FDA Warning Letters Week of 3/15/2020: Intentional Data Governance Failures, HCT/P

FDA is halting domestic pharma inspections based on a recent article from RAPS.  Shortly after the RAPS article published, the FDA announced they have temporarily postponed domestic routine surveillance inspections until such time as it is safe for them and the companies they inspect to resume.  It’s telling that they didn’t put a re-evaluation date on this as they did for the halt in international inspections.

FDA posted four warning letters in areas we cover: two to pharma firms, including the one to Cipla Limited we’ve been watching for, and two to HTC/P manufacturers.  The other pharma warning letter serves as an egregious example of data integrity deficiencies.


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DRUGS | Cipla Limited

Cipla Limited (India) received a warning letter on February 25, 2020 based on the outcome of an inspection of a facility in Goa, India ending September 27, 2019.  The form 483 that precipitated this warning letter included 12 observations and was 38 pages long.  The inspection lasted 11 days and one of the investigators was Thomas Arista.  The firm has ceased manufacture in two sterile units until remediations have been completed.

Considering the type of deficiencies here, no import alert is noted as being implemented.  The firm, however, did suspend production from two sterile units.  FDA notes they will need to remediate these violations before they resume production from the US markets.

Deficiencies include but are not limited to:

  • The firm’s cleaning of equipment is not adequate.  Investigators identified multiple residues inside of exhaust ducts.  (Note: read the form 483 for more detail, 6 ½ pages worth).  The exhaust ducts are connected to equipment based on information in the form 483.  Testing performed on residues collected from manufacturing equipment confirmed the presence of multiple active ingredients.  The firm noted that 261 of 268 batches tested did not show traces of cross-contamination and that the firm believes that the visible residue in the exhaust duct “…did not pose a risk of contamination to your drug products.”  The FDA deemed their response to the form 483 to be inadequate.  The firm did not identify the source of cross-contamination.  Further, FDA notes that testing of reserve samples alone is not sufficient to determine the scope of cross-contamination.  The investigations were inadequate to determine source of the cross-contamination so that remediation could be taken.  When unknown peaks were noted, they were not identified.  The firm blamed challenges with analytical methods for the failure to identify peaks but did not provide data to show these challenges were resolved.  Finally, the firm did not perform a toxicological assessment to identify those active ingredients that may present a risk to patients.
  • The firm identified excessive HEPA filter failures in a short period of time, often in adjacent rooms.  The firm failed to adequately investigate these >45 filter failures.  The most likely cause of the failures was gasket deterioration and lack of timely replacement.  These failed HEPA failures “compromised” approximately 80 batches of product intended for US distribution.  There is no assurance that all batches produced under inadequate conditions have been thoroughly evaluated, and that your firm has identified all contamination hazards associated with your sterile process.”
  • The firm failed to perform adequate smoke studies to determine laminar flow of air in aseptic areas.  Smoke studies did not include interventions.  Smoke studies did not include the use of the mobile trolley during dynamic conditions where equipment parts and utensils are transferred during filling line set up and movement of sterilized stoppers into the cleanroom.

DRUGS | Windlas Healthcare Private Limited

Windlas Healthcare Private Limited (India) received a warning letter on March 10, 2020 based on the outcome of an inspection ending August 30, 2019.  The firm was placed on import alert on January 21, 2020.  FDA recommends that the firm hire qualified consultant(s) to help them come into GMP compliance.

All three deviations identify egregious and apparently very intentional failures in data governance and data integrity, including manipulations of electronic laboratory data.  Among other requests, FDA is asking for independent assessments of the issues.

The deficiencies identified include but are not limited to:

