• ADVANCED Bulletproof CAPA Investigations Class
• Fifth Annual FDA Inspections Summit
• MedCon 2010
• Free Articles
• Recent FDA Inspection Trends
• Global Regulatory Links
• Free Compliance Resources
• FDA Revises Pharma GMPs
• FDA Exempts Most Phase 1 Clinical Material from Pharmaceutical GMP Regulation
  
• FDA No Longer Enforcing GLPs for Devices
• Final cGMPs for Dietary Supplements

ADVANCED Conducting Bulletproof CAPA Investigations Class

For two 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 being offered in 2010:  in Raleigh, NC (March), Bethesda, MD (June), and San Juan, Puerto Rico (September). The brochure is available here.

Class topics include FDA regulatory requirements and expectations, how FDA inspects CAPA systems and a firm's investigations, managing CAPA, tips on selecting and training investigators, 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 throughout the United States over the past few years in Boston, Chicago, Minneapolis, Philadelphia, Raleigh, San Diego, the 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 10 years.

Curious about the kinds of things that 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 described below.

Converting CAPA to an Advantage

Fifth Annual FDA Inspections Summit

The Fifth Annual FDA Inspections Summit will be 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 their FDA inspections, to provide current information re: FDA enforcement and inspection trends, to better protect patients by improving the overall compliance of the industry, and to provide practical information that participants can immediately use. Barbara Immel has been fortunate to serve as conference chairperson since the conference's inception. In 2009, seventy-five percent of the participants were directors, vice presidents and managers at over 100 organizations. Participants from Canada, Costa Rica, Denmark, India, Ireland, and the United States attended the conference in 2009. FDA speakers last fall included:

* Deb Autor, Director, Office of Compliance, CDER
* Leslie Ball, Director, Division of Scientific Investigations, Office of Compliance, CDER
* Evelyn Bonnin, District Director, Baltimore District Office, Office of Regulatory Affairs
* Christine Drabick, Consumer Safety Officer, Bioresearch Monitoring Branch, CBER
* Lori Lawless, Consumer Safety Officer (Device Investigator), Baltimore District Office, Office of Regulatory Affairs
* Stephanie Shapley, Bioresearch Monitoring Specialist, Office of Regulatory Affairs
* Kimberly Trautman, Consumer Safety Officer and Device CGMP Expert, CDRH
* Larry Spears, Deputy Director for Regulatory Affairs, CDRH

Recent FDA Inspection Trends

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)
*  QC Unit Responsibilities (211.22 d)
*  Personnel Qualifications (211.25 a)
*  In-Process/Drug Controls (211.110 a)
*  Written Procedures (211.100 a)
*  Complaint Files (211.198 a)
*  Procedure Deviations (211.100 b)
*  Laboratory Controls (211.160 b)
*  Stability Testing (211.166 a)
*  Laboratory Control SOPs (211.160 a)

Top device observations used in Turbo EIR* (FY 2007)

*  CAPA Activities/Documentation (21 CFR 820.100 b)
*  Complaints (820.198 a)
*  Quality Audit (820.22)
*  CAPA Procedures (820.100 a)
*  Medical Device Report Procedures (803.17)
*  Process Validation (820.75 a)
*  Management Responsibility (820.20)
*  Design Controls (820.30 a)
*  Document Controls (820.40)
*  Management Review (820.20 c)

Top Five Citations -- Biological Drugs

*  Batch Review (Investigations) (21 CFR 211.192)
*  QC Unit Responsibilities (211.22)
*  Production Procedures (211.100)
*  Control of Microbial Contamination Procedures (211.113 b)
*  Changes to Approved Applications (601.12)

Top Five Citations -- Biological Devices

*  CAPA Procedures (21 CFR 820.100 a)
*  Nonconforming Product (820.90)
*  Complaints (820.198)
*  Contamination Control (820.70 e)
*  Production and Process Controls (820.70 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.

Global Regulatory Links

European Union

Pharmaceutical GMPs

Medical Device Directives

Canada

Japan

          Ministry of Health, Labor and Welfare (English index)

World Health Organization

WHO GMPs

Australia

United States

Drug cGMPs

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. 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

Cosmetics   

Food CGMPs

Veterinary Biologics

Human Tissue

Medical Gases

Part 11 Electronic Records, Electronic Signatures

          U.S. GLPs

          FDA Compliance Program Guidance Manual on GLPs

          OECD GLPs

          OECD GLP Guidance Documents

Good Clinical Practices (GCPs)

ICH Guidelines

On September 8, 2008, FDA issued a final rule changing the pharmaceutical GMPs (21 CFR 210 and 211). The changes became effective December 8, 2008. This follows on the heels of an earlier (and different) revision to exempt most phase 1 clinical material (but not all) from the need to follow 21 CFR 210/211 when manufacturing the clinical material, discussed in detail below.

Key changes 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 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. Fortunately, 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. 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 is a highly experienced, thoroughly trained employee, and that the computerized system is thoroughly validated and remains in a validated state. Using a sole, human verifier applies to only the specific GMP tasks discussed above.

History. On April 4, 2008, FDA withdrew the direct final rule dictating 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 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.

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 above). 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, has been a frequently cited deficiency in recent 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. Pharmaceutical Technology asked Barbara Immel to write an article on the proposed changes. "FDA's Direct Final Rule to Change the Pharmaceutical GMPs" was published in June 2008. This article has received rave reviews. 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. A link to the final regulation and to our comments submitted to FDA concerning this proposed rule are shown below.

Final Rule

Comments Submitted by Immel Resources LLC

FDA Exempts Most 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 Barbara Immel (A Brief History of the GMPs), submitted with our comments to the agency.

FDA removed an enforceable standard (the regulation) in favor of using a guidance document, which is not legally binding. This approach contradicts European Union requirements, which require that companies follow Annex 13 of their GMPs in producing clinical material. Problems with the FDA final Phase 1 guidance document include it allows the same person who made the clinical material to release it, and it does not require that that individual be a trained QC unit (Quality Assurance) professional. This is a direct contradiction of both U.S. and European Union GMPs, and of common sense. Clinical trial material, destined to be used by some of the most vulnerable patient populations (including the terminally ill) should require a knowledgeable check and balance before it is released. Immel Resources strongly believes that all clinical trial material should be released by an experienced, knowledgeable, QC unit (Quality Assurance) professional, and that this individual should be different from the person who manufactures the material. Even in publishing, a proofreader, copyeditor, editor, and author all doublecheck a single article before it is published. Quality checks for experimental material going into human beings for the first time are much more critical. For clinical and commercial material, a knowledgeable quality check protects patients and clinical trial volunteers from harm, and it also protects your organization (from lawsuit, regulatory action, disqualification, etc.).

Many knowledgeable QA and regulatory compliance experts feel that this decision 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.

Final Rule

FDA No Longer Enforcing GLPs for Devices

FDA's Center for Devices and Radiological Health (CDRH) announced at a public meeting in May 2007 that they were no longer enforcing good laboratory practice (GLP) regulations for devices (21 CFR 58). With the change in administration and the new Commissioner, Dr. Margaret Hamburg, this policy may well be reversed. But here is a synopsis of what FDA announced in 2007 at the Annual Meeting for the Society for Quality Assurance.

FDA representatives publicly stated at that meeting that 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.

cGMP regulation