biotech essay needed. please read first before responding. must have background in biotech before consideration

ESSAY EXAM

A Case Study in RegulationBackgroundOn January 17, 2006, FDA issued a direct final rule/proposed rule to exempt investigational drugs and biologics for phase 1 human clinical trials from the CGMP regulation. As you know, it is a requirement that all clinical and commercial drugs and biologics, such as vaccines, be made per cGMP regulation. At the same time, FDA issued a draft guidance providing recommendations on manufacturing Phase 1 material (to replace the formal, legal cGMP regulation). FDA was proposing regulating Phase 1 material by means other than cGMP regulation, to rely on the broad applicability of the Food, Drug, and Cosmetic Act (which states that drugs not made per cGMPs are adulterated, but does not provide specifics) and the information submitted by sponsors in Investigational New Drug (IND) Applications. FDA stated that they were taking the action “to streamline and promote the drug development process.”PreparationRead the following documents to prepare yourself for an essay response on this proposed rule: Guidance for Industry: INDs – Approaches to Complying to cGMP during Phase I (read sections I through V)Power of Storytelling article by Barbara ImmelBarbara Immel comments on Direct Final/Proposed RuleOptional: Chipping Away the GMPs (Powerpoint slides as a pdf) by Barbara Immeladocuments up loaded here: http://www.mediafire.com/?06xqic8t0qxv3uuEssayThe events and comments surrounding this move by FDA to eliminate formal cGMP adherence for Phase I studies lead the Agency to withdraw the rule on May 2, 2006 due to the significant adverse comments they received by individuals and groups, such as the Immel Group. This result is important because it is a timely reminder of the complexity involved in changing regulation and also the impact that the public can have on shaping how the FDA regulates this industry.Write a three-page essay (12-pt font, double-spaced) based on your experience in this course and the preparatory readings above addressing the following prompt:Reflect on the how history has shaped the GMPs and the purpose of Phase I clinical trials. Identify the most compelling points in ensuring that GMPs remain in effect for Phase I trials or, alternatively, outline how Phase I trials could be expedited by limiting applicability of GMPs. GradingGrading rubric is in zip filePost-scriptNote that in fall 2008, the FDA did ultimately approve this rule for GMPs in Phase I clinicals. They did make some amendments but it is not too different from what you’ll read for this assignment. You do NOT need to address the fact that this is now approved in your essay. will provide previous lecture reading materials if needed

essay material/.DS_Store

__MACOSX/essay material/._.DS_Store

essay material/Chipping-Away_immel

Chipping Away at the GMPs:
Understanding FDA’s Proposal to Exempt Material for Phase 1
Clinical Trials from CGMP Regulations, and new Draft Guidance

Prepared for Participants of the
30th Annual International GMP Conference,

University of Georgia, March 2006
by Barbara Immel, President, Immel

Resources LLC, and Editor, Immel Report ™
©2006, Immel Resources LLC, Petaluma, California, (707) 778-7222, immel@immel.com,

www.immel.com

mailto:immel@immel.com

Overview
 What FDA is proposing

 Proposed rule and direct final rule
 Draft guidance to replace CGMP regulation

 FDA’s mission and history
 Recent events

 Patient deaths in phase 1 trials
 Pharmacy compounding experience
 Medical device experience

 Draft guidance
 Why logic may be flawed
 What your organization can do
 Questions and answers
 ©2006, Immel Resources LLC

Disclaimer
 The following are opinions of Immel

Resources LLC only. This presentation is not
intended to replace the advice of an
experienced quality assurance or regulatory
compliance professional. Please ensure that
you are following all applicable regulations
and consult with an experienced quality
assurance or regulatory compliance
professional regarding any questions that you
may have.

What FDA is Proposing
Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs:
http://www.fda.gov/ohrms/dockets/98fr/06-353.htm, Proposed Rule, Current Good Manufacturing Practice
Regulation and Investigational New Drugs, http://www.fda.gov/ohrms/dockets/98fr/06-350.htm

 On January 17, 2006, FDA published a
proposed rule and a direct final rule in the
Federal Register to amend current good
manufacturing practice (CGMP) regulations
for human drugs, including biological
products, to exempt most investigational
“Phase 1” drugs from complying with the
CGMP regulation (21 CFR 210/211).

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

http://www.fda.gov/ohrms/dockets/98fr/06-350.htm

What FDA is Proposing
Source: Draft Guidance for Industry on Investigational New Drugs; Approaches to Complying with Current Good Manufacturing Practice
During Phase 1; Availability, http://www.fda.gov/ohrms/dockets/98fr/06-352.htm, and INDs – Approaches to Complying with CGMP
During Phase 1 Draft Guidance, January 2006, http://www.fda.gov/ohrms/dockets/98fr/05d-0286-gdl0001

 At the same time, FDA published a draft
guidance entitled “INDs – Approaches
to Complying with CGMP During Phase
1” to provide guidance (to replace the
existing regulation) to provide
“recommendations on approaches to
statutory compliance” to manufacture
Phase 1 material.

http://www.fda.gov/ohrms/dockets/98fr/06-352.htm

http://www.fda.gov/ohrms/dockets/98fr/05d-0286-gdl0001

FDA’s Phase 1 Proposals

 Written comments on the rule(s) are due by April 3,
2006, and for the draft guidance by March 20, 2006.

 If timely significant adverse comments are received,
the agency will publish a notice of significant adverse
comment in the Federal Register withdrawing the
direct final rule.

 If FDA receives no significant adverse comments
within the specified comment period, the agency will
confirm the effective date of the final rule in the
Federal Register, and the final rule will go into place
on June 1, 2006.

Significant Adverse Comment
Source: Guidance for FDA and Industry, Direct Final Rule Procedures, Nov. 21, 1997, http://www.fda.gov/cber/gdlns/drctfnlrl

 Explains why rule would be inappropriate
 Includes challenges to rule’s underlying premise or

approach
 Explains why rule would be ineffective or

unacceptable without the change
 Is serious enough to warrant a substantive response

in notice and comment process
 A comment recommending a rule change in addition

to the rule is not a significant adverse comment
unless the comment also states why this rule would
be ineffective without the additional change

 Comments that are frivolous, insubstantial or outside
the scope of the rule will not be considered significant

http://www.fda.gov/cber/gdlns/drctfnlrl

Rationale
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 “This action is intended to streamline
and promote the drug development
process while ensuring the safety and
quality of the earliest stage
investigational drug products, those
intended for use in Phase 1 clinical
trials.”

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Rationale
Source: FDA Press Release, FDA Issues Advice to Make Earliest Stages Of Clinical Drug Development More Efficient, January 12, 2006,
http://www.fda.gov/bbs/topics/news/2006/NEW01296.html

 “The Food and Drug Administration (has)
announced steps to advance the earliest
phases of clinical research in the development
of innovative medical treatments. FDA’s goal
is to improve the process for bringing safe
and effective drugs for potentially serious and
life-threatening diseases, such as cancer,
heart disease and neurological disorders, to
the market.”

http://www.fda.gov/bbs/topics/news/2006/NEW01296.html

Rationale
Source: FDA Press Release, FDA Issues Advice to Make Earliest Stages Of Clinical Drug Development More Efficient, January 12, 2006,
http://www.fda.gov/bbs/topics/news/2006/NEW01296.html

 “The problem is that researchers conducting very
early studies were required to follow the same
manufacturing procedures as those companies that
mass produce products for broad scale distribution,”
said Janet Woodcock, MD, FDA Deputy Commissioner
for Operations. “These requirements are so
burdensome for early phase 1 studies that many
leading medical research institutions have not been
able to conduct these studies of discoveries made in
their laboratories. Today, for the first time, medical
researchers are getting specific advice from the FDA
about how to safely prepare products for exploratory
studies.”

http://www.fda.gov/bbs/topics/news/2006/NEW01296.html

Rationale
Source: FDA Press Release, FDA Issues Advice to Make Earliest Stages Of Clinical Drug Development More Efficient, January 12, 2006,
http://www.fda.gov/bbs/topics/news/2006/NEW01296.html

 “The documents released .. are part of FDA’s
commitment to modernize existing CGMP
regulations to streamline clinical
development. These efforts are part of the
Agency’s Critical Path Initiative, launched in
March 2004. The goal of the Critical Path
Initiative is to reduce the time and resources
expended on candidate products that are
unlikely to succeed, by creating new tools to
distinguish earlier in the process those
candidates that hold promise.”

http://www.fda.gov/bbs/topics/news/2006/NEW01296.html

Proposed Change
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 An investigational drug for use in a Phase 1 study, as
defined in Sec. 312.21(a) of this chapter, is subject to
the statutory requirements set forth at 21 U.S.C.
351(a)(2)(B). The production of such drug is exempt
from compliance with the regulations in part 211 of
this chapter. However, this exemption does not apply
to an investigational drug for use in a Phase 1 study
once the investigational drug has been made available
for use by or for the sponsor in a Phase 2 or Phase 3
study, as defined in Sec. 312.21(b) and (c ) of this
chapter, or the drug has been lawfully marketed. If
the investigational drug has been made available in a
Phase 2 or 3 study or the drug has been lawfully
marketed, the drug for use in the Phase 1 study must
comply with part 211.

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Background
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 Phase 1 studies are the first introduction of
an investigational new drug into humans.

 Phase 1 studies are designed to establish
basic safety of the compound, and to
determine the metabolism and
pharmacologic actions of the drug in
humans.

 Number of subjects is limited to no more
than 80 patients per phase 1 trial.

 Phases 2 and 3 enroll larger numbers of
subjects, with the aim to test the
effectiveness of the product.

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 FDA is proposing regulating phase 1 material by
means other than CGMP regulations. How?

 1) By Federal Food Drug & Cosmetic Act that deems
a drug adulterated if its manufacturing does not
conform to CGMPs (statutory requirement).

 2) By investigational new drug (IND) submissions of
sponsors, which include a chemistry, manufacturing,
and controls (CMC) section.

 FDA states that it may place an IND on clinical hold
if study subjects are exposed to unreasonable and
significant risk, or if IND does not contain sufficient
information to assess risks to subjects.

 FDA states that it may also terminate an IND if it
discovers that the manufacturing of the
investigational material is inadequate.

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 Although unstated, FDA currently does not commonly
inspect during phase 1 studies unless for cause.

 FDA says that it believes the change is appropriate
because many issues presented by production of
investigational drugs intended for use in relatively
small phase 1 clinical trials are different from issues
presented by production of drug products for use in
larger Phase 2 and Phase 3 clinical trials or for
commercial marketing.

 FDA is considering additional guidance and
regulations to clarify agency’s expectations re: CGMP
requirements for phase 2 and 3 studies.

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 FDA adds many requirements in 21 CFR 211 do not
apply to limited production of investigational drugs
for phase 1; for example, fully validated
manufacturing processes, rotation of stock for drug
product containers, repackaging and relabeling of
drug products, and separate packaging and
production areas.

 This rule, if approved, would apply to investigational
biological products that are subject to CGMP
requirements, including recombinant and non-
recombinant therapeutic products, vaccine products,
allergenic products, in vivo diagnostics, plasma
derivative products, blood and blood products, gene
therapy products, and somatic cellular therapy
products (including xenotransplantation products).

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 So, Agency is proposing that production of an
investigational new drug for use in a phase 1 study
conducted under an IND when drug has not yet
been, or is not being, manufactured for use in phase
2 or 3 studies or for an already approved use, is not
subject to requirements in 21 CFR 211.

 Once an investigational drug product has already
been manufactured and is available for use in phase
2 or 3 studies or for an already approved use,
investigational drug product used in any subsequent
phase 1 study must comply with 21 CFR 211.

 “The action taken should be noncontroversial, and
the agency does not anticipate receiving any
significant adverse comment on this rule.”

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 Rule would affect drug manufacturers, chemical
manufacturers, and laboratories that manufacture
drugs on a small scale for use in phase 1 clinical
trials.

 The agency states that they believe that for drug
manufacturers that product Phase 1 material in
house and approved drug products, this rule will
reduce the amount of documentation they produce
and maintain when they manufacture a phase 1
drug. In some cases, it should also reduce the
amount of component and product testing.

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 FDA states that it lacks data to estimate the extent of
cost savings. Some examples where substantial
savings may be realized are the level of testing and
analyzing components and in-process materials.
These costs typically range from $50 to $1,200 per
component tested.

 The extent of the need for SOPs and methods
validation may also be greatly reduced. FDA
estimates that large drug manufacturers that produce
phase 1 drugs in-house could potentially save 24-40
hours per IND (or lead some large firms to product
phase 1 material in house, rather than contracting
the work out).

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 For chemical manufacturers and labs,
requirement may increase time required
for developing SOPs for quality,
process, and procedural controls. May
be in incremental increase in training
costs to educate employees on the
CGMPs. We estimate additional 12 to 24
hours may be required depending on
experience of firm and its employees on
CGMPs.

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 Agency notes that they do not keep a database of
facilities manufacturing phase 1 materials, so do not
have a number affected by rule.

 In 2003, FDA received 350 research and 500
commercial INDs. Not all affected by this rule, since
the majority are for drug products that already have
approvals. Since about 30% of INDs are for new
molecular entities each year, agency estimates that
the rule would affect about 255 INDs per year.

 Since companies produce multiple drug products for
phase 1 trials in given year, and use different
companies to produce them, FDA does not know how
many entities would be affected each year.

 Estimated patient impact: 255 INDs per year X 80
patients = 20,400 patients affected.

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 FDA estimates that 65% of entities
submitting NDAs and BLAs to FDA are small
entities. The Small Business Administration
defines biologic product manufacturers as
small if they employ fewer than 500 people,
and drug manufacturers as small if they
employ fewer than 750 people.

 FDA believes that all of the entities affected
by this rule have personnel with skills
necessary to comply with requirements.

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 Agency adds that does not know experience levels of
affected entities.

 Estimate savings to large manufacturers from
reduced SOP and validation requirements for phase 1
drug production in-house, assuming time savings of
32 hours per application, fully loaded wage rate of
$45 and 90 INDs per year (35% of 255) would be
$1,440 per IND.

 For chemical manufacturers and laboratories,
assuming all would incur costs and assuming average
of 18 hours per application for writing SOPs and
training, a fully loaded wage rate of $45, and 165
INDs (65% of 255) would be $810 per IND.

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Specifics
Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs,
Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 FDA states that they do not know the number
and size distribution of entities affected by
this rule, they believe the impact on them will
be negligible and should “actually reduce the
compliance burden for some.” “To clarify the
requirements for the manufacture of drugs
for phase 1 trials, we have prepared a draft
guidance document with recommendations
for compliance.”

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

Guidance
Source: INDs – Approaches to Complying with CGMP During Phase 1, Draft Guidance, U.S. Food and Drug
Administration, January 2006, http://www.fda.gov/cber/gdlns/indcgmp

 Draft guidance applies to investigational new human drug and
biological products (including finished dosage forms used as
placebos) intended for human use during phase 1 development.
Examples of investigational biological products covered by this
guidance include investigational recombinant and nonrecombinant
therapeutic products, vaccine products, allergenic products, in
vivo diagnostics, plasma derivative products, blood and blood
components, gene therapy products, and somatic cellular therapy
products (including xenotransplantation products) that are subject
to the CGMP requirements of 501(a)(2)(b) of the FD&C Act.

 The guidance applies to investigational products whether they are
produced in small- or large-scale environments because such
studies are typically designed to assess tolerability or feasibility for
further development of a specific drug or biological product.

 Guidance does not apply to human cell or tissue products; clinical
trials for products regulated as devices, or already approved
products that are being used during phase 1 studies (e.g.. for a
new indication).

http://www.fda.gov/cber/gdlns/indcgmp

Rationale
Source: FDA Press Release, FDA Issues Advice to Make Earliest Stages Of Clinical Drug Development More
Efficient, January 12, 2006, http://www.fda.gov/bbs/topics/news/2006/NEW01296.html

 In its draft guidance, “FDA outlines a
suggested approach to complying with
current good manufacturing practice (CGMP)
requirements for drugs intended for use
solely in phase 1 studies. With this new
guidance and an accompanying regulation,
FDA formally recognizes specific standards for
the manufacture of small amounts of drug
product for phase 1 studies and formulating
an approach to CGMP compliance that is
appropriate for the particular stage of drug
development.”

http://www.fda.gov/bbs/topics/news/2006/NEW01296.html

Guidance
Source: INDs – Approaches to Complying with CGMP During Phase 1, Draft Guidance, U.S. Food and Drug
Administration, January 2006, http://www.fda.gov/cber/gdlns/indcgmp

 The draft guidance describes FDA’s current thinking regarding
controls for special production situations (e.g., a laboratory
setting, exploratory studies, multi-product and multi-batch
testing) and specific product types (e.g.,
biological/biotechnology, aseptically processed products) of IND
products manufactured for use during phase 1 clinical trials as
described in the scope section of the guidance. As the new rule
will specify if finalized, the particular requirements in part 211
need not be met for most exploratory products manufactured
for use during phase 1 clinical trials.

 When finalized, this guidance will replace the 1991 “Guideline
on the Preparation of Investigational New Drug Products
(Human and Animal)” for the production of IND products for
phase 1 clinical trials described in the scope section of the
guidance. Phase 2 and 3 trials will continue to be subject to
those portions of parts 210 and 211 that are applicable.

http://www.fda.gov/cber/gdlns/indcgmp

Concerns re: Draft Guidance
Source: INDs – Approaches to Complying with CGMP During Phase 1, Draft Guidance, U.S. Food and Drug
Administration, January 2006, http://www.fda.gov/cber/gdlns/indcgmp

 Provides recommendations; not legally binding
 Would be used (per current proposals) to replace an existing

regulation for phase 1 material
 As currently written, appears insufficient to protect patients
 As currently written, appears insufficient to manufacture

material safely
 Does not harmonize with EU requirements that Qualified Person

release investigational material
 Assumption that sponsors or others would read or follow it (or

learn enough about CGMPs, aseptic processing, etc.) without a
regulation requiring them to do so

 Assumption that a reader would be able to review a 17-page
document and manufacture material safely per basic GMP
principles, particularly for biologic products, or aseptic/sterile
dosage forms

http://www.fda.gov/cber/gdlns/indcgmp

Concerns Re: Draft Guidance
Source: INDs – Approaches to Complying with CGMP During Phase 1, Draft Guidance, U.S. Food and Drug
Administration, January 2006, http://www.fda.gov/cber/gdlns/indcgmp

 Allows non QC unit (non QA) personnel to release product; allows same

individual who performed production to also release or reject batch
 Insufficient facilities, equipment, and environmental controls for aseptic,

sterile or biological products (particularly injectable or inhaled products.)
Allows GMP work and research to be done in same area; recommends that
equipment used for sterilization be qualified

 Insufficient training requirements (very difficult to train or learn aseptic
technique, even for experienced laboratory employees)

 Appears to allow reduced testing (for example, strongly recommends
performing confirmatory ID testing for APIs)

 Does not require approval of proposed changes (but record and give
rationale)

 Does not appear to require method validation (recommends tests be done
under controlled conditions, follow written SOPs)

 Recommends the use of aseptic techniques to prevent microbial and
endotoxin contamination if you are manufacturing aseptically

 Recommends that testing of biological/biotechnological products for safety-
related purposes such as viral loads, bioburden, detoxification of bacterial
toxins, viral clearance or inactivation, and clearance of antibiotics be done

http://www.fda.gov/cber/gdlns/indcgmp

Concerns Re: Draft Guidance
Source: INDs – Approaches to Complying with CGMP During Phase 1, Draft Guidance, U.S. Food and Drug
Administration, January 2006, http://www.fda.gov/cber/gdlns/indcgmp

 Does not yet appear to discuss or limit movement from animal colony to
human production area

 Does not yet discuss routine, periodic auditing (one of most important
quality systems) and require careful selection of contractors

 Does not seem to acknowledge the skills and experience needed of
primary QA individual

 Recommends keeping a record (such as a log book) containing relevant
information concerning all components; recommends establishing
acceptance criteria for specified attributes of each component.

