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Inside the Global Regulatory Dialogue


VOL. 5, NO. 3


Drug GMP Warning Letters from 2012 Q1 2014 Show FDAs Enforcement Focus Shifting Overseas:
Foreign Labs Draw Particular Attention.............................................................................................................3
FDA Data Integrity Findings Continue at Indian Firms, Highlighting Challenges in Changing a
Facilitys Quality Culture.....................................................................................................................................19
Component Testing Gains Prominence in Drug Product GMP Warning Letters as FDA Focus Intensifies on OTC Topicals and Upstream Supply Chain.........................................................................................30
Wave of FDA Warning Letters to Injectable Compounders in Q1 2014 Follows 2013 Inspection Blitz
and Legislative Empowerment; Recipients Among Those Applying for Outsourcing Status..................36
Comments on FDAs Draft Compounding Guidances Reflect Complex Factors and Varied Stakeholders Involved...................................................................................................................................................40
Compounding Drivers and Problems Dissected by Merck Pharmacy Expert at April PDA Annual

ICH Q8-11 Oriented Submission and GMP Expectations for Process Validation and Other
Quality Issues Taking Shape in Europe..........................................................................................................50
U.S.: Comments on NDA/ANDA Processes Global Ingredient Archival System BA/BE Draft Guidance Vial
Overfills Orphan MAb Sameness ISPE Metrics Pilot Geo-spatial Mapping
EUROPE: Drug Approval Fast Track Sterilization Processes Variation Stability Requirements UK Biologics
Research Center MHRA 2014-2015 Business Plan Advanced Therapies Regulation Post-authorization Q&A
EDQM CEP Policy EDQM Anti-Counterfeiting Database Applications/Advice Procedures Immungenicity
Concept Paper GDP Q&A Quality System GMPs
INTERNATIONAL: Brazil Withdrawal Notification EMA/TGA Orphan Drug Collaboration FDA/EMA QbD
Initiative WHO Hold Times

2014 2014
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Bethesda, MD 20814

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Warning Letters from 2012 Q1 2014 Show FDAs GMP Enforcement Focus
Shifting Overseas; Foreign Labs Draw Particular Attention
An analysis of FDA drug GMP warning letters issued since
the beginning of 2012 highlights the agencys increasing
focus on enforcement outside the US and on laboratory
practices at foreign facilities, in particular.

FDAs current budget proposal indicates that its effort to

beef up enforcement abroad is accelerating. To achieve
greater parity, the agency is projecting a significant shift in
resources from domestic to foreign drug GMP inspections
beginning in FY 2014.
FDA is targeting a 40% reduction in the number of routine
domestic GMP inspections (not including pre-approval)
from 967 in FY 2013 to 591 in both FY 2014 and FY 2015, and
a 30% increase in foreign GMP inspections from 604 in FY
2013 to 843 in each of the two succeeding years.

Foreign API, Topical and Injectable Letters

Outpace Domestic
The 2012 through Q1 2014 warning letter numbers would
have been even more skewed toward the international arena
if FDAs inspection crackdown on large scale injectable
compounders in the US had not been in full swing in the
wake of the meningitis crisis that surfaced in the fall of 2012
(see IPQ Special Report November 2012, and story on p.
Altogether almost 20% of drug GMP warnings issued in
this timeframe went to sterile compounders across the US,
including nine of the 11 that went out in Q1 2014.
The early-2014 bolus reflects the passage of the Drug Quality
and Safety Act (DQSA) late in 2013. The compounding
provisions of DQSA in Title 1 of the act clarified and
strengthened FDAs ability to take enforcement action










Finished Dosage Form Manufacturer

















The roadmap for an increased enforcement effort overseas

was laid out in FDAs Beyond Our Borders initiative
(see IPQ Monthly Update September 2011, pp. 27-34), and
given further support by the passage in mid-2012 of the FDA
Safety and Innovation Act (FDASIA), and its generic drug
user fee and supply chain provisions, in particular (see IPQ
Monthly Update January 2014, pp. 13-20).

Number of Warning Letters

In 2012, for the first time, foreign warnings began

outpacing those issued domestically. Between 2012
and the first quarter of 2014, 47 drug GMP warning
letters were issued internationally compared to 43
in the U.S.

GMP Warning Letters, 2012-Q1 2014


against the large-scale compounders on both CGMP and

drug approval non-compliance grounds. The act also defines
a new outsourcer category, which will give those that
qualify relief from the drug approval and labeling rules, but
not from relevant drug GMP requirements (ibid.). Title 2 of
DQSA sets up the ground rules for establishing a tracking
and tracing system for prescription drugs.
As would be expected, weighted particularly
heavily on the international side were the warning
letters that went out to API manufacturers 12 out
of 15 of these addressed foreign facilities. However,
notably, warning letters were also more numerous
abroad to finished dosage manufacturers making
both injectables (11 of 17) and topicals (14 of 22).
Surprisingly, topical manufacturers have been the leading
target of warning letters since 2012 eclipsing in number
those issued to oral, injectable and API manufacturers (see
story on p. 30).
The compliance attention on OTC topicals in the recent
warning letter data reflects, in part, FDAs ongoing effort to
get non-monograph-compliant/unapproved drugs off the
market an effort that has been expanding abroad, as the
warning letter data indicates.

India Plants Flagged by FDA and EMA

An analysis of the foreign letters by country shows that
India received nearly 30% of the letters issued abroad (13 of
48), while Canada was second with 12%, and Mexico third
with 10% (see box below).



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Nearly half of the Indian firms receiving letters produce APIs.
Sharpening FDAs enforcement focus on India has been the
recurrent findings of data integrity issues at Indian facilities
(see story on p. 19). Of the 13 warning letters issued to
Indian plants since 2012, seven specifically address a lack of
integrity of their records, procedures, and/or interactions
with FDA investigators.

Foreign Warning Letters 2012-2014

The following is a breakdown of the foreign drug GMP
warning letters issued from 2012 through Q1 2014 by the
country where the facility was located. Countries in which
only one letter was received not included below were
Australia, Austria, Denmark, Ireland, Italy, Jamaica,
Poland, Serbia, and United Arab Emirates (UAE).

accounting for 14 of the 34, or about 40%. China was second

with 10 NCSs, or about 30% of the 2013 total. Only 3%
(three of 92) of FDAs GMP warning letter total in 2012-2014
involved Chinese facilities. Two facilities in South Korea
and the UK were given NCS status, with one plant in each
of seven other non-U.S. countries appearing on the list.
The database also contains a section for good distribution
practice (GDP) non-compliance statements. Only one GDPrelated NCS appears, resulting from a March, 2014 inspection
of a wholesaler in the Czech Republic, MaxPharma. The NCS
states that the firm does not comply with GDP requirements
in that it does not have authorized storage facilities, did
not apply for a variation to the distribution authorization,
and did not report required data.


Foreign Labs in Focus


FDA warning letters provide a portal into the deeper

regulatory trends impacting pharmaceutical manufacturers,
and a review of the 2012-14 cohort reveals some significant
shifts in the enforcement sands.




















Notably, none of the three warning letters issued to

firms in China specifically reference data integrity.
All three address topical production.
The Chinese firms receiving warning letters, all in 2012, were:
Jianerkang Medical Dressing, Jintan City, Jiangsu (June)
Shanghai Huhui Daily Use Chemical Products, Shanghai
(November), and Fercy Personal Care Products, Zhejiang
Of concern at all three firms was the approval of procedures
and methods by the quality unit, investigations, and process/
sterilization validation. Shanghai and Fercy were also cited
for selling unapproved drugs, and for the lack of facility
Another significant concern highlighted in the warning letter
to Fercy was the firms decision to terminate the inspection
that resulted in the warning letter three days earlier than
previously agreed.
In December 2013, EMA updated the public version
of its EudraGMDP database to include GMP noncompliance statements (NCSs). In 2013, there were
34 facilities added to the list, making sterile and
non-sterile products and APIs.

Funneling from what investigators uncover on the shop

floors through FDAs compliance management to company
executives, the concerns addressed in the warning letters
indicate where the greatest risks to product quality lie
across the industry and where the agency will, in turn, be
placing its attention to try and get them addressed. In one
sense, warning letters reflect FDA enforcement priorities in
another, they drive them.
Emerging into high relief as FDA increases its
attention on the international arena are significant
gaps in how firms are handling their laboratory
operations and data.
Following the dialectic
process, the mounting evidence is driving the
agency to further ramp up its lab focus abroad and
domestically as well.
What the investigators are finding both at the dosage and
API levels abroad is that the analytical methods being used
are not always validated.
They are also finding that controls are not in place to assure
that problematic results are recognized and dealt with and
not buried, discarded or manipulated and that the required
tests are actually being performed as recorded.
Given the frequency of the agencys findings that those
controls are lacking particularly in India, which supplies a
significant percentage of the APIs, generics and OTC products
on the US market laboratory scrutiny will continue to be
central on FDAs inspection radar screen.

India also led in the number of NCSs listed by EMA in 2013



Finding Lab Issues Require Expertise

methods provisions of 211.165(e).

FDA International Pharmaceutical CGMP Actions

Action Type

FY 2010 FY 2011 FY 2012 FY 2013

Inspection Reports





Insp. Report Reviews,






Warning Letters Issued





Untitled Letters Issued

Import AlertsCGMP
Violations (66-40)




Import Alerts resulting

from foreign regulatory
authority inspections



Import AlertsHeparin





The greater focus on lab operations in overseas inspections

reflects, in part, the broader review that investigators employ
when applying FDAs system-based inspection approach
overseas. Foreign inspections generally cover all six systems
quality, laboratory, production, materials management,
facilities and equipment, and packaging and labeling as
compared to those domestically, which may only focus on
the quality system and one of the other five, not necessarily
including the lab.
Another factor is the frequent participation in international
inspections of chemists and microbiologists, who are more
experienced in evaluating lab operations and data.
In a presentation at the University of Georgia/FDA
International GMP Conference in Athens, GA in
mid-March, Office of Regulatory Affairs (ORA)
National Pharmaceutical Inspection Expert Sharon
Thoma commented on this lab focus in the foreign
Noting that a lot of investigators do not feel comfortable
in the laboratories and may avoid them, Thoma said that
she is excited to see that FDA is looking for and finding
more of these lab issues. I think that you are going to see
that more and more as we get more scientifically based, she
The agency investigator went on to explain how the concern
with lab methods and data integrity is playing out in a
notable surge in enforcement attention by FDA on incoming
component testing (see story on p. 30). Her review of the FY
2012 and 2013 foreign warning letters found that
component testing (211.84(e)) was the second leading cite
(in a tie with process validation (211.110(a)), behind the lab

While not addressed by Thoma, FDAs concern with the

evaluation of incoming components has been especially
noticeable in the large number of GMP warning letters that
have gone out to OTC topical manufacturers over the past
few years.
The focus on GMP control at topical producers and on
component testing, in particular reflects the number of
ingredients topicals contain and the potential for microbial
contamination to find its way into the products, which may
be used on or near wounds. Accordingly, cleaning and
stability programs have been other key areas of concern in
the topical letters.

