Computer Software Assurance Draft

The FDA published on 13-Sep-2022 the long-awaited draft of the guidance “Computer Software Assurance for Production and Quality System Software,” and you may, based on all the emails and posting be wondering just how radical a change this is.

It’s not. This guidance is just one big “calm down people” letter from the agency. They publish these sorts of guidance every now and then because we as an industry can sometimes learn the wrong lessons.

This guidance states:

  1. Determine intended use
  2. Perform a risk assessment
  3. Perform activities to the required level

I wrote about this approach in “Risk Based Data Integrity Assessment,” and it has existed in GAMP5 and other approaches for years.

So read the guidance, but don’t panic. You are either following it already or you just need to spend some time getting better at risk assessments and creating some matrix approaches.

Data Integrity Warning Letter

In July 2022, the U.S. FDA issued a Warning Letter to the U.S. American company “Jost Chemical Co.” after having inspected its site in January 2022. The warning letter listedfour significant areas:

  • Failure of your quality unit to ensure that quality-related complaints are investigated and resolved, and failure to extend investigations to other batches that may have been associated with a specific failure or deviation.”
  • “Failure to establish adequate written procedures for cleaning equipment and its release for use in manufacture of API.”
  • “Failure to ensure that all test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and purity, and failure to ensure laboratory data is complete and attributable.”
  • “Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data, and failure to establish and follow written procedures for the operation and maintenance of your computerized systems.”

I offer them the above clip as a good mini-training. I recently watched the show, and my wife thought I was going to have several heart attacks.

In a serious nature, please do not short your efforts in data integrity.

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.

Enforcement Actions Take Too Long

There is a strong case to be made that enforcement actions take way too long with the FDA, and as a result our drug and food supply are less safe than they should be.

Take the consent decree from last week with Morton Grove Pharmaceuticals Inc. The Warning Letter was from March 2017 from an Inspection that ended in February 2016. So from inspection to consent decree, it took over five-and-a-half years. No matter where you sit on the regulatory action landscape, I hope you see a problem with that timing.

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:

  1. Failure to validate the process
  2. Failure to test to specification
  3. 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.