international pharmaceutical quality

Transcription

International
Pharmaceutical
Quality
™
MAY/JUNE 2009 | Vol. 3, No. 3 |
www.IPQpubs.coM
ANALYSIS OF FDA AND EU GMP ENFORCEMENT ACTIVITY shows
inadequate investigation of manufacturing and product nonconformances to be the most pressing concern on both sides of the
Co n te n ts
2 FDA Links GMP, Drug Approval Problems
Atlantic. FDA warning letters and injunctions are frequently link-
3 Advent, KV, Actavis Totowa Enjoined
ing GMP problems with the manufacturing of products that do not
8 FDA 2006 Compliance Guide Spurs have the required new drug approval or do not meet OTC monograph standards, as the agency’s crackdown on the various types
of unapproved drugs continues. In upgrading deviation investigation systems, regulators are looking for human factors analysis
and a deeper understanding of the flaws in the quality system out
of which the operator errors stem. FDA’s foreign warning letters
reveal the growing focus on supply chain control. For biologics,
the challenges of vaccine production are getting increased inspection attention as this product segment expands. FDA is concerned
that Biological Product Deviation Reports are not always getting
submitted on time.
Bill Paulson, Editor-In-Chief
Injunctions
10 Implement ICH Q8-10 and Save On Compliance
11 Warning Letters Reveal FDA Hot Buttons
12 GMPs, Application Integrity Cited At Ranbaxy
14 OOS Investigations, Records At Issue Abroad
16 75% Of Warning Letters Cite OOS Investigations
17 To Err Is Human, But Not GMP
20 Vaccine Manufacturing Draws Attention
24 Vaccine Deviation Reports Often Late
VOICES FROM THE DIALOGUE: • FDA drug GMP warning letters issued in 2008/2009 (Appendix I, pp. 25-30)
• MHRA GMP inspector Andrew Hopkins on top MHRA inspection findings (Appendix II, pp. 31-35)
• Parexel consultant David Chesney on forces impacting FDA enforcement (Appendix III, pp. 36-41) • CDER
compliance official Joe Famulare on recent GMP injunctions (Appendix IV, pp. 42-45)
A significant proportion of FDA warning letters and almost
all of the injunction actions citing drug GMP problems over
the past three years have also involved findings that the firm
was manufacturing and distributing products not meeting
drug approval and branding requirements.
that it would be more aggressively exercising its enforcement discretion against “the universe of unapproved, illegally marketed drug products” and the firms marketing
them. FDA estimated that several thousand products may
be implicated.
FDA’s recent enforcement activity indicates that marketing unapproved drug products will escalate the agency’s
response when GMP problems are found.
The compliance guide (7132c.02 – “Marketed New Drugs
Without NDAs or ANDAs”) provides a compelling justification of the agency’s concern with these products and of
its risk-based enforcement approach. Included in the CPG is
an informative appendix containing a history of the relevant
legislative/regulatory developments over the past century.
In mid-2006, the agency fired a shot across the bow in a
revised compliance policy guide (CPG) and related releases
Inside The Global Regulatory Dialogue™
International Pharmaceutical Quality
The appendix helps explain the categories and regulatory
status of the drugs involved and defines the boundaries of
the agency’s current enforcement initiative.
Key events outlined in the appendix include: the 1938 Food,
Drug and Cosmetic (FD&C) Act requiring that new drugs
be approved for safety; the 1962 “Kefauver” amendments to
the Act requiring new drugs to be proven effective as well
as safe to obtain marketing; and the Drug Efficacy Study
Implementation (DESI) initiative begun in the 1970s, which
enforced the findings of a large scale review of the efficacy of
drugs approved or marketed as safe prior to 1962.
Following several dozen infant deaths from a high
potency Vitamin E intravenous injection named
E-ferol and Congressional prompting in 1984, CDER
assessed the number of pre-1962 drug products not
specifically covered under DESI and expanded its
compliance effort to include all unapproved prescription (Rx) products.
The CPG explains that some unapproved marketed products are undergoing DESI reviews in which final determination regarding efficacy has not yet been made. In most cases,
FDA has made an initial determination that the products lack
substantial evidence of effectiveness, and the manufacturers
have requested a hearing on that finding. The guide notes
that, in accord with its longstanding policy, FDA will not take
action against the products subject to an ongoing DESI proceeding until the proceeding is concluded.
FDA Links GMP, Drug Approval Problems
The underlying concern behind the 2006 compliance policy
guide is that drugs that have not undergone FDA approval
or do not conform to monographs have not established their
safety and efficacy nor the adequacy and accuracy of the
directions and warnings in the labeling.
High on the radar screen, the CPG states, will be unapproved
drugs that: • pose safety risks • lack evidence of effectiveness
• contain fraudulent health claims • compete with approved
products, and • are reformulated to evade an FDA enforcement action.
Also drawing attention, the CPG indicates, will be unapproved drugs manufactured by firms with actionable compliance problems in other areas such as GMPs and adverse
event reporting. The CPG directs that enforcement actions
taken in these situations should encompass the unapproved
drugs “even if there are other unapproved versions of the
drug made by other firms on the market.”
FDA’s “carrot and stick” approach in the unapproved
drugs arena has included a widely attended educational
workshop in 2007 and the establishment of an unapproved drugs coordinator in its new drug reviewing
division to help companies figure out how to get implicated products through the FDA approval process.
For over-the-counter (OTC) drug products, the pivotal action
was FDA’s implementation in 1972 of a review process on
OTC drugs by therapeutic class that would result in monographs setting forth allowable claims, labeling, and active
ingredients for each class. Drugs marketed in accordance
with a final monograph are considered to be generally recognized as safe and effective (GRAS/GRAE) and do not require
FDA approval of a marketing application.
In general, the agency has been proactive in encouraging firms
to work voluntarily with the agency to bring currently unapproved products into compliance. Center for Drug Evaluation
and Research (CDER) Office of Compliance Director Deborah
Autor has joined other FDA officials in pointing out at public
conferences that avenues for assistance have been established
and stressing that the agency “would like to see companies
come in and voluntarily comply [rather than] taking all these
products off the market by enforcement.”
Final monographs have been published for a majority of OTC
drugs, and tentative final monographs are in place for almost
all remaining categories.
[Editor’s Note: A discussion by Autor of the unapproved
drugs initiative and other current compliance office priorities
is provided in the January/February 2008 IPQ on pp. 35-44.]
FDA has also finalized a number of “negative” monographs
that list therapeutic categories – for example, OTC daytime
sedatives – in which no OTC drugs can be marketed without NDA approval. The agency has also issued a list of
active ingredients that cannot be used in OTC drugs without approved applications due to inadequate GRAS/GRAE
data.
However, the agency has also been wielding the stick when
its entreaties and offers of assistance go unheeded.
FDA has been targeting specific classes of unapproved
products deemed higher risk. Since the CPG was
issued, at least 10 product groups have been pursued
(see box on p. 3).
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The class actions have generally involved a Federal Register
announcement and news release in which the agency states
its intention to take enforcement action against all unapproved products containing a specific drug.
The announcements include an explanation of why the drug
class is a health risk and give a date by which product marketing must be discontinued if new drug approval has not
been obtained. After that point, the announcements warn
that the products and the companies marketing them may be
subject to immediate enforcement action. FDA also has usually issued a Q&A document about the particular enforcement action and class of drug involved.
The actions extend to the companies marketing the products
that do not take heed in the form of warning letters, seizures
and injunctions.
FDA’s most recent class action came at the end of
March. Targeted were 14 unapproved Rx narcotic drugs
widely marketed in several dosage forms. The targeted
products included high concentrate morphine sulfate
oral solutions and immediate release tablets containing
morphine sulfate, hydromorphone or oxycodone.
Warning letters were issued to nine companies that further
enforcement action may follow if they did not stop manufacturing and distributing the products. The companies
were Boehringer Ingelheim Roxane, Cody Labs, Glenmark
Pharmaceuticals, Lannett, Lehigh Valley Technologies,
Mallinckrodt, Physicians Total Care, Roxane Labs, and
Xanodyne Pharmaceuticals.
Following the warning letter issuance, FDA received feedback from the pain management community that the market
removal of unapproved morphine sulfate oral solution 20
mg/ml would impose hardship on palliative care patients. In
April, the agency extended the period of enforcement discretion until 180 days after any firm receives approval for the 20
mg/ml morphine or if/when alternatives become available.
Recent injunction actions make clear that FDA is ratcheting up its enforcement response in particular where
unapproved products combine several of the risk factors and the manufacturer’s overall quality system is
deficient as well.
Explaining the agency’s motivation for the unapproved
drugs initiative in a New York Times editorial in late 2007,
then Commissioner Andrew Von Eshenbach pointed out that
these factors are often confluent.
UNAPPROVED DRUG CLASSES TARGETED BY FDA
2006
• carbinoxamine drug products
• quinine sulfate drug products
2007
• ergotamine-containing drug products
• hydrocodone drug products
• timed-release drug products containing guaifenesin
• trimethobenzamide HCl suppositories
2008
• ophthalmic balanced salt solution products
• injectable colchicine products
• topical drug products containing papain
2009
• unapproved narcotics containing morphine sulfate,
hydromorphone or oxycodone
Noting that unapproved drugs are sometimes referred to as
“legacy drugs,” the Commissioner stressed that “a legacy
is not a substitute for drug approval. Individual experience, anecdotal evidence and marketing history are insufficient bases for concluding that a drug is safe and effective.
In fact, experience demonstrates that unapproved drugs are
often unsafe, ineffective, inappropriately labeled and poorly
manufactured.”
Since the initiative began in mid-2006, FDA has taken enforcement action against more than two dozen companies found
to have significant violations of cGMPs or adverse event
reporting requirements and to be making unapproved drugs
(see box below). In eight cases, the action has escalated to the
injunction level.
FDA Enjoins Advent, KV, Actavis Totowa
There have been three injunction actions in the last six months
that fit the model of involving a combination of GMP problems with the manufacturing of multiple unapproved drugs.
The most recent of the injunctions, reaching the consent decree stage in April, involved the manufacturing
operations of East Windsor, New Jersey-based Advent
Pharmaceuticals and its manufacturing subsidiary
in Westminster, Maryland (Neilgen Pharmaceuticals
doing business as Unigen).
FDA’s release on the injunction notes that the companies were
contract manufacturing and distributing more than 50 unapproved drug products primarily in the Rx cough/cold area.
The consent decree, signed by the CEO/President of the
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FIRMS DRAWING ENFORCEMENT ACTION FOR CGMPS AND UNAPPROVED DRUGS
The following are firms against which FDA has taken enforcement action since 2006 for a combination of significant violations of cGMP and/or adverse event reporting requirements and the marketing of unapproved drugs. The enforcement activity
has included warning letters, seizures and injunctions.
Abraxis Bioscience
Warning Letter (December 2006)
Actavis Totowa
Warning Letter (August 2006)
Injunction (January 2009)
Advent Pharmaceuticals/Neilgen Pharmaceuticals
Warning Letters (1997, 2001, 2002 and May 2006)
Injunction (April 2009)
American Hormones
Warning Letter (January 2008)
Amerifit Brands
Warning Letter (November 2007)
Cascadia Manufacturing
Concept Laboratories
Concord Laboratories
Warning Letter (July 2006)
C.R. Canfield
Warning Letter (2004)
Injunction (September 2006)
Deltex Pharmaceuticals
Warning Letter (October 2008)
Elge
Warning Letter (May 2008)
Farmacia La Salud
Warning Letter (March 2008)
G&W Laboratories
KV Pharmaceutical
Warning Letters (2000 & 2002)
Seizure (July 2008)
Injunction ( March 2009)
Midland Pharmaceutical
Warning Letter (March 2008)
Newman (Medi-Stat)
Warning Letter (June 2008)
Omega Tech Labs
PharmaFab
Warning Letters (2002 & 2004)
Injunction (April 2007)
Pharma Pac
Warning Letter (April 2009)
Primapharm
Prime Enterprises
Warning Letter (January 2009)
Scientific Laboratories
Injunction (May 2008)
Sheffield Laboratories (Faria)
Syntho Pharmaceuticals and Intermax Pharmaceuticals
Warning Letters (two in 2003)
Injunction (August 2006)
TME Enterprises
Warning Letter (December 2007)
Vintage Pharmaceuticals
Warning Letter (February 2008)
Vita-Erb
Warning Letters (1997, 2002 & 2004)
Injunction (November 2006)
companies involved, Bharat Patel, calls for the defendants to
destroy their existing drug supply and prohibits them from
manufacturing and distributing new drugs without FDA’s
approval. Like most such consent decrees, the firms must
retain outside experts to advise them on cGMP compliance
and obtain written authorization from FDA to resume operations. Again following the norm, financial penalties for noncompliance are specified.
facturing unapproved drugs. The inspections “also revealed
numerous and recurring violations” of cGMP requirements
and that Unigen and Advent had “failed to respond adequately” to the issues raised.
The release explains that FDA sought the injunction after
multiple inspections were conducted showing the company
had failed to comply with previous warnings about manu-
The company also ran into trouble with the Drug Enforcement
Agency (DEA) around 2000 as part of the agency’s crackdown on pharmaceutical companies whose products end up
Neil Laboratories, part of CEO Patel’s New Jersey
operations, received warning letters in 1997 and 2001
addressing a variety of GMP concerns.
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in clandestine labs that manufacture illegal drugs. Between
1999 and 2001, DEA issued several warning letters to Neil
focused on the distribution of products containing ephedrine
and pseudoephedrine found to be purchased for the illicit
manufacture of methamphetamine.
In 2003, Patel agreed to surrender Neil Labs’ registration
with DEA to manufacture “List 1” chemicals and agreed not
to manufacture and distribute OTC pharmaceutical products
containing the listed drugs.
In late 2002, FDA addressed a warning letter to Patel pointing
to the out-of-compliance status of Neil Labs extended-release
guaifenesin. The OTC monograph system does not include
provision for extended-release dosage form products and
they are considered new drugs requiring an approved application for marketing, which Neil Labs had not obtained.
In May 2006, FDA issued Patel another warning letter extensively detailing both cGMP problems and Neil Labs’ continued manufacturing of unapproved extended-release Rx
drugs that were also not appropriately labeled for use (“misbranded”). Guaifenesin-containing products again figured
prominently in the list of those generating drug approval
concern.
A third section of the 2006 warning letter targeted the firm’s
manufacturing of misbranded drug products for OTC use.
Cited in particular was the lack of warning and tamperevident packaging information for a handful of aspirin and
cough/cold products.
The GMP issues centered on lack of validation of the analytical methods used to confirm that products met specifications,
and inadequate stability methods and justification of expiration dating – problems, FDA noted, that were highlighted
also on the 2001 warning letter. Lab computer security and
common use of individual passwords, maintenance of lab
records, and supervisor training were other issues raised in
the 2006 letter.
The 2006 Neil Labs warning letter addressed the range of
concerns that would motivate the recent injunction action
against Patel’s operations. It also foreshadowed the unapproved drugs compliance policy guide nearing release at the
time and set the pattern for the warning letters and injunction
actions combining cGMP and approval non-compliance that
have been characteristic since then.
A month earlier in March, a similarly motivated
injunction action led to the signing of a consent decree
by St. Louis Missouri-based Rx drug manufacturer
KV Pharmaceuticals and its ETHEX and Ther-Rx
subsidiaries.
The injunction likewise prevents KV and its officers from
manufacturing and shipping drugs until both an independent
expert and FDA officials conduct inspections of the facilities
and certify that they are in compliance with regulations and
the decree. It does provide that KV may request of FDA that
it be permitted to resume manufacturing and distribution of
certain products before the company is cleared to resume full
operations. The decree specifies that it will remain in place
until the defendants sustain continuous cGMP compliance
and meet new drug approval requirements for six years.
The immediate cause for the FDA injunction against KV was
inspection findings between December and February that the
company was significantly out of GMP compliance and was
continuing to manufacture unapproved drugs. As a result of
these inspections, KV recalled all products manufactured and
distributed from its facilities. The decree specifies that KV
would destroy the products recalled since May 2008.
Like Advent’s, KV’s compliance problems extend back
through the previous decade.
KV received a GMP warning letter in 2000, focused on lab
controls. Specifically of concern to FDA was the overwriting of test data entries and lack of supervisory review of
raw material analytical data, which “resulted in acceptance
and use of raw materials that failed to meet specifications.”
Also of concern was the firm’s failure to take appropriate corrective action when several batches of a topical cream were
found to be contaminated with foreign material.
At the same time as Neil Labs in October 2002, KV also
received a similarly-worded warning letter about marketing unapproved guaifenesin extended-release products. As
in the Neil letter, FDA explained that it had not previously
expended its “scarce enforcement resources to address such
unapproved drugs,” but was motivated to take the guaifenesin action by the approval of an NDA for a guaifenesin
extended-release tablet expectorant the previous July.
In a May 2007 release, FDA announced that it was adding
“timed-release” cough/cold drug products containing
guaifenesin to its growing list of unapproved product class
actions. FDA estimated that about 20 firms were implicated,
and noted that only Adams Respiratory Therapeutics had
obtained the requisite approval. Other companies, the release
stated, will have 90 days to stop manufacturing and 180 days
to cease shipping the products. Afterwards, companies will
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5
have to have the required FDA approval or face regulatory
action, the agency warned.
KV found out in July 2008 that the warning was sincere
when the agency informed the company it was seizing
$24 million worth of unapproved KV drugs including
guaifenesin extended-release combinations.
The seizure followed an inspection in early 2008 of several
of the company’s plants where FDA investigators found that
the company was not complying with the 2007 enforcement
notice and was continuing to market timed-release products
containing guaifenesin as well as a variety of other unapproved new drugs, including narcotics and products for
cough/cold, topical wound healing, skin bleaching, and gastrointestinal conditions.
In explaining the seizure, FDA emphasized that approval for
products in timed-released form is necessary as “improperly
manufactured timed-release product may release the active
ingredients too quickly, too slowly, or not at all, making the
product unsafe or ineffective.”
CDER Office of Compliance Director Autor stressed in the
release that “FDA will take action against companies that
continue to manufacture or market an unapproved product after the marketing or distribution cessation date.” She
warned in addition that “when a company does not heed a
cessation date relating to a specific product, the FDA will take
enforcement action relating to the company’s other unapproved drugs.”
