Contract Manufacturing Operations and You--the "You" Part

There's a saying that goes: “If it's left up to two people to water the horse, the horse will go thirsty.” So when it comes to the shared responsibilities between the sponsor and their contract manufacturer, it's important to ensure that the product does not die of thirst.

The growing trend toward outsourcing has not been lost on Rick Friedman, Director FDA Division of Manufacturing & Product Quality. From all indications, it is one of his inspection priorities to ensure the sponsor is carrying the water bucket.

He emphasized at the 2010 PDA/FDA meeting mid-September in Washington, DC, that sponsors should expect to hear questions during inspections about how their companies are making sure that their CMOs are actually being monitored.

There are tools at the sponsor’s disposal to help ensure that both parties are going into the relationship with their eyes open and to establish expectations. These include:

·       Due diligence audits to identify potential risks up front

·       Quality Agreements to establish who does what and whose procedures and standards apply

·       Supply Agreements to establish the business requirements and financial terms

However, after the dance is done and the CMO is integrated into the supply chain, remember “they” are “you,” and “you” are ultimately responsible for product quality.

This was made clear in the “lecture” portion of the Warning Letter to River's Edge Pharmaceuticals¹:

Although you have agreements with other firms that may delineate specific responsibilities to each party (e.g., quality control responsibilities), you are ultimately responsible for the quality of your products. Regardless of who manufactures your products or the agreements in place, you are required to ensure that these products meet predefined specifications prior to distribution and are manufactured in accordance with the Act and its implementing regulations, including CGMP regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Part 211.

So, in addition to the tools that initiate the relationship, there are also tools to ensure the sponsor exercises ultimate responsibility for product quality—and these must not be delegated:

·       Auditing (GMP) the contract manufacturing facility

·       Trending of product quality data and quality system performance

·       Approving changes that potentially affect the validated process and product

·       Approving batch rework, reprocessing, culling/inspection

·       Observing your product being manufactured

·       Deciding the final batch disposition (accept or reject)

Taking ultimate responsibility makes sense. After all, CMOs have their own problems. Their problems become incremental problems to you.

Take the most recent example of Contract Pharmacal Corporation², a full-service contract manufacture.

This firm received a Warning Letter on October 14 that ran the gamut and also cited repeated violations from previous inspections. FDA recommended that they engage a third party consultant having appropriate CGMP experience to assess their facility, procedures, and systems on a routine basis to ensure their drug products have their appropriate identity, strength, quality, and purity. (See The QA Pharm 9/25/10, When FDA Recommends a Consultant—Implications for the Pharma QCU.)

So be involved and develop not only a legal relationship, but also an active partnership that works well together all the way down to the shop floor.

But can there ever be “too involved, or too controlling?”  That depends.

The worst case I ever saw was the outright bullying of a CMO by a big name, global pharma company—because they could. The CMO that was hungry for business took their regular beating—because they had to.

So, to the sponsor who likes to throw his weight around, I say—Be careful what you ask for, you might get it. Demanding unreasonable launch dates; constantly making last minute schedule changes; and insisting that it be your exact SOPs adopted as their quality system infuse volatility throughout the CMO. For this you get happy smiles and unwanted variation in the form of half-baked processes, last-minute training of the operators, and complexity due to “one more difference” in the way something has to be done at the CMO.

To the CMO, I say—Be careful what you promise. You may get the business, but are you truly engineered for the sponsor’s products? Does the sponsor expect shortcuts? Are you staffed to deal with the inefficiencies as a result of mercurial sponsors that make demands much better than they can forecast and plan?

Ether way, you are in it together—but the sponsor is the “Responsible You.”

¹ River's Edge Pharmaceuticals, LLC, Warning Letter 10-ATL-05, May 20, 2010.

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm220315.htm.

² Contract Pharmacal Corporation, Warning Letter 10-ATL-15, October 14, 2010.

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm229354.htm.

The QA Pharm