant must submit a review copy of the application. Each of the
technical sections described above are required to be separately bound with a copy of the
application form.
(3)Field copy. The applicant must submit a field copy of the application that contains the (a)
technical section described above, (b) a copy of the application form, (c) and a certification that
the field copy is a true copy of the archival and review copies of the application.
(4)Binding folders. The applicant may obtain from FDA sufficient folders to bind the archival,
the review, and the field copies of the application.
(5)Electronic format submissions. Electronic format submissions must be in a form that FDA can
process, review, and archive. FDA will periodically issue guidance on how to provide the
electronic submission (e.g., method of transmission, media, file formats, preparation and
organization of files).
G. Pre-launch Activities
Simultaneously with the NDA, marketing strategy is evolving, price negotiations are being
conducted with suppliers/distributors, and promotional materials are being developed. The
construction of commercial plant is in progress in anticipation of approval for selling the new
drug.
Once market approval has been received from the FDA, the drug sponsors must prepare a global
penetration strategy plan. The commercial plant can be owned and operated by the sponsor of the
drug or medical device or outsourced to a FDA-approved Contract Manufacturing Organization
(CMO). A promotional campaign is also launched. The pre-launch phase ends when the new
drug is distributed.
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H. Launch Activities
The drug or medical device is launched over a period of years in various global markets and
usually follows a product cycle.
I. The Product Sales Cycle
For a specific medical indication, initially there is a ramp-up period. During this time in the
product sales cycle, annual sales increase in a linear fashion.
Following the ramp-up period, the product reaches a plateau or mature phase and sales are
maintained. Sales then decline when competition is realized.
The growth phase for a product can be extended by reapplying for NDA approval of the drug for
different medical indications and/or patient groups. However, total product sales eventually
decline through the approval of generic versions of the product by the company’s competitors or
through planned cannibalization of the product by the initial drug developer. The timing of the
latter activity is crucial and the objective is the introduction of generics versions of the product or
new drug entities for the same medical indications by the product developer before the
competition penetrates the market.
V.
FDA Regulation to Gain Market Approval of Biologics in the US
a) What are Biologics
As described in Section II (above), not all drugs intended for use in humans exist in such as
plentiful supply that they cab be purified from a natural source. Likewise it may not be possible
to synthesize a particular drug starting from simple chemical precursors. Drugs that don’t meet
the former criteria, may able to be developed from "new" biotechnology techniques (called
“genetic engineering” ) that enable scientists to modify the genetic material in cells, tissue or
whole organisms at the cellular or molecular level. For example bacteria and mammalian cells
may be grown up in large culture vessels and engineered to produce large quantities of a protein
such as human insulin. The human insulin produced would next be purified to a high degree and
formulated into a drug that can be repeatedly administered to human patients. Such compounds
like human insulin that are made through genetic engineering are called “biopharmaceuticals,”
“biologic compounds,” or just “biologics.”
b) Biologics Clinical Trials Manufacturing
Sufficient amounts of a biological drugs (“a biologic”) formulated from a protein molecule are
often made by scaling-up the stable genetic expression of the protein in an appropriate cellular
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host system and fermentation of the cells in appropriate bioreactors. This is followed by largescale recovery of the protein from other cellular constituents and concentration and purification
of the protein to homogeneity under GMP conditions to produce “bulk drug substance.” Drug
substance is then formulated with appropriate buffers, stabilizers, and additives; filled; and
finished to produce “drug product” which is supplied for administration to human subjects
during clinical trials. Sponsors for the market approval of biologics in the US must follow many
of the same Camps, and GCPs described above for the approval of “small molecule”
pharmaceutical drugs. A key regulatory distinction however is that although both
pharmaceuticals drugs and biologics make use of an IND, the FDA application for biologics
follows a final pathway to market approval via a Biological License Application or “BLA”. See
Applications for FDA Approval of a Biologic License (21 CFR Part 601). Processes and
regulations unique for biologics are described below.
1. Common Genetic Expression Systems for Biomanufacturing
Biologic protein drugs have most commonly been made utilizing bacterial, yeast, and
mammalian host genetic expression systems. A more recent development has been the use of
either transgenic large animals or transgenic plant crops to produce large amounts of
biomanufactured proteins.
1. E. coli Bacterial Expression System
Originally protein biologics were developed by inserting the gene encoding the desired
protein into an Escherichia coli (E.coli ) bacterial host system. Insulin, growth hormone, and
Neupogen (G-CSF or granulocyte colony stimulating factor) are today produced in this manner.
The advantage of E. coli production is that proteins can be made using a well characterized
production system that is relatively cost effective and easy to scale-up through fermentation of
the fast growing cells in bioreactors. Protein therapeutics production and purification using this
system also has an extensive regulatory and commercial track record. However using current E.
coli production technology, not all proteins can be produced because of mis-folding of the
protein molecular backbone or the inability of the host cellular systems to modify the protein
background structure by adding the necessary carbohydrates and other moieties that contribute to
the activity of the macromolecule (“post-translation modifications”). Without these posttranslational modification steps, many proteins are unable to fold into their three-dimensional
shape, which determines how they interact with other proteins for biological activity. Therefore
many complex protein macromolecules that require extensively post-translational modification
for activity, such as human monoclonal antibodies cannot currently be properly produced in E.
coli and must be produced in phylogenically higher Eukaryotic organisms such as yeast, fungi,
mammalian and plant cells.
