FDA just proposed changes to the pharmaceutical good
manufacturing practices (21 CFR 210/211). The proposal has been issued
both as a direct final rule and as a proposed rule with comments
due February 19, 2008. If no significant adverse comments are
rule will become final April 17, 2008. The agency has also withdrawn
their more detailed 1996 proposed revision to the GMPs, which included
requirements for validation, process validation, method validation,
out-of-specification (OOS) results
and other investigations, and putting at least one product batch on
testing each year. We hope that your organization will review the
proposed changes and submit any comments that you may have to the
agency by February 19, 2008.
changes include adding bioburden testing as an
example of in-process testing, adding sterilization as a way to clean
equipment, requiring the validation of all aseptic and sterile
processes, eliminating the specific, EPA water standard (water fit for
human consumption is being proposed instead), and eliminating the need
petition FDA to use an asbestos containing filter (fiber releasing
filters are still unacceptable unless there is no other way to
manufacture). Proposed changes also include a one person double
check, rather than two, if an automated system is used and a human
being verifies that the work has been done correctly. This has been
proposed when adding materials to the batch, determining calculation of
yield, verifying the cleaning of equipment, and verifying each critical
step in manufacturing on the batch record. It is not yet a stated
requirement in the proposed changes that only a qualified
person may perform this verification. Details on the proposed changes
are found in the Direct Final Rule (link below).
The agency is taking an incremental
approach to revising the GMPs, which Immel Resources agrees with. The
agency has not yet addressed the long-standing revision of labeling
controls, the revision of Part 11 on electronic records and signatures,
or codifying recommendations currently contained in a
patchwork quilt of guidance documents for validation, sterile
processing, and handling OOS results. The European Union
and Canada, on the other hand, routinely revise or update their
initial take on the proposed changes is that the water standard
should be more specific to
incorporate concepts of potable water (free from microorganisms or
harmful substances). What is considered "water fit for human use" may
be a different standard in developed vs. developing nations, which now
pharmaceutical ingredients and drug products for the U.S. and world
markets. We feel that caution is advised in a one-person verification
automated systems when adding materials to the batch and verifying
cleaning. Why? An error in these operations would be difficult to
detect in the product, and may lead to patient injury or product
recall. Although all GMP operations must be performed by trained and
qualified personnel, we believe it should be a stated requirement that
person who performs such a verification be an experienced or qualified
Finally, the agency should finish its revision to Part 11
(promised since 2003-2005), particularly since they are proposing
allowing a machine to perform initial verification of critical
manufacturing steps, and also because there have been significant
issues when using computerized systems in clinical trials. We believe
that many of the changes in the proposed 1996 revisions are still valid
(for example, there was a wonderful proposed revision to 21 CFR
211.192, on OOS and other investigations), and we would like to see key
recommendations in guidance documents codified (easier to interpret and
FDA has apparently dropped its last
reorganization plan for their field
force, although it is possible that agency leaders may still plan a
future reorganization via the ORA Moving Forward work being done now.
There was significant opposition to
FDA's reorganization plan in both the House and Senate, from both
political parties, including language prohibiting the agency from
making most of the proposed changes in both a Draft Food and Drug
Safety Bill and also in appropriations language concerning the agency's
08 budget. Our thoughts on the proposal are in the two recent
Details of the proposed FDA field
reorganization and a brief analysis are
contained in our recent two-part editorial, The FDA is in Trouble,
appearing in the October 2007 and November 2007 issues of
BioProcess International. Their circulation is 30,000 mid to upper
level managers in the biopharmaceutical industry in the US, Europe, and
* David Elder,
Director, Office of
Former FDA speakers
included: Carl Anderson, Michael Beatrice, Andrea Chamblee, David
Chesney, John Godshalk, Stephanie Gray, Robert Lewis, Steven Niedelman,
Tamera Norton Smith, and Janis Olson.
