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* Michael Beatrice, Vice President, Corporate Regulatory and Quality, Abbott Laboratories * David Chesney, Vice President of Strategic Compliance Services, Parexel Consulting * Steve Kuwahara, Founder, GXP Biotechnology LLC * David Mitchell, Senior Director of Regulatory and Quality Assurance, Reata Pharmaceuticals * Steve Niedelman, Senior Consultant, Crowell & Moring LLP * Tracy Panella, Compliance Excellence Program Director, Global Quality Compliance, Wyeth Pharma * Hugh Riddell, Quality Assurance Senior Manager, Regulatory Compliance, Schwarz Pharma Manufacturing, Inc. * James Vesper, Founder, LearningPlus We are deeply indebted to all of our participants, and to all the current and former FDAers and industry experts who make this conference possible. To register, or for further information, please contact FDAnews at +1 (703) 538-7600, or Barb Immel at (707) 778-7222.
For two years
running,
CAPA and investigations have been among the top FDA Form 483
deficiencies of
drug, device, and biologic manufacturers. In partnership with FDAnews, Immel Resources is
presenting an advanced version of our Conducting Bulletproof
CAPA
Investigations class. Course dates for 2010 are being set, and will be
announced shortly. Class
topics include FDA regulatory requirements and expectations, how FDA
inspects CAPA systems and a firm's investigations,
managing CAPA, tips on selecting and training investigators, CAPA
best practices, a refresher on how to conduct an
investigation, root cause analysis, report writing, interviewing
techniques, required FDA
notifications, the importance of good surveillance systems (including
auditing, customer complaints, supplier controls, and management
reviews), preventive action, and risk management as it
applies to CAPA. This class has been offered throughout the
United States over the past few years in
Boston, Chicago, Minneapolis, Philadelphia, Raleigh, San
Diego, the San
Francisco Bay Area, and San Juan, Puerto Rico. Immel Resources has been
teaching classes on CAPA,
investigations, root
cause analysis, and writing reports for deviations and failure
investigations, for approximately 10 years, and GMP classes for more
than 20 years. Curious about what we
discuss in detail in class? Links to our two latest articles on
CAPA, published in Medical Device
& Diagnostic Industry, are
shown below.
Latest Articles Here are recent articles written by company founder Barbara Immel which have been published in the trade press. Barbara Immel served as the regulatory compliance columnist for BioPharm magazine (with two columns: GMP Issues, and Compliance Briefing) for more than 10 years. Many of our earlier articles are available as well, with the list provided here. CAPA "Converting CAPA to an Advantage," Medical Device & Diagnostic Industry, April 2009 Article provides a refresher on key points of a CAPA system, tips on selecting and training investigators, how to initiate a CAPA system for clinicals, and provides a recommended reading list. "Best Practices: Managing a CAPA System," Medical Device & Diagnostic Industry, June 2006 Article discusses how to establish and maintain a robust corrective and preventive action system, including key practices and 20 tips on training employees how to conduct a problem investigation. Pharma GMPs "FDA's Latest Direct Final Rule to Change the Pharma GMPs," Pharmaceutical Technology, June 2008. Article provides an in-depth review of FDA's latest proposed changes to the GMPs and current FDA inspection trends for drugs, biologics, and medical devices. Article was published in hard copy. If you would like a copy, please call us at (707) 778-7222 or write us at immel@immel.com, and we will send you one. FDA Field Reorganization (two-part editorial) "The FDA is in Trouble: And so are we, Part 1," BioProcess International, October 2007 "The FDA is in Trouble: And so are we, Part 2," BioProcess International, November 2007 Part 1 discusses