A newer but untried technology however is in the developmental stage. Researchers in
Switzerland and the UK have engineered E. coli to carry a vital piece of cell machinery that adds
sugar molecules to newly-synthesized proteins (a process known as glycosylation). The scientists
discovered that the bacterium, Campylobacter jejuni, uniquely contains glycosylation machinery
similar to the type found in Eukaryotic organisms. They then developed a technique for
transferring this machinery into the E. coli bacterium, which is widely used in the industrial
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production of proteins. The discovery has important implications for process technology as it
opens up the possibility of producing complex human proteins in E. coli. However this new
system is currently in the early stages of study and characterization.
2. Pichia Yeast Expression System
Pichia pastoris is a robust yeast expression system that produces high levels of recombinant
proteins. The Pichia system is stable, durable and cost-effective. Pichia grows on simple media
and secretes low amounts of endogenous protein, making it easier to recover and purify the
desired recombinant protein. However it is well known that the Pichia system works best for
proteins that do not depend on extensive post-translation modifications for their activity. For
example, single chain monoclonal antibodies that have reactivity to an antigen can be expressed
in the Pichia system but full antibody molecules are inactive because they lack the sugar
(carbohydrate) structures, called N-linked glycans, which give the molecule its full biological
function and human identity.
Recently, GlycoFi, Inc. based in Lebanon, New Hampshire, USA has published in the
Proceedings of the National Academy of Sciences work that may allow for the addition of other
complex structure to proteins produced in Pichia pastoris. The GlycoFi scientific team
genetically re-engineered the secretory pathway of P. pastoris to perform a series of sequential
glycosylation steps to mimic the early processing of N-glycans in humans. They were able to
eliminate non-human glycosylation from the yeast by deleting the initiating alpha-1,6mannosyltransferase gene. Then by inserting several combinatorial genetic libraries that allow
for the production of human-like glycosylation structures they produced N-linked glycans in the
proper location in a the structure of a human reporter protein. However, only a few of the yeast
strains transformed with the mannosidase/leader library displayed protein with high homogenous
levels of the desired N-glycans of the (Man)(5)-(GlcNAc)(2) type. However this is a major
breakthrough that open the door to the possibility of engineering yeast to perform complex
human-like glycosylation.
3. Mammalian Cell Culture
For mammalian cell culture protein production systems, the manufacturing process begins with
the construction of the Master Cell Bank. This involves genetically-engineering a host
mammalian cell to produce the protein of interest. Typically a Chinese hamster ovary (CHO) cell
line, or a mouse NSO myeloma cell line are used as the host cells. These host cells multiply
quickly, are relatively hardy, and grow well in culture. When a cell line is created that produces
high levels of the desired protein, the cells can be grown by scaling-up the production of the host
cells in suspension culture going from a frozen vial to roller bottles or spinner flasks and then
into large bioreactors (see Figure 3 illustrated the production process for a monoclonal antibody
in CHO cells).
The first step in mammalian cell culture biologics production is to create a Master Cell Bank. It
will serve as a depository or the source of all cells used in the production of clinical and
commercial scale quantities of the protein under development. The creation and characterization
of the master cell bank typically takes between four weeks to four months. Each vial in the
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Master Cell Bank (comprised of at least 100 vials) must be identical. The FDA’s “Point to
Consider Documents,” give extensive details on how to create and characterize a Master Cell
Bank.
Once a master cell line has been created, the next step is bioprocessing. This covers two phases
of activity: the growth of the cells and the recovery and purification of the protein product. The
genetic expression of the protein of interest must remain stable during both of these processes.
Currently there are two methods used to grow cells: batch fermentation and continuous perfusion
fermentation. In batch fermentation, cells derived from the Master Cell Bank are progressively
grown in larger and larger volumes over a period of three to four weeks to provide a seed culture
for large fermentation tanks. This gradual step-up in volume allows for the rapid growth of
mammalian cells to the large bioreactor (final production tank) stage. This large bioreactor
typically hold between 4,000 to 20,000 liters of culture medium. The final production bioreactor
is often inoculated with mammalian seed cultures that have been grown up in smaller-sized
bioreactors (80 to 400 liters). Once the seed culture is added to the large tank, the cells are grown
for an additional 10-14 days until they reach an optimal density. After that point the cells are
geared for optimal protein production. The addition of nutrients to provide the cells with optimal
conditions for cell growth and protein production can be reached by one of three ways. Media
components may be added with the addition of the cells to the bioreactor (“batch mode”) or
through the continuous administration of precise amounts over times (“perfusion method”). If
fresh media is not added continuously but is replenished from bulk components added once or
twice after the cell growth has been established in the bioreactor, this is termed “fed-batch”
mode.
The determination of the bioreactor parameters for optimal cell growth and protein production
takes many months and involves the detailed analyses of cell growth, cell density, and cell
stability during the growth phase and protein characterization and stability during the production
phase. Care is taken to prevent post-translational modifications that result in a decrease in the
stability and/or bioactivity of the protein.
