Andrx Pharma on receiving end of 9-item 483 for OOS, QC violations by knockjob54

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									!ol.%!&&&'%(o.%)                                                                                      *+g+st%/001

(234%                            CIC%
Post-approval changes often      Post-approval changes often unnecessary,
unnecessary, continuous
improvement could avoid          continuous improvement could avoid them;
them; guidance in offing
                      Page 1     guidance in offing
                                 By Joseph Pickett
Patient harm not key in          Managing Editor
prosecutions, U.S. attorney
says                 Page 1      PHILADELPHIA , Many product             the Division of Postmarketing
                                 changes made in the post-approval       Evaluation, told the Drug Information
Part 11 risk assessment ‘not     world are reactive in nature, usually   Assn. (DIA) annual meeting that he is
an alternative’ to compliance    due to FDA observations or product      seeing a variety of regulatory approaches
with predicate rules Page 2      failure. These changes can be avoided   where firms are taking the lead to change
%                                through continuous improvement,         and support change in terms of data and
Big pharma to begin rollout                                              regulatory strategies.
                                 such as, analysis of a database of
of SAFE electronic sig                                                          PI think this global picture permits
system in 2007          Page 2   manufacturing experiences, product
                                 process deviations and retrospective    us to move forward to design a quality-
%                                                                        assessment system. Good focus on post
Validation plan should           analysis to establish a design space,
                                 according to a senior CDER official.    approval issues is a more effective way to
include risk prioritization of
all company systems, says               Eric Duffy, Ph.D., director of   move forward,Q he said.
Acambis quality exec                                                     [see Duffy, page 5]
                        Page 3   ComDlEa>Fe7e>HorFeme>t%
Technology seen as ‘holy         Patient harm not key in prosecutions,
grail’ in tracking products,
improving product validation     U.S. attorney says
                       Page 4    By Jeannette Cezanne
                                 New England Correspondent
                                 CAMBRIDGE, MA , In the                  from the tools on the regulatory side,Q
;+ma>%dr+gs%                     prosecution of violations of FDA        Sheehan said. PThe issues go to the
Allergy Laboratories,            regulations, harm to patients may be    integrity of the process.Q The
Oklahoma City, OK Page 6         excluded from the judiciary process.    successful prosecution of these cases
                                        Those are startling words on     rests on the ability to prove that the
American I.V. Products,          the surface, but as James Sheehan,      drug or medical device companyJs
Hanover, MD         Page 7       associate attorney in the U.S.          conduct was both illegal and
                                 AttorneyJs office in Philadelphia       intentional.
Andrx Pharmaceuticals, Ft.       explained at an Aug. 22-24 FDA                 These issues carry certain
Lauderdale, FL     Page 8        Regulatory and Compliance               ramifications that explain why harm
                                 Symposium at Harvard University, it     to patients, seemingly at the core of
3*8(&(A%92BB284%                 is one of the odd ways that the law     medical-fraud prosecutions, is in a
Access Financial, ATCSF,         works.                                  sense irrelevant.
Herbal Remedies, Herbin                 PThe tools used to prosecute            The Department of Justice, via
Tonics, OSU Corp., Robert        health-fraud cases are very different   [see Sheehan, page 5]
Sargent, Concord Labs,
Sheffield Labs, BioGenex
Labs, Cardiac Science
                     Page 9
Page 2 — August 2006                                                                         !ALIDATION TIMES

2leFtro>EF%reFords%                       comfortable to give warning letters on    you may be able to print out the
                                          Part 11 in medical devices.               results. But if the data was crunched
Part 11 risk                                        PI often see us use the         by that system, it is an electronic
                                          concept of risk assessment to mean        record and Part 11 applies.
assessment ‘not                           that we need to do less validation, and             He added that while there is
an alternative’ to                        often it means we need to do more,Q
                                          he noted. Further, Huss stressed that
                                                                                    great anticipation for the Part 11
                                                                                    rewrite, he is not optimistic it will
compliance with                           firms must not base their risk
                                          assessment on the type of system. PI
                                                                                    come out by the end of the summer,
                                                                                    as promised by FDA most recently.
predicate rules                           have been in companies where they
                                          said that they donJt validate
                                                                                    PSome people on the Part 11
                                                                                    committee have told me, awhen itJs
By Joseph Pickett                         spreadsheets. ThatJs dumb as hell. ItJs   published youJll be as surprised as I
Managing Editor                           how you use the system that is            am,JQ he said.
PHILADELPHIA , When                       important, not the type of system.                  Huss noted with interest that
conducting a risk assessment of                                                     a Part 11 meeting that was scheduled
computer systems for compliance                                                     for June 2004 was canceled due to the
with 21 CFR Part 11 pertaining to           “I have been in                         death of President Reagan, and was
electronic records, it is important to      companies where                         never re-scheduled. PIJve never seen a
think of risk in how it applies to your     they said that they                     meeting canceled so fast and not re-
patient, product or safety. What you        don’t validate                          scheduled,Q he quipped. He noted
should not do is gauge risk based           spreadsheets. That’s                    that the delay stems from the fact that
upon whether FDA has issued 483s in         dumb as hell. It’s how                  FDA is trying not to offend anyone
certain areas, because at that point        you use the system                      with the re-write. Also to blame are
you are conducting risk assessment on                                               power struggles going on within the
                                            that is important, not
getting caught, said Harry Huss,                                                    agency regarding the regulation of
director of compliance policy and           the type of system.”                    Part 11.
program support services, Charles                                                             Regarding a petition sent to
River Labs.                                                                         FDA last year by industry to withdraw
          He added at the June DIA                 PIf you use an Excel             Part 11, he noted, Pit was terribly
meeting here that despite FDAJs talk      spreadsheet to document how you           flawed and poorly thought through.
of Part 11 enforcement discretion and     dose neonates with a potentially toxic    Even the people most opposed to
narrow interpretation, PFDA is            drug, yeah, validate the hell out of      Part 11 at the agency couldnJt swallow
making it clear they intend to enforce    that one.Q                                it.Q Predicate rules were left hanging
predicate rules,Q he noted. PThe                   Huss noted that a chief          out there, so the petition just fizzled
agency feels they have all the            pathologist at a company he visited       out.
ammunition they need to enforce           spent several minutes explaining how
virtually every aspect of Part 11,        there was no need to validate a           2leFtro>EF%reFords%
except for electronic signatures.Q        spreadsheet. PItJs just a spreadsheet,
          FDAers he has spoken with,      you plug in numbers and it tells you      Big pharma to
including Charles Snipes, Ph.D,           what the dose is,Q the pathologist
director of CDERJs Division of            explained.                                begin rollout of
Scientific Investigations, and Linda
Tollefson, director of the Surveillance
                                                   But then he noticed that one
                                          of the dosage algorithms was wrong        SAFE electronic
and Compliance at the Center for
Veterinary Medicine, stated that they
                                          because another pathologist had not
                                          changed the workbook title or the         sig system in 2007
do not Pfeel hamstrung that Part 11       algorithm. PSo for four studies, the      By Joseph Pickett
has been withdrawn.Q They added           patients got 10 times the dose they       Managing Editor
that the current Good Laboratory          should have.Q That is why you             PHILADELPHA , The Secure
Practice (GLP) guidelines Pare really a   validate based upon use of the system,    Access For Everyone (SAFE)
template for Part 11 requirements.Q       not type of system, he emphasized.        initiative , an industry effort to
          In a recent meeting with the    Also, be sure to understand the type      create a trusted, secure and legally
aforementioned FDAers, he noted           of record you are using, the executive    enforceable electronic signature
they pointed out to him: PIf your risk    said. PThe fact that you can print out    application for business and clinical
assessment says you donJt need to         the document doesnJt mean you donJt       transactions , will be rolled out
validate something in the medical         have an electronic record.Q For           more aggressively in the next two
device area, you are in error.Q He        example, if you are doing body            years as big pharma firms, such as,
noted that FDA seems particularly         weights for 300 animals for 760 days,     Pfizer and GlaxoSmithKline begin
!ALIDATION TIMES                                                                               August 2006 — Page 3