 Recommends that lab testing of the investigational product be performed
as appropriate to evaluate identity, strength, potency, purity, and quality
attributes.

 Recommends that for known safety-related concerns, specifications should
be established and met.

 Does not seem to acknowledge the years of hard work and effort in getting
R&D groups, new companies, universities to comply (or that organizations
with “shared space” usually have conflicting priorities, difficulty following
requirements)

http://www.fda.gov/cber/gdlns/indcgmp

Exploratory Studies Guidance
Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl

 This guidance clarifies what preclinical and clinical issues
(including chemistry, manufacturing, and controls issues)
should be considered when planning exploratory studies.
Once finalized, it will represent FDA’s thinking on this topic.

 The phrase exploratory IND study is intended to describe a
clinical trial that is conducted early in phase 1, involves
very limited human exposure, and has no therapeutic or
diagnostic intent (such as screening studies, microdose
studies).

 Such exploratory IND studies are conducted prior to the
traditional dose escalation, safety, and tolerance studies
that ordinarily initiate a clinical drug development program.
The duration of dosing in an exploratory IND study is
expected to be limited (e.g., 7 days).

http://www.fda.gov/cder/guidance/7086fnl

Exploratory Studies Guidance
Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl

 “Existing regulations allow a great deal of flexibility in
terms of the amount of data that need to be submitted
with any IND application, depending on the goals of the
proposed investigation, the specific human testing
proposed, and the expected risks. The Agency believes that
sponsors have not taken full advantage of that flexibility.
As a result, limited, early phase 1 studies, such as those
described in this guidance, are often supported by a more
extensive preclinical database than is required by the
regulations.”

 “Because exploratory IND studies present fewer potential
risks than do traditional phase 1 studies that look for dose-
limiting toxicities, such limited exploratory IND
investigations in humans can be initiated with less, or
different, preclinical support than is required for traditional
IND studies.”

http://www.fda.gov/cder/guidance/7086fnl

Concerns re: Guidance
Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl

 “It is expected that all preclinical safety studies supporting the safety of
an exploratory IND application will be performed in a manner
consistent with good laboratory practices (GLPs)… GLP provisions apply
to a broad variety of studies, test articles, and test systems. Sponsors
are encouraged to discuss any need for an exemption from GLP
provisions with the FDA prior to conducting safety related studies, for
example, during a pre-IND meeting. Sponsors must justify any
nonconformance with GLP provisions (21 CFR 312.23 (a)(8)(iii).”

 “The common theme throughout this guidance is that, depending on
the study, the preclinical testing programs for exploratory IND studies
can be less extensive than for traditional IND studies. This is because
the approaches discussed in this guidance, which involve administering
sub-pharmacologic doses of a candidate product or products, the
potential risks to human subjects are less than for a traditional phase 1
study.”

 “This guidance describes some exploratory approaches…that will
enable sponsors to move ahead more efficiently with the development
of promising candidate products while maintaining needed human
subject protections.”

http://www.fda.gov/cder/guidance/7086fnl

FDA Mission
Source: Food, Drug and Cosmetic Act (FD&C Act, Sec. 903, U.S.C. 393),
http://www.fda.gov/opacom/laws/fdcact/fdcact9.htm

 (a) IN GENERAL. – There is established in the
Department of Health and Human Services the Food
and Drug Administration (hereinafter in this Section
referred to as the “Administration”).

 (b) MISSION. – The Administration shall –
 (1) promote the public health by promptly and

efficiently reviewing clinical research and taking
appropriate action on the marketing of regulated
products in a timely manner

 (2) with respect to such products, protect the public
health by ensuring that –

 (A) foods are safe, wholesome, sanitary, and
properly labeled;

 (B) human and veterinary drugs are safe and
effective;

http://www.fda.gov/opacom/laws/fdcact/fdcact9.htm

FDA Mission
Source: Food, Drug and Cosmetic Act (FD&C Act, Sec. 903, U.S.C. 393),
http://www.fda.gov/opacom/laws/fdcact/fdcact9.htm

 (C) there is reasonable assurance of the safety and
effectiveness of devices intended for human use;

 (D) cosmetics are safe and properly labeled; and
 (E) public health and safety are protected from

electronic product radiation;
 (3) participate through appropriate processes with

representatives of other countries to reduce the burden
of regulation, harmonize regulatory requirements, and
achieve appropriate reciprocal arrangements; and

 (4) as determined to be appropriate by the Secretary,
carry out paragraphs (1) through (3) in consultation
with experts in science, medicine, and public health, and
in cooperation with consumers, users, manufacturers,
importers, packers, distributors, and retailers of
regulated products.

http://www.fda.gov/opacom/laws/fdcact/fdcact9.htm

Tragedy and Response:
A Brief History of Regulation in the U.S.
Source: A Brief History of the GMPs: The Power of Storytelling, Immel Resources LLC, earlier
published as The BioPharm Guide to GMP History, by B. Immel, November 2002

 1902 Biologics Control Act
(diphtheria vaccine) (requires inspections and

testing of biologic products for purity and strength)

 1906 Pure Food and Drug Act
(Upton Sinclair’s The Jungle) (illegal to
manufacture/sell adulterated or misbranded
food or drug products; accurate labeling required)

 1938 Food, Drug, and Cosmetic Act
(sulfanilamide) (safety; authorized inspections)

 1962 Drug Amendments of 1962
(thalidomide) (efficacy; required drugs to be tested
in animals before people; informed consent, ADEs)

 1963 First GMPs published
 1978 Current GMPs published

 1980 Infant Formula Act
(sodium chloride)

 1982 Tamper-Resistant Packaging
(acetominophen)

 1983 “Guide to Inspection of Computerized
Systems”

 1987 “Guide to Inspection of Bulk Drug
Manufacture
(L-Tryptophan)

 1990 Safe Medical Devices Act
(heart valve)

 1990s on Updated, Revised Regulations

The Belmont Report
Ethical Principles and Guidelines for the Protection of Human Subjects of Research, April 18, 1979,
http://www.fda.gov/oc/ohrt/irbs/belmont.html

 Scientific research has produced substantial social benefits. It has also
posed some troubling ethical questions. Public attention was drawn to
these questions by reported abuses of human subjects in biomedical
experiments, especially during the Second World War. During the
Nuremberg War Crime Trials, the Nuremberg code was drafted as a set
of standards for judging physicians and scientists who had conducted
biomedical experiments on concentration camp prisoners. This code
became the prototype of many later codes intended to assure that
research involving human subjects would be carried out in an ethical
manner.

 Three basic principles, among those generally accepted in our cultural
tradition, are particularly relevant to the ethic of research involving
human subjects: the principles of respect for persons, beneficence, and
justice…

 Respect for persons incorporates at least two ethical convictions; first,
that individuals should be treated as autonomous agents, and second,
that persons with diminished autonomy are entitled to protection….
Two general rules have been formulated as complementary
expressions of beneficent actions in this sense: (1) do no harm and (2)
maximize possible benefits and minimize possible harms…

http://www.fda.gov/oc/ohrt/irbs/belmont.html

The Belmont Report
Ethical Principles and Guidelines for the Protection of Human Subjects of Research, April 18, 1979,
http://www.fda.gov/oc/ohrt/irbs/belmont.html

 An injustice occurs when some benefit to which a person is
entitled is denied without good reason or when some burden is
imposed unduly. Another way of conceiving the principle of
justice is that equals ought to be treated equally.

 For informed consent, “there (should be) no undisclosed risks to
subjects that are more than minimal….

 “In balancing these different elements, the risks and benefits
affecting the immediate research subject will normally carry
special weight. On the other hand, interests other than those of
the subject may on some occasions be sufficient by themselves
to justify the risks involved in the research, so long as the
subjects’ rights have been protected. Beneficence thus requires
that we protect against the risk of harm to subjects and also that
we be concerned about the loss of the substantial benefits that
might be gained from research.”

http://www.fda.gov/oc/ohrt/irbs/belmont.html

The Declaration of Helsinki
World Medical Associations, Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects, 1983 and
1989, http://www.fda.gov/oc/health/helsinki83.html and http://www.fda.gov/oc/health/helsinki89.html

 “Concern for the interests of the subject must always prevail
over the interests of science and society…

 “Physicians should abstain from engaging in research projects
involving human subjects unless they are satisfied that the
hazards involved are believed to be predictable….

 “In any research on human beings, each potential subject must
be adequately informed of the aims, methods, anticipated
benefits and potential hazards of the study and the discomfort it
may entail….

 “The potential benefits, hazards and discomfort of a new
method should be weighed against the advantages of the best
current diagnostic and therapeutic methods….

 “In research on man, the interest of science and society should
never take precedence over considerations related to the well-
being of the subject.”

http://www.fda.gov/oc/health/helsinki83.html

http://www.fda.gov/oc/health/helsinki89.html

Recent, pertinent events

 Patient deaths in phase 1 trials
 Johns Hopkins
 University of Pennsylvania

 Pharmacy compounding experience
 Medical device experience
 ©2006, Immel Resources LLC

Johns Hopkins
Sources: FDA Warning Letter, http://www.fda.gov/foi/warning_letters/g3936d , FDA Enforcement Story
2003, http://www.fda.gov/ora/about/enf_story/ch3/cder1.htm, Johns Hopkins Magazine, February 2002, Trials
& Tribulations, http://www.jhu.edu/~jhumag/0202web/trials.html, FDA Disqualified/Restricted/Assurances Lists
for Clinical Investigators, http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm

 Healthy volunteer Ellen Roche, 24 years old, died as
result of participating in a phase 1 safety trial in 2001

 Physician conducting trial, Dr. Alkis Togias, restricted
by FDA for 3 years

 FDA issued warning letter 21 months after Ellen’s
death, and offered restricted agreement

 Within five days of inhaling experimental compound,
Ellen was admitted to intensive care with respiratory
distress. She died within a month of lung failure.

 Dr. Togias had submitted an IND to FDA years earlier
(1997) to study capsaicin in lungs; FDA prohibited
him from initiating that study

http://www.fda.gov/foi/warning_letters/g3936d

http://www.fda.gov/ora/about/enf_story/ch3/cder1.htm

http://www.jhu.edu/~jhumag/0202web/trials.html

http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm

 Violations
 Did not submit IND application for use of

unapproved new drug
 Informed consent failed to disclose inhalation of

hexamethonium bromide experimental use of drug
 Informed consent failed to disclose material

chemical grade, labeled for laboratory use only,
with labeling stating: “Do not breathe dust; may
be harmful if inhaled”

 Consent form not updated to include unexpected
adverse events experienced by first two subjects
in trial (persistent cough/shortness of breath)

http://www.fda.gov/foi/warning_letters/g3936d

http://www.fda.gov/ora/about/enf_story/ch3/cder1.htm

http://www.jhu.edu/~jhumag/0202web/trials.html

http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm

University of Pennsylvania
Sources: U.S. Department of Justice Press Release, http://66.98.181.12/newsources/uofp /, FDA warning letters,
http://www.fda.gov/foi/warning_letters/m3897n , http://www.fda.gov/foi/warning_letters/m3435n , Washington Post, February
10, 2005, http://www.washingtonpost.com/wp-dyn/articles/A1213o6-2005Feb9.html and FDA Restricted List,
http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm, Online News Hour, Feb. 2, 2000,
http://www.pbs.org/newshour/bb/health/jan-june00/gene_therapy_2-2.html, and Dec. 8, 1999,
http://www.pbs.org/newshour/bb/health/july-dec99/gene_therapy.htm

 Jesse Gelsinger, an 18-year-old teenager, died in
1999 during a phase 1 gene therapy trial.

 Clinical investigators: James Wilson, Mark Batshaw,
and Steven Raper, have all been restricted, with
restrictions more severe for principal investigator

 Trial investigating use of genetically engineered
adenovirus to ameliorate an enzyme deficiency,
omithine transcarbamylase deficiency (OTCD)

 Some individuals are born with OTCD, which is a
deficiency in an essential enzyme needed to form
urea; coma and death can occur with OTCD

http://66.98.181.12/newsources/uofp /

http://www.fda.gov/foi/warning_letters/m3897n

http://www.fda.gov/foi/warning_letters/m3435n

http://www.washingtonpost.com/wp-dyn/articles/A1213o6-2005Feb9.html

http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm

http://www.pbs.org/newshour/bb/health/jan-june00/gene_therapy_2-2.html

http://www.pbs.org/newshour/bb/health/july-dec99/gene_therapy.htm

 Deaths in monkeys during preclinical testing
 Jesse’s disease was being well controlled by medication
 Jesse died within a few days of having compound infused into

his liver
 U.S. government prosecuted investigators and their

organizations, alleging:
 Trial produced toxicities in humans that should have resulted in its

termination, but study continued
 Reports misrepresented actual clinical findings submitted to FDA,

NIH, and IRBs
 Informed consent process did not disclose all anticipated toxicities
 Violations of Civil False Claims Act in submitting false statements to

FDA and IRBs
 Physicians contend conduct at all times lawful and appropriate
 Their employers paid fines of $517,496 and $514,622 to settle

the case

http://66.98.181.12/newsources/uofp /

http://www.fda.gov/foi/warning_letters/m3897n

http://www.fda.gov/foi/warning_letters/m3435n

http://www.washingtonpost.com/wp-dyn/articles/A1213o6-2005Feb9.html

http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm

http://www.pbs.org/newshour/bb/health/jan-june00/gene_therapy_2-2.html

http://www.pbs.org/newshour/bb/health/july-dec99/gene_therapy.htm

Pharmacy Compounding Experience
Sources: Pharmacy Compounding, FDA Consumer Magazine, July-August 2000,
http://www.fda.gov/fdac/features/2000/400_compound.html, FDA Compliance Policy Guide, Sec. 460.200, Pharmacy Compounding,
http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg460-200.html, FDAMA, http://www.fda.gov/cder/guidance/105-
115.htm#SEC.%20127, Steven Galson, Congressional Testimony, October 23, 2003,
http://www.fda.gov/ola/2003/pharmacycompound1023.html

 Pharmacy compounding law is part of 1997 Food,
Drug and Modernization Act (FDAMA)

 Limited to Rx requests; may not compound large
quantities of commercially available drugs

 List of acceptable ingredients, approved products,
monographs or USP drugs

 Serious problems: 3 infants died of intravenous
solution incorrectly prepared by pharmacy, 1 patient
blind in one eye due to pharmacy-prepared eye drops
that were not sterile

http://www.fda.gov/fdac/features/2000/400_compound.html

http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg460-200.html

http://www.fda.gov/cder/guidance/105-115.htm

http://www.fda.gov/ola/2003/pharmacycompound1023.html

Pharmacy Compounding Experience
Sources: FDA Enforcement Story 2003, http://www.fda.gov/ora/about/enf_story/ch3/cder1.htm#pc, FDA warning letters to Med-Mart
Pulmonary Services, September 30, 2002, http://www.fda.gov/foi/warning_letters/g3527d.htm, FDA warning letter to Carneys Drug,
May 27, 2003, http://www.fda.gov/foi/warning_letters/g4057d.htm, FDA press release, Nov. 15, 2002, Nationwide Alert on Injectable
Drugs Prepared by Urgent Care Pharmacy, http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01171.html, Steven Galson,
Congressional Testimony, October 23, 2003, http://www.fda.gov/ola/2003/pharmacycompound1023.html,

 Carneys Drug, Rochester, NH – Fentanyl lollipops (narcotic
analgesic) without required labeling (safety hazard for children)

 Urgent Care Pharmacy, Spartanburg, SC – contaminated
methylprednisolone acetate injection – rare fungal (wangiella)
meningitis, six patients affected, one died

 Med-Mart Pulmonary Services, Novato and Bakersfield, CA –
Class I recalls of albuterol inhaler due to Serratia liquefaciens

 Since 1990, FDA has found at least 55 quality problems with
compounded products

 In 2001, FDA survey of 29 programs (including hormonal
products, antibiotics, anesthetics, steroids, sterile injectables,
ophthalmics, and asthma medications) found 34% of tested
products failed one or more tests. Many were subpotent (59%
– 89% of labeled strength)

 In some operations, large quantities are being made in
advance of receiving prescription, copying approved
commercial drug, subpotent/superpotent issues

http://www.fda.gov/ora/about/enf_story/ch3/cder1.htm

http://www.fda.gov/foi/warning_letters/g3527d.htm

http://www.fda.gov/foi/warning_letters/g4057d.htm

http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01171.html

http://www.fda.gov/ola/2003/pharmacycompound1023.html

Medical Device Experience
Source: Immel Report, “Downregulating the FDA – Part I, Inspections,” September-October 2005 Issue, Medical
Devices Current Good Manufacturing Practice, http://www.fda.gov/cdrh/fr1007ap

 Deadly class I recalls have increased more than
300% since 1998

 Greatest number of warning letters from FDA are
being issued to medical device firms, with a large
number to sponsors, clinical investigators and IRBs

 For investigational devices, only part of CGMP
(Quality System Regulation) which must be followed
is Design Controls

 Question: Could there be a link between not
following CGMPs for investigational devices, hasty or
rushed clinical or product development, and the
deadly recalls, warning letters, and compliance
problems?

http://www.fda.gov/cdrh/fr1007ap

Why Logic May Be Flawed
 Patient safety concerns. If material is going into humans, it should be

made under a minimum, CGMP regulation.
 Phase 1 is foundation of trial
 Guidance is not legally binding, nor easily enforceable
 Question: Does agency yet have enough experience with phase 1 or

earlier (medical research, etc.) situations to be making proposal?
What data do FDA have that supports this proposal? (ADEs in phase 1
and their root causes, common inspectional findings during phase 1
or treatment IND inspections, survey or analysis of phase 1
operations, etc.)

 Assumption that individuals will learn aseptic technique, CGMPs,
without regulation requiring them to

 Assumption that individuals will be able to learn enough about GMP or
especially aseptic processing to produce clinical material safely by
reading a guidance document

 Guidance is currently 17 pages long; aseptic or sterile products very
difficult to make

 While Immel Resources is not concerned about pioneer firms, we are
very concerned about firms or medical research institutions which
have never made clinical materials before.

Why Logic May Be Flawed
 Assumption that will speed products to market (our experience tells us

that it may delay products to market: if not reproducible or sufficiently
documented, or if patients injured. Phase 2 is typically “big push” in
small companies in implementing all CGMP systems.)