highlights of the recent proposed field reorganization. Part 2 discusses why the plan was flawed. International Biologic Requirements and FDA Budget Cuts "Compliance Briefing: Increased International Requirements and FDA Cuts," BioPharm International, February 2007 Article discusses FDA's persistent, inadequate funding and mentions the predecessors to an advocacy group formed to request continued sufficient funding for the agency, The Alliance for a Stronger FDA (www.strengthenFDA.org). Device Clinical Trials "Building Quality into Device Clinical Trials, Part 1," Medical Device & Diagnostic Industry, July 2006 "Building Quality into Device Clinical Trials, Part 2," Medical Device & Diagnostic Industry, October 2006 Part 1 discusses how to better ensure human subject protection and strengthen the sponsor-IRB relationship. Part 2 discusses sponsor responsibilities in detail, including tips on organizing a submission to expedite FDA review. Investigational Drugs and Biologics "Chipping Away at the GMPs: FDA's Phase 1 Proposals," BioProcess International, September 2006 Article provides compelling reasons why the agency's proposal/direct final rule to exempt phase 1 investigational drug and biologics from the CGMP regulation was flawed. This article is reprinted with our permission from our Immel Report article of the same name. FDA Inspection Trends "Current Trends in FDA Inspection Findings and How to Avoid Compliance Pitfalls," BioPharm International Global Compliance Supplement, September 2006 Article provides common deficiencies cited on FDA Form 483s re: good laboratory practices, good clinical practices, and good manufacturing practices for drugs, biologics, medical devices, and active pharmaceutical ingredients. Article also provides tips on internal auditing and recommended training ideas, with a bibliography of FDA compliance resources. This article was published in hard copy. If you would like a copy, please call us at (707) 778-7222 or write us at immel@immel.com and we will send you a copy. Problem Investigations On Problem Investigations, Part 1, BioProcess International, April 2003 On Problem Investigations, Part 2, BioProcess International, May 2003 Part 1 explains when an investigation is warranted, root cause analysis basics, and required timelines. Part 2 discusses how to analyze, research, and document a problem investigation. These articles were published in hard copy. If you would like a copy of them, please call us at (707) 778-7222 or write us at immel@immel.com and we will send you copies. Electronic Records "Part 11: New Guidance Provides Little Guidance," Medical Device & Diagnostic Industry, January 2004 Article discusses FDA's current approach to 21 CFR Part 11, Electronic Records, Electronic Signatures, their use of enforcement discretion, a checklist on implementing Part 11 (a Part 11 plan), as well as inventory form ideas and recommended resources. Here are recent FDA inspection trends for facilities
manufacturing drugs, biologics, and medical devices. Top 10 current good
manufacturing practice drug observations in Turbo EIR* (FY 2007) * Production
Record Review (Investigations) (21 CFR 211.192) Top device observations used
in Turbo EIR* (FY 2007) * CAPA
Activities/Documentation (21 CFR 820.100 b) Top Five
Citations -- Biological Drugs * Batch
Review (Investigations) (21 CFR 211.192) Top Five
Citations -- Biological Devices * CAPA
Procedures (21 CFR 820.100 a) * Turbo EIR is the software program used by FDA investigators
to report any deficiencies and prepare FDA Form 483 inspectional
observations. FDA investigators also use this program to write
establishment inspection reports (EIRs). Sources: P. Campbell, FDA, "FY 2007 Compliance Update Issues
(483s)," GMP Conference, March 2008; L. Spears, FDA, "Warning Letters
and Managing Related Legal Issues," 3rd Annual FDA Inspections Summit,
October 2008, M. Malarkey, FDA, "Challenges in
Biologics Compliance," 2nd Annual FDA Inspections Summit, October 2007.