implementation, a Nextar                    meeting on the training materials was        Iaster%Dla>>E>g%
Therapeutics senior executive stated        in May, with a second round of
here June 20.                               review occurring now. The goal,              Validation plan
         Tam Woodrum, senior                Woodrum noted, is to get the training
director of IT quality and                  program under six hours.                     should include
competence, told the DIA annual
meeting that SAFE has met with
                                                      The working group also is
                                            compiling a compliance matrix that           risk prioritization
some resistance because
implementation has been slower than
                                            includes a series of scenarios and
                                            checklists that can be used on the           of all company
expected. PThere are many laws
between other states and countries
                                            validation side. It also includes an
                                            internal SOP matrix for the
                                                                                         systems, says
governing the use of electronic
signatures,Q he said. PRegulators want
                                            procedural controls, which she
                                            stressed Pare not out-of-the-box
                                                                                         Acambis quality
to make sure that the result is a legally
enforceable signature.Q
                                            compliant. You must have
                                            appropriate internal processes in
                                            place.Q                                      By Joseph Pickett
                                                      Also in the works is a             Managing Editor%
   “There are many laws                     European Agency for the Evaluation           ARLINGTON, VA , It is vital that
   between other states                     of Medicinal Products (EMEA) pilot,          a system-validation, master plan
   and countries                            the goal of which is to ensure the           include a validation program for every
   governing the use of                     electronic signatures will be valid in       computer system in a company, each
                                            Europe. EMEA recently stated that            of which should be prioritized
                                            the SAFE initiative Pcan be                  according to risk, with a complete
   signatures,” he said.                                                                 justification of that ranking, the
   “Regulators want to                      implemented in a way that is
                                            compatible with the European                 quality director for Acambis stated
   make sure that the                                                                    here Aug. 18.
                                            UnionJs digital signature directives,Q
   result is a legally                      she said.                                               Felicia Ford-Rice, speaking at
   enforceable                                                                           an Institute of Validation
   signature.”                                                                           Technology conference, cautioned
                                              “One program is an                         that it is important to conduct all
                                                                                         validation programs listed in the
          However, the system is                                                         master plan. PYou can have a great
                                              program that is
superior to a firm having its                                                            plan on paper, but if you donJt
                                              putting together a                         actually carry out the plan, FDA will
employeesJ signatures and initials
                                              manual to walk                             not like it,Q she said. If yours is a new
registered with FDA. PSAFE is not
                                              auditor[s] through                         company, Ford-Rice added, it is okay
just business-to-regulator, but also
business-to-business, it is a central         how SAFE works,” he                        if systems are not fully validated. PJust
repository,Q he said. PThe types of           said.                                      provide a schedule to the agency
standards you have with SAFE is (sic)                                                    detailing how you are going to
broader than with just business-to-                                                      complete the validation of your
regulator.Q                                           Another pilot is being             systems. But you canJt just write a
          Woodrum noted that SAFE           conducted with the National Cancer           plan and not do anything with it for
is essential because research shows         Institute (NCI), where form 1572 was         years.Q
that 40b of RcD costs involve               worked through using 50 clinical                        She advised that when
handling paper. PThere are a lot of         investigators at eight clinical sites. The   providing FDA with a description of
possibilities to cut costs if we handle     pilot now will be conducted on               your firmJs systems, you should put
information electronically.Q                studies involving more than 13,000           them into an attachment. PIf you put
          Also, there is a working          patients.                                    this into the body of the document, it
group within industry that is working                 Woodrum noted that there           is very verbose.Q
with FDA on SAFE. POne program              are Pmany partnerships underwayQ                        According to the Acambis
is an auditor-familiarization program       with other vendors to ensure that off-       executive, a validation master plan
that is putting together a manual to        the-shelf systems work with SAFE.            organizes requirements according to
walk auditoresf through how SAFE                      Further, Johnson&Johnson           human and technical resources,
works,Q he said. The next piece is          is working with SAFE in ways other           documentation and testing /
how to move from this manual to an          than electronic signatures , it is           implementation/maintenance. PThe
in-person training program. The             having its 78,000 employees use the          master plan lists and defines the
manual is complete, and the first           system for authentication purposes.          systems and equipment requiring
Page 4 — August 2006                                                                         !ALIDATION TIMES