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Figure 3. Monoclonal Antibody Production in Mammalian Cell Lines
During the production phase the protein of interest may either stay within the body of the cells or
secreted pass the cell membrane into the liquid media of the bioreactor (the latter offering the
easiest protein recovery scheme). Under the former conditions, the cells must be broken apart
and the protein of interest released into an appropriate liquid media. In either case, the intact or
broken cells are collected by filtration and removed from the liquid media.
The protein of interest in the spent liquid media is then purified through a series of two to four
chromatography (separation) steps. In addition, processes to inactivate and remove viral
contaminants must also be included in the production process. The protein may also be prepared
in a more concentrated form or transferred into a new liquid media for interim storage. The
protein concentrate is then formulated into its final product form and filled into vials for
administration to human patients (“finished product”).
4.
Transgenic Large Animals
To produce transgenic animals the gene coding for the biologic product in humans is inserted
into the egg of another animal species such as a rabbit, pig, goat, sheep or cow. When fully
grown, the transgenic animal carries specifically-altered DNA that is integrated into its genome.
For biopharmaceuticals, this foreign DNA (the transgene) contains the genetic information that
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specifically directs secretion of a target recombinant protein into milk. The recombinant
transgenic protein is produced in milk along with the host animal’s own milk proteins, during
lactation after the birth of offspring.
On a per cell basis, productivity of a recombinant protein in the transgenic animal’s milk glands
is similar to the mammalian cell culture systems, but since mammary gland cells are so much
more dense, the concentrations of product per liter in transgenic milk is considerably higher.
From a capital cost and maintenance point of view, lactating animals are far less expensive than
traditional stainless steel bioreactors or fermenters (upstream cost) than traditional systems. A
per gram costs on the order of $100 per gram of recombinant protein has been reported using
transgenic animals. This is very competitive with microbial culture and several companies have
emerged that specialize in transgenic animal technology (i.e., Genzyme Transgenics Corp.,
Framingham, MA; PPL Therapeutics, Ltd., Edinburgh, Scotland and Blacksburg, VA; and
Pharming b.v., Leiden, The Netherlands). These companies have utilized cows, sheep, goats,
pigs and rabbits as transgenic production models.
Some disadvantages to the transgenic production of recombinant proteins are the long length of
time and high cost required to produce suitable lactating animals. For example, for a transgenic
goat, it takes 18 to 28 months to go from the first introduction of the transgene to full lactation,
and this time varies from species to species and between individual animals of the same species.
For a cow, this period can vary from 33 to 47 months. Also, considerable more time and costs
are involved in the task of going from one “founder” animal to a herd necessary for large-scale
production even with advanced cloning techniques. Lastly, even if the large herds of animals
could be produced comprised of genetically-engineered clones, “living bioreactors” offer a lot
more complexity than traditional bioreactors including possible variation in the concentration
and bioanalytical properties of the recombinant protein during different phases of the lactation
cycle in animals. However, the FDA has issued a “Points to Consider” document in 1995
covering the regulatory issues of concern to product developers employing transgenic animal for
the manufacturing of therapeutic proteins and these should be addressed in order to validate the
transgenic animal approach from a regulatory standpoint.
5. Transgenic Plants
Within the past five years, transgenic plants have emerged as a potentially very effective way for
the low-cost, large-scale production of therapeutic proteins. Transgenic expression systems have
been developed for many types of crop plants, including corn, tobacco, potato, tomato, canola,
rice and non-crop plants such as lemna (duckweed).
Plant transgenics offers the advantages of the stable introduction of foreign genes in an easy and
efficient matter that allows for quick and cost-effective biomass production either in seeds or
plant tissue. Plants also do not harbor human infectious agents such as viruses and prions
because these agents cannot replicate in plants. Plants also generally lack closely related
structural homologs that can pose purification problems. For example, plants do not make their
own antibodies that have to be separated from the human transgene products.
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Human therapeutic proteins have been made in corn, tobacco, and potatoes and even in fruits
such as the banana. However, although plants perform many complex protein processing steps,
such as isoprenylation, oligomerization, disulfide bridge formation and proteolytic cleavage,
these processes may not be identical to those that occur in humans unless the human-like
pathways can also be geneticaly-enginerred into plant cells.
b) Differences and Similarities between Biologics Development and New Drug Product
Development Regulations
Biological products are a subset of drugs; therefore both are regulated under provisions of the
FDC Act.
Following initial laboratory and animal testing that show that investigational use in humans is
reasonably safe, biological products (like other drugs), can be studied in clinical trials in humans
under an investigational new drug application (IND) in accordance with the regulations at 21
CFR 312. If the data generated by the studies demonstrate that the product is safe and effective
for its intended use, the data are submitted as part of a marketing application.
Whereas a new drug application (NDA) is used for drugs subject to the drug approval provisions
of the FDC Act, a biologics license application (BLA) is required for biological products subject
to licensure under the PHS Act. The Act requires a firm who manufactures a biologic for sale in
interstate commerce to hold a license for the product.