 FDA has detailed regulation (21 CFR 58, Good Laboratory Practices) for
preclinical or animal testing, also is still requiring GMPs for phase II and
III – why drop protection during phase I?

 Question: Are members of the agency seeking to indemnify companies,
physicians, or medical researchers from accountability in phase I?

 Are human beings who volunteer for phase 1 clinical trials less valuable
than animals? Are patients in phase 1 trials less valuable than patients in
phase 2 or phase 3 trials? Are human beings who volunteer for phase 1
trials expendable since there are fewer of them?

 It costs nothing for agency to keep CGMP regulations on books
 Question: Is the agency throwing in the towel? Recognizing that they do

not have the staff to enforce or routinely inspect in human clinical trials?
 APIs currently regulated off FD&C Act statutory authority, but ICH Q7A

for APIs contains 57 detailed pages.

Why Logic May Be Flawed
 Question: Is this a flawed use of risk management concept? Are the

numbers involved more important than the species involved?
 Estimated savings are minimal ($1,440 per IND – same cost to send

1 person to an industry two-day seminar) for risks involved
 Estimated additional cost of $810 per IND for chemical producers and

laboratories who have not yet made product does not yet appear to
address costs involved in facility, equipment, or contracting work out,
particularly for aseptic/sterile products (unless that is a given)

 Question: Is Agency becoming more of a research-enabling or
product marketing agency rather than a consumer protection agency?

 Does agency want to write many warning letters for violative firms or
organizations? Or issue restricted agreements to clinical investigators
or take them to court if there are more patient deaths in phase 1?

 Agency’s mission: where two standards apply, stricter should prevail.
 History has shown that paper reviews do not work (it’s why FDA was

granted inspectional authority), and that not performing necessary
testing can be deadly (sulfanilamide, etc.)

Why Logic May Be Flawed
 Has Agency yet done a root cause analysis of what is causing dramatic

increase in medical device deadly class I recalls, and increased number
of warning letters? Why emulate device sector without understanding
why there are compliance issues?

 Does not acknowledge the confusion that is already resulting in some
individuals thinking that they may use non-GMP material in phase 1

 Informed consent will need to change to inform patients of change in
standard, increased risk to patients

 Ethical considerations: Per Belmont Report, Declaration of Helsinki –
individual patient’s rights outweigh all other rights, and patients should
be treated equally

 So what? Why should we care about this? Because all of us know (or
will know) someone or a family member who will consider participating
in clinical trial.

 From a QA perspective, cannot allow harm to come to patient if know it
can be prevented. Protecting the patient is number one.

Questions
 Are CGMP requirements in phase 1 truly the

impediment to scientific exploration or
innovation?

 Are CGMPs truly that burdensome?
 Why does this new rule apply to phase 1 and

not phases 2 and 3?
 Is the agency just seeking to deregulate

something (anything) where it may affect the
fewest people?

 Will “GMP Lite” really improve drug
development?

Recommendations

 I hope that the agency will consider withdrawing the direct final

rule, and keeping phase 1 material for humans under the
protection of the CGMP regulation.

 One option would be issuing proposed GMPs for investigational
drugs as FDA had originally considered. If so, the draft guidance
could be used as a start to those proposed GMPs.

 Another option is that the draft guidance could be finalized and
replace the earlier 1991 guidance as planned, but with no
exemption of phase 1 material from CGMP regulation.

 A third option would be proposing and taking the phase 1
guidance through the ICH process.

 Your opinion may differ. My hope is that individuals and
organizations with experience manufacturing clinical and
commercial product will take the time to think about and send in
any written comments that they may have to the agency.

What You Can Do
 Read FDA proposals and draft guidance, discuss them with your

staff, and send any written comments your organization has, if
you choose to do so, to FDA by the comment due dates.

 When submitting comments, please be specific.
 If you are commenting on the proposed or direct final rule,

state if you are for or against the rule, and why.
 Use reasoning, logic, and good science.
 Attach any references.
 Include the docket number.
 Ensure all comments are relevant.
 State why the rule is inappropriate.
 Provide a challenge to the rule’s underlying premise or state

why the rule is ineffective or unacceptable.
 Issues should be serious enough to warrant a substantive

response from the agency, and should sufficiently challenge the
agency’s view that the rule is needed.

What You Can Do
 To comment on the draft guidance, Docket 2005D-

0286, send your comments by March 20, 2006.
 You may send them electronically to:

http://www.accessdata.fda.gov/scripts/oc/dockets/co
mments/SEARCHRESULTS.CFM

 Or send two copies of your written comments to:
 Docket No. 2005D-0286

Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

http://www.accessdata.fda.gov/scripts/oc/dockets/comments/SEARCHRESULTS.CFM

What You Can Do
 To comment on the proposed or direct final rule

to exempt phase 1 material from CGMP regulation
(these rules are identical; any comments received will
be applied to both) or Docket 2005N-0285, send your
comments by April 3, 2006.

 You may send them electronically to:
http://www.accessdata.fda.gov/scripts/oc/dockets/co
mments/SEARCHRESULTS.CFM

 Or send two copies of your written comments to:
 Docket 2005N-0285

Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

http://www.accessdata.fda.gov/scripts/oc/dockets/comments/SEARCHRESULTS.CFM

Recommended Reading
 Direct Final Rule, Current Good Manufacturing Practice

Regulation and Investigational New Drugs,
http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

 Proposed Rule, Current Good Manufacturing Practice Regulation
and Investigational New Drugs,
http://www.fda.gov/ohrms/dockets/98fr/06-350.htm

 INDs – Approaches to Complying with CGMP During Phase 1
Draft Guidance, January 2006,
http://www.fda.gov/ohrms/dockets/98fr/05d-0286-gdl0001

 Exploratory IND Studies Guidance, January 2006,
http://www.fda.gov/cder/guidance/7086fnl

http://www.fda.gov/ohrms/dockets/98fr/06-353.htm

http://www.fda.gov/ohrms/dockets/98fr/06-350.htm

http://www.fda.gov/ohrms/dockets/98fr/05d-0286-gdl0001

http://www.fda.gov/cder/guidance/7086fnl

Review
 What FDA is proposing

 Proposed rule and direct final rule
 Draft guidance to replace CGMP regulation

 FDA’s mission and history
 Recent events

 Patient deaths in phase 1 trials
 Pharmacy compounding experience
 Medical device experience

 Draft guidance
 Why logic may be flawed
 What your organization can do
 Questions and answers
 ©2006, Immel Resources LLC

Thank You

 Thank you all for participating
 Charlie Gammill, University of Georgia

GMP Conference
 To all of my clients and subscribers,

mentors, friends, and current and
former members of the agency who
have helped me to formulate my
thoughts on this subject

About Us
 Barbara Immel is president of Immel Resources LLC, where she helps

pharmaceutical, biopharmaceutical, and medical device companies
improve their quality systems and compliance track records. Since 1996,
Immel Resources LLC has worked with more than 100 firms.

 Barbara is currently editor of the Immel Report newsletter, which
provides advice and guidance for managers in FDA-regulated industry.
She is also a member of BioPharm Magazine’s Editorial Advisory Board,
and served as their GMP columnist for 10 years. Before starting her
company, Barbara gained more than 12 years of hands-on experience in
quality assurance and regulatory compliance at Syva Co., Chiron Corp.,
and Syntex Corp. She is the author of the Quality Assurance chapter of
Dekker’s Encyclopedia of Pharmaceutical Technology. She has taught at
UC Berkeley, Stanford University, and the University of Wisconsin at
Madison.

 Please keep us in mind as you need assistance with quality assurance,
regulatory compliance, or training projects. And please contact us with
any comments on this presentation. Thank you very much.

 Phone: (707) 778-7222 Email: immel@immel.com

mailto:immel@immel.com

Chipping Away at the GMPs:�Understanding FDA’s Proposal to Exempt Material for Phase 1 Clinical Trials from CGMP Regulations, and new Draft Guidance
Overview
Disclaimer
What FDA is Proposing�Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm, Proposed Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, http://www.fda.gov/ohrms/dockets/98fr/06-350.htm
What FDA is Proposing�Source: Draft Guidance for Industry on Investigational New Drugs; Approaches to Complying with Current Good Manufacturing Practice During Phase 1; Availability, http://www.fda.gov/ohrms/dockets/98fr/06-352.htm, and INDs – Approaches to Complying with CGMP During Phase 1 Draft Guidance, January 2006, http://www.fda.gov/ohrms/dockets/98fr/05d-0286-gdl0001 �
FDA’s Phase 1 Proposals
Significant Adverse Comment�Source: Guidance for FDA and Industry, Direct Final Rule Procedures, Nov. 21, 1997, http://www.fda.gov/cber/gdlns/drctfnlrl �
Rationale�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Rationale�Source: FDA Press Release, FDA Issues Advice to Make Earliest Stages Of Clinical Drug Development More Efficient, January 12, 2006, http://www.fda.gov/bbs/topics/news/2006/NEW01296.html�
Rationale�Source: FDA Press Release, FDA Issues Advice to Make Earliest Stages Of Clinical Drug Development More Efficient, January 12, 2006, http://www.fda.gov/bbs/topics/news/2006/NEW01296.html�
Rationale�Source: FDA Press Release, FDA Issues Advice to Make Earliest Stages Of Clinical Drug Development More Efficient, January 12, 2006, http://www.fda.gov/bbs/topics/news/2006/NEW01296.html�
Proposed Change�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Background�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Specifics�Source: Direct Final Rule, Current Good Manufacturing Practice Regulation and Investigational New Drugs, �Direct Final Rule: http://www.fda.gov/ohrms/dockets/98fr/06-353.htm
Guidance�Source: INDs – Approaches to Complying with CGMP During Phase 1, Draft Guidance, U.S. Food and Drug Administration, January 2006, http://www.fda.gov/cber/gdlns/indcgmp �
Rationale�Source: FDA Press Release, FDA Issues Advice to Make Earliest Stages Of Clinical Drug Development More Efficient, January 12, 2006, http://www.fda.gov/bbs/topics/news/2006/NEW01296.html
Guidance�Source: INDs – Approaches to Complying with CGMP During Phase 1, Draft Guidance, U.S. Food and Drug Administration, January 2006, http://www.fda.gov/cber/gdlns/indcgmp �
Concerns re: Draft Guidance�Source: INDs – Approaches to Complying with CGMP During Phase 1, Draft Guidance, U.S. Food and Drug Administration, January 2006, http://www.fda.gov/cber/gdlns/indcgmp �
Concerns Re: Draft Guidance�Source: INDs – Approaches to Complying with CGMP During Phase 1, Draft Guidance, U.S. Food and Drug Administration, January 2006, http://www.fda.gov/cber/gdlns/indcgmp �
Concerns Re: Draft Guidance�Source: INDs – Approaches to Complying with CGMP During Phase 1, Draft Guidance, U.S. Food and Drug Administration, January 2006, http://www.fda.gov/cber/gdlns/indcgmp �
Exploratory Studies Guidance�Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl �
Exploratory Studies Guidance�Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl �
Concerns re: Guidance�Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl �
FDA Mission�Source: Food, Drug and Cosmetic Act (FD&C Act, Sec. 903, U.S.C. 393), http://www.fda.gov/opacom/laws/fdcact/fdcact9.htm
FDA Mission�Source: Food, Drug and Cosmetic Act (FD&C Act, Sec. 903, U.S.C. 393), http://www.fda.gov/opacom/laws/fdcact/fdcact9.htm
Tragedy and Response:�A Brief History of Regulation in the U.S.�Source: A Brief History of the GMPs: The Power of Storytelling, Immel Resources LLC, earlier published as The BioPharm Guide to GMP History, by B. Immel, November 2002
Tragedy and Response:�A Brief History of Regulation in the U.S.�Source: A Brief History of the GMPs: The Power of Storytelling, Immel Resources LLC, earlier published as The BioPharm Guide to GMP History, by B. Immel, November 2002
The Belmont Report�Ethical Principles and Guidelines for the Protection of Human Subjects of Research, April 18, 1979, �http://www.fda.gov/oc/ohrt/irbs/belmont.html�
The Belmont Report�Ethical Principles and Guidelines for the Protection of Human Subjects of Research, April 18, 1979, �http://www.fda.gov/oc/ohrt/irbs/belmont.html�
The Declaration of Helsinki�World Medical Associations, Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects, 1983 and 1989, http://www.fda.gov/oc/health/helsinki83.html and http://www.fda.gov/oc/health/helsinki89.html�
Recent, pertinent events
Johns Hopkins�Sources: FDA Warning Letter, http://www.fda.gov/foi/warning_letters/g3936d , FDA Enforcement Story 2003, http://www.fda.gov/ora/about/enf_story/ch3/cder1.htm, Johns Hopkins Magazine, February 2002, Trials & Tribulations, http://www.jhu.edu/~jhumag/0202web/trials.html, FDA Disqualified/Restricted/Assurances Lists for Clinical Investigators, http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm
Johns Hopkins�Sources: FDA Warning Letter, http://www.fda.gov/foi/warning_letters/g3936d , FDA Enforcement Story 2003, http://www.fda.gov/ora/about/enf_story/ch3/cder1.htm, Johns Hopkins Magazine, February 2002, Trials & Tribulations, http://www.jhu.edu/~jhumag/0202web/trials.html, FDA Disqualified/Restricted/Assurances Lists for Clinical Investigators, http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm
University of Pennsylvania�Sources: U.S. Department of Justice Press Release, http://66.98.181.12/newsources/uofp /, FDA warning letters, http://www.fda.gov/foi/warning_letters/m3897n , http://www.fda.gov/foi/warning_letters/m3435n , Washington Post, February 10, 2005, http://www.washingtonpost.com/wp-dyn/articles/A1213o6-2005Feb9.html and FDA Restricted List, http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm, Online News Hour, Feb. 2, 2000, http://www.pbs.org/newshour/bb/health/jan-june00/gene_therapy_2-2.html, and Dec. 8, 1999, http://www.pbs.org/newshour/bb/health/july-dec99/gene_therapy.htm
University of Pennsylvania�Sources: U.S. Department of Justice Press Release, http://66.98.181.12/newsources/uofp /, FDA warning letters, http://www.fda.gov/foi/warning_letters/m3897n , http://www.fda.gov/foi/warning_letters/m3435n , Washington Post, February 10, 2005, http://www.washingtonpost.com/wp-dyn/articles/A1213o6-2005Feb9.html and FDA Restricted List, http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm, Online News Hour, Feb. 2, 2000, http://www.pbs.org/newshour/bb/health/jan-june00/gene_therapy_2-2.html, and Dec. 8, 1999, http://www.pbs.org/newshour/bb/health/july-dec99/gene_therapy.htm
Pharmacy Compounding Experience�Sources: Pharmacy Compounding, FDA Consumer Magazine, July-August 2000, http://www.fda.gov/fdac/features/2000/400_compound.html, FDA Compliance Policy Guide, Sec. 460.200, Pharmacy Compounding, http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg460-200.html, FDAMA, http://www.fda.gov/cder/guidance/105-115.htm#SEC.%20127, Steven Galson, Congressional Testimony, October 23, 2003, http://www.fda.gov/ola/2003/pharmacycompound1023.html
Pharmacy Compounding Experience�Sources: FDA Enforcement Story 2003, http://www.fda.gov/ora/about/enf_story/ch3/cder1.htm#pc, FDA warning letters to Med-Mart Pulmonary Services, September 30, 2002, http://www.fda.gov/foi/warning_letters/g3527d.htm, FDA warning letter to Carneys Drug, May 27, 2003, http://www.fda.gov/foi/warning_letters/g4057d.htm, FDA press release, Nov. 15, 2002, Nationwide Alert on Injectable Drugs Prepared by Urgent Care Pharmacy, http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01171.html, Steven Galson, Congressional Testimony, October 23, 2003, http://www.fda.gov/ola/2003/pharmacycompound1023.html,
Medical Device Experience�Source: Immel Report, “Downregulating the FDA – Part I, Inspections,” September-October 2005 Issue, Medical Devices Current Good Manufacturing Practice, http://www.fda.gov/cdrh/fr1007ap �
Why Logic May Be Flawed
Why Logic May Be Flawed
Why Logic May Be Flawed
Why Logic May Be Flawed
Questions
Recommendations
What You Can Do
What You Can Do
What You Can Do
Recommended Reading
Review
Thank You
About Us

__MACOSX/essay material/._Chipping-Away_immel

essay material/con_immel

April 3, 2006

Docket 2005N-0285
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

Re: FDA’s direct final rule/proposed rule to exempt phase 1 investigational drugs and
biologics from the current, good manufacturing practice (CGMP) regulation

Dear Members of the U.S. Food and Drug Administration,

Thank you for the opportunity to comment on the agency’s direct final rule/proposed rule
to exempt phase 1 investigational drugs and biologics from the CGMP regulation. I am opposed
to this rule, and believe that a guidance document, which is not legally binding, should not be
used to replace an existing regulation that provides the minimum requirements for the safe
manufacture of drugs or biologics for human beings. I believe that this rule may place patients in
phase 1 in jeopardy.

Puts patients at risk, and is not legally binding

Guidance documents are not legally binding, and no one is required to follow them. They also
cannot be enforced. Drugs or biologics made for use in human beings should be made per
CGMP regulation, which provides the minimum, legal requirements to make them safely. In
addition to putting patients at risk, this approach will make it very difficult to investigate or
prosecute serious cases, and to prove what “current good manufacturing practice” is. This
approach assumes that new sponsors would keep proper records, perform necessary testing, or
keep retention samples for later investigations, or that they would take the time to learn and
follow CGMP if there were no regulation requiring them to do so (why would they incriminate
themselves?). FDA had always considered proposing CGMPs for investigational drugs (Preamble,
Final Rule, Current Good Manufacturing Practice in Manufacturing, Processing, Packing or
Holding, 1978). Comments received on the direct final rule/proposed rule and draft guidance may
be incorporated instead into a proposed rule on CGMPs for investigational drugs and biologics.

Unethical

In the proposed rule, FDA states that phase 1 material being made for the first time and for
which an Investigational New Drug application (IND) has been submitted to FDA may be made
using the guidance document (rather than the CGMP regulation), but if the material is already
available in phase 2 or 3 clinical trials, or commercially available, the phase 1 material would
have to be made per CGMP regulation. This would mean that some Phase 1 material would be
made per CGMP regulation, and some may not. Patients or healthy volunteers in phase 1 are
already shouldering the biggest burden of any participants because they are the first humans to
receive the compound. Of the patients who participate, many of them are chronically ill,
terminally ill, or immunocompromised. Introducing the possibility that the material they receive
may be contaminated or superpotent, and not manufactured per the same standard as material

Docket 2005N-0285
Page 2 of 7

used in other phase 1 trials, is unethical. This is a clear violation of the ethical principles
governing the conduct of human research. The Belmont Report states that “an injustice occurs
when some benefit to which a person is denied without good reason, or when some burden is
imposed unduly. Another way of conceiving the principle of justice is that equals ought to be
treated equally.” And the Declaration of Helsinki states that “in research on man, the interest of
science and society should never take precedence over considerations related to the well-being of
the subject.”

