The Top Ten Warning Letter Observations about the Pharmaceutical Quality Unit

The responsibilities of the Pharmaceutical Quality Unit are defined in the CGMPs and practices clarified in guidance documents. (See The QA Pharm, August 7, 2011.)

Just as it is with any legal matter, case histories help us understand how the law is applied in specific situations. That’s the reason it is a good practice to regularly review Warning Letters on the FDA website.

Here’s my condensed list of issues the FDA has had with the Quality Unit as seen in Warning letter observations.

This is the list you don’t want to be on.

1.    QU failed to establish a system to ensure that…[fill in the blank for anything that went wrong]

2.    QU failed to document the responsibilities applicable to the quality control unit in procedures, and fully perform these responsibilities.

3.    The personnel performing laboratory tests… were not trained.

4.    QU failed to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products.

5.    QU failed to fully perform and/or document the review of batch production records to determine compliance with all established, approved written procedures before a batch is released or distributed.

6.    QU failed to ensure that all tests are in conformance with the established specifications and that these are met prior to the release of drug products for distribution.

7.    QU did not review production records to assure that no errors had occurred or, if errors had occurred, that they had been fully investigated, conclusions made and followed-up.

8.    QU failed to investigate complaints involving the possible failure of a drug product to meet any of its specifications.

9.    Failure to submit NDA-Field Alert Reports (FARs) within three (3) working days of receipt of information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug products

10.  And my personal favorite…a designated QU has not been established.

The QA Pharm

The Top Ten Responsibilities of the Pharmaceutical Quality Unit

The pharmaceutical Quality Unit has been the target of many FDA Warning Letters for not establishing an effective system to prevent product quality and CGMP compliance problems. 

We have seen instances where the ultimate “no confidence” vote is cast when third-party experts are either recommended by FDA, or court ordered to take over their duties. (See The QA Pharm 9/25/10.)

Therefore, it’s very important to have a clear understanding of the regulatory responsibilities of the Quality Unit and to ensure that those responsibilities are effectively executed.

Remember—the Quality Unit is the only job description that appears in the Code of Federal Regulations!

Here’s my compiled list from FDA regulations and guidance documents that defines the job of the Quality Unit.

(It’s like being given the answers in the back of the book—and not just the odd-numbered problems.)

1.    To establish the quality system

a.  Establish the quality management system to describe how the firm complies
CGMPs and operates to maintain a state of control

b.  Keep current with good industry practices, and applicable to the mission of your operation.

2.    To audit compliance to the quality system

a.  Audit for compliance to policies and procedures: on paper vs. practice

b.  Report on the performance of the quality system, including trends, that help
decision making for targeted actions

3.    To establish procedures and specifications

a.  Ensure that procedures and specifications are appropriate and followed

b.  Ensure that the procedures and specifications of firms under contract are also appropriate and followed, i.e., maintain control and take responsibility for third-party services providers (contract manufacturers, contract laboratories, etc.)

4.    To establish manufacturing controls

a.  Ensure that appropriate manufacturing in-process controls are implemented

b.  Ensure in-process controls are performed during manufacturing operations and results are satisfactory

5.    To perform laboratory tests or examinations

a.   Perform laboratory testing of components, containers, in-process materials, packaging materials and drug product using validated methods against scientifically-derived, fit-for-purpose specifications

b.  Approve or reject drug products manufactured, processed, packed, or held under  contract by another company, i.e., final product release is not delegated to a contractor

c.  Perform retests or reexamine approved components, drug product containers and closures after long storage or exposure to adverse conditions

6.    To review and approve or reject all things CGMP

a.  Review and approve/reject any document that gives work instructions and set requirements such as procedures, protocols, test methods, and specifications—including changes to these documents

b.  Review and approve/reject reprocessing and rework procedures

c.  Review and approve/reject production batch records and make the final decision to release a product lot into commerce.