FDA form 356h (example: http://www.fda.gov/ohrms/dockets/ac/05/briefing/20054086B1_01_B-Merck-Form356h.pdf ) is used for BLA submissions. However, the overall
development track (preclinical through clinical studies) is very similar to that described above
for pharmaceutical drugs (see Section IV.A, above).
One caveat to the above is that the manufacturing process for a biological product usually
different from the process for drugs. This is because, in many cases, there is limited ability to
identify the identity of the clinically active component(s) of a complex biological product, such
products are often defined by their manufacturing processes. Changes in the manufacturing
process, equipment or facilities could result in changes in the biological product itself and
sometimes require additional clinical studies to demonstrate the product's safety, identity, purity
and potency. Traditional drug products usually consist of pure chemical substances that are
easily analyzed after manufacture. Since there is a significant difference in how biological
products are made, the production is monitored by the agency from the early stages to make sure
the final product turns out as expected See: http://www.fda.gov/cder/biologics/qa.htm.
Issuance of a biologics license is a determination that the product, the manufacturing process,
and the manufacturing facilities meet applicable requirements to ensure the continued safety,
purity and potency of the product.
According to the FDA, “safety” means the relative freedom from harmful effects, direct or
indirect, when a product is prudently administered, taking into consideration the character of the
product in relation to the condition of the recipient at the time.
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“Purity” means relative freedom from extraneous matter in the finished product, whether or not
harmful to the recipient or deleterious to the product. Purity includes but is not limited to relative
freedom from residual moisture or other volatile substances and pyrogenic substances.
The word “potency” is interpreted by the FDA to mean the specific ability or capacity of the
product, as indicated by appropriate laboratory tests, to yield a given result. See:
http://www.fda.gov/cder/biologics/qa.htm.
c) Submitting a Biologics License Application for FDA Market Approval of a Biologic
In this stage, all information (i.e. efficacy, toxicology, process, drug-drug interactions, side
effects, etc.) are combined and submitted to the FDA as a Biologics License Application (BLA).
Like the NDA used to gain market approval for a “small molecule” pharmaceutical drug,
information on a particular a biologics may already been submitted to the FDA in the pre-clinical
and clinical trial stages. Therefore it is also necessary in the NDA to included answers to FDA
questions that may have been previously proposed by the agency’s division responsible for
reviewing the application. Also, as discussed about pharmaceutical drugs (see Section IV above),
simultaneously with preparing the FDA application for the biologic, marketing strategy is being
proposed, price negotiations are being conducted with suppliers/distributors, the construction of
a commercial plant has been planned, and promotional materials are being developed in
anticipation of approval for selling the biologics
In the biologics license application (BLA), a sponsor submits data derived from nonclinical
laboratory which demonstrate that the manufactured product meets prescribed requirements of
safety, purity, and potency; with respect to each nonclinical laboratory study, either a statement
that the study was conducted in compliance with the requirements set forth FDA Regulations 21
CFR Part 58, or, if the study was not conducted in compliance with such regulations, a brief
statement of the reason for the noncompliance.
The sponsor must also submit statements regarding each clinical investigation involving human
subjects contained in the application, that it either was conducted in compliance with the
requirements for institutional review set forth in 21 CFR Part 56; or was not subject to such
requirements in accordance with 56.104 or 56.105, and was conducted in compliance with
requirements for informed consent set forth in 21 CFR Part 50.
A full description of manufacturing methods; data establishing stability of the product through
the dating period; sample(s) representative of the product for introduction or delivery for
introduction into interstate commerce; summaries of results of tests performed on the lot(s)
represented by the submitted sample(s); specimens of the labels, enclosures, and containers, and
if applicable, any Medication Guide required under 21 Part 208 proposed to be used for the
product; and the address of each location involved in the manufacture of the biological product
shall be listed in the biologics license application.
The applicant must also include a financial certification or disclosure statement(s) or both for
clinical investigators as required by 21 CFR Part 54. An application for a biologics license shall
not be considered as filed until all pertinent information and data have been received by the Food
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and Drug Administration. The applicant shall also include either a claim for categorical
exclusion under 25 CFR Part 30 or 25.31, or an environmental assessment under 25.40.
The applicant, or the applicant's attorney, agent, or other authorized official shall sign the
application.
An application for most biological products subject to licensure needs to be handled as set forth
in FDA 21 CFR Part 600 through 680.
However, to obtain marketing approval for a biological product subject to licensure which is a
therapeutic DNA plasmid product, therapeutic synthetic peptide product of 40 or fewer amino
acids, monoclonal antibody product for in vivo use, or therapeutic recombinant DNA-derived
product, an applicant should submit a biologics license application in accordance with Parts 600
through 680 except that the following sections are not be applicable to such products: 600.10(b)
and (c), 600.11, 600.12, 600.13, 610.11, 610.53, and 610.62 of this chapter.
Approval of a biologics license application or issuance of a biologics license shall constitute a
determination that the establishment(s) and the product meet applicable requirements to ensure
the continued safety, purity, and potency of such products. Applicable requirements for the
maintenance of establishments for the manufacture of a product subject to this section shall
include but not be limited to the good manufacturing practice requirements set forth in parts 210,
211, 600, 606, and 820 of 21 CFR. See:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=601.2.