validation, parameters to be validated     You have to have that system in your     analysis, it moves regulators to
and the regulatory risk,Q she noted.       environment using your data, and         wonder what else might be wrong in
          The master plan should           then validate it.Q                       the company.
provide an introduction, purpose and                                                          ThereJs no question that
scope (including assumptions,              8J&K%                                    non-compliance can be expensive.
inclusions, exclusions and limitations),                                            McGrory cited the $839 million in
a systems description, functional          Technology seen                          restitution levied on Bristol-Myers
department tasks and responsibilities,                                              Squibb to defer prosecution on a
acceptance criteria, and deviation         as ‘holy grail’ in                       charge of conspiring to commit
policy and definitions.                                                             securities fraud for the companyJs
          Also, the validation master      tracking products,                       failure to disclose its Pchannel-
plan should feature the product life                                                stuffingQ activities in 2000 and 2001.
cycle, standards and regulatory            improving                                Policy controls, including regulatory
requirements, timelines, risk
assessment, required documentation,        product validation                       constraints, corporate objectives,
                                                                                    trade agreements and market
review and approval responsibilities,      By Jeannette Cezanne                     dynamics, ensure that companies
revalidation and references.               New England Correspondent                found to be in violation will be
          Ford-Rice also described the     CAMBRIDGE, MA , Radio-                   prosecuted.
importance of a user requirement           frequency identification (RFID),                   Any technology solution for
specification (URS), which describes       which FDA and industry have pushed       pharmaceutical manufacturers needs
how the computerized system is to          as a means of thwarting counterfeiting   to address all of these challenges. By
perform. PThe URS defines the              of prescription and OTC drugs, was       capturing and validating all channel
required functions to be performed         hailed at a conference here Aug. 24 as   data, including orders in real-time,
by the system, external interfaces,        a means of also improving                technology can build a complete and
operating environment, time and cost       pharmaceutical manufacturing.            comprehensive system of record of
constraints, performance with respect                John McGrory, CEO of           the manufacturer's distribution
to speed, availability and response        Edge Dynamics, Redwood City, CA,         channel. This solution then analyzes
time, and physical security.               told the second annual FDA               the record to evaluate orders, balance
                                           Regulatory and Compliance                inventory levels in the channel,
  “You would say it                        Symposium at Harvard that                manage service fill rates, limit
  needs to be able to                      technology is a tremendous asset in      unauthorized distribution and
                                           managing complex pharmacology,           compensate wholesalers for the
  interact with system
                                           distribution flows of product, money     reporting services that they provide.
  X,” Ford-Rice said.                                                                         Each order processed must
                                           and information.
          PThe URS generally is the                  But mistakes can occur at      be documented for regulatory and
most problematic document because          any point along the flow from            auditing purposes and, to enhance
it involves the end user,Q she said.       manufacturer to wholesaler to            patient safety, there has to be deep
While some in the industry describe        pharmacy to patient, including           analysis of channel documents to
the document as Pblue sky,Q Pyou           primary and secondary distribution       detect unusual activities further
donJt want to include requirements         and brokerage shipments.                 downstream. Poor channel control
that cannot be met.Q                                 PRobust channel commerce       can result in a number of byproducts,
          One audience member asked        requires transparency, accountability    among them counterfeit drugs.
that in a user requirement, if you have    and control,Q McGrory said. PIt can                Enterprise technology needs
a computer system that has a lot of        enable improvements in financial         to rise to the challenges of regulation
sensors that are related and are           performance, regulatory compliance,      and compliance, he said. Legacy
capturing data, do you put the sensors     market integrity and patient safety.Q    technology provides very limited
in the documentk                                     Given that there are a         analytics; current-generation systems
          PYou would say it needs to       number of compliance issues making       provide some analytics, but itJs the
be able to interact with system X.         it mandatory to follow certain           next-generation systems, thanks in
That system probably has its own           procedures (whether because of the       part to extensive RFID use, which
requirements. You say that it needs to     Sarbanes-Oxley Act, SEC reporting,       will provide deep real-time analytics.
interact with that system to get the       government pricing, etc.), and that in             An enterprise-class solution
data you want.Q                            commercial operations compliance         includes reliability, scalability,
          She also reminded                comes into play in a number of areas,    transactionability, auditability and
participants that when you buy a           it becomes extremely expensive to not    compliance. All of these areas can be
computerized system, Pyou are buying       comply with regulations. Moreover, if    provided by the technology partner
a system, not a validated program.         there is poor data collection and        either as on-premise or as hosted
!ALIDATION TIMES                                                                           August 2006 — Page 5

solutions, and all of them will ensure    %
                                          !"    Revised or changed                   %protocol (including patient selection
better accountability and                  % manufacturing process was               %and endpoints), and participant
responsibility for the industry.
         Given all of this, PRFID is
                                           % inadequately described;                 %protections.
                                           !" Inadequate rationale for a
                                           %                                         %           The second question is: how
the holy grail,Q said McGrory. The                                                    did the product obtain approvalk Two
capability to identify and track           % change;                                 %thousand AEs go unreported every
products gives in turn the ability to      !" Inadequate documentation on
                                           %                                         %year, and here, noted Sheehan, case
accumulate and validate accurate data.     % whether or not a control change
                                                is needed;
                                                                                     %law is significantly helpful: in U.S. v.
         The visibility provided by        %                                         %Caputo, the Pdefendant intentionally
this technology allows an accurate         !" Insufficient controls for
knowledge of the inventory level by
                                           % incoming materials. PSeveral            %avoided information about potential
eliminating the discrepancy between        % citations have been made on             %safety hazards,Q while in a 2004
                                                                                      Massachusetts case, a product was
inventory record and physical              % materials control,Q he said;            %said to be misbranded Pif,Q said
inventory. RFID technology can             !" Justification for a specification
                                           %                                         %Sheehan, Pyou knew the product was
prevent or reduce the sources of           % not adequate; and,                      %likely to fail more frequently then
errors.                                    !" Stability of data analysis.
                                           %                                         %disclosed in your labeling and you do
         The important PpedigreeQ ,                  For drug products, Duffy
the chain of custody document ,
                                           %                                         %not disclose (that) to FDA.Q
                                          continued, many of the same issues                     Fraud on payer programs is,
now difficult to track, will be            %
                                          remain. Some of these are inadequate       %
                                                                                      Sheehan noted, a Pgrowing area of
simplified and mechanized once             %
                                          description of process, control of         %liability.Q Payers rely on the labeling
RFID is used throughout the                %
                                          materials and labeling deficiencies.       %and on FDA approval as the basis for
industry. Other benefits will include      %
                                          Submissions for cleaning validation        %making payments. The development
the reduction of labor costs, a           also are not needed.
                                           %                                         %of relationships between salespeople
simplification of business processes                 He added that many post-
and a reduction in inventory
                                           %                                         %and decision-makers, while nothing
                                          approval changes may not even be
inaccuracies.                              %
                                          necessary to submit. PSome of the          %new, is being better scrutinized,
                                                                                      especially when occurring on a larger
                                          ones we see that are not needed            %scale than in the past. Kickbacks are
Duffy                                      %
                                          include analytical site changes;           %not uncommon, and nor are
Co>tE>+ed%Hrom%Dage%L%                     %
                                          stability-testing, site changes; and       %Ppayments to physicians, health plans,
He noted that risk-based evaluation       ,packaging site changes.Q
                                           %                                         %advisory panels, PBMs epharmacy
                                                     Finally, Duffy stated: POur
allows better use of resources, which      %                                         %benefit managersf and pharmacy
                                          analysis of post-approval submissions
is what FDA does when it receives          %
                                          will result in a guidance to permit        %directors to advocate for, promote or
submissions. PSubmissions are triaged                                                 write for a given product.Q In 2005,
                                          everyone to have a common                  %for example, the chief pharmacist of
upon arrival and a risk assessment is
made. We review the assignment             %
                                          understanding of new approaches.Q          %the Pennsylvania Department of
based upon that assessment.Q              He did not mention when this
                                           %                                          Welfare was fined $27,000 for
Duffy said that a primary issue at        guidance would be published.
                                           %                                          accepting money from Pfizer while
FDA is to facilitate implementation of    %%                                          serving on a state committee selecting
newer technologies, which leads to the
development of a knowledge                Sheehan
                                                                                                The Schering-Plough GMP
framework.                                Co>tE>+ed%Hrom%Dage%L%                      consent decree in 2002 set case law
         He said that he does not see      %                                          for fraud on payers in the situation
as much of that Pgood, solid               %
                                          the U.S. AttorneyJs office, looks at        where the product or the quality of
developmentQ through the NDA              fraud specifically as it relates both to
                                           %                                          the product are not as advertised.
process. PThis is reflected,Q he noted,   FDA and to payer programs.
                                           %                                         .PThe disclosure/false claims can be
Pby the fact that there are so many       Investigating FDA fraud involves            for the same product,Q noted
                                          answering several questions, according
supplements that need to be
                                           %                                         %Sheehan; the two prosecutions do not
                                          to Sheehan.
implemented soon after approval.Q
                                           %        How did the product
                                                                                     %need to be separate. On the other
         The agency has seen an                                                       hand, Pthe fraud statutes on false
                                          (medicine or medical device) get           %claims is (sic) the oldest and most
increase in the number of
supplements submitted within two          approvedk This question usually
                                           %                                         %extensive case law, so it is used more.Q
years of approval. PFirms may not         involves false statements about clinical
                                           %                                         %          And, he said, this is where
have been really equipped to move in      trials. They can include questions         %the issue of human harm comes into
                                          about the productJs reported results
the manufacturing setting,Q he said.
                                           %                                         %the equation.
                                          (product efficacy, number of adverse
         Some of the more common
                                          events (AEs) associated with trials),
                                                                                     %Sheehan said prosecutors look first at
deficiencies he has seen in                                                           where the most successfully
                                          the companyJs compliance with              %prosecuted cases were , what he
supplements are:
Page 6 — August 2006                                                                                       !ALIDATION TIMES