As you know, FDA has a detailed regulation governing preclinical (or animal) testing (21
CFR 58), which requires a Quality Assurance Unit. With this proposal, FDA is continuing to
require CGMP regulation be followed to manufacture material for phases 2 and 3. Questions: Are
patients and volunteers in phase 1 less valuable than an animal? Are patients in phase 1 less
valuable than patients in phases 2 and 3? Why drop the protection of the CGMP regulation in
phase 1?

Ignores recent experience

The history of regulation in the United States is a response to tragedies that have occurred, and an
attempt to prevent future tragedies from occurring. In the press release announcing the proposals,
Janet Woodcock, MD, FDA Deputy Commissioner for Operations, states “the problem is that
researchers conducting very early studies were required to follow the same manufacturing
procedures as those companies that mass produce products for broad scale distribution. These
requirements are so burdensome for early phase 1 studies that many leading medical research
institutions have not been able to conduct these studies of discoveries made in their laboratories.”

In the recent past, we have had two patient deaths in phase 1 trials conducted at leading
medical research institutions, Johns Hopkins and the University of Pennsylvania. In the Johns
Hopkins case, clinical material was made using an unapproved drug, chemical grade, labeled “do
not breathe dust… may be harmful if inhaled” yet it was administered by inhalation, resulting in
the death of a healthy patient. In the University of Pennsylvania case, an experimental gene
therapy compound shown to have caused the deaths of monkeys in preclinical testing was infused
into Jesse Gelsinger, an 18 year old boy. Jesse subsequently died.

And in March 2006, six formerly healthy young males, all under the age of 40, were
made seriously ill and suffered major organ failure, due to an experimental monoclonal antibody
they received by injection in a phase 1 clinical trial in England. As you know, the Hippocratic
Oath which physicians must follow states, ”Do no harm.”

Lacks common sense

In the recent past, there have also been both pharmacy compounding and medical device
experiences that are directly applicable to this discussion.

Pharmacy Compounding Experience. We have had several deadly recalls, three
infant deaths, one adult death, and blindness associated with drugs compounded by pharmacists.
If trained pharmacists are not always able to safely make these products, particularly sterile or
aseptic products, why would anyone assume that a medical researcher or other employee would
be able to make them safely by reading a 17-page guidance document?

The infant deaths were associated with intravenous solutions compounded by a pharmacy
which were not sterile. There have been several deadly, recent class I recalls due to drugs
compounded by pharmacists which have been contaminated, such as the methylprednisolone
injection contaminated with a rare fungus (wangiella) which caused meningitis in six patients and

Docket 2005N-0285
Page 3 of 7

the death of one. Other deadly recalls of pharmacy-compounded products have included an
albuterol inhaler for asthmatics that was contaminated with Serratia liquefaciens, which as you
know may cause respiratory infections, sepsis, or death. One patient was also recently blinded in
one eye due to using eyedrops prepared by a pharmacy that were not sterile.

Medical Device Experience. In the medical device industry, the number of deadly recalls
has increased more than 300% since 1998. The single largest group of FDA warning letters for
noncompliance are currently being issued to medical device firms, including a large percentage
going to sponsors, clinical investigators, and institutional review boards involved in device
human clinical trials. The only part of CGMP that must be followed when manufacturing
investigational devices is that portion of device CGMP concerning design controls (which
requires formal, documented reviews at the end of each design phase during product development,
having an uninterested party present and actively contributing during those reviews, etc.)

Questions: Has the agency yet done a root cause analysis to determine what is causing the
deadly product recalls, warning letters, and compliance problems in the device sector? Why
would the agency want to emulate this sector (in reducing CGMP requirements for investigational
drugs or biologics) without first understanding what is causing the problems in the device sector?

Violates U.S. and European Union CGMPs, and lacks understanding of QC unit role

The draft guidance published with the proposed rule allows the same person who manufactured
the material to release it to the clinic, and allows a non-QC unit employee to release material.
This is a clear violation of U.S. current good manufacturing practice, which requires that a
member of the Quality Control unit (QC unit) release product. It is also a clear violation of the
European Union CGMPs, which require that a Qualified Person (qualified by training and
experience) release investigational and commercial material. Even pharmacists learn that
that when compounding sterile or aseptic product, they must incorporate necessary checks and
balances.

This approach does not appear to recognize the importance of having an experienced
and knowledgeable QC unit (or person) to manufacture the materials safely. The agency is
undermining the QC unit, the one group inside organizations that is responsible for ensuring
patient safety and enforcing CGMP requirements. If a quality assurance unit is required for
animal testing, why would the agency propose that one is not needed to release investigational
material being used in human beings for the first time?

Off mission

The mission of the U.S. Food and Drug Administration, mandated by Congress in The
Food, Drug and Cosmetic Act (Sect. 903, U.S.C. 393) states that the Food and Drug
Administration shall “promote the public health by promptly and efficiently reviewing
clinical research and taking appropriate action on the marketing of regulated products in a
timely manner” and “with respect to such products, protect the public health by ensuring
that …human and veterinary drugs are safe and effective.” The direct final rule states that
the agency is making this proposal “to streamline and promote the drug development
process.” If my understanding is correct, this is outside the scope of the agency’s mission.
The FDA was established to serve as a consumer protection agency, and a check and a
balance on regulated industry. The Congressional mandate includes promptly and
efficiently reviewing clinical research and taking appropriate action on the marketing of
regulated products in a timely manner, not becoming a drug development organization.

Docket 2005N-0285
Page 4 of 7

Insufficient testing requirements

The guidance document issued with the proposed rule strongly recommends performing
confirmatory identity testing on active pharmaceutical ingredients, but it does not require it. This
is a violation of current, good manufacturing practice. As you recall, in the sulfanilamide tragedy
that occurred in the 1930s in the United States, diethylene glycol (the equivalent of antifreeze)
was used in manufacturing an “elixir” of sulfanilamide, without sufficient testing or controls, and
resulting in the death of more than 100 patients, many of them children. The guidance document
recommends but does not require that testing of biological/biotechnology products be done for
safety-related purposes such as viral loads, bioburden, detoxification of bacterial toxins, viral
clearance or inactivation, and clearance of antibiotics. The guidance document recommends but
does not require that laboratory testing of the investigational product be performed “as
appropriate to evaluate identity, strength, potency, purity, and quality attributes.” This is clearly
insufficient.

Insufficient aseptic or sterile information

The guidance, which if under the current proposal, would be used to replace the existing CGMP
regulation for the manufacture of some phase 1 materials, contains little more than one page on
manufacturing sterile or aseptic products, and makes no reference to media fills. Manufacturing
sterile or aseptic dosage forms requires a higher level of skill and judgment. The agency’s
guidance on Sterile Drug Products Produced by Aseptic Processing is very detailed and contains
63 pages. Even though the current CGMP regulation does not contain detailed information on
manufacturing sterile or aseptic product, it is illogical to assume that a drug manufacturer,
chemical manufacturer or (medical research) laboratory making clinical material for the first time
would be able to follow this guidance and make sterile or aseptic material safely. It is illogical to
assume that they would read or become familiar with other FDA guidance documents or take the
time to learn or follow CGMP without having to do so per a CGMP regulation.

Insufficient employee training requirements

The direct final rule states that even though the agency does not know how many entities would
be affected by the rule, that they believe that “all of the entities affected by this rule have
personnel with skills necessary to comply with requirements.” This is illogical. The amount of
training required for aseptic technique alone is substantial, and not yet well described in the
guidance.

Based on assumptions; no data provided

The FDA acknowledges that they do not know how many entities may be affected by this rule,
and that they do not keep a database of firms affected by this rule. Since FDA only performs
limited inspections of phase 1 material manufacturers (such as “for cause” or during treatment
INDs), what data do FDA have to support their position? What are the results of the agency’s “for
cause” inspections, treatment IND inspections, or adverse drug events reported during phase 1?
What do the data show? Does the agency have enough information to be making this proposal?
What data are FDA using to support their position?

Proponents of this approach state that ICH Q7A, Good Manufacturing Practice for Active
Pharmaceutical Ingredients, an internationally harmonized guidance, has been successfully used

Docket 2005N-0285
Page 5 of 7

without the need for a regulation. ICH Q7A also has 57 detailed pages, and is used to
manufacture material that will be further processed before being delivered to patients. The draft
phase 1 guidance is currently 17 pages long and provides recommendations for drugs and
biologics that may be delivered by injection or inhalation, resulting in patient injury or death if
the material is improperly prepared or contaminated. FDA also at least inspects API
manufacturers, although again, the agency does not routinely inspect in phase 1 unless for cause
(or in certain specified circumstances, such as for Treatment INDs).

Too risky for estimated benefits

The proposed savings of $1,440 per IND in documentation, training, and other “reduced”
requirements (or the equivalent of paying tuition to send one person to an industry two-day
seminar) is not justified by the additional risk to patients in phase 1. In addition, the potential
costs (estimated at an additional $810 per IND for chemical manufacturers and laboratories which
have never made these materials before) is a gross underestimation of how much it will cost to
manufacture sterile or aseptic product for the first time. The draft guidance does not yet discuss
required equipment or facilities for these types of products, such as biosafety cabinets, isolators
and other equipment. Nor does it limit movement from an animal colony to the human
manufacturing environment (which is required in the European Union CGMPs; not limiting this
movement has caused contamination in facilities manufacturing material for humans.)
As far as how many people may be affected by the proposed rule each year, using the
agency’s estimate of 255 INDs per year, and estimating up to 80 patients per trial, would mean
that approximately 20,400 patients and volunteers would be affected. This is a substantial number
of people who would be exposed to more risk.

Confusing

When the agency takes an existing regulation, and attempts to negate portions of the regulation
using guidance documents, or issuing a rule that affects part of the rule (but not all), the agency
causes a great deal of confusion in industry. I have already received one email message from a
regulatory affairs executive who stated that from now on, when they plan to use non-GMP
material in a phase 1 trial, they will provide more data for FDA in their chemistry, manufacturing
and controls (CMC) section of the IND.

Surprising

Even though the agency has the authority to issue a direct final rule, it is surprising that the
agency would choose to handle any rule concerning current good manufacturing practice in this
way – in which “significant adverse comment” would be required to prevent the rule from
becoming final. It is also surprising that some members of the agency believed that “the action
taken should be noncontroversial, and the agency does not anticipate receiving any significant
adverse comments on this rule,” as stated in the direct final rule.

Illogical

The agency states in the direct final rule that they would regulate phase 1 material by means other
than the CGMP regulation, namely by using the Federal Food, Drug, and Cosmetic Act (FD&C
Act, which states that all drugs must be made per CGMPs or they are adulterated, but does not

Docket 2005N-0285
Page 6 of 7

give specifics) and the information submitted by sponsors in an IND. The agency states that it can
place an IND on clinical hold if study subjects are exposed to unreasonable and significant risk,
or if the IND does not contain sufficient information to assess risks to patients. FDA also states in
the direct final rule that it may terminate an IND if it discovers that the manufacturing of the
investigational material is inadequate. Obviously, however, many of these actions may be after
the fact, and well after patients have been injured in the trial.

The agency was given inspectional authority for a reason, and that is because paper
reviews are insufficient. Questions: Is the agency throwing in the towel? (since the agency lacks
the resources to routinely perform inspections during clinical trials?) Are some members of the
agency seeking to indemnify medical researchers from accountability for their actions? Does the
agency want to issue warning letters to institutions that do not meet basic CGMPs, or send
restricted agreements to clinical investigators for failure to comply with existing regulations, after
patients are injured? Is someone in the agency attempting to make CGMP regulation the
scapegoat for the slowdown in new molecular entities? Common sense dictates that you drive
quality as early as possible into the process, not reduce the basic quality required up front.

May delay products to market

Proponents of this proposal believe that it will speed products to market. In our experience, it may
delay products to market. Phase 1 material is the foundation of the trials, and would be used to
prove the safety of the compound in humans. For sterile or aseptic drugs or biologics, you must
validate any sterilization or aseptic process used before manufacturing phase 1 clinical material,
and for biologic products, must also ensure the necessary viral inactivation or clearance,
detoxification of bacterial toxins, and so on.

If phase 1 material is not reproducible, not well-documented, or not well-controlled, the
results of the trial will be meaningless. Typically phase 2 is the “big push” inside a small start-up,
working to get its first product on the market. Why? Not only because of the criticality of the trial
results, but also because the organization is working very hard to get all of their GMP systems in
place, such that the material that they manufacture for the phase 3 and largest trials is
bioequivalent to the material that they would be making for commercial production. If for any
reason, an organization were to interpret the agency’s current proposal as loosening the basic
requirements needed for phase 1, it could jeopardize not only patients and the results of the trial
but also any later stage trials.

Obviously if the material injures patients, it will delay the further development of the
compound, and rightfully so. If more patients are seriously injured or die in phase 1 studies, or if
patients or volunteers feel that pharmaceutical companies and medical researchers are not looking
after their self interests, who then will volunteer to participate in clinical trials?

Conclusion

Is it possible for our society to learn from the mistakes of the past? Or are we doomed to repeat
them? The CGMP regulation was established in 1963 in response to the thalidomide tragedy, in
which an estimated 10,000 babies were born deformed due to a compound (that turned out to be
teratogenic) that was prescribed to pregnant women for the treatment of morning sickness or
insomnia. The CGMPs were substantially revised in 1978, in the wake of the large volume
parenteral tragedies in the 1970s, in which patients died of sepsis due to improperly prepared,
sterile injectable products. In the preamble to the 1978 regulation, the FDA Commissioner made

Docket 2005N-0285
Page 7 of 7

clear that the CGMP regulation applied to both clinical and commercial material, and that the
agency was considering publishing CGMPs for investigational materials.

In the aftermath of the death of the formerly healthy 24 year old Ellen Roche, as a direct
result of her participating in the flawed phase 1 trial at Johns Hopkins, Edward Miller, CEO of
Johns Hopkins Medicine, stated in Johns Hopkins Magazine that:

“There has got to be a cultural change here…. We’re going to have to raise the bar
higher. There can’t be any slippage. None….

“In some ways, I’d say there’s an antibody response by our faculty to following those
rules and regulations, because it’s thought to stifle creativity….

“There has to be some consequence of non-compliance. There will be some people who
always believe that they are above the rules. The institution cannot take the risk of having
one [person] bring the institution down.”

The key, says Miller, lies in having everyone at the institution embrace the idea that
federal regulations are in place for good reason: patient safety. “If we only call it
compliance, we’re not going to get anywhere,” Miller says. There’s got to be a buy-in
that there’s really value added to this. If we follow the rules, will it be safer for patients to
come to us and trust their care to us, whether it’s in clinical investigation, or clinical
treatment? I don’t really think we can separate these two, to tell you the truth. We have to
have a culture in which everybody is trying to do the right thing, the right thing all the
time.”

I hope that the agency will consider withdrawing the direct final rule, and issuing
proposed CGMPs for investigational drugs, as the agency had always considered doing. Options
include finalizing the draft guidance, to provide further clarification or recommended approaches
during phase 1, but keeping phase 1 material within the protection of the CGMP regulation.

Sincerely,

Barbara Immel
President, Immel Resources LLC
Editor, Immel Report™

Attachments:

1) A Brief History of the GMPs: The Power of Storytelling Article
2) Chipping Away at the GMPs Tutorial (Powerpoint Slides), 30th Annual GMP Conference,

University of Georgia, earlier delivered as an audioconference for BioPharm Magazine

__MACOSX/essay material/._con_immel

essay material/Guidance_exemptPhase1

Guidance for Industry

INDs — Approaches to
Complying with CGMP

During Phase 1

Draft Guidance

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 90 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments
should be identified with the docket number listed in the notice of availability that publishes in
the Federal Register.

For questions regarding this draft document contact (CDER) Monica Caphart at 301-827-9047 or
(CBER) Christopher Joneckis at 301-435-5681.

U.S. Department of Health and Human Services
Food and Drug Administration

Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)

January 2006

CGMP

G:\6164dft
1/9/2006

Guidance for Industry

INDs — Approaches to
Complying with CGMP

During Phase 1

Additional copies are available from:

Office of Training and Communication
Division of Drug Information, HFD-240

Center for Drug Evaluation and Research
Food and Drug Administration

5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm

Office of Communication, Training and
Manufacturers Assistance, HFM-40

Center for Biologics Evaluation and Research
Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448
http://www.fda.gov/cber/guidelines.htm.

(Tel) Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services
Food and Drug Administration

Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)

January 2006

CGMP

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation
TABLE OF CONTENTS

I. INTRODUCTION………………………………………………………………………………………………. 1

II. BACKGROUND ………………………………………………………………………………………………… 2

III. SCOPE ………………………………………………………………………………………………………………. 3

IV. STATUTORY AND REGULATORY REQUIREMENTS …………………………………… 4

V. RECOMMENDATIONS FOR COMPLYING WITH THE STATUTE ……………….. 4
A. Personnel……………………………………………………………………………………………………………………….. 6
B. Quality Control Function ……………………………………………………………………………………………….. 6
C. Facility and Equipment ………………………………………………………………………………………………….. 7
D. Control of Components ………………………………………………………………………………………………….. 7
E. Production and Documentation………………………………………………………………………………………. 8
F. Laboratory Controls ………………………………………………………………………………………………………. 8

1. Testing……………………………………………………………………………………………………………………………. 8
2. Stability ………………………………………………………………………………………………………………………….. 9

G. Container Closure and Labeling …………………………………………………………………………………….. 9
H. Distribution……………………………………………………………………………………………………………………. 9
I. Recordkeeping……………………………………………………………………………………………………………….. 9

VI. SPECIAL PRODUCTION SITUATIONS …………………………………………………………. 10
A. Screening Studies/Microdose Producers………………………………………………………………………… 10
B. Multi-Product Facilities………………………………………………………………………………………………… 10
C. Biological and Biotechnological Products………………………………………………………………………. 11

1. General Considerations ………………………………………………………………………………………………….. 11
2. Multi-Product Facilities………………………………………………………………………………………………….. 12
3. Gene Therapy and Cellular Therapy Products…………………………………………………………………… 12
4. Multi-Batch Producers……………………………………………………………………………………………………. 12

D. Sterile Products/Aseptically Processed Products ……………………………………………………………. 13

GLOSSARY………………………………………………………………………………………………………………… 15

REFERENCES……………………………………………………………………………………………………………. 17

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

Guidance for Industry 1
2

INDs — Approaches to Complying with CGMP During Phase 11

4
This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 5
thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 6
bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 7
the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 8
staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 9
the appropriate number listed on the title page of this guidance. 10
11

12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40

I. INTRODUCTION

This guidance is intended to assist persons producing drug and biological products
(investigational drugs) for use during phase 1 development (21 CFR 312.21(a)) in complying
with relevant current good manufacturing practice as required by § 501(a)(2)(B) of the Federal
Food, Drug, and Cosmetic Act (FD&C Act). Controls for producing an investigational new drug
for use in a phase 1 study are primarily aimed at ensuring subject safety. The Agency believes
that applying quality control (QC) principles to the production of investigational products (i.e.,
interpreting and implementing CGMPs consistent with good scientific methodology) will
facilitate the initiation of investigational studies in humans and protect study subjects. When
finalized, this guidance will replace the 1991 Guideline on the Preparation of Investigational
New Drug Products (Human and Animal) for the production of IND products for phase 1 clinical
trials described in the Scope section of this guidance.

