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Third Annual FDA
Inspections Summit Hosted by FDAnews, the conference features three tracks: drugs and biologics, medical devices, and clinical trials. The purpose of the conference is to help organizations better prepare for their FDA inspections, to provide current information re: FDA enforcement and inspection trends, to discuss "hot topics" and tips to improve common problematic areas, and to better protect patients by improving the overall compliance of the industry. The conference drew a stellar group of participants, and a stellar group of speakers, including FDA and industry leaders. Current FDA speakers included: * David Elder, Director of Enforcement,
Office of Regulatory Affairs Seventy-nine percent of our participants this year were managers, directors, vice presidents and senior executives. Barbara Immel, president of Immel Resources LLC, served as conference chairperson, planning the conference with Jeff Grizzel and Craig Rotzler, Conference Managers of FDAnews, and all of our speakers. Organizations participating this year included: Abbott, Alcon Laboratories, Allergy Medical Group, Alpharma, Amgen, AMICAS, Amylin Pharmaceuticals, Apopharma, Astrazeneca, Auxilium Pharmaceuticals, Baxa Corporation, Becton Dickinson, Biomerieux, Boehringer Ingelheim, Boehringer Ingelheim Roxane Inc., Boston Scientific, Bridgepoint Medical, BSB Medical, Cangene, Celgene, Cequent Pharmaceuticals, Ceregene, Cleveland Clinic, Convatec, Covidien, CR Bard, Debio RP SA, DJO, Eleme Medical, Eisai, Ethicon, Ferndale Laboratories, Forest Research Institute, Great Lakes Research Services, Henry Schein, Human Genome Sciences, Inverness Medical Innovations, Ironwood Pharmaceuticals, King Pharmaceuticals, LNK International, MedImmune, Medtronic, Medrad, Miramar Labs, Northstar Neuroscience, Novo Nordisk, NuSkin Enterprises, Orthopediatrics, Paragon Medical, PharmaChem Technologies, Pharma Quality Europe, Philips Healthcare, Philips Respironics, Practical Solutions, Qiagen, Reata Pharmaceuticals, Roche, Sanofi-Aventis, Schering-Plough, Schwarz Pharma, Takeda Pharmaceuticals, University of Miami, U.S. Department of Health and Human Services, U.S. Department of Veteran Affairs, Office of Research Oversight; Wyeth, and Zimmer. We hope that you can join us at the Fourth Annual FDA Inspections Summit next fall. To register, please contact FDAnews toll-free at (888) 838-5578, or at +1 (703) 538-7600. FDA Revises Pharma GMPs On
September 8, 2008, FDA issued a final rule changing the pharmaceutical
GMPs (21 CFR 210 and 211). The changes become effective December 8,
2008. This is a different revision than the phase 1 exemption discussed
below. Earlier this year, on April 4, 2008, FDA withdrew the
direct
final rule concerning 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 U.S. 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. The good news is that 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.
Other changes that they have put through 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 they made 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. 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 below). 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, was a frequently cited deficiency in 2007 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. Immel Resources presented a 90-minute audioconference on
the FDA's New Drug GMPs: What You Need to
Train Your Staff on November 6, 2008 via FDAnews to help
organizations prepare to implement the new GMPs. Earlier this year, Pharmaceutical
Technology
had asked us to write an article on the proposed changes. "FDA's Direct
Final
Rule to Change the Pharmaceutical GMPs" ran in their June 2008
issue. This article has received rave reviews. If you do not receive Pharmaceutical
Technology and 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 agency's final rule and to our comments submitted to FDA concerning this proposal are shown
below. Comments Submitted by Immel Resources LLC FDA Issues Final
Rule Exempting Phase 1 Clinical Material from Pharmaceutical GMPs (21
CFR 210/211) Despite receiving significant adverse comment from the public
and regulated industry, FDA issued a final rule exempting 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) on
July 15, 2008. The exemption became effective September 15, 2008.
Please note: Phase 1 clinical material and all drugs must be
manufactured per the GMPs (The U.S. Federal Food, Drug and Cosmetic Act
requires this.) However, the agency has
removed an enforceable standard (the regulation) in favor of using a
phase 1 guidance document,
which is not legally binding. This approach also contradicts European
Union requirements, which require that companies follow
Annex 13 of their regulations in producing clinical material. The agency's Phase 1 guidance document allows the same person
who
made the clinical material to release it, and does not require that
that individual be a trained QC unit (Quality Assurance) professional.