This list is provided as a service. It is not an all-inclusive list, nor does it replace the advice of an experienced quality assurance or regulatory compliance professional. Please note: This information was current at the time that it was posted on this web site. Please ensure that you are using the most current version of these documents, and following all applicable regulations. European Union Canada Drug GMPs
GMP 2009 GMP and Guidance Document Page (Links to GMPs for biological drugs, human blood/blood components, clinical drugs, medical gases, and positron emitting radiopharmaceuticals) Device Requirements Medical Device Regulations ISO 13485/ISO 13488 Information Japan
Ministry of Health, Labor and
Welfare (English index) MHLW Ministerial Ordinances on GQP and GMP 2005, and Pharmaceutical Affairs Law, Enforcement Ordinance and Enforcement Regulations 2005/07 In hard copy: Balogh International Online/electronic: Jouhou Koukai Pharmaceutical GMPs in a CD-ROM with other international pharmaceutical requirements: Drumbeat Dimensions World Health Organization
Australia
United States Drug cGMPs 21
CFR 210 and 21
CFR 211 (for human and animal drugs,
therapeutic biologics,
and as guide to active pharmaceutical ingredients)
Revision of
Certain Labeling Controls Preparation
of investigational materials Final
Guidance:
Investigating
Out-of-Specification (OOS) Test Results for Pharmaceutical Production Process
Validation: General Principles and Practices (draft) Guideline
on General
Principles of Process Validation (previous) FDA
Compliance Program Guidance Manual on Drug Manufacturing Inspections FDA
Compliance
Program Guidance Manual on
Inspections of Licensed, Therapeutic Biological Drugs FDA
Compliance Program Guidance Manual on Inspections of Biological Drug
Products (vaccines, etc.) Biotechnology
Inspection Guide Quality System Regulation
FDA Guide to Inspections of Quality Systems (QSIT Manual) FDA Guide to Inspections of Medical Device Manufacturers FDA Inspection of Medical Device Manufacturers FDA CGMP/Quality Systems Guidances FDA Design Control Guidance FDA Medical Device Quality Systems Manual FDA General Principles of Software Validation Guidance FDA Bioresearch Monitoring Page Global Harmonization Task Force Guidances Risk management principles Process validation guidance Supplier quality guidance AdvaMed Points to Consider (CAPA) AdvaMed Points to Consider (Management Controls) AdvaMed Points to Consider (Design Controls) Blood
Product CGMPs Cosmetics
Facility requirements for
licensed veterinary biologics
Dietary Supplement cGMPs For a discussion of the new rule, see also the bottom of this page. Tissue proposed and final rules
FDA Compliance Program Guidance Manual on Inspecting Human Cells, Tissues, and Cellular/Tissue-based Products Guidance and proposed regulation
Part 11
Electronic Records, Electronic Signatures Good Laboratory Practices (GLPs) FDA
Compliance Program Guidance Manual on GLPs Good Clinical Practices (GCPs) FDA regulations re: Clinical
Trials
European Union Clinical Trial Guidelines European Clinical Trials Directive ICH Harmonized Tripartite Guideline for Good Clinical Practice E6 FDA Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance FDA Compliance Program Guidance Manual, Clinical Investigators FDA Compliance Program Guidance Manual, Sponsors, CROs, and Monitors FDA Compliance Program Guidance Manual, IRBs HIPAA Statute and Rules Other Useful Guidances (a partial list) Active Pharmaceutical Ingredients ICH Harmonized
Tripartite Guidance
Compliance ResourcesGood Manufacturing Practice Guide for Active Pharmaceutical Ingredients Q7 FDA Guidance for Industry: Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients FDA Compliance Program Guidance Manual on APIs FDA Enforcement Story Issued annually, this document contains excellent information to include in a senior management compliance briefing or advanced CGMP training class. FDA Compliance Program Guidance Manual (CPGM) The CPGM provides instructions for FDA staff, and contain questions that you may be asked in your next inspection. Sections are available for foods, cosmetics, biologics, bioresearch monitoring (GLP/GCP compliance), drugs, veterinary medicine and devices. FDA Warning Letters FDA posts warning letters on their web site; they can be searched by company, subject, date, issuing office, or regulation citation, and are great training tools. FDA Frequently Requested 483s FDA posts frequently requested 483s or inspectional observations on their web site. Most are for GMP issues; however, several concern GLP and GCP violations. FDA Enforcement Report Issued twice a month, this publication contains information on recent recalls reported to, and classified by, FDA. FDA Investigations Operations Manual (IOM) This is FDA's primary document on inspection policy and procedures for FDA investigators. It covers sampling, inspections, investigations, regulatory actions and recall activities. FDA Revises Pharma GMPs On
September 8, 2008, FDA issued a final rule changing the pharmaceutical
GMPs (21 CFR 210 and 211). The changes became effective December 8,
2008. This follows on the heels of an earlier (and different) revision
to exempt most phase 1 clinical material (but not all) from the need to
follow 21 CFR 210/211 when manufacturing the clinical material,
discussed in detail below. Key changes include requiring the validation of all
aseptic processes and also of depyrogenation processes (the validation
of all sterilization processes was already required). An additional
change is that if an automated
system is used to perform a critical step such as adding materials to
the batch, weighing, measuring or subdividing components, determining
calculation of yield, verifying the cleaning or maintenance of
equipment, and verifying each critical step on the batch record, a
sole, human verifier (rather than a two-person double-check) is
required, after the automated step performs the function. Fortunately,
the agency did not put through their
dangerous proposed elimination of required water testing of source or
feed water (40 CFR 141), which states required testing and maximum
contaminant levels for coliforms (E
coli), nitrates, selenium, fluorides, radium, and turbidity.