This guidance is being issued concurrently with a direct final rule (and companion proposed
rule), which specifies that the particular requirements in Part 211 (21 CFR 211) need not be met
for most investigational drugs manufactured for use during phase 1 development. Instead, the
Agency recommends the approaches outlined in this guidance for complying with § 501(a)(2)(B)
of the FD&C Act.

FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.

1 This guidance has been prepared by an Agency working group with representatives from the Center for Drug
Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and the Office of
Regulatory Affairs (ORA), at the Food and Drug Adminstration.

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76

II. BACKGROUND

The FD&C Act specifies that drugs must be manufactured, processed, packed, and held in
accordance with current good manufacturing practice (CGMP), or they are deemed to be
adulterated. In September 1978, FDA implemented revised CGMP regulations for drug and
biological products (see 21 CFR Parts 210 and 211). These regulations were written primarily
with commercial manufacturing in mind. Although the Agency stated at the time that the
regulations applied to all types of pharmaceutical production,2 we indicated in the preamble to
the regulations that we were considering proposing additional regulations governing drugs used
in investigational clinical studies.

In 1991, the Agency issued the Guideline on the Preparation of Investigational New Drug
Products (Human and Animal). However, the 1991 document did not discuss all manufacturing
situations, including, for example, small- or laboratory-scale production of investigational new
drugs. In addition, the 1991 document did not address fully the Agency’s expectation that an
incremental approach to manufacturing controls would be taken during investigational drug
development, which for most products includes a change in production scale.

This guidance (once finalized) and the regulation it complements, once finalized, will represent
the Agency’s effort to proceed with its plans to formally describe an approach to aide
manufacturers in implementing manufacturing controls that are appropriate for the stage of
development. The use of this approach recognizes that some controls and the extent of controls
needed to achieve appropriate product quality differ not only between investigational and
commercial manufacture, but also among the various phases of clinical studies. Consistent with
the Agency’s CGMP for the 21 Century initiative,3 where applicable, manufacturers are also
expected to implement controls that reflect product and production considerations, evolving
process and product knowledge, and manufacturing experience.4

This guidance describes FDA’s current thinking regarding controls for special production
situations (e.g., a laboratory setting, exploratory studies, multi-product and multi-batch testing)
and specific types (e.g., biological/biotechnology products, aseptically processed products) of
investigational new drug (IND) products manufactured for use during phase 1 clinical trials as
described in the Scope section of this guidance. As the new rule specifies, the particular
requirements in Parts 211 (21 CFR 211) need not be met for certain exploratory products
manufactured for use during phase 1 clinical trials.

2 Preamble to the CGMP 1978, comment #49. “The Commissioner finds that, as stated in 211.1, these CGMP
regulations apply to the preparation of any drug product for administration to humans or animals, including those
still in investigational stages. It is appropriate that the process by which a drug product is manufactured in the
development phase be well documented and controlled in order to assure the reproducibility of the product for
further testing and for ultimate commercial production. The Commissioner is considering proposing additional
CGMP regulations specifically designed to cover drugs in research stages.”

3 See http://www.fda.gov/cder/gmp/21stcenturysummary.htm.

4 We are considering issuing additional guidance and/or regulations to clarify the Agency’s expectations with regard
to fulfilling the CGMP requirements when producing investigational drugs for phase 2 and phase 3 clinical studies.
G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

77
78
79
80
81
82
83
84
85
86

87
88
89
90
91
92
93
94
95
96
97
98
99

100
101

102

103
104

105
106
107
108
109
110
111
112

When finalized, this guidance will replace the 1991 Guideline on the Preparation of
Investigational New Drug Products (Human and Animal) for the production of IND products for
phase 1 clinical trials described in the Scope section of this guidance. Phase 2 and 3 production
will continue to be subject to those portions of 210 and 211 that are applicable.

III. SCOPE

This guidance applies to the following:

The
envi
furth
has a
been
21 C
irres

This

If cl
cont

We
chem
appl
man
thro
G:\616
1/9/20

Investigational new human drug and biological products (including finished dosage forms
used as placebos) intended for human use during phase 1 development, including, for
example, investigational recombinant and nonrecombinant therapeutic products, vaccine
products, allergenic products, in vivo diagnostics, plasma derivative products, blood and
blood components, gene therapy products, and somatic cellular therapy products (including
xenotransplantation products) that are subject to CGMP requirements of § 501(a)(2)(B) of
the FD&C Act.
guidance applies to investigational products whether they are produced in small- or large-scale
ronments because such studies are typically designed to assess tolerability or feasibility for
er development of a specific drug or biological product. However, if an investigational drug
lready been manufactured by an IND sponsor for use during phase 2 or phase 3 studies or has
lawfully marketed, manufacture of such a drug must comply with the appropriate sections of
FR Part 211 for the drug to be used in any subsequent phase 1 investigational studies,
pective of the trial size or duration of dosing.

guidance does not apply to the following:

• Human cell or tissue products regulated solely under Section 361 of the PHS Act

• Clinical trials for products subject to the device approval or clearance provisions of the
Food, Drug, and cosmetic Act

• Investigational new drugs manufactured for phase 2 and 3 studies

• Already approved products that are being used during phase 1 studies (e.g., for a new
indication)

arification on applicability of this guidance to a specific clinical study is needed, please
act the appropriate center with responsibility for review of the IND.

recommend that this guidance be used as a companion to other guidances describing the
istry, manufacturing, and control (CMC) information submitted and reviewed in an IND

ication for phase 1 studies (References 1, 2, 3). At this stage of development, in many cases,
ufacture of the active ingredient and the final investigational product will be accomplished
ugh a series of steps within a single facility. Producers of new active pharmaceutical
4dft

06
3

Contains Nonbinding Recommendations
Draft — Not for Implementation

ingredients (also referred to as an API or drug substance) must also conform with CGMP as
required in § 501(a)(2)(B) of the FD&C Act. Guidance on CGMP for the manufacture of new
API for some products used in clinical studies is also available (Reference 4). Such producers
should implement controls appropriate to the stage of development and, thus, may want to
consider the recommendations described in this guidance.

113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158

IV. STATUTORY AND REGULATORY REQUIREMENTS

Section 501(a)(2)(B) of the FD&C Act requires drugs, which include investigational new drugs,
to comply with current good manufacturing practice:

A drug…shall be deemed adulterated…if…the methods used in, or the facilities or
controls used for, its manufacture, processing, packing, or holding do not conform to or
are not operated or administered in conformity with current good manufacturing
practice to assure that such drug meets the requirements of this chapter as to safety and
has the identity and strength, and meets the quality and purity characteristics, which it
purports or is represented to possess

Certain of the requirements of 21 CFR Parts 211, which implement section § 501(a)(2)(B) of the
FD&C Act, were directed at commercial manufacture of products, typically characterized by
large, repetitive, commercial batch production (e.g., those that address expiration dating
(§ 211.137(g)), and warehousing (§ 211.142) and are not relevant to the manufacture of most
drugs for investigational use for phase 1 studies.

In addition, section 505(i) of the FD&C Act (21 U.S.C. 355(i)) directs FDA to promulgate
regulations governing investigational drugs to protect human subjects enrolled in investigations.
Under these regulations (21 CFR 312), sponsors must submit information — for example CMC
information (§ 312.23(a)(7)) — about a drug or biological product when submitting an IND
application (References 1, 2, 3). FDA reviews the submitted information to determine whether
the drug to be used in the investigation has the identity, quality, purity, strength, and potency
necessary to ensure the safety of the subjects in the proposed phase 1 study. In certain
circumstances, the Agency may choose to conduct an inspection (e.g., if there is insufficient
information to assess the risks to subjects or if the subjects would be exposed to unreasonable
and significant risk). Alternatively, the Agency could decide to place a proposed or ongoing
phase 1 investigation on clinical hold or terminate the IND. Such actions can also be taken if
there is evidence of inadequate quality control procedures that would compromise the safety of
an investigational product.

V. RECOMMENDATIONS FOR COMPLYING WITH THE STATUTE

This guidance outlines approaches that sponsors and producers of phase 1 investigational new
drugs can use to comply with the requirements of CGMP under section 501(a)(2)(B) of the
FD&C Act. These recommendations are designed to provide approaches to CGMP that
appropriately address factors associated with the production of clinical supplies for use in most

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

phase 1 studies. The recommendations will also help provide an appropriate quality framework
for a variety of investigational new drugs manufactured in various situations.

159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182

• 183

• 184
185

• 186
187
188

• 189
190
191
192

193
194
195
196
197
198
199
200
201
202

During product development, the quality and safety of investigational drug products are
maintained, in part, by having appropriate quality control (QC) procedures in effect. Using
established or standardized procedures will also facilitate the production of equivalent or
comparable investigational product for further clinical study as needed.

Adherence to QC procedures during phase 1 development occurs largely through having:

• Written procedures that are well defined
• Equipment that is adequately controlled
• Data from production, including testing, that are accurately and consistently recorded

Producers may have acceptable alternative ways of meeting the objectives described in this
guidance. It is the responsibility of the sponsors/producers to provide and use such methods,
facilities, and controls to ensure that the investigational drug meets appropriate standards of
safety, identity, strength, quality, and purity. Producers of investigational products should
consider carefully how to best ensure the implementation of standards, practices and procedures
that conform to CGMP for their specific product and production operation.

A number of technologies and resources are available for use that can facilitate conformance
with CGMP and help streamline product development. Some examples include:

Use of disposable equipment and process aids, which can reduce cleaning burden

Use of prepackaged Water For Injection (WFI) and presterilized containers, which can
eliminate the need for additional equipment or qualifying existing equipment

Use of process equipment that is closed (i.e., product not exposed to the environment
during processing), which can alleviate the need for stricter room classification for air
quality

Use of contract or shared production facilities and testing laboratories, for production and
testing (including specialized services) of investigational product. Some academic
institutions have developed shared production and testing facilities that can be used by
institutional sponsors.

Because the sponsor is responsible for important aspects of the clinical investigation, we
recommend that sponsors and producers consider carefully the risks from the production
environment that might adversely affect the resulting quality of an investigational product,
especially when the investigational product is produced in laboratory facilities that are not
expressly or solely designed for their production. For example, of particular importance is the
susceptibility of a product to contamination or cross contamination with other substances (e.g.
chemicals, biological substances, adventitious agents) that may be present from previous or
concurrent research or production activities.

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

203
204
205

206
207

208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231

232
233

234
235
236

237
238

239
240
241
242
243
244

We recommend the following:

• A formal evaluation of the production environment to identify potential hazards

• Taking of appropriate actions prior to and during production to minimize risks and
safeguard the quality of the investigational product

Some recommendations pertaining to specific areas of CGMP follow. Consistent with the statute
(§ 501(a) (2) (b)), CGMP must be in effect for the production of each investigational drug batch
used in clinical trials. The following recommendations provide for flexibility to allow producers
to implement controls appropriate for their specific situation and application. Producers should
establish production controls based on a risk assessment for the product and manufacturing
process and follow good scientific and quality control principles when implementing specific
practices and procedures for CGMP.

A. Personnel

All personnel should have the education, experience and training or any combination thereof to
enable that person to perform the assigned function. In particular, personnel should have the
appropriate experience to prepare the investigational product and be familiar with QC principles
and acceptable methods for complying with the statutory requirement of CGMP, such as the
recommendations outlined in this guidance.

B. Quality Control Function

We recommend that every producer establish a QC plan and document that plan in writing. For
example, a sound QC plan should provide for the following functions:

• Responsibility for examining the various components used in the production of a product
(e.g., containers, closures, in-process materials, packaging materials, and labeling) to
ensure that they are appropriate and meet defined, relevant quality standards

• Responsibility for review and approval of production procedures, testing procedures, and
acceptance criteria

• Responsibility for releasing or rejecting each clinical batch based upon a cumulative
review of completed production records and other relevant information (e.g., procedures
were followed, product tests performed appropriately, acceptance criteria met)

• Responsibility for investigating and initiating corrective action if unexpected results or
errors occur during production

We also recommend that QC responsibilities be performed independently from production
responsibilities. When activities such as testing, commonly performed by dedicated QC
personnel in commercial manufacture, are performed by production personnel, adequate controls
should be in place (e.g., segregation of testing from production so as to not contaminate testing
or negatively affect test results).

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

245
246
247
248
249
250
251
252
253
254
255
256
257
258

259

260

261
262

263
264
265

266
267
268
269

270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287

However, in limited circumstances, depending on the size and structure of an organization, all
QC functions could be performed by the same individual. For example, in some small
operations, it may be justified to have the same individual perform both production and QC
functions, including release or rejection of each batch. Under such circumstances, we
recommend that another qualified individual not involved in the production operation carry out
an additional, periodic review of production records. It is important to note that quality should
be the responsibility of all personnel involved in manufacturing

C. Facility and Equipment

Any facility, including a laboratory, used for production of investigational drugs for use in phase
1 studies should have adequate work areas and equipment for the intended task:

• Sufficient space, clean environment, appropriate construction

• Appropriate lighting, ventilation, and heating

• Appropriate cooling, plumbing, washing, and sanitation

• Appropriate air handling systems (e.g., laminar flow hoods) to aid in preventing
contamination and cross-contamination of product

• Appropriate equipment that will not contaminate the product or otherwise be reactive,
additive, or absorptive with the product and that is properly maintained, calibrated,
cleaned, and sanitized at appropriate intervals following written procedures

We recommend that all equipment used for a particular process be identified and documented in
the production record. We also recommend that the provisions in section VI.D, Sterile
Products/Aseptically Processed Products, be followed for investigational products prepared using
aseptic processing.

Use of procedural controls in an appropriate facility promotes orderly production and aids in
preventing contamination, cross contamination and mix-ups (see Section VI.B).

D. Control of Components

We recommend there be written procedures describing the handling, review, and acceptance and
control of components used in the production of an investigational product. Components should
be controlled (e.g., segregated, labeled) until they have been examined or tested, as appropriate,
and released for use in production. It is important to handle and store components in a manner
that prevents degradation or contamination. We recommend keeping a record (e.g., log book)
containing relevant information on all components. Information to record would include receipt
date, quantity of the shipment, supplier’s name, component lot number, investigational product
batch number, storage conditions, and corresponding expiration date.

We recommend establishing acceptance criteria for specified attributes on each component. For
some components, all relevant attributes or acceptance criteria may not be known at this stage of
product development. However, attributes and acceptance criteria selected for assessment
should be based on scientific knowledge and experience for use in the specific investigational

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309

310
311

312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332

drug. The component attributes and acceptance criteria will be reviewed in the IND application
(Ref 1-3).

We recommend that the certificate of analysis (COA) and/or other documentation on each lot of
component be examined to ensure that it meets established acceptance criteria for specified
attributes. For some materials (e.g., human and animal derived), documentation should include
information on sourcing and/or test results for adventitious agents, as appropriate. If
documentation for a component is incomplete, testing for the incomplete attribute of the
component is recommended. For each batch of the drug substance (or API), we strongly
recommend performing confirmatory identity testing, regardless of whether documentation has
been provided.

E. Production and Documentation

We recommend that production of investigational products follow written production procedures
that provide the following:

• A record of laboratory testing and production data that details the components,
equipment, and procedures used. We recommend that sponsors retain documentation
sufficient to replicate the production process. Similarly, if production of a clinical batch
is initiated but not completed, we recommend that the record include an explanation of
why production was terminated.

• A record of changes in procedures and processes used for subsequent batches along with
the rationale for any changes

• A record of the microbiological controls that have been implemented (including written
procedures) for the production of sterile processed investigational new drugs that are
covered by this guidance. We also recommend the use of aseptic techniques and the
control of in-process components designed to prevent microbial and endotoxin
contamination (see Section VI.D, Sterile Products/Aseptically Processed Products).

F. Laboratory Controls

1. Testing

Analytical tests used in production (e.g., testing of components, in-process material, packaging,
drug product) should be scientifically sound (e.g., specific, sensitive, and accurate) and
reproducible for the specified purpose. We recommend that tests be performed under controlled
conditions and follow written procedures describing the testing methodology.

Laboratory testing of the investigational product to evaluate identity, strength, potency, purity,
and quality attributes should be performed, as appropriate. Specified attributes should be
monitored, and acceptance criteria applied appropriately. For known safety-related concerns,
specifications should be established and met. For some product attributes, all relevant
acceptance criteria may not be known at this stage of product development. This information
will be reviewed in the IND submission (References 1, 2, 3).

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375

We recommend that laboratory equipment be calibrated at appropriate intervals and be
maintained according to established written procedures to ensure reliability of test results. We
recommend that personnel verify that the equipment is in good working condition when samples
are analyzed (e.g., systems suitability).

We further recommend that a representative sample from each product batch be retained. When
feasible, we recommend that the sample consist of twice the quantity necessary to conduct release
testing (excluding any testing for pyrogenicity and sterility). We recommend that the samples be
appropriately stored and retained for at least 2 years following study termination, or withdrawal of
the IND application.

2. Stability

We recommend that sponsors initiate a stability study using representative samples of the
investigational new drug to monitor the stability and quality of the product during the clinical
investigation (i.e., date of manufacture through date of last administration).

G. Container Closure and Labeling

When an investigational new drug covered by this guidance will be stored or shipped, the
product should be suitably packaged to protect it from alteration, contamination, and damage
during conditions of storage, handling, and shipping. We recommend that labeling and storage
operations be controlled to prevent the possibility of mix-ups.

