FDA’s COOPERATIVE MANUFACTURING GUIDELINES FOR LICENSED BIOLOGICS

FDA's COOPERATIVE MANUFACTURING GUIDELINES FOR LICENSED BIOLOGICS recognize four types of shared manufacturing arrangements: "short supply," "divided," "shared" and "contract." The guidance, published in the Nov. 25 Federal Register, defines each type of arrangement by the relative role of the manufacturers involved and specifies what FDA will look for from each in the PLA/ELA approval process.

The long-awaited policy statement provides guidance to makers of biological and biotechnology products on obtaining FDA approval for products manufactured under cooperative arrangements. FDA said the intention of the guidance is to accommodate agency regulations to the realities of biotech development where companies may not have the capabilities alone to perform all steps in the manufacturing process. Current regs allow PLAs to be obtained only if an establishment shows it can perform the whole manufacturing process.

A "short supply" arrangement, as defined by the policy, allows a licensed biologic manufacturer to obtain from an unlicensed manufacturing facility source materials which are in short supply due to peculiar growth requirements or scarcity of the source organism required for manufacturing. In filing an application, FDA emphasized that the licensed manufacturer must be able to assure that the product will be made at the unlicensed facility "in full compliance with applicable regulations." The unlicensed facility's manufacturing must be limited to "the initial and partial manufacturing of a product for shipment solely to the licensee." FDA warns that the provisions for short supply arrangements "have limited applicability" and apply only in "unusual circumstances."

"Divided" manufacturing arrangements allow two manufacturers, each licensed to produce a biological product in its entirety, to manufacture that product jointly. They must submit amendments to their PLAs describing what will be done at each facility and the labeling on intermediate and end products. In considering such proposed arrangements, FDA said it will be concerned with the ability of companies "to demonstrate acceptable methods of handling finished product adverse reaction and defect reports."

The impetus for the policy statement is FDA's recognition that a biologics manufacturer seeking licensure may not have the ability to perform all operations at its own manufacturing establishment. Shared and contract manufacturing arrangements are intended to compensate for this limitation.

Under a "shared" manufacturing arrangement, two or more manufacturers "perform different aspects of the manufacture of a product, neither performs nor is licensed to perform all aspects of the manufacture and each manufacturer holds product and establishment license applications." To be eligible for separate licenses, each party must perform critical manufacturing steps on the product "which may alter structure and specificity and that may affect its safety, purity, or potency," the guidance states.

However, if a company that has been instrumental in product development conducts several final manufacturing steps that would not otherwise qualify it for separate licensure, FDA says it will consider the firm eligible for separate product and establishment licenses.

The guideline makes clear that the manufacturer of the final product under a shared manufacturing arrangement has primary responsibility for "providing data demonstrating the purity, potency, safety, and effectiveness of the end product," and for any post-approval obligations. In addition, the manufacturer must demonstrate the "technical knowledge and expertise to identify any manufacturing problems or errors occurring at any stage in the manufacture of the product."

Under "a contract" manufacturing agreement, only one of the parties holds a license, and the other performs a step or steps in the manufacturing process not generally considered critical enough to warrant licensure. Examples of steps that would not warrant separate establishment and product licenses are chemical and biological testing, formulation, sterile filling, lyophilization and labeling. When these steps are conducted outside the licensed facility under a contract manufacturing agreement, compliance with the terms of the license at the contract facility is the responsibility of the license holder.

Separate licensure generally allows FDA to act as an intermediary between firms engaged in joint manufacture and permits them to avoid disclosing proprietary information to one another. However, because information on the contract facility must be included in the ELA, the guidance says, "the license holder should have access to floor plans, equipment validation and other production information from the contract site necessary to assure purity and potency of the product."

For both divided and shared manufacturing arrangements, the guidance explains how to meet the requirement that the name, address, and license number of each participating licensed establishment appear in labeling. The requirement may be met by putting the intermediate product manufacturer information in the description section of the product package insert, the guidance states. It is not necessary to include contract facility information on package labeling of a finished product.

* The policy statement has been a long time in the works at FDA. In 1986, the agency was considering a formal statement to extend the divided manufacturing policy established in November 1983 for monoclonal antibodies to other biologicals. At that time, FDA said the guidance could be issued as early as the first half of 1987. It is now being published at a time when the Center for Biologics Evaluation and Research is gearing up for an expected influx of biotechnology applications.