This means that rigorous testing of source or feed water is still
required. If you intend to implement a
sole, human verifier (rather than a two-person double-check), Immel
Resources recommends that you
ensure that the individual is a highly experienced, thoroughly trained
employee, and that the computerized system is thoroughly validated
and remains in a validated state. Using a sole, human
verifier applies to only the specific GMP tasks discussed above. History. On April 4, 2008,
FDA withdrew the
direct
final rule dictating these proposed changes because
the agency received significant adverse comment. This
is the second time in two years that FDA has issued direct final
rules to change the pharma GMPs, and because of comments received, the
second time in two years that FDA has revoked their direct final rules
before incorporating comments received in a final rule. What is a direct final rule? A direct final rule requires that comments received meet the agency's definition of "significant adverse comment" or the rule simply goes through, without taking into consideration comments received. We believe FDA should issue any proposed changes to the GMPs only as proposed rules using usual notice-and-comment procedures. This process is required by the Federal Food, Drug, and Cosmetic Act (FD&C Act). We believe FDA may be subverting the Administrative Procedures Act and the intent behind the FD&C Act in dictating the pharmaceutical GMPs unless significant adverse comment is received. We also believe FDA's actions concerning the pharmaceutical GMPs are clearly deregulatory. In making the proposal, FDA withdrew
the more detailed 1996 proposed revision to the GMPs. The 1996 proposed
revision
included
requirements for validation, process validation, method validation,
computer validation,
investigations and out-of-specification (OOS) results, and putting at
least one product batch each year on
stability
testing. This withdrawal is surprising given that the top GMP
deficiencies in facilities manufacturing drug and biologic products
continue to be tied to problems with production-record review
(investigations), validation, responsibilities of the quality control
(QC) unit, and laboratory controls (see also Recent FDA Inspection
Trends above). We also find it surprising that the agency did not make
computer validation a stated GMP requirement, particularly since they
are allowing automated systems to perform the first part of a critical
step, with a sole, human verifier, and since compliance with 21 CFR
211.68, the section of the regulations that discusses the requirements
for automated
systems, has been a frequently cited deficiency in recent FDA warning
letters. It has been said that no change to the pharmaceutical GMPs is
minor, since it requires the retraining of all GMP personnel, and also
a
review of company SOPs, batch records, and equipment logs for the need
for any
revisions. Pharmaceutical
Technology asked Barbara Immel to write an article on the
proposed changes.
"FDA's Direct
Final
Rule to Change the Pharmaceutical GMPs" was published in June 2008.
This article has received rave reviews. If you would like a copy of the article,
please call or
write us at (707) 778-7222 or immel@immel.com and we will send you one.
