What's New

FDA's Proposed Change to Pharma GMPsNew

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 received, the 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 The agency has also withdrawn their more detailed 1996 proposed revision to the GMPs, which included requirements for validation, process validation, method validation, out-of-specification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 stability 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.

Proposed 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 to 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 regulations.

Our 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 manufacture active pharmaceutical ingredients and drug products for the U.S. and world markets. We feel that caution is advised in a one-person verification of 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 the person who performs such a verification be an experienced or qualified operator.

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 enforce).

Direct Final Rule

Proposed Rule

Withdrawal of 1996 Proposed Revision to the GMPs

Proposed 1996 Revision to GMPs

FDA Reorganization Plan Update New

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 Import Safety Bill and also in appropriations language concerning the agency's FY 08 budget. Our thoughts on the proposal are in the two recent editorials below.

Recent Editorials New

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 Canada.

October Editorial

November Editorial

FDA Inspections SummitNew

Mark your calendars -- the 3rd Annual FDA Inspections Summit will be held in October 2008. Additional details of the conference will be published soon. The conference is hosted by FDAnews. The conference features three tracks: drugs and biologics, medical devices, and clinical trials. Last year's conference drew a stellar group of participants from many companies worldwide -- and a stellar list of speakers, many of them current and former FDA. FDA speakers at the Fall 2007 conference included:

* David Elder, Director, Office of Enforcement, ORA
* David Kalins, Field Liaison, Director of Risk Management Operations, CDRH
* Doreen Kezer, Special Investigations Branch Chief, CDRH
* Mary Malarkey, Director, Office of Compliance and Biologics Quality, CBER, and
* Edwin Rivera Martinez, Chief, Manufacturing Assessment and Preapproval Compliance Branch, CDER

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.

Organizations participating in 2007: Abbott, Abraxis BioScience, Abiomed, Aceto, Affymax, Altana Pharma, American College of Radiology, Ascent Healthcare Solutions, Astra Zeneca, Auxilium Pharma, Becton Dickinson, Benchmark Electronics, Biomerieux, Boehringer Ingelheim, Boston Scientific, Breath Diagnostics, Caraco Pharmaceutical Laboratories, Carestream Health, Centocor, Cequent Pharmacetuicals, Chugai Pharma, Cirrus Pharmacetuicals, ConvaTec, Covidien, CR Bard, CryoLife, Dentsply Maillefer, Digene, Eli Lilly, Endo Surgery, Formatech, Fort Wayne Metals, GBSC, Genentech, Georgetown University, Gideon Richter, GTC Biotherapeutics, Henry Schein, Humco Holding Group, Johnson & Johnson, LUX Biosciences, Mannkind, MedPointe, MedImmune, Medtronic, Merck, NeuroPace, Olive Branch Family Medical Center, Organon, Otsuka, Patheon, Parexel, Perrigo, Pfizer, Pharma Quality Europe, Playtex, Pozen, PPD, PROCAPS S.A., Promeco, S.A. de C.V., SAIC Frederick, Sanofi Pasteur, Schwarz Pharma, Sidley Austin LLP, Stryker, Solvay Pharmaceuticals, Steris, Talecris, UCB Pharma, Vertex Pharmaceuticals, WL Gore, and Wyeth.

Fifty-nine percent of 2007 participants were managers, directors, vice presidents and senior executives. Participants from Canada, Columbia, France, Italy, Mexico, and Switzerland joined us, as well as participants from across the United States. Barbara Immel, president of Immel Resources LLC, has been asked to serve as conference chairperson again, and is delighted to be planning the conference with Jeff Grizzel of FDAnews. We hope that you can join us at the 3rd Annual Summit in October 2008.

CAPA Classes New

CAPA systems 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 training.

Course brochure

Best Practices: Managing a CAPA System

32nd Annual International GMP ConferenceNew

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.       

GMP Conference

Immel Resources Services

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Latest Articles

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 write 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.

FDA Field Reorganization (two-part editorial)
"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).

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 (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.

Problem Investigations
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.

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.

Global Regulatory Links

This list is provided as a service to our readers. 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

Pharmaceutical GMPs

Medical Device Directives

Active Implantable Medical Devices (AIMDD)
Medical Device Directive (MDD)
In Vitro Diagnostic Directive (IVDD)



          Ministry of Health, Labor and Welfare (English index)

          To purchase English-language translations of newly revised pharmaceutical and medical device GMPs:
          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



United States

Drug cGMPs

For human and animal drugs, therapeutic biologics, and as guide to active pharmaceutical ingredients

Revision of Certain Labeling Controls

Preparation of investigational materials
All clinical material for the U.S. must be produced according to current good manufacturing practices.

Aseptic Processing Guidance

Final Guidance: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production

Guideline on General Principles of Process Validation

CPG on Validation

FDA Compliance Program Guidance Manual on Drug Manufacturing Inspections

FDA Compliance Program Guidance Manual on Inspections of Licensed, Therapeutic Biologics

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 top of this page. 

Human Tissue

Good tissue practice (final rule)

Medical Gases

GMP draft guidance

Part 11 Electronic Records, Electronic Signatures

Good Laboratory Practices (GLPs)

          U.S. GLPs

          FDA Compliance Program Guidance Manual on GLPs

          OECD GLPs

          OECD GLP Guidance Documents

Good Clinical Practices (GCPs)

HIPAA Regulations

Other Useful Guidances (a partial list)

ICH Guidelines

Active Pharmaceutical Ingredients

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 No Longer Enforcing GLPs for Devices

FDA's Center for Devices and Radiological Health (CDRH) recently announced that they are no longer enforcing good laboratory practice (GLP) regulations for devices (21 CFR 58). FDA announced the policy change in May 2007 at the Annual Meeting for the Society for Quality Assurance. FDA does not intend to take enforcement action if a nonclinical laboratory is not following GLPs. Although CDRH may still perform audits of GLP and non-GLP studies, they will be performing data audit and data verification, rather than focusing on GLP requirements. Stated rationale:

* Historically, CDRH review divisions have not required animal safety studies to follow GLP
* Many marketed devices did not follow GLP
* Not feasible to require current manufacturers to follow GLP, especially if showing equivalence to predicate
* Inspections may be issued for non-GLP or GLP animal studies
* Focus on data audit or verification
* Less emphasis on GLP requirements
* More emphasis on auditing safety studies that support high-risk products
* OAI (inspections rated official action indicated, leading to enforcement action) applies to sites with data reliability issues, data falsification, omission, etc.

Comments are from experienced GLP experts: GLPs are critical for determining which experimental therapies are safe to test in clinical trials or research in people, that this policy change will have a significant negative impact on the quality of the data submitted to FDA in support of device applications, and that failure to have data integrity at the beginning of research will affect the quality of data throughout the clinical trials and into the initial postmarket surveillance. Other comments: the problem with not enforcing regulations is that you remove an enforceable standard for how research is conducted and the question is, Where does this stop? At what point does safety testing of medical devices, drugs, and biologics (and food additives) become unnecessary?

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).

cGMP regulation

Interim final rule

Proposed 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
Direct Final Rule
Current Good Manufacturing Practice Regulation and Investigational New Drugs; Direct Final Rule

Proposed Rule

Current Good Manufacturing Practice Regulation and Investigational New Drugs; Companion Document to Direct Final Rule

Draft Guidance
INDs -- Approaches to Complying with CGMP During Phase I (pdf)

Copyright 2007, Immel Resources LLC, Petaluma, CA USA, (707) 778-7222, www.immel.com, immel@immel.com

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