July 2006

REGULATIONS

FDA Withdraws Seven CMC and Stability Guidance Documents

The US Food and Drug Administration (Rockville, MD, www.fda.gov) is withdrawing seven guidance documents "because some of the principles in these guidances are inconsistent with the agency's initiative, Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century (CGMP Initiative)." The withdrawal was announced in a recent issue of the Federal Register (1).

The FDA Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are withdrawing the following guidances, originally issued individually or jointly:

• Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application (CDER, February 1987);

• Submitting Documentation for the Stability of Human Drugs and Biologics (CDER and CBER, February 1987);

• Stability Testing of Drug Substances and Drug Products (Draft) (CDER and CBER, June 1998);

• Drug Product: Chemistry, Manufacturing, and Controls Information (Draft) (CDER and CBER, January 2003);

• Submission of Chemistry, Manufacturing and Controls Information for Synthetic Peptides (CDER and CBER, November 1994);

• BACPAC I: Intermediates in Drug Substance Synthesis; Bulk Actives Postapproval Changes: Chemistry, Manufacturing, and Controls Documentation (CDER and CBER, February 2001);

• Drug Substance: Chemistry, Manufacturing, and Controls Information (Draft) (CDER and CBER, January 2004).

(The Center for Veterinary Medicine is revising rather than withdrawing the last two documents listed. The revised guidances are available on http://www.fda.gov/cvm).

According to FDA's Federal Register notice, "the withdrawals are part of a continuing review of all FDA guidances. We will continue to review our guidances for their consistency with the CGMP Initiative and may withdraw or revise other guidances if they do not reflect our current thinking or to align them with the concepts of the CGMP Initiative, the Quality by Design Initiative, or Question-based Reviews." The agency is developing new guidance documents to conform with these initiatives. Until they arrive, FDA directs the human-drug pharmaceutical industry to International Conference on Harmonization's (ICH) guidances, on FDA's Web site (2):

• M4: Common Technical Document (CTD) for the Registration of Pharmaceuticals for Human Use (CTD) (October 2001);

• M4: The CTD—Quality (August 2001);

• Q1A(R2): Stability Testing of New Drug Substances and Products (November 2003);

• Q1B: Photostability Testing of New Drug Substances and Products (November 1996);

• Q1C: Stability Testing for New Dosage Forms (May 1997);

• Q1D: Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (January 2003);

• Q1E: Evaluation of Stability Data (June 2004);

• Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV, Revision 1 (July 2004);

• Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (December 2000);

• Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (August 1999);

• Q7: Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (August 2001);

• Q8: Pharmaceutical Development (Draft) (February 2005);

References

1. US Food and Drug Administration, Guidance for Industry on Chemistry, Manufacturing, and Controls Information; Withdrawal and Revision of Seven Guidances, Federal Register 71 (105), 31194–31195 (June 1, 2006), DOCID:fr01jn06-73, http://a257.g.akamaitech.net/7/257/2422/01jan20061800/edocket.access.gpo.gov/2006/E6-8417.htm, accessed June 14, 2006.

2. FDA, "Guidance Documents" (Rockville, MD), http://www.fda.gov/cder/guidance/index.htm, accessed June 14, 2006.

–Douglas McCormick

WARNING LETTER

Wyeth Pharmaceuticals Cited for CGMP Violations

Noting several violations in current good manufacturing practice regulations, the US Food and Drug Administration issued a Warning Letter to Wyeth Pharmaceuticals's (Collegville, PA, www.wyeth.com) manufacturing facility in Puerto Rico. The site manufactures, processes, and packages dosages of the company's "Triphasil," "Prempro," "Effexor," "Duofem," "Gestodene," "Caltrate," and "Inderal" tablets, as well as "Advil" liquid gels, caplets, and gel caplets.

The letter, resulting from a November and December 2005 inspection, details five major deficiencies:

1. "failure to thoroughly investigate the unexplained discrepancies or out-of-specification results in batches of Triphasil 21 and Triphasil 28 tablets manufactured" (21 CFR 211.192);
2. "failure to clean and maintain the packaging equipment at appropriate intervals to prevent contamination that would alter the safety, strength, quality of the drug products manufactured" (21 CFR 211.67[a]);
3. "failure to adequately inspect packaging and labeling equipment prior to its use to assure that all drug products have been removed from previous operations" (21 CFR 211.130[e]);
4. "failure to submit NDA Field Alert Reports within three working days of becoming aware of information concerning any significant chemical, physical, or other change or deterioration in the distributed drug product" (21 CFR 314.81);
5. "failure of your quality control unit to review production records to assure that errors have not occurred and to fully investigate errors that have occurred during the manufacturing of your drug products" (21 CFR 211.22[a]).