7.    To ensure investigation of nonconformance

a.  Ensure investigation is conducted and root cause is eliminated for production and control record errors, discrepancies, and failure to meet specification, including quality attributes

b.  Review complaints to determine if it relates to a failure to meet specification, if so investigate and report to FDA if it is serious and unexpected

8.    To keep management informed

a.  Report on product, process and system risks—and keep management informed

b.  Report on outcome of regulatory inspections and ensure responses are complete and managed to verifiable closure—and keep management informed

c.  Keep management informed—get it?

9.    To describe responsibilities in writing

a.  Have a complete and compliant procedure that describes responsibilities

b. Follow the procedure

10. To remain independent

a.  Ensure there is no conflict of interest between regulatory responsibilities and actual daily activities

b.  Be independent reviewer and approver with respect to manufacturing and process/ product development units

How does your Quality Unit compare?

Please contact me to discuss how we can work with your senior staff and quality leadership to ensure your Quality Unit has robust processes to fulfill its regulatory responsibility, as well as help you to become an anticipating organization--rather than reactive.

The QA Pharm

References

• Federal Register Vol. 43, No 190 – Friday, September 29, 1978, “Preamble to the Drug CGMPs”
• The Code of Federal Regulations Part 210 and 211
• Guidance for Industry, Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations (September 2006)
• ICH Q10 Pharmaceutical Quality System (June 2008)

Cartoon: The QA Quarantine Cage

The QA Pharm

Are Commitments Made to FDA to be taken Seriously?

Responses to FD483’s and Warning Letters are usually fully of commitments. They involve “what” will be done to correct compliance problems, and “when” it will be done. FDA has even started to ask “how” they will be done, meaning—Do you have the resources to do the work?

If these questions are not fully addressed in the FD483, then FDA will say so in the subsequent Warning Letter in the part where they acknowledge receipt of the firm’s FD483 response—and the inadequacy of it.

My first point is that there is no excuse for an inadequate response to an FD483 or a Warning Letter.

There are plenty of Warning Letters on the FDA website that provide examples of poor responses and what the FDA thinks about them. There’s no excuse for not knowing how to respond. (Also see The QA Pharm, October 10, 2010.)

Reasons for poor responses are:

·       Arrogance (What problem? Let me explain why we have no problem.)

·       Bad advice from house counsel (Dance around the edges, but never admit having a problem.)

·       Minimalism (Commit as little as possible and don’t look for other problems.)

·       Being far removed from the problem (Responses are so bad that it makes your technical insiders embarrassed.)

·       No root cause (Doing lots of stuff, but very little directed toward the real problem.)

·       Poor writing skills. (Difficult to follow the story line, because you have no idea what you want to say.)

My second point is never, ever miss a commitment date.

If anyone were to ask the leadership of any company under FDA enforcement action whether FDA commitments should be taken seriously, the response would be a resounding “Of course.”

Yet actions say differently.

It continues to amaze me how many companies miss commitment dates. And even more amazing—the senior management had no clue they had missed them. This is totally unconscionable and an indicator why the company has compliance trouble in the first place.

Reasons for missing commitment dates are:

·       No system to track responses and commitments

·       Responses and commitments are buried with hundreds of other TrackWise records, most of which are also overdue

·       Overly project managed until there is more planning than action

·       Lack of visibility as a standing agenda item in the management boardroom

·       No accountability at any level for results

·       Agency responses are kept a secret, or not sufficiently distributed to employees

·       Those responsible for doing the work had no idea that a commitment was made

The best way to think about the seriousness of a commitment to the FDA is to remember that the FDA already suspects a noncompliant firm to be untrustworthy—or at best they are neutral about their credibility. To not deliver on a commitment date just confirms their suspicion and puts the relationship between the firm and FDA on shaky ground.

Not providing an adequate response simply indicates being out of the mainstream of pharmaceutical industry know-how. And missing commitment

dates is nothing less that breaking a promise.

How would you feel if you were not taken seriously?

The QA Pharm