As a publicly traded company on the New York Stock
Exchange, KV has been more forthcoming about its consent
decree. In a March release, KV pointed to the general marketing constraint until cGMP compliance was attained, adding
that it would not distribute certain products, including its
prenatal vitamins and hematinic products, until clearing
FDA’s ANDA or NDA processes.
KV’s Interim CEO David Van Vliet affirmed that the company had been “working diligently with the FDA for the last
two months to reach agreement on a clear path forward to
permit KV to resume manufacturing and marketing its products. Since December, when new management took over at
KV, our team has taken significant steps to enhance our systems and procedures, and we will continue to do so.”
An injunction action against Actavis Totowa, which
reached the consent decree phase in December 2008,
followed a very similar pattern to the KV and Advent
cases in the confluence of GMP and drug approval
non-compliance.
Actavis Totowa has three New Jersey facilities – two in
Totowa and one in Little Falls – and is a wholly owned subsidiary of Actavis, a generic pharmaceutical company based
in Reykjavik, Iceland. Two of the New Jersey facilities do oraldose manufacturing and one is a packaging facility.
FDA initially turned up the heat on Actavis Totowa with a
warning letter issued in August 2006 addressing inspection
findings earlier in the year regarding adverse drug experience (ADE) reporting. The letter highlights a cross section of
FDA’s key concerns as it reviews a firm’s ADE practices.
The letter starts by pointing to a handful of “potentially serious and unexpected drug events dating back to 1999 for products such as Digoxin, Phentermine and Phenazopyridine that
were not reported to FDA.”
The entry further maintains that the information in the reports
it was submitting were not always complete or accurate; for
example, regarding the previous condition of patients, concomitant medication, event recurrence and follow-up information obtained from patients and physicians. Nor was it
submitting unexpected cases outlined in the published literature, FDA said.
Paralleling the prominence the investigation of unexpected
results and deviations has on the GMP side, the letter asserted
that Actavis was not always investigating serious and unexpected ADE reports. Two cases in particular were cited where
serious or fatal adverse events reported to the firm had not
been followed up on as of the time of the inspection.
Again paralleling the concern on the GMP side, FDA further maintained that Actavis was not reviewing all the ADE
data to cull out the serious and unexpected cases for special
action. Nor was it following procedures for submitting periodic safety reports, with the result noted that at least 26 ADEs
had never been reported to FDA. A final entry focused on not
having adequate procedures for investigating, completing,
recording and evaluating the ADEs.
In evaluating Actavis Totowa’s response to the inspection
findings, the warning letter noted that several of the observed
deficiencies were longstanding, and “there was no indication
of how or why the lack of compliance was not identified by
your firm and why it was allowed to continue for such an
extended period of time.” FDA further questioned whether
or not the firm had insight into this situation and was reviewing other regulatory requirements to assure compliance in
those contexts.
The letter then transitions to the finding during the inspec-
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tion and other submitted information that Actavis was manufacturing “numerous prescription drugs without approved
applications.” As in the cases of KV and Advent, a guaifenesin extended-release combination was among those specifically named.
The letter proceeds to ask that Actavis provide a list of all
drugs it was manufacturing with the ANDA number or “a
statement describing the basis on which you claim for a new
drug an exemption from the drug approval requirements” –
an enforcement approach that effectively shifted the burden
of proof from FDA to the firm.
Actavis Totowa’s compliance difficulties continued
in 2007 when it received another warning letter – this
time focused on GMP deviations uncovered during
an inspection in the summer of 2006 at its Little Falls,
New Jersey facility.
The warning letter, issued in February 2007, begins with
the concern that is now front and center across FDA’s GMP
enforcement activities – namely the investigation of process
deviations and out-of-specification (OOS) test results.
Of related concern was the uncovering at Actavis of OOS test
results in laboratory raw data that were not documented in
lab notebooks, and products that were “released based on
retesting without any justification for discarding the initial
out-of-specification test results.”
The Actavis Totowa warning letter serves as a primer
on FDA’s Guidance for Industry on “Investigating
OOS Test Results for Pharmaceutical Production,”
which had just been published in final form the previous October.
Observed during the inspection, the letter states, were
“numerous instances where manufacturing process deviations occurred and in-process specifications were not met,
yet there is no indication that actions were taken promptly
to investigate or correct the deviations and the products were
approved for release and distribution by your quality control unit.” Additionally, “instances were noted where your
firm’s quality control unit reviewed and approved test data
and reports that were inaccurate and incomplete and as such
did not follow established procedures.”
Among specific examples cited in the letter were instances
where analysts aborted and failed to complete chromatographic testing runs after an OOS test result was obtained.
The OOS chromatographic data was not recorded in lab notebooks, and instead “a new sample preparation was injected
within the same chromatographic run without supervisory
approval,” in conflict with the firm’s OOS procedures.
Similar examples were provided involving content uniformity, dissolution and impurity testing where original results
were discarded without a documented justification.
FDA also found “numerous discrepancies” between the electronic data files and documentation in laboratory notebooks.
Further, the firms QCU was not found to be paying adequate
attention to tablets that did not meet in-process specifications during tablet compression operations to avoid releasing
OOS tablets. Instead, instances were cited where compression problems were recorded in investigation reports several
weeks after they occurred.
Other issues involved the identification and control of
rejected in-process materials to prevent their later use, and
inadequate procedures for conducting bulk holding time
studies. FDA also found fault with Actavis’ cleaning validation studies and with the firm’s master and batch production
and control records, which did not include complete procedures for documenting the collection of samples. Equipment
qualification and procedures for maintaining manufacturing
equipment were other areas of concern.
The 2007 warning letter went on to explain why FDA
was not satisfied with the corrective actions and
“Quality System Improvement Plan” described in the
firm’s response to the inspection findings.
In its initial response, Actavis Totowa had disagreed with
several specific observations listed on the August FDA483. However, the update report from Actavis in November
stated that all observations listed on the 483 were “correct
and constructive” and that the firm had identified the need
for improvements in operational procedures and practices at
the Little Falls, N.J. facility. FDA noted that it did not actually
agree with the original assertions that certain of the observations listed on the 483 were not accurate.
The letter acknowledges that Actavis’ correspondence did
“appear to adequately address many of the cGMP deviations
found” during the mid-summer inspection. However, FDA
expressed concern about the quality of the drug products
released from the facility “under the serious lack of cGMP
controls found during the inspection.” The firm’s response,
the agency said, “provides no assurance that the records
and conditions of manufacturing and testing of each lot of
drug products released and marketed by your firm will be
evaluated to assure that the released drug products” meet
standards.
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7
The letter foreshadows the consent decree in advising Actavis
Totowa to seek third party help. “We feel that to provide such
assurance, your firm should promptly initiate an audit program by a third party having appropriate cGMP expertise
to provide assurance that all marketed lots of drug products
that remain within expiration have their appropriate identify,
strength, quality and purity.”
The warning letter goes on to require of Actavis within 15
working days to provide “a written list of all released lots
of finished drug products that remain within expiration date
that are associated with any out-of-specification test results
during their manufacture” as well as “a brief description
of the actions taken to insure that the lots were suitable for
release.”
Pushing FDA further toward the injunction mode was
an inspection between March and May 2008 of Actavis’
Riverview Drive facility in Totowa. FDA again found
“significant cGMP violations” and that Actavis was
continuing to manufacture unapproved drugs.
The inspection resulted in Actavis Totowa recalling all products manufactured and distributed from its three facilities.
As in the KV case, the consent decree specifies that Actavis
destroy the recalled product.
Following the normal injunction pattern, the company can
resume operations only after an expert certifies that the drugs
comply with the cGMP requirements and have FDA approval,
and the agency inspects to confirm compliance.
Among the list of about three dozen unapproved oral drug
products manufactured by Actavis associated with the injunction action were guaifenesin combinations, vitamin combinations and oxycodone and hydrocodone-containing narcotics.
In a release following the signing of the December, 2008 consent decree, Actavis Totowa’s parent company stressed that
the injunction only affected Actavis’ operations at the New
Jersey facilities. Noting that distribution would be halted
until the enumerated GMP requirements were met and follow-up FDA inspections were passed, Actavis expressed
optimism that commercial production at the Totowa facilities
would resume “shortly.”
“We have been working with the FDA to address compliance
issues at the Totowa facilities,” Actavis’ Chief Legal Officer
John LaRocca indicated in the release. “We have an entirely
new management team in place at Little Falls and have
invested significantly to reinforce systems and procedures
intended to better ensure robust, sustainable compliance.”
He added that the agreement with FDA was “a positive step”
and “one we have looked forward to reaching. We will continue to work with the FDA to show that we have addressed
all of the agency’s compliance and manufacturing issues.”
Actavis explained that prior to reaching the agreement,
PAREXEL had been engaged to assess the Actavis Totowa
facilities and that the consulting firm would continue to work
with Actavis Totowa to facilitate ongoing compliance with
the consent decree.
Actavis made good on its prediction that product reintroduction would begin in a relatively short timeframe.
In mid-April, the company announced the reintroduction to
the market by its Actavis Totowa subsidiary of oxycodone 15
mg and 30 mg tablet products. Based on a recently completed
FDA inspection, Oxycodone was the first product cleared
by the agency for release from the company’s Little Falls,
N.J. facility since the product-wide recall in August 2008.
Subsequent inspections, as outlined in the decree, will follow,
the firm said.
“Through an extensive process, Actavis re-qualified all
equipment and utilities for production and packaging – and
we re-qualified and revalidated all methods used to release
products from our Totowa facilities,” the firm’s VP of Quality
Compliance and Technical Services Nasrat Hakim explained.
Actavis’ CEO Doug Boothe added that oxycodone is one
of the many products the company “will have back on the
market in the coming months.”
FDA 2006 Compliance Policy Guide Spurs Injunctions
Injunction activity involving both GMP and drug approval
non-compliance intensified in the second half of 2006 following the release of FDA’s unapproved drugs compliance
policy guide and the launching of the accompanying enforcement initiative.
In most cases, these injunctions have involved across-theboard recalls of the “adulterated,” unapproved and misbranded products recently made in the implicated facilities.
In turn, the imposed hurdles to resume manufacturing and
marketing are, in the main, superimposable.
In August 2006, a consent decree following the pattern
was signed by Syntho Pharmaceuticals and Intermax
Pharmaceuticals and their mutual officers located on Long
Island, New York. The unapproved products named in
the decree included guaifenesin combos and several other
cough/cold and pain relief products.
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Brainerd, Minnnesota-based Canfield, a manufacturer of drug
products used in dentistry, agreed to a consent decree a few
months later in the same cGMP/unapproved product mold.
Included in the injunction were unapproved dental products
for “dry socket,” a condition in which the socket does not
heal properly following the extraction of a tooth, available
nationwide through dental practices.
In a release explaining the consent decree, FDA underscored
the warning in the CPQ on unapproved drugs that the agency
may focus its enforcement on products which, in addition
to lacking required approval, violate other parts of the FDC
Act. Canfield, the release states, “has not corrected its cGMP
violations – which include releasing products for distribution without proper testing and failing to conduct studies to
determine appropriate expiration dates – despite repeated
inspections, efforts, and warnings by the agency advising the
firm of significant compliance deviations that require prompt
corrective action.”
The release quotes then CDER Director Steven Galson in
stressing that “unapproved drugs and drugs that do not meet
cGMP requirements are a public health concern because they
may not satisfy quality standards, or standards for safety,
effectiveness and labeling.” In turn, Galson added, “confronting these issues through enforcement actions and other
strategies is a key part of FDA’s comprehensive drug safety
efforts.”
Springfield, Missouri-based Vita-Erb, a manufacturer of
medicated shampoos, pain relieving gels, antimicrobial hand
cleansers, and a liquid herbal-extract drug product, was
enjoined in November, 2006.
The injunction order explains that FDA had conducted eight
inspections of Vita-Erb since 1997, most recently in October
2005. “During each of these inspections,” the order states,
“FDA documented many of the same or similar cGMP violations that were observed during the most recent inspection.”
The finding of significant cGMP deviations had resulted in
warning letters following a December 1997 inspection and an
April/May 2002 inspection. Canfield had promised corrective action to address the issues raised on the various 483s
and warning letters, the order notes.
FDA also issued a warning letter to Vita-Erb in April 2004
addressing the manufacture of unapproved/misbranded
drugs. Follow-up investigation by FDA, the injunction order
states, showed that the firm had subsequently introduced an
unapproved pain-relieving gel and was marketing the herbal
extract drug product named in the warning letter under
another name.
In December 2006, FDA announced its class action
against unapproved drugs containing quinine, and
provided an update on its six-month old unapproved
drugs initiative.
A key health concern motivating the action against quinine,
an antimalarial, was its widespread use in treating leg cramps
– a use for which risks outweigh the benefits, CDER’s Galson
commented in the release. The unapproved products, FDA
explained, did not contain the extensive warnings regarding
serious adverse events associated with quinine use, potentially serious interactions with other drugs, and the conditions under which quinine should and should not be used,
nor were safe dosing levels established. Only one quinine
drug product, Mutual Pharmaceutical’s Qualaquin, had been
FDA-approved as an antimalarial treatment with the appropriate cautionary labeling.
Noting the issuing of several warning letters and the injuncttions filed in federal courts, FDA stressed in the release that it
expected to “further accelerate its enforcement efforts against
marketed unapproved drugs in 2007.
The release also highlighted the “very large number of registrants” for the upcoming January workshop intended to businesses on how to steer products through the drug application
and OTC monograph processes. This “tremendous response
to the workshop” is encouraging, CDER Compliance Office
Director Autor stated, and provides “a clear indication that
manufacturers are heeding our warning to bring unapproved
drugs into compliance.”
“The presence of unapproved drugs on the U.S. market is in
stark contrast to our current approach to drug safety because
those drugs may not meet modern standards for safety, effectiveness, quality, and labeling,” Acting Commissioner Von
Eschenbach commented in the release. “As part of our drug
safety efforts, we are committed to ensuring all marketed
drugs have the required FDA approval.”
Rising to the injunction level in the 2007-2008 period
were GMP/unapproved drug enforcement actions
against PharmaFab and Scientific Laboratories.
A consent decree was signed with Grande Prairie, Texasbased PharmaFab in April 2007. The company at the time
was a major manufacturer and distributor of more than 100
different Rx and OTC drug products, including cough/cold,
ulcer and postpartum hemorrhage products.
As for Actavis Totowa, a key GMP area of FDA concern at
PharmaFab was the lack of investigation of manufacturing
MAY/JUNE 2009
9
failures. Other GMP issues behind the injunction were not
recording and justifying deviations from written manufacturing procedures, lack of an effective QC unit and failing to
establish reliable expiration dates for products. Unapproved
drugs cited in the action included several cough/cold
extended/sustained release products.
A consent decree also following the pattern was concluded
with Scientific Laboratories, located in Columbia, Maryland,
in May 2008. The company is a contract manufacturer and
distributor of various Rx cough/cold products. After warning the firm, FDA took the injunction route when it found
that GMP problems remained uncorrected and marketing of
some unapproved cough/cold suspension and liquid formulations was continuing.
Implement ICH Q8-10 And Save On Compliance
At the University of Georgia’s annual International GMP
Conference in Athens, Georgia in March, CDER Office of
Compliance Deputy Director Joseph Famulare and Atlanta
District Senior Compliance Officer Philip Campbell both
highlighted the prominence of the unapproved drugs effort
in the recent FDA enforcement data.
In a presentation at the conference on recent enforcement
trends, Campbell noted his surprise to find the significant
percentage of warning letters that included the distribution
of unapproved drugs. The message in this data, he stressed,
is that “if we come out to your firm and find that you are distributing unapproved new drugs and we find GMP deficiencies, the likelihood of your receiving a warning letter goes up
pretty significantly.”
The oversight of unapproved drugs “is not something that
we enter into lightly,” Campbell commented, pointing
out that “requiring the appropriate GMPs, the appropriate
approval for a drug product, ultimately leads to higher cost
as an unfortunate consequence.” But for both counterfeit and
unapproved drugs, he said, “we don’t have any knowledge
about any testing that may or may not have gone on with
respect to the safety of that product even though it may be a
product that has been around for a long time.”
FDA knows that “people are very married” to some of these
old products, “but if there are reasons for us to believe that
they are unsafe, and [since] we have not had an opportunity
to look at the procedures that are used to manufacture them
to know whether they are really safe in the iteration that they
are being presented, we have a responsibility to look at them.
And unfortunately, when another drug company does the
right thing and goes through all the processes and gets the
approval, it costs them. So in effect it raises the cost of the
product. It is an unfortunate consequence, but one we feel
is necessary to make sure that the public is getting a product
that is safe.”
The focus on unapproved drugs in recent GMP-related
injunction actions is particularly noteworthy in the
context of the limited number of injunctions FDA has
pursued recently.
Campbell remarked that “the most surprising statistic” that
he found in his review for the Georgia presentation was that
only five injunctions were issued in FY 2008 across all districts
and commodities, compared to a normal baseline of about a
dozen. Only one was issued for drugs during that timeframe,
which focused on GMPs and unapproved drugs (Scientific
Laboratories), as have the few drug injunctions issued since,
he pointed out.
As he reviewed these recent drug injunction cases, what
“struck” Campbell was their compliance history.
“All of them involved a series of violative inspections on
the part of the agency. In fact, one of them had had six questionable inspections since 2005. There also was a history of
repeated warnings from the agency in our attempts to try to
work this out on a voluntary basis. It involved the 483s. It
involved meetings at the district office. It involved warning
letters – in one instance, multiple warning letters, which we
are not supposed to be doing. But there was a very clear pattern. At the end of these numerous attempts to try and work
it out, we had to go to more stringent action, which was the
injunction.”
Discussing their infrequent use recently, Campbell emphasized that injunction actions take a lot of work on behalf of
the agency – are “very resource intensive” – and “nobody
likes these things.”
“We beg you to come in to the district office and discuss these
issues. We send you warning letters. It gets to the point that
we enjoin folks that just won’t get it for whatever reason.
They are not interested in getting it or they don’t have a clue
as to what the expectations are…. If you ever find yourself
in the position of being enjoined, you really have nobody to
blame but yourself, because we certainly have made every
effort to work it out in other ways.”