Among specific concerns, the letter describes consumer complaints of the presence of foreign metal objects (e.g., screws, washers, ejector pins) within bottles of finished product and in-plant discovery in the filler machine of two tablets from a previously run batch of a different product, even after a complete line clearance had been performed.

Of particular moment is the extensive description of the failure to properly identify the root cause of unknown peaks detected in Triphasil samples tested over a period of several months. In one case, expired samples were used. Specifically, the investigators expressed concern "that while the investigation has been ongoing for months, the affected lots remain in the market. In addition, there is no assurance that other lots are not affected by the same unknown."

The letter does acknowledge, however, the company's February 2006 statement that a toxicological assessment concludes that the extractable "does not pose a safety concern," a statement reiterated by company spokesman Douglas Petkus, who pointed out that the company recalled some lots of Triphasil and that "there have been no reports of any impact on patient safety and product safety."

–Maribel Rios

RESTRUCTURING

Schering-Plough Restructures Manufacturing Operations

Schering-Plough Corporation (Kenilworth, NJ, www.schering-plough.com) announced plans to phase out manufacturing operations at its Manati, Puerto Rico site, expecting to discontinue operations there by the end of 2006. The company also will reduce its workforce at manufacturing facilities in Las Piedras, Puerto Rico and in Kenilworth and Union, New Jersey.

The actions will eliminate roughly 1100 positions, primarily in 2006. Approximately 600 regular, full-time positions will be eliminated in Puerto Rico, including 550 in Manati and 50 in Las Piedras. Schering-Plough expects to continue to employ roughly 475 people in Las Piedras. The company also will eliminate 500 regular, full-time positions in Kenilworth and Union.

Schering-Plough expects these actions to generate annual cost reductions of $100 million in 2007. Total expenses associated with these actions will be between $235–260 million: $60–70 million for severance; $85 million for fixed asset and inventory write-offs; and $90–105 million for accelerated depreciation and closure costs. The company will incur $130 million of these expenses in the second quarter of 2006, with the balance in the second half of 2006.

–Patricia Van Arnum

REGULATIONS

CDER and CBER Issue Guidance on ICH Q8 Manufacturing Submissions

The US Food and Drug Administration's Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and Research (CBER) have released a new Guidance for Industry: Q8 Pharmaceutical Development.

The document suggests which elements drug makers should include in the Pharmaceutical Development section of International Council on Harmonization (ICH) Common Technical Document (CTD) submissions.

"The Pharmaceutical Development section," says the Guidance, "provides an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management," demonstrating the manufacturer's ability to "design a quality product and its manufacturing process to consistently deliver the intended performance of the product."

The 12-page Guidance suggests elements that should be included in discussions of drug substances, excipients, formulation development, and physico-chemical and biological properties.

The Guidance reflects the science-and risk-based approach of the September 2004 Critical Path initiative. Although it describes minimum levels of information required in each section of a submission, the Guidance also suggests a solid return for submissions that go beyond the minimum to describe the knowledge gained during development clearly and show how it evolved: Demonstrating "a higher degree of understanding of material attributes, manufacturing processes, and their controls" can justify "an expanded design space" and bring more regulatory flexibility via:

1. risk-based regulations;
2. postapproval process improvements, within the design space, without further regulatory review;
3. fewer postapproval submissions;
4. real-time quality control, reducing end-product release testing.

The Guidance closes with a half-page glossary, which summarizes the key concepts:

1. Continuous process verification: An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated.
2. Design space: The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory postapproval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.
3. Formal experimental design: A structured, organized method for determining the relationship between factors affecting a process and the output of that process. It is also known as design of experiments.
4. Lifecycle: All phases in the life of a product from the initial development through marketing until the product's discontinuation.
5. Process analytical technology (PAT): A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.
6. Process robustness: Ability of a process to tolerate variability of materials and changes of the process and equipment without a negative impact on quality.
7. Quality: The suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity.

–Douglas McCormick

Bristol-Myers Squibb Selects Massachusetts Site for New Biologics Facility

Bristol-Myers Squibb Company (BMS, New York, NY, www.bms.com) selected Devens, Massachusetts as the site for its new, large-scale, multiproduct, bulk biologics facility. Earlier this year, BMS's board approved $660 million to build the new plant.

Construction will begin in September 2006, and the facility is projected to be operationally complete in 2009. Commercial production of biologic compounds is anticipated to begin in 2011. The site initially will require 350 employees, with a modular design that can accommodate up to 550 staff.

–Patricia Van Arnum