H. Distribution

As it relates to phase 1 trials, the term distribution includes the transport of an investigational
new product covered by this guidance to clinical investigators and, ultimately, to the subjects
enrolled in the study. Products should be handled in accordance with labeled conditions (e.g.,
temperature) to ensure retention of the quality of the product. A distribution record of each batch
of investigational new drug covered by this guidance must be sufficiently detailed to allow
traceability and facilitate recall of the product if necessary (§ 312.57).5

I. Recordkeeping

As indicated in previous sections, we recommend that sponsors keep complete records relating to
the quality and operation of the production processes, including:

• Equipment maintenance and calibration
• Production records and related analytical test records
• Distribution records
• All quality control functions
• Component records

5 IND regulation 21 CFR 312.57 governs the retention of all records required by Part 312 (see 21 CFR 312.57(C)).

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

376
377
378
379
380
381
382
383
384
385
386
387
388
389

Under the applicable IND regulations, sponsors must retain records for at least 2 years after a
marketing application is approved for the drug, or if an application is not approved for the drug,
until 2 years after shipment and delivery of the drug for investigational use is discontinued and
the FDA is notified.6

VI. SPECIAL PRODUCTION SITUATIONS

A. Screening Studies/Microdose Producers

A screening study, which is performed under an exploratory IND application, is intended to
compare the properties of related active moieties to screen for the preferred compound or
formulations for additional clinical development under a traditional IND application (Reference
5). Screening studies involve single-dose or short-term (e.g., <7 days of dosing) studies in humans of up to 5 chemically or pharmacologically related new chemical entities. 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 Microdose studies are defined as studies in which participants are administered a single dose of less than 1/100th of the dose calculated to yield a pharmacological effect of the test substance based on primary pharmacodynamic data obtained in vitro and in vivo (typically doses in, or below the low microgram range) and at a maximum dose of ≤ 100 micrograms. These types of investigational studies are often performed in small-scale laboratories or research organizations. 7 In such cases, special considerations are warranted. For example, when the same area or room is used for both the production of investigational products and research, we recommend that the sponsor segregate the operations sufficiently to • Promote the orderly handling of materials and equipment • Avoid contamination of equipment and product by other substances, personnel, or environmental conditions • Prevent mix-ups Reagents and components used for investigational product production may be stored safely in the same area as those used for research as long as they are properly labeled and organized in a manner that avoids mix-ups or unintended use. Finally, we recommend that equipment be used for a single purpose (i.e., research only or production only) at any given time. B. Multi-Product Facilities 6 Ibid. 7 A draft guidance entitled Exploratory IND Studies issued in April 2005. The guidance clarifies what preclinical and clinical issues (including chemistry, manufacturing, and controls issues) should be considered when planning exploratory studies. Once finalized, it will represent the Agency's thinking on this topic. G:\6164dft 1/9/2006 10 Contains Nonbinding Recommendations Draft — Not for Implementation 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 Ideally, we recommend that one product be produced in an area or room at any given time separate from unrelated activities. However, the same area or room could be used for multiple purposes, including production of other investigational products or laboratory research, provided that appropriate cleaning and control procedures are in place to ensure that there is no carry-over of materials or products or mix-ups. We recommend that in such cases, the design or layout of an area promote the orderly handling of materials and equipment, the prevention of mix-ups, and the prevention of contamination of equipment or product by substances, previously produced products, personnel, or environmental conditions. Additional controls could include procedures for clearing the room of previous product materials, product segregation, component segregation, and use of unique identifiers. We recommend that the implemented controls be assessed periodically to evaluate their effectiveness. Appropriate corrective action should be taken as a result of this assessment, or when other events warrant. C. Biological and Biotechnological Products 1. General Considerations Some biological and biotechnology investigational products, including those made from pathogenic microorganisms, spore-forming microorganisms, transgenic animals and plants, live viral vaccines, and gene therapy vectors, warrant additional containment considerations. We encourage early discussions with the applicable Agency center (i.e., product and facility group with responsibility for the product) prior to engaging in the production of such IND products. The production process is critical to ensuring the correct composition and safety of biological and biotechnology products. For these products, it can be difficult to distinguish changes in quality attributes, or predict the impact of observed changes in quality attributes on safety. This is especially true for phase 1 studies where knowledge and understanding of an investigational new drug is limited and where comprehensive product characterization is often unavailable, especially for products that are difficult to characterize. Therefore, it is critical, beginning with phase 1 studies, to adequately control and document the production process in conjunction with appropriate testing to reproduce comparable IND product as necessary. Retained samples (e.g., drug substance, drug product, intermediate, in-process material) that can be subsequently analyzed for comparison, can provide important links in reproducing comparable biological and biotechnological products. We recommend that appropriate equipment qualification and controls in production be in place to ensure that units with safety-related functions (e.g., viral clearance, virus/toxin attenuation, pasteurization) will perform as intended. Specific testing may also serve to complement these functions. We recommend that testing for safety-related purposes such as viral loads, bioburden, detoxification of bacterial toxins, virus clearance or inactivation, and clearance of substances (e.g., antibiotics, chemicals) be used in production and that adventitious agent testing be established as appropriate. G:\6164dft 1/9/2006 11 Contains Nonbinding Recommendations Draft — Not for Implementation 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 . 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 Of particular importance in evaluating the environment to be used for production (see section V) is the susceptibility of biotechnology and biological products to contamination with biological substances including microbial adventitious agents (e.g., bacterial, viral, mycoplasm) that may remain from previous research or production activities. 2. Multi-Product Facilities In addition to the recommendation in section VI.B, we recommend that multi-product facilities have cleaning and testing procedures in place that ensure prevention and/or detection of contamination by adventitious agents. To the extent possible, dedicated equipment and/or disposable parts (e.g., tubing) is recommended. For multi-product areas, we recommend that procedures be established to prevent cross-contamination and that demonstrate removal of the previously manufactured product from shared equipment and work surfaces, especially if live viral and vector processing occurs in a production area. 3. Gene Therapy and Cellular Therapy Products Due to the wide variety and unique production aspects of investigational gene and cellular therapy products, producers should consider the appropriateness of additional or specialized controls. Although we recommend that investigational cell and gene therapy products be produced following the recommendations in this guidance, we recognize that it may not be possible to follow each recommendation. For example, with some cellular products, it may be impossible to retain samples of the final cellular product due to the limited amounts of material available. We recommend that reasons for adopted approaches be included in the records on the investigational product. 1 487 4. Multi-Batch Producers We are aware that, in some cases, investigational biological and biotechnology products covered by this guidance may be produced as frequently as one batch per subject in phase 1 studies (e.g., therapeutic vaccines, cell therapies, gene therapies). Production of multiple batches will allow additional production and testing information to accumulate in an accelerated manner as compared to more conventional products. It is also important to have and adhere to appropriate control procedures that enable the consistent manufacture of comparable drug substance and drug products. When producing multiple batches of the same investigational product, we recommend that producers periodically conduct and document internal performance reviews. We recommend that such a review assess the control and consistency of the production process and overall product quality. This review would fall outside of routine production operations and would be conducted to assess procedures, practices, and information, including data generated from production and investigational new drug testing. Based on the review, appropriate modifications and corrective actions can be taken to control procedures and production operations. The data generated with each batch can also allow the producer to establish and/or refine acceptance criteria as experience and knowledge permits and, therefore, to achieve more consistent investigational new drug production. G:\6164dft 1/9/2006 12 Contains Nonbinding Recommendations Draft — Not for Implementation 508 509 510 511 512 513 514 • 515 516 517 518 519 520 521 522 523 524 525 526 527 528 • 529 530 • 531 532 • 533 534 • 535 536 • 537 • 538 539 • 540 541 542 • 543 544 545 546 547 548 549 D. Sterile Products/Aseptically Processed Products We recommend that special precautions be taken for investigational new drugs intended to be sterile. Thorough consideration should be given to controls for aseptic processing. The following examples are recommendations that should be considered: Conducting aseptic manipulation in an aseptic workstation under laminar flow conditions (e.g., an air classification of Class 100). Some examples of workstations include a laminar air flow workbench, biosafety cabinets, or barrier isolator system. • Disinfecting the entire aseptic workstation as appropriate (e.g., before aseptic manipulation, or between different operations during the same day). • Ensuring that items within a laminar airflow aseptic workstation not interrupt the airflow. • Disinfecting gloves or changing them frequently when working in the laminar flow hood. • Disinfecting the surface of nonsterile items (e.g., test tube rack, and the overwrap for sterile syringes and filters) with sterile disinfectant solution before placing them in the laminar flow hood. Performing manipulations of drug or components subsequent to a sterilizing step under appropriate conditions. Documenting and following all procedures intended to maintain the sterility of the components, in-process materials, and final product. Qualifying sterility tests (e.g., USP <71>) to demonstrate that the test article does not
interfere with the test.

Employing aseptic technique and control of microbiological impurities in components
designed to prevent microbial and endotoxin contamination.

Training personnel using aseptic techniques in those techniques.

Qualifying for use equipment used for sterilization; performing appropriate calibration;
keeping maintenance records.

Creating documentation to support the use of sterile components and disposable
equipment (e.g., filters, bags, containers) in the form of Sterilization/certification of
analysis, or demonstration that the sterilization method is validated.

Ensuring that release of the final product by the QC unit, or person, include an acceptable
review of production records demonstrating that aseptic procedures and precautions were
followed.

• Ensuring that final products are not released until acceptable results of sterility testing are
known. We understand that products with a short shelf-life (e.g., radiopharmaceuticals,
cellular products) may have to be released while results of the sterility test are pending
based on results from other relevant tests (e.g., assessment of sterile filtration by bubble

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

point filter integrity test, cell product — a negative gram stain, or other rapid microbial
detection test and negative endotoxin test)). We recommend that positive results from
sterility or other relevant tests result in an investigation to determine the cause of
contamination followed by corrective action if warranted.

550
551
552
553

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599

GLOSSARY

Acceptance Criteria – numerical limits, ranges, or other suitable measures for acceptance of test
results that the drug substance or drug products or materials at other stages of their manufacture
should meet

Active Pharmaceutical Ingredient (API) (or Drug Substance) – any substance or mixture of
substances intended to be used in the manufacture of a drug (medicinal) product and that, when
used in the production of a drug, becomes an active ingredient of the drug product. Such
substances are intended to furnish pharmacological activity or other direct effect in the diagnosis,
cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the
body.

Batch – a specific quantity of a drug or other material intended to have uniform character and
quality, within specified limits, and produced according to a single production order during the
same cycle of manufacture

Component – any ingredient intended for use in the manufacture of a drug product, including
those that may not appear in such drug product

Contamination – the undesired introduction of impurities of a chemical or microbiological
nature, or of foreign matter, into or onto a raw material, in-process material, or IND product
during production, sampling, packaging, or repackaging, storage or transport

Cross-Contamination – contamination of a material or IND product with another material or
product

Drug product – a finished dosage form (e.g., tablet, capsule, solution) that contains an active
drug ingredient generally, but not necessarily, in association with inactive ingredients. The term
also includes a finished dosage form that does not contain an active ingredient, but is intended to
be used as a placebo.

In-process material – any material fabricated, compounded, blended, or derived by chemical
reaction (e.g., intermediate) that is produced for, and used in, the preparation of the drug product

Investigational new drug (IND product) – a new drug or biological drug that is used in a
clinical trial. The term also includes a biological product that is used in vitro for diagnostic
purposes.

Microdose studies – studies in which participants are administered a single dose of less than
1/100th of the dose calculated to yield a pharmacological effect of the test substance based on
primary pharmacodynamic data obtained in vitro and in vivo (typically doses in, or below the
low microgram range) and at a maximum dose of ≤ 100 micrograms.

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

Production – all operations involved in the preparation of an IND product from receipt of
materials through distribution including processing, storage, packaging, labeling laboratory
testing and quality control

600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
618

Screening study – a study that is performed under an exploratory IND application, is intended to
compare the properties of related active moieties to screen for the preferred compound or
formulations for additional clinical development under a traditional IND application.

Specification – a list of tests, references to analytical procedures, and appropriate acceptance criteria
that are numerical limits, ranges, or other criteria for the tests. It establishes the set of criteria to which a
drug substance or drug product should conform to be considered acceptable for its intended use.
Conformance to specification means that the material, when tested according to the listed
analytical procedures, will meet the listed acceptance criteria

Sponsor – person who takes responsibility for and initiates a clinical investigation

Quality Units – an organizational unit that fulfills quality control responsibilities. This can be in
the form of separate QC units or a single individual or group, depending upon the size and
structure of the organization.

G:\6164dft
1/9/2006

Contains Nonbinding Recommendations
Draft — Not for Implementation

619
620
621
622
623
624

625
626
627

628
629
630

631
632

633

REFERENCES

1. FDA Guidance for Industry Content and Format of Investigational New Drug

Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized,
Therapeutic, Biotechnology-derived Products.

2. FDA Draft Guidance for Industry Instructions and Template for Chemistry,
Manufacturing, and Control (CMC) Reviewers of Somatic Cellular Therapy
Investigational New Drug Applications (INDs), August 15, 2003

3. FDA Guidance for Industry Instructions and Template for Chemistry, Manufacturing,
and Control (CMC) Reviewers of Human Gene Therapy Investigational New Drug
Applications (INDs), November 8, 2004.

4. FDA Guidance for Industry Q7A Good Manufacturing Practice Guidance for Active
Pharmaceutical Ingredients, Section 19

G:\6164dft
1/9/2006

I. INTRODUCTION
BACKGROUND
III. SCOPE
IV. STATUTORY AND REGULATORY REQUIREMENTS
RECOMMENDATIONS FOR COMPLYING WITH THE STATUTE
A. Personnel
B. Quality Control Function
C. Facility and Equipment
D. Control of Components
E. Production and Documentation
F. Laboratory Controls
1. Testing
2. Stability

G. Container Closure and Labeling
H. Distribution
I. Recordkeeping

VI. SPECIAL PRODUCTION SITUATIONS
A. Screening Studies/Microdose Producers
B. Multi-Product Facilities
C. Biological and Biotechnological Products
1. General Considerations
2. Multi-Product Facilities
3. Gene Therapy and Cellular Therapy Products
4. Multi-Batch Producers

D. Sterile Products/Aseptically Processed Products

GLOSSARY
REFERENCES

__MACOSX/essay material/._Guidance_exemptPhase1

essay material/historyGMP_1

A Brief History of the GMPs

The Power of Storytelling
“If you have an important point to make, don’t try to be subtle or clever. Use a pile driver. Hit the point once.
Then come back and hit it again. Then hit it a third time with a tremendous whack!” – Winston Churchill

This article was writ ten by Barbara Immel, president of Immel
Resources LLC, a consulting and publishing fi rm specializing in
com pli ance, quality as sur ance, and train ing for the pharmaceutical,
biologics, medical device and related industries.

Barbara is the editor-in-chief of the Immel Report, a newsletter providing
advice and guidance for managers in FDA-regulated industries. She
is also on the Editorial Advisory Board of BioPharm Magazine, where
she has served as their GMP and regulatory compliance columnist
since 1996. Her ar ti cles have also ap peared in Phar ma ceu ti cal Technology,
Phar ma ceu ti cal Tech nol o gy Europe, BioProcess International, and Med i cal Device
and Di ag nos tic Industry.

Originally this article appeared in the August 2000 is sue of BioPharm
Magazine, and in the November 2002 supplement, The BioPharm Guide
to GMP History. Reprint permission was grant ed
by the publisher, Advanstar Com mu ni ca tions,
Eu gene, Oregon.

Friedich Nietzche once said, “If you know the why for living, you can endure any how.” Everyone in
our industry should know the story of how the good
manufacturing practices (GMPs) have come to be.

To obtain and maintain GMP compliance, every
manager and supervisor should provide frequent,
mean ing ful GMP reminders, train and develop all
employees, and fully participate in formal, ongoing training
programs. Senior management must state publicly and
make it clear through their actions that following GMPs is
the only way their company does business.

THE 1900s
Early in this country’s history, traveling medicine shows
sold bottles of ointment or “miracle elixir” from the backs
of wagons. Such medication was said to be good for aches
and pains; for catarrh, rheumatism, and gout — of course
it completely cured cancer — and it worked on horses too.
Luckily, those days are long gone.

In 1905, a book called The Jungle helped catalyze
public opinion for change. “Muckraker”social reformer
Upton Sinclair wrote about the Chicago meat packing
industry — the unsanitary conditions in which animals
were slaughtered and processed and the practice of selling
rotten or diseased meat to the public. He also reported
that ground meat sometimes contained remains of
poisoned rats and even unfortunate workers who fell into
the machinery. Sinclair’s main interest was in bringing
attention to the miserable working conditions and the plight
of the impoverished factory workers, many of whom were
immigrants (1).

The Pure Food and Drug Act. The Jungle had a major
impact on the American public. Congress passed the Pure
Food and Drug Act in 1906, and for the fi rst time it became
illegal to sell con tam i nat ed (adulterated) food or meat. Also
for the fi rst time, labeling had to be truthful — no longer
could anyone promise on a label “the moon and the stars.”

Syrup to calm “colicky” babies and “tonics” for
adults often contained alcohol, opium, or morphine,
which addicted many people who used them. So the
1906 Act also required selected dangerous ingredients to
be labeled on all drugs. Inaccurate or false labeling was
called misbranding, and that became illegal. “Misbranded”
applies to statements, designs, or pictures in labeling that

are false or misleading as well as to the failure to provide
required information in labeling (2). Over the years, the
word “adulterated” has been expanded to include products
manufactured without following GMPs.

Before the publication of The Jungle, Harvey Wiley
and others had been pressing for such a law for 25 years.
The Act created one of the fi rst government reg u la to ry
agencies, now known as FDA, and it also allowed for the
seizure of illegal foods and drugs (3). Wiley later became
chief chemist of the bureau given authority to enforce
that act (the Bureau of Chemistry, U.S. Department of
Agriculture), a forerunner of FDA (4).

Biologic products were fi rst regulated a few years
before The Jungle, when at least 12 children died from
a diphtheria antitoxin that was contaminated with live
tetanus bacilli (3). Congress responded to that tragedy by
passing the Biologics Control Act of 1902, which required
in spec tions of manufacturers and sellers of biological
products and testing of such products for purity and
strength (5).

THE 1930s
A 1933 FDA exhibit of dangerous food, medicines, medical
devices, and cosmetics illustrated the shortcomings of the
1906 law. “America’s Chamber of Horrors,” included a
womb supporter (also used as a contraceptive) that could
puncture the uterus if inserted incorrectly; a weight-loss

Compliance Leadership TM Series

The Power of Storytelling Page 2
drug that caused death; a hair remover that caused baldness,
even if not used on the head; lotions and creams that could
cause mercury poisoning; hair dyes that could cause lead
poisoning; and an eyelash dye that blinded women (3).
Eleanor Roosevelt took that exhibit to the White House,
asking Americans to campaign for stronger consumer
protections. A tragedy was waiting around the corner that
would make her case for her.

Sulfa drugs were introduced in 1935. Many
man u fac tur ers began making the new anti-infectives. One
company used di eth yl ene glycol, a poisonous solvent
and chemical analog of anti-freeze, in an oral “elixir of
sulfanilamide.” Before the problem was discovered, 107
people died, many of them children (3).

In response, Congress passed the Federal Food, Drug
and Cosmetic (FD&C) Act of 1938. For the fi rst time
companies were required to prove that their products were
safe before marketing them (3). Still the major act covering
our subject matter on the books, it extended FDA oversight
to cosmetics and therapeutic devices, explicitly authorized
factory inspections, required standards for foods, and added
injunctions to previous penalties of seizures and criminal
prosecutions (6).

THE 1940s AND 1950s
In 1941 nearly 300 people were killed or injured by one
company’s sulfathiazole tablets, a sulfa drug tainted with
the sedative, phenobarbital. That incident caused FDA to
revise man u fac tur ing and quality control requirements,
leading to what would later be called GMPs (6). The Public
Health Services (PHS) Act passed in 1944 covered a broad
spectrum of concerns, including regulation of biological
products and control of communicable diseases (7).

Also during the WWII era, batch certifi cation by
FDA became a requirement for certain drugs. It required
com pa nies to submit samples from each lot to FDA for
testing, and the agency would give permission for their
release. That practice, begun in 1941 for insulin and 1945
for penicillin, was later expanded to include all antibiotics.
By 1983, the requirement for batch certifi cation of drugs
was dropped (7).