At a session at the UGA conference on process validation under the new quality regulatory paradigm, CDER
compliance official Famulare also noted the amount of
work injunctions entail and that they are pursued only
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as a last resort after other voluntary approaches have
repeatedly not born fruit. He also stressed the unapproved drug component of the recent GMP-related
actions.
Without naming the company involved, Famulare cited the
circumstances around the KV injunction as a just-enacted
case study. He highlighted a stipulation in the judge’s injunction order, in particular, as providing insight into the growing quality-by-design (QbD) regulatory emphasis and the
emerging lifecycle validation thinking.
The order stipulates that the “defendant shall establish and
follow scientific product development and manufacturing
process design procedures at all facilities to control all significant variables, including material attributes and processing parameters, affecting the process materials and final drug
product specifications and quality attributes.”
The recent injunction, Famulare said, is one example of what
can happen when firms are processing multiple products not
in a state of control. These legal enforcement actions, “have
as their central core the lack of process validation and many
related issues that go into that including the development,
the science, the technology, the use of investigations, handling of deviations, etc.”
The CDER compliance official expanded further on the linkage between the recent drug injunction actions and the value
of implementing the new ICH Q8-10 paradigm at an ISPE
conference in Washington, D.C. in early June. He discussed
the injunctions as case studies in the failure of the quality
system and the costs of not implementing the ICH guidelines
through the product lifecycle.
[Editor’s Note: Famulare’s incisive analysis at the ISPE
conference of the recent GMP/unapproved drug injunction
actions in the context of the ICH quality system principles
and the cost of non-compliance is provided in Appendix IV
of this issue.]
Warning Letters Reveal FDA Hot Buttons
Campbell noted that the number of product seizures has similarly been at an historical low point over the last two years,
with only six recorded in 2007 and eight in 2008.
CDER was involved in five of the eight. Three of these
involved dietary supplements containing an unapproved
drug, and another a cosmetic product with an unapproved
drug that can cause optic nerve damage. The most significant
seizure in 2008, the field official pointed out, was that of $24
million in unapproved drugs en route to an injunction (KV
Pharmaceuticals).
The only seizure coming to Campbell’s attention in FY
2009 as of mid-March involved heparin contaminated
with over-sulfated chondroitin sulfate (OSCS) – a substance that mimics heparin’s anticoagulant activity.
In November, U.S. marshals seized 11 lots of heparin
from Cincinnati-based Celsus Laboratories. The heparin had been manufactured from material imported
from China.
Since the serious adverse events and deaths from OSCScontaminated heparin began to surface in early 2008, FDA
has put in place a comprehensive inspection and import controls program and has acted to remove from the market heparin materials and products contaminated with OSCS (IPQ,
May/June 2008).
The seized Celsus heparin – which had entered the U.S.
before the establishment of import controls for the drug –
was tested for the presence of OSCS as part of this FDA initiative. To date, the effort has prompted 13 recalls of multiple
contaminated medical products containing heparin from several companies.
FDA had informed Celsus during an April 2008 inspection
and again in a follow-up letter the following month that the
company’s actions to notify customers about a contaminant
in its heparin were insufficient to assure an effective recall.
FDA advised customers of Celsus not to use the contaminated
heparin product and notified Japanese, Canadian, Australian,
European Union (EU), and other international authorities of
related shipments.
In reviewing the warning letter component of FDA’s
enforcement activity, Campbell affirmed that they
remain an effective tool, involving notifying top management of significant problems in the effort to work
things out on a voluntary basis. Across centers, there
were 445 warning letters issued in FY 2008, compared
to the eight seizures and five injunctions.
There are more warning letters being issued for devices than
drugs. One factor is that the field recommendations for drugs
have to be cleared through CDER at headquarters. If the
CDER compliance staff can’t be convinced by the field office
that the warning letter “is a good use of the agency’s limited resources, than it is not going to be approved,” Campbell
pointed out.
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11
“They have clearly raised the bar as to what it will take to
trigger the issuance of a drug GMP warning letter – there is
no question about that. The expectation is, once it gets issued,
that the district will closely monitor these warning letters and
work with the firms involved to make sure they are implementing the corrective actions that they need to and we are
scheduling the inspections in a timely manner.”
In preparing for the presentation, Campbell conducted
an “unofficial” review of warning letters issued domestically addressing GMP concerns between November
2007 and December 2008 to see where attention was
focused.
Production record review (CFR 211.192), which encompasses
the failure to react to OOS results, appeared most frequently,
cited in 17, or two-thirds of the letter cohort. Closely following was lab controls, cited in 16.
Written procedures and the quality control unit were the next
in the order, followed by in-process testing and production/
process control. Campbell noted that all six of these categories were also on the top ten sites on the 483s issued, “so there
were no surprises here.”
The seventh most common cited observation in the warning
letter cohort, the testing and control of components, did catch
Campbell’s attention. At issue here, he explained, is the adequate testing of incoming components themselves, verification of certificates of analysis and, in general, establishing the
adequacy of suppliers. “So it is obviously something we are
already starting to look at over the last year,” he remarked.
In preparing his presentation, Campbell also informally surveyed field drug investigators on issues they
are especially concerned with.
Data integrity emerged as a front runner concern. The issue
“just will not go away, which is very surprising to me because
it is the most damaging observation that we can make against
your firm,” Campbell commented. It involves the “improper
handling of failures by the firm – the role of management in
those decisions. Is it a culture that causes this, or a lab supervisor that decided to do it on his own?” Data integrity issues,
he noted, cut “across all commodities that we regulate,”
including food and device firms.
Another related concern highlighted in the survey was how
a firm responds to out-of-spec and out-of-trend results. At
issue is “the ignoring of these results, the failure to investigate, the failure to respond.” Key questions, Campbell said,
include “who is involved in the reporting chain of these out-
of-spec results? Who from management is involved in these
decisions? Are they involved?”
Supplier issues were also highlighted, which “obviously is
a big deal” in today’s complex supply chain environment,
Campbell pointed out.
Investigators also expressed particular concern with
firms that are transferring products into a facility and
not really doing due diligence before they ramp up
production and start distributing these products. “We
expect more of this to occur as firms downsize and
products are bought and sold,” Campbell commented.
“If you are bringing a new product into your facility that you
purchased from somebody else, take a very close look at the
initial validation work that was done on that product,” the
field compliance officer advised. “When you start manufacturing it for the first time in your facility, make sure you are
aware of any unexpected out-of-trend or out-of-spec results.
Is it really responding as it was supposed to respond? Is it
performing as it was supposedly performing during the initial validation? Be very sensitive to those changes that are
unexpected and make sure that you do an adequate investigation for any out-of-trend or out-of-spec results that you see
during that period of time.”
GMPs, Application Integrity Cited at Ranbaxy
The FDA investigator concerns reported by Campbell at the
UGA conference intersect in the enforcement action FDA has
been involved with at India-based Ranbaxy Laboratories.
Ranbaxy’s compliance problems with the agency worsened
in September 2008 when it received a pair of warning letters
from FDA’s compliance office addressing GMP problems at
its Dewas and Paonta Sahib plants in India.
In a release on the warning letters, FDA announced that
“because of the extent and nature of the violations,” the
agency was issuing an “import alert” under which any API
or sterile and non-sterile finished drug products manufactured at the facilities may be detained at the U.S. border. Over
30 different generic drugs were implicated.
The Dewas warning letter does provide for an exception in
the case of the firm’s ganciclovir API, due to Ranbaxy being
the sole source supplier. The terms of continued import, the
agency explained, would have to be discussed and “would
likely include third-party supervision and verification of
each batch prior to release.”
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FDA said that its compliance office would also recommend
denial of approval of any NDA or ANDA listing the plants as
the manufacturer of APIs or finished drug products.
processing was involved] and the firm’s responses,” and led
FDA to the conclusion that warning letters were the appropriate response.
The release announced that the agency’s action did not
involve removing products from the market, since FDA did
not have hard evidence to date that the products already
shipped by Ranbaxy were defective. Nor were products from
other Ranbaxy facilities impacted, since “FDA has inspected
those facilities and to date, they have met U.S. cGMP requirements for drug manufacturing.”
The warning letter on the Dewas facility documented a variety of concerns involving aseptic practice, contamination prevention, and media fills, as well as inadequate investigation
of sterility failures in API batches and of release spec failures
in non-sterile product batches.
The warning letter issued regarding Ranbaxy’s Dewas
facility reflected the findings from an inspection conducted by FDA in early 2008. The findings involved
“significant” GMP problems in the plant’s manufacturing and control of sterile and non-sterile finished
products and APIs.
Areas of concern in the letter included: • the facility’s betalactam containment program, which appeared inadequate to
assure against cross-contamination • inadequate batch production and control records • inadequate failure investigations, and • inadequate aseptic processing operations.
The deficiencies found during an inspection in March 2008
at the Paonta Sahib facility and referenced in that warning
letter related to the manufacturing of mostly finished oral
solid finished dosage forms. They involved: • lack of assurance that responsible individuals were overseeing GMP steps
• inaccurate written records of equipment cleaning and use •
incomplete batch production and control records, and • inadequate procedures for the review and approval of production
and control records.
FDA’s response to the findings at the Paonto Sahib facility
was heightened by the facility’s previous record of GMP noncompliance. The agency had already issued a warning letter
to the Paonto Sahib plant in June 2006 citing significant deficiencies related to its stability testing program. Included in
the findings were the failure to maintain complete records
of data related to stability sample testing, and deficiencies
related to storage, inventory management, and testing of stability samples at defined intervals.
In April and May 2008, Ranbaxy submitted lengthy written responses to the recent inspection findings. The warning letter release notes that the agency evaluated its findings,
Ranbaxy’s responses, and the firm’s overall inspectional history. The evaluation “required substantial time due to the
complex scientific and technical nature of both the identified
deficiencies, particularly at the Dewas site [where aseptic
In the aseptic area, the deviation investigation concerns
involved inadequate confirmation of the root cause, the
accuracy of the batch records and investigation report, and
the assessment of environmental and personnel monitoring
sample results.
FDA was also concerned that the firm’s response did not
address how the investigation of the API batch sterility failures would be completed to assure the identification of the
root cause and CAPA implementation, and which controls
would be implemented to ensure the completeness and accuracy of the report data.
For the non-sterile product investigations, the concern was
the lack of records identifying the assignable cause and the
implementation of corrective measures. FDA further noted
that the actual weights and measures of a specific excipient
were not documented and that the lack of this information
prevented verification that the correct amounts of excipients
were dispensed for the two failed lots in question.
Incomplete discrepancy investigations were also at issue in
the warning letter on the Paonto Sahib facility.
The central issue there, though, involved invalid signoffs on equipment cleaning and production and control records where the required supervisory review/
oversight had not taken place.
During the March 2008 inspection, the warning letter points
out, FDA’s inspection team “documented numerous instances
where persons or supervisors reportedly verifying equipment cleaning activities or supervising or checking significant manufacturing steps were not present at the… facility on
the dates or times that these activities occurred.”
FDA asked for an explanation from Ranbaxy “why your
firm’s quality control unit did not detect and document these
deficiencies during their batch production and control record
review and what actions will be taken to assure these deficiencies do not extend to other batches of the same or other
drug products manufactured at the Paonta Sahib facility and
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13
FDA’S VIEW OF RANBAXY’S DEWAS ASEPTIC OPERATIONS IN 2008
After pointing to a variety of specific deficiencies in aseptic practices, the September 2008 warning letter on Ranbaxy’s
Dewas facility provided a succinct summary of FDA’s view of the plant’s design and operations. The summary indicates that
the plant’s return to cGMP compliance would not involve a quick fix. The discussion speaks to the QbD and lifecycle process
validation concepts FDA is seeking to foster.
We are concerned that your aseptic operations are conducted under extensive steps, manual handling, and inadequate
equipment usage…. For example, manual operations under aseptic conditions should be conducted with minimum operator intervention and no exposed critical surfaces and product. Therefore, it is not appropriate to try to overcome major
flaws in clean room design and equipment by attempting to validate difficult to perform, intensive manual procedures.
These manual practices have the potential to increase the risk of contamination on critical surfaces and are considered inadequate manufacturing practices which can not be justified nor validated.
Furthermore, design concepts and use of contemporary equipment and automation technologies should be explored and
assessed for suitability to prevent unnecessary activities that could increase the potential for introducing contaminants into
the aseptic environment. We recommend that you conduct an extensive evaluation of your facilities for opportunities to
minimize steps and manual handling. Additionally, appropriate equipment and usage in all related aseptic operations for
APIs and finished dosage forms should be evaluated. Please provide this evaluation in your response showing improvements to current operations.”
to improve the QCU’s handling of such issues.”
The letter then stresses that these recordkeeping deficiencies
“heighten our concerns regarding the conduct, adequacy,
and oversight of the quality system at the Paonto Sahib site;
in particular, the integrity and reliability of records for equipment cleaning and batch production and control.”
FDA did not let its concern drop, but continued its
investigations into the situation at Paonto Sahib that
extended into the integrity of its application filings.
In February 2009, the agency announced its conclusion that
the facility had “falsified data and test results in approved
and pending drug applications,” and that its investigation
was ongoing. Also at issue were “certain drugs manufactured in the U.S. that relied on data from the Paonta Sahib
facility. The release explained that in addressing the falsified
data, “the FDA has invoked its Application Integrity Policy
(AIP) against the Paonta Sahib facility.”
Under its AIP, FDA asked Ranbaxy to cooperate with the
agency to resolve the questions of data integrity and reliability and to implement a “corrective action operation
plan,” (CAOP) which would include a third-party independent audit of applications associated with Paonta Sahib.
Implementing the AIP means that FDA stops all substantive
scientific review of new or pending applications that contain
data generated by the facility.
The agency again reaffirmed, however, that it did not have
evidence that products manufactured at the facility did “not
meet their quality specifications” or presented health risks.
As part of the mandated CAOP, Ranbaxy has hired a third
party to review the integrity issues raised by FDA and
develop a report back to the agency. The firm stresses that the
AIP applies only to the Paonta Sahib-related applications.
OOS Investigations, Records At Issue Abroad
Altogether, nine of the 43 drug GMP warning letters issued
by FDA during 2008 and 2009 through May involved facilities outside the U.S.
Four of these plants were located in China, two in India and
one each in Japan, France and the U.K. (see Appendix II). The
foreign warning letters for human drugs are issued directly
by the Office of Compliance’s Division of Manufacturing and
Product Quality, under the direction of Richard Friedman.
The other Indian firm receiving a warning letter was Lupin
Ltd. located in Bhopal. The letter was issued in May 2009
addressing the findings at a late 2008 inspection of the
firm’s sterile and non-sterile dosage form and sterile API
operations.
As at the Ranbaxy facilities, recordkeeping as well as contamination controls were central concerns raised in the Bhopal
context.
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FDA found “numerous boxes” of production, control and distribution records awaiting destruction, which were found to
contain at least some records less than a year old. Also implicated were log books from 2006-2007 containing information
related to equipment usage and system functioning which
need to be retained, the letter points out. The letter asks
for “further explanation as to the reason for their planned
destruction and which other production-related documents
are destroyed under” the firm’s policy.
equipment and cleaning procedures, and • did not have an
adequate vendor qualification program. The investigation
indicated that the OSCS contamination stemmed from the
raw materials Changzhou was purchasing for its bulk heparin manufacturing.
Discrepancies in information provided during the inspection
was also at issue. Lupin’s corporate quality management had
explained during the inspection that the Bhopal plant had
no involvement with Lupin’s Mandideep production facility,
yet 20 boxes containing Mandideep plant documents were
observed at the Bhopal site. The letter asks Lupin to explain
the discrepancy.
These involved the manufacturing relationship between
Shanghai No. 1 Biochemical & Pharmaceutical Co., located in
Shanghai, and Qingdao Jiulong Biopharmaceuticals, located
in Jiashou City. The warning letters were based on inspection
of the two sites in August 2008.
The contamination control issues included personnel monitoring and smoke study performance, media fill documentation, building cleanliness, and vial reject handling.
The facility’s failure investigations also raised some concern.
A related issue was Lupin’s contention during the inspection and in responding to the 483 that QA monthly reports
are internal reports not subject to GMP requirements and
are “used as a management tool only.” The letter notes that
the reports include information such as testing summaries,
OOS results, audits, complaints, and changes implemented
and are used by corporate management to apprise them of
potential adverse quality trends. The FDA compliance office
states in the warning letter that it had reviewed the information collected and agreed with the inspection team that the
QA monthly reports are subject to GMP requirements.
Heparin API manufacturing was the FDA inspection
target at three of the four Chinese API facilities that
have received warning letters since the beginning of
2008.
A warning letter was issued to Changzhou SPL in April 2008
based on FDA’s investigation into the heparin crisis and
Baxter’s supply chain (IPQ, May/June 2008). Changzhou was
the manufacturer and supplier for Wisconsin-based Scientific
Protein Labs, which in turn was supplying Baxter with the
heparin API found to be contaminated with over-sulfated
chondroitin sulfate (OSCS).
The warning letter to Changzhou cited investigation findings that the firm: • was not adequately evaluating the effectiveness of its impurity removal process • had not verified
USP methods in actual use • had inadequately qualified its
FDA’s ongoing investigation into the heparin supply
chain resulted in two more warning letters being
issued a year later in April 2009.
Basically, FDA found that Qingdao Jiulong was serving as an
undeclared “shadow factor” for the Shanghai company – a
situation that agency compliance officials have been cautioning about in managing the international supply chain (IPQ,
Nov./Dec. 2008)
The inspection evidence indicated that Shanghai “did not
appear to have ever manufactured” heparin sodium for the
U.S. market, contrary to what the firm had declared in its
drug master file (DMF), and that Qingdao Jiulong had served
as a subcontractor since 2001. The submission of the untrue
statements to FDA meant that the agency did not have the
opportunity to inspect the Qingdao facility. Shanghai had
only identified Qingdao as an “alternate” manufacturing site
in 2008, the warning letter noted.
According to the Shanghai letter, the investigators also “found
that the manufacturers’ labels had been removed from the 5
kg bags during the repackaging operation and the bags were
placed inside aluminum drums used to ship the heparin
sodium to the U.S.; the bags were then sealed and identified
with the Shanghai No. 1 label.”
The letter added that although 148 lots of this heparin sodium
were shipped to the U.S., “we note that no drug products
made with these lots have been marketed in the U.S. at this
time.”