On October 1, 2003, FDA transferred certain product oversight responsibilities from the Center
for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research
(CDER). This consolidation provides greater opportunities to further develop and coordinate
scientific and regulatory activities between CBER and CDER, leading to a more efficient,
effective, and consistent review program for human drugs and biologics. FDA believes that as
more drug and biological products are developed for a broader range of illnesses, such
interaction is necessary for both efficient and consistent agency action. Under the new structure,
the biologic products transferred to CDER will continue to be regulated as licensed biologics.
To see which product classes have been transferred and which will remain at CBER, please refer
to Transfer of Therapeutic Products to the Center for Drug Evaluation and Research.
The therapeutic biological products now under CDER's review include:

Monoclonal antibodies for in-vivo use

Cytokines, growth factors, enzymes, immunomodulators; and thrombolytics

Proteins intended for therapeutic use that are extracted from animals or microorganisms, including
recombinant versions of these products (except clotting factors)
Other non-vaccine therapeutic immunotherapies
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Approval to market a biologic is granted by issuance of a biologics license (including US license
number) as part of the approval letter. FDA does not issue a license certificate. The US License
number must appear on the product labeling.
VI.
FDA Regulation to Gain Market Approval of Medical Devices in the US
a) The Medical Device Classification
The Office of Device Evaluation (ODE) of The Center for Devices and Radiological Health
(CDRH) is responsible for the FDA’s program areas through which medical devices are
evaluated or cleared for clinical trials and marketing. The ODE classifies medical devices based
on their similarity to devices that have already been approved and marketing in the U.S., and
based on regulatory controls. The device class also determines the type of application that needs
to be filed with the FDA.
Device Class and Regulatory Controls are:
i. Class I General Controls
 With Exemptions
 Without Exemptions
ii. Class II General Controls and Special Controls
 With Exemptions
 Without Exemptions
iii. Class III General Controls and Premarket Approval
In general, classification is risk-based, that is, the risk the device poses to the patient and/or the
user is a major factor in the class it is assigned. Class I includes devices with the lowest risk and
Class III includes those with the greatest risk. As indicated above, all classes of devices are
subject to General Controls. General Controls are the baseline requirements of the Food, Drug
and Cosmetic (FD&C) Act that apply to all medical devices, Class I, II, and III. In addition,
some specific devices have exemptions and special controls, as listed in the FDA’s Medical
Device Classification Database, that need to be consider during the application process.
To find the classification of your device, as well as whether any exemptions or special controls
may exist, you need to find the FDA regulation number that is the classification regulation for
your device. There are two methods for accomplishing this: going directly to the classification
database and search for a part of the device name, or, if you know the device panel (medical
specialty) to which your device belongs, go directly to the listing for that panel and identify your
device and the corresponding regulation.
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FDA classification also depends on the intended use of the device and upon indications for such
use. For example, a scalpel's intended use is to cut tissue. A subset of intended use arises when a
more specialized indication is added in the device's labeling such as, "for making incisions in the
cornea". More specialized indication may require special controls.
If your device is classified as Class I or II in the FDA’s classification database, and if it is not
exempt, a 510k will be required for marketing. All Class I and II devices that are exempt are
suspect to the limitations on exemptions.
For Class III devices, a premarket approval application (PMA) will be required unless your
device is a preamendments device (on the market prior to the passage of the medical device
amendments of 1976), or substantially equivalent to such a device, and PMA's have not been
called for. In that case, a 510k will be the route to market.
b) Premarket Notifications or 510(k)
In general, a premarket notification or 510(k) is required for Class I and Class II medical devices
that are not exempt and Class III devices that are pre-ammendment devices (“on the market prior
to the passage of the medical device amendments in 1976, or substantially equivalent to such a
device”). At least 90 days before placing a medical device into commercial distribution, a
medical device developer must submit to the FDA a premarket notification, commonly known as
a "510(k)." In addition, for Class III, devices, the 510(k) submitter must include information to
substantiate that the device is "substantially equivalent" to a pre-ammendment device. The FDA
will review the 510(k) submission and a device may not be marketed as a 510(k) device until the
submitter receives written clearance from FDA.
c) Premarket Approval Applications (PMAs)
Under the Federal Food, Drug, and Cosmetic Act (the Act) and the FDA regulations, Code of
Federal Regulations, Title 21 (the Regulations), a manufacturer or others must submit a
Premarket Approval Application (PMA) for FDA review and approval before marketing Class
III devices that are not a preamendment device and do not represent a significant risk to human
subjects. The PMA submitter must provide reasonable assurance that the device is safe and
effective for its intended use and that it will be manufactured the device in accordance with
current good manufacturing practices (cGMP). Before applying to the FDA for conducting a
clinical trial, the sponsor must also obtain informed consent from the human subjects that will be
involved in the medical device study and the approval of an institutional review board (IRB).
As part of the review process for a new device, the FDA may present the PMA to an expert
advisory panel for its recommendations. After obtaining the panel recommendations, the agency
makes a determination to approve the PMA, deny it, or request additional information. When the
FDA either approves or denies the PMA, it must publish a notice in the Federal Register to
inform the public of the decision and make available a summary of the safety and effectiveness
data upon which the decision is based. This publicly-available summary does not include
proprietary data or confidential information submitted by the applicant.
