Whistleblower protection

The FDA recently completed its “Internal Review of Agency Actions Related to the U.S. Infant Formula Supply.”

In general, this report has few real planned actions and does not fill me with the hope of internal changes driving improvement.

One of the recommendations really stood out to me. Finding 2 states “Inadequate processes and lack of clarity related to whistleblower complaints may have delayed the FDA’s response to those complaints. A complaint sent via mail and other delivery systems by a confidential informant to agency leaders at FDA’s White Oak campus was not delivered to the addressees.”

Recommendation: The FDA should identify clear definitions for the terms “whistleblower,” “confidential informant,” and “informant,” and develop policies and provide training to staff regarding how to identify, escalate, and appropriately manage confidentiality of such complaints. The agency should also consider connecting complaints from such individuals to information received from product safety complaints, and product manufacturing concerns systems to support more complete access to all safety information. The FDA is evaluating how best to integrate this data to gain a holistic view of all FDA-regulated products and/or manufacturing facilities. The FDA should also review and update its mail and package delivery procedures to ensure that all mail and packages are delivered and received by addressees in a timely manner.
FDA Evaluation of Infant Formula Response

There is a real lack of whistleblower protection in this industry. Often when you hear about a crisis, from baby formula to Theranos to the opioid epidemic you have you have to ask “where were the good people at that company.” It can be rather disheartening. It has long been worrisome that the FDA does not have strong whistleblower protection in place, and to see how definitely that contributed to this debacle is just plain scary.

Being Small and Speciality Does not Exempt from the GMPs

Specialty Process Labs LLC is a specialty API manufacturer of natural desiccated thyroid. Which is, yes, what you might think it is. And as far I can tell, mostly ships direct to compounding pharmacies and patients. This month they got a warning letter.

The warning letter highlights:

Failure to validate the process
Failure to test to specification
Failure to exercise sufficient controls over computerized systems

All three of these observations make me rather glad my loved-ones take levothyroxine and I am deeply aware of all the difficulties in that drug supply.

Focusing more on the computer system, it is an unsurprising list of bad access controls, change controls not controlled, and failure to validate excel spreadsheets.

The last observation really stood out to me:

“Manufacturing master batch records held in electronic form on your company’s shared drive do not have restrictions on user access. Your quality unit personnel stated that there are no restrictions for any personnel with login credentials to access new and obsolete master records. Our investigator observed during the inspection multiple versions of batch records were utilized for API lot production.”

This is truly a failure in document access and record management. And it is one I see a lot of places. The core requirement here is really well stated in the PIC/S Data Integrity Guidance requirement 8.4 “Expectations for the generation, distribution and control of records.” Please read the whole section, but pay close attention to the following:

Documents should be stored in a manner which ensures appropriate version control.
Master documents should contain distinctive marking so to distinguish the master from a copy, e.g. use of coloured papers or inks so as to prevent inadvertent use.
Master documents (in electronic form) should be prevented from unauthorised or inadvertent changes.
Document issuance should be controlled by written procedures that include the following controls:
- details of who issued the copies and when they were issued; clear means of differentiating approved copies of documents, e.g. by use of a secure stamp, or paper colour code not available in the working areas or another appropriate system;
- ensuring that only the current approved version is available for use;
- allocating a unique identifier to each blank document issued and recording the issue of each document in a register; – numbering every distributed copy (e.g.: copy 2 of 2) and sequential numbering of issued pages in bound books;
- where the re-issue of additional copies of the blank template is necessary, a controlled process regarding re-issue should be followed with all distributed copies maintained and a justification and approval for the need of an extra copy recorded, e.g.: “the original template record was damaged”;
- critical GMP/GDP blank forms (e.g.: worksheets, laboratory notebooks, batch records, control records) should be reconciled following use to ensure the accuracy and completeness of records; and
- where copies of documents other than records, (e.g. procedures), are printed for reference only, reconciliation may not be required, providing the documents are time-stamped on generation, and their short-term validity marked on the document

There are incredibly clear guidelines for these activities that the agencies have provided. Just need to use them.

FDA CDER Quality Management Maturity White Paper

FDA’s Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER) recently published a white paper proposal on the development of a rating system to measure a firm’s quality management maturity (QMM) as a way to mitigate drugs shortages and enhance the quality of finished drug products. These ratings would be publicly available. This is very aligned in thought to the recent NAS study recommendations in a paper commissioned by Congress.

This fits nicely within the recent draft guidance on metrics, and the two are definitely meant to fit together.

I am a big advocate of this work. I definitely want to see the particulars, but this is a long time coming and greatly needed. Frankly, the best way to make them happen is to require the QMM to be a factor in purchasing decisions for Medicaid/Medicare and the Veterans Hospitals (and more if possible).

The agency will be holding two workshops on quality management maturity, on May 24 and May 25. The first workshop will address CDER’s QMM program and the second will discuss quality ratings.

FDA Prescription Drug User Fee Renewals

Senators grill industry groups over FDA user fee agreements to fund the agency through 2027

I am not a huge fan of PDUFA. It puts the wrong cast on things. Fees are something I pay for a service, and it should put me in the driver’s seat (well except for airlines and everyone hates that). We tax for government services. Making the FDA dependent on pharma creates an imbalance in power that quite frankly shouldn’t exist.

The extent of statutorily required industry input in the drug regulation and reauthorization processes has increased as a result of the PDUFA reauthorization. The centrality of user fees to the modern FDA has led some observers to express concern that they have contributed to “corrosive capture” of the agency (i.e., a weakening of regulatory independence and of the ability of the agency to uphold traditional efficacy and safety standards) by shaping discourse about how drugs should be regulated or by enabling an unhealthy culture of closeness between the FDA and industry. Each successive PDUFA has required the FDA to be increasingly responsive to industry concerns.

The FDA plays a crucial role in protecting the health of the public while approving new treatments in a timely fashion. Thirty years of experience with user fees has shown that, in the face of inadequate public funding of the personnel budget of the FDA, increased funding by its egulated industries can indeed improve regulatory timelines. This increased speed has also raised questions related to the decisions being made and the growing reliance of the agency on financial support from the companies it regulates, as the user-fee model has fundamentally changed the way that the FDA interacts with industry. In a different political climate, adequate public funding in place of user fees would allow the FDA to continue its current performance levels while adding further confidence that the public remains the primary client of the FDA.