Two weeks before the end of 2015, PharmaCompass compiled a list
of all the non-compliances issued in 2015 by major
global regulatory agencies.
Little did we know that, while the world was wrapping up for
the holidays, the U.S.
Food and Drug Administration (FDA) would be busy issuing warning
letters to Sun
Pharmaceuticals (Sun) and Cadila
Healthcare Ltd (Cadila / Zydus Cadila).
The facilities cited in the warning letters, for both Indian generic majors, are primary contributors to their revenues in the United States. While Sun’s Halol facility was cited in the warning letter, in Cadila’s case, the warning letter was issued for violating manufacturing standards at two of their production facilities, Zyfine and Moraiya. Data integrity issues at ZyfineThe data
integrity violations mentioned in the warning letter related to Zyfine, which
produces active pharmaceutical ingredients (APIs), did not come as a complete
surprise.PharmaCompass had covered most of
the data integrity concerns mentioned in the warning letter in May 2015 (read: Serious GMP concerns
uncovered at Lupin (ANVISA) and Zydus Cadila (USFDA)) Zyfine had glaring
data-integrity observations which ranged from:
Records were not made readily available during the inspection; the Vice President, Corporate QA stated that the requested document was located at an employee’s home.
During
the FDA walk through the inspectors found five original and rewritten
records, which were falsified.
Inspectors
found rough notebooks in the scrap yard as well as the engineering and QA
offices.
Documents
were signed and dated by individuals who were not present at the site.
Reprocessing
was performed without review and approval of the quality unit.
Batch
records were not reviewed by production and QA personnel before release.
Washing
and toilet facilities lacked soap.
Cadila’s response stating that papers found were “personal notebooks intended only for meeting and other discussion notes” failed to sway the FDA.
A turnaround challenge at MoraiyaThe Moraiya
facility accounts for 60 percent of Cadila’s revenues in the United States, its largest market,
had no data integrity issues mentioned in the warning letter. However,
the task ahead for Cadila is formidable since PharmaCompass reviewed the Form
483 issued to the Moraiya facility by obtaining it from FDAZilla.com. The
September 2014 inspection found that, in 2013, Cadila had failed to adequately
review 106 consumer complaints (out of 106 complaints received) and in 2014, up
to the date of the inspection, they failed to adequately review another 132
consumer complaints (out of 132 complaints received).At the time
of the inspection, Cadila had already taken the decision to recall products
like Warfarin 2mg (due to oversized tablets), Promethazine 25mg (due to mixed tablets in the
same bottle) and Atenolol 25mg (due to “thicker appearance”). However, the inspectors got “no assurance” that the quality system at Cadila was under control and stated that the “deficiency appears to be a pattern of problem at your site”.Eleven responses later, the FDA still remained unconvinced and mentioned, in the warning letter, that “persistent failures indicate that your manufacturing process is not in a state of control.”
“Bottles containing Zydus (Cadila) products mixed with other Zydus (Cadila) products”At Moraiya, Cadila’s use of the same packaging line to bottle different products created problems as nine customer complaints were received “of bottles containing Zydus (Cadila) products mixed with other Zydus (Cadila) products”.The view at the time of the inspection was that the “mix-up might have taken place possibly at the pharmacy” which did not convince the FDA inspectors since the “two mixed products contained within the complaint bottle, were packaged on the same line at the same facility”. As a result of the FDA’s inspection, Cadila re-opened investigations related to the nine consumer complaints about product mix-ups and found manufacturing deficiencies that could have led to the mix-ups.
While Cadila initiated a product recall of several lots, the FDA still believes that the scope of Cadila’s activities are insufficient. Facility problems at Sun
Pharmaceuticals In the case of Sun Pharmaceuticals, the warning letter wasn’t a complete surprise for us.
PharmaCompass had asked the question almost 6 months ago, “Sun has a new quality head, why?” and subsequent news indicated that Sun’s problems were more than just their integration challenges with the acquisition of Ranbaxy.
However, on reviewing the warning letter issued by the FDA, the alarming concern about Sun’s sterile manufacturing operations is that the FDA found their “aseptic processing
equipment is not properly designed”.
Smoke studies or unidirectional airflow studies are performed to determine how the movement of air and personnel during aseptic operations could pose risks to product sterility. Almost every warning letter issued to sterile manufacturing operations is related to an organization’s inability to conduct smoke studies to the level of FDA’s expectations.
In Sun’s case, the concerns related to the adequacy of the facility were to be addressed by conducting smoke studies, by November 15, 2014.
However, their three responses dated December 12, 2014; February
10, 2015; and May 5, 2015 did neither submit a revised smoke test nor a
satisfactory new smoke study.
Sun’s case was definitely not helped by the fact that during the inspection, the inspector documented the “presence of leaks in the form of water stains and ceiling damage in the parenteral manufacturing area personnel corridor. The FDA investigator observed
buckets with water collected from ceiling leaks and other leaks in this
manufacturing area.”
The FDA in their warning letter has asked Sun to describe
any major equipment and facility upgrades that are planned.
It seems that without changes in the physical infrastructure at Sun’s Halol facility, a key anchor to their business in the United States, it will not meet the FDA’s expectations. Our View
Manufacturing non-compliances dominated pharmaceutical news
headlines last year.
As we’re still at the early stage of 2016, where people are making New Year resolutions, the big resolution manufacturers should make is what the FDA clearly says in their warning letter to Sun Pharmaceuticals.
“It is essential that executive management systematically improve their oversight of manufacturing quality to ensure sustainable quality assurance”.
View our UPDATED
non-compliances compilation In case you missed some of the compliance news, PharmaCompass
has compiled all the FDA Warning Letters, Import Alerts and EDQM (European Directorate for the Quality of Medicines) Non-Compliance Reports issued in 2015
for easy access. A special word of thanks to FDAZilla.com –makes actionable FDA information accessible.
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