FDA Sends Warning Letter to Luitpold Pharmaceuticals
SILVER SPRING, Md., Sept. 13, 2011 - The FDA today posted on its website a warning letter sent to Luitpold Pharmaceuticals identifiying "significant violations of Current Good Manufacturing Practice regulations for Finished Pharmaceuticals." The agency said the violations caused drug products to be adulturated. The letter is below.
August 31, 2011
WARNING LETTER NYK-2011-33
VIA UNITED PARCEL SERVICE
Mary Jane Helenek
President and CEO
Luitpold Pharmaceuticals, Inc.
One Luitpold Drive
Shirley, New York 11967
Dear Ms. Helenek:
During our February 9, 2011 to March 15, 2011
inspection of your pharmaceutical manufacturing facility, Luitpold
Pharmaceuticals, Inc., located at One Luitpold Drive, Shirley, New
York, investigator(s) from the Food and Drug Administration (FDA)
identified significant violations of Current Good Manufacturing
Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21,
Code of Federal Regulations, Parts 210 and 211. These
violations cause your drug product(s) to be adulterated within the
meaning of section 501(a)(2)(B) of the Federal Food, Drug, and
Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)] in
that the methods used in, or the facilities or controls used
for, their manufacture, processing, packing, or holding do not
conform to, or are not operated or administered in conformity with,
CGMP.
We have reviewed your firm’s response of
April 5, 2011, and note that it lacks sufficient corrective
actions.
Specific violations observed during the inspection
include, but are not limited, to the following:
1.
Your firm does not have adequate written procedures for production
and process controls designed to assure that the drug products you
manufacture have the identity, strength, quality, and/or purity
they purport or are represented to possess [21 C.F.R. §
211.100(a)]. For example:
a.
The (b)(4) threshold used by your firm to
trigger an investigation, as per your Standard Operating Procedure
(SOP) 103.14, “Master Production and Control Records,”
is not appropriately defined or scientifically justified. SOP
103.14 requires the initiation of an investigation if
(b)(4). This (b)(4) reject
limit is uniformly applied to all products you
manufacture. Furthermore, the investigation instructions in
SOP 103.14 contradict the need for an investigation if the number
of vials rejected during inspection exceeds the reject
limit. Notably, if the rejection limit is exceeded,
(b)(4).
In your response, your firm states that you will conduct a
thorough review of every product and apply statistical criteria to
establish scientifically justifiable reject limits. Your
response, however, is inadequate because you do not commit to
assess the different types of observed particulate matter or
develop appropriate criteria for each type of particulate
matter. In addition, adequate interim controls had not
been implemented at the time of your response to improve risk
mitigation of this recurring problem during ongoing
production.
b. You have not
adequately justified the sample sizes used by the QC Microbiology
Laboratory to determine sub-visible particulates
via (b)(4) method in your small volume
parenteral products. Your firm based your lot or batch
acceptance/rejection criteria on a
(b)(4). According to your SOP 302.11,
(b)(4). Your response is inadequate because
the inspection plans referenced in the SOP (302.110) and protocol
PR-90-195 do not adequately address detection of the atypical
variability present in your current manufacturing
operation. It is important that each lot is appropriately
sampled and tested for particulate matter prior to its
release. While your response indicates that adjustments are
being made, the SOP is unclear as to what inspection level you are
using, and the corresponding (b)(4) and
(b)(4) values are incorrect as demonstrated in the
following:
- Your response states that your future statistical sampling plan is based on using the valid (b)(4) value from (b)(4) at a batch size between (b)(4) and (b)(4) at an (b)(4) sampling plan letter (b)(4). In your response your firm committed that all Particulate Matter testing will be based on (b)(4) inspection with an (b)(4) of (b)(4). However, (b)(4), equates to an (b)(4), which is inconsistent with your commitment of an (b)(4). For (b)(4), to achieve an (b)(4), you will have to use (b)(4). For (b)(4) to achieve an (b)(4) at (b)(4) with lot sizes of (b)(4) to (b)(4), you will have to use (b)(4) with accept on (b)(4).
- For fill sizes less than 25 ml, you are collecting (b)(4) samples (b)(4), this equates to a lot disposition action on (b)(4) with corresponding (b)(4) and (b)(4) respectively. This is not equivalent to an (b)(4) plan as claimed in your SOP.
- There is no scientific rationale for selecting (b)(4) for lot release and (b)(4) for retain sample inspections. According to (b)(4)
c. SOP
103.05, “(b)(4),” does not provide
adequate instructions to assure correction of significant
deviations and CAPA implementation. For example, the root
cause analysis provisions do not include extending the
investigation to other lots, examining trends for a product or
deviation category, or evaluating adequacy of limits (e.g., for
incoming raw materials, drug product).
This contributed to your failure to resolve the particulate
contamination, which is a persistent and serious issue at your firm
for many years. For example in 2009, there
were (b)(4) lots with observed particulate
matter and since 2010, there have been over (b)(4)
lots observed with particulate matter. Your failure to follow
written procedures, complete investigations, adequately scrutinize
different defect types, determine root cause, and implement
appropriate corrective action resulted in exposure of patients to
adulterated drugs.