A link to the final regulation and to our comments submitted to FDA concerning this proposed rule are
shown
below. Comments
Submitted by Immel Resources LLC FDA
Exempts Most Phase 1
Clinical Material from Pharmaceutical GMPs (21
CFR 210/211) Despite
receiving significant adverse comment, on July 15, 2008, FDA issued a
final rule exempting most phase 1 clinical material -- the first time
people are exposed to a new drug or biologic compound -- from the
pharmaceutical GMP regulation (21 CFR 210/211). The exemption became
effective September 15, 2008. If the compound is
already in
use in a phase 2 or phase 3 trial, or if the compound is already
marketed, the clinical material must be manufactured following the GMP
regulation, 21 CFR 210/211. If , however, an organization is
manufacturing a drug
compound for use in a phase 1 trial for the first time, the
organization does not need to follow the GMP regulation (21 CFR
210/211) when manufacturing the material, although they must follow
some standard of GMP in that manufacture (all drugs must be
manufactured per the GMPs, per the U.S. Federal Food, Drug and Cosmetic
Act.) FDA has issued a final guidance document with their recommendations on GMPs to follow when manufacturing a compound for use in a phase 1 trial for the first time. Links to the final rule, the final guidance, and to our article on the proposed rule, Chipping Away at the GMPs, are shown below, along with a GMP history article written by Barbara Immel (A Brief History of the GMPs), submitted with our comments to the agency. FDA
removed an enforceable standard (the regulation) in favor of using
a guidance document,
which is not legally binding. This approach contradicts European
Union requirements, which require that companies follow
Annex 13 of their regulations in producing clinical material. Problems
with the FDA final Phase 1 guidance document include it allows the same
person
who
made the clinical material to release it, and it does not require that
that individual be a trained QC unit (Quality Assurance) professional.
This is a direct
contradiction of both U.S. and European Union GMPs, and of common
sense. Clinical trial material, destined to be consumed or used by some
of the most vulnerable patient populations (including the
terminally ill) should require a knowledgeable check and balance before
it is released. Immel Resources strongly believes that all clinical
trial material should be
released by an experienced, knowledgeable, QC unit (Quality
Assurance) professional, and that this individual should be different
from the person who manufactured the material. Even in publishing, a
proofreader, copyeditor, editor, and the author all doublecheck a
single article before it is published. Quality checks for experimental
material going into human beings for the first time are much more
critical. For clinical and commercial
material, a knowledgeable quality check protects patients and clinical
trial volunteers from harm, and
it also protects your organization (from lawsuit, regulatory action,
disqualification, etc.). Many knowledgeable QA and regulatory compliance
experts feel that this
decision will put an estimated 20,000
volunteers in phase 1 clinical trials at greater risk each year, as
they clearly stated in their comments to the agency. Let's
hope that wiser minds prevail, and that this decision is overturned. Chipping Away at the GMPs A Brief History of the GMPs: The Power of Storytelling FDA
No Longer
Enforcing GLPs for Devices * Historically, CDRH review divisions have
not required animal safety
studies to follow GLP More comments from experts include they were surprised FDA would put such statements in writing in a presentation, adding that regulations have the force of law and bind both the agency and the public, and that the agency cannot ignore its own regulations. Additional comments: The argument that GLPs don't fit devices or that companies are small and can't afford to comply is bogus, so if you're a clinical subject you should only participate in trials sponsored by big companies? The experts concluded that subjects in device clinical studies and the public deserve the same level of safety testing as that required in pharmaceutical trials. Since the GLPs apply to preclinical studies submitted to FDA in support of research and marketing applications (such as IDEs, 510(K)s, and PMAs) -- and since the regulations have the force of law, Immel Resources recommends that companies comply with the GLPs, including carefully selecting and ensuring that any contract laboratories you hire are meeting the GLPs. It has not been our experience that "podium policy" is supported in serious cases involving patient injury, or that "podium policy," however well meaning, will withstand scrutiny in a lawsuit. Final cGMPs for Dietary Supplements FDA recently published current, good manufacturing practices for dietary supplements. The rule has a three-year phase-in for small businesses. Companies with more than 500 employees have until June 2008 to comply, companies with less than 500 employees have until June 2009 to comply, and companies with fewer than 20 employees have until June 2010 to comply. FDA also published an interim final rule allowing manufacturers to petition the agency to not perform 100% identity testing of their ingredients. Many people believe the final rule is a watered down version of the proposed rule. The final rule does not require a quality control unit (even though the proposed rule did), and does not require that all batches of finished product be tested to ensure that they conform to specifications before the batch is released (in the weaker, final rule, a subset of finished batches may be tested instead). Interim final rule Proposed rule
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(707) 778-7222, www.immel.com, immel@immel.com |
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