FDA Means Business – Watch Out Contract Facilities and Product Owners!
Written by Bob Pollock • May 28, 2013
On Friday May 24, 2013, FDA published a draft guidance entitled Contract Manufacturing Arrangements for Drugs: Quality Agreements. The Guidance defines the who, what, and where of contact manufacturing, and outlines what the FDA's expectations are relative to the Quality Agreement between the Owners (defined by FDA as “the person that places the product into interstate commerce, whether the product is covered by an approved application or not”), and Contract Manufacturing Operations (CMOs) or contact facilities (“outside entities performing [any] manufacturing operation for the product Owner”).
While the concentration on Quality Agreements has been relied upon by industry, historically strongly suggested by FDA, and has been the subject of various ICH Guidance documents, this recent issuance by FDA is believed to be a harbinger of a wave (perhaps a tidal wave) of enforcement action targeting CMOs, contract facilities and Owners that may not have or have ill-defined Quality Agreements. The document provides FDA's “current thinking on defining, establishing, and documenting the responsibilities of each party (or all parties) involved in the contract manufacturing of drugs subject to Current Good Manufacturing Practice (CGMP). In particular, we [FDA] describe how parties involved in the contract manufacturing of drugs can utilize Quality Agreements to delineate their responsibilities and assure drug quality, safety, and efficacy. This guidance applies to the commercial manufacturing of Active Pharmaceutical Ingredients (APIs or drug substances, or their intermediates), finished drug products, combination products, and biological drug products. For the purposes of this guidance, the term “manufacturing” includes processing, packing, holding, labeling operations, testing, and operations of the Quality Unit.”
The FDA goes on to say that “[O]wners may benefit from using contracted facilities in many ways, including enhanced speed and efficiency in specific processes, expertise in a specific technology, and expanded capacity. In all cases, the Owner is responsible for assuring that drugs introduced for interstate commerce are neither adulterated nor misbranded as a result of the actions of their selected Contracted Facilities. All Contracted Facilities must assure compliance with applicable Current Good Manufacturing Practices for all manufacturing, testing or other support operations performed to make a drug(s) for the Owner.” (emphasis added)
The Guidance outlines the statutory and regulatory basis for concept of the Quality Agreement and establishes the link between current final Guidance (e.g., ICH Q7, ICH Q9 and ICH Q10) and the FDA expectation that well-defined Quality Agreements are necessary to assure that the requirements for complying with cGMPs are clearly spelled out by the parties involved. With respect to ICH Q10, the Agency highlights the following points:
“Before outsourcing manufacturing activities, the Owner should conduct a risk review that evaluates the extent of controls required for the particular supplier and the particular product or service covered by the agreement, and based on this risk, assess the oversight appropriate and assess the suitability and competence of the potential Contracted Facility(ies) to carry out the activity (e.g., audits, material evaluations, qualification).
Owners and Contracted Facilities should define the responsibilities and communication processes for quality-related activities of the involved parties, and document these in a written agreement between the Owner and Contracted Facility.
Owners should monitor and review the performance of the Contracted Facility and identify and implement any needed improvements.
All parties performing manufacturing operations should monitor incoming ingredients and materials to ensure they are from approved sources using the agreed supply chain.
These principles of quality management extend to contract manufacturing, and FDA expects parties engaged in contract manufacturing operations to implement quality management practices. This guidance is intended to build upon the quality management principles and recommendations outlined above and illustrate key points in developing and executing contracted manufacturing arrangements.”
The Guidance also outlines FDA expectations relative to:
Documenting contract manufacturing arrangements in Quality Agreements
Defining what is a Quality Agreement
Establishing the appropriate elements of the Quality Agreement along with outlining responsibilities of each party to the agreement
There are also some illustrative examples of some common problems in contracted manufacturing arrangements that FDA has seen and provides ways in which those problems can be resolved. But FDA reiterates that regardless of the type of operation that the contracted facility performs, the Quality Agreement DOES NOT exempt contracted facilities from cGMP requirements related to the operations they perform.
We expect that the issuance of this document will result in an increase in enforcement activity relative to the area of contracted facilities and could well start a series of Warning Letters and 483 observations for virtual companies, owners, as well as contracted facilities that may have thought that their Quality Agreements may have somehow insulated them from FDA action.