GMP issues were also raised by FDA at Shanghai.
The inspection found that the firm lacked lab testing records for heparin released from the facility to
the U.S., and that Shanghai had not adhered to its
DMF commitment to perform the tests reported on its
Certificate of Analysis.
Inadequate deviation investigations – in this case, involving
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15
the OSCS contamination – was also at issue. “Although your
firm quarantined some of the contaminated material apparently produced by Qingdao Jiulong in 2008, you permitted
at least 19 lots to be shipped to the U.S.,” the letter states. “In
addition, your firm failed to conduct an investigation into the
cause of this repeated, unacceptable contamination. Instead,
you requested that Qingdao Jiulong investigate the contamination, although the product was repackaged and relabeled
at your facility.”
Nor did FDA’s companion inspection of Qingdao Jiulong go
smoothly. Again, the investigation of the OSCS contamination was a central GMP concern.
The facility did not show that it had investigated the contamination problem and FDA did not find the quality systems in
place to assure against such contamination, including those
for batch quality reviews and investigations. In the letter, FDA
requested “complete product quality review reports covering
the manufacturing of heparin sodium for all lots that remain
within expiration” and spelled out exactly what such reports
should cover.
Deviation investigation concerns were also central
in the warning letters to foreign API manufacturers Tomita Pharmaceutical Co. (Naruto-City, Japan)
and Synkem (Chenove Cedex, France) and to injectable product manufacturer Dabur Oncology (Bordon,
U.K.).
The focus of the warning letter to Dabur issued in April 2009
was the investigation of out-of-limit (OOL) environmental monitoring samples collected from isolators used in the
production of injectable paclitaxel and OOS results from inprocess assay testing of process validation samples taken for
injectable methotrexate.
With regard to the firm’s deviation investigations, FDA noted
instances where the root cause was determined to be analytical error. “We expect that any analytical error be fully documented, and that without a definite root cause determination,
the original OOS results would be considered to be legitimate
and would be included as part of the decision to release the
associated batch,” FDA stressed.
Other issues raised in the Dabur Oncology letter involved
equipment maintenance, visual inspection procedures, isolator and lab equipment qualification, lab record signoff and
QC unit record review.
Attribution of OOS results to laboratory error without adequate confirmation and closing out investigations short
of proving the root cause were also addressed in the May
2009 warning letter to French non-sterile API manufacturer
Synkem along with other investigation and CAPA-response
shortcomings. FDA noted that it had found similar deficiencies related to OOS investigations and the lack of corrections
during a May 2000 inspection.
75% of Warning Letters Cite OOS Investigations
Altogether, 33 of the 43 drug GMP warning letters issued in
2008 and 2009 through May have specifically cited inadequacies in the firm’s investigation of manufacturing and product
nonconformances. In many of these, deviation/OOS investigations were a primary focal point.
The investigation issue is squarely on the front burner
in EU regulator inspections as well.
Discussing recent MHRA inspection findings within and outside the U.K at a conference sponsored by the University of
Rhode Island (URI) in late March, British medicines Health
Agency (MHRA) Senior GMP Inspector Andrew Hopkins
noted that inadequate and untimely investigations are an
“incredibly common” finding.
[Editor’s Note: Hopkin’s insights on the top MHRA inspection findings are provided in Appendix I of this issue. He cites
the deficiencies being found in key problem areas and offers
advice on MHRA GMP expectations and viable compliance
approaches.]
“The first day of the inspection we will ask to see deviations
lists and then we will start picking them out,” he explained.
“When we look at investigations systems [and there is a] nonconformance, we expect to see a robust investigation. We
expect it to be done in a timely manner.”
What that means, Hopkins continued, is that “first of all you
have to have a system where you do that critical assessment
almost straight away” on how likely it is to affect product
either being manufactured or on the market. “You can then
do your triage, and say, ‘okay, it is quite a low level – we are
going to take a couple of months to close that one out. It is
high level – we need to do it in a couple of days.’”
The lack of regular management review of these quality indicators is a related recurrent citation, Hopkins said. Firms
should have an organized system for deviations that tracks
and trends root causes and overdues and flags problems
for senior management’s attention. Management can then
respond with the support or emphasis needed to fix them.
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“Quite often,” the MHRA inspector said, the investigation reports are “three-liners where people haven’t
really considered the full impact of what they are looking at. What was the root cause? What are they going to
do about it? If you don’t assess the root cause, how can
you possibly fix the problem?”
He advised companies as a training process and “good learning curve” before inspectors arrive to sit down with the
managers of the various departments and go through the
deficiencies and ask the questions the inspector would ask.
“Because once people have been through that pain” of the
investigation scenario “it is a lot easier to understand what
you actually need to get written down.”
Hopkins emphasized that the MHRA uses FDA’s guidance
on OOS investigations, since it is “probably the best guidance
document that is out there” on the subject. Manufacturers
should “make sure your OOS system follows that,” he
advised.
He further suggested that when contract labs are being used,
to “make sure you know which OOS system they are following. Are they following yours or are they following their
own?” Also, “make sure they notify you of non-valid OOSs.
So if it turns out to be a lab error, make sure they let you know
about it and why.”
This leap to attributing OOS results to lab error with no
thought given to the potential for manufacturing error to be
involved is something investigators often see, he cautioned.
“Be careful you don’t get taken down the route of it is always
lab error.”
Industry consultant Debra Pagano, a former top FDA drug
investigator and preapproval manager, commented at the
URI meeting that firms should also pay attention to OOS
results in preparing for preapproval inspection reviews.
Check to see whether or not deviations found on development batches apply to the pending product, and be prepared
to share that knowledge with investigators asking questions
about them, she advised.
those very carefully.”
The former FDA field manager echoed Hopkins at the URI
meeting in recommending that firms incorporate into their
inspection preparation programs an investigator-type scrutiny of their deviation management programs.
Davis cautioned, however, that improving the quality of
investigations in the quality system is not something that
can be done at the last minute, but involves thinking about
each one and getting it right before sign-off. “You can’t do it
a month before the inspection,” he said. Good investigations
need to be “an everyday process.”
[Editor’s Note: As Mid-Atlantic Region Director and head
of FDA’s policy-setting field drug committee, Davis was
actively involved in developing agency policy on OOS
investigations. His presentation on the elements of a good
investigation program and its importance in being prepared
for regulatory inspections is included as Appendix I in the
March/April issue of IPQ.]
To Err Is Human, But Not GMP
In upgrading deviation investigation systems, regulators
are now looking for firms to apply a more QbD/CAPA perspective, incorporating human factors analysis and a deeper
understanding of the flaws in the quality system out of which
the operator errors stem.
They caution about routinely blaming the deviations on
human error and then simply applying retraining as the fix
without understanding the systemic factors involved.
Human error is the most repeated deviation root cause
and retaining the individual the most common corrective action, Davis commented. However he noted, “a
lot of companies now are finally getting to the point of
trying to figure out what is causing human error.”
Industry consultant Richard Davis stressed that inprocess test results need to be taken seriously as well.
“There is a reason why people are making mistakes. It can
be the complexity of the manufacturing or the function that
you are asking them to perform. It can be lack of training and
knowledge or experience. It can be the clarity of the instructions,” Davis pointed out.
Davis noted that he has been seeing more FDA 483 observations recently that talk about in-process controls and not
paying attention to in-process test failures. Disregarding this
data when passing finished product testing is not acceptable,
he said. “We need to make sure that if we have in-process
variability and manufacturing process failures, we address
“We have designed features and functions in our companies
[where] there is no way that somebody can perform this function correctly every time. So when we are looking at human
error we have to start getting below that first cut. We know
that a mistake was made. We need to understand why, and
we need to start addressing them.”
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17
Investigation programs and the tolerance for deviations provides a clear barometer of a firm’s culture, Davis stressed, and
improving that culture needs to happen from the top down
through supervisory intervention.
Rodriquez discussed the provisions related to experience
and training of employees, supervisors and consultants in 21
CFR 211 of the GMPs as well as the training-related guidance
in ICH’s API guideline Q7A, Q9 and FDA’s quality systems
guideline.
The former FDA field manager summed up his advice for
improving deviation investigations and reports: “Address
the repeated deviation events and repeated root causes, start
trying to find real, sustainable and effective corrective actions
– and believe me FDA looks at this very carefully – and then
effectively reduce and control human error.
A “very key issue,” the FDA investigator pointed out, is the
provision in 211.25(c) that there be “an adequate number
of qualified personnel” both to perform and supervise the
operation.
At the March University of Georgia GMP Conference,
FDA National Drug Expert Investigator Rebeca
Rodriquez gave an insightful presentation on the role
of training in the success of a quality system, in which
she explored the human factors theme.
“Quite often when I see problems in a company that can
somewhat be related to training, it is also related to inadequate supervision. There might not be enough supervisors
or they might not be supervising as they should be, or there
are not enough people there to perform their functions, and
therefore they are making more mistakes because they are
trying to rush and do more work than they can actually do.”
TYPES OF HUMAN ERRORS
At the March University of Georgia conference, FDA National Drug Expert Investigator Rebeca Rodriguez, pointed out that the
effectiveness of training as a preventive or corrective action will depend on the type of human error that it is intended to prevent or correct. She commented on five different types of human error that are uncovered during inspections.
• Organizational/systemic: For example, when the work culture priority in the company is efficiency and productivity.
Of course, efficiency and productivity are important, but so is quality. So there has to be a balance. Some companies put
quite too much emphasis on productivity. And the managers lead by example and people are just cutting corners the same
as the managers, and they are therefore taking product and regulatory risks to reduce cost and increase profits. And some
companies have gone so far as to say that they would take the risk of doing this or that, because they don’t expect FDA to
catch them doing it.
• Procedural (SOPs): Sometimes SOPS are not clear, or the instructions are contradictory. I saw a company during an
inspection that was having pretty serious problems with their cleaning procedures. They were having a lot of cleaning verification or evaluation sample failures. And sure enough when I went to the SOPs, they were not clear. When I interviewed
the operators, they were doing different things. But it was not the operator’s fault, it was the company’s fault,, because the
SOPs were not clear in the first place. How do you train someone in SOPs that are not clear?
• Careless work: That is another type of human error, where people are forgetful. They are not paying attention to what
they are doing, or they are careless. Sometimes people have serious personal problems, they have a lot of stuff in their
minds. This happens. But also the work environment may have an influence on these types of errors. For example if you
have an operation where you have to rely on the person’s memory to execute some steps correctly, you [may be] setting
that person up for failure.
• Voluntary/intentional: The SOP is inadequate and the employees know the SOP is wrong and they just don’t follow it.
Many times we see that employees do backdating, sometimes following instructions from managers.
• Involuntary: Errors due to human variability. We know there are going to be errors. We are just human. We are all human.
But what can we do to minimize them? It depends on the type of error, as I said.
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In commenting on training issues at the URI conference, MHRA’s Hopkins made a relevant comment that
senior managers also need training, and that investigators often find this missing, especially in the U.K.
effectiveness,” Hopkins explained. For example, “for more
complex changes in procedures we might expect some sort
of formal assessment – going through with the training and
making sure they understood what they just read.”
He cited a recent visit to a site that “had new senior managers,
a new QA manager. She had never been trained in the recall
procedure or the deviation procedure for a QA manager.
And I asked them why not. ‘Well she has worked in industry. She knows how deviation systems work. She knows how
recall systems work.’ Yes, but she doesn’t know the number
she is supposed to ring for a recall. She doesn’t know which
bit she is responsible for. For the deviations, she didn’t know
that she was supposed to close her initial report within three
days. Therefore every single report I looked at was over two
weeks old.”
Rodriquez pointed out that, while the Q7A guidance
on training generally lines up with the U.S. GMPs, one
area where Q7A gives more detail is training records.
“Senior managers need training as well,” Hopkins stressed.
“They don’t just know by osmosis everything that is right
about your procedures.”
In general, MHRA investigators will expect firms to show
that the appropriate training has occurred and that it has
been effective. “We are quite happy to see different levels of
The ICH guideline specifies that records of training should be
maintained, including the content of the training. In the past,
FDA investigators have found companies were not always
able to explain the training content. However, Rodriquez
“has seen a great improvement in this area.”
Noting the flexibility in the GMPs regarding training frequency, she explained that the Q9 risk management principles can be used “to determine the adequacy of training and
the frequency.”
She stressed that FDA’s quality systems guideline emphasizes personnel development, not just training. It highlights
the role of management in supporting a problem-solving
ERROR PRECURSOR LIST
The following is a listing of potential causes of mistakes related to: • task demands • work environment • individual capabilities, and • human nature. The list, included in a study of laboratory errors prepared by the U.S. Department of Energy, was
presented by FDA National Drug Expert Investigator Rebeca Rodriguez in discussing pharmaceutical training issues at the
March UGA conference.
Task Demands
• Time pressure (in a hurry)
• High workload (memory requirements)
• Simultaneous, multiple tasks
• Repetitive actions, monotonous
• Irrecoverable acts
• Interpretation requirements
• Unclear goals, roles & responsibilities
• Lack of or unclear standards
Individual Capabilities
• Unfamiliarity with task/First time
• Lack of knowledge (mental model)
• New technique not used before
• Imprecise communication habits
• Lack of proficiency/Inexperience
• Indistinct problem-solving skills
• “Hazardous” attitude for critical task
• Illness/Fatigue
Work Environment
• Distractions/Interruptions
• Changes/Departures from routine
• Continuing displays or controls
• Workarounds/OOS instruments
• Hidden system response
• Unexpected equipment conditions
• Lack of alternative indication
• Personality conflicts
Human Nature
• Stress (limits attention)
• Habit patterns
• Assumptions (inaccurate mental picture)
• Complacency/Overconfidence
• Mindset (“tuned to see”)
• Inaccurate risk perception (Pollyanna)
• Mental shortcuts (biases)
• Limited short-term memory
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and communicative organizational structure and advises
that training needs to have the necessary depth and breadth
to encompass the operational activities, quality system and
work culture.
Training also must be supported by and synergistic with
other elements of a quality system, such as: product development and knowledge transfer; trending of data; CAPA;
audits; and succession planning. In turn, the effectiveness of
training, Rodriquez stressed, “will ultimately be determined
by the robustness of the quality system.”
Noting the different types of human errors that may be
involved (see box on previous page), the FDA investigator
pointed to two basic types of approaches in the literature to
preventing them: the “person” approach and the “system”
approach.
The person approach includes coaching. The problem with
coaching is that it may result in the employee being afraid to
report problems and covering them up instead. Revising procedures, retraining and disciplinary measures also fall into
this category. Rodriquez commented that “unfortunately”
she sees a lot of retraining by itself, which makes her “real
uncomfortable.”
The systems approach, on the other hand, “takes into consideration that humans are fallible and that errors are to be
expected. And because you know that, you develop CAPAs
to change the conditions under which employees work, and
you develop systems with barriers, safeguards and redundant operations to help prevent those errors.”
Vaccine Manufacturing Draws Attention
The challenges of vaccine manufacturing are getting
increased regulatory inspection attention as this product segment expands.
“There are some challenges with vaccine manufacturing that
the traditional biotech people have already worked through,”
industry consultant Rebecca Devine noted in introducing the
discussions at a PDA vaccines interest group session at the
association’s annual meeting in Las Vegas in April. Devine
was formerly involved in developing manufacturing-related
policy for the Center for Biologics Evaluation and Research
(CBER).
For monoclonal antibodies, she pointed out, the platforms
“are pretty straightforward,” generally using CHO cells. Not
so for the more novel vaccine cell types “where there are a lot
more quality and manufacturing issues – for example, with
adventitious agents, testing, sourcing of the materials.” In
addition, bulk manufacturing may require aseptic processing, for example for live vaccines.
At a URI conference on vaccines in March, CBER Office
of Vaccines Research and Review Director Norman
Baylor stressed the regulatory challenges presented by
these manufacturing complexities.
Technological advances have resulted in vaccine development
being one of the fastest growing segments in the biomedical
industry, Baylor said, noting that vaccine manufacturing is
evolving in both the production systems used and the types
of vaccines developed.
He explained that vaccines in general require more stringent
regulatory oversight because of the complexities of the manufacturing process. They are difficult to analyze for product
consistency, and the high demand for safety heightens the
importance of a well-characterized manufacturing process.
Particularly challenging for the new technologies is reproducing the manufacturing from the research through scaleup where millions of doses may be involved.
The limitations of traditional vaccines have led to the emergence of new vaccine strategies and routes of administration,
the CBER official commented. Regulatory issues involving
cell substrates and improving the sensitivity and reliability
of test methods extend across vaccine product classes. But
there are also product specific issues; for example, regarding
potency and efficacy assays. The variety of expression systems being explored for the production of viral like particles
for vaccines against viruses raise special concerns.
The big challenge for FDA, Baylor concluded, is to be in a position to develop new scientific and regulatory requirements to
evaluate new vaccines that are relevant to the technologies
used to produce them. Novel vaccine approaches, such as
vectored vaccines and novel delivery systems, “require complex testing for product characterization and assay validation” and improved assays for evaluating them.
Vaccine manufacturers are regulated by CBER and fall
under the inspection purview of the agency’s “Team
Biologics.”
The team has responsibility for conducting post-marketing inspections of licensed biologic drugs and devices.
Established in 1997, it represents a partnership between the
field’s Office of Regulatory Affairs and CBER.
The “Core Team” includes about 10 specially trained field
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investigators located nationwide. Team Bio also encompasses
CBER product specialists, ORA and CBER compliance officers and respective management, any of which may participate in the inspection and/or the assessment of the results.
The post-market inspections may be conducted jointly. CBER
takes the lead on preapproval inspections.
In accord with the shift in product review responsibilities,
in October 2007 the inspection oversight of CDER-regulated
therapeutic products was transferred from Team Biologics to
the district offices.
With the exception of those for IVDs, Team Biologics inspections follow the model for drug GMP inspections in taking
a systems-based approach, as outlined in the Compliance
Program Guidance Manual, “Inspection of Biologic Drug
Products” (CPG 7345.848). The CPG identifies the six key
systems to be covered – quality, production, facilities/equipment, materials, packaging/labeling and laboratory control – and the three “critical elements” within each of them:
• standard operating procedures (SOPs) • training, and •
records.
