What's New

NewFifth Annual FDA Inspections Summit is a Success

The Fifth Annual FDA Inspections Summit was just held November 3-5, 2010, at the Marriott Bethesda North Hotel and Conference Center in Bethesda, MD. Hosted by FDAnews, the conference offers three tracks: drugs and biologics, medical devices, and clinical trials. The purpose of the conference is to help organizations better prepare for FDA inspections, to better comply with FDA regulations, and to better protect patients and consumers. Barbara Immel has been fortunate to serve as conference chairperson since the conference's inception. Seventy-five percent of participants are directors, vice presidents and managers. FDA speakers this fall included:

* Deb Autor, Director, Office of Compliance, CDER
* Eric Blumberg, Deputy Chief Counsel for Litigation, Office of Chief Counsel
* Lori Lawless, Consumer Safety Officer, Medical Device Specialist, Baltimore District Office, Office of Regulatory Affairs
* Mary Malarkey, Director, Office of Compliance and Biologics Quality, CBER
* Michael Marcarelli, Director of Bioresearch Monitoring, CDRH
* Ann Meeker-O'Connell, Division of Scientific Investigations, Office of Compliance, CDER
* Stephanie Shapley, Bioresearch Monitoring Specialist, Office of Regulatory Affairs
* Larry Spears, Deputy Director for Regulatory Affairs, CDRH

Former FDAers who spoke this fall included:

* Mark Brown, Partner, King & Spalding
* Dave Chesney, Vice President of Strategic Compliance Services, PAREXEL Consulting
* John Godshalk, Senior Consultant, Biologics Consulting Group, Inc.
* Seth Mailhot, Counsel, Nixon Peabody
* Steve Niedelman, Senior Consultant, Crowell & Moring LLP
* Edwin Rivera-Martinez, Vice President, Technical, PAREXEL Consulting
* Vicky Stoakes, President, IntegRx, Inc.
* Monica Wilkins, Senior Director, Corporate Quality Assurance and Compliance, Abbott Laboratories

We are deeply indebted to all of the speakers who make this conference possible. Please mark your calendars for the Sixth Annual FDA Inspections Summit to be held October 4-6, 2011 at the Hyatt Regency in Bethesda. More details coming soon. Hope to see you there!

NewADVANCED Conducting Bulletproof CAPA Investigations Class

For many 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. Three courses are scheduled for 2011: April 13-14 in Raleigh, NC; July 13-14 in Chicago, IL; and September 14-15 in Boston, MA.

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 investigations, CAPA 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 throughout the United States over the past few years in Boston, Chicago, Minneapolis, Philadelphia, Raleigh, San Diego, 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 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) 778-7222.

Converting CAPA to an Advantage

Best Practices: Managing a CAPA System

CAPA Basics: Corrective and Preventive Action

On CAPA and Investigations

NewMedCon 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

Free Articles

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.

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 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 immel@immel.com and we will send you one.

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 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.

Global Regulatory Links

The following is not an all-inclusive list. This information was current at the time that it was posted on this web site, and is provided for easy reference. Please ensure that you are using the most current version of these documents, and following all applicable regulations.

European Union

Pharmaceutical GMPs

Medical Device Standards (see links on left for Active Implantable, In Vitro Diagnostic, and Medical Device Directives)


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)

Medical Device Information
ISO 13485/ISO 13488 Information


          Drug GMPs (Ministerial Ordinance on GMP)

          Device GMPs (Ministerial Ordinance on QMS)

          Pharmaceuticals and Medical Devices Agency Japan (English index)

          Ministry of Health, Labor and Welfare (English index)

          You may also purchase English-language translations of pharmaceutical and medical device GMPs online at Jouhou Koukai

World Health Organization



          Australian Regulatory Guidelines for Medical Devices (ARGMD)

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)

Manufacturing requirements, including in-process changes to the cGMPs

Preparation of investigational materials
All clinical material for the U.S. must be produced according to current good manufacturing practices. See also the Phase 1 Final Guidance for FDA suggestions concerning the production of phase 1 clinical material. Please also see the brief discussion on FDA Exempts Most Phase 1 Clinical Material from Pharmaceutical GMP Regulation below. You may also wish to see FDA's original guidance on the subject, Guideline on the Preparation of Investigational Drug Products (Human and Animal).

Aseptic Processing Guidance

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)

CPG on Validation

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

Medical Device CGMPs

Blood Product CGMPs

          Blood and blood components


Food CGMPs

Veterinary Biologics

Facility requirements for licensed veterinary biologics

Dietary Supplement cGMPs
          For a discussion of the new rule, see also the bottom of this page. 

Human Tissue

Medical Gases

Guidance and proposed regulation

Part 11 Electronic Records, Electronic Signatures

Good Laboratory Practices (GLPs)

          U.S. GLPs

          FDA Compliance Program Guidance Manual on GLPs

          OECD GLPs and Guidance Documents

          Japanese GLPs (Ordinance on GLP)

Good Clinical Practices (GCPs)

HIPAA Statute and Rules

Other Useful Guidances (a partial list)

ICH Guidelines

Active Pharmaceutical Ingredients

Free Compliance Resources

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), with the changes becoming effective December 8, 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 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 now required, after the automated step performs the function. Fortunately, 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 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 performing the sole check is a highly experienced, trained 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. Pharmaceutical Technology asked Barb to write an article on the proposed changes. "FDA's Direct Final 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 immel@immel.com and we will send you one.

Final Rule

Comments Submitted by Immel Resources LLC

FDA Exempts Most (but not all) 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 (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.

Final Rule

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).

cGMP regulation

Interim final rule

Proposed rule

Copyright 2010, Immel Resources LLC, Petaluma, CA USA, (707) 778-7222, www.immel.com, immel@immel.com

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