called Plooking in the rearview mirror             prove in those cases than it is in            be established.
to know where to go next.Q                         human-harm ones. Whistleblowers                        These are the cases that are
          By and large, these successes            who come to the U.S. Attorney are             most successful. They are Pless
have been in the false claims arena,               told immediately that their first step        complex and easier to put together,Q
 %                                                                                               said Sheehan, thus making it possible
Sheehan added. In focusing on intent,              must be the companyJs compliance
the Department of Justice is focusing              division, because once compliance has         that harm to patients , the logical
on false and/or misleading                         been informed of the wrongdoing, the          focus of the prosecutions , might be
information, and intent is far easier to           company can no longer assert that it          excluded from the judicial process
%                                                  didnJt know about it, and intent can          altogether.
%   *>alysEs%oH%5)6s72&8s%Hor%AIN%
%         valEdatEo>%Ess+es%                                                       In addition, Pwritten procedures for cleaning and
% By Joseph Pickett, Managing Editor                                     maintenance failed to include parameters relevant to the
%                                                                                  Further, the report documented that the cleaning
;+ma>%dr+gs%                                                             and sanitizing validation report for the phenylephrine
23-item 483 for Allergy                                                  hydrochloride injection USP and L-cysteine hydrochloride
                                                                         injection USP did not include suitability studies for the use of
Labs citing aseptic                                                      an undisclosed method for detecting phenyephrine
                                                                         hydrochloride and L-cysteine hydrocholoride following the
processing, sanitation                                                   cleaning process to ensure that no drug residues were present.
                                                                                   Also, procedures for the cleaning and maintenance

procedures, equipment                                                    of equipment were deficient regarding maintenance and
                                                                         cleaning schedules, including sanitizing schedules. For
                                                                         example, Pthe firm has not established a written procedure to
cleaning                                                                 prevent drug product contamination,Q the 483 stated.
          Allergy Laboratories, Oklahoma City, received a                          Further, the bulk drug solution mixing tanks were
23-item 483 for its sterile drug manufacturing facilities                not cleaned and sanitized prior to being placed into the Vial
because its aseptic processing areas were deficient regarding            Wash Room from a non-classified storage area. Next,
the system for monitoring environmental conditions. Further,             Pprocedures for the cleaning and maintenance of equipment
its written procedures for sanitation were not followed,                 are deficient regarding the protection of clean equipment
according to FDA records. The report also documented                     from contamination prior to use.Q For example, the bulk drug
numerous failures in the cleaning and maintenance of                     solution mixing tanks were not covered or held in a manner
equipment.                                                               that would prevent environmental contamination while being
          The firm further received a 20-item 483 following an           stored in a non-classified storage following cleaning.
inspection of its allergenic extract manufacturing facilities (see                 The company also was cited because Pequipment
below). Only the 483s were available as this publication went            used in the manufacture, processing, packing or holding of
to press.                                                                drug products is not of appropriate design to facilitate
          The sterile drugs audit, prepared by FDA                       operations for its intended use and cleaning and
investigators Margaret Annes and Lloyd Payne from the                    maintenance.Q Specifically, the water for injection system was
Dallas District Office, revealed that AllergyJs environmental            designed or constructed of a material that could promote
sampling of non-viable and viable particulates in two                    microbial contamination of the finished product. Further,
undisclosed production areas were not adequate to determine              there was clear, flexible plastic tubing used to connect an
the air and surface qualities. Also, Penvironmental surface              undisclosed part to the water for injection storage tank at one
monitoring of viable particulates in the eundisclosedf Vial              sample port. This resulted in a biofilm on the interior surface
Wash Room and Sterile Gowning Room is performed eat                      of the tubing.
incorrect intervalsf.Q                                                             In addition, sampling and testing plans for drug
          The FDAers also found the firm to be deficient in its          products were not described in written procedures, which
written procedures for cleaning and maintenance. For                     included the method of sampling and number of units per
example, Pthe firm has not validated the procedures used to              batch to be tested. PSpecifically, the firm does not have an
clean and sanitize the processing equipment and production               SOP that addresses out-of-specification (OOS) investigations
areas,Q according to the 483. Also, a finalized validation               conducted by contract labs. There is no SOP that allowesf the
report for the ephedrine sulfate injection USP drug product              firm to re-test or re-sample a drug component if the initial
was not developed.                                                       tests from the contract lab indicate the product does not
                                                                         conform to specifications.Q
!ALIDATION TIMES                                                                                             August 2006 — Page 7

