Answers
10/03/1989
Generic Investigations
October 3, 1989
GENERICS INVESTIGATIONS
FDA is continuing efforts to resolve all uncertainties that have come to
be associated with the production of generic drugs and the manner in which
they are approved. The agency has revamped the management of its generic
drug operations (see Talk Paper T89-34, May 15, 1989) and put in place
stricter controls in the way generic drug applications are processed (in a
letter to industry March 15, 1989). On July 10, FDA published in the
Federal Register proposed regulations implementing 1984 legislation
providing for quicker and simpler approval procedures for generic drugs.
Within the next few weeks FDA expects to propose additional regulations to
require manufacturers, or the laboratories they contract to test their
products, to retain samples of any new drugs for a period of at least five
years. The rules would apply to innovator and generic products and any
reference drugs subjected to bioavailability or bioequivalence testing, and
also require that the samples be made available to FDA on request. In
addition to looking at many manufacturers' versions of the top 30 generic
drugs and 20 of the top generic companies, FDA is also continuing to
investigate 11 firms originally targeted in April for various deficiencies
as well as two more firms later identified as needing special inspections --
Sidmak Laboratories and Pharmafair Inc. -- for a total of 13 such special
inspections.
THIRTY TOP GENERIC DRUGS: FDA announced Aug. 16, a comprehensive
program to sample and analyze the 30 most prescribed generic drugs and their
brand-name counterparts (see Talk Paper T89-51, Aug. 16, 1989). The
products involved represent three-fourths of all new generic drug
prescriptions. The drugs are being checked for potency, dissolution,
composition and other specifications at 16 FDA laboratories around the
country. To date, the agency has collected 1,874 samples (not including
duplicates) and analyzed 1,827 of them. Several hundred remain to be
collected. Nearly all of the products tested were found to be within
acceptable specifications, but about 1.6 percent (a rate approximating
normal industry conditions) were found to be deficient in potency or
dissolution. In the first recall stemming from this testing, Pharmaceutical
Basics Inc. of Denver, Colo., on Sept. 27 recalled l6 lots of its antifungal
nystatin tablets because they may be subpotent. FDA expects to release a
summary of its test findings on the 30 drugs by the end of October.
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TWENTY TOP GENERIC COMPANIES: On Aug. 23, FDA began inspecting 20 of
the leading generic and brand-name drug companies among the over 300 firms
that manufacture generic products. The firms being inspected were selected,
not because of any wrongdoing, but because they were major producers of
generic drugs. (See Talk Paper T89-52, Aug. 23, 1989). At this time all
inspections are ongoing and no final conclusions have been reached. The
agency expects to complete this inspection program by Nov. 16.
QUANTUM PHARMICS, AMITYVILLE, N.Y.: Quantum Pharmics is among the top
20 generic firms. FDA recently uncovered information that indicates data
may have been misrepresented in materials submitted in connection with
applications to market three products. The firm's parent company,
Wyeth-Ayerst Laboratories, has recently informed FDA that Quantum has
suspended* production and distribution of all of Quantum's 21 generic
drugs. The investigation of Quantum is continuing and FDA is still
reviewing the results of the inspections and has not reached any conclusions
about the drugs involved.
Separate from the inspection of the 20 top generic firms, FDA had
already targeted 13 firms for investigation. The following is a summary of
the findings to date of these ongoing inspections:
1. PHARMACEUTICAL BASICS (PBI), DENVER COLO.: PBI vice president Raj
Matkari on May 15 pleaded guilty to giving an unlawful gratuity to former
FDA supervisory chemist Charles Chang (see also paragraph 8 on American
Therapeutics). On Sept. 7, FDA sent a regulatory letter to the firm because
of Good Manufacturing Practice (GMP) violations at its Morton Grove, Ill.,
plant that makes oral and topical liquids. (In a separate action that
predates FDA's current investigation of the generics industry, PBI in Sept.