Method Validation For Vaccine Testing

of Concern at Sanofi
in a July 2012 warning letter addressing vaccine production
at Sanofi Pasteur, concern about the validation of lab
methods used to detect mold and yeast was juxtaposed
against internal non-conformance reports citing 58
instances of possible mold detection in an 18-month period.
The letter addresses the findings during inspections
conducted in March-April 2012 of Sanofi Pasteur vaccine
sites in Toronto, Canada, and Marcy lEtoile, France.
Regarding the Toronto findings, the letter maintains
that sterility for all lots of TheraCys BCG live
vaccine manufactured since the last successful
validation of the method in 2000 cannot be
Attempted re-validation of the method conducted from
March through April 2012 failed acceptance criteria,
indicating there is no assurance that the test method is
capable of detecting yeast and/or mold in the product. The
BCG vaccine is used in the prevention of tuberculosis.
Investigators pointed to no less than 58 documented nonconformances relating to the isolation of mold in aseptic
processing areas of the Toronto facility since August 2010.
The letter also expressed other sterility-related concerns,
including vial handling in the aseptic processing area,
allowing facility personnel and an FDA investigator to enter
a washing and sterilizing area directly from a live vaccine
testing area, and nesting birds in the air handling intake
CBER Office of Compliance Director Mary Malarkey
included, as part of the warning letter, 20 specific
observations from the 483 issued to the Toronto plant along
with commentary on the responses finding many of them
inadequate and requests for additional information.



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Two 483 observations from the Marcy lEtoile, France plant
were also addressed related to the production of haemophilus
conjugated vaccine. Requested by Malarkey were progress
reports on finding root causes and implementing corrective
actions for lots that had extended filtration times and
displayed an adverse trend on bacterial content.
Sterility concerns were also cited by Australia's at
the Toronto facility a month after the 2012 FDA
inspection that prompted the warning letter. A
recall of four lots of the TB vaccine followed the
two inspections.
Sanofi shut down part of the Toronto plant for remediation,
which resulted in a shortage of the BCG vaccine that the
company does not anticipate being able to resolve until the
end of 2014.
In the wake of the compliance, recall and shortage
problems, the firm brought on board industry veteran and
former Genentech VP Anders Vinther as Chief Quality
Officer, a position that reports to the CEO. Vinther has
played an important role in advancing quality system
concepts and their application in the biotech industry, and
has served in various capacities at PDA, including as the
associations Chairman of the Board.

Mexican Oral Dose Firm Also Cited for Methods

Method validation also came up on the OTC side in the context
of method specificity for pediatric tablets manufactured at
Mexicos Selder S.A.
An April 2013 warning letter asserts that the firm did not
conduct specificity testing as part of its validation for an
HPLC method used to test Childrens XL-3 Chewable
Tablets an OTC acetaminophen product.
The agency requested that the firm include in its response a
detailed review of all analytical test methods it employs to
ensure that they have been properly validated and verified
that they are adequate for actual conditions of use. Also
requested was a list of revisions made to the analytical
methods as a result of the review.
Other deficiencies investigators uncovered caused
the agency to question the effectiveness of the
Mexican firms quality system to achieve overall
compliance with CGMP at the facility.
Specifically noted were several instances of equipment
qualification that was lacking and incomplete laboratory
data. FDAs Office of Manufacturing and Product Quality
(OMPQ) Director Steve Lynn asked Selder to seek the
advice of a third-party consultant for assistance with a

complete evaluation to determine the improvements that you

will need to make at your firm in order to meet the CGMP
requirements for the manufacture of OTC drug products.

Lab Records Also at Issue Overseas

Recent examples of lab problems related to 211.194(a), which
requires lab records to be complete, can be found in warning
letters to Taiwan-based Beanne Chemical (December
2012), Canada-based Apotex (February 2013), concerning
its Toronto plant, and India-based Wockhardt (July 2013).
Beanne and Apotex produce sterile products at the plants
referenced in the letters, while Wockhardt was cited for
solid oral dose manufacturing at its facility in Aurangabad,
Of concern at Wockhardt was a failure to document all lab
tests performed and the integrity of the data produced.
Integrity problems were prominent outside the lab as well
in the warning letter (see story on p. 19).
At Beanne, investigators expressed concern that raw
data used to support the release of finished product
lots was not available.
During the inspection, raw data from the finished product
testing described in the firms certificates of analysis was
requested. However, the firms management stated that it
did not maintain records of the raw data.
We are concerned, the letter to Beanne emphasized,
that the certificates of analysis include test results for
total aerobic microbial count, Escherichia coli, Staphylococcus
aureus, Pseudomonas aeruginosa, arsenic, lead, mercury, and
skin irritation, but no raw data is available to ensure that
the analyses were conducted correctly or that the results
reported were within specifications.
Accuracy of lab records related to environmental
monitoring (EM) was a focal point in the August
2012 inspection of the Apotex site in Toronto that
led to the warning letter.
An FDA investigator observed a microbiologist reading an
EM plate and recording a result of zero. The investigator,
however, noted one colony forming unit (CFU) on the plate.
Although the firms microbiologist corrected the observation
when the error was pointed out, no further action was
taken to determine the impact of the finding on the finished
Failure to document positive results for a microbial plate,
Acting Director of FDAs Office of Manufacturing and
Product Quality Michael Smedley noted in the letter, raises
concerns about the accurate reporting of results in your



records. He added that accurate and reliable microbial
data management is essential to support the reliability
of aseptic manufacturing.

related to reports from finished drug manufacturers, which

have alerted the agency to difficulties or problems or
failures in their product that they attribute to the API.

Inadequate Lab Controls Top API Findings

I would say in the last two or three years we have seen a

relatively large increase in the number of inspections that
were generated in that way, she commented.

Lab controls have also been found lacking at overseas API

At an ICH Q7 training workshop co-sponsored
by PIC/S and PDA in February 2014 in Bethesda,
Maryland, FDA investigator and pre-approval
manager Karen DOrazio discussed the regulatory
framework for API inspections, current FDA
thinking and guidance regarding APIs, and the
most common deficiencies the agency is seeing in
API inspections (see box below).
The top citation for APIs, she pointed out, is inadequate
lab controls. The areas in which the agency is seeing
the most lab control deficiencies include: method
validation scientifically sound and appropriate specs
and test procedures investigation of out-of-specification
(OOS) results documentation of controls and product
performance, and the stability testing program.
DOrazio commented that she has seen the same types of
issues in pre-approval as well as routine inspections for
both APIs and finished drugs.
The agency investigator also discussed directed
inspections for API manufacturers resulting from
problems with APIs that finished dosage firms have
reported to the agency.
In addition to being an inspector, DOrazio is also involved
in FDAs field alert program. In that capacity, she has
recently seen a fair number of directed inspections

The issues pointed to by DOrazio are also being

reviewed by FDA at API contract testing labs. A
March 2012 warning letter to an API testing lab in
Cucutitlan, Mexico, UNAM, included citations in
two of the problem areas she highlighted OOS
investigations and documentation of controls.
Investigators asserted that the firm had no procedure in place
for investigating OOS results. The letter requested that in its
response UNAM include an OOS investigation procedure
along with the associated training documentation. FDA
suggested that the OOS procedure include: a requirement
for initiation of an investigation without delay an
evaluation of the root cause of the result justification of
any re-sampling and/or retesting a system for assuring
corrective actions are implemented, and notification to the
firms client of any OOS result.
The letter also points to the firms lack of documentation of API
samples tested on its atomic absorption spectrophotometer
for a 12-year period from 1999 through 2011, and an associated
lab notebook that did not contain the raw data from the tests.
Also of concern was a lack of records indicating routine
calibration of the spectrophotometer as well as of an HPLC
unit and an analytical balance.

Two Big Pharma API Plants Draw Warnings

While most of the drug GMP warning letters since 2012


At an ICH Q7 training workshop co-sponsored by PIC/S and PDA in February 2014, FDA investigator and
pre-approval manager Karen DOrazio discussed the regulatory framework for API inspections, current FDA
thinking and guidance regarding APIs, and the most common deficiencies the agency is seeing in API inspections.
Our authority to regulate API manufacturers derives from the [Food, Drug and Cosmetic] Act itself, and
from section 704(a)(1). There it authorizes the FDA to do factory inspections if the drugs are manufactured
for introduction into interstate commerce. This is important. It doesnt specifically limit drug production
sites to U.S. territory, which is particularly important given the global impact of our inspections today.
Also, in section 201(b) of the Act, interstate commerce is defined as commerce between any state and any place outside
thereof. So products outside the U.S. and the firms producing them are considered to be in interstate commerce.
So now we know what we can inspect. But what are drugs themselves? How do we define drugs? From the act,



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section 201(G) defines drugs as articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of
diseaseintended to affect the structure or any function of the body. So the definition is not limited to drug products,
i.e. finished drug forms. This is important for our discussion of APIs.
The FDA definition of bulk drug components comes from the preamble to the 1978 revisions to the cGMP regulations.
Bulk drug components are defined as ingredients intended for use in the manufacture of a drug product. One more
definition from the FDA comes from our 21CFR part 210, which defines an active ingredient as any component intended
to furnish pharmacologic effect, and it includes components that may undergo chemical change in the manufacture of
a drug product.
One more definition of note then is the Q7A definition of an active pharmaceutical ingredient: Any substance or
mixture of substances intended to be used in manufacture of a drug product...intended to furnish pharmacological
activity or other direct effect.
Knowing this, knowing what FDA can inspect, and knowing what we define a drug to be not just a finished drug
product but also an active ingredient then we go into our actual regulation of the APIs.
They are subject primarily to the adulteration provisions of section 501(a)(2)(B) of the act, which requires all drugs
to be manufactured in conformance with good manufacturing practices. This is important because our regulations
for drugs, 21CFR 210 and 211, really dont apply to APIs, except in that small case of sterile APIs after the point of
Also, the cell culture fermentation uses language from related FDA regulations and that is discussed in section 18 of
Q7. So for us as regulators, it is a very nuanced use of 211 in terms of informing us as to what good manufacturing
practice is. In 2001, FDA adopted Q7 as a guidance document and continues to use Q7 as representative of FDA
thinking on the subject of APIs.
Another guidance document that is used internally and that is open to the public domain is our active pharmaceutical
ingredients process inspections guidance, which is 7356.002F. In that you find incorporate a systems-based inspection
approach. It was implemented in 2006, and there were some minor changes in 2013. One thing of note for that
particular guidance is that it doesnt cover biotechnology derived APIs for that you need to go to another document,
which is inspections of biologically licensed therapeutic drug products.
I think the take home message for this is that we really do not have much in the way of regulations a really small
amount of regulation but everything derives from the act itself.