Your response provides an outline of a new investigation
process and the commitment to reexamine prior
investigations. Your response is deficient since you have not
included or implemented a revised procedure as part of your
response.
2.
Your firm has not thoroughly investigated the failure of a batch or
any of its components to meet its specifications whether or not the
batch has already been distributed, or extend those investigations
to other batches of drug product that may have been associated with
the specific failure or discrepancy [21 C.F.R. §
211.192].
For example, your firm failed to conduct a thorough
investigation or extend such investigations to other unexpired lots
when a 12 month reserve sample of Potassium Phosphate (lot 0048)
revealed translucent visible particles. Without adequate
justification, your firm’s Deviation Report (DR) 2457 stated
the root cause was glass delamination resulting from a
manufacturing variation in the 5ml (b)(4)
glass (lot 1001055). Your firm failed to extend the
investigation to other unexpired lots of Potassium Phosphate made
with the same (b)(4) glass. Between
February 2nd and 10th, 2011, two additional
lots of Potassium Phosphate (lots 0625 and 9065) were found with
translucent visible particles.
In your response, your firm describes the enhancement of the
investigation process with quality oversight and management
controls, reexamination of previously conducted investigations, and
the implementation of a comprehensive investigation
process. However, your response is inadequate because you fail
to determine the root causes of the other particulates identified
in your products. In the absence of a root cause determination
and the lack of implemented corrective action, other
products could contain particulate matter
contaminants. An analysis of the potential impact of the
particulates observed in your marketed lots should be included in
your response to this letter.
Lack of thorough particulate and product failure
investigations are repeat violations from October 2010, October
2009, and November 2008 inspections.
3. Your firm failed
to withhold containers from use until each lot of components, drug
product containers, and closures had been sampled, tested, or
exampled, as appropriate, and released by the quality control unit
[21 C.F.R. § 211.84(a)]. Your firm also has not
established the reliability of the supplier’s analyses
through appropriate validation of the supplier’s test results
at appropriate intervals for the drug product containers [21 C.F.R.
§ 211.84(d)(3)]. For example:
- Your firm failed to withhold from use, until after quality control testing and release, numerous lots of glass vials. These lots were conditionally released in accordance with your SOP 804.13, (b)(4) which allows for this inappropriate practice. In addition, these glass vial lots were provided by non-certified supplier locations.
- You have not established the reliability of the supplier’s analyses for containers at appropriate intervals. Your practice also violates your SOP 303.01, “Inspection and Release of Packaging Components,” for the (b)(4) glass vials, which states that you will conduct USP and Functional & Dimensional testing (b)(4).
Your response is inadequate because you did not address the
corrections to your supplier computer software that will identify
the manufacturing location for each lot of glass received to ensure
that appropriate testing is conducted. Your response also fails to
address a global review of all components to ensure that all
components, drug product containers, and closures are appropriately
tested to ensure the reliability of the supplier’s
analyses.
4. Your firm has
failed to routinely calibrate, inspect, or check automatic
equipment in accordance to an adequately written program designed
to assure proper performance [21 C.F.R. §
211.68(a)].
For example, the SOP, SOP 601.23, Validation of the
(b)(4) for the annual qualification of the
(b)(4) does not include a requirement to evaluate
contamination particle sizes discovered in your products from past
investigations or recovered from an external forensic
laboratory. The (b)(4) are qualified to
identify particle size ranges (b)(4) and
(b)(4). However, past investigations have
identified particles less than (b)(4) and greater
than (b)(4). In some cases, the
(b)(4)have only been qualified to evaluate
(b)(4) particle size. For example,
(b)(4) has been qualified only with
(b)(4) sized particles in the most recent
validation dated 10/21/10.
You response fails to provide assurance that the annual
qualification of the (b)(4) demonstrate they can
effectively remove vials with particulate matter, and do so across
sufficiently representative vial sizes and types. We also note
that your response, which states that
an (b)(4) rejection rate of test vials on the
(b)(4) is acceptable performance, contradicts the
qualification acceptance criteria in your SOP 601.23,
“(b)(4),” that
requires (b)(4) to reject
(b)(4) or more test vials with
particulates.
The violations cited in this letter are not intended to be an
all-inclusive statement of violations that exist at your
facility. You are responsible for investigating and
determining the causes of the violations identified above and for
preventing their recurrence and the occurrence of other
violations. It is your responsibility to assure
compliance with all requirements of federal law and FDA
regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.
If, as a result of receiving this Warning Letter or in
general, you are considering making a decision that will result in
a decreased number of finished drug products or active
pharmaceutical ingredients produced by your manufacturing facility,
FDA requests that you contact CDER's Drug Shortages Program
immediately, as you begin your internal discussions, at
drugshortages@fda.hhs.gov in order to ensure that your action(s)
does not adversely affect the public health.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture the drug product(s) manufactured at this facility, and provide the date(s) and reason(s) you ceased production.
Your reply should be sent to the following address: U.S. Food
and Drug Administration, 158-15 Liberty Avenue, Jamaica, NY 11433.
Attention: Lillian C. Aveta, Compliance Officer.
Sincerely,
/S/
Ronald M. Pace
District Director
New York District
Posted: September 2011