are an area of intense FDA scrutiny. Many FDA Form 483
observations and warning letters cite CAPA deficiencies. When FDA
inspectors identify problems with a CAPA system, they will inevitably
target the organization's entire quality system. In partnership with FDAnews, Immel Resources is
presenting our Conducting Bulletproof CAPA
Investigations class in 2008. The schedule will
be published soon. Plans are to offer 2008 classes in Philadelphia,
Chicago, and the San Francisco Bay Area. From 2006-2007, the class
was offered in Boston, Raleigh, NC; San Juan, Puerto Rico, Minneapolis,
MN, and San Diego, CA. Topics include root cause analysis, problem
investigation/CAPA toolkit, managing CAPA, required FDA notifications,
report writing, interviewing, best practices, and tips on auditing and
Best Practices: Managing a CAPA System
32nd Annual International GMP Conference
The 32nd Annual International GMP Conference will be held March 10-13, 2008 at the University of Georgia at Athens. Sponsored by the College of Pharmacy, this is the longest-running GMP Conference in the United States. Early registrants may stay at the Georgia Center, a conference center and hotel on campus, and where the conference is held. This year's program includes a discussion between the current FDA Commissioner and a senior executive at a major pharmaceutical company. Topics covered include inspection trends, international regulatory news, recent FDA proposals, drugs, biologics, and combination products. For further information, call Gary Dykstra, Director of Biomedical Continuing Education and Strategic Planning, at (678) 407-5133.
We all must
remain current with FDA trends
and current, industry
practice. To avoid compliance problems with FDA and world regulatory
agencies, call us today,
toll-free at (866) 778-7222 in the
Free Sample Issue of Immel Report
Written and edited by an industry insider with 25 years of hands-on, industry experience, the Immel Report provides:
Here's what readers say:
The following are our latest articles in the trade press.
If you are unable to obtain a copy of one of these, please call or
us at (866) 778-7222 (in the US) or at +1 (707) 778-7222, or email us
at immel@ immel.com, and we will send you a copy.
"The FDA is in Trouble: And so are we, Part 1," BioProcess International, October 2007 (article search and free registration required)
"The FDA is in Trouble: And so are we, Part 2," BioProcess International, November 2007 (article search and free registration required)
Part 1 discusses highlights of 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 inadequate funding and two advocacy groups formed to request sufficient funding for the agency, FDA Alliance (www.strengthenFDA.org) and Coaltion for a Stronger FDA (www.fdacoalition.org).
"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 (free registration required)
Article provides compelling reasons why the agency's proposal to exempt phase 1 investigational drug and biologics from the CGMP regulation was flawed.
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.
"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.
On Problem Investigations, Part 1, BioProcess International, April 2003 (article search and free registration required)
On Problem Investigations, Part 2, BioProcess International, May 2003 (article search and free registration required)
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.
"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.
GMP 2002 (html) GMP 2002 (PDF)
Medical Device Regulations
ISO 13485/ISO 13488 Information
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
For human and animal drugs, therapeutic biologics, and as guide to active pharmaceutical ingredients
of investigational materials
Quality System Regulation
FDA Guide to Inspections of Quality Systems (QSIT Manual)
FDA CGMP/Quality Systems Guidances
FDA Design Control Guidance
FDA Medical Device Quality Systems Manual
FDA General Principles of Software Validation Guidance
Global Harmonization Task Force Guidances
Risk management principles
Process validation guidance
Facility requirements for licensed veterinary biologics
Dietary Supplement cGMPs
For a discussion of the new rule, see also the top of this page.
Good tissue practice (final rule)
GMP draft guidance
Electronic Records, Electronic Signatures
Good Laboratory Practices (GLPs)
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
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
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
FDA Withdraws Phase 1 Direct Final Rule
FDA withdrew their direct final rule to exempt phase 1 material from the CGMP regulation in Spring 2006 because they received significant adverse comment. FDA has said that comments that they have received regarding the withdrawn rule will be considered in developing a final rule using the usual notice-and-comment procedures. Immel Resources was opposed to this rule, as we believe that it would have put patients and volunteers in phase 1 trials at risk. An edited version of our comments submitted to the agency are shown below (Chipping Away at the GMPs). We hope that the agency will use the comments received to draft GMPs for investigational drugs, as they had always considered doing.
Chipping Away at the GMPs
A Brief History of the GMPs: The Power of Storytelling
Current Good Manufacturing Practice Regulation and Investigational New Drugs; Direct Final Rule
Current Good Manufacturing Practice Regulation and Investigational New Drugs; Companion Document to Direct Final Rule
INDs -- Approaches to Complying with CGMP During Phase I (pdf)
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