The globalization of commercial drug production has increased reliance on vendors for raw materials and finished products,
a situation that requires policies and systems to ensure that all parties understand responsibilities for meeting quality
standards. FDA seeks to help manufacturers that hold market authorizations to maintain clear and effective relations with
contractors through new guidance issued in May 2013 (1). The document encourages the use of written quality agreements (QAs)
specifying contractor obligations to follow rules and implement quality processes.
The guidance document is the latest in a series of advisories, legislation, and compliance actions that address regulatory
requirements for ensuring production of quality medicines. The FDA Safety & Innovation Act (FDASIA) of 2012 includes a provision
(section 711) specifying that cGMPs include the implementation of quality oversight and controls over manufacture of drugs.
This requirement applies to materials used in drug manufacturing, as well as finished products. Recent warning letters, moreover,
emphasize that a manufacturer is responsible for infractions or noncompliance of its suppliers and vendors.
These actions reflect ongoing concerns about lax practices at contract manufacturing organizations (CMOs) that lead to drug
shortages and delay approval of new drugs and biologics. Manufacturing difficulties at Lonza and at Boehringer Ingelheim's
Ben Venue Laboratories have led to shortages in "essential" medicines. GlaxoSmithKline recently blamed CMO problems for shortages
in its treatment for restless leg syndrome. In addition, FDA delayed approval of Allergan's new migraine therapy Levadex (dihydroergotamine)
in April because of difficulties producing this inhaled product by Exemplar Pharma.
FDA's guidance, Contract Manufacturing Arrangements for Drugs: Quality Agreements, provides specific strategies for manufacturers to ensure drug quality from third parties. The document maps ways to define
and document the responsibilities of all parties involved in commercial production of human and animal drugs, biotechnology
products, combination products, and APIs. The Office of Manufacturing and Product Quality (OMPQ) in the Center for Drug Evaluation
and Research (CDER) prepared the guidance document in cooperation with staff from the Center for Biologics Evaluation and
Research (CBER), the Center for Veterinary Medicine, and the Office of Regulatory Affairs. FDA encourages manufacturers to
submit comments on the draft guidance by July 29, 2013, particularly examples of agreements and cases illuminating contracting
FDA regulations don't require specific written agreements between pharmaceutical companies and third-party contractors, unlike
the European Union, which mandates formal technical agreements between authorized manufacturers and all suppliers and contractors.
FDA instead advises "owners" of a finished product to implement QAs with "contracted facilities" to clarify and document each
party's obligations and responsibilities for ensuring compliance with GMPs and other regulations. FDA proposes that a QA stand
separate from commercial contracts and specify the products or services involved, effective dates and termination, dispute
resolution, and points of contact. A communication plan in the QA should explain processes for disclosing problems, such as
how manufacturing deviations should be investigated, documented, and resolved. Change control is an important issue and requires
clear procedures for handling new raw materials, establishment locations, manufacturing processes, testing procedures, manufacturing
equipment, and other changes.
A main theme is that the owner of a new drug application is ultimately responsible for any failings or shortcomings by contractors.
While all parties to a contract must prevent adulteration or misbranding, FDA emphasizes that owners cannot escape responsibility
by pointing to vendor failings. Recent FDA warning letters to manufacturers of dietary supplements similarly cite legal precedents
for holding the "final distributor" responsible for ensuring that its products comply with GMPs. In an April 26, 2013 warning
letter to the owner of Pristine Bay LLC (Vianda) of Cincinnati, Ohio, FDA notes that although the firm may contract out certain
manufacturing operations, "it cannot by the same token contract out its ultimate responsibility to ensure that the dietary
supplements...are not adulterated" (2). While such statements are not new, attorneys Paul Hyman and Katie Bond of the lawfirm
Hyman, Phelps, & McNamara, in the FDA Law Blog, comment that they are unusual in specifically citing the "Park doctrine" to bolster FDA warnings that a company and its
officers might be held liable for acts by a third-party contractor (3).