         The next violation in the 483 noted that actual yield                       !"    Personnel performing sterility testing were observed
and percentages of theoretical yield were not determined at                                with exposed skin;
the conclusion of each appropriate phase of manufacturing                              !" A technician was seen sanitizing hands immediately
the drug product. For example, the 483 stated, Pthe firm is                                before touching finger touch plates used for
not reconciling the use of the bulk solution during filling                                personnel monitoring;
operations. The firm does not document the amount of bulk                              !" A technician was observed adjusting cleanroom
solution left in the carboy after filling operations have been                             clothing;
                                                                                       !" There was no assurance that the results obtained
         Also, the company did not determine the theoretical
                                                                                           from the surface monitoring of the laminar air-flow
amount of vials that were to be filled from the bulk solution
                                                                                           (LAF) hoods were valid;
that was manufactured, and it did not compare the theoretical
vs. actual yields of filled vials to determine if an investigation                     !" The base of the viable air-monitoring devices utilized
was required.                                                                              in the sterile filling area were rusty and exhibited
                                                                                           flaking paint;
   !%BPe%CPeFQlEst%R%*llergy%9aSoratorEes%                                             !" Personnel were observed wiping the surface of the
   ! Aseptic processing flaws                                                              LAF hood after filling final product and prior to
   !%Written sanitation procedures not followed                                            performing surface monitoring.
                                                                                           In the materials system, the audit noted: PThere are
          Further, AllergyJs written records of major                            no incoming checks or specifications for filters used in sterile
equipment cleaning and use were not included in individual                       filtration and tubing used in the manufacturing of allergenic
equipment logs. For example, PThe firm does not document                         extracts.Q
the use and cleaning of their mxing tanks in individual                                    Also, there were no incoming checks for petri dishes
equipment logs. The firm does not have dedicated mixing                          utilized in preparation of environmental-monitoring
tanks for the Ephedrine Sulfate Injection USPrQ                                  plates.The firm could not be reached for comment.
          In the second inspection, investigators Julie Bringger                 Allergy Laboratories, Oklahoma City, 8/9-29/05, 10/3-7,
and Jennifer Bridgewater from Center for Drugs also found                        25/05, Doc. 109855M, $6 plus retrieval.
that the firm lacked validation studies to support the current
packaging and shipping practices. PPackaging and shipping
conditions consist of placing the extracts in uninsulated
                                                                                 Lack of acceptance criteria
cardboard boxes wrapped with a thin plastic strip, placing
Styrofoam chips throughout the box and shipping the final
                                                                                 and validation flaws nets
container un-refrigerated to the customer,Q the report noted.
There was no assurance by Allergy Labs that this shipping
                                                                                 6-item 483 for American I.V.
                                                                                         American I.V. Products (AIV), Hanover, MD, was
procedure maintained final product at the labeled
                                                                                 hit with a six-item 483 because it failed to establish
                                                                                 acceptance criteria prior to the performance of validation
          Further, the report noted the following violations
                                                                                 activities, and also prior to the performance of verification
relating to cleanroom practices and conditions:
  !ALIDATION TIMES                                    4Eg>%+D%Hor%a%s+SsFrEDtEo>%to%!alEdatEo>%BEmes.%T))5%Hor%L/%mo>tPly%Ess+es%Dl+s%
  Kenneth Reid, Editor & Publisher
  9oseph Pickett, Managing Editor
                                                      Name/Title: ____________________________________________________________
  D. Michele Duarte, Assistant Managing Editor
  Kathy Thorne, Circulation (301) 540-3971            Company: _____________________________________________________________
                                                      Address: ______________________________________________________________
  Editorial Advisory Board
  Elaine Messa,                                       City/State/Zip: __________________________________________________________
  Quintiles Consulting, Irvine, CA                    Phone: (     ) ____________________Fax: (          ) ________________________
  Ken Muhvich, Ph.D.
  MICRO-Reliance LLC, Baltimore, MD                   E-mail: (to receive news updates) _________________________________________
  Bruce Mackler, Ph.D.
                                                      Payment options: (check one) " Check Enclosed " P.O. Enclosed " Bill Us
  Life Sciences Management Group, Rockville, MD
                                                      Charge: " Visa " MC " AmEx " Diners%%
  Editorial offices: (703) 779-8777                   4Eg>at+reW%(reY+Ered%o>%all%orders)%[%\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\%
  Fax: (703) 779-2508                                 CredEt%Card]%\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\%2^D.%KateW%\\\\\\\\\\\\\\\%
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  208 South King Street, Suite 303                    JoreEg>%s+SsFrESers%add%T50%delEvery.%Ja^%yo+r%order%to%(60L)%_/)-/5`a%or%Fall%
  Leesburg, VA 20175                                  (60L)%_50-6`aL.%br'%maEl%toW%%3asPE>gto>%&>HormatEo>%4o+rFe%Co.%/0`50-C%JrederEFQ%
Page 8 — August 2006                                                                                 !ALIDATION TIMES

          Conducting the inspection was investigator Lori          the labeling that is attached to the transducer. The records do
Lawless from the Baltimore District Office. The EIR was not        not include the labeling that is applied to the final packaging.Q
available as this publication went to press. The report stated               American I.V. noted in response: PThe lack of
that American I.V. could not provide a protocol or previously      device and packaging labels in the device history record was
established acceptance criteria for the performance of             immediately addressed during the facility inspection. Copies
validation tests used to determine if the design inputs met        of the labelsrwere placed in the device history recordrand
user needs.                                                        copies of labeling for kits manufactured after number
          Next, the firm Pcould not provide a protocol or          eundisclosedf were made from units that were found in
previously established acceptance criteria for the testing of      inventory.Q
the ultrasound transducersrthis testing was designated as                    In response to the firmJs corrections, FDA wrote:
design verification used to determine if the design inputs met     PThese documents appear to address the observations found
design inputs,Q according to the EIR.                              in the 483rCorrective actions taken will be verified during
          The companyJs written response stated: PThe              your next inspection.Q
protocol for validating the device design for AIV FMTs has         American I.V. Products, Hanover, MD, 7/29-8/17/05,
been written and approved. The provided protocol will be the       Doc. 109857M, $6.50 plus retrieval.
template for future design validation protocols.Q Also,
American I.V. noted that for future device developments,
Pthere is a requirement to develop documented validation           Andrx Pharma on receiving
protocols for testing production units under actual or
simulated use conditions. The protocol will ensure that the        end of 9-item 483 for OOS,
devices conform to defined user needs and intended users.Q
          Also, a process whose results could not be fully
                                                                   QC violations, control
verified by subsequent inspection and test was not validated
and approved according to established procedures.
PSpecifically, the firm does not have a protocol for, nor has                Andrx Pharmaceuticals, Ft. Lauderdale, FL, was
performed, the process validation for their manufacturing          slapped with a nine-item 483 in a March-April inspection
process used to manufacture the FMT 10834 ultrasound fetal         because it did not perform investigations of OOS results.
monitor transducers,Q the report stated.                           Also, the firmJs quality control unit was inadequate, and the
          Next, the firm responded that formal specifications      firm had faulty control procedures, which did not validate the
for the fetal monitoring devices, including acceptance criteria,   performance of manufacturing processes.
were written and approved in April 2005. PWe feel that to go                 The audit was performed by investigators Ileana
back and create written protocols for the previous                 Barreto-Pettit, Jennifer Menendez, Rebeca Rodriguez and
eundisclosedf testing does not add any value to the program        analyst Jennifer Hollstrom from FDAJs Maitland, FL, District
at this time.Q                                                     Office. The EIR was not available at press time.
                                                                             According to the report, Andrx failed Pto thoroughly
   !%BPe%CPeFQlEst%R%*merEFa>%&.!.%                                review any unexplained discrepancy and the failure of a batch
   ! Acceptance criteria not established                           or any of its components to meet any of its specifications
   !%OOS procedures not followed                                   whether or not the batch has been thoroughly distributed.Q
                                                                             Specifically, the firm did not perform adequate
          Next, procedures were not followed for the control       investigations with scientifically justifiable conclusions to
of products that did not conform to specifications. For            incidents of OOS results or production deviations and/or
example, one of the firmJs work instructions lacked                failed to implement appropriate corrective actions for the
documentation that undisclosed non-conformities were               root cause determination.
identified or investigated. In another work instruction, Pthere              The report stated that the sC unit Pfailed to
is no documentation that the non-conformity epertaining to         adequately review Ketoprofen Validation Protocol and
PCB boardsf was identified or investigated. The PCB boards         Report No. 002PV005 and, as a result, it released and
are used to manufacture fetal monitor transducers.Q                distributed between March and July 2005 six batches of
          American I.V. stated in response that it had designed    Ketoprofen ER capsules (lot #Js: 520E017, 520F0368,
a protocol to validate the transducers in question. PFor future    520E018, F520F0840, F520F1030, and F520F1031) that were
medical devices,Q the company noted, Pprotocols will be            manufactured with a process that showed significant
written and production/manufacturing process validated to          variability and was not adequately validated.Q
that protocol. This process has been implemented by the                      Next, the sC unit did not ensure that Phase I
company.Q                                                          Laboratory Investigations were adequately investigated,
Next, the device history record did not include the primary        documented and trended after they were removed from an
identification labels and labeling for each device. For            undisclosed system in September 2005 and transferred to a
example, Pthe device history records for kitsrmanufactured         manual logbook.
from March 10, 2005, through July 25, 2005, do not include                   Regarding control procedures, FDA documents
                                                                   noted that the sC unit approved Doc. No. 0002PV05 titled
!ALIDATION TIMES                                                                                August 2006 — Page 9