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d) PMA Supplementation
After a PMA has been approved, the PMA holder may request approval of changes to be made.
For example, it may request changes to the device, its labeling or packaging, or the
manufacturing processes used for device production. The FDA will determine if these changes
affect the safety or effectiveness of the device. The FDA’s review of a PMA supplement may be
easy or difficult depending on the type of device, the significance of the change, and the
complexity of the technology. Some PMA supplements can be as complex as that in the original
application. Although the statutory timeframe is 180 days for PMA Supplements, FDA is
committed to reviewing these in shorter timeframes and has reduced review timeframes through
the use of real-time supplement process, 30-day notices, and expedited reviews.
The PMA is the standard FDA application for a Class III medical device that is not a preamendment device. However there are two special PMA-type filings that a sponsor may want to
consider: a Humanitarian Device Exemption (HDE), and an Investigational Device Exemptions
(IDE).
e) Humanitarian Device Exemptions (HDEs)
An approved HDE authorizes marketing of a humanitarian use device (HUD). An HDE
application is essentially the same as a PMA in both form and content but is exempt from the
device effectiveness requirement of a PMA. Even though the HDE is not required to contain the
results of scientifically valid clinical investigations demonstrating that the device is effective for
its intended purpose, the application must contain sufficient information for FDA to determine,
as required by statute, that the device does not pose an unreasonable or significant risk of illness
or injury to patients, and that the probable benefit to health outweighs the risk of injury or illness
from its use. An HDE application must also contain information that will allow FDA to make the
other determinations required by the act.
f) Investigational Device Exemptions (IDEs)
Under 21 CFR of the Medical Device Act and Regulations, an individual, institution or company
may sponsor the clinical investigation of a medical device that may present a significant risk to
humans. The IDE must contain information concerning the study’s investigational plan, report of
prior investigations, device manufacture, IRB actions, investigator agreements, subject informed
consent form, and proposed device labeling, cost of the device, and other matters related to the
study. FDA has 30 calendar days from the date of receipt of the application to approve or
disapprove an IDE exemption.
g) IDE Amendments
Although not provided for in the IDE regulations, all submissions related to an original IDE that
has been submitted, but not approved, are referred to as "IDE amendments." Identification of
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IDE amendments enables FDA to track each IDE from the time it is originally submitted until
the time it is approved.
After an IDE is approved, related submissions are called "supplemental applications" under the
regulations. The IDE regulation requires the sponsor of an investigation of a significant risk
device to submit a supplemental application for a number of reasons. For example, a sponsor
must submit a supplement if there is a change in the investigational plan when such a change
may affect the scientific soundness of the study or the rights, safety, or welfare of the subjects.
Supplemental applications also are required for the addition of investigational sites. This
regulation also requires the submission of various reports, which are logged in as supplements to
IDE applications. These include reports on unanticipated adverse effects of the device; recall and
device disposition; failure to obtain informed consent; and annual progress reports, final reports,
investigator lists, and other reports requested by FDA.
h) Product Development Protocols (PDPs)
The PDP process is based upon early consultation between the sponsor and the FDA leading to a
device development and testing plan acceptable to both parties. It minimizes the risk that the
sponsor will unknowingly pursue (with the associated waste of capital and other resources) the
development of a device that FDA will not approve. A PDP is allowed under the 1976 Medical
Device Amendments to the Food, Drug, and Cosmetic Act that allows for two product pathways
for a Class III device with a significant risk profile: a PMA with an IDE exemption or, with prior
FDA permission, the notice of completion of a PDP.
The PDP process incorporates four discrete stages of FDA review: a PDP Summary Outline;
FDA/Advisory Panel review of the full PDP; consideration and, where appropriate, pre-approval
of design modifications and protocol revisions made during execution of the PDP; and action on
the sponsors Notice of Completion.
The FDA review of the PDP Summary may take up to 30 days. The FDA/Advisory Panel review
of the full PDP may take up to 120 days. The FDA must declare the PDP "completed" or "not
completed" within ninety days of receiving the sponsors Notice of Completion. The PDP process
includes an inspection of the sponsor’s Quality System Regulation Inspections that are on file
with the FDA. If the sponsor does not have an established satisfactory inspection history, a GMP
inspection will be made by the FDA. If the requirements of the PDP are met, the Agency will
declare the PDP complete and the sponsor may manufacture the medical device.
i) Medical Device Code of Federal Regulations (CFRs)
Medical devices are subject to the general controls of the Federal Food Drug & Cosmetic
(FD&C) Act which are contained in the final procedural regulations in Title 21 Code of Federal
Regulations Part 800-1200 (21 CFR Parts 800 - 1299). These controls are the baseline
requirements that apply to all medical devices necessary for marketing, proper labeling and
monitoring its performance once the device is on the market.