Basically the guide calls for investigators to assure that for
each of the six systems: there are detailed written approved
procedures and that these are followed; personnel are trained
for their specific job function and in current GMPs for each
manufacturing operation or QC function; and records are
maintained concurrently with the operation being performed
and accurate and detailed enough to provide a complete history of the work.
FDA concern with vaccine production was reflected in
two major vaccine manufacturers, Merck and Novartis,
drawing FDA warning letters during 2008.
The two warning letters are as much indicative of the complexity of the operations involved as their level of GMP noncompliance. The letters shed light on where FDA’s GMP
concerns lie in the vaccine manufacturing arena.
In line with the recent warning letter cohort as a whole, both
the Merck and Novartis letters had as a central focus the
investigation of OOS results.
The Novartis letter was issued in January 2008 based
on an inspection of the firm’s vaccines and diagnostics
facility in Marburg, Germany in September 2007. The
inspection dealt with the manufacture of rabies vaccine (RabAvert) and unpreserved diphtheria/tentanus
toxoids concentrate.
INVENTORY OF FIRMS COVERED BY TEAM
BIOLOGICS
(domestic and foreign sites as of May 2009)
• 28 vaccines and related products
• 42 plasma-derived products and their recombinant analogues
• 15 allergenic extracts
• 26 in vitro diagnostics (IVDs)
• 1 cell therapy hydromorphone or oxycodone
For the rabies vaccine, the inspection centered on how the
firm responded to the finding of Candida guilliermondii contamination in lots of RabAvert. The contamination was found
in a lot in October 2006 and again in June 2007 as part of an
investigation into inactivation failures. The second lot was
retested for safety and sterility and found non-sterile.
The root cause for the sterility failures was determined to be
low levels of contamination of individual bottles of a lot of
media with Candida during aseptic filling of the media lot.
However, FDA noted in the letter that another 15 lots that
came into contact with the media lot “did not undergo a
second sterility test as was performed during the investigation of previously manufactured lots” and were submitted to
the agency for release.
The warning letter notes that 12 of 96 bottles from the suspect media lot remained after the sterility failure finding in
October 2006. All of the 12 were discarded from production
“without subjecting the media to sterility testing to determine the extent of the contamination.”
The warning letter also pointed to the incomplete investigation of three rabies vaccine batches which failed viable
rabies virus testing after the virus inactivation process. The
RabAvert batches were rejected and Novartis suspended
production of the rabies vaccine in February 2007. The investigations were found incomplete “in that they did not identify a root cause for the virus inactivation failures, and did
not include an evaluation of the cleaning processes and procedures for product contacting equipment to determine if
equipment cleaning is effective in preventing cross contamination of the inactivated batches.”
FDA did its own investigation and alleged that changes in the
firm’s cleaning procedures were not appropriately validated.
The agency further found fault with Novartis’ stability evaluation in not using containers and closure systems for stability sample storage representative of the final container, and
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21
for an inadequate validation study on the use of connectors
for the media formulation area in that the final report did not
address the reason for or the potential effects on the study of
deviations in sample hold times and media leakage. Also of
concern was a variation noted from the firm’s procedures on
viral inactivation time on the rabies virus suspension.
The letter noted that Merck had received numerous customer
complaints citing over-pressurization of vials. Again the concern was that the follow-up investigations did not address
the possibility of ingress as the reason for the problem, and
“did not consider the possibility that the packing method
might not be functioning as validated.”
FDA said the findings were “indicative” of the QC unit not
fulfilling its responsibility to assure the quality of components
and in-process materials. The CBER warning letter asks for
detail on how the Novartis facility would attain GMP compliance with regard to bulk lot production and process controls and investigations. The description should include how
the firm would “use all of the relevant information to conduct thorough investigations to ensure that adequate steps
are taken to evaluate whether deviations impact product, and
to implement effective corrective and preventive actions.”
Other examples of investigation shortcomings involved
reviewing other lots that may have been affected when fibers
were observed during filling, and lack of investigation when
vaccine lots had failed visual inspection.
The letter further commented that Novartis appeared to have
addressed the individual FDA 483 items from the inspection,
but the firm’s response “addresses these issues individually
and not as part of a comprehensive corrective action plan.”
Merck received the warning letter in April 2008
addressing an inspection ending the previous January
of the firm’s West Point, Pennsylvania facility. The
plant manufactures several licensed vaccine products
and their bulk substances and components.
Focusing first on the product side, the letter begins with the
finding that the firm had not “thoroughly investigated any
unexplained discrepancy of a batch or any of its components
to meet any of its specifications, whether or not the batch has
already been distributed, and to extend the investigation to
other batches of the same drug product and other drug products that may have been associated with the specific failure
or discrepancy.”
Giving examples, the letter notes that Merck had submitted a Biological Product Deviation Report (BPDR) to FDA in
October 2006 due to an OOS finding at the two-month stability time point for Varivax III. The product had been shipped
abroad and then returned to the U.S. before being placed on
stability, and was not licensed in the U.S. at the time of the
deviation. Merck’s investigation concluded that the failure
was due to ingress into the vial headspace during shipment.
However, FDA noted, the investigation did not include testing of other potentially affected products such as ProQuad
“to determine if there were any detrimental effects on these
products.”
FDA further asserted that Merck’s SOPs for handling complaints were not adequate – for example, in only directing
that a lot history be performed for a particular final finish or
packaging/labeling lot number. “Complaints such as leaking
vials/syringes and various container/closure defects would
be associated with a fill lot number, and a fill lot number
may be associated with several final finish lot numbers,” the
agency stressed.
Discussing vaccine inspection findings at a dinner meeting of
PDA’s New Jersey chapter in May, New Jersey District investigator Ann Marie Montemurro cited the finding at Merck as
an example of investigator concern with complaint handling
and investigation at vaccine and other biological facilities.
Montemurro is Team Leader for the Team Biologics “Core
Team” and participated on the Merck inspection.
Without naming Merck as the recipient of the observation
under discussion, Montemurro explained that “the firm”
was getting “a lot of complaints on vials and syringes,” and
would do trace backs looking at the packaging lot number.
“However, they could have six or seven packaging lots made
from one fill lot. They never took it back to the fill lot. So that
was something we saw as a deviation.” When the investigation team actually went back and looked at the other lots
potentially affected, she said, there was a larger trend than
their data had indicated.
Failure investigations were also addressed in the warning letter section on Merck’s handling of bulk drug
substances and drug components.
FDA maintained that the firm had not quarantined “numerous process intermediates” associated with the use of filter
membranes that were identified to cause foaming during filtration. The foaming was found to be associated with leaching of an unwanted substance into process intermediates that
were used to further manufacture product lots of different
vaccines.
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The agency also cited the firm’s investigation into leaks discovered during recharge of a lot that concluded there was
no impact. The investigation report had an unsigned and
undated chronology of events based on a notebook maintained by the production manager whose relevant pages
were found to be missing.
A third example involved a sterility failure of a Pedvax bulk
lot. The investigation, the letter maintains, failed to assess
a recent change in the steam-in-place (SIP) cycle for a tank
involved in the process. The validation of this SIP change
was subsequently implicated during investigation of the failure of a media challenge, which led to the recall of several
PedVaxHIB and COMVAX lots, the letter notes.
Merck recalled ten lots of its haemophilus b (meningococcal protein) conjugate vaccine PedvaxHIB and two
lots of COMVAX, which combines the haemophilus
b conjugate with hepatitis B recombinant vaccine, in
December 2007 while the FDA inspection was in process. About 1 million doses were involved.
In a release, Merck said that the recall was a “precautionary
measure” being taken because the company could not “assure
sterility for these specific vaccine lots.” The firm explained
that it had identified the presence of Bacillus cereus during
routine testing of the manufacturing equipment used to produce the implicated products, although sterility tests of the
vaccine lots themselves prior to their release had not found
any contamination.
Merck advised that the potential for contamination of any
individual vaccine was low, and, if present, the level of contamination would be low. Also, there were no concerns about
the efficacy of the vaccine lots, and Merck had not received
any reports involving B. cereus-related infection in children
who had received vaccine from the lots.
The company said that it was suspending production of the
Hib conjugate vaccines and did not expect to resume distribution until the fourth quarter of 2008. The other manufacturer, Sanofi Pasteur, likely would not be able to immediately
make up the difference for enough product to vaccinate fully
all children for whom the vaccine is recommended, Merck
added, noting that CDC was recommending that health providers temporarily defer administering the routine Hib vaccine booster dose except in high-risk children.
The warning letter to Merck also addressed bulk container closure systems, including those used for Pedvax
and RECOMBIVAX .
FDA maintained that the firm had failed to assure that these
systems provided “adequate protection against foreseeable
external factors in storage and use that can cause deterioration or contamination of bulk drug substances and sterile
solutions used in production.”
During her presentation at the May PDA meeting, investigator Montemurro discussed this observation (again without attribution) as an example of recent Team Bio findings
involving the material system.
The first example cited in the warning letter was that the container closure study did not include assessment of the affect
of the storage conditions. Montemurro explained that the
bulk products were stored frozen in a plastic carboy with
a screw top, which had a specific torque applied to it.
Merck had done the container closure studies applying
the torque, but did not measure the effect of the freezing and the long term storage on that torque rate. The
question remained, she said, if the applied torque “was
enough to account for the backoff torque that you are
going to see when you store something frozen for that
long.”
The second example included in the letter involved inadequate validation study of the storage of sterile filtered
solutions.
Montemurro explained that FDA looked at the issue due to
the sterility failure in the Pedvax. To the FDA questioning,
Merck responded that it had validated the container closure
system, prompting further investigator inquiry.
The Team Bio inspector made a larger point that firms should
not use validation status as a rationale for not pursuing an
investigation into “validated” areas when problems occur.
This was a “recurring theme” during the Merck inspection,
Montemurro said. In this case, the cause of the sterility problem was not found to be the container closure, but something
else that the firm’s original investigation had eliminated as a
validated area.
In the warning letter, CBER requested a meeting with Merck
senior management to “further discuss the issues cited in
this letter and your proposed responses to address them”
in the effort to facilitate the remediation efforts. “Given the
potential contributions of safe, pure and potent vaccines to
the public health,” FDA said, “we encourage frequent interactions between your technical staff and FDA in an effort to
help Merck move forward with corrective actions as rapidly
as possible.”
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Also receiving a biologic product-related warning
letter during the 2008-2009 timeframe was Genzyme.
A letter was issued in late February 2009 addressing
inspection findings in the fall of 2008 at the firm’s
Allston, MA plant.
As in the Merck case, the letter delineated issues involving
both drug products (Fabrazyme, Cerezyme and Myozyme)
and bulk substances and components.
The drug product discussion focused on the firm’s microbiological contamination control procedures – in particular its
air flow studies.
At issue in the bulk substance area was bioburden monitoring after hold times of intermediates or pooled buffers
during purification of Fabrazyme, Myozyme and Cerezyme.
The letter also maintains that Genzyme’s current procedural
and automated in-process controls for formulating pooled
buffers did not assure that the pooled buffers would meet
their specifications. FDA asserted that the firm’s follow up
to these “documented deviations did not include training
of operators or those supervising formulation operations.”
Genzyme’s maintenance of certain bulk process equipment
and computer systems in a validated state was also cited.
Vaccine Deviation Reports Often Late
Biological product deviation reporting is an issue that is not
infrequently raised on biologic inspections.
In a presentation at the URI vaccines conference in March,
CBER Office of Compliance and Biologics Quality Director
Mary Malarkey stressed that firms are not always submitting
the reports on time, particularly in the vaccines area.
Where 96% of the 169 BPDRs submitted in FY 2008 for allergenic products were within the requested 45 day reporting
time, only 60% of the 97 vaccine reports made that deadline.
In vitro diagnostics were in the middle range with 77% of 78
IVD reports made within 45 days.
Noting the problem of late reports, Malarkey advised
firms not to do a complete investigation before submitting the report, but to file the report ASAP with the
knowledge available and complete the investigation
in as timely a fashion as possible.
compared to 100% of those filed by allergenic manufacturers
and about 80% by IVD firms.
Malarkey stressed that reporting electronically provides for
more effective and efficient processing and use of the information provided. She stressed that CBER wants to help facilitate
electronic reporting by the vaccine industry in particular.
Overall, BPDRs increased 8% in FY ’08 compared to the
previous year. The increase largely reflected a spike in
vaccine reports, which increased by 37 or more than a
third.
Product specification issues were the primary cause of the
reports, accounting for 65% for all product types.
Quality control and distribution problems accounted for 10%
of the filings, followed by labeling deviations and process
controls at around 8%, testing deviations at 6%, and incoming material issues at 2%.
Among vaccines, 50 of the 97 reports involved product specification deviations. Leading causes were the spec not being
met or foreign material in the product. Other problems noted
in the filings were components not meeting specifications,
missing stoppers or crimps, and stability failures for potency,
purity, moisture, pH and preservatives.
QC/distribution problems accounted for 20 vaccine reports.
These included reports on product shipped or stored at incorrect temperatures, inadequate seals, and broken/cracked
vials.
Process controls generated nine vaccine reports during the
year. Use of an unapproved filter, media fill problems, equipment not performing properly and sanitization not being performed correctly were among the causes.
Testing problems generated seven vaccine reports, including safety, sterility, identity and stability testing not being
performed or documented or performed correctly. Labeling,
including multiple labels, product or carton label missing, or
lot number missing, resulted also in seven vaccine BPDRs.
Another issue for vaccine manufacturers is their slow conversion to electronic filing (eBPD). Only 11 of the 97 reports
submitted by vaccine firms in FY ’08 were done electronically,
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APPENDIX I
FDA DRUG GMP WARNING LETTERS ISSUED IN 2008/2009
The following is a list of the 43 drug, therapeutic biologic and vaccine warning letters issued by FDA during 2008
and 2009 (through May) that address GMP concerns. The company receiving the warning letter, the location, the
letter date, the date of the inspection generating the letter, and any associated recalls are included in the listing,
along with a brief description of the main areas of concern cited. The warning letters are categorized by the types
of products covered during the relevant inspection: • injectable (10) • miscellaneous (10) • topical (6) • API (6) •
oral solids/liquid (5) • transdermal (2) • veterinary (2) • inhalation (1) • repacker (1).
INJECTABLE
Catalent Pharma Solutions
Location: Raleigh, North Carolina
Letter date: March 2008
Inspection date: November 2007
• Deviation investigations in water and air sampling • cleaning/disinfection of aseptic processing rooms/equipment • microbial contamination
prevention procedures: (environmental monitoring result review) • analytical methods validation (sterility, bioburden) • sampling, growth promotion testing
Columbia Presbyterian Medical Center
Location: New York, New York
Letter date: December 2008
Inspection date: June 2008
Products: PET
• discrepancy investigations • establishing and following QC test
procedures • medial fill growth promotion • analytical equipment
maintenance
Cyclotron Center of NE Florida
Location: Orange Park, Florida
Letter date: January 2009
Inspection date: August 2008
Products: PET
• sterilization activities and testing • endotoxin testing procedures
• incoming material evaluation • discrepancy investigations • production quality oversight • equipment maintenance
Dabur Oncology
Location: Bordon, United Kingdom
Letter date: April 2009
• environmental monitoring in isolators • equipment maintenance
• visual inspection procedures • isolator and lab equipment qualification • discrepancy investigations • lab record signoff • QC unit record
review
Genzyme
Location: Cambridge, Massachusetts
Letter date: February 2009
Inspection date: September/October 2008
Products: therapeutic biologics – dosage,
bulk and components
Finished product: • microbial prevention procedures (air flow and line
speed validation)
Bulk and component: • production/process controls (bioburden monitoring, buffer control and training followup) • equipment maintenance (interior of columns, cryoshippers) • computer system maintenance
IBA Molecular
Location: Sterling, Virginia
Letter date: October 2008
Inspection date: May 2008
Products: PET drugs
• Analytical test procedures: (endotoxin and sterility retesting) • media
fill sterilization testing • discrepancy investigations and corrective action
• aseptic technique • equipment inspection
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Merck
Location: West Point, Pennsylvania
Inspection date: November 2007, January 2008
Products: vaccines – dosage, bulk and components
Recalls: Haemophilus b conjugate vaccine; haemophilus b
conjugate/hepatitis B vaccine (sterility assurance)
Finished product: • batch deviation investigations • complaint handling
procedures • production/process controls: (inspection equipment validation and inspection, process control limit review) • computer validation •
lab control deviation handling
Bulk and components: • production/process controls: bulk holding times
• discrepancy investigations • component stability • cleaning procedures
• equipment maintenance • container/closure storage assessment
Novartis Vaccines and Diagnostics
Location: Marburg, Germany
Inspection date: September 2007
Products: vaccines
• Production/process controls: (media sterility assurance and storage,
stability study on vaccine concentrate, validation study deviation follow
up, viral inactivation procedure) • Discrepancy investigations (sterility and viral inactivation) • Equipment cleaning/maintenance (validation
studies).