PProcess Validation Protocol , Manufacture of                      of metformin HCl extended-release tablets, 500 mg lot no.
KetoprofenQ to evaluate the accuracy of scale reading versus       F571F0692 was specifically for content uniformity testing.
an undisclosed type of reading for the sustained-release           During analytical testing, one of the capsules failed to meet
coating process as the difference in dissolution performance       the Stage 1 established specification of an undisclosed
at the eighth hour.                                                ingredient label claim and another tablet was toward the low
          FDA added: PFive commercial batches of ean               end of the specification range.
undisclosed productf were manufactured under this validation                  The root-cause analysis indicated analyst error and
protocol, which resulted in three batches (52050, 55797 c          two additional capsules were extracted with the results
520E018, sublot#4) that failed dissolution specifications at       replacing the original OOS capsules, the 483 stated. The
the eighth hour, and a batch (57043) that deviated from the        investigation revealed that the analyst observed a gelatin like
target capsule fill weight specified in the manufacturing batch    mass of material at the bottom of one of the flasks and a
record in order to meet dissolution specification at the eighth    piece of undissolved gel at the bottom of the other flask after
hour.Q                                                             adding diluting solvent A.
          Next, FDA cited the use of instruments and                          As a result, these two flasks were stirred for an
apparatus not meeting established specifications.                  additional 60 minutes, which is longer than the procedure or
PSpecifically, in December 2005,Q the report stated, Pthe sC       the eight other flasks, according to FDA documents. The
unit determined the need to replace the flow rate valves of all    analyst who performed the sC method transfer stressed the
eundisclosedf apparatuses as a result of frequent clogging,        importance of full tablet disintegration before adding diluting
flow rate problems and increased bubble formation that             solvent A or the material will clump. PThe firm concluded
randomly caused aerraticJ dissolution results.Q                    that based on the physical observation of the two stock
                                                                   solutions in question proper active extraction did not take
   !%BPe%CPeFQlEst%R%*>dr^%NParmaFe+tEFals%                                   Following the audit, Andrx said in a press release
   ! Quality audits inadequate                                     that it Pprovided FDA with a detailed response to the 483,
   !%No corrective actions for OOS results                         which included a proposed corrective action plan. FDA has
                                                                   not commented on the companyJs response or corrective
                                                                   action plan. Andrx is working to resolve the cGMP issues at
          However, the quality unit failed to adequately           its facility as quickly as possible. The timing of that resolution
monitor the implementation of its corrective action and, as a      is uncertain, and is not solely in our control.Q
result, the valves were not installed and the use of these         Andrx Pharmaceuticals, Ft. Lauderdale, FL,
dissolution baths with potentially malfunctioning valves           3/16-4/18/06, Doc. 109849M, $5.50 plus retrieval.
continued for dissolution testing of all cartia, diltia, taztia,
metformin, naproxen sodium, and ketoprofen drug
          Further, written records of investigations into
unexplained discrepancies did not include the conclusions                  ! 3ar>E>g%9etter%*>alysEs%R%%
and follow-up. For example, the 483 stated, Pthe cleaning              KetaEls%oH%Qey%JK*%Uar>E>g%letters%
swab failure investigations reported under TWRs 1545, 1555,            released%E>%d+ly%/001%tPat%Fo>taE>%
2194, 2259 disclosed that the root cause was the failure to            FEtatEo>s%Hor%valEdatEo>%Ess+es.%2aFP%letter%
thoroughly rinse or clean equipment or that the cleaning               Es%Ta%Dl+s%retrEeval.%%
procedures were not specific enough.Q                                  By Michele Duarte and Joseph Pickett%
          The agency added that the sC unit also failed to
follow up on these findings and none of the SOPs involved
in these investigations had been revised to make the rinsing       %
and/or cleaning instructions more specific.                        ;+ma>%dr+gs%
          Additionally, the FDAers wrote, Pthere is a failure to
thoroughly review any unexplained discrepancy and the              Several firms receive warning
failure of a batch or any of its components to meet any of its
specifications whether or not the batch has been thoroughly        letters for questionable
          Specifically, the firm did not perform adequate
                                                                   erectile dysfunction drug
investigations with scientifically justifiable conclusions to
incidents of OOS results or production deviations and/or
                                                                   claims, including sildenafil
failed to implement appropriate corrective actions for the                  FDA in July dispatched several warning letters to
root-cause determination.                                          firms that, according to the agency, have been making false
          The deficiencies included the following: The             claims about erectile dysfunction drugs. The following firms
investigation report TWR #1691 for finished product testing        were cited:
Page 10 — August 2006                                                                                !ALIDATION TIMES