API Inspections
When we do our onsite inspections of APIs, they tend to fall into several categories. One would be a surveillance
inspection, which is a routine GMP inspection and part of our work plan. Another would be a pre-approval inspection.
And the other could be a directed inspection. The types of directed inspections that we might have would be a followup to a regulatory action like a warning letter.
The other type of directed inspection that I have been more familiar with because, in addition to being an inspector,
I also run our field alert program we have actually seen recently a fair number of directed inspections related to
reports from finished drug manufacturers who have alerted us to the fact that APIs might have been the cause of
difficulties or problems or failures in their finished drug product. I would say in the last two or three years we have seen
a relatively large increase in the number of inspections that were generated in that way.
The other thing about onsite inspections of APIs is, because the primary areas where they are manufactured are out of the
U.S., 70-90% of our inspections are out of country for APIs. And pre-notification is required for the foreign inspections only.
Our onsite inspections are conducted as GMP qualifying inspections of APIs as they are assigned to us. They may
be product-specific. And really what we are trying to do is use a systems coverage to determine the ability of the
firm to produce any API using the same systems of controls and procedures, whether it be for chemical synthesis,
fermentation, biotech, etc.



Top Five Citation Areas for APIs
DOrazio went on to discuss the top five GMP deficiencies seen by agency investigators in
GMP inspections. She noted that as a pre-approval inspection (PAI) manager, she has seen
the same types of issues in PAIs for finished drugs as well. Specific concerns within the
five areas cited by DOrazio are listed.
Lab controls
method validation scientifically sound and appropriate specs and test procedures OOS investigations documenting lab controls at the time of performance stability testing
Quality system
approval or rejection of APIs approval of quality related documents complaint investigations
regular quality reviews evaluation of the potential impact of proposed changes on the quality of APIs.
Equipment cleaning, maintenance & validation
equipment maintenance cleaning procedures equipment validation cleaning, storage, sanitization, and sterilization to prevent contamination or carry over qualification of critical equipment
Records and reports
batch production records inclusion of complete data derived from all tests in the lab control records
written procedures for production activities, quality responsibilities, laboratory processes, materials
management, and laboratory controls
have gone to smaller firms and compounders, a half-dozen
of them were issued to big pharma. Four of these related
to injectable manufacturing and two encompassed API
The API letters went to Boehringer Ingelheim (BI) in May
2013 for an API, oral solid, and inhalation dosage form
site in Germany, and to SmithKline Beecham (SKB) a
GlaxoSmithKline (GSK) subsidiary in March 2014, for an
API site in Ireland. Both cited two areas DOrazio discussed
as common problem areas for APIs investigations and
quality unit approval or rejection of batches.
Notably, both letters focused on contamination
of APIs particulates at BI, and industrial
waste at SKB and concerns with the related
The warning letter to BI asserts that while the firm was aware
of extrinsic foreign particles in multiple API lots produced
in 2008 and 2009, the decision was made to use the lots to fill
capsules and produce final dosage forms. FDA expresses
concern that BI did not begin a formal action to mitigate the
presence of foreign particles in its API until 2012.
The letter also points to a complaint BI received from a cus
tomer that identified foreign particles in an API batch it
received, manufactured in 2009, and the firms conclusion that
the complaint was not confirmed in spite of internal evidence
of the particulate contamination. A September 2011 complaint

by a customer for particles was classified as confirmed,

leading the agency to question the designation criteria used.
Your conclusion of confirmed or not confirmed is
inconsistent, the letter emphasizes, as both complaints
were related to the presence of foreign particles found in
your APIs, but your final conclusions were different. The
agency requested that the firm provide it with the corrective
actions taken to prevent foreign particle contamination in
its APIs.
At SKBs site in Ireland, the focus was on API
batches that were contaminated with material from
a pharmaceutical waste tank, which contained
APIs, intermediates, and solvents, and the adequacy
of the firms investigation and disposition of the
FDA compliance official Lynn expressed concern in the letter
that different batches were tested for the contamination by
different analytical methods, resulting in some batches being
distributed while others were rejected. While the standard
analytical testing performed on some batches did not detect
significant amounts of the contaminants, leading to the
lots being approved, the additional testing on other lots
revealed that they had been exposed to significant amounts
of the contaminants, and those lots were rejected.
Also at issue was the firms SOP regarding notification to
customers of deviations that have the potential to impact



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product quality and the firms choice not to escalate the
contamination event by notifying its customers. We are
concerned that your firm does not consider the entry of
pharmaceutical waste streams into your manufacturing
process a significant deviation with a potential quality
impact, the agency emphasized.

Atlanta District Director John Gridley advised the firm that

a recent inspection at another Baxter facility also cited a
pattern of inadequate corrections and interventions. While
the response to that locations deficiencies appears adequate,
we expect appropriate correction at all Baxter facilities in this
critical area, he emphasized.

Rounding out SKBs warning letter were citations for

chromatograms in which impurity peaks were ignored
and not investigate by lab analysts, and process validations
that were approved using non-consecutive lots when three
consecutive lots, as mandated by the firms procedure, could
not be achieved.

India Plant Adds to Hospiras Compliance


Baxter Injectable Plants Cited In NC & PR

Baxter drew a warning letter in May 2013 addressing
findings at two of its injectable facilities at its Marion,
North Carolina, plant in late 2012, and at its Jayuya, Puerto
Rico plant in early 2013.
FDA noted in both cases that there were repeat
observations and that similar concerns had been
found at other Baxter facilities.
At the North Carolina plant, agency investigators found
numerous HEPA filters, supporting grid work, filter
screens, and screen tracks, that contained varying amounts
of discolored areas, chipping paint, multicolored coalescing
droplets, and clumps of dark material that FDA testing later
revealed was mold.
The agency inspectors asserted that maintenance personnel
had documented possible mold on the clean side of
HEPA filters supplying air to large volume parenteral
production lines at least as far back as July 2010, but that
no samples had been taken by the firm to determine what
the material was. This was a repeat observation from an
inspection at the same plant earlier in 2012.

In May 2013, Hospiras injectable manufacturing plant in

Sriperumburdur India was warned for violations uncovered
during an October 2012 inspection period. The problems
were similar to those found at its beleaguered Rocky Mount
facility earlier that year (see IPQ Monthly Update Jan./
Feb. 2013, pp. 2-11).
Included were citations related to aseptic technique and
other personnel practices, process validation, smoke studies,
and media fills.
Compliance official Smedley expressed his concern in
the letter on the Indian site regarding the similarity of the
violations, and requested that the firm provide a current
global corrective action plan for domestic and foreign
Hospira facilities. He advised that the plan should include
a comprehensive training module on aseptic process
techniques for all employees involved in aseptic process
operations and how the firm will measure the effectiveness
of the training.
Agency concerns at the Rocky Mount plant,
expressed in lengthy 483s since 2008 and underscored
in a warning letter in April, 2010 (see IPQ Monthly
Update September 2010, pp. 14-15) would typically
have resulted in a plant closing, potentially under
a consent decree, until the remediation could be
assured by the agency.

In focus at Baxters Puerto Rico plant were the

adequacy of investigations, manufacturing defects
that could lead to compromised product sterility,
and late field alert reports.

However, the role Hospira plays in supplying medically

necessary injectables and the threat to the healthcare system
if that supply were disrupted led the agency to work with
the company in achieving the overhaul while production

FDA pointed out in the 2013 letter that its concerns regarding
investigations into sterility compromises in large volume
parenteral (LVP) bags that were the subject of customer
complaints and a product recall was a repeat citation
from a 2011 warning letter. Cited were numerous open
investigations regarding foreign material found in the bags
that purported to be sterile.

The firm took a quality-by-design (QbD) oriented approach

to compliance remediation and quality improvement at the
North Carolina injectable manufacturing facility focusing
more heavily on identifying and monitoring critical process
steps than on reviewing batch records (see IPQ Monthly
Update Jan./Feb. 2013, pp. 2-11).

Also at issue in the 2013 letter were consumer complaints

identifying at least ten membrane leaks and 155 inadequatelyfitting blue caps on the LVP bags during the period of
November 2011 to March 2013. The letter characterized
these as critical defects that can impact the sterility and
stability of the products.