  • The firm did not retain accurate and complete data from laboratory testing.  Investigators noted that unknown peaks were not reported or integrated as the company’s procedures require.  The peak detection function was disabled multiple times during testing for residual solvents.  Upon retesting as requested by the FDA investigator, [redacted]% of unknown impurities were identified in the API that was used to manufacture multiple batches of tablets distributed in the US.  Test sequences were canceled in some laboratory runs.  Passing data are reported but not failing results.  Among the reasons that FDA deemed the firm’s response inadequate included their lack of information on the impact that the laboratory errors and failures may have on other laboratory tests and results.
  • The investigations into laboratory incident testing results are inadequate.  They lack scientific rationale for root cause determinations.  In the absence of scientific justification, the firm invalidated failing results and only reporting passing retest results.  The firm’s response was deemed inadequate because: it did not assess the entire laboratory system and ensure that analysts were competent to perform the work they were doing; it did not include a retrospective review of all investigations to ensure that root causes were justified; CAPAs were implemented to prevent recurrence.
  • The Quality Unit failed to provide oversight of manufacturing operations.  The FDA investigators arrived at the firm only 30 minutes after announcing the inspection.  They observed cartload and trash bags containing shredded documents being carted offsite.  The firm stated that the root cause of this was “…inadequate awareness of data integrity principles, training and education, supervision, and problem-solving capabilities.”   In another example, live-feed cameras showed production staff signing documents and passing them to one another.  When the investigator asked to visit this area he was directed to a different, incorrect, area.  FDA notes “This incident delayed our investigator and prevented contemporaneous verification of the activities being performed.”
  • And finally, FDA notes Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture.”  They are asked to address the ‘long form” of the FDA requirements for data integrity remediation.

HCT/P BIOLOGICS | Banco Vida Corp. and Laboratorio Banco Vida

Banco Vida Corp. and Laboratorio Banco Vida (Puerto Rico) received a warning letter on March 4, 2020 based on the outcome of an inspection ending September 18, 2019.  Based on the text in deficiencies, the firm manufactures cord blood products.

The warning letter includes an interesting footnote: This letter applies solely to products manufactured for autologous use or allogeneic use in a first-degree or second-degree blood relative.  Accordingly, references in this letter to HCT/Ps do not include other products manufactured by your firm.  FDA intends to communicate with Banco Vida Corporation separately regarding these products.”  It will be interesting to see if the “communication” results in additional enforcement action against another group of products, and this is something we will follow.

The warning letter identifies seven deficiencies, which include but are not limited to:

  • Failure to screen donor cells and tissues by reviewing the relevant medical history of the donor for risk factors and clinical evidence of communicable disease.  Trying to make a point here, FDA provides 10 examples.
  • The firm failed to use FDA cleared/licensed or approved tests in evaluating donor health status.
  • The BSC used for processing of cord blood is not subject to environmental monitoring.
  • The manufacturing process is not validated.
  • Practices used in the processing of cord blood were not performed in a way to minimize introduction of contamination.
  • Failure to document and trend deviations related to good tissue practices and report as required in 21 CFR 1271.350(b) or other regulations.
  • Failure to establish and maintain procedures for complying with requirements in 21 CFR 1271.

HCT/P BIOLOGICS | Invitrx Therapeutics Inc.

Invitrx Therapeutics Inc. (Lake Forest, CA) received a warning letter on March 16, 2020 based on the outcome of an inspection ending April 3, 2019.  The firm manufactures products for allogenic use including human umbilical cord blood.

The first part of the warning letter consists of FDA’s position that these products do not meet the requirements for an exemption identified in 21 CFR 1271.15.  Further, the firm’s website advertises the products as being useful to treat a variety of disease states.  Some GMP deficiencies cite 21 CFR 1271 and others cite 21 CFR 211, both with a focus on their failure to address donor qualification and sterility assurance of final product.

FDA also cautions the site about their exosome products and directs them to FDA’s safety notice on this product group posted December 6, 2019.  Note that the link provided in the warning letter yields “page not found.”  FDA clearly makes a point about the firm’s GMP compliance with the seventeen, often multi-part, deficiencies.  The firm recalled products manufactured from cord blood of a donor who tested positive for Hepatitis B.  They also temporarily ceased receipt of product from an unnamed location.

A selection of the deficiencies identified include, but are not limited to the following:

  • The company does not have a responsible person to determine and document eligibility of cell/tissue donors.
  • Material from a cord blood donor who tested positive for Hepatitis B was manufactured into product and distributed.
  • HTC/P products were distributed without a statement of donor eligibility.
  • The firm failed to validate the aseptic process used to manufacture products, and personnel practices observed by the investigator do not adequately protect against contamination.
  • Failure to reject batches due to microbial growth on the cord blood donor plate.
  • The cleaning process of BSCs is not validated nor is there a rationale for cleaning agents used and/or their rotation.
  • The firm failed to investigate sterility failures since March 2018.
  • The firm has not established a system for EM and personnel monitoring.
  • Products have a 2-year expiry with no data to support that dating.

 

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