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j) Steps to Obtaining Marketing Clearance from CDRH
Essentially, there are three steps to obtaining market clearance for a medical device from FDA’s
CDRH:
STEP ONE in the marketing process is to make absolutely sure that the product that you wish to
market is a medical device, that is, does it meet the definition of a medical device in section
201(h) of the FD&C Act. For example, the product may be a drug or biological product that is
regulated by a component in the FDA other than the Center for Devices and Radiological Health
(CDRH) and for which there are different provisions in the FD&C Act. Or your product may be
a medical device and is also an electronic radiation emitting product with additional
requirements.
STEP TWO is to determine how FDA may classify your device - which one of the three classes
the device may fall into. Unless exempt, FDA will classify your device. Classification identifies
the level of regulatory control that is necessary to assure the safety and effectiveness of a medical
device. Most importantly, the classification of the device will identify, unless exempt, the
marketing process (either premarket notification [510(k)] or premarket approval (PMA)) the
manufacturer must complete in order to obtain FDA clearance/approval for marketing.
STEP THREE is the development of data and/or information necessary to submit a marketing
application, and to obtain FDA clearance to market.
Medical devices are cleared for the US market via 510(k) submissions and PMA applications
(see sections b and c above). For some 510(k) submissions and most PMA applications, clinical
performance data is required to obtain clearance to market. In these cases, conduct of the trial
must be done in accord with FDA's Investigational Device Exemption (IDE) (see section f
above). For additional information, see the FDAs web pages on :
510k Information
PMA Information
Exempt Device Information
k) Other Requirements Besides Marketing Clearance
Besides gaining market clearance there are other FDA requirements for medical devices:
i. Premarket Requirements: Labeling, Registration, Listing
Before marketing clearance is obtained the manufacturer must assure that the device is properly
labeled in accordance with FDA's labeling regulations. Once clearance for marketing is obtained,
the manufacturer must register their establishment and list the type of device they plan to market
with the FDA. This registration and listing process is accomplished by the submission of FDA
Form 2891 and 2892.
ii. Postmarket Requirements: Quality System, Medical Device Reporting
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Once on the market, there are postmarket surveillance controls with which a manufacturer must
comply. These requirements include the Quality Systems (QS) (also known as Good
Manufacturing Practices, GMPs) and Medical Device Reporting (MDR) regulations. The QS
regulation is a quality assurance requirement that covers the design, packaging, labeling and
manufacturing of a medical device. The MDR regulation is an adverse event reporting program.
iii. Requirements for In Vitro Diagnostic Devices
In vitro diagnostics (IVDs) are medical devices that analyze human body fluids, such as blood or
urine, to provide information for the diagnosis, prevention, or treatment of a disease. The device
classification for these devices can be found under 21 CFR 862, 21 CFR 864, and 21 CFR 866.
iv. Clinical Laboratory Improvement Act (CLIA) of 1988
In addition to FDA regulation under the Food, Drug, and Cosmetic Act, in vitro diagnostic (IVD)
devices are also subject to the Clinical Laboratory Improvement Amendments (CLIA) of 1988.
This law established quality standards for laboratory testing and an accreditation program for
clinical laboratories.
The requirements that apply vary according to the technical complexity in the testing process and
risk of harm in reporting erroneous results. The regulations established three categories of testing
on the basis of the complexity of the testing methodology: a) waived tests, b) tests of moderate
complexity, and c) tests of high complexity. Laboratories performing moderate- or highcomplexity testing or both must meet requirements for proficiency testing, patient test
management, quality control, quality assurance, and personnel. These specific requirements do
not apply to tests in the waived category. See the FDAs Product Complexity Database at
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCLIA/search.cfm. The FDA's CLIA
homepage is at http://www.fda.gov/cdrh/clia/index.html .
In January 2000 the categorization of commercially marketed in vitro diagnostic tests under
CLIA was transferred from the Center for Disease Control (CDC) to FDA. CDRH's Office of
Device Evaluation (OIVD)/Division of Clinical Laboratory Devices (DCLD) will determine the
appropriate complexity categories for clinical laboratory devices as they evaluate premarket
submissions. Waived products, devices exempt from premarket notification, and devices under
premarket review by other FDA centers also will be processed by DCLD. Responsibilities
currently assigned to CDC, including review of test systems, assays, or examinations not
commercially marketed as IVD products, will remain with CDC. See
http://www.fda.gov/cdrh/oivd
Specific labeling requirements for IVDs can be found under 21 CFR 809. Additional guidance
can be found under "Device Advice Labeling Requirements for In Vitro Diagnostic Devices."
For the current list of tests that have been CLIA-Waived by FDA, see:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfClia/testswaived.cfm.
This concludes our Regulatory Primer discussion. Please proceed to the test questions on the
following page in order to determine your understanding of the above discussions.
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VI.
Test Questions
You will be asked to answer 25 multiple-choice test questions. If you pass with a score of at least
85% (20 of the 25 questions are answered correctly), you have demonstrated a good
understanding of the United States Regulations for Medical Products. If you score below 80%,
go back and read again the sections relevant for the questions that you answered incorrectly. In
the latter case, this process should help to improve your understanding of the subject matter.
Choose the letter of the best correct answer for the various multiple choices questions.