In an early February 2014 conference call on 2013

earnings, Hospira CEO Michael Ball said that his
firms was recently verbally advised by FDA that the
status of our Austin facility and the pharmaceutical
operations at Rocky Mount have been changed to
VAI [voluntary action indicated]. Subsequent to
the 2010 warning letter, he said, the company has




invested $200 million in remediating the North
Carolina plant.
Since the conference call, Hospira has announced injectable
product recalls and recall extensions for a variety of
products and reasons, including particulates found inside
vials identified either by the company or by customers. The
notices do not indicate at which Hospira site the products
were manufactured.
Included in the recalls were:
seven lots of injectable propofol, due to a glass defect
located on the interior neck of the vial and free-floating
metal particulates identified from a retained sample

customer report of orange and black particulate within

the solution and embedded within the glass vial,
identified by Hospira as iron oxide


one lot of a preservative-free bupivacaine injection,

due to a confirmed customer report of discolored
solution with visible particles embedded in the glass as
well as discolored solution, and
one lot of preservative-free morphine injection, after
customer reports of either a loose crimp or no crimp on
the flip-top vial.

one lot of injectable lidocaine, due to a confirmed


At the opening session of FDLIs annual meeting in Washington, D.C. in late April, FDA Commissioner Margaret Hamburg highlighted the significant changes the agency is making to expand its effectiveness in the
global arena.
We have a lot on our plate, but across all of our domains of activity, the challenges get ever more complex as we
must also grapple with our dramatically changing global marketplace. This change, in which the foods we eat and the
medicines and medical devices we use increasingly come in whole or part from countries other than our own, has
enormous ramifications for the work FDA does, and the people we work to protect.
And the numbers are astounding. 50% of fresh fruits and nuts, 20% of vegetables, and over 80 % of seafood consumed
in America comes from abroad. Similarly, 40% of finished drugs come from outside our borders, and 80% of active
ingredients manufacturers are located outside the US. Further, half of all medical devices are imported.And the
volume of imports only continues to rise.
The fundamental shifts that are taking place as a result of globalization have huge implications for our ability to ensure
the safety and quality of products manufactured elsewhere and the integrity of supply chains as those products
move through an increasingly complex network of producers, manufacturers, packagers, distributors, exporters and
importers. I would argue that this transformation also comes with huge economic and national security challenges as
As for FDA, we have already begun to reorganize our structure and transform from a domestic agency operating in a
globalized world to a truly global agency fully prepared for a complex regulatory environment that takes into account
the risks across a products life. This requires new reliance on enhanced intelligence, information and workload sharing
with the help of regulatory partners, data-driven risk analytics, and allocation of resources achieved through public and
private partnerships.
Most importantly, our job requires greater coordination of regulatory standards and practices across nations to ensure
safety and quality, regardless of where a product is produced. We are working through bilateral and multilateral
agreements, as well as through international organizations, specialized partnerships and various coordinating bodies.
And at the highest levels, we have embarked on creating a new model or framework for global governance.
But specifically with respect to our work at FDA, much has happened in recent years. We have greatly enhanced
our ability to do targeted border screening as products come in, using a computer driven, risk-based program called
PREDICT to identify imports that need fuller examination versus those commodities at low risk that can proceed


MARC 2014


- MA
But that alone is not enough. We must work to enhance safety and quality long before these products reach our
shores. We have enhanced overseas inspections and now haveFDA officesin many parts of the world. This is proving
very beneficial, but again, we must do more. We cannot inspect our way to safety with some 300,000 facilities in about
150 countries making products for export to the United States that we must oversee.
That is why the collaboration with both industry and our regulatory counterparts is increasingly vital. The rapid and
profound rise of global commerce and trade requires that we continue to evolve and meet new demands. We can take
comfort in the knowledge that we have significantly strengthened our ability to respond to these challenges and know
where and how we must do more.
Similarly, the rapid advances in science and technology offer great opportunity but place new and evolving demands
on us and the products we regulate.
Understanding the seriousness of these challenges structural, scientific, economic, and global is one reason why,
when I took over as Commissioner, I could not settle for incremental changes in how FDA intends to conduct business
for the 21st century. I am confident that the changes we are putting in place are sufficiently important and on track to
survive well into the future. I believe that they are, in fact, absolutely essential.
And so we will continue to implement changes that fundamentally transform how we address these challenges before
us, how our agency interacts with regulated industry and other stakeholders, and how the public understands and
supports the mission of this important and unique agency.
It will require the work not just of the FDA, but of partners such as FDLI, to ensure the continuing alignment of our
public health and medical care mission with the important regulatory and legal framework. I look forward to our
ongoing work together, with continuity of purpose, renewed commitment to key principles, and a sense of the dynamic
and changing world we live in that demands flexibility, resilience and an eye to the future.


Come to to find all the important CMC/review and GMP/inspection
developments in the US, Europe and internationally.
All the stories that appear in IPQs real-time In the News web coverage and in our
Monthly Update are indexed and searchable on our website
--with the relevant document links you need ready at hand.

We do the work so you dont have to.

Visit and relax.



FDA Drug GMP Warning Letters Issued in 2012-Q12014
The following is a chronological listing of all 92 of the drug GMP warning letters issued between the beginning of 2012 and the first quarter of 2014, categorized into U.S. and International. The key concerns that each
of the warning letters address and links to the letters themselves are provided.

United States (2014)

Company Name
Pentec Health


Leer Date

Product Type

Areas Cited
Sanitary condions Microbial control SOPs

Village Ferlity




Total Pharmacy

Houma, LA



Village Pharmacy





Woburn, MA




Orlando, FL



Nora Apothecary




Avella of Deer

Phoenix, AZ



Recsei Labs

Goleta, CA
Cary, NC



Microbial control SOPs Environmental

monitoring Personnel evaluaon Equipment
tesng Drug approval
Sanitary condions Microbial control SOPs
Personnel clothing Environmental monitoring
Stability tesng Conformance tesng Identy
tesng Drug approval
Sanitary condions Serilizaon SOPs Microbial
control SOPs Personnel clothing Environmental
Monitoring Complaint handling Operaon
segregaon CAPA Drug approval
Sanitary condions Microbial control SOPs
Personnel evaluaon Container Closure System
Drug approval
Sanitary condions Microbial control SOPs
Personnel clothing Environmental monitoring
Stability tesng Conformance tesng CAPA
Drug approval
Microbial control SOPs Stability SOPs Spec
conformance Environmental monitoring
Operaon segregaon CAPA Drug approval
Microbial control SOPs Environmental
Monitoring Personnel clothing CAPA Drug
Component tesng Drug approval
Equipment Maintenance Invesgaons
Stability SOPs Microbial control SOPs Personnel
clothing Sanitary condions Drug approval

Internaonal (2014)
Smruthi Organics
Canton Labs


Cork, Ireland









Invesgaons Process conformance

Data integrity(deleon, trial tesng, batch
blending, acvity logs) Invesgaons

Data integrity(data retenon, deleon)

Equipment maintenance Cleaning validaon
Producon SOPs Complaint handling
Invesgaons Quality unit resources Stability
tesng Impurity profile tesng
Oral Solid
Data integrity(computer access, sample weight
Tempe, AZ & 01/31/14
Failure to maintain complete records API
Tracking andIALOGUE
Idenficaon API labeling Identy
tesng Drug approval

United States (2013)



- MA

Tempe, AZ &
Hong Kong,


Ameriderm Labs

Paterson, NJ



Allergy Labs

City, OK





Green Valley




Fenwal, a




Maricao, PR



Lake Mary,




Cranbury, NJ


Oral Solid

Healthcare Corp.

Marion, NC
& Jayuya, PR



V-SAB Medical

Los Alamitos,






Alexion Pharma.












Keystone Labs

Medi-Fare Drug
Home Health
Abbey Color


Failure to maintain complete records API

Tracking and Idenficaon API labeling Identy
tesng Drug approval

United States (2013)

Container tesng Lot release tesng In-process

tesng Spec conformance Process control SOPs
Equipment cleaning Deviaons from SOPs
Component Tesng Identy tesng
Microbial control SOPs Cleaning SOPs
Invesgaons Environmental monitoring
Equipment evaluaon Microbial control SOPs
Equipment Maintenance Control records
Container closure leachable tesng
Area segregaon Equipment cleaning Stability
tesng Environmental monitoring Microbial
control SOPs Personnel clothing Conformance
tesng Drug approval
Sterility SOPs Personnel clothing control SOPs
Environmental monitoring Spec conformance
Stability SOPs Drug approval
Labeling SOPs Complaint handling
Deviaon/OOS invesgaons FARs
Drug rejecon Equipment
cleaning/maintenance Stability tesng
Environmental monitoring Microbial control SOPs
Personnel clothing Conformance tesng Drug
Deviaon invesgaons Complaint handling
Process SOPs Validaon tesng Identy tesng
Component tesng
Deviaon & OOS invesgaons Equipment
cleaning Environmental monitoring Quality SOPs
Container closure FARs
OOS Invesgaons Stability tesng
Environmental monitoring Microbial control SOPs
Air supply Drug approval
Spec conformance Quality SOPs Stability
tesng Quality unit SOPs Component tesng
Drug approval
OOS Invesgaons Quality unit responsibilies
Building maintenance Equipment suitability
Equipment Cleaning Microbial control SOPs
Water quality validaon Identy tesng Drug
registraon Component tesng Drug approval
Air supply Personnel clothing Microbial control
SOPs Environmental monitoring Stability tesng
Spec conformance Drug approval

Water quality validation OOS Invesgaons

Stability tesng

Identy tesng Stability tesng Component






Fort Worth,
Tulsa, OK



Identy tesng Stability tesng Component

tesng Drug approval


Oral Solid



In-process tesng SOPs OOS invesgaons

Drug approval
Cross-control tesng Area segregaon
Packaging operaons Equipment cleaning
Deviaon invesgaons


, India


Oral Solid

Agila Specialies




Jabones Pardo




Promed Exports






Aar Drugs

2 in Tarapur,






Oral Solid

Fresenius Kabi

West Bengal,



Ebewe Pharma
Ges MBH Nfg KG

Unterach am



Healthcare India

dur (T.K.),
India &
, India
North Ryde,



Microbial control SOPs Appropriate site for



API, Oral Solid

OOS invesgaons Data integrity(retesng,

discarding, computer access) Stability tesng
Complaint handling


Oral Solid

Environmental controls Quality SOPs Deviaon


Physicians Total

Internaonal (2013)

Posh Chemicals

RPG Life Sciences

Pharma. Services
of Australia

Data Integrity(trial tesng, computer access,

documentaon) In-process tesng CAPA
Computer access control Conformance tesng
Stability tesng
Microbial control SOPs Environmental
monitoring Area segregaon Deviaon
invesgaons Building maintenance
Conformance tesng Data integrity(computer
Identy tesng Conformance tesng Stability
SOPs Quality control SOPs Equipment
maintenance Component tesng Drug approval
Environmental monitoring Cleaning and
disinfecon Deviaon/OOS Invesgaons
Computer access control Method validaon
Data integrity(audit trails, falsificaon)
Component Tesng
Data Integrity(quality acvity records, record
keeping, audit trails, computer access)
Deviaon/OOS invesgaons
FDA inspector access Data integrity(trial tesng,
retesng) Batch producon and control records
Lab control mechanisms Toilet cleaning SOPs
Worker training
API Batch Combinaon Data integrity(trial
tesng, response to OOS, retesng, computer
access) FDA inspector access
Change approval Conformance tesng