This is a direct
contradiction of U.S. and European Union GMPs, and also of common sense. So, to clarify, if 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. 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 GMP
regulation, 21 CFR 210/211. Immel Resources was, and is, opposed to this change. Most
knowledgeable QA and regulatory compliance experts feel that this
decision is a mistake, and that it will put an estimated 20,000
volunteers in phase 1 clinical trials at greater risk each year. Let's
hope that wiser minds prevail, and that this decision is overturned.
Immel Resources'
comments concerning the danger of this approach are summarized in the
cover article of our newsletter, the Immel
Report, below, Chipping Away at the GMPs. Also shown below are
links to the final rule and final guidance, and to a GMP history
article written by Barbara Immel (A Brief History of the GMPs). Chipping
Away at the GMPs 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.
Conducting Bulletproof CAPA Investigations Classes CAPA systems
and investigations are an area of intense FDA scrutiny. In 2007, 63% of
the GMP warning letters issued to drug and biologic firms cited
problems with investigations, with 80% of them citing problems in the
handling of out-of-specification (OOS) results. For medical device
firms, in 2007 68% of the GMP warning letters issued cited CAPA
deficiencies, with 49% of them citing multiple CAPA deficiencies. When
FDA
inspectors identify problems with a CAPA system or how the organization
handles investigations, they may
target the company's entire quality system. In partnership with FDAnews, Immel Resources is
presenting our public Conducting Bulletproof CAPA
Investigations class at the following locations in 2008: March 5-7, 2008 San Francisco Bay Area (Emeryville) April 30-May 2, 2008
Chicago July 16-18, 2008
Philadelphia November 19-21, 2008
Raleigh Class topics include how to conduct an
investigation, root cause analysis, tips on managing CAPA
investigations, required FDA
notifications such as field alerts, biologic product deviation reports,
and medical device reports,
report writing, interviewing techniques, selecting
and training investigators, CAPA best practices, risk management as it
applies to CAPA, tips on handling OOS investigations, and tips on
auditing and
training. During 2006 and 2007, the class was offered multiple times in
Boston, San
Juan, Puerto Rico, Minneapolis, Raleigh, and San Diego. To register,
please contact FDAnews at the link below. To offer the class on site at
your location, please contact Barb Immel at Immel Resources, + 1 (707)
778-7222. To give you an idea of how we think, one of our recent
articles
on CAPA is provided free of charge below. Conducting
Bulletproof CAPA Investigations Classes We all must
remain current with FDA trends
and current, industry
practice. To avoid compliance problems with FDA and world regulatory
agencies, call us at (707)
778-7222, or write us at immel@immel.com.
Since 1996, we have helped many companies improve their compliance
track
records. We are quality systems experts. Services:
Free Sample Issue of Immel Report Written and edited by an industry insider, the Immel Report provides:
Here's what readers say:
Chipping Away at the GMPs To start your subscription, call us at (707) 778-7222, or email us at immel@immel.com. Latest Articles The following are our recently published articles in the
trade
press. "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. If you do not receive Pharmaceutical Technology, and you would like a copy of this article, please call us at (707) 778-7222 or write us at immel@immel.com, and we will send you a copy. 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 recent proposed field reorganization. Part 2 discusses why the plan was flawed. If you do not receive BioProcess International, and you would like a copy of these editorials, please call us at (707) 778-7222 or write us at immel@immel.com and we will send you copies. International Biologic Requirements and FDA Budget Cuts "Compliance Briefing: Increased International Requirements and FDA Cuts," BioPharm International, February 2007 Article discusses FDA's inadequate funding and mentions the predecessors to a combined advocacy group formed to request sufficient funding for the agency, The Alliance for a Stronger FDA (www.strengthenFDA.org). Immel Resources is a member of this organization. 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 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. 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. CAPA "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. 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. If you do not receive BioProcess International, and you would like a copy of these articles, 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. European Union Medical
Device Directives Canada Drug GMPs
GMP 2002 (html) GMP 2002 (PDF) 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 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 Guideline on General
Principles of Process Validation FDA
Compliance Program Guidance Manual on Drug Manufacturing Inspections FDA Compliance
Program Guidance Manual on
Inspections of Licensed, Therapeutic Biologics 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 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. Good tissue practice (final rule)
GMP draft guidance
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 Clinical Trials Directive information 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 Regulations Other Useful Guidances (a partial list) Active Pharmaceutical Ingredients ICH Harmonized
Tripartite Guidance
Good 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 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. 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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