1988, as a result of FDA scrutiny, recalled 50 million carbamazepine
tablets, a drug to help control epileptic seizures, because of dissolution
problems. Fifteen unexpected seizures and two deaths were reported among
persons on the drug, but these can and do occur with other anti-convulsives
and insufficient data were available to determine if any resulted from the
recalled product (see Press Release P88-29, Sept. 21, 1988). The
investigation and recall have been completed, the dissolution problem has
been corrected, and shipments of carbamazepine continue.)
2. VITARINE PHARMACEUTICALS, SPRINGFIELD GARDENS, N.Y.: In June 1989,
FDA announced that Vitarine was suspending* distribution of 13 products and
recalling 12 more because it was determined that false information had been
submitted to FDA and that certain products were not being made in accordance
with GMPs (see Talk Paper T89-36, June 1, 1989). It was later disclosed
that the firm had submitted brand-name products as its own for
bioequivalence testing in support of its applications to market
triamterene-hydrochlorothiazide, the generic form of Dyazide. This
misrepresentation extends to four other drug products not yet approved by
FDA: verapamil HCl SR (sustained-release) tablets, albuterol sulfate SR
tablets, propranolol HCl LA (long-acting) capsules and methylprednisolone
tablets. The inspection of Vitarine was the first in which evidence of
fraud was found in records provided in support of generic drug
applications. FDA has recently moved to withdraw approval of 25 of
Vitarine's generic products; on Aug. 22, the firm agreed to remove them from
the market.
3. PAR PHARMACEUTICALS, SPRING VALLEY, N.Y.: On May 17, David Brancato,
a former FDA review chemist, pleaded guilty to receiving unlawful gratuities
from an officer of Par and its subsidiary Quad Pharmaceuticals. Quad was
also responsible for paying illegal gratuities to former FDA chemist Walter
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Kletch who was sentenced Sept. 22. In July, officials of Par acknowledged
that the formulation used in the production of its generic form of Maxzide
was not the same as the formulation FDA had approved on the basis of the
firm's application. (Maxzide is an antihypertensive drug that is similar to
Dyazide.) Moreover, it was learned that Par was responsible for various
additional manufacturing deficiencies including falsification of production
records. As a result the firm has recalled its generic version of Maxzide
from the market along with its muscle relaxant, Orphengesic Forte tablets,
and the epilepsy drug, valproic acid (see Talk Paper T89-47, July 24,
1989). Par also recalled on Aug. 1, megestrol acetate tablets, an
anticancer drug, because of problems with bioequivalence. On Aug. 3, Par's
June letter of approval to market 500 mg. chlorzoxazone tablets was
rescinded. The firm objected but agreed not to market the product. Later,
on Aug. 22, FDA began taking steps to revoke approval for Par to market
three products because the firm's applications were found to contain false
information -- two already under recall, the hydrochlorothiazide-triamterene
tablets (generic Maxzide) and Orphengesic Forte tablets as well as
Orphengesic tablets. Par on Aug. 25, recalled Decon Decongestant SR tablets
and dexchlorpheniramine maleate TR (timed-release) tablets, both sold under
various labels, because they failed dissolution and/or stability testing.
It has been learned that Par kept certain production information "off the
record" and selectively recorded or omitted from official records important
manufacturing data. The investigation of Par is continuing.
4. BOLAR PHARMACEUTICALS, COPIAGUE, N.Y.: On Aug. 28, 1989, FDA
announced that is was taking steps to withdraw Bolar Pharmaceuticals'
approval to market its generic version of Dyazide (see Talk Paper T89-53,
Aug. 28, 1989). On Sept. 28, FDA notified the company that it was changing
the product's official therapeutic rating from therapeutically equivalent to
"presumed to be therapeutically inequivalent until adequate information
becomes available to make a full evaluation" (see Talk Paper T89-57, Sept.