In 1955, Jonas Salk discovered a way to vaccinate
against polio (8). Many manufacturers began making his
polio vaccine. One company failed to inactivate the virus
completely in a single lot. About 60 individuals inoculated
developed polio, and another 89 of their family members
(mothers, fathers, brothers, sisters, and grandparents)
contracted polio from them (9). We vaccinate our children
to prevent them from getting a disease and also as a public
health measure to protect society from the spread of
disease.

THE 1960s
Thalidomide was marketed in Europe as a sleeping pill and
to treat morning sickness. When regulatory agencies gave
permission to sell the drug for that indication, they had no
knowledge of its serious side effects. It turned out to be

teratogenic: It caused serious deformities in developing
fetuses. Children whose mothers took thalidomide in the
fi rst trimester were born with severely deformed arms and
legs. An estimated 10,000 cases of infant deformities in
Europe were linked to thalidomide use (3).

The product was not allowed on the market in the
United States. The drug reviewer responsible for the
thalidomide application in the United States was Frances
Kelsey. In 1962 President Kennedy awarded her the
President’s Distinguished Federal Civilian Service Award,
the highest honor a government employee may earn as a
civilian (3).

Thalidomide galvanized public opinion. Two
leg is la tors, Kefauver and Harris, pushed more stringent
legislation through Congress that required companies to
test not only to ensure that products were safe, but that they
were ef fi ca cious for their intended uses. Regulating clinical
trials, the amendments required drugs to be tested in
animals before people. They made investigators responsible
for supervising drugs under study. Manufacturers were
expected to inform participants if a drug was being used
for investigational purposes and to obtain their consent
before testing it on them. Drugs had to be shown to work
before going on the market. Manufacturers were required to
report unexpected harm (adverse events). FDA was given
authority to regulate advertising of prescription drugs (3).
And in 1963, the fi rst GMPs for fi nished pharmaceuticals
were made fi nal (10).

THE 1970s
The 1970s were a watershed for product regulation. In
1978, good manufacturing practices for drugs (21 CFR
Parts 210 and 211) were greatly expanded and medical
devices (21 CFR 820) and GMPs were, for the fi rst time,
made fi nal. They were intended to help ensure the safety
and effi cacy of all products:

The regulations . . . contain the minimum current good
man u fac tur ing practice for methods to be used in, and
the facilities or controls to be used for, the manufacture,
processing, packing, or holding of a drug to assure
that such drug meets the requirements of the act as to
safety, and has the identity and strength and meets the
quality and purity characteristics that it purports or is
represented to possess. (11)

GMP requirements for devices were intended “to
govern the methods used in and the facilities and controls
used for the design, manufacture, packaging, labeling,
storage, installation, and servicing of all fi nished medical
devices intended for human use,” as described in the most
recent revision (12).

Good Laboratory Practices (GLPs) were made fi nal in
1979. They defi ne:

good lab o ra to ry prac tic es for con duct ing nonclinical
lab o ra to ry stud ies that sup port or are in tend ed to
sup port ap pli ca tions for re search or mar ket ing
per mits for prod ucts reg u lat ed by the Food and Drug

Important Defi nitions: Drugs, Biologics, and Devices
The following defi nitions describing the major dif fer enc es
between drugs, biologicals, and devices, are abstracted from
the Requirements of Laws and Regulations Enforced by the
U.S. Food and Drug Administration (2).

Drugs
The Food, Drug & Cosmetic (FD&C) Act defi nes drugs as
“articles intended for use in the diagnosis, cure, mitigation,
treat ment, or prevention of disease in man or other animals”
and “articles (other than food) intended to affect the structure
or any function of the body of man or other animals.” It is
the intended use that determines whether something is a
drug. Thus, foods and cosmetics may be subject to the drug
re quire ments of the law if therapeutic claims are made for them.
The FD&C Act prohibits adul ter a tion or misbranding of any drug
and requires that “new drugs” be reviewed and approved by
FDA before they go to market. Drug applications typically fall
into three categories: a New Drug Application (NDA), a New
Animal Drug Ap pli ca tion (NADA), or an Abbreviated New Drug
Ap pli ca tion (ANDA) for generic products.

Biologicals
The Public Health Services Act defi nes a biological product as
“any virus, therapeutic serum, toxin, antitoxin, vaccine, blood,
blood component or de riv a tive, allergenic product, or analogous
product . . . applicable to the prevention, treatment, or cure of
diseases or injuries of man….” Biologics include such vitally
important products as polio and measles vaccines, diphtheria
and tetanus toxoids, and skin test substances as well as
whole blood and blood com po nents for transfusions. Biological
products are subject to all the adulteration, misbranding,
and reg is tra tions provisions of the FD&C Act. Because most
biological products are derived from living organisms, they are

by their nature potentially dangerous if improperly prepared
or tested. Under the PHS Act, manufacturers wishing to ship
biological products in interstate com merce or for import or
export must obtain the ap pro pri ate U.S. license(s). Previous
licensing requirements called for both an Establishment and a
Product License Application (ELA and PLA) to be fi led. That has
recently been streamlined into the single Biologics Licensing
Application (BLA).

Devices
Medical devices include several thousand health products, from
simple items such as thermometers, tongue de pres sors, and
heating pads to IUDs, heart pacemakers, and kidney dialysis
machines. Under the FD&C Act, a device is defi ned as “any
health care product that does not achieve its principal intended
purposes by chemical action in or on the body or by being
metabolized.” Products that work by chemical or metabolic
action are regulated as drugs. The term “devices” also includes
components, parts, or ac ces so ries of medical devices,
diagnostic aids such as re agents, antibiotic sensitivity disks,
and test kits for in vitro (outside the body) diagnosis of diseases
and other con di tions. Three classes of medical device exist:

• Class I, General Controls (registration of man u fac tur ers,
record keeping and labeling requirements, com pli ance with
GMPs)

• Class II, Special Controls (including per for mance
stan dards, post market surveillance, and patient registries)

• Class III, Pre market Approval (implanted and life-
sup port ing or life-sustaining devices). Devices “sub stan tial ly
equiv a lent” to others may be fi led using a 510(K)
application; all others, and all Class III devices, require fi ling
a pre market approval application (PMA).

Ad min is tra tion, in clud ing food and color additives,
animal food additives, human and animal drugs,
medical devices for human use, biological products,
and electronic products. Compliance with this part
is intended to assure the quality and integrity of the
safety data fi led. (12)

A few years earlier, the Medical Device Amend ments
(signed as law in 1976) strengthened FDA’s authority to
oversee medical devices. The law was precipitated by
incidents involving a contraceptive intrauterine device
(IUD) that about two million women were using. Many
users were seriously injured (3). The product was taken off
the market in 1975 because it was associated with a high
incidence of pelvic infections, infertility, and some deaths
(13).

The Medical Device Amendments required
man u fac tur ers of most medical devices (particularly
moderate- or high-risk devices) to provide FDA with
safety and ef fec tive ness data before marketing them.
Furthermore, the law provided for a system of pre- and
postmarket oversight including FDA inspections to ensure
that companies follow GMPs, keep appropriate records on
the design and man u fac ture of their products, and maintain
systems for handling complaints (14).

THE 1980s AND 1990s
In 1980, Congress passed the Infant Formula Act giving
FDA authority to create and enforce standards and specify
nutritional requirements for commercial infant formulas.
That followed 1979 reports that more than 100 infants were
made seriously ill by a lack of chloride in two soy-based
formulas (15). Manufacturers are now required to analyze
each batch of formula for nutrient levels and make safety
checks, conduct stability tests, code each container with
a lot number, keep detailed records of production and
analysis, and so on (16). The food GMPs (21 CFR Part
110), which include special provisions for infant formulas,
were fi nalized in the 1980s.

In 1982, 12-year-old Mary Kellerman told her parents
that she felt like she had a cold. They gave her an extra-
strength Tylenol ac e tami nophen capsule, and within a few
hours she died. Six other people died in this tragic incident,
including three members from one family (two brothers and
one of their wives) and a woman who had just given birth to
her fourth child (17).

Johnson & Johnson announced a nationwide recall of
31 million bottles of Tylenol. Their investigation revealed
that a criminal tamperer (who has never been found or
prosecuted) had opened up and laced some capsules with
cyanide. The company destroyed all 31 million bottles of
the largest-selling over-the-counter medicine in the country.

The Power of Storytelling Page 3

A GMP Timeline
1902 Biologics Control Act
Tragedy: At least 12 children die of tetanus contracted from
contaminated diphtheria vaccine. Result: Requires in spec tions
and testing of biologics manufacturers’ facilities and products.

1906 Pure Food and Drug Act
Creates one of the fi rst government regulatory agencies (now
known as FDA); the culmination of 25 years of lobbying, this
act makes it illegal to sell “adulterated” or “misbranded” food or
drugs.

1938 Federal Food, Drug and Cosmetic (FD&C) Act
Tragedy: Sulfanilamide made with poisonous solvent causes
107 deaths. Result: Requires manufacturers to prove the safety
of products before marketing.

1941 Two Unrelated Events
Insulin Amendment requires FDA to test and certify purity and
potency of insulin. Tragedy: nearly 300 deaths and injuries from
distribution of sulfathiazole tablets tainted with phe nobar bit al.
Result: FDA revises manufacturing and quality controls
dras ti cal ly, the beginning of what will later be called GMPs.

1944 Public Health Services Act
Regulates biological products and control of communicable
diseases.

1962 Kefauver-Harris Drug Amendments
Tragedy: Thalidomide causes birth defects in thousands of
European babies. Result: Manufacturers must prove effi cacy of
products before marketing them and ensure stricter control over
drug testing.

1963 GMPs for Drugs (28 FR 6385)
Good manufacturing practices for manufacturing, processing,
packing, or holding fi nished pharmaceuticals were fi rst
published.

1975 CGMPs for Blood and Blood Components Final Rule
Establishes minimum current good manufacturing practices for
blood establishments in the collecting, processing, com pat i bil i ty
testing, storing, and distributing of blood and blood components.

1976 Medical Device Amendments
Tragedy: the Dalkon Shield IUD seriously injures many patients.
Response: New law strengthens FDA authority to oversee
medical devices.

1978 CGMPs for Drugs and Devices (21 CFR 210–211 and
820)
A major rewrite for the drug GMPs and GMPs for medical
devices were published. These regulations establish minimum
current good manufacturing practices for manufacturing,
processing, packing, or holding drug products and medical
devices.

1979 GLPs (21 CFR 58) Final Rule
Establishes good laboratory practices for conducting nonclinical
laboratory studies that support applications for research or
marketing permits for human and animal drugs, medical
devices for human use, and biological products.

1980 Infant Formula Act
Tragedy: 100 children reported seriously ill linked to lack of
chloride in soy-based formulas. Result: Congress gives FDA
authority to set and enforce nutritional and quality standards.

FDA issued tamper-resistant packaging regulations for
all over-the-counter human drug products and in cor po rat ed
them into the GMPs. Congress passed the Federal Anti-
Tampering Act in 1983, making it a crime to tamper with
packaged consumer products (18). The acetaminophen
tragedy had a major impact on the industry. Not only do
we need to provide ongoing GMP training to all of our
em ploy ees, making sure they are adequately and thoroughly
trained and supervised, but now we worry about how
murderers could use our products to harm the public.

Guidance documents. In the 1980s, FDA began
pub lish ing a series of guidance documents that have
had a major effect on our interpretation of current
good man u fac tur ing practice. One such document was
the “Guide to Inspection of Computerized Systems in
Drug Processing” published in 1983, which gave early
expectations for the functioning of computer systems and
perhaps signaled the beginning of computer validation
(19). Of course, the very famous “Guideline on General
Principles of Process Validation” in 1987 outlined current
thinking or expectations of process validation for drugs
and devices (20). Such documents, including the Points to
Consider, provide guidance only on principles and practices
that are not legal requirements. However, typically they
refl ect current agency thinking and expectations.

L-tryptophan. Active pharmaceutical ingredients (APIs)
used to be called bulk pharmaceutical chemicals (BPCs).

The terminology recently changed to refl ect the fact that
some active ingredients are made using biological rather
than chemical processes. The term “new chemical entity”
(NCE) is also now often referred to as a “new mo lec u lar
entity” (NME) for the same reason.

The naturally occurring amino acid, L-tryptophan,
used to be widely promoted as a dietary supplement and
was used as an aid for insomnia, depression, obesity, and
for children with attention defi cit disorder. In 1989, an
epidemic of eosinophilia-myalgia syndrome (EMS) was
linked to dietary supplements containing L-tryptophan.
The Centers for Disease Control (CDC) identifi ed more
than 1,500 cases of EMS, including at least 38 deaths, that
were associated with L-tryptophan. In tests run by both
FDA and the Mayo Clinic, impurities were confi rmed in
some L-tryptophan products on the market. One impurity
was called Peak X. Although its signifi cance remains
unknown, Peak X was found in one case of EMS associated
with L-tryptophan in 1991. Unfortunately, the exact cause
of the 1989 epidemic and of the EMS associated with
5HTP continue to be unclear, in part because 5HTP is
synthesized from L-tryptophan in the body. Research has
not yet conclusively resolved whether EMS was caused by
L-tryptophan, by 5HTP, by one or more impurities, or by
some other factors (21).

Some 70–80 % or more of the APIs used to

The Power of Storytelling Page 4

A GMP Timeline (continued)

manufacture products for the United States come from
sources outside the country, where man u fac tur ing standards
may not be as stringent. For this reason, both the European
Union and the United States recently pub lished draft
guidance documents for the manufacture of APIs. Recently,
the International Conference on Harmonization (ICH), a
consortium of individuals from Europe, North America,
and Japan, published “ICH Q7A on Good Manufacturing
Practice Guidance for Active Pharmaceutical Ingredients.”
(22) This document has been published and accepted in
Europe, Japan, and the United States, and it is considered the
de facto standard for manufacturing active pharmaceutical
ingredients.

Illegal catheters. Most of the cases in this rep re sen ta tive
history were mistakes and/or mysteries, meaning that the
individuals or companies involved had no intention or desire
of harming anyone. The acetaminophen poisoning case was
clearly criminal. Let’s look at a different kind of criminal
case.

In 1996, three former executives of a company that
made balloon heart catheters in the United States each were
sentenced to 18 months in prison followed by two years

of supervised release for conspiring to defraud FDA by
selling illegal heart catheters. The company itself pled
guilty to similar charges in 1993 and agreed to pay $61
million for health fraud. (The U.S. government estimated
that total sales of illegal catheters had amounted to $77
million.) It had been the fi rst company to obtain approval
to market a balloon angioplasty catheter in this country,
and from 1980 to 1985 it was the only distributor of heart
catheters in the United States.

Heart catheters are used in angioplasty to clear
clogged arteries. In 1987, the company began to redesign
those already approved by FDA and sold the new version
without obtaining approval. The redesigned catheters
often mal func tioned, but the company failed to report
those problems to FDA. The company learned during
illegal human clinical trials that the catheter tips broke
off in the arteries of two percent of patients, but it kept
that in for ma tion from FDA. The agency approved the
redesigned device in January 1989, unaware of the tip
breakage problem. Within three months, the company
received 33 reports of tip breakage, so it redesigned the
catheter again, again without informing FDA, and in

The Power of Storytelling Page 5

1982 Tamper-Resistant Packaging Regulations Issued for
OTC Products
Tragedy: Acetaminophen-capsule poisoning by cyanide causes
7 deaths. Result: Revision of GMPs to require tamper-resistant
packaging.

1983 Two Unrelated Regulatory Events
The “Guide to the Inspection of Computerized Systems in Drug
Processing” initiates tighter controls on computers and com put er
validation. Federal Anti-Tampering Act makes it a federal crime to
tamper with packaged consumer products.

1987 Guideline on General Principles of Process Val i da tion
Agency expectations regarding the need for process validation
are outlined.

1990 Safe Medical Devices Act
Tragedy: Shiley heart valves and other incidents. Result: FDA
given authority to add preproduction design controls and tracking
of critical or implantable devices to CGMPs; requires notifi cation
of serious device problems by user facilities to FDA. The agency
gains ability to order device recalls.

1992 Generic Drug Enforcement Act
Precipitated by illegal acts involving abbreviated new drug
applications. Result: Creates debarment penalty.

1996 Two Unrelated Events
Proposed revision to U.S. CGMPs for Drugs and Biologics
(21 CFR 210–211) adds detail for validation, blend uni for mi ty,
prevention of cross-contamination, and handling out-of-
specifi cation results.

“ICH Guidance for Industry: E6, Good Clinical Practice:
Consolidated Guidance” becomes the de facto standard for
conducting human clinical trials.

1997 CGMPs for Medical Devices (Quality System
Reg u la tion) Final Rule
Major revision to current good manufacturing practices for
medical devices becomes effective, with design controls in
R&D the major change (design controls effective June 1998;
rest of rule June 1997).

1997 Electronic Records Final Rule (21 CFR 11)
Requires controls that ensure security and integrity of all
electronic data.

1998 Draft Guidances
“Manufacturing, Processing, or Holding Active Phar ma ceu ti cal
Ingredients” and “Investigating Out-of-Specifi cation (OOS)
Test Results for Pharmaceutical Production.”

1999 QSIT Inspection Handbook
New FDA technique for inspecting device companies focuses
on four major subsystems: management controls, design
controls, production and process controls, and corrective and
preventive action.

2001 ICH Q7A API Guidance
ICH’s “Good Manufacturing Practice Guidance for Active
Pharmaceutical Ingredients (APIs)” is adopted by the United
States, Europe, and Japan, and becomes the de facto
manufacturing standard for APIs.

2002 Drug Manufacturing Inspections Compliance Manual
New FDA technique for routine drug manufacturing
inspections focuses on two or more systems, with mandatory
coverage of the quality system. Other systems are: facilities
and equipment, materials, production, packaging and labeling,
and laboratory controls.

March began distributing the redesigned catheters.
Upon learning of the malfunctions, FDA informed

the company that its catheters were illegal and subject
to seizure. In June 1989, the company recalled previous
versions or models. When FDA told the company that its
latest model violated the law as well, it recalled that model,
modifi ed it, renamed it, and continued to distribute it. When
FDA told the company it needed a premarket approval
application for the model on the market, the company
discontinued selling it and reintroduced the original
model, which had major problems that had ne ces si tat ed
the redesign in the fi rst place. Finally, FDA seized all the
catheters and witnessed their destruction (23).

Those heart catheters were associated with at least
one death and with emergency heart surgery for at least
20 patients (24). A grand jury handed down a 393-count
indictment against the three former executives and others
in 1995. In sentencing those former executives, the judge
emphasized that “corporate entities do not commit crimes;
people do,” and that “executives running other companies
who might engage in such conduct should bear in mind the
prison terms imposed in this case” (23).

Defective heart valves. The Bjork-Shiley Convexo-
Concave mechanical heart valve was manufactured and
sold between 1979 and 1986. About 86,000 of those valves
are believed to have been implanted in patients worldwide,
including 30,000 in the United States. In a small number of
cases, the valves experience a “strut fracture” failure that
necessitates immediate cardiac surgery.

