Tag: gmp deficiencies

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.

Catalent Belgium Form 483 and Contamination Control

The FDA recently released a Form 483 it handed to Catalent Belgium following an inspection of its 265,000 square-foot facility in Brussels in October 2021. Catalent is a pretty sizable entity, so it is very valuable to see what we can learn from their observations.

Failure to adequately assess an unexplained discrepancy or deviation

“Standard Operating Procedure STB-QA-0010, Deviation Management, v21 classifies deviations as minor, major or critical based on the calculation of a risk priority number, with a HEPA filter failure within a Grade A environment often classified as minor. Specifically, Deviation 327567 (Date of occurrence 04 March 2021) was for a HEPA filter failure on the <redacted> fill line, with a breach at the HEPA filter frame.”

This one is more common than it should be. I’ve recently written about categorization and criticality of events. I want to stress the term potential when addressing impact in the classification of events.

Control barriers exist for a reason. You breach that control barrier in any way, you have the potential to impact product or environment. It is really easy for experienced SMEs to say “But this has never had any real impact before” and then downgrade the deviation classification. Before long it becomes the norm that HEPA filter failures are minor because they never have impact. And then one does. Then there are shortages or worse.

It is important to avoid that complacency and treat each and every control barrier failure to the same level of investigation based on their potentiality to impact.

The other problem here is failure to identify trends and deal with them. I can honestly say that the last thing I ever want anyone, especially an inspector, to write about something where I have quality oversight is a failure to investigate multiple control barrier events.

“Other GMP manufacturing areas have a similar elevated level of HEPA filter failures, with the root cause of the HEPA filter failures unknown. There is no CAPA in support of correction action. Your firm failed to ensure your investigations identify appropriate root causes and you failed to implement sustainable corrective action and preventive action (CAPA).“

Contamination Control function

Observation 2 and 3 are doozies, but there is probably a lack of expertise involved here. The site is using out-of-date and inadequate methods in their validation. Hire a strong contamination control expert and leverage them. Build expertise in the organization through a robust training program. Connect this to all relevant quality systems/processes.

Corrective Maintenance and Troubleshooting

“Equipment and facilities used in the manufacture of drug product are not adequately maintained or appropriately designed to facilitate operations for their intended use.“

The asset control lifecycle matters, and corrective maintenance can not be shorted.

This is starting to feel a lot like my upcoming presentation at the 2022 ISPE Aseptic Conference where I will be speaking on “Contamination Control, Risk and the Quality Management System”

“Contamination Control is a fairly wide term used to mean “getting microbiologists out of the lab” and involved in risk management and the quality management system. This presentation will evaluate best practices in building a contamination control strategy and ensuring its use throughout the quality system. Leveraging a House of Quality approach, participants will learn how to: Create targeted/ risk based measures of contamination avoidance; Implement Key performance indicators to assess status of contamination control; and ensure a defined strategy for deviation management (investigations), CAPA and change management.”

Maybe we can talk more there!

GMP mistakes are costly

In the continual saga of companies making fundamental GMP mistakes, Gilead has recalled two lots of its coronavirus treatment drug Remdesivir because of the “presence of glass particulates.”

If only there existed international standards on visual inspection and there were a solid set of best practices on lyophilization.

Oh, wait there are.

But then Gilead has a multi-year track record in deficiencies in their testing and manufacturing processes. In all fairness, they are contracting manufacturing to Pfizer’s McPherson site…..oh wait that site got an FDA 483 in 2018 specifying significant violations of good manufacturing practices, such as an inadequate investigation into the detected presence of cardboard in vial samples.

We deserve better manufacturers. Companies need to take the quality of their products seriously. We are always improving or we are always one step away from the sort of press Gilead gets.

Critical ATMP Deficiencies

ERC The Netherlands B.V. received thirteen deficiencies from a recent inspection, one of which was classified as a critical deficiency.


These were mainly related to five main components:

  • Quality and safety of starting materials. Inspection of chemicals and consumables is insufficient.
  • The quality and safety of the final product is not guaranteed. The product is not sufficiently defined and characterized.
  • The effectiveness of a gama irradiation step, and therefore the safety of the product, is not guaranteed.
  • The change for the transition from Contractor 1 to Contractor 2 for gamma irradiation of cells has not been carried out as referred to in the GMP for ATMPs.
  • Prevention of (cross) contamination is not sufficiently guaranteed. 
  • The environmental monitoring program and personnel monitoring are inadequate.

Reviewing this together with Emergent’s 483 (and resulting actions) starts to define a set of concerns in the ATMP world.

Latest Emergent News

Today Janet Woodcock issued a statement “FDA Continues Important Steps to Ensure Quality, Safety and Effectiveness of Authorized COVID-19 Vaccines” which links to the April 2021 Form 483 of the Baltimore facility.

  • Failures to investigate deviations
  • Failures for material management
  • Failures for gowning
  • Failures of the cleaning program
  • Failures in facility design
  • All around failure for contamination control
  • Failure to have a comprehensive training program

I have requested hearings from my congressional representatives. The path where Emergent received so much money from the federal government to lead to this place is frightening.