Inspections Summit is a Success
Former FDAers who spoke this fall included:
* Mark Brown, Partner, King & Spalding
For many years
CAPA and investigations have been among the top FDA Form 483
drug, device, and biologic manufacturers. In partnership with FDAnews, Immel Resources is
presenting an advanced version of our Conducting Bulletproof
Investigations class. Three courses are scheduled for 2011: April 13-14
in Raleigh, NC; July 13-14 in Chicago, IL; and September 14-15 in
Topics include FDA regulatory requirements
and expectations, how FDA
inspects CAPA systems and a firm's investigations,
managing CAPA, tips on selecting and training people who conduct
best practices, a refresher on how to conduct an
investigation (problem investigation toolkit), 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 repeatedly
United States over the past few years in
Boston, Chicago, Minneapolis, Philadelphia, Raleigh, San
Francisco Bay Area, and San Juan, Puerto Rico.
Immel Resources has been
teaching classes on CAPA,
cause analysis, and writing reports for deviations and failure
investigations, for nearly a decade.
Curious about what we
discuss in class? Links to two of our articles on
CAPA, published in Medical Device
& Diagnostic Industry, are
shown below, along with a recent blog entry on CAPA Basics that Carl
Anderson asked us to write (Carl's
Blog on FDA and GxP stuff). Also linked below is a recent
presentation Barbara Immel gave on CAPA and investigations at the
inaugural MedCon 2010 Conference. If you'd prefer to offer the class on
site, and tailor it for your employees, please give us a call at (707)
CAPA Basics: Corrective and Preventive Action
On CAPA and Investigations
MedCon Conference for Medical Devices
Mark your calendar for the Second Annual MedCon Conference to be held May 3-5, 2011 at Xavier University in Cincinnati, Ohio. MedCon is an annual medical device conference co-sponsored by the Food and Drug Administration and nonprofit Xavier University. The conference features three tracks: clinical, quality, and regulatory. FDA speakers in 2010 included Steven Silverman, Senior Advisor to the CDRH Director, Theresa Thompson, Cincinnati District Director, Kimberly Trautman, CDRH Office of Compliance, Gina Brackett, Compliance Officer, Steve Rabe and Virginia Connelly, both of FDA's Office of Regulatory Affairs, Sharon Kapsch of CDRH, and Phil Pontikos, National Medical Device Expert. Barb Immel served as chair of the quality track for the inaugural meeting and she continues to serve as a member of the steering committee. Barb spoke on CAPA and investigations at the 2010 meeting, and has been asked to speak on Training at the 2011 meeting. If you work for a medical device or combination products company, we hope to see you at next year's MedCon. Copies of all of the 2010 presentations are available here.
Here are articles written by Barbara Immel which have been published in the trade press. Barb served as the regulatory compliance columnist for BioPharm magazine (with two columns: GMP Issues, and Compliance Briefing) for more than a decade. Many of our earlier articles are available as well, with the list provided here.
"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.
"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 email@example.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 proposed FDA 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 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 meet FDA requirements and expedite 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. A copy of the original article is available here.
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 firstname.lastname@example.org and we will send you one.
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 email@example.com and we will send you copies.
"Part 11: New Guidance Provides Little Guidance," Medical Device & Diagnostic Industry, January 2004
Article discusses FDA's earlier 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. November 2010 update: as a result of several high-profile industry cases involving data integrity and fraud, FDA has trained its investigators to better detect data integrity issues and fraud. FDA is expected to once again be inspecting firms for Part 11 compliance.
Device Standards (see links on left for Active Implantable, In
Vitro Diagnostic, and Medical Device Directives)
GMP and Guidance Document Page
(Links to GMPs for biological drugs, human blood/blood components, clinical drugs, medical gases, and positron emitting radiopharmaceuticals)
Medical Device Information
ISO 13485/ISO 13488 Information
World Health Organization
21 CFR 210 and 21 CFR 211 (for human and animal drugs, therapeutic biologics, and as guide to active pharmaceutical ingredients)
Manufacturing requirements, including in-process changes to the cGMPs
of investigational materials
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)
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
Electronic Records, Electronic Signatures
Good Laboratory Practices (GLPs)
FDA regulations re: Clinical Trials
European Union Clinical Trials 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 Statute and Rules
Other Useful Guidances (a partial list)
Active Pharmaceutical Ingredients
ICH Harmonized Tripartite GuidanceFree Compliance Resources
Good Manufacturing Practice Guide for
Active Pharmaceutical Ingredients Q7
FDA Guidance for Industry: Q7A Good Manufacturing
Practice Guidance for Active Pharmaceutical
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
September 8, 2008, FDA issued a final rule changing the pharmaceutical
GMPs (21 CFR 210 and 211), with the changes becoming effective December
2008. Key changes included requiring the validation of all
aseptic processes and also of depyrogenation processes (the validation
of all sterilization processes was already required). In addition, if
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
now required, after the automated step performs the function.
the agency did not put through the 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
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 performing the sole check is a highly
employee, and that the computerized system is validated
and remains in a validated state. Using a sole, human
verifier is only allowed for the specific GMP tasks discussed above.
The final rule, along with comments submitted by Immel Resources re:
the proposed rule, are shown below.
Technology asked Barb to write an article on the
Rule to Change the Pharmaceutical GMPs" was published in June 2008.
We believe that this article and our comments were taken into
consideration by the agency in developing their final rule. If you would like a copy of the article,
please call or
write us at (707) 778-7222 or firstname.lastname@example.org and we will send you one.
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
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
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 (see below). Links to the final rule, the final guidance, and our article on the proposed rule, Chipping Away at the GMPs, are shown below, along with a GMP history article written by Barb Immel (A Brief History of the GMPs), submitted with our comments to the agency.Phase 1 Final Guidance
Chipping Away at the GMPs
A Brief History of the GMPs: The Power of Storytelling
Final cGMPs for Dietary Supplements
FDA recently published current, good manufacturing practices for dietary supplements. The rule has been phased in over a three year period, but all dietary supplement manufacturing companies which wish to sell their products in the United States must meet the cGMP requirements. Companies with more than 500 employees had until June 2008 to comply, companies with less than 500 employees had until June 2009 to comply, and companies with fewer than 20 employees had until June 2010 to comply. The following includes links to the final regulation, an interim final rule, and the proposed rule. If you would like to see copies of FDA 483s or Establishment Inspection Reports of dietary supplement manufacturers, please see the ones available in the FDA ORA FOIA Electronic Reading Room. If you would like to see how FDA requires their investigators to conduct cGMP inspections of dietary supplement manufacturers, please see FDA's new Compliance Program Guidance Manual on Dietary Supplements. Just FYI, FDA published an interim final rule allowing manufacturers to petition the agency to not perform 100% identity testing of their ingredients.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 final rule, a subset of finished batches may be tested instead). Interim final rule
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