Pharmalucence
Location: Bedford, MA
Letter date: September 2008
Inspection date: April 2008
• Microbiological contamination prevention (bacterial filtration retention
validation, aseptic technique, steam sterilization validation, environmental monitoring, airflow and microbiological evaluation) • QC unit investigations • container depyrogenation • protective apparel • facility and
equipment maintenance • microbiological testing (documentation, visual
inspection)
Primapharm
Location: San Diego, California
• discrepancy investigations • microbiological contamination procedures (monitoring, personnel ingress, media fill SOP) • environmental
monitoring system (surface sampling, sample timing, personnel alert/
action limits) • finished product inspection • cleaning system • equipment maintenance system • process validation • annual product review
• drug approval/branding
MISCELLANEOUS
American Hormones
Location: Wappingers Falls, New York
Inspection date: December 2006
Products: Capsules, gels
• Compounded drug approval/branding • stability testing • in-process
testing • equipment cleaning procedures • batch testing • production
procedures • component testing • complaint handling
Concept Laboratories
Location: Chicago, Illinois
Letter date: August 2008
Letter date: December 2007/January 2008
Products: Orals, topicals
• QC unit OOS investigations • process validation • process control procedure discrepancy justification • equipment cleaning validation • lab
testing records • drug approval/branding
Lupin Limited
Location: Bhopal, India
Letter date: May 2009
Inspection date: November 2008
Products: finished dose and sterile API
• batch production record retention • personnel monitoring in aseptic
area • smoke study performance • computer system review/performance • component reject labeling • media fill documentation • building maintenance • discrepancy investigations
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Mallinckrodt (Covidien)
Location: Maryland Heights, Missouri
Inspection date: March 2008
Products: Radiopharmaceuticals – oral and injectable
• Release limit • in-process control procedures • QC unit oversight of
control procedures/specs/investigations
Olay (Proctor and Gamble)
Location: Cayey, Puerto Rico
Inspection date: August/October 2008
Products: cleanser, nasal spray
• discrepancy/complaint investigations • following cleaning SOPs • process change validation • complaint handling procedures • line sanitization practices
Pharma Pac
Location: De Kalb, Mississippi
Inspection date: June/July 2008
Products: oral liquids, topicals
• drug approval/branding • QC unit • production procedures • in-process and release testing procedures • stability data to support expiration
dating • environmental controls • complaint handling procedures
Ranbaxy Laboratories
Location: Dewes. India
Inspection: January/February 2008
Products: API and finished
• beta-lactam containment control program • batch production and control records • discrepancy investigations • QC unit oversight • aseptic
operations (sterile API)
Ranbaxy Laboratories
Location: Paonta Sahib, India
Products: finished
• equipment cleaning record review/sign-off • batch record review/signoff • QC unit record review and discrepancy investigations
Sage Products
Location: Cary, Illinois
Products: Oral rinses, skin cloths
Recalls: Chlorhedrine cloth (microbial contamination)
• microbial limits specifications • environmental monitoring procedures
• annual product reviews
Vintage Pharmaceuticals
• Microbial contamination prevention (establishing and following testLocation: Huntsville, AL
ing procedures, discrepancy investigations, records maintenance, lot
release) • drug approval/branding
Inspection date: July, August 2007
Products: Oral liquids, topicals
Recalls: primidone tabs (subpotent); perphenazine tabs
(tablet separation); hydrocortisone otic sol. (impurity);
bacitracin ointment and hemorrhoidal suppositories
(microbial specs)
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TOPICAL
Cascadia Manufacturing
Location: Bellevue, Washington
Inspection date: February 2008
Products: mouth care patches
• release testing and criteria (potency, microbial) • in-process testing
procedures (mixing) • component testing (microbial, identity and after
storage) • equipment cleaning (practices, procedures and records)
• equipment/facility construction • batch production records • QC unit
establishment • lab test methods • complaint handling procedures
• discrepancy investigations • equipment maintenance procedures
• stability prvogram • labeling/packaging material handling procedures
• drug approval
G&W Laboratories
Location: South Plainfield, New Jersey
Letter date: July 2008
Products: Ointments, suppositories
Recalls: hemorrhoidal ointment (potency/cGMP)
• Product and in-process material release decision-making • process
change during scale-up • equipment cleaning/maintenance • discrepancy investigations • in-process material testing • drug approval/
branding
Omega Tech Labs
Location: Boise, Idaho
Inspection date: January, February 2008
• Drug approval/branding • batch testing • QC unit procedures • production procedures and control records • discrepancy investigations
Prime Enterprises
Location: Miami Lakes, Florida
Inspection date: July 2008
• Drug approval/branding • deviation investigations and batch remixing • OOS batch release • stability testing • process validation • annual
product review • master production records (mixing times) • yield
determination
Taro Pharmaceuticals
Location: Brampton, Canada
• stability program • discrepancy investigations • QC unit batch review/
rejection
Xttrium Laboratories
Location: Chicago, Illinois
Inspection date: July/December 2008
Products: skin cleansers, oral rinses
• sanitary conditions • discrepancy investigations • microbial prevention
procedures • annual product reviews • analytical procedures • complaint handling procedures
ORAL SOLIDS/LIQUIDS
Caraco Pharmaceutical Laboratories
Location: Detroit, Michigan
Inspection date: May/June 2008
Recalls: Metformin tabs (tablet weight variation)
• QC unit (record review, discrepancy investigations, batch release, procedure/spec oversight, component recordkeeping, procedure change
control) • in-process specification setting • equipment maintenance
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Deltex Pharmaceuticals
Location: Rosenberg, Texas
• QC unit procedures • lab controls (incoming API, tannate specification,
microbial growth testing) • supplier analysis validation • discrepancy
investigations • batch record notation • drug approval/branding
Elge
Location: Rosenberg, Texas
Inspection date: January/February 2008
Recalls: Cough/cold susp. (subpotent)
• lab controls (incoming API, tannate specification) • deviation investigations • supplier analysis validation • stability testing program • drug
approval/branding
Nostrum Pharmaceuticals
Location: Kansas City, Missouri
Inspection date: October/November 2008
• stability evaluation of new API supply • discrepancy investigation (stability data) • cleaning performance, verification and procedures • method
verification (impurities) • supplier evaluation • computer validation
Sandoz
Location: Wilson, North Carolina
Recalls: alprazolam ER tabs, trifluoperazine tabs (dissolution); estradiol inj., succinylcholine (impurity); midodrine
tabs (subpotent); lisinopril tabs (metal contamination);
metoprolol ER tabs (cGMP)
• process validation • discrepancy investigation completion • batch testing documentation • master record completeness • internal specification documentation/justification • computer system controls • following
QC unit procedures
API
Changzhou SPL
Location: Changzhou, China
Inspection date: February 2008
Recalls: Heparin API (foreign substance)
• impurity removal evaluation • crude material supplier evaluation • test
method verification • equipment suitability
Pucheng Chia Tai Biochemistry
Location: Pucheng, China
• Batch production test records • QC unit: structure, procedures, and
activities
Qingdao Jiulong Biopharmaceuticals
Location: Jiaoshou City, China
Inspection date: July/August 2008
Recalls: heparin sodium (contamination)
• system for supplier control and contamination prevention • deviation
and complaint investigation into over-sulfated chondroitin sulfate contamination • technology transfer review • product quality review
Shanghai No. 1 Biochemical & Pharmaceutical
Location: Shanghai, China
Recalls: heparin sodium (contamination)
• veracity of declared manufacturing location and labeling • batch testing as per DMF and COAs • discrepancy investigations into over-sulfated
chondroitin sulfate
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Synkem SAS
Location: Chenove Cedex, France
• discrepancy investigations • QC unit document review/approval • discrepancy investigations • raw material supplier qualification • product
quality reviews
Tomita Pharmaceutical Company
Location: Tokushima, Japan
Inspection date: July, August 2007
• Laboratory system: (analyst worksheets, deviation investigations, computer system validation and security)
TRANSDERMAL
Newman (Medi-Stat)
Location: Mobile, Alabama
Letter date: June 2008
• Compounded drug approval/branding • component testing • batch
testing • equipment qualification • stability testing • QC unit oversight •
production and control records • lot numbering • batch production and
control procedures and records
Noven Pharmaceuticals
Location: Miami, Florida
Inspection date: June, July 2007
Recalls: Methylphenidate patch (peel force spec)
• Liner release (specification and stability)
VETERINARY
Jer-Vic (Foy’s Pigeon Supplies)
Location: Beaver Falls, Pennsylvania
Inspection date: January 2008
• Repackaged animal drug approval • component testing • dedicated
areas for repackaging
Virbac
Location: Bridgeton, Missouri
Letter date: December 2008
• QC unit authority/investigations • following warehousing procedures •
lab testing procedures • HPLC calibration • OOS stability investigations
• labeling claim approval
INHALATION
Farmacia La Salud
Location: Caguas, Puerto Rico
Letter date: March 2008
• Compounded drug approval/branding • microbiological contamination
prevention procedures • sterility testing performance • batch release
testing • equipment cleaning/maintenance procedures • component
testing and release • batch recordkeeping • complaint handling • distribution tracking.
REPACKER
Whitney Labs
Location: Ormond Beach, Florida
Products: solid/liquid orals
Recalls: methadone oral sol. (mislabeling)
• QC unit establishment • automated packaging line validation • procedure following/documentation • discrepancy/complaint handling and
investigation • component/container evaluation • employee training •
stability program and expiration dating • reserve sample retention •
annual product review procedures
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APPENDIX II
MHRA GMP INSPECTOR ANDREW HOPKINS ON TOP MHRA INSPECTION FINDINGS
At a University of Rhode Island-sponsored conference on inspections in late March, British Medicines Health
Agency (MHRA) Senior GMP Inspector Andrew Hopkins discussed recent MHRA inspection findings within and outside the UK. Among the problem areas most commonly being cited are: • quality management systems • quality
system documentation • design and maintenance of premises • supplier and raw material control • potential for
microbial contamination, and • environmental monitoring. Hopkins discussed inspection deficiencies related to
these areas and advised on MHRA GMP expectations. His comments in the first four areas are included below. A
discussion by Hopkins of microbial contamination and environment monitoring concerns is included in Appendix
1 of the January/February 2009 issue of IPQ. Prior to joining the British agency in 2005, Hopkins worked for about
two decades in the pharmaceutical industry in QC, QA and production.
Quality Management Systems
• Incomplete or tardy recording and investigation of complaints and incidents: That is really common, incredibly common. The first day
of the inspection we will ask to see deviations lists and then we will start picking them out…. When we look at investigational systems, any
non-conformance, we expect to see a robust investigation. We expect it to be done in a timely manner. So that means first of all you have a
system where you do that critical assessment almost straight away. ‘I have got an incident. It has happened. How likely is it to affect product
that we are continuing to make,… product that is out on the market.’ You can then do your triage, and say, ‘okay, it is quite a low level – we
are going to take a couple of months to close that one out. It is high level – we need to do it in a couple of days.’
• No regular management review of quality indicators: We also expect you to have some sort of management review process. We expect
you to be looking at your deviations. We expect you to have your deviations. We expect them to be in some sort of spread sheet or database,
or even a manual system. But you need to have some system for saying, ‘this was raised on the 1st of January. Our expectation within the
SOP is that it is closed within 31 days,’ or whatever [timeframe] you choose to set yourselves. It has been closed – fine. Or it hasn’t been
closed, therefore it needs to be elevated to senior management.
We expect you to trend those sorts of things. We expect you to trend the root cause and we expect you to trend overdues. So that when
you find that it is the engineering department who never completes their investigations on time, you have some sort of senior management
review that says, ‘okay, we have noticed you guys are always behind schedule. Why is that? Is it a prioritization issue? Is it a resource issue?
Or do you just not care?’ Whichever the answer is, the senior management can then help support you by either giving people more time,
more people, or helping them to care.
• Lack of quality improvement/CAPA processes: What we mean by that is it is not just reacting to incidents that go wrong. It is actually
proactively looking at things to say, ‘okay, where are we going now with this in the future? How are we going to improve before something
goes wrong? So looking at web sites, looking at the EU GMPs, the FDA requirements – feeding into a system that says ‘did you know the
requirements now are heading this way. Annex 1 has just changed and perhaps we need to make sure we are complying with Annex 1 – that
sort of improvement process.
What I should have talked about as well [regarding] investigations [is that] quite often we look at investigations and they are three liners
where people haven’t really considered the full impact of what they are looking at. What was the root cause? What are they going to do about
it? If you don’t assess the root cause, how can you possibly fix the problem?
When I was in industry, we had a QA manager who, just before the FDA came to visit us, pulled out all of the deviations written on the site.
As part of the training process, he sat down with all of the head managers of various production departments and quality assurance and QC,
and, as an FDA investigator might, went through these deficiencies, these investigations, asking ‘what did you mean by that. What happened
after that? And it is amazing what a good learning curve that is. Because once people have been through that pain, [that investigation sce-
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nario], it is a lot easier to understand what you actually need to get written down.
The other thing about investigations is that it is a good idea to involve somebody independent from those investigations, so that they can
sit down and ask all of the questions that I normally come in and ask: ‘You said you did that, but why did you do that? And why didn’t that
matter? You had an autoclave failure, why are the other 16 batches okay?’ You need to ask those questions. Very often we will ask those
questions and everybody will go, ‘oh, I know we had a meeting about that, and I spoke to him.’ But it is not written down anywhere. You
need to write it down and get it clear so that if you happen to be the one who wins the lottery next week and disappear, everybody on
site knows what is going on.
• Insufficient change control: Start with the premise that any change needs formal control. Then if you need to void it afterward, fine.
But always start with that scenario. And it is not just on changing the piece of equipment. It might be on changing the throughput of the
site. That should be controlled by change control systems.
I saw a site in the UK which makes vaccines. They had an issue whereby they increased their capacity by 20% from one season to the
next. What they hadn’t realized is that their whole system was teetering on the edge of capability. When they increased by 20%, they had
a complete fallover – something like 50% sterility failure. Funny enough they…tried to release the other 50%. You need to think about
what is your capacity for the site? If I change it, what happens to it? How do I control that? Do I need more resource? If it is a sterile area,
do I need to allow longer blow-downs? Do I need to change the cleaning [approach]? All sorts of things. Think outside the box when you
are looking at change. It isn’t just specifically, ‘I am changing that valve and is it the same or not?’
Like-for-like changes are another particular favorite of mine. If you have an automated packaging line and you swap the camera for
another camera, is that a like-for-like change? Possibly, possibly not, but you need to think about it. If you change a vacuum pump, is that
a like-for-like change? No, definitely not. There are a number of sites where they have like-for-like change which will go to the criticality
of equipment and allow it to be done with no formal control whatsoever.
• Ineffective self-inspection systems: We will always look at your self-inspection system. Firstly, have you got one? Are you doing
them in a timely manner? We are very aware that times are hard at the moment. One of the first things that goes when times get hard is
training. The other thing that tends to happen is that the self-inspection procedure goes out the window. So you have this lovely schedule
that says we are going to do this, this and this, and you don’t do any of it.
So like your investigation system, you need to have some sort of escalation process that says: ‘This is the program we have agreed.
We will allow a month either way, and if we don’t do it in that time, then we expect it to be escalated to senior management for them to
review – why are we not complying with our procedures and what are we going to do about it?
• Recall systems incomplete and untested: This is common in the U.S. You might have a requirement where you actually need to tell
us about it and …what is going on. Another common one in the U.S. is that the EU GMPs require you periodically to retest your recall
procedure. Not everybody has picked up on that. What we mean by that is to run a simulation.
• Non-compliance with previous inspection commitments: That will get you straight into critical mode. Not necessarily will it stay
there, but if we look at it and find several examples of where you haven’t done what you told us you were going to do, it may well go
over to IAG [Inspection Action Group], which may take regulatory action against any licenses you are named on. So please talk to us on
that one.
Quality System Documentation
• Lack of control of procedures and specifications: Frequently – possibly not so much in U.S., but it is still quite common – when we
ask to see in a drawer, out comes the version of the document that is three versions old. So be aware of that and use it as part of the
inspection readiness and audit as well. Don’t just look on the desk during your self-inspection program. Look in those hidden corners.
Specifications are often out of date as well. Again make sure you have an up-to-date copy of the CTA [Clinical Trial Applications] or
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the MA [Marketing Application]. If they have changed it, you need to know about it. So make sure that is written into your technical
agreement.
• SOPs lacking detail or missing certain activities: We quite often say, ‘okay Mr. Operator now running the packing line, how are you
doing what you are doing and what are you doing?’ And they will talk us through it, and he will know exactly what he is doing. And then
we will ask to look at the procedure, and it won’t bear any relevance at all to what is written in the procedure.
The chances are your operator is actually doing what is the right thing. You have written your procedure wrong. So when you write your
procedures, get your operators involved. They know what is going on. I love the process flows. Get your operators involved in process
flows. Because quite often what happens is that you will go through procedures that say we do this, that or the other, and the operator
will say, ‘oh yea, do you know we have never done it that way, because we can’t actually do that, and what we do is this.’ So talk to your
operators and update the procedures and make sure they are right.
Quite often we still find unofficial aide memoires or procedures scattered around labs and areas. If when you do your self-inspection you
find lots of unofficial documents, that is a really good indicator that your procedures are not up to scratch.
• Inadequate recording of training and effectiveness: We expect you to show that you have trained somebody. And we expect you to
show that that training has been effective. And we are quite happy to see different levels of effectiveness…. For more complex changes
[in procedures] we might expect some sort of formal assessment – going through with the training and making sure they understood
what they just read.
A really common one, especially in the UK funny enough, is that senior managers don’t appear to ever need training. I don’t know why. I
have been to a site a while ago and they had new senior managers, a new QA manager. She had never been trained in the recall procedure or the deviation procedure for a QA manager. And I asked them why not. ‘Well she has worked in industry. She knows how deviation systems work. She knows how recall systems work.’ Yes, but she doesn’t know the number she is supposed to ring for a recall.
She doesn’t know which bit she is responsible for. For the deviations, she didn’t know that she was supposed to close her initial report
within three days. Therefore every single report I looked at was over two weeks old. Senior managers need training as well. They don’t
just know by osmosis everything that is right about your procedures.
• Technical agreements missing or incomplete: You need to have technical agreements in place. You need to have them with labs.
You need to have them with suppliers. You need to have them with the QPs as well. If your QP is not actually working for your company,
there needs to be an agreement between you saying who is responsible for what, how the information gets passed. If people have technical agreements, quite often they don’t have sufficient detail of who is responsible for what. And if they do have sufficient detail, they
then don’t have a system for reviewing.
In the U.S. you have had annual product reviews for a number of years, so a lot of people will say, ‘yeah, the EU has introduced PPQRs
(Periodic Product Quality Reviews) a couple of years ago, but we have been doing APRs for ages, so we don’t need to worry about that.’
There are a few differences in the PPQRs – one of which is that you need to review your technical agreements every year. It doesn’t mean
that you revise them, but you do need to review them every year and make sure they are appropriate and make sure they are there.
• Documentation of maintenance and calibration activities: I love engineering departments. They keep me busy. Frequently we will
go and look at maintenance and there won’t be a specification for what people are doing. There will just be a simple note saying, ‘yup,
we came and did the monthly maintenance.’ You need to have something saying what you are going to do, when you are going to do it.
Again, like your self-inspection and your deviations, what leeway you are allowed. So if my maintenance says I am going to do planned
preventive maintenance on it every six months, am I allowed a month here or there? Define that.