- MA
CMI Cosmec

am Rhein,
Catania, Italy
Hong Kong,


Asada Milling


Wyeth Lederle
Peking Medicine

P.A. Benjamin


API, Oral










l Solid




Oral Liquid

Quality unit responsibilies OOS/deviaon

invesgaons Complaint handling
Identy tesng Equipment cleaning Master
producon records Drug registraon
Component tesng
Spec conformance Stability tesng Process
validaon Component tesng
OOS invesgaons FARs
Quality unit responsibilies/SOPs Quality SOPs
Process validaon Spec conformance Stability
tesng Employee training Identy tesng
Component tesng Drug approval
Quality unit responsibilies/SOPs Process
validaon Equipment cleaning & maintenance
Identy tesng Batch record SOPs Stability
tesng Component tesng
Microbial control SOPs OOS invesgaons
Process validaon Laboratory records
Environmental monitoring CAPA
OOS invesgaons CAPA Spec conformance
Process control SOPs
OOS invesgaons Quality unit responsibilies
Identy tesng Microbial control SOPs
Equipment cleaning Process validaon
Component Tesng Drug approval

United States (2012)


Saint Louis,



I Shay Cosmecs

Gardena, CA



Stat Rx USA



Oral Solid





DPT Lakewood





Respiratory Care
Soluons Group

Ocala, FL



Norman, OK



Center, OH

Record access Component tesng Stability

SOPs Conformance tesng Cleaning SOPs
Equipment calibraon Drug approval
Microbial control SOPs Specificaon and test
SOPs Producon and process controls
Equipment cleaning Stability tesng program
Component tesng
Returned drugs evaluaon Stability tesng SOPs
Reserve samples of drug product
OOS invesgaons Microbial control SOPs
Microbial control/SOPs Process validaon
Environmental monitoring Employee training
Stability tesng Data integrity(batch records)
Equipment SOPs Complaint handling Spec
conformance Producon records Drug approval
Component tesng Complaint handling
Deviaon invesgaons Container conformance
Drug approval
Microbial control/SOPs Drug approval

Spec Conformance Quality unit responsibilies

Stability studies
Computer access controls Master batch record
controls Quality unit responsibilies Quality
SOPs Drug approval





Soluons Group
Nusil Technology
Meds IV
Warner Chilco
APP Pharma.
Biochem Labs

Center, OH



Fajardo, PR






Oral Solid






Oral Solid



Island, NYC


Princeton, NJ

Beanne Chemical




Hameln Pharma.

Tainan City,


















France &
Vrsac, Serbia







Taiwan Three
Mast Pharma.
Novo Nordisk
Shanghai Huhui
Daily Use

Personal Care
Medical Dressing
Sanofi Pasteur


Computer access controls Master batch record

controls Quality unit responsibilies Quality
SOPs Drug approval
OOS SOPs Equipment cleaning Water
validaon Crical process parameters
Microbial control Environmental monitoring
Drug approval
OOS invesgaons Quality unit CAPA
Deviaon invesgaons Microbial control SOPs
Complaint handling Quality unit SOPs
Identy tesng Stability tesng Method
Validaon Equipment cleaning Data integrity
(computer access controls, maintaining test
records) Reference standardizaon
Method validaon OOS invesgaons Control
records Equipment qualificaon
Deviaon Invesgaons CAPA

Internaonal (2012)


Process validaon In-process tesng Stability

tesng Laboratory records Equipment
qualificaon Cleaning validaon
Employee training Microbial control SOPs
Environmental monitoring
Spec conformance Component tesng
Process validaon Quality standards evaluaon
Employee training Drug approval
Microbial control SOPs Equipment cleaning
Environmental monitoring OOS invesgaons
Component tesng Quality control unit Process
validaon Equipment qualificaon Stability
tesng Identy tesng Drug registraon Drug
Component tesng Spec conformance Quality
unit SOPs Master producon records Employee
training Labeling
Component tesng Quality unit SOPs Spec
conformance Stability tesng Drug registraon
FDA access
Microbial control SOPs/validaon Component
tesng Deviaon invesgaons Stability tesng
Method validaon
Method Validaon Environmental monitoring
Cleaning SOPs Microbial control SOPs Stability
tesng Quality SOPs Change control Process
validaon Process control SOPs Deviaon/OOS
invesgaons CAPA
Quality SOPs Environmental monitoring
Microbial control SOPs Change control SOPs
Deviaon/OOS invesgaons
Water system validaon Spec conformance
Equipment cleaning Building maintenance




- MA




Internacional de
B.M.P. Pharma
Selder S.A. de

Mexico City,



Mexico City,




Oral Solid


Ras al


Oral Solid











Cross-control tesng Area separaon





Microbial control SOPs Deviaon invesgaons

Batch records
Microbial control SOPs Equipment cleaning
Process and control SOPs Data integrity(retenon,
access, pre-dang)

UNAM Facultad
De Estudios
Farma Quimia
Nobilus Ent
Gulf Pharma.

Water system validaon Spec conformance

Equipment cleaning Building maintenance
Deviaon/OOS invesgaons Method suitability
tesng Change control SOPs
Data integrity(retenon) Stability tesng
Employee training Quality unit Component
Area segregaon
Stability tesng Method validaon Quality
SOPs Control records In-process tesng Drug
OOS invesgaons Component tesng
Equipment calibraon Spec conformance
Lab records Equipment calibraon Reference
standards OOS invesgaon SOPs Employee
Spec conformance Control records Stability
tesng Identy tesng Process validaon
Spec conformance In-process tesng Stability
tesng Labeling Equipment design Equipment
Quality unit Quality SOPs Process validaon
Equipment calibraon



July 21-22, 2014

Gaithersburg Marriott Hotel, Gaithersburg, MD




Best Practices
for Managing
Emerging Trends
and Challenges
of CMO Oversight
and Other Service

Forum Co-chairs:
Siddharth Advant, ImClone Systems Corporation
Julia Edwards, Genentech, a Member of the Roche Group
Jeffrey Staecker, Genzyme, A Sanofi Company


to browse


for program

updates at


European GMPs
and the Role of the
Qualified Person (QP)
The Impact of EU Directives and Guidelines
on the Supply Chain

Jersey City, NJ (New York City Metro Area), USA July 8-9, 2014
A conference organised by the ECA Academy and the European QP Association



Richard M. Bonner

Understand European GMPs

Chairman of the ECA Foundation and

the European QP Association

The European Pharmaceutical Legislation

FDA Speaker

Import/ Export


EU PQR versus US APR

Dr Rainer Gnibl

The US Quality Unit versus the EU QP

EU-GMP Inspectorate, Germany

Tor Grberg
Medical Products Agency, Sweden

Dr Bernd Renger
Immediate Past Chair of the
European QP Association, Germany

Martine Tratsaert
Johnson & Johnson, Belgium

Mark Tucker, Ph.D

form. FDA Investigator
and Compliance Officer, USA

EU GMP Update

Understand the Role of the QP

Duties and Responsibilities

The EU Discretion Paper and the Release of Batches

Supply Chain and Supplier Qualification

Clinical Trial Supplies: IMP Handling in Europe and the Role of the QP
The Role of PIC/S in a globalising World
The View of the FDA

Delegates Voices:
The chemistry between speakers and delegates was great.
Very interactive conference, very informative with real life examples.
Great broad coverage on topics relating to the QP.
I really enjoyed a conference that also addresses IMPs ! Thank you!

Media Partners:


FDA Data Integrity Findings Continue at Indian Firms, Highlighting
Challenges in Changing a Facilitys Quality Culture
FDA investigators are continuing to uncover serious data
integrity issues at facilities in India, including repeat citations
highlighting the challenges regulators face in getting
companies to make changes in their quality culture.
Since the middle of 2013, seven Indian firms have received
warning letters referencing the integrity of their records,
procedures, and interactions with FDA investigators.
Those letters followed in the wake of an equal number of
warnings issued from the beginning of 2012 to mid-2013
addressing integrity problems, three of which involved
plants in India.
[Editors Note: For an in-depth analysis of the drug GMP
warning letters issued by FDA from 2012 through mid-2013
thatreference data integrity see IPQ Monthly Update
July/Aug. 2013, pp. 2-8. The story focuses in particular on
the issues that surfaced during that time frame at RPG,
Fresenius Kabi, Wockhardt, and Ranbaxy. A listing of
all 14 of the letters from 2012 through April 2014 that cite
data integrity is provided below. The earlier IPQ coverage
extended through the letter issued to Wockhardt in mid-July
2013. The Aarti Drugs letter in the listing was issued in late
July 2013 and was not part of the earlier coverage.]
Large generic company Wockhardt, already on FDAs data
integrity watch list from a warning letter received at one
of its plants in July, 2013, was delivered a second letter in
November covering two other facilities that manufacture
oral solid and injectable products.
Along with Wockhardt, four API manufacturers in India
(Aarti Drugs, Posh Chemicals, Canton Labs and Smruthi
Organics), one injectable firm (Agila Specialties) and one oral
solid manufacturer (USV) also received letters that focused
in part on integrity lapses.
In addition, data integrity issues were raised in 483s
issued to Sun Pharma and Ranbaxy in December
2013 and January 2014, respectively. Both resulted
in import alerts on products manufactured at the
implicated facilities.
Problems were found at the Ranbaxy facility in spite of the
company already being under a consent decree that was
signed in 2012, arising from significant integrity issues
uncovered at another two of its key India plants(ibid.).
Sun announced in March that it was purchasing Ranbaxy
from Daiichi Sankyo, and that fixing Ranbaxys compliance
problems was a top priority. Suns own compliance

problems were not referenced in the announcement.

In late April, an Indian court temporarily halted Suns $3.2
billion purchase of Ranbaxy Laboratories until it decides on
a petition for a probe into alleged insider trading.