*FFess%JE>a>FEal' eloomE>gto>'%I(%                                 perform normallyQ; and, PaZimaxx VigaJ produces firmer and
          FDA objected to the firmJs marketing of the product      longer lasting erections.Q
Libidus on its website. According to the warning letter, a                  PThese statements suggest that your product does
laboratory analysis conducted by FDA concluded that Libidus        not contain sildenafil,Q FDA stressed. PThey also falsely
contains acetildenafil, an analogue of sildenafil. Sildenafil is   suggest that the product does not have the potential to cause
the active pharmaceutical ingredient (API) in Pfizer’s Viagra,     side effects.Q The company could not be reached for
an FDA-approved drug that is used to treat erectile                comment. Doc. 13916W
dysfunction. Thus, the product is a drug for which Access
Financial had not filed an NDA.                                    ;erSE>%Bo>EFs'%99C'%eeverly%;Ells'%C*%
          Additionally, the agency stated in the July 11 letter               FDA objected to the companyJs marketing of the
that it objected to various statements made on Access              product Nasutra on its website. According to the warning
FinancialJs website describing Libidus, including, but not         letter, a laboratory analysis conducted by FDA concluded that
limited to: PSo while erectile dysfunction (ED) drugs like         Nasutra contains acetildenafil, an analogue of sildenafil.
Viagra, Cialis (sic) and Levitra treat impotency by redirecting    Sildenafil is the API in Pfizer’s Viagra, an FDA-approved
blood flow, Libidus goes one step further by also fixing the       drug that is used to treat erectile dysfunction. Thus, the
problem at the libido levelQ; PYour penis will become              product is a drug for which Herbin Tonics had not filed an
engorged to give better pleasure to your loverQ; PYour             NDA.
erection will be firm, and your penis will be rock hardrfor as                And, the July 11 letter noted, neither the product
long as you desire.Q No comment was forthcoming from the           labeling nor the website list any negative side effects, such as,
firm before deadline. Doc. 13906W                                  the fact that patients who take nitrates and consume Nasutra
                                                                   are at risk of life-threatening hypotension, as well as other
*BC4J'%4a>%Jra>FEsFo%                                              side effects associated with ED drugs. The firm was not
          FDA objected in the July 11 warning letter to the        available for comment. Doc. 13917W
companyJs marketing of the product Neophase on its
website. According to the warning letter, a laboratory             b4f%CorD.'%eeverly%;Ells'%C*%
analysis conducted by FDA concluded that Neophase                             FDA objected to the companyJs marketing of the
contains homosildenafil, an analogue of sildenafil.                product Actra-Rx on its website. According to the warning
Sildenafil is the API in Pfizer’s Viagra, an FDA-approved          letter, a laboratory analysis conducted by FDA concluded that
                                                                   Actra-Rx contains methisosildenafil, an analogue of sildenafil.
drug that is used to treat erectile dysfunction. Thus, the
                                                                   Sildenafil is the API in Pfizer’s Viagra, an FDA-approved
product is a drug for which ATCSF has not filed an NDA.
                                                                   drug that is used to treat erectile dysfunction. Thus, the
          Additionally, FDA noted that the product labeling        product is a drug for which OSU had not filed an NDA.
for Neophase does not declare that it contains                                Additionally, the agency objected in the July 11 letter
homosildenafil. And, neither the product labeling nor the          to various statements made on OSUJs website describing
website list any negative side effects, such as, the fact that     Actra-Rx, including, but not limited to: PActra-Rx helps
patients who take nitrates and consume Neophase are at             diabetics hypertension high blood pressureQ; PActra-Rx is the
risk of life-threatening hypotension, as well as other side        most effective and safest natural erection producing natural
effects associated with ED drugs.                                  drug that promotes a completely safe and healthy, and all
          The firm could not be contacted for comment.             natural transformationQ; PRock hard erections guaranteedQ;
Doc. 13907W                                                        and PExperience the joy of longer and harder erections.Q
                                %                                             FDA also pointed out that the product labeling does
;erSal%8emedEes'%CasDer'%3:%                                       not declare that Actra-Rx contains methisosildenafil. And, the
          FDA objected to the firmJs marketing of the product      website also states that Actra-Rx Phas no side effects and is
Zimaxx on its website. According to the warning letter, a          extremely effective for diabetics and very safe for persons
laboratory analysis conducted by FDA concluded that                suffering from hypertension,Q even though methisosildenafil
Zimaxx contains sildenafil, the API in Pfizer’s Viagra, an         likely exhibits similar pharmacological action to sildenafil.
FDA-approved drug that is used to treat erectile dysfunction.      The company could not be reached for comment.
Thus, the product is a drug for which Herbal Remedies had          Doc. 13918W
not filed an NDA.
          Additionally, the agency objected in the July 12         8oSert%4arge>t'%eatavEa'%(:%
warning letter to various statements made on Herbal                         FDA objected to SargentJs marketing of the product
RemediesJ website describing Zimaxx, including: PeZimaxxf          Vigor-25 on his website. According to the warning letter, a
may help to achieve maximum results from lack of sexual            laboratory analysis conducted by FDA concluded that Vigor-
desire dysfunction performance stamina and vitalityQ;              25 contains piperidenafil, an analogue of vardenafil.
PaZimaxx VigaJ helps increase blood flow to the lower              Vardenafil is the API in GlaxoSmithKline’s Levitra, an
extremities and therefore hell2s sexually dysfunctional men        FDA-approved drug that is used to treat erectile dysfunction.
                                                                   Thus, although Sargent markets Vigor-25 on his website as an
!ALIDATION TIMES                                                                                August 2006 — Page 11