What isn’t acceptable is for me to turn up on site and say, ‘okay, let’s look at your planned preventive maintenance schedule,’ and find
that the entire sterile area is three or four months behind schedule, and the answer I then get is ‘yea, but we have some big orders in
so we kept it going and delayed the planned preventive maintenance.’ You can’t just do that. If you really want to do that, then get QA
buy in, do a risk assessment, do a deviation to support it. I personally wouldn’t do it. But if you really want to do it, make sure you do it
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formally – risk-assess it. We are big into risk assessments these days.
Calibration activities: Make sure you get ‘as found’ as well as adjusted results. If you don’t get ‘as found,’ how do you know what has
been going on for the last three, six months, and that everything you have made is still okay?
Design And Maintenance Of Premises
• Use of low quality building fabrics leading to easily damaged walls and doors which become difficult to clean: This one was
quite high on the U.S. list last year especially around aseptic areas. Annex 1 talks about easily cleanable areas. And when we go and look
at an area and it has got holes in the wall or plaster or ledges, or even in one instance wooden bits in there, you get quite concerned by
that. But it is true of all clean areas – you need to make sure that what it is built from is appropriate. If you find in your self-assessment
process it isn’t appropriate, then build a deviation, build an action plan. If it is a reasonable action plan, you probably won’t get a deficiency. If it is a hole in the wall with dust coming out, then you probably will get a deficiency. But if it is a reasonable assessment and
documented, there is a good chance you are already moving away from a deficiency. If the risk assessment is written the week before I
turn up, then you might still get a deficiency.
• Incorrect airflows and pressure differentials to prevent cross contamination: I have been to several cytotoxic/non-cytotoxic sites
last year. On one site in the U.S., we started in the non-cytotoxic area, and we went to the packing line and there were various issues
there, but I won’t go through that. We went to the vial sterilization area and came out, looked through the aseptic window for non-cytotoxics, walked to the warehouse where people were coming in an out of the outside doors with the same clothes as they were wearing
everywhere else, carried on wandering through the process. Eventually our tour guide said, ‘and this is the cytotoxic washer.’ How have I
gotten from the cytotoxic area all the way down to the non-cytotoxics without once changing? They just hadn’t thought about it. Pressure
differentials weren’t in place, so they weren’t containing materials. That one went to IAG.
I saw another site where they had pressure differentials maintained to support their cytotoxic processing. It was explained to me, ‘this
is how we do it. We have individual booths for each area where there is cytotoxic processing.’ They all have negative [pressure]. It is all
single pass through air, so it is all being dumped onto the neighbors. As I stood and watched the process, three operators stood and had
a conversation in the door with the door open for about five or ten minutes – no pressure differential whatsoever.
• Sterile area changing rooms: They need to make the grade that you are going into at rest. Please be aware of that. They need to be
designed properly. If you have a sterile area changing room, which is a nice long changing room like they quite often are, make sure the
air flow is from the clean end to the dirty end, not vice-versa. It is amazing, that sounds quite obvious. But frequently we don’t see that.
Make sure it is big enough, so that if there is somebody my size or bigger hopping around on one foot trying to put on a sterile suit, they
are not crashing into the wall or other operators. Make sure it is big enough for what you are doing.
Be aware that Annex 1 actually talks about having a separate changing room for coming out as well. That is quite nice to have. It is not
a must have, but it is a good idea to have thought about it. I think what happens with sterile changing rooms is everyone designs the
sterile area and they can fit all of their equipment in. Just about, but it is not quite big enough so they push the wall a little bit further,
and you end up with a changing room that is just not big enough. So think about that.
• Goods receipt areas of insufficient size: Probably a similar [issue] for goods receipt areas. Frequently we go to a goods receipt area
and it is piled high because unusually for the day of the inspection they have had more deliveries then they would normally have any
other time of year. And it is piled high with stuff, and then you find the quarantined stuff is actually in the non-quarantine rack.
Supplier And Raw Material Control
• Insufficient assurance of supplier adequacy: A hot topic at the moment. Obviously we have seen some real issues coming out of
China. You need to make sure that your raw materials are of appropriate quality.
• No evidence that APIs have been manufactured to GMP: Your poor old QP who is legally responsible for all of this makes a decla-
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ration that you are in compliance with GMP, and that the API used is in compliance with GMP. So make sure that he or she actually has
the evidence to make that statement.
• TSE risks inadequately controlled: That again is quite common for us over here. You need to understand that in the UK specifically,
TSE is a really highly perceived, politicized risk – way beyond any scientific support. You need to be aware of that. So you need to have
a policy that says how you deal with TSE risks certainly if you are dealing with the UK and with the EU as well. There is a guidance now
that you need to follow [SI 2003/1680; CPMP NFG 410 rev2]. Anything from cows – make sure you have a TSE statement for; if your
tallow in your punch room is not TSE certified, that you know whatever it has come from.
• No vendor recertification or secondary/backup to suppliers: So that is quite common as well. You go through your approval process, you approve your supplier, and then you do nothing. You just leave him on your supplier list for the next 10 years without ever
going back, without sending them a questionnaire, whatever. So you need to have a follow-up mechanism for making sure you revisit
these people.
• No system to address problems with suppliers, e.g. audit or increased testing: You have this system: The first three deliveries
have to be fully tested, then you move on to the reduced testing regime. What happens if you have a problem? You need to have in that
same procedure something that says ‘if we have a problem with the supplier, we are going to reevaluate the testing regimes’ – so how
you deal with that. ‘We might even remove them from the listing.’
• Poor sampling facilities: A colleague of mine was in North America but not the U.S. and he saw a sampling facility for a sterile site.
The sampling facility was literally just a room off a warehouse. There was no local extraction, there was not pressure differentials. They
were sampling their vials in the warehouse – just opening up the trays and taking out a vial from the trays. You need to think about how
you protect the products. Although you may not need to classify that area, you need to make a GMP cleaning area and then you may
need to monitor that area.
• Insufficient identification testing (Annex 8): Again, quite commonly in the U.S., everybody is using square root plus 1. We don’t
accept square root plus 1. Annex 8 says that you must sample every container for identification purposes. That is the starting point. It
does allow you the leeway for moving away from that if you have validated systems and audited suppliers, etc. But our benchmark starting point is that you have to sample every container for identification purposes.
Potential For Microbial Contamination
• Poor clean room and aseptic practices
• Materials passed into sterile areas with insufficient sterility assurance
• Inappropriate transfer of partially sealed vials to lyophiliser
• Inappropriate handling of vials prior to oversealing
• No program for routine drain sanitization
Environmental Monitoring
• Wash bays, cold stores and water systems not monitored microbiologically
• No monitoring during or following building work
• No viable monitoring close to point of fill for aseptic products
• Poor handling and positioning of settle plates in critical zones
• Poor or no continuous particle monitoring in critical zones
• No assessment of recovery or growth promotion
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APPENDIX III
PAREXEL CONSULTANT DAVID CHESNEY ON FORCES IMPACTING FDA ENFORCEMENT
At a conference on GMP inspections in late March sponsored by the University of Rhode Island, PAREXEL Consulting
Strategic Compliance Services VP David Chesney discussed some of the factors that could influence inspection
policies and GMP enforcement in the near term. Factors discussed include: • the new administration • key FDA
positions being filled • foreign offices • investigator hirings • Q8-10 • criminal actions • Turbo EIR, and • new FDA
guidances. Chesney’s presentation reflects the depth and breadth of his career in the FDA field force and afterwards
consulting with industry management on compliance problems firms are facing.
A New Administration: Change and Peanut Butter
I was asked to talk about what there is in the crystal ball that we can look at that might be useful to understand or know about going forward
in the near future related to inspections. We could talk about future casting of FDA trends probably all day here and come up with a panoply
of different things involving the emergence of new technologies and where medicine is going and just a whole variety of things. But if you boil
that down to what is really close, maybe appearing on the horizon now, and is specifically related to inspections, the world starts to shrink a
little bit….
Two big factors: One that we have been hearing about through this long election year, and that is the general topic of change. That was the
theme, if there was one, to this whole political process that we have just lived through. And the other one, believe it or not, is peanut butter.
And I will say some more about that as we get into this.
[FDA Minneapolis District Drug Expert Investigator Sharon Thoma] mentioned something about the continuing resolution and the FDA budget
and where the resources are coming from. One of my favorite quotes when I was in the government and I didn’t have to worry about revenues
so much as I do now is the line: ‘No one’s life, liberty or property is safe while the legislature is in session.’ That has been attributed to a lot
of people [including] Benjamin Disraeli, the former Prime Minister of the U.K. Of course, it was rendered a little bit differently in the version
attributed to him: ‘No man’s life, liberty or property is safe whilst the parliament is in session.’ That is kind of how you feel when you work for
the government. You are just really not sure what Congress in its beneficence is going to do for your budget. A little bit different story in the
private sector as we know. But when you are in the government, you have that hanging over your head all of the time.
So now we have a new President… elected on a slate where he has promised a lot of change. He has two absolutely beautiful children that
he has brought into the White House. And he wakes up and the young one is going off to school with her Hanna Montana lunch box with a
peanut butter sandwich in it. And he starts reading the newspapers and says ‘hmm, that might be a salmonella-contaminated peanut butter
sandwich.’ How would you feel if you were a new President elected on a platform of change? So he goes on the Today Show on February 2
[which generated the following media report:] “President Barack Obama is ordering a complete review of the Food and Drug Administration. In
an interview that aired Monday, Obama said the ‘agency’s failure to recognize and intercept the peanut butter was only the latest of numerous
instances over the last several years in which the agency has not been able to catch some of these things as quickly as I expect them to catch
them.’’’
Every new administration that comes in says something along that line. They always tend to order a clean sweep. This one is no exception. But
those of you who have been around this agency and industry for a number of years know the history of FDA is always linked to major change
happening in reaction to crisis. If you go back to 1906, the Pure Food and Drug Act, it was the muckraking book ‘The Jungle”….Then we had
the elixir sulfanilamide crisis and we got the 1938 act. Then thalidomide and we got the Kefauver-Harris amendments. Then in the early ‘80s,
we had the Tylenol tampering business and we got tamper evident packaging, and we got the modifications to the general criminal laws in the
United States to make tampering of consumer products a serious felony, and so on.
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Whenever there have been these times that have galvanized public opinion, those are when the real times of change have happened at
FDA. We are in another one of those times – witness heparin, witness toothpaste, witness diethylene glycol, witness peanut butter. All
these things tend to coalesce around the notion that FDA is not doing its job. And that is not necessarily a judgment against the agency
or the people, because FDA generally enjoys a pretty good reputation with the consuming public and deservedly so. But it does reflect a
concern that the agency is not able to do what it is capable of doing because of lack of resources or the way it is structured or some other
reasons.
The conventional wisdom is that the Democrats don’t like the industry and they are more for big government, so whenever we get a
Democratic administration, enforcement is going to go up and FDA is going to get tougher. And when the Republicans come in, we are
going to see the opposite effect. Yeah, sort of – in the number of years that I have been doing this there is probably some general truth to
that. On the other hand, the strongest enforcement-oriented FDA commissioner I lived under was probably David Kessler. But he was a
Republican. People tend to forget that. They associate him with Clinton. But he was appointed by Bush 1, and Clinton kept him. He actually
had served as a staffer for Orrin Hatch, who is not exactly a liberal.
So when Kessler came in, he arrived as a Republican. He ended up being one of the strongest enforcement-minded Commissioners that
the agency has had. Remember the seizures of fresh orange juice that wasn’t really fresh? I think those of us in the agency thought the
man was nuts when he did that because there were so many other important priorities.
But you know there was a very Republican reason why David Kessler was so enforcement oriented. He wanted to restore the public’s
confidence in the strength of the agency’s enforcement mission so that other reforms like PDUFA and expedited approval could be put in
place without the public worrying that the agency was in the pocket of the regulated industry. He felt that if the enforcement component
was strong, the public would be more supportive and more willing to let FDA experiment with reforms that would actually benefit the
industry. Interesting how he made that connection. I actually heard him say that at private meetings, explain the whole thing. I found that
to be a very interesting public policy position that he took.
Key FDA Positions To Be Filled
There are some key positions now technically vacant at FDA that when filled will have some impact on the inspection and enforcement
tone moving forward. These are ones you should watch.
The first, of course, is the commissioner. We now have Margaret Hamburg from the New York City Health Department, who has been put
forth as Obama’s nominee for commissioner. [Editor’s Note: Hamburg was confirmed by the Senate in May as FDA Commissioner.]
She has a very interesting and very strong bio. She does have a very strong enforcement track record. She is a physician as most
commissioners over the years have been – not all, but the majority. Her particular background, I believe, is infectious disease. And she
has a lot of connection with the food side of things – more than most commissioners have had in the past. Most have been more from
the pharmaceutical side of things. But she has more of a food safety-oriented background. The deputy commissioner was the other front
runner for the top job – Joshua Sharfstein, city health director from Baltimore. He is more pharmacology oriented.
So some have speculated, is this a precursor to splitting FDA into two entities – a single food agency and a drug and device agency
somewhat akin to what we have with the MHRA in the UK? Hard to say. I don’t think we know if that will happen. I know it has been
talked about forever. The earliest memory I have of that kind of discussion was probably from 1973, when the Consumer Product Safety
Commission was cleaved off from FDA, created as a new stand-alone agency. So things like that have happened. The Drug Enforcement
Administration, if you go back many years, was called the Bureau of Narcotics and Dangerous Drugs. And if you go back before that it was
called the Bureau of Drug Abuse Control (BDAC) and it was part of FDA. So if you trace the history of what we now have as DEA far enough,
it came out of FDA. So there is precedent for that. Are we on the cusp of that kind of change? Don’t know. What would the implications be
for inspections going forward? Hard to say, but those are interesting things to watch.
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Also within the FDA, watch for a permanent appointment as the chief counsel, the agency’s top lawyer. Gerald Masoudi recently departed
that post, a Bush Administration appointee. On his way out he said what all lawyers leaving that post always say, something to the effect
of: ‘We don’t decide the enforcement priorities for the agency. We are just the lawyers. The agency is the client. They are in the driver’s
seat.’ Not exactly – not in my opinion and not from my experience. The influence of the Office of Chief Counsel is extraordinary on the
enforcement process. They have to support it. Right now if you get a warning letter, before it is sent to you it has to be cleared by the Office
of Chief Counsel. So I am not going to believe that they are just kind of innocent bystanders making sure that all the legal niceties are taken
care of. They are hugely influential internally, and their advice is excellent, and there are some brilliant attorneys in there – some people
who have devoted their whole lives to this who are really good, and they do and should have some influence on the process.
Likewise the top position for the field, the Associate Commissioner for Regulatory Affairs, I believe is still in an acting capacity, Mike
Chappell. So that hasn’t been filled. Recently, David Elder….has been moved over from the Office of Enforcement within ORA to fill the
Office of Regional Operations slot. It is kind of like going from QA to manufacturing, if you want to look at it that way. It is a lateral move for
David. But the Office of Enforcement is a very strong unit within the Office of Regulatory Affairs and really has pan-agency responsibility
for enforcement policy as opposed to legal interpretation.
So as these positions get filled and the people and the type of thought process and the attitudes that they bring to the job become more
clear, we will see that reflected, I am sure, in the change that the current administration has said they want to bring to the process. Exactly
where it is going to go we don’t yet know, but we can make some pretty good educated guesses.
Foreign Offices Will Have Impact
On the foreign side, FDA has recently established offices in China…in Beijing, Shanghai and Quanzhou [see the Nov./Dec. issue of IPQ,
p. 20]. A friend of mine who began his FDA career with me in the same district office almost 37 years ago, Mike Kravchuk, has been
appointed as the deputy director in China. He is not the country head there, but he will be over the investigators that are going to be
stationed in China. This is not a huge operation going over there. You are talking about just a small group of people, but nevertheless a
presence.
So the activities in China and eventually in India will increase as companies move operations over there and as Chinese and Indian
companies begin to penetrate the U.S. market. And believe me they want to. I have been spending a fair amount of time in South Korea
lately and I just came back from Shanghai last February. I talked to a lot of companies over there, visited the high tech park in the Pudong
area of Shanghai. An enormous number of companies are there. Some of them are local in-country places, little biotech firms and such,
others are large and sophisticated firms... Anyway, they are over there and they would love this part of the market. And they are working
hard to understand what they have to do to get there.
New Investigators And The Learning Curve
Within FDA, there is a generational change taking place. Guys like me are retiring, or going off to being consultants or working for [industry]
or doing something else with their lives, and FDA has lost a lot of key leadership positions over the last few years. That is okay. That
happens all the time. That is as it should be. It is somebody else’s turn to come in and take the reins. And as that happens, once again
they will bring fresh ideas and new approaches. They will be confronted with challenges that those of us who were there a few years ago
didn’t have to face. And that is going to create some change obviously.
One of the more immediate factors is [the number of new investigators – including, as Sharon Thoma noted, 42 in her Minneapolis District].
Do you think you might see a few newer people showing up to inspect your company who don’t have a lot of FDA experience? Sharon and
I were talking at the break this morning, many of these folks are very well qualified – probably have a level of academic preparation that
is outstanding. But if any of you went to work for FDA, you would have a huge piece of that job that you don’t really know anything about,
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which has to do with the agency’s own procedures, how to conduct inspections, what it means to develop evidence (because your work
may be needed to support litigation). There is a whole part of the job that you have to learn. So those folks are going to be on a learning
curve for a while.
To some extent, those of us in the industry may find ourselves ‘training’ the new people for a while. That certainly happened to me. When I
was new, I owed quite a debt to some people who were in the industry at that time. They were very tolerant of my early fumblings. [MHRA
investigator Andrew Hopkins] told us the other day that he came to his job with 20 years of experience, but… had to start as somebody
who was not fully accredited until he learned the job. And that is what is happening right now. So in the near term, you are going to have
a greater likelihood of seeing FDA investigators who are still figuring out what it means to be in that job….
ICH Q8-10 Will Influence FDA Expectations
Looking at the international scene: As we mentioned yesterday when we were talking about Phase 1 clinical trial materials, they are
subject only to the statutory standard for GMP and they are governed by a guideline rather than a regulation. That has been the case for
API right along. The GMP regulations are for finished pharmaceuticals. But ICH Q7 has been accepted and even adopted as a rule of law
in a number of countries around the world, and has become over time pretty much the default international standard for GMP in the API
industry. Even if it doesn’t enjoy the status of a regulation in the United States, it has a highly influential positioning.