FDA Warning Not Heeded by Wockhardt

Wockhardts problems detailed in the July 2013 warning
letter were based on a six-day inspection of its Biotech Park
facility in Waluj, India the previous March(ibid.). The letter
provides eye-opening insights into the integrity lapses and
efforts to cover them up that FDA has been finding in India.
Two days after the July letter was issued, agency investigators
began simultaneous inspections of two of the companys
other plants in India a second facility located in Waluj, and
one in Chikalthana. Similar and repeat observations during
the inspections led to a second warning letter to the firm five
months later in December, addressing the findings at both
Observations cited in the December letter that were the same
as those noted in July included: performing trial sample
analysis QC laboratory computer instruments on which
lab personnel could delete raw data files, and operations
personnel performing manufacturing stepswithout a batch

Warning Letters Since 2012

Specifically Citing Data Integrity Issues

Country Product Type Date

Smruthi Organics




Canton Labs










Inj., oral


Agila Specialies




Posh Chemicals




Aar Drugs






Inj., oral


Fresenius Kabi




RPG Life Sciences


API, oral






Compania Internacional de Comercio




Biochem Labs




Gulf Pharma Ind.







- MA
record or a manufacturing form to document the results

that Maharashtra FDA officials sought an explanation as to

why GMPs are not being followed.

The repeat observations indicate that your quality

unit is not exercising its responsibilities and may
not have the appropriate authority or ability to carry
out its responsibilities, according to the December
letter. FDA was particularly concerned about
the firms inability to implement a robust and
sustainable quality system.

The Indian news source reported that last December

the Indian state agency instituted a three-member
special investigation team (SIT) comprising drug
inspectors from Ahmednagar, Solapur and Mumbai
to inspect the three pharma plants.

It is apparentthat Wockhardt is not implementing global

and sustainable corrective actions, the letter states. FDA
strongly recommended that Wockhardts executive
management immediately undertake a comprehensive
and global assessment of its manufacturing operations to
ensure that your systems and processes, and ultimately,
the drug products you manufacture, conform to FDA
requirements for safety, efficacy, and quality.
Using language identical to that in the July letter, the agency
also highly recommended that Wockhardt hire a third
party auditor with experience in detecting data integrity
problems to assist you with this evaluation and to assist
with your overall compliance with CGMP. The letter
adds that it is the firms responsibility to ensure that data
generated during operations is accurate and that the
results reported are a true representation of the quality of
its drug products.
In responding to the letter, FDAs Office of Manufacturing
and Product Quality (OMPQ) Director Steve Lynn asked
Wockhardt to provide a list of all the batches of drug
products shipped to the U.S. market that relied upon missing,
inaccurate, or unreliable test data.
Just prior to the December letter, FDA issued an
import alert restricting entry into the US of human
drug products manufactured at the two plants.
After the letter was issued, a second import alert, described
as detention without physical examination of veterinary
drugs from the plants, was announced. While the company
had reportedly sold its animal health division in 2009 to the
French veterinary care company Vtoquinol, Wockhardt
may have been manufacturing veterinary drugs on a contract
basis in a way that was not apparent earlier to FDA.

State FDA in India FDA Weighs In

In late March, the Food and Drug Administration for the
Indian state Maharashtra issued show cause notices to
the Wockhardt plants that had received the FDA warning
letters, according to the Indian newspaperDNA.
DNAwas reportedly informed bya source from Wockhardt

The inspection report, which was obtained byDNA, cited

significant violations of GMPs and general sanitation
expectations, including: biomedical waste dumped openly
up to 114 rusted drums containing glycerine used in
making injections lying unused for months a proliferation
of insects and rodent excreta, and used gloves and medicine
packs lying in the open.
An official from the inspecting team explained toDNAthat
empty trial tablet packs, which are produced to check
packaging norms, were dumped in the open, and could
have easily been stolen or illegally recycled for use with
counterfeit medicines.
He also noted that 5,000 vials of agar gel, which is used as
culture medium for injectable products, were lying in the open
presenting an ideal breeding ground for the uncontrolled
growth of microorganisms, threatening contamination of the
State FDA commissioner Mahesh Zagade confirmed
in late March in an interview withDNAthat
the show cause notices were issued and that
Wockhardt has been asked to respond.
According to theDNAreport, Zagade said that if drug
inspectors find that the plants do not step up their compliance
level, suspension or cancellation of manufacturing license
may be initiated.
Since 40% of the medicines being produced in Indian plants
are exported abroad, India needs to be wary of faulty
practices to ensure its export market, he emphasized.
On April 22, Wockhardt announced a further
suspension imposed by Indian regulators.
The firm said that the State Drug Controller in Himachal
Pradesh has suspended the manufacture, sale or distribution
of its fixed-dose combo drug made up of dicyclomine HCl
10 mg, tramadol HCl 50 mg and acetaminophen 325 mg.
Wockhardt said the drug accounted for 3% of its sales last
year and that is was appealing the suspension.
The suspension resulted from a tip to the Indian agency
that some of the ingredients the company used to make
the painkiller had been banned by the Indian government,




Himachal Pradesh state drug regulator Navneet Marwah
He explained that the action was taken after receiving
complaints from consumers, adding that his office has
reported the problem to the federal authorities and that the
ban would remain in place until action was taken at that
The suspension was revoked on April 26 after the federal
agency investigated and said it found no problems with
the products safety and efficacy, a state drug regulator

Ranbaxy Had Similar Issues

Data integrity issues reported by FDA in the Wockhardt
warning letters were similar to those that led to the Ranbaxy
consent decree in January 2012 (see IPQ Monthly Update
February 2012, pp. 23-30).
The decree stemmed from investigations by FDA beginning
in 2008 that revealed numerous problems with Ranbaxys
drug manufacturing and testing at facilities in both India and
the US, and data integrity problems at its India operations,
including backdating of tests and submitting test data for
which no test samples existed(see IPQ May/June 2009).
In May 2013, the firm pleaded guilty to three felony
counts of violating federal drug safety laws and
four of making false statements to FDA.
The issues at Ranbaxy continued to garner media attention as
more information surfaced from former Ranbaxy employee
whistleblower Dinesh Thakur, which outlined a culture of
fraud and corruption(see IPQ Monthly Update July/Aug.
2013, pp. 2-8.)
In a statement released after the guilty plea was entered,
Ranbaxy noted that the settlement involved conduct that
occurred several years ago. Ironically, Ranbaxy CEO Arun
Sawhney said in the statement that todays announcement
marks the resolution of this past issue.

Ranbaxys Past Is Prologue

An FDA inspection at a Ranbaxy plant just eight months
after the guilty plea indicated that the companys problems
had not been resolved.
In January 2014, FDA inspectors visited a Ranbaxy
facility in Toansa, in a rural area north of New Delhi,
and found data integrity and GMP issues similar
to those uncovered in the previous inspections of
Ranbaxy sites that led to the warning letter and
consent decree.

Investigators discovered workers running analytical tests

repeatedly until they got the desired results, computer
systems that allow deletion of raw data by operators, and
back-dating of forms including those specifically used
to comply with the terms of the firms consent decree
according to the FDA 483 issued after the inspection.
In addition to the data integrity issues, the investigators also
found GMP problems in the laboratory, including unusable
equipment, open windows that could not be closed, flies too
numerous to count, and a defective refrigerator containing
a pool of water where working standard sample containers
were stored.
Investigators emphasized that the same lab observations were
previously noted and discussed with company management
during an inspection close-out meeting in December 2012.
Shortly after the inspection, FDA placed an import
alert on the APIs made at the Toansa plant. The
agency had already restricted imports from three
other Ranbaxy facilities in India, including those
in Paonta Sahib, Dewas and Mohali, resulting from
previous poor inspections.
Ranbaxy voluntarily suspended all shipments of APIs from
Toansa and a second Indian plant in Dewas after the FDA ban,
Ranbaxys parent company, Tokyo-based Daiichi Sankyo,
said in a Feb. 25 statement. Ranbaxy is continuing to make
finished products for non-U.S. markets using API inventory
from Toansa and Dewas and from external sources.
In late March, Indian authorities withdrew the Toansa sites
written confirmation effectively suspending the export
of products, as the confirmation must accompany APIs
shipped to foreign countries.
The announcement came only days after Indian-based Sun
Pharma announced it would buy Ranbaxy in a $3.2 billion
all-stock deal with Daiichi Sankyo. The combined entity will
be the worlds fifth largest generics maker with $4.2 billion
in revenue, with the U.S. accounting for $2.2 billion.
EMA said in early April that a team of inspectors from
Germany, the U.K., Ireland, Switzerland, and Australia
performed an unannounced inspection at the Toansa facility
following the FDA import ban, and found issues similar to
those found by FDA. EMA is planning an inspection of the
Ranbaxy Dewas plant in June. The European agency said
it will not permit any imports from the two facilities until it
has confirmed that the problems have been fixed.
Both Ranbaxy and Sun recently announced product
recalls, both for oral solid products.
In mid-March, Sun initiated a voluntary recall of nearly




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3,000 bottles of metformin hydrochloride extended release
tablets after a customer complained of the presence of some
gabapentin tablets, a drug used to treat seizures, in a bottle.
In late April, Ranbaxy announced a Class II recall that it
had begun in February of nearly 30,000 packs of an allergyrelief medicine containing loratadine and pseudoephedrine
sulphate extended release tablets for packaging defects. The
product was manufactured by the firms Ohm Labs plant in
New Jersey, which is the companys only facility currently
making generics for the U.S.

