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`6/13/2016
`
`Document
`
`Pharma ·n e lige ce
`
`1tnforma
`
`Pink Sheet
`Phonna irrtdlig;e11c,. I iflforma
`
`FISONS' OPTICROM, IMFERON MAY BE
`OFF U.S. MARKET UNTIL LATE 1992 AS
`THE COMPANY UPGRADES U.K.
`MANUFACTURING PLANT TO MEET
`FDA QUALITY CONTROL CONCERNS
`
`By The Pink Sheet I Email the Author I View Full Issue
`Word Count: 850 I Article# 00530510003 I Posted: December 23 1991 5:00
`AM
`
`Executive Summary
`
`Fisons' Opticrom (cromolyn sodium) eye drops and lmferon injectable iron are
`unlikely to be reintroduced in the U.S. until the second half of 1992 while the
`company deals with quality control problems turned up in a series of recent FDA
`inspections, Fisons reported Dec. 11. Reintroductions of the two products during
`the second half of next year would mean the company would have taken two
`years to resolve regulatory problems with the products. Fisons issued Class I
`and Class II recalls of Opticrom anti-allergic prescription eye drops and a Class
`Ill recall of lmferon in July 1990. Opticrom has been unavailable in the U.S. since
`the recall and lmferon has not been in supply since May 1991. Fisons is hoping to
`bring the two products back to market after an anticipated FDA inspection of the
`company's upgraded U.K.-based manufacturing facility in the first quarter of
`1992. The firm does not expect "full normality" to be restored until the end of the
`year, the company said. FDA has inspected the Fisons plant in Holmes Chapel,
`England three times since February 1990, most recently in November. The first
`inspection revealed "significant drug CGMP [current good manufacturing
`practices] deviations" for three Fisons products sold in the U.S.: Opticrom,
`lmferon and the lntal inhaler, the FDA investigators noted in their report.
`[Emphasis added by FDA.] The FDA investigators listed a total of 30
`"objectionable conditions" observed during the February 1990 inspection.
`Fisons' problems with Opticrom dated back to mid-1989, FDA discovered, when
`the company experienced over 100 positive sterility tests over a three-month
`period. Fisons attributed all but one positive test to lab contamination, FDA said,
`despite positive results from a second testing lab. FDA objected to the absence
`of an adequate investigation into the source of the contaminant and speculated
`that it was most likely "product contamination originating with the water system,"
`which had "several significant discrepancies." Among the 11 objections cited for
`lmferon injection were: the iron dextran active ingredient was not tested for
`purity prior to use in the batch formulation; the "pyrogen-free" water system was
`deficient; empty bulk solution transport vessels were stored outside with open
`covers; filtered lmferon solutions were being stored in beer kegs that were
`
`https://www.pharmamedtechbi .com/publications/the-pink-sheet/53/051/fisons-opticrom-imferon-may-be-off-us-market-until-late-1992-as-the-company-upgrade... 1/3
`
`Pharmacosmos, Exh. 1063, p. 1
`
`

`
`DOCUT1ent
`6'13'2016
`considered "not of pharmaceutical quality"; and the firm did not perform visible
`particulate evaluations on each lot manufactured. lntal inhalers have had aerosol
`leakage problems since early 1987, FDA reported, and Fisons changed the valve
`design without obtaining prior NOA approval. FDA found that the valve change
`was not an improvement, but that the "new valve was reported as cheaper than
`the old valve." The inspectors also criticized Fisons' "deceptive" aerosol leakage
`tests, which eliminated low- weight inhalers from testing even though they may
`have been low weight due to aerosol leakage. In response to the violations cited
`by FDA, Fisons requested a second inspection in May 1991. FDA found that the
`company "had not made substantial corrections to the previously observed GMP
`deviations" for the manufacture of lmferon. The Inspectors also concluded that
`"the firm's reported corrections to eliminate aerosol leakage [for the lntal
`inhaler] have not corrected the defect." Both Opticrom and lmferon, which are
`manufactured exclusively in the U.K., "remain on the import alert list," FDA noted
`in its inspection report. The lntal inhaler was apparently allowed to stay on the
`market In the U.S. due to a decision by FDA based on the "medlcal necessity of
`the product." Fisons subsequently decided to do "a more comprehensive
`overhaul" of the Holmes Chapel facility to meet FDA requirements, the company
`said. The third inspection in November 1991 was limited to the lmferon
`manufacturing process, which will apparently require further improvements
`before receiving FDA approval. Fisons also has submitted a supplemental NOA
`for a new lntal inhaler valve manufactured by Vespec, the firm said. Opticrom has
`not been produced at the Holmes Chapel plant since November 1990 when
`British health authorities revoked the company's license to manufacture and
`release sterile products. The license revocation letter stated: "'The levels of
`quality assurance of sterile products as demonstrated by end product, and in(cid:173)
`process microbiological testing are not of an acceptable standard,"' according to
`the FDA report. The license has not yet been reinstated, the company said.
`Fisons estimates that the withdrawal of Opticrom and lmferon from the U.S.
`market wlll result In "a loss of profit of some (BRmSH POUND)33 mll.," or around
`$ 60 mil. in 1991. Additional costs include an estimated $ 36 mil. as a result of
`"the disruption caused to production activities arising from upgrading at the main
`U.K. plant to supply the U.S. market." The disruption in the supply of Opticrom to
`other markets is costing the firm around$ 27 mil. ((BRITISH POUND)15 mil.), with
`the "total Impact on profits" amounting to approxlmately $117 mll. ((BRITISH
`POUND)65 mil.), Fisons reported. In response to what it described as
`"increasingly stringent standards set by the U.S. FDA," Fisons also has
`appointed a new divisional technical director as well as 71 new managers in the
`area of "technical management and quality control" for the pharmaceutical
`division, the company said.
`
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`htlps:/lwww.pharmamedtechbi.com/publicalionsJlhe.pink-sheet/53/051/lisons-opticrom-imferon-may-be-olf-us-market-unti l-late-1992-as-th&-compeny-upgrade.. . 213
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`Pharmacosmos, Exh. 1063, p. 2
`
`

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`6'13'2016
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`DOCUT1ent
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`htlps:/lwww.pharmamedtechbi.com/publicalionsJlhe..pink-sheet/53/051/lisons-opticrom-imferon-may-be-olf-us-market-unti l-late-1992-as-th&-compeny-upgrade.. . 313
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`Pharmacosmos, Exh. 1063, p. 3