Questions and Answers

MedImmune Warning Letter

When did FDA identify the manufacturing problems at MedImmune that led to the Warning Letter?

FDA instituted annual post approval inspections of influenza vaccine manufacturers in 2005 to facilitate early detection and resolution of problems in manufacturing. During the 2006 annual inspection of MedImmune, FDA identified some issues related to the firm's manufacture of FluMist bulk monovalent lots and discussed them with MedImmune management. This year's inspection, conducted from March 21 to 29, revealed that some of these issues had not been adequately addressed by the firm and had continued.

What steps is the agency taking?

FDA inspected MedImmune's Liverpool, UK, facility from March 21 to 29, 2007. At the conclusion of the inspection, FDA issued a list of inspectional observations (FDA Form 483) to the firm, identifying concerns related to the firm's manufacture of bulk monovalent lots used to manufacture the trivalent influenza vaccine (FluMist, Influenza Virus Vaccine Live, Intranasal). After determining that the firm's response to the FDA Form 483 was inadequate to address the serious deviations from current good manufacturing practice, FDA issued the Warning Letter.

To facilitate the firm's remediation efforts, FDA requested a meeting with the firm's officials and encouraged regular interactions between FDA and MedImmune.

Why did FDA issue this Warning Letter?

FDA's practice, depending upon the nature of the regulatory violation, is to give individuals and firms an opportunity to take voluntary and prompt corrective action before the agency initiates an enforcement action. Warning Letters are issued to achieve voluntary compliance and to establish prior notice. The use of Warning Letters and the prior notice policy are based on the expectation that most individuals and firms will voluntarily comply with the law.

Warning Letters are issued only for violations of regulatory significance. Significant violations may lead to enforcement action if not promptly and adequately corrected. A Warning Letter is the agency's principal means of achieving voluntary compliance with applicable laws and regulations.

Will the Warning Letter impact the availability of MedImmune's influenza vaccine for the 2007-2008 flu season?

FluMist is currently approved for immunization of healthy children and adolescents 5-17 years of age and healthy adults 18-49 years of age against influenza disease caused by influenza types A and B contained in the vaccine.

At this time, the deficiencies noted during the FDA inspection of MedImmune's Liverpool manufacturing facility are not expected to significantly affect the availability of FluMist for the 2007-2008 flu season, but we will review the progress made by the company on a regular basis. Following receipt of a Warning Letter, manufacturers can continue to manufacture their products while simultaneously making corrective actions.

What will the firm have to do to come into compliance?

The firm will need to address the issues identified in the Warning Letter, including corrective actions that are in the process of being taken or will be taken. To facilitate the firm's remediation efforts, FDA has requested a meeting with the firm's officials and encouraged regular interactions with appropriate staff at MedImmune. The agency intends to remain actively engaged with the firm to resolve the issues as quickly as possible.

What are "bioburden excursions"?

"Bioburden" means the number of live microorganisms (e.g., bacteria and mold) present in a sample. Bioburden is generally expressed as CFU (colony forming units) per ml (milliliter). Bioburden excursion means that the amount of bioburden in the sample (CFU/ml) exceeds the alert or action limit set by the manufacturer. When action limits are exceeded, the manufacturer should conduct investigations and implement corrective actions based on the results of the investigations.

Why is bioburden expected in the early steps of influenza vaccine manufacturing?

The early steps of influenza vaccine manufacture involve growing the influenza vaccine viruses in hen's eggs. These early steps in the manufacturing process are not sterile, and therefore some bioburden is expected in the viral harvests obtained from the eggs. However, bioburden should be monitored to ensure the manufacturing process is in control. When bioburden action limits are exceeded, the manufacturer should conduct investigations and implement corrective actions based on the results of the investigations. The viral harvests obtained from the eggs are further processed and subjected to a filtration step that should yield monovalent lots that are sterile. Although the viral harvests exceeded the bioburden action limits in some instances at MedImmune in 2006-2007, all of the filtered monovalent lots and the final trivalent vaccine product met all specifications, including sterility.

Are any other manufacturers affected?

No, this Warning Letter applies only to MedImmune's Liverpool manufacturing facility.

What is the expected availability of influenza vaccines for the 2007-2008 flu season?

Currently, a large supply of influenza vaccine is expected to be available from multiple manufacturers for the 2007-2008 flu season. While we will not know precisely until later in the year the total number of doses that will be available, we believe the supply will be at least as robust as it was for the 2006-2007 flu season.

What is Current Good Manufacturing Practice (CGMP) regulations?

The CGMP regulations provide the methods to be used in and the facilities or controls to be used for the manufacturing, processing, packing or holding of a drug to assure the drug meets the requirements of the Federal Food, Drug and Cosmetic Act as to safety and has the identity and strength, and meets the quality and purity characteristics it is represented to possess.

What does "monovalent" mean?

Each monovalent concentrate is made from a specific single virus strain. Three monovalent concentrates are subsequently mixed together to make the trivalent vaccine, which protects against three different types of influenza virus.

What does "trivalent" mean?

A trivalent influenza vaccine protects against three different types of influenza viruses (H3N2, H1N1 and B). The trivalent influenza vaccine is a combination of three monovalent components that are combined to make the final vaccine product.

Will this issue affect MedImmune's efforts to develop an avian (H5N1) influenza vaccine?

FDA has no reason to believe it will affect the firm's H5N1 vaccine development efforts.

Does this Warning Letter impact FDA's ability to approve any pending applications?

In general, FDA may approve a BLA or a supplement to a BLA only when the compliance status of the applicable product(s) and establishment(s) is acceptable. However, FDA can approve a BLA supplement when it represents an improvement or change intended to help the manufacturer achieve compliance.

MedImmune submitted a supplement to its biologics license application for FluMist to extend the indication to children less than 5 years of age, without a history of wheezing or asthma. What is the status of this supplement?

As MedImmune publicly disclosed, FDA issued a complete response letter for the supplement. FDA review staff continue to interact with the firm with regard to this supplement.

What is a complete response letter?

At the end of a complete review cycle for a pending license application or supplement, FDA issues an action letter. FDA's Center for Biologics Evaluation and Research issues one of three types of action letters at the end of a complete review cycle - approval letters, complete response letters, or denial letters. A complete response letter summarizes the deficiencies, and where appropriate, describes for the applicant actions necessary to move the application toward approval. After issuing a complete response letter, FDA continues to work with sponsors to resolve any outstanding issues.