1. Examples of medical products that require FDA approvals for marketing in the United States
are?
a. pharmaceutical drugs
b. biologics
c. medical devices
d. combination products
e. all of the above
2. The administration of tissue plasminogen activator (TPA) to decrease a severe blockage in a
blood vessel that supplies nourishment for the heart is an example of a pharmaceutical drug
developed for a human disease indication?
(a ) True
(b) False
3. A combination product is a medical product that is cleared by the FDA for use in the
treatment of two or more human disease indications?
(a ) True
(b) False
4. Modern day drug development still relies mainly on serendipity and happenstance for the
discovery of lead therapeutic molecules?
(a ) True
(b) False
5. Structural genomics is an example of a rational approach to drug discovery?
(a ) True
(b) False
6. Proteomics involves the characterization of proteins and their interaction in molecular
pathways and cascades within cells?
(a ) True
(b) False
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7. The FDA relies on documented adherence to GLP requirements by nonclinical laboratories in
judging the acceptability of safety data submitted in support of research and/or marketing
permits. The FDA uses these data to answer questions regarding?
a. the toxicity profile of the article (i.e., molecule or compound).
b. the observed “no adverse effect” dose level in the test system.
c. the risks associated with clinical studies involving humans or animals.
d. the potential teratogenic, carcinogenic, or other adverse effects of the article.
e. all of the above
8. What documentation is required to be filed with the United States Food and Drug
Administration (FDA) to allow testing of a drug in humans to begin?
(a ) A Pre-Clinical Testing Application (PTA)
(b) An Investigational New Drug Application (IND)
(c) A New Drug Application (NDA)
(d) None is required
9. During Phase I Clinical Trials, small numbers of healthy volunteers are tested with the drug
to determine it’s duration in the bloodstream and the drug’s initial safety profile?
(a ) True
(b) False
10. Pharmaceutical drug products are produced for human clinical trials in the United States
following the FDA’s Current Good Manufacturing Practices (CGMP) regulations?
(a ) True
(b) False
11. The overarching philosophy articulated in both the CGMP regulations and in robust modern
quality systems is that quality need not be built into the product because testing alone can
ensure the product is reliable?
(a ) True
(b) False
12. If human subject consent forms have been approved by a sponsor’s Institutional Review
Board (IRB), the sponsor does not need to submit these documents to the FDA to gain
medical device market approval?
(a ) True
(b) False
13. Root cause analysis with corrective action to help understand the cause of a deviation and
potentially prevent recurrence of a similar problem is an important concept of Corrective and
Preventive Action (CAPA).
(a ) True
(b) False
14. Use of a Contract Manufacturing Organization (CMO) by a sponsor to manufacture a human
pharmaceutical drug is prohibited by FDA regulations?
(a ) True
(b) False
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15. Once the FDA approves a New Drug Application (NDA), physicians may prescribe the drug
to human patients?
(a ) True
(b) False
16. Currently all approved bioactive protein drugs are manufactured using bacteria or yeast cells
in culture?
(a ) True
(b) False
17. Steps in the mammalian cell culture system for the production of monoclonal antibody drugs
includes?
(a) Establishment of a Master Cell Bank
(b) Cell growth
(c) Protein recovery and purification
(d) Viral inactivation
(e) All of the above
18. Changes in the manufacturing process, equipment or facilities could result in changes in the
biological product itself and sometimes require additional clinical studies to demonstrate the
product's safety, identity, purity and potency?
(a ) True
(b) False
19. Part of the FDA approval process to market a biologic in the United States is through the
submission of a Biologic License Application (BLA)?
(a ) True
(b) False
20. The Center for Drug Evaluation and Research (CDER) is solely responsible for the FDA’s
program area through which medical devices are evaluated or cleared for clinical trials and
monitoring?
(a ) True
(b) False
21. The risk that a medical device may pose for human patients is not one of the considerations
that the FDA has used to classify medical devices?
(a ) True
(b) False
22. The FDA’s application procedure for a Class III medical device that is not a pre-amendment
device (on the market prior to the passage of the medical device amendments in 1976, or
substantially equivalent to such a device) is called?
a) A Humanitarian Device Exemption (HDE)
b) A Premarket Approval (PMA) Application
c) A Premarket Notification or 510(k)
d) None of the above
23. Before marketing clearance for a medical device is obtained, the manufacturer must assure
that the device is properly labeled in accordance with FDA's labeling regulations?
(a ) True
(b) False
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24. Once clearance for the marketing of a medical device is obtained, the manufacturer does not
need to register their establishment nor list the type of device they plan to market with the
FDA?
(a ) True
(b) False
25. When all in vitro diagnostic (IVD) devices are cleared for marketing through adherence to
FDA regulation under the Food, Drug, and Cosmetic Act, they are no longer subject to
regulations under the Clinical Laboratory Improvement Amendments (CLIA) of 1988?
(a ) True
(b) False
The correct answers to the above questions are given in the next and last page of this document.
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The correct answer to the multiple-choice question from this Regulatory Primer are:
1.
2.
3.
4.
5.
e
a
b
b
a
6.
7.
8.
9.
10.
a
e
b
a
a
11.
12.
13.
14.
15.
b
b
a
b
a
16.
17.
18.
19.
20.
b
e
a
a
b
21.
22.
23.
24.
25.
b
b
a
b
b
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