This new guidance builds on earlier advisory documents from FDA and the International Conference on Harmonization (ICH) that
encourage manufacturers to adopt quality management approaches. The ICH Q7 guidance addresses quality issues related to APIs,
while the Q9 document recommends risk management in evaluating suppliers and contract manufacturers. Q10 on pharmaceutical
quality systems details how quality risk-management approaches can ensure control of outsourced activities. Q10 recognizes
that pharmaceutical companies are responsible for ensuring that outsourced activities are under control; it's not enough,
the regulators agree, to assume that other parties in the supply chain adhere to global standards and that regular audits
of suppliers and routine testing of materials is sufficient to ensure product quality.
FDA also addressed third-party responsibilities in a November 2008 CBER and CDER guidance on establishing cooperative manufacturing
arrangements for licensed biologics (4). That guidance describes a range of cooperative arrangements and also notes that the
licensed manufacturer is responsible for compliance with product and establishment standards even if it does not own the facilities
engaged in significant manufacturing steps. While this guidance focuses on manufacturer agreements with contract manufacturers,
additional FDA guidances may address relations with vendors of APIs and other ingredients and contractor auditing, among other
Despite the benefits of a formal quality agreement for a manufacturer to ensure contractors follow standard operating procedures
and that final products meet specifications, the negotiating process can be tricky on all sides. A large pharmaceutical company
will want multiple CMOs and suppliers to follow its standards and requirements. However, that would require each CMO to contend
with diverse procedures and policies from multiple clients. Consequently, many contracts leave it to the CMO to take steps
necessary to ensure a quality product, but such lack of specificity can lead to problems if there are deviations or if a batch
fails to meet specifications.
In commenting on the draft guidance, FDA would like input from industry on whether QA templates would be helpful, or if further
standardization will create only more difficulties. Case studies that illustrate ways to deal with the complexities of contract
negotiations would be helpful, said Paula Katz, OMPQ acting branch chief, at last month's PDA/FDA Pharmaceutical Supply Chain
Workshop in Bethesda, Maryland.
When FDA inspects a CMO, "both parties will be on the hook" if there's a problem with the drug, said Katz, noting that a QA
that spells out ahead of time the responsibilities of each party can help deal with problem situations. Katz acknowledged
that there are challenges in negotiating QAs, but that FDA expects manufacturers to have some kind of agreement in place with
just about everyone they do business with, even if the document only lays out a minimum level of compliance that the firm
expects from the contractor. The bottom line, she said, is for manufacturers to demonstrate how they "have control and oversight"
Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, email@example.com
Read Jill's blogs at http://PharmTech.com/wechsler.
1. FDA, Guidance for Industry, Contract Manufacturing Arrangements for Drugs: Quality Agreements, Draft Guidance (FDA Silver Spring, Md., May 28, 2013).
2. FDA, Warning letter to Pristine Bay, L.L.C. dba Vianda, dated April 26, 2013,
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2013/ucm350469.htm, accessed June 14, 2013.
3. P. Hyman and K. Bond, http://Fdalawblog.net/, May 29, 2013.
4. FDA, Guidance for Industry: Cooperative Manufacturing Arrangements for Licensed Biologics (FDA, Rockville, Md., November 2008).