I think what we will see in the near future is a similar effect with ICH Q8 plus the annex to that document, Q9 and Q10 having more and
more influence on FDA expectations. You know FDA can’t enforce an expectation only a regulation. But nevertheless the expectations are
important, because what they do when you are an investigator, if you have an expectation and it is not met, while you may not be able
to enforce that as a deficiency, that serves in your mind to be a predictor that there will likely be deficiencies if you dig a little further. So
when the expectation is not met it may prompt you to look further, spend more time, look for the effects of the expectation not having been
met and link those back to what are hard and fast requirements. So I think we will see increasing influence of this triumvirate of new ICH
guidelines.
Certainly the influence of international inspectorates within the U.S. is going to increase, and FDA is going to increase its presence
and influence abroad…. Look for more and closer cooperation between FDA and its international counterpart agencies. I think this is
something that will undoubtedly happen. It has already in fact taken place.
Criminal Actions May Increase
On the enforcement side, I will stick my neck out and make a prediction: I think we are going to see FDA bringing more criminal prosecution
cases. I don’t think it is ever going to return quite to where it was in the 1970s and before when FDA established policy in the areas for
which it is responsible largely through bringing cases and development of case law. The agency years ago shifted out of that mode and
began making that policy through notice and comment rulemaking, through regulations. But when I was a new investigator in 1972, a
lot of what was important to us then to understand is what did the precedent cases say? Many of those were criminal cases. In the early
days of my career, we criminally prosecuted people for having too many rats in their warehouse. That was the way you went. Nowadays,
it is consent decrees of permanent injunction or consent decrees to resolve product seizure actions. It has been on a different footing for
a number of years.
I think we may see more criminal prosecution cases. I think it will still be highly selective, but the influences are the public outrage and the
demands for accountability that we are seeing for companies and executives stemming from the economic crisis and related scandals in
the financial world. I think it all began with Enron, and it has kind of been snowballing ever since. And certainly we are hearing that now.
Listen to the news – when they talk about Bernie Madoff or the people that got the bonuses at AIG, what are you hearing? It is that kind
of time in which we live where for FDA to return to criminal prosecution as a more frequently used tool may be more acceptable in the
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public’s mind and in that of the U.S. Attorney’s Office and the judiciary than it has been in recent years.
A couple of recent examples: May 2007, Purdue Frederick. Three executives were criminally prosecuted under the strict liability doctrine
for misbranding of oxycodone. Now this was not a GMP case. Misbranding is labeling related. In fact, the details in this case were that they
were alleged to have wrongfully promoted their particular version of this narcotic as non-addictive or less addictive than everybody else’s,
which was a false and misleading claim.
What is strict liability? Under the U.S. Food and Drug Law there is something called the doctrine of strict liability. Yesterday [MHRA
investigator Andrew Hopkins] mentioned that if something goes wrong in the U.K., the QP can go to jail. It doesn’t happen very often, but
that is where the ax falls. Well in the U.S. it is the CEO. Even if he or she knows absolutely nothing about the violations and didn’t intend
for them to happen, under strict liability doctrine, the higher up you are in the hierarchy of the company, the bigger target you have on your
chest. So it works a little differently here than it does in Europe.
So these three executives were criminally prosecuted for acts of the corporation, because FDA’s longstanding enforcement position
has been that companies are not disembodied entities. They act through the actions of individuals, or they fail to act properly because
individuals fail. So they went after the individuals in that case.
Also there has been a large-scale criminal investigation involving Peanut Corporation of America. If FDA can get its hands on the people
that are responsible for the heparin matter, I am sure they would have some things to talk about. Other somewhat recent criminal
prosecutions, this one goes back a little ways, but the endovascular technologies case in San Mateo California involving [an] abdominal
aortic aneurism stent, where the company was accused of lying to FDA about the number and severity of adverse events connected with
that product. They were criminally prosecuted. They went under what is called a corporate integrity agreement with the HHS Office of
Inspector General, plead guilty to the charges of lying to the government and paid a $92 million fine.
So these things do happen, and I would not be surprised if we see more examples of that in the current era that we find ourselves in. In a
couple of the plea agreements in the Purdue Frederick case, they even mention specifically: ‘I will enter a plea of guilty to count 2 of the
attached information charging me with the strict liability misdemeanor offense of misbranding a drug.’ So here is an individual that didn’t
even fight it – plead guilty and right in the guilty plea mentions the fact that this is on the grounds of strict liability, meaning that by virtue
of the position that he held in the company he was responsible, by definition, for the acts of the company.
Think your senior executives don’t need training? Think again. When I do training for corporate suite level people, we talk about strict
liability, because it is personal when it comes to that, at least in this country – maybe not in other countries, but here it is a big deal. These
pleas were entered in May of 2007, fairly contemporary cases. I wouldn’t be surprised if we see some more of them….
Turbo EIR Data Has Limitations
When those kinds of things [like contaminated peanut butter] happen, the public in this country gets pretty excited, and this creates an
environment where it is easier, in fact it is imperative, for FDA to start thinking about how they are going to do business differently….
I would look in the near future to see both the numbers of inspections go up, the number of OAI [Official Action Indicated] classifications go
up, and very likely the number of enforcement actions as well. In our practice, we work mostly with clients who have some sort of problem
with the agency – a warning letter, a regulatory meeting, a failed preapproval inspection or worse – and our business is picking up. While
everybody else is kind of struggling to keep their heads above water, we are already noticing this effect. We are getting more calls, we are
getting called in by law firms. And it is not just us. I am sure our competitors that work with us in the same space are seeing the same
thing. So we are anticipating an increase in that....
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The question was asked about why are we always seeing the same things [in the FDA inspection findings] year in and year out. Well one
reason is that under the quality system approach that FDA has, the quality system is always looked at. It is a mandatory component of
every inspection. So due to the fact that they are looking at that more often, you would expect that there are going to more violations, just
as a one-to-one correlation.
The other thing is the impact of this Turbo EIR tool, the Turbo Establishment Inspection Report. When you use Turbo, you have an
observation… you go into Turbo, you pick the CFR section and it gives you this boilerplate wording that says that the quality unit didn’t do
the right thing, and then you give your specific example of what you actually saw underneath that. If you look at 483s, sometimes it is a
stretch to make a connection between what was actually observed and the citation that the investigator happened to pick that generated
the boilerplate wording….
The [FDA inspection] numbers come from the Turbo EIR database. So what we get is a situation where the devil is in the details, and a lot
of these things about the quality system or the quality unit being inadequate are things you get to by two or three steps: Because we found
this problem over here in the corner in that part of the operation, and it is a real problem, obviously there must be an ineffective quality unit
because if there was an effective system, this wouldn’t have happened. So it is not a per se evaluation of the quality unit itself, saying it
is inadequate. It is saying, ‘something happened over here. Because that happened, clearly the quality unit wasn’t minding the store.’ So
it is kind of difficult to go from the statistics that Turbo gives you to really what happened here. And I have rarely seen the numbers sliced
and diced down to that level of detail. And frankly I don’t think you can, because I don’t think they can save [the information] in a way that
makes it very easy to do that.
Turbo EIR has only been officially in use since about 2002… It doesn’t capture API manufacturers either, so there are some limitations.
But the whole concept of Turbo EIR was born in the mid-90s when I was still with the agency… [in the interest of] creating a database. It
took a while to become institutionalized within FDA. The idea behind it was that wouldn’t it be nice to be able to do trending, just as the
industry does trending on the things they find, on inspection observations. [The thought was] that if we are going to create something with
a database, maybe we can figure out a way to make the wording more uniform and get more consistency and uniformity across 483s, and
we could actually take that from the computer and lift it from the body of the report and save a lot of time, be more efficient. They began
working along those lines, and the result ultimately was Turbo, which does a good job on a lot of levels, but it does tend to fog what is
really going on sometimes. In order to really truly understand a Turbo citation, you have to look at the specifics that the investigator has
written down there, and then you are getting somewhere.
New GMP Guidance
Some of the more common everyday things that we may expect to have some influence on us in the near future: The preapproval
inspection compliance program is, we hope, close to reissuance, at least we have been hearing that for some time. It is expected to be in
a form more closely linked to the systems-based inspection approach, so there should be a little bit more cohesion between the PAI and
the general GMP.
Further drafts and final guidance documents are also in the works that will probably have some impact: Clinical trial materials other than
Phase 1 – there is already a guideline on that. The new validation guidance came out recently. There were some changes to the GMP
regulations last September…. Minor editorial changes for the most part were made to the GMPs…. So it is a moving target. You have to
keep your eye on the GMP ball all of the time.
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APPENDIX IV
CDER COMPLIANCE OFFICIAL JOE FAMULARE ON RECENT GMP INJUNCTIONS
The following is a discussion by CDER Office of Compliance Deputy Director Joseph Famulare of recent cGMP/
unapproved drug-related injunction actions. At an ISPE conference in Washington, D.C. in early June, Famulare
discussed the injunctions as case studies in the failure of the quality system and the cost of not implementing the
principles in the ICH guidelines Q8-10. He did not specifically name the firms involved, but the cases fit the injunction
actions at KV (March 2009), Actavis Totowa (December 2008) and Advent/Neilgen (April 2009), respectively, which
are analyzed in this issue of IPQ.
[Pfizer Executive Director Roger Nosal] talked about what is the value of QbD and what is the investment. I thought I would talk about some
recent quality system failure enforcement case studies to show the expense of not being able to fully implement these tools….
[The diagram provided in the Q8 annex defines] how GMP works with the quality system, going back from development through discontinuation
of the product – so the important emphasis of development and how the quality system applies there going through the whole lifecycle of the
product….
Our GMPs are minimum standards. What we did with Q10 is to try to augment the GMPs by describing the pharmaceutical quality system
throughout the lifecyle of the product. It is intended to be used together with regional GMP requirements – again, as a basis to see how GMPs
and quality systems are meant to work hand in hand.
Injunction Case Study No. 1 (KV Pharmaceuticals)
Now going through some of these case studies and some of the problems: Of course, this is the type of publicity a company does not
want when we file a consent decree of permanent injunction. The only success is that the case has been settled when a consent decree is
announced, and we want to lead down a path of finding corrections to the problems a company has had.
Here you just see a brief snippit from an FDA press release about such a situation where a company was shipping what we call ‘adulterated’
drugs – also some that lacked approval.
Delving into some of the GMP areas: Obviously they violated sections of the Act, and there were serious nonconformances with GMPs,
demonstrated by inconsistent manufacturing practice and processes, numerous manufacturing problems – poorly controlled equipment,
dissolution failures and content uniformity failures. The firm also manufactured and distributed unapproved new drugs.
So when we think about the cost of quality, some of these negative factors are really costly to a company. And here are some graphic
illustrations about what this lack of quality had demonstrated.
These are some opiate-type tablets that the company manufactured. You can see clearly, with lack of process performance and product
understanding, when they went to commercialization they really [don’t] know how to control their process. What you can see pretty clearly
is that, yes, these are all meant to be the same dosage forms, but through what was meant to be a consistent process, they were producing
different size tablets, and when analyzed, some of these analyzed out in the 140% range of opiate-type products. Some of these resulted in
Class I recalls, some of these in Class II’s.
So what happened from development, tech transfer and manufacturing? What are the key quality issues that were lacking here? Did they have
a good understanding of the flowability, the operation of the tablet press? We are still waiting for the answers on these.
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Some key milestones as to the cost of quality for this company: After an increasing crescendo of problems, a comprehensive inspection
was begun, and before the inspection was over, every product that the firm had on the market was recalled. That is what little confidence
there was in quality. By the time the inspection was over with, we were into having a complete shutdown, signing of a consent decree, until
such time as the firm can produce products of sufficient quality to meet the GMP requirements. So here is what the costs were.
What we did in analyzing the situation is try to look at some of the [cGMP] problems that were cited in this particular situation [and relate
them to the missing pharmaceutical quality system (PQS) element]:
• The failure to follow the responsibilities for the quality control unit [211.22(d)], and relating that to the quality system element of
management review.
• Having manufacturing processes that caused quite a bit of variability as you can see in those previous graphic illustrations
[211.110(a)] – where was the process performance and product quality monitoring system? Maybe it was already too late given
some of the development problems.
• Failure to review and approve changes to written procedures by the quality control unit [211.110(a)] – change management
system.
• Failure to follow written production and control procedures. Our famous or infamous validation cite [211.100(b)] – the process
performance and product quality monitoring system failed.
• Reviewing and approving drug product production and control units by the quality unit and determine compliance with all approved
procedures prior to release [211.192] – CAPA.
• Failure to have documented investigations. What happened when they had failures? Well, they made some changes which we said
were poorly controlled and still had problems [211.192]. So again the CAPA system was not working at all – not getting to root
cause.
• And failure to clean, maintain and sanitize equipment [211.67(a)] – process performance and product quality monitoring system.
So you can see the real relationship of not having a robust quality system, let alone meeting the minimum GMP standard.
As I showed you, a consent decree was signed quickly. And the consent decree itself had to reinforce the need to establish systems to
assure sustainable compliance to GMP. Again, here is the FDA in a court-ordered document trying to bring a firm into quality and a quality
system – not an efficient way either for the regulator to do business.
In this particular instance, part of that press release were quotes by Dr. Woodcock emphasizing the need for companies to comply with
GMPs and approval requirements, and that consumers need to be confident that drugs meet our manufacturing requirements for identity,
strength, purity and quality, and have been evaluated by the FDA for safety and efficacy. So you can see the challenge that we face in trying
to explain to consumers who expect that their drugs are of sufficient quality for use, safety, etc. – having to have such a massive recall
and a major company having to shut down.
Injunction Case Study No. 2 (Actavis Totowa)
The second case study really followed a very similar path… resulting in a consent decree on Dec. 23 of last year involving the company
and their officers for failing to follow GMPs. This firm already had received two warning letters, and the quality system inspection in March
of last year found: no corrective actions were taken to address previous GMP deficiencies; widespread GMP [problems] involving product
quality and analytical method deficiencies; and lack of quality management infrastructure or oversight.
Again this is another extreme case – all 48 products manufactured and distributed by the firm from its facilities were recalled.
I won’t go through all of these, but the issues are now starting to sound familiar: not having management and procedural controls; the
MAY/JUNE 2009
43
ability to investigate – to conduct investigations and to write them up where there were batch failures and unexplained discrepancies
– looking at how they extend to other batches; laboratory controls that didn’t include the establishment of scientifically sound test
procedures; written production and process controls were not followed; and execution of production and process control functions.
Again, briefly in this chart we have related [the cGMP deficiency to the missing PQS element]:
• The failure of the quality control unit [211.22(d)] to management review.
• Validated steps in the process in terms of reviewing/approving those changes [211.110(a)] under the change management
system
• Failure to follow written production and process controls [211.100(b)] – the process performance and product quality monitoring
system
• [211.192] – poor CAPA controls as I mentioned in the previous example
• And equipment sanitization and use problems [211.67(a)] – process performance and product quality system problems.
So you can see how we are challenged day by day and spending our time in the failure mode, and how we need to adjust to upfront
quality.
The consent decree was signed and entered into by the firm, basically stopping all operations until they comply with U.S. law and GMPs.
Interesting when you look through a court-ordered decree, the defendant would have to establish and document management controls
over quality assurance and quality control for the firm’s facilities. It also mandates that QA and QC be vested, and the individual should be
authorized and include establishment and implementation of quality assurance and a quality control program – all things that should be
done, but now under a court-ordered decree. And again the company will have to complete a comprehensive corrective action program
before manufacturing operations would be able to resume.
Case Study No. 3 (Advent Pharmaceuticals/Neilgen Pharmaceuticals)
One more case study: This one is interesting because it had a parent company and another facility in two different states. But the end
result was the same: barring the distribution of adulterated and misbranded drugs. The company had quite a number of unapproved
drug products in its list of products that they marketed – again [raising] the problem of not even having any sort of review for safety and
effectiveness prior to approval or adequate directions for use on the label.
Again the regulator, FDA, had to spend quite a bit of time through multiple inspections looking at numerous and recurring violations of GMP
requirements, and continued manufacture of unapproved drugs. And both of these firms, which were under one corporate umbrella, did
not respond adequately to FDA’s inspection findings.
What was interesting about this is that since 2001, FDA had issued two warning letters and conducted six inspections at the parent firm
– one warning letter in 2001, one in 2006. What was going on is that as we found a particular problem or a particular set of products that
were problematic, the solution was rather than to correct them, move them to the other facility. So we were going back and forth. FDA
had conducted five inspections of the subsidiary company. So the first warning letter in June of 1998 occurred there. They didn’t correct
the things by 2000. And then in 2007 we were back there again finding significant problems. And again some of those unapproved drug
products in the warning letter from the parent company ended up in the subsidiary company.
So this is starting to sound like a familiar theme now – the failure to implement basic GMPs and how they relate to the pharmaceutical
quality system elements:
• Review and production records (noting errors) and having proper rejection and approval procedures [211.22(a) & (c)] – process
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MAY/JUNE 2009
performance and product quality monitoring system.
• Lack of annual product review [211.180(e)(2)] – relating that to management review.
• Lack of responsibility in the quality control unit [211.22(d)] – again related to management review.
• Failure to have really good validation programs and to validate in process controls [211.110(a)] – process performance and
product quality monitoring system.
• Lack of controls over computerized systems in terms of changes made [211.68(b)] – failure in the change management system.
• Equipment cleaning and qualification [211.67(a)&(b)], calibration programs [211.68(a)], and also written procedures for warehousing
of drug products [211.142(b)] – so again, very common theme of the process performance and product quality monitoring system
failure.
• Establishing the reliability of suppliers in raw materials received [211.84(d)(2)] and following written procedures for storage
conditions [211.142(b)] – process performance and product quality monitoring system
• And also having an adequate number of qualified personnel in order to conduct operations [211.25(c)] – management review.
This time we finally got a handle on both firms and sought a permanent injunction for repeated history of GMP violations, failure to
comply with previous warnings, avoiding enforcement actions by moving things back and forth as I mentioned earlier, and continued
manufacturing of drugs in violation of the law. Both firms did sign a consent decree in April of 2009.
International Pharmaceutical Quality™ (ISSN 1937-6898) is published by IPQ
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international pharmaceutical quality

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