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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at the GMPs: Understanding FDA’s Proposal to Exempt Material for Phase 1 Clinical Trials from CGMP Regulations, and new Draft Guidance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, [email protected],
www.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Proposed rule and direct final rule Draft guidance to replace CGMP regulation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Draft guidance Why logic may be flawed What your organization can do Questions and answers ©2006, Immel Resources LLC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.
©2006, Immel Resources LLC
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).
©2006, Immel Resources LLC
What FDA is Proposing Source: Draft Guidance for Industry on Investigational New Drugs; Approaches to Complying with Current Good Manufacturing Practice During Phase 1; Availability, http://www.fda.gov/ohrms/dockets/98fr/06-352.htm, and INDs – Approaches to Complying with CGMP During Phase 1 Draft Guidance, January 2006, http://www.fda.gov/ohrms/dockets/98fr/05d-0286-gdl0001.pdf
At the same time, FDA published a draft guidance entitled “INDs – Approaches to Complying with CGMP During Phase 1” to provide guidance (to replace the existing regulation) to provide “recommendations on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.
©2006, Immel Resources LLC
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.
©2006, Immel Resources LLC
Significant Adverse Comment Source: Guidance for FDA and Industry, Direct Final Rule Procedures, Nov. 21, 1997, http://www.fda.gov/cber/gdlns/drctfnlrl.pdf
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
©2006, Immel Resources LLC
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.”
©2006, Immel Resources LLC
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.”
©2006, Immel Resources LLC
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.”
©2006, Immel Resources LLC
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.”
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.
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.
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.
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.
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).
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.”
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.
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).
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.
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.
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.
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.
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.”
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.pdf
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).
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.”
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.pdf
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.
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.pdf
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
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.pdf
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
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.pdf
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)
Exploratory Studies Guidance Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl.pdf
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).
Exploratory Studies Guidance Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl.pdf
“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.”
Concerns re: Guidance Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl.pdf
“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.”
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;
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.
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
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
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...
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."
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."
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.pdf, 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
Johns Hopkins Sources: FDA Warning Letter, http://www.fda.gov/foi/warning_letters/g3936d.pdf, 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
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)
University of Pennsylvania Sources: U.S. Department of Justice Press Release, http://66.98.181.12/newsources/uofp.pdf/, FDA warning letters, http://www.fda.gov/foi/warning_letters/m3897n.pdf, http://www.fda.gov/foi/warning_letters/m3435n.pdf, 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
University of Pennsylvania Sources: U.S. Department of Justice Press Release, http://66.98.181.12/newsources/uofp.pdf/, FDA warning letters, http://www.fda.gov/foi/warning_letters/m3897n.pdf, http://www.fda.gov/foi/warning_letters/m3435n.pdf, 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
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
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
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
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.pdf
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?
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
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
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.pdf
Exploratory IND Studies Guidance, January 2006, http://www.fda.gov/cder/guidance/7086fnl.pdf
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
©2006, Immel Resources LLC
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: [email protected]
- 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.pdf�
- 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.pdf�
- 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.pdf�
- 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.pdf�
- 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.pdf�
- 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.pdf�
- 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.pdf�
- Exploratory Studies Guidance�Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl.pdf�
- Exploratory Studies Guidance�Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl.pdf�
- Concerns re: Guidance�Source: Exploratory IND Studies, January 2006, http://www.fda.gov/cder/guidance/7086fnl.pdf�
- 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.pdf, 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.pdf, 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.pdf/, FDA warning letters, http://www.fda.gov/foi/warning_letters/m3897n.pdf, http://www.fda.gov/foi/warning_letters/m3435n.pdf, 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.pdf/, FDA warning letters, http://www.fda.gov/foi/warning_letters/m3897n.pdf, http://www.fda.gov/foi/warning_letters/m3435n.pdf, 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.pdf�
- 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.pdf
essay material/con_immel.pdf
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.pdf
essay material/Guidance_exemptPhase1.pdf
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
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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
or
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
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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
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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
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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.
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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.doc 1/9/2006
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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
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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.doc
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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.
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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
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phase 1 studies. The recommendations will also help provide an appropriate quality framework for a variety of investigational new drugs manufactured in various situations.
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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.
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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).
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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
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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).
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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.doc 1/9/2006
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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.
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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.doc 1/9/2006
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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.
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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.
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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
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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.
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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.
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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
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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.
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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
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- 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.pdf
essay material/historyGMP_1.pdf
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
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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
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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.
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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
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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
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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.
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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
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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)
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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.
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(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.pdf.
(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.pdf.
(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.pdf.
(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
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