Pherbal sex enhancement,Q FDA pointed out that the product         specifications; and, inadequate qualification studies for room
is a drug for which Sargent had not filed an NDA.                  temperature stability.
          Similarly, the agency objected to various statements               Finally, the company was cited for failure to
made on SargentJs website describing Vigor-25, including, but      maintain equipment at appropriate intervals to prevent
not limited to: PVigor-25 Male Potency is an herbal                malfunctions or contamination that would alter the safety,
supplement developed to help boost your sexual pleasure and        identity, strength, quality or purity of the drug products.
improve your sexual performanceQ; PVigor-25 is a complete          Doc. 13909W
herbal supplement and works in as quickly as 25 minutesQ;
and, PVigor25 gives you the stamina and energy you need
when You need it.Q The company was not available for               Sheffield cited for OOS, QC
comment. Doc. 13919W
                                                                              An Oct. 17-19, 2005, inspection of Sheffield Labs,
Concord Labs nets letter for                                       New London, CT, found significant deviations from FDAJs
                                                                   current GMP regulations for finished pharmaceuticals.
faulty investigations                                                         Significant deviations included failure of the sC unit
          A Feb. 23 through March 22, FDA investigation of         to have adequate written procedures to ensure that product
the Concord Labs, Fairfield, NJ, the maker of colchicine           failures, failure investigation results, OOS results and stability
tablets, hyoscyamine sulfate tablets and nitroglycerin             failures were properly communicated to clients with whom
sublingual tablets, documented deviations from current GMP         the manufacturer contracted its products.
regulations.                                                                  Sheffield also was cited in the July 24 warning letter
          Deviations noted in the July 11 letter included that     for failure of its sC unit to be responsible for approving all
written records were not always made of investigations into        procedures and specifications impacting on the identity,
unexplained discrepancies, nor did investigations of               strength, quality and purity of drug products.
unexplained discrepancies extend to other batches of the                      For example, FDA emphasized that SheffieldJs sC
same drug product or other drug products that may have             unit did not review or approve the analytical methods used to
been associated with specific failures or discrepancies.           analyze the debriding ointment, cervical cream, lidocaine
          For example, product samples tested in conjunction       hydrochloride, hydrocortisone acetate and capsaicin products
with a complaint regarding loose caps on nitroglycerin tablets     it contracted out, nor did its sC unit assure that these
produced OOS results for assay and content uniformity.             methods were properly validated.
          And, the company did not perform further                            Finally, the agency pointed out that Sheffield
examination of product retains or a review of the batch            failed to establish the reliability of the suppliersJ test results
record. Thus, the sample results were invalidated due to           through full testing; failed to evaluate the sS of each drug
product damage from environmental exposure; but, FDA               product to determine the need for changes in drug product
noted, there was no provision for this in the firmJs written       specifications or manufacturing procedures; and failed to
procedures.                                                        file NDAs for amino acid cervical cream and papain-urea-
          Concord also was hit with failure to maintain            chlorophyllin ointment, which are considered new drugs.
separate or defined areas or other such control systems            FDA noted as well that there were no adequate directions
necessary to prevent contamination and mix-ups in the              for the aforementioned products to ensure in the PIs that
course of manufacturing and processing operations; and
                                                                   these products were safe for their intended uses.
failure to provide adequate measures to control air
                                                                              The agency acknowledged written responses from
contamination and recirculation of dust from production
areas where air was recirculated.                                  Sheffield dated Nov. 2, 2005, and Jan. 6, 2006, but found
          For example, no monitoring of the system was             them inadequate in that they did not provide timetables for
conducted to demonstrate that the volume of air supplied           all of the proposed CAPAs ecorrective and preventive
was sufficient to maintain appropriate air pressure                actionsf in the letters. Sheffield also completely failed to
differentials between manufacturing rooms, corridors and           address several of the investigational observations, FDA
pharmacy rooms; and, no studies were conducted to assure           added. The firm was not available for comment.
that the system removed contaminants from the production           Doc. 13920W
area and that cross-contamination did not occur. Further,
modifications made to the air-handling systems of production       IedEFal%devEFes%
rooms, to add exhaust ventilation, were not validated to show
their effectiveness at the time of installation.                   QS failures lead to warning
          Other violations included failure to establish master
production and control records for each drug product,              letter for BioGenex
including statements of the maximum and minimum                            During an FDA investigation of BioGenex Labs,
percentages of theoretical yields; use of deficient test devices   San Ramon, CA, conducted from Feb. 1 through March 9,
for which apparatus did not meeting established                    the agency determined that the manufacturer of pathology
Page 12 — August 2006                                                                               !ALIDATION TIMES

related stains, antibodies and in vitro diagnostic test kits was   chairs, and low resident (safety) beds, was not in
not in conformance with current GMP requirements of sS             conformance with the current GMP requirements of the sS
regulations for medical devices. Significant deviations            regulation for medical devices.
included, but were not limited to the following.                              sS regulation violations noted during the
          BioGenex was cited in the July 27 warning letter for     inspection and in the July 10 warning letter included failure
failure of management with executive responsibility to ensure      to establish adequate complaint-handling (C-H) procedures
that an adequate and effective sS had been fully                   for receiving, reviewing, evaluating and documenting
implemented and maintained at all levels of the organization;      complaints by a formally designated unit.
failure to control products that did not conform to                           Care Products was further cited for failure to
specifications; failure to establish procedures for the control    analyze processes, work operations, concessions, quality
of finished devices to ensure that only devices approved for       audit reports, service records, returned products and other
release were distributed; and failure to establish procedures to   sources of quality data to identify existing and potential
control the design of the device to ensure that specified
                                                                   causes of nonconforming product or other quality
design requirements were met.
                                                                   problems; and, for failure to establish adequate procedures
          The agency acknowledged written response letters
from BioGenex, dated March 30 and May 25, but concluded            for the identification, documentation, validation or
that the responses were inadequate because the specific            verification, review and approval of design changes before
documentation to demonstrate the implementation of CAPA            their implementation.
had not been provided by the company. The firm could not                      The agency pointed out that Care Products neglected
be reached for comment.                                            to establish any written, C-H procedures; maintain records of
Doc. 13922W                                                        complaints the firm received for the past eight years; maintain
                                                                   an electronic, complaint database; use a complaint form to
                                                                   document sources of information to report a femur fracture
Cardiac Science cited for                                          injury that occurred in a nursing home after a used firmJs
                                                                   Model 740 shower gurney; or, document appropriate
failure to control                                                 justification for not reporting the complaint of a femur
                                                                   fracture injury to FDA and not maintaining any complaints
non-conforming products                                            that represented an MDR emanufacturing device reportf-
          During an FDA investigation of Cardiac Science’s         reportable events in a separate file.
Deerfield, WI-location, April 11, 26, FDA determined the                      According to the warning letter, the firm also failed
manufacturer of automated external defibrillators was not in       to maintain product procedures, including procedures for
conformance with the current GMP requirements of the sS            inspections, tests or verification activities for acceptance of
regulation for medical devices.                                    incoming product; procedures to control product that did not
          Violations included in the July 27 letter included       conform to specified requirements; procedures to ensure that
failure to adequately maintain procedures to control products      device history records for each batch, lot or unit were
that did not conform to specified requirements and failure to      maintained to demonstrate that devices were manufactured in
adequately maintain procedures for rework to ensure that the       accordance with the device master record; or, procedures for
products met current, approved specifications.                     quality audits.
          Cardiac Science was further audited for neglecting to               In the warning letter, FDA emphasized that it
adequately validate and approve according to established           Precognizes that your firm tried to obtain additional
procedures processes that could not be fully verified by           information regarding the use of your product and the
subsequent inspections and tests.                                  circumstances of the patient fall through your distributor and
          For example, Printed Circuit Board Assembly 120-         your own insurance company.Q But, the agency added, PYour
2060-002 was not validated after changes were made and the         firm cannot delay reporting the medical AE to FDA.
Rev C board was released for production on April 23, 2004,         Regardless of whether the fall was due to a potential user
FDA noted. The company was not available for comment.              error in letting the side rail down, a potential defective
Doc. 13924W                                                        locking mechanism or a potential design weakness in the
                                                                   locking mechanism, your firm should have submitted an
                                                                   initial MDR injury report to FDA by June 2, 2006, within 30
Care Products slapped with                                         days of first becoming aware of the medical AE.Q
letter for complaint                                                          FDA acknowledged the firmJs response letters
                                                                   dated June 19 and June 29, but concluded that they were
procedures                                                         inadequate in that Care Products had not implemented a
                                                                   CAPA by which required, specific actions, with expected
         Between June 12 and 16, FDA investigators
                                                                   timeframes, would take place correct the deficiencies
determined that Care Products, McAlflen TX, a
                                                                   initially noted by the agency. The firm could not be
manufacturer and distributor of shower gurneys/wheeled
stretchers, shower chairs, manual mechanical walkers and           contacted for comment before deadline. Doc. 13925W

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