Imports Also Banned from Sun Pharma Plant

Ranbaxys purchaser Sun Pharma also found itself in
regulatory trouble after a late-2013 FDA inspection, which
resulted in an import alert in mid-March, 2014.
Notably, the same FDA investigators who inspected Ranbaxy
in January had previously inspected Suns cephalosporin
facility located at Karkhadi, Gujarat in India in November
Peter Baker and Dipesh Shah, both consumer safety officers
based in FDAs India office. The plant is one of 25 that Sun
owns, and accounts for less than 1% of the companys sales.
The form 483 issued by the investigators at
the conclusion of the inspection was obtained
byEconomic Times of India(ET), which published
many of the observations.
Drug products failing to meet established specifications
and quality control criteria are not rejected, the 483 noted.
Investigators identified multiple torn/partially destroyed
raw data CGMP manufacturing and quality records.
Their review of the records, the 483 reports, identified the
practice of maintaining duplicate versions of cGMP raw data
records. Undesirable data was found to be changed in the
official versions in order to meet specifications.
The 483 also reported observations of poor
characterizing the toilet facilities as in a state of
total disrepair.
The two urinals present in the washing and toilet facility
provided for quality control laboratory male employees
were found to drain directly onto the floor. Urine was found
to be collected in and around an open drain. A strong smell
of urine was observed throughout your firms quality control
environment, the 483 states.
Investigators also noted a garbage dump in the perimeter
of the manufacturing area and various forms of infestation.
Buildings used in the manufacture, processing, packing
or holding of drug products are not free of infestation by

rodents, birds, insects and other vermin.

Ironically, two years earlier, Sun Pharma had been
asked by FDA to step in to fill a shortage when
Johnson & Johnson was no longer able to supply
its injectable cancer drug Doxil to the marketdue
to compliance problems at its Doxil contractor,
Bedford, Ohio-based Ben Venue.
Compliance problems uncovered during mid-2011
inspections by FDA and EMA at the Ben Venue facility
resulted in the site halting manufacturing, and eventually
led to critical shortages of the drug(see IPQ Monthly
Update November 2011, pp. 48-50). Injectable Doxil is
used in multiple treatment regimens, including treatment of
ovarian cancer after failure of platinum-based chemotherapy.
The drug is also indicated for use in AIDS-related Kaposis
sarcoma and multiple myeloma.
In response to the shortage, FDA allowed the importation of
Lipodox, an injectable Doxil substitute manufactured by Sun
that had not been approved in the U.S. (see IPQ Monthly
Update March 2012 pp. 11-13). In 2013, FDA approved a
generic version of Suns drug for the U.S. market that further
helped ease the shortage.
Temporary importation of unapproved foreign drugs
is considered in rare cases when there is a shortage of an
approved drug that is critical to patients and the shortage
cannot be resolved in a timely fashion with FDA-approved
In 2009, FDA ordered manufacturing to be halted at Suns
Detroit-based unit after a string of recalls over manufacturing
defects. Three years later, the FDA cleared the subsidiary to
resume operations with two products.

Other Indian Firms Banned

In 2013, FDA banned about 20 plants in India from exporting
drugs to the U.S. and warned several others.
The most recent import alert was placed on
Canadian-basedApotex plant in Bangalorein early
April, due to significant GMP deviations.
The alert covers the companys drugs and antibiotics, with the
exception of riluzole, used in the treatment of amyotrophic
lateral sclerosis, commonly known as Lou Gehrigs disease.
Apotex received a warning letter in early 2013 for issues
discovered during an August 2012 inspection of its
Richmond Hill, Ontario, Canada facility. The letter pointed
to GMP concerns regarding: microbial control SOPs OOS
investigations process validation laboratory records
environmental monitoring, and CAPA.




An import alert was also placed on APIs coming
from Canton Labs facility in Vadodara, India after
its receipt of a warning letter at the end of
February (see story on p. 3).

It is not that people dont know or people are stupid it is

regulatory maturity. We learn from mistakes. And we learn
from things that can happen and from risks that we didnt
see before.

Topping the warning letter was the finding during an

inspection a year earlier that Canton was reporting on
its CoAs that batches were meeting microbial and metal
impurities limits without actually doing the testing or having
any supporting data.

Regulatory maturity can also manifest itself in terms of

the investigator performing the inspection, with more
experienced investigators better able to uncover problems.

Data Integrity Warning Letters Examined

At a PharmaLink conference in March in Cincinnati, Ohio,
co-sponsored by FDA and Xavier University, National Expert
Investigator Rebeca Rodriguez provided her perspective on
the problems the agency is seeing with data integrity in the
context of warning letters issued to foreign firms in 20132014(see box below for Rodriguez complete remarks on this
Although data integrity issues are more frequently
discovered in certain countries, Rodriguez emphasized that
FDA is not targeting any particular country.
The recurrence of warning letters citing data integrity
problems to firms in particular countries may be reflective
of a number of factors, she said, including: regulatory
maturity experience of the investigator, and location of
the firm within a country.
The regulatory maturity of both the country
regulators and the inspected firms is an important
factor, Rodriguez commented. She explained that
regulatory maturity comes from experience and
knowledge of what things can happen.

I know for a fact, the FDA expert said, that some of the
[agency] people involved in the data integrity warning letters
are people who have a lot of experience, because they have
worked with these systems themselves. They know the lab
systems and how to work with them.
Rodriguez also pointed to the geographical location
of a firm as an important factor in being able to
attract and retain the expertise it needs to become
and remain compliant.
I have seen companies that have very knowledgeable
people, but their area of expertise is maybe for the same
processes, but for food establishments, not for drugs. I have
seen people who mean well. They were knowledgeable of
the processes, but they were not knowledgeable of the drug
It is not only the country, but even within a city, the expert
investigator commented. One company she is familiar with
face problems in getting people with the right expertise
due to its location outside of an area where people wanted
to live. They wanted to live near the nice city, not an hour
away. I have seen this with some companies that are having
trouble hiring the right expertise because their sites are not
located where people want to be.


At a Xavier University/FDA PharmaLink conference in March, FDA National Expert Investigator Rebeca Rodriguez explored the data integrity issues the agency has communicated to firms through warning letters
during 2013 and 2014. She specifically addressed: ignoring bad lab data lab documentation and audit
trails computer system security the use of post-it notes and other uncontrolled documents signing off
on steps before they have taken place blending API batches, and the impact on supplier firms.
I looked at warning letters that were issued to foreign and domestic firms in 2013 and 2014. I particularly looked at four
warning letters that were issued to drug manufacturers including one API manufacturer, and 13 foreign firms. Some
of these warning letters were issued to multiple facilities of the same company. Some of these warning letters were
also issued for OTC manufacturers, re-packers, re-labelers, contract labs, etc. But the bulk were mostly to API and
finished drug product manufacturers.
When I was looking at those warning letters, what really stood were data integrity observations data integrity issues
with foreign establishments. I dont know how familiar you are with the issues, but it has been in the news




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We are really not targeting any particular country. But the data integrity problems may reflect on several factors
regarding regulatory maturity of the companies and the country. There are a number of things that may be playing
into this recurrence of warning letters to particular countries.
Part of those warning letters were also related to the integrity of data that is coming from computer systems, which
is also part of data integrity. That was the point in showing warning letters relating computer systems to the integrity
issues. And there also was a failure to review and investigate production and QC laboratory deviations. Those are the
three things that stood out to me in those warning letters.
The data integrity issues were mostly related to HPLC processing methods for example, people runningmultiple
runs of the same samplesand changing integration parameters until they got the results they expected or wanted.
That is obviously not acceptable. That is basically testing into compliance. For whatever reason I am not saying it
was intentional, I am not going there it was happening.
Another issue that was found during these inspections was the documentation trail of the computer systems, of the
chromatographic systems, was disabled. Theaudit trailbasically tells you every time someone performs a critical
operation with a signature that the system documents that step, and that that action was taken. That trail was
disabled. They were changing data and changing parameters. Whatever the functions that the audit trail was supposed
to follow were not being documented. The absence of that audit trail was enabling people to delete data and change
operation parameters, integration parameters, and that kind of stuff. They used the same password and username.
That is a clear no-no. But we still find these things. I, myself, have found companies that are still doing this.
Another issue that the investigators found was that the system did not protect the data. It was possible to access the
system andmake changes or deletionsto the system. These are just similar iterations of the same issue the failure
to implement access controls to the system.
Excel spreadsheets were also mentioned. Calculations in the spreadsheets were not protected. People could make
changes to the formulas that were in the spreadsheets. This is pretty much the same stuff. These are just some of the
issues that were cited related to computer systems.
There were also less complex issues. Speaking of complexity or lack of complexity, in this particular case, people were
usingpost-it notesor small pieces of paper to write stuff, and then they were transferring that to worksheets or formal
documentation. That kind of practice lends itself to people documenting the data to meet whatever expectations they
have. So that is completely unacceptable.
And also, people were performing multiple runs of the same samples, and calling them different names such as trials
or demos, until they got the ones that were acceptable. Out-of-specification (OOS)results were ignoredand not
investigated they were accepting only the good results.
I thought this one was really interesting. In this case, the reason for the continuous testing and re-testing was that the
company was having API batches that failed. They wereblending the bad batcheswith the good batches and they
were running them again, so then they got a good result. The blending of a bad batch and a good batch is a GMP
violation in itself. Then they covered that up in the re-testing practice.
In this particular case, the managers of the company claimed in their response to the 483 that they didnt know why
operators were doing that. Personally, I have a hard time believing that. I dont have any stake in the company or
that batch. I am not getting the money for that batch. So I dont know how this practice was not being encouraged by
management. I just really wonder when I see stuff like this.
Other issues that they found were that people werepre-documentingoperations. If they were going to perform
a step, they would fill in the data before they performed a step. So that was a little bit of foreseeing an event or
something. This happened not only in lab operations, it was happening in manufacturing operations as well they
were not documenting operations as they were performed.