As of November 1998, about 620 fractures had been
reported to Shiley worldwide. In roughly two-thirds of
those cases, a patient died following the fracture. The
company, which no longer makes heart valves, has entered
into a settlement agreement with the government to pay for
the costs of valve strut failures and replacement surgeries,
including hospital care, medical supplies, and the usual fees
of physicians, surgeons, and other health care pro fes sion als.
Furthermore, Shiley and its parent company will pay the
costs incurred by each patient from admission through
discharge, including emergency services. They will also pay
for any complications directly resulting from the treatment
over a reasonable period thereafter (25).

Obviously, that is a very serious case. When we
discuss the case in GMP classes, I often ask, “How many
defects do you think that you can have in a heart valve?”
(The answer, of course, is none.) Implantable devices
are especially dangerous when something goes wrong.
A diffi cult decision must be reached: whether it is better
for the patient to continue with the device or whether the
risks necessitate removal. Patients must be well enough
to survive ex plan ta tion, opening them up (literally and
fi guratively) to in fec tion, possible additional complications,
another recovery period, and so on.

Medical device safety. In response to the Shiley heart
valve and other cases, Congress passed the Safe Medical
Devices Act of 1990, for the fi rst time giving FDA authority
to go into R&D regularly. The act authorized addition of

preproduction design controls to the CGMP regulations;
when FDA analyzed device recalls over a six-year period, it
found that about 44 % of quality problems leading to recalls
were attributed to errors or defi ciencies designed into
those devices. When the agency analyzed software-related
recalls, it found that over 90 % of all software-related
device failures were design related, particularly the failure
to validate software before routine production (12).

In the 1990 Act, Congress authorized FDA to make its
medical device regulations more thorough and consistent
with other world standards, such as ISO 9000. The act
required nursing homes, hospitals, and other facilities using
medical devices to report to FDA all incidents in which a
medical device probably caused or contributed to a death
or serious injury. Manufacturers are required to conduct
postmarket surveillance on permanently implanted devices
whose failure might cause serious harm or death and to
establish methods for tracing and locating patients having
those devices. The Act also authorized FDA to order device
product recalls (7). During the 1990s, the medical device
regulations went through a major revision, with one major
change being in design control, or the need to formally
review and document product design at pre de ter mined
stages. The fi nal rule became effective in June 1997; the
design control portion of the regulations became effective a
year later in June 1998.

In the late 1990s, FDA turned to a more directed
inspectional approach to medical devices called the Quality
System Inspection Technique (QSIT). That approach calls
for focusing on several key systems, including management
controls, design controls, production and process controls,
and corrective and preventive actions (26).

Also in the 1990s, proposed revisions to the GMPs for
drugs and biologics were issued. Although those revisions
were not yet fi nal when this article went to press, they do
represent FDA’s current thinking. The Electronic Records
Final Rule (21 CFR Part 11), requires controls that ensure
the security and accuracy of all data and computer systems
used. Part 11 will have sweeping ramifi cations on the
industry for years to come, and is perhaps the biggest
change in our industry since CGMPs were fi rst published.

International harmony. Besides producing the API guide,
ICH has been working on a number of quality, safety, and
effectiveness documents. As these documents are adopted
or made fi nal by ICH, they become “industry practice” in
all participating countries. The 1996 ICH E6 guidance on
good clinical practices has become the de facto standard
on performing human clinical trials (27). A number of
other FDA guidance documents, in clud ing a draft guidance
on handling out-of-specifi cation results, recently became
available (28). Even though guidelines and draft guidances
are not legally binding, they represent current thinking on
their subject matter and tend to be adopted rapidly and/or
viewed as “current industry prac tice.”

Generic drug scandal. Congress passed the Generic
Drug Enforcement Act of 1992 to impose debarment and
other penalties for illegal acts involving abbreviated drug

The Power of Storytelling Page 6

The Power of Storytelling Page 7
applications (6). The 1992 Act resulted from a bribery and
fraud case in which executives of one or more generic
companies bribed FDA reviewers (one for as little as
$1,000 in gift certifi cates). Rather than testing its own
generic version of a drug, the company tested the brand
name version instead and sent those results with a generic
application.

Although typically executives (presidents, vice
presidents, chairmen, and so on) are indicted in fraud or
other cases, the lowest-ranking employees successfully
prosecuted in the generics companies falsifi ed Certifi cates
of Analysis, destroyed samples, directed others to change
manufacturing pro ce dures, and falsifi ed records to hide or
conceal man u fac tur ing changes (29,30). Be sure to train all
employees in your company to record data thoroughly and
accurately. Teach them that making a false entry, falsifying
dates or backdating, signing for someone else, making up
data, and signing for something they did not do is fraud,
and the consequences can be severe.

Individuals found guilty in the generic drug scandal
were “debarred” from working in the industry. The names
of all such individuals can be found along with many of
their stories on the FDA web site. Check that potential
job candidates are not on that list before you make a job
offer. When you submit any marketing application to FDA
(whether an NDA, ANDA, BLA, 510(K), or PMA) you
must certify in writing that no one who has been debarred
worked on the product.

Similarly, before hiring any clinical trial investigators,
check their backgrounds to ensure that they are not
“disqualifi ed.” Disqualifi cation can occur if an
in ves ti ga tor repeatedly or deliberately fails to comply with
regulatory requirements, or if he or she has submitted false
information to a study sponsor. Studies from individuals
who become disqualifi ed will be under great scrutiny and
may be disallowed (31). With the recent death of a young
man participating in a gene therapy trial, clinical trials
undoubtedly will be under increased scrutiny (32).

Making better changes. The Scale-Up and Post-Approval
Change (SUPAC) documents presented on the FDA web
site provide guidance on what is needed before changes to
approved drug applications can be made. The documents
itemize the types of information or studies required
based upon the mag ni tude or risk of proposed changes.
For biological products, companies are now preparing
“comparability protocols” to address proposed changes.

Abbreviated, routine drug inspections. In 2002, FDA went
to a new, abbreviated inspection technique, focusing on
two or more systems, including mandatory coverage of the
quality system, in routine drug manufacturing inspections.
The other systems? Facilities and equipment, materials,
production, packaging and labeling, and laboratory
controls. FDA has said publicly that they consider a
company to be “out of control if any system is out of
control.” (33)

Brave New World? In a recent consent decree, one
of the world’s largest diagnostics companies agreed to
stop manufacturing and distributing many of its in vitro
diagnostic tests until it corrects manufacturing problems.
The company immediately paid a $100 million civil
money penalty and agreed to pay the U.S. Treasury 16%
of the gross sales of all medically necessary devices (the
company’s entire profi t portion) until confi rming that those
products are produced by GMPs. In addition, it agreed to
pay $15,000 per day per process on medically necessary
products until each process is validated and $15,000 per
day of operation until it is GMP compliant. (34)

In the most expensive consent decree to date, a major
pharmaceutical and over-the-counter (OTC) company
agreed to pay a record $500 million dollars to the U.S.
Treasury, to disgorge profi ts made by the company on
drug products produced over the past three years that were
made in violation of CGMPs. The company also agreed
to future monetary payments of up to $175 million dollars
and to disgorge additional profi ts should it fail to meet the
timelines of the decree. The action follows 13 inspections at
four East Coast and Puerto Rico plants since 1998 in which
FDA found signifi cant violations of CGMP regulations.
The decree affects 125 different prescription and OTC
drugs produced at those facilities. As part of the consent
decree, the company has agreed to suspend manufacturing
of 73 other products. (35)

LOOKING TO THE FUTURE
As we enter the 21st century, let’s remember that we

are all responsible. We will see things in our day-to-day
work that others will not, or we may reach a conclusion
faster than someone else. In all the classes I teach, I
always ask people to speak up — and continue to do so
until important issues are addressed. Otherwise patients,
com pa nies, or employees may suffer.

Our industry exists to relieve suffering or pain, and to
fi nd cures for diseases. It also is highly regulated. Because
of the tragedies that have occurred, most people see the
reg u la tions and world regulatory agencies as checks and
balances on industry, believing as I do that we all have a
similar goal in common — to bring innovative, safe, and
effective products to market.

ACKNOWLEDGMENTS
Special thanks to Diane Brooks-Smith, a compliance
executive with BD Biosciences (San Jose, CA) for an
excellent talk she gave years ago that was the impetus for
this article; and to John Swann, FDA historian (Rockville,
MD) for all his help and contributions.

REFERENCES
(1) S. Ward, “Summary of The Jungle by Upton Sinclair,”

SparkNotes Online Study Guide: (TheSpark.com Inc.,
Cambridge, MA, 1999), www.sparknotes.com/guides/jungle.

For additional reprints of this article (Order#: RP10-03/Rev-01),
please contact Immel Re sourc es LLC at:

616 Petaluma Blvd. North, Suite B
Petaluma, California 94952 USA
Email: immel@immel.com
Web Site: www.immel.com
Tel: 707-778-7222
Fax: 707-778-1818

The Power of Storytelling Page 8

(2) Requirements of Laws and Regulations Enforced by the U.S.
Food and Drug Administration (FDA, Rockville, MD, revised
1997), www.fda.gov/ opacom/morechoices/smallbusiness/
blubook.htm.

(3) Offi ce of Women’s Health, FDA Milestones in Women’s Health:
Looking Back as We Move into the New Millennium (FDA,
Rockville, MD, 2000), www.fda.gov/womens/milesbro.html.

(4) FDA History: FDA Commissioners and Their Predecessors,
U.S. Food and Drug Administration, Rockville, MD, rev. 6
April 2000, www.fda.gov/opacom/morechoices/comm1.html.

(5) R. Roberts, “Safety Assessment in Pediatrics,” Center for Drug
Evaluation and Research, U.S. Food and Drug Administration,
8 July 1999, www.fda.gov/cder/present/dia-699/sa-dia99/
index.htm.

(6) Center for Drug Evaluation and Research, Time Line:
Chro nol o gy of Drug Regulation in the United States (FDA,
Rockville, MD), www.fda.gov/cder/about/history/time1.htm.

(7) “Milestones in U.S. Food and Drug Law History,” FDA
Backgrounder: Current and Useful Information from the Food
and Drug Administration (FDA, Rockville, MD, August 1995),
www.fda.gov/opacom/backgrounders/miles.html.

(8) “Jonas Salk, MD — Biography” (American Academy of
Achievement, 2000), www.achievement.org/autodoc/halls/sci.

(9) I.B. Stehlin, “Assessing Risks with Polio Vaccines,” FDA
Consumer 29(10) (December 1995), www.fda.gov/fdac/
features/095_vacc.html.

(10) Federal Register, “Drugs; Current Good Manufacutring
Practice in Manufacture, Processing, Packing or Holding,”
Part 133, 28 FR 6385, June 20, 1963

(11) Code of Federal Regulations, Food and Drugs, “Current
Good Manufacturing Practice in Manufacturing, Processing,
Packing, or Holding of Drugs,” revised April 2000, Title 21
Part 210–211 (U.S. Printing Offi ce, Washington, DC).

(12) Code of Federal Regulations, Food and Drugs, “Medical
Devices: Current Good Manufacturing Practices (CGMP)
Final Rule,” revised April 1999, Title 21 Part 820 (U.S.
Printing Offi ce, Washington, DC).

(13) Code of Federal Regulations, Food and Drugs, “General:
Good Laboratory Practice for Nonclinical Laboratory
Studies,” revised April 2000, Title 21 Part 58 (U.S. Printing
Offi ce, Washington, DC).

(14) T. Nordenberg, “Protecting Against Unwanted Pregnancy: A
Guide to Contraceptive Choices,” FDA Consumer 31(3) (April
1997), www.fda.gov/fdac/features/1997/397_baby.html.

(15) T. Nordenberg, “FDA and Medical Devices: After 20 Years, a
Look Back, a Look Ahead,” FDA Consumer 30(10) (December
1996), www.fda.gov/fdac/features/096_mdev.html.

1962 Drug Amendments,” FDA Consumer (June 1981).
(16) “The Story of the Laws Behind the Labels, Part III: (16)

Offi ce of Special Nutritionals, Overview of Infant Formulas
(FDA, Center for Food Safety and Applied Nutrition,
Washington DC, August 1997).

(17) Center for Food Safety and Applied Nurtition, Offi ce of
Special Nutritionals, “Overview of Infant Formulas”
(FDA,Washington DC, August 1997)

(18) T. Kaplan, “The Tylenol Crisis: How Effective Public Relations
Saved Johnson & Johnson” (Penn State University Personal
Web Pages, PA,1998), www.personal.psu.edu/users/w/x/
wxk116/tylenol/crisis.html.

(19) National Center for Drugs and Biologics, “Guide to Inspection
of Computerized Systems in Drug Processing” (FDA,
Rockville, MD), February 1983, www.fda.gov/ora/inspect_ref/
igs/csd.html.

(20) Center for Drug Evaluation and Research, “Guideline on
General Principles of Process Validation” (FDA, Rockville,
MD), May 1987, www.fda.gov/cder/guidance/pv.htm.

(21) Center for Food Safety and Applied Nutrition, FDA Talk
Paper: Impurities Confi rmed in Dietary Supplement 5-
Hydroxy-L-Tryptophan (FDA,Washington, DC, 31 August
1998).

(22) International Conference on Harmonization, “Guidance for
Industry: Q7A, Good Manufacturing Practice Guidance fro
Active Pharmacetucal Ingredients” (FDA, Rockville, MD,
August 2001), www.fda.gov/cder/guidance/4286fnl .

(23) P. Kurtzweil, “Ex-Bard Executives Sentenced to Prison,” FDA
Consumer 30(10) (December 1996), www.fda.gov/fdac/departs/
096_irs.html.

(24) D.A. Kessler, Commissioner of Food and Drugs, Hastings
Lecture (Washington, DC, 10 December 1993), www.fda.gov/
bbs/topics/SPEECH/SPE00045.htm.

(25) S. Sciacca, “Shiley Annual Hospital Administrator Letter:
Heart Valve Program” (Pfi zer Inc., New York, December 1998),
www.hcfa.gov/news/pr1999/shiley_letter.htm.

(26) Offi ce of Regulatory Affairs, Guide to Inspections of Quality
Systems (FDA Rockville, MD, August1999), www.fda.gov/ora/
inspect_ref/igs/qsit/qsitguide.htm.

(27) International Conference on Harmonisation, Guide for Industry:
E6, Good Clinical Practice — Consolidated

Guidance (Geneva, Switzerland), April 1996. Published in
the Federal Register, 62(90) 9 May 1997, pp. 25691-25709,
www.fda.gov/cder/ guidance/959fnl .

(28) Draft Guidance for Industry: Investigating Out-of-Spec i fi ca tion
(OOS) Test Results for Pharmaceutical Production, (FDA,
Rockville, MD), September 1998, www.fda.gov/cder/guidance/
1212dft .

(29) Offi ce of Regulatory Affairs Compliance Reference: De bar ment
List, (FDA, Rockville,MD), www.fda.gov/ora/compliance_ref/
debar/default.htm.

(30) T. Nordenberg, “Inside FDA: Barring People from the Drug
Industry,” FDA Consumer 31(2), www.fda.gov/ora/compliance_
ref/debar/297_debar.htm.

(31) Offi ce of Regulatory Affairs Compliance Reference: Biore search
Monitoring (BIM0) Disqualifi ed/Restricted/Assurance List for
Clinical Investigators, (FDA, Rockville, MD), www.fda.gov/
ora/compliance_ref/default.htm.

(32) “New Initiatives to Protect Participants in Gene Therapy
Trials,” HHS Press Release, CBER (FDA, Rockville,
MD), 7 March 2000,www.fda.gov/bbs/topics/NEWS/
NEW00717.html.

(33) “Compliance Program Guidance Manual for FDA Staff:
Drug Manufacturing Inspections Program 7356.002” (FDA,
Rockville, MD, February 2002, www.fda.gov/cder/dmpq/
compliance_guide.htm.

(34) C. Lewis, “Investigators’ Reports: Manufacturing Misdeeds
Cost Abbott Record-Breaking Payments, “ FDA Consumer
34(3) (May-June 2000). Available at www.fda.gov/fdac/
departs/2000/300_irs.html.

(35) FDA News: “Schering-Plough Signs Cosent Decree with
FDA, Agrees to Pay $500 Million” (FDA, Rockville, MD, 17
May 2002)– IR

<< /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /All /Binding /Left /CalGrayProfile (Dot Gain 20%) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Warning /CompatibilityLevel 1.4 /CompressObjects /Tags /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJDFFile false /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /ColorConversionStrategy /LeaveColorUnchanged /DoThumbnails false /EmbedAllFonts true /EmbedJobOptions true /DSCReportingLevel 0 /SyntheticBoldness 1.00 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams false /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveEPSInfo true /PreserveHalftoneInfo false /PreserveOPIComments false /PreserveOverprintSettings true /StartPage 1 /SubsetFonts true /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /DownsampleColorImages true /ColorImageDownsampleType /Bicubic /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages true /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >>
/ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >>
/JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >>
/JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >>
/AntiAliasGrayImages false
/DownsampleGrayImages true
/GrayImageDownsampleType /Bicubic
/GrayImageResolution 300
/GrayImageDepth -1
/GrayImageDownsampleThreshold 1.50000
/EncodeGrayImages true
/GrayImageFilter /DCTEncode
/AutoFilterGrayImages true
/GrayImageAutoFilterStrategy /JPEG
/GrayACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >>
/GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >>
/JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >>
/JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >>
/AntiAliasMonoImages false
/DownsampleMonoImages true
/MonoImageDownsampleType /Bicubic
/MonoImageResolution 1200
/MonoImageDepth -1
/MonoImageDownsampleThreshold 1.50000
/EncodeMonoImages true
/MonoImageFilter /CCITTFaxEncode
/MonoImageDict << /K -1 >>
/AllowPSXObjects false
/PDFX1aCheck false
/PDFX3Check false
/PDFXCompliantPDFOnly false
/PDFXNoTrimBoxError true
/PDFXTrimBoxToMediaBoxOffset [
0.00000
0.00000
0.00000
0.00000
]
/PDFXSetBleedBoxToMediaBox true
/PDFXBleedBoxToTrimBoxOffset [
0.00000
0.00000
0.00000
0.00000
]
/PDFXOutputIntentProfile ()
/PDFXOutputCondition ()
/PDFXRegistryName (http://www.color.org)
/PDFXTrapped /Unknown
/Description << /FRA
/ENU (Use these settings to create PDF documents with higher image resolution for improved printing quality. The PDF documents can be opened with Acrobat and Reader 5.0 and later.)
/JPN
/DEU
/PTB
/DAN
/NLD
/ESP
/SUO
/ITA
/NOR
/SVE
>>
>> setdistillerparams
<< /HWResolution [2400 2400] /PageSize [612.000 792.000] >> setpagedevice

__MACOSX/essay material/._historyGMP_1

essay material/rubric_essays_10oct08

__MACOSX/essay material/._rubric_essays_10oct08

Turn in your highest-quality paper
Get a qualified writer to help you with

“ biotech essay needed. please read first before responding. must have background in biotech before consideration ”

Get high-quality paper

Guarantee! All work is written by expert writers!

Still stressed from student homework?

Get quality assistance from academic writers!

Order now