28, 1989). Bolar is the first company to have a product's rating downgraded
because of uncertainties involving information associated with the product's
bioequivalence testing. Unrelated to ongoing investigations, FDA recently
discovered information indicating that in 1982 Bolar submitted samples of
the brand-name product, Mellaril, made by Sandoz for treating depression and
anxiety, to an independent laboratory in place of its own thioridazine
tablets for bioequivalence testing. The agency's investigation of Bolar is
continuing.
5. BARRE-NATIONAL, BALTIMORE, MD.: FDA found manufacturing deficiencies
and deviations during inspections conducted from March to June of 1989. The
firm also was found to have withheld results of failed stability tests.
Before the inspections the firm recalled several products for subpotency,
stability and other problems. Later, it suspended* distribution of 20
products and recalled hydrocortisone lotion, flurandrenolide lotion, another
topical steroid and theophylline syrup, a bronchodilator.
6. SIDMAK LABORATORIES, EAST HANOVER, N.J.: Sidmak manufactured a
dangerously superpotent prescription vitamin that contained 50 times the
labeled quantity of vitamin D. It was distributed based on inaccurate test
results determined by its contract testing laboratory, Quality Research
Laboratories Inc. The product was recalled in May of this year (see Press
Release P89-23. May 24, 1989). Sidmak also makes the anticonvulsant drug,
phenytoin, a generic version of Dilantin that was recalled in Sept. 1987
because of various GMP deficiencies.
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7. SUPERPHARM, BAYSHORE, N.Y.: An investigation that started in May of
Superpharm discrepancies and irregularities in research and development
records involving six different products led the firm to stop manufacturing
diazepam, a generic version of Valium. Superpharm had previously stopped
marketing four other products; only one of the six products, lorazepam,
remains on the market. This investigation is continuing.
8. AMERICAN THERAPEUTICS INC. (ATI), BOHEMIA, N.Y.: ATI is a firm
which, along with its president, Raju Vegesna, was named in criminal
informations filed in connection with illegal payments to Charles Chang.
Chang pleaded guilty to accepting illegal gratuities May 17 and was
sentenced today. On Aug. 3, 1989, FDA rescinded a recent letter of approval
for 500 mg. chlorzoxazone tablets, a muscle relaxant, based on an ongoing
inspection that reported GMP problems and discrepancies in records.
Although ATI is not marketing the product, the firm has filed suit against
FDA seeking to nullify the agency's action. Also, ATI is recalling five
lots of its generic form of Maxzide because of dissolution problems.
9. PHARMAFAIR, HAUPPAGUE, N.Y.: Since 1983, Pharmafair has had a
history of manufacturing problems and in 1986 entered into an agreement with
FDA not to distribute drugs until corrections in manufacturing procedures
were made. Distribution of the products involved have resumed; however, the
firm earlier this year recalled its entire 1988 production of 2.5 and 10
percent phenylephrine HCl ophthalmic solution because it did not conform to
specifications and numerous lots of the antibiotic nystatin oral suspension
due to excessive variation of potency.
10. ABLE LABORATORIES, SOUTH PLAINFIELD, N.J.: Inspections of Able have
not resulted in findings of any significant problems.
11. ZENITH LABORATORIES, NORTH VALE, N.J.: FDA found several minor GMP
problems at Zenith's Puerto Rico plant, but that location is inactive at
this time and no further action is warranted.
12. QUAD PHARMACEUTICALS, INDIANAPOLIS, IND.: Quad, a subsidiary of Par
Pharmaceuticals, was involved through its former president, Dilip Shah, in
paying illegal gratuities to the three former FDA chemists -- Chang,
Brancato and Kletch. Inspection of the firm's facilities found no
significant GMP deficiencies.
13. WATSON LABORATORIES, CORONA, CALIF.: FDA found several significant
GMP deficiencies in recordkeeping and laboratory operations and issued a
regulatory letter to the firm Sept. 8, 1989.
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* A suspension -- the cessation of manufacturing and/or distribution of
a product -- is usually temporary. Except in certain cases, marketing may
be resumed after the problem that led to the suspension is resolved.