Those are the data integrity issues that were reported in multiple warning letters. And it was to one particular country.
When I look at this, I wonder what the outcome of this is, because some of these firms were placed on import
detention. Basically, they cant sell product to the U.S., though in some cases the FDA had to allow some things into
the U.S. for very specific reasons.
But what does a company do when their supplier of a critical API cannot supply because they have been placed on
import detention? What does a U.S. manufacturer do about that? It is a huge problem. Could that U.S. manufacturer
have prevented these problems to some extent by doing their homework and qualifying their supplier? That is a
question. I am not concluding anything. These data integrity issues are not always easy to find. On the other hand, in
these particular cases, they seemed to be pretty extensive practices. There were things that the investigators readily

Data Integrity Findings Impact Shareholder

Following Rodriguez to the podium at the Xavier/FDA
conference in March, MHRA GMDP Inspections Group
Manager Mark Birse provided an analysis of the impact
of the data integrity observations on the market value of a
Birse provided a case study that involved
inspections conducted simultaneously by FDA and
MHRA during which many of the data integrity
deficiencies Rodriguez pointed out in her talk were
uncovered. While neither mentioned the firms
name, Wockhardt clearly fits the profile.
The UK official noted that the share price for the firm involved
had quadrupled during 2012. However, as inspections
revealed deficiencies that resulted in FDA import alerts and
EU statements of non-compliance (SNC), the value of the
company declined rapidly(see box on following page).
The three inspections conducted are represented in the
figure by red circles. During first inspection, MHRA was
on site at exactly the same time as FDA, Birse noted, and
uncovered many of the same integrity issues.
The first stock price drop occurred when FDA issued an
import alert, followed by a smaller drop after EU issued an
A second MHRA inspection of a different site coincided
with the issuance of an FDA warning letter to the company
that resulted from the first inspection. During the second
inspection, the company issued a statement to the press that
the inspection was not going well, Birse commented, at
which point the stock price hit rock bottom.
After the stock drop, the firm issued another statement to
the press to try and put a positive spin on things, at which
point the price went up slightly. But then in the EU we
issued a statement of non-compliance for site two and a
statement of non-compliance for site three, which we had

inspected, he explained.
All in all, all of the good work that that company had
previously been doing building up share prices for investors
was just destroyed, Birse said.
Just imagine how much stock value was being lost during
that time. Imagine if a small slice of that had been taken off
and been spent on quality actually doing the right thing.
They would not be in this position now if they had really
thought about it.

MHRA Data Integrity Expectations Outlined

Birse went on to discuss his agencys expectations for a
companys review of data integrity during its internal audits.
The expectations were published on MHRAs website in
December (see box below).

MHRA Expectations for Data Integrity

Self Auditing
The following expectations regarding self inspections by pharma firms were announced by
the UKs MHRA in December, 2013:
The MHRA is setting an expectation that pharmaceutical manufacturers, importers and contract laboratories,
as part of their self-inspection program, must review the
effectiveness of their governance systems to ensure data
integrity and traceability.
This aspect will be covered during inspections from the
start of 2014, when reviewing the adequacy of self inspection programs in accordance with Chapter 9 of EU
It is also expected that in addition to having their own
governance systems, companies outsourcing activities
should verify the adequacy of comparable systems at the
contract acceptor.
MHRA invites companies that identify data integrity
issues to contact them by email at:




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Cost of Non-Compliance to Wockhardt
The following charts depict the impact on Wockhardt share price in the wake of the adverse
inspection findings by FDA and MHRA, which included the lack of data integrity. The three
red circles in the second chart represent the MHRA and FDA inspections.

Share Price During 2012

Share Price During 2013

U S F D A Im p o rt A le rt
S ite 1

E U S N C S ite 1
E U S N C S ite 3

U S F D A W L S ite 1

E U S N C S ite 2

S ite 2 In sp e ctio n findings re a ch P re ss

We thought long and hard about what a company is going

to do if it finds data integrity problems, Birse commented.
Are they going to come to us? We do invite you to come
and tell us if you find data integrity issues.
He emphasized the double-edged sword nature of the
endeavor. If you find a data integrity issue, we want you to
come and discuss it with us. Now it may be that it is so serious
that we still end up having to take regulatory action. But at
least we can sit down and have a sensible discussion.
What the agency does not want to have happen is firms
finding data integrity issues and burying them. We really

need to engage and have sensible discussions if you do find

those issues so we can work through them together.

Detecting and Preventing Data Integrity

At an ICH Q7 training workshop cosponsored by PIC/S
and PDA in February 2014 in Bethesda, Maryland, FDA
Division of International Drug Quality Director Carmelo
Rosa reviewed aspects of data generation and traceability,
the systems used to generate it, and the controls that should
be in place to ensure its integrity.




He listed eight questions firms should ask when examining
data and the systems producing it (see box below).

respect for them because of the difficulties of identifying

these types of problems.

Keys to Prevent & Detect Data Integrity

To be effective, investigators need to understand the systems

they are evaluating and how to look at the process from a
different perspective.

At the ICH Q7 training workshop, FDAs Rosa

presented the following list of questions to ask
when examining data and the systems used to
assure its integrity:
Is the data reliable, trustworthy and verifiable?
Was the data generated following GMPs ?
Is the data traceable and/or referenced to original raw
data and reviewed by a reliable quality structure ?
Are the appropriate controls in place to ensure that all
data is reported?
How long in a process can an employee go w/o direct
How do you know all the data is available?
Do you have mechanisms to ensure the data is authentic, retrievable?
Where critical data are being entered manually, is
there an additional check on the accuracy of the entry?
This can be done by a second operator or by the system

If the data is complete,...if the data is reliable and consistent

and accurate, then you have good data integrity, he said.
That is what we expect from firms.
On the other hand, a firms inability to detect and prevent
poor data integrity practices raises serious concerns about
the lack of a quality systems effectiveness and the decisions
made using that data, Rosa emphasized.
Regarding active pharmaceutical ingredient manufacturing
operations, the agency director pointed out that production
needs to have sufficient control to prevent unauthorized
changes to data as clearly stated in Q7. There should be
controls to prevent omissions in the data to avoid systems
being turned off and data not captured. This is a problem
area FDA is seeing more and more.

Finding Integrity Problems is Difficult

Rosa stressed that it can be difficult for FDA investigators
and inspectors from other regulatory agencies to find data
integrity problems. You cant just go into a facility and
have data integrity just jump out at you.
Investigators may only have four or five days to perform
an inspection, and finding the evidence of wrongdoing
and documenting it is a very tough job, he commented. I
haveall the respect in the world for the investigators. I have
been there. I have done many inspections. I have the highest

Rosa declined to share how agency investigators are

trained to find integrity lapses. I am not going to
tell you is our bag of tricks, he said. I cant.
One reason he chose not to share the information is because
many firms are not using that information to get better at
what they do. Unfortunately, some of them are using that
information to cut corners and get more sophisticated in
how to hide data integrity issues.
Rosa commented that he sees all foreign GMP inspection
reports, and has seen how sophisticated some companies
are becoming in deceiving and engaging in these types of
bad practices.

Establish Audit Trails

Rosa emphasized the importance of recording any changes
made and of having an audit trail that traces back to original
raw data.
He noted that the agency has seen many quality units in
which an analytical or quality package is received, and those
responsible for approving it review it, sign off on it, but
dont spend time going into the system to see the audit trail.
They dont go into the system to see if there were failing
results that were not reported. They dont take the time to
look at and challenge the data that they are reviewing. That,
of course, is a gap in that operation.
Rosa pointed to the importance of the quality
system reviewing data to help prevent and detect
data integrity issues.
Is the reference to the raw data and the review done
by a reliable quality structure? he asked. Why is this
important? If you have wrongdoings on the floor, and you
have a broken quality system, the rest doesnt matter...How
can you rely on the quality system when they are aware of
and are not actually responding or doing the right things to
bring that operation under a state of compliance?
All data must be reported, not just selective data that supports
a desired outcome. Computer files that are discarded or
ignored should be easily retrievable.
Also important for industry to consider, Rosa commented, is
the length of time an employee can go unsupervised. How
much can an employee, an analyst or operator do on his
own without being supervised or without somebody having
direct oversight and challenging the operation?

Challenging Authority Problematic

Rosa explained that there are countries and places where it
is almost seen as a sin to challenge an authority to challenge





higher level management.
He commented that some cultures instill a sense
of respect for elders and people in positions of
authority at a very young age, and breaking away
from that is difficult.
When I look at my dad, I still bow my head, he said. That
is the sense of respect that we had growing up for the people
who had authority over us. And that is no different than
what we see in some firms and some cultures there is just
such high respect for that authority that, God forbid, we try
to tell them, this is wrong, I cant do it.
In such cultures, it is especially important to make sure that
the entire operation and culture understand the expectations
of regulators, but also of what good GMPs mean.
Who? When? What? And how is the data collected? How
is the data processed? Is the data reviewed and is the data
reported? Who does it? When was it reported? What data are
we looking at? And how is it reported? Just basic questions
to keep in mind.

Capitol Hill Briefed on Problems in India

Searching for Safety, an organization that tracks and reports
on counterfeit and substandard medicines, sponsored a
briefing in late February in a Congressional meeting room
on FDA, India and substandard drugs.
About four dozen congressional staff, FDA, White House
and State Department representatives attended the
Presenters at the briefing and the topics they discussed
Ranbaxy whistleblower Thakur outlined problems
with substandard generic drugs and manufacturing
processes in India, their causes, and what could be done
to solve them(see box below).
Amir Attaran, a Professor of Law and Medicine at the
University of Ottawa, discussed the risks of substandard
and falsified medicines, especially those made in India.
He cited obsolete Indian laws and a lack of oversight
by Indias FDA as primary reasons for concern about the
quality of drugs made there.
Harry Lever, a senior cardiologist at the Cleveland
Clinic, discussed the problems resulting from his
increasing encounters with inferior quality medicines
and how clinical outcomes from generic medicines made
abroad generally compare unfavorably with those made
in the U.S. He presented anecdotal evidence showing
that his patients taking the cardiac drug metoprolol
succinate experienced adverse symptoms that seemed
to improve when they were switched from an Indianmade version of the drug to a U.S.-made product.
Preston Mason, a member of the Cardiovascular

Division at Brigham and Womens Hospital and Harvard

Medical School, presented his extensive research into
poor quality atorvastatin (generic Lipitor), which he
maintained shows that generic Lipitor samples from
overseas had elevated and alarming levels of impurities
compared to those produced in the U.S.

Hamburg Proposes India Observing FDA

A week before the late-February briefing, FDA Commissioner
Margaret Hamburg traveled to India to meet with
government officials on quality and other regulatory topics.
Hamburgs visit included the signing of a
Statement of Intention to clarify the points
on which both countries will cooperate, such
as: sharing of CGMP compliance and facility
information, India investigators observing FDA
inspections, and enhancing communication and
public meeting collaboration.
Thakur, Attaran and American Enterprise Institute Adjunct
Scholar Roger Bates, who organized the late-February
briefing, commented on Indian agency officials observing
FDA inspections in an op-ed piece inForbesin late March.
Allowing the officials access to FDA inspection methods
may inadvertently make it easier for Indian companies
to cheat, they wrote. Congress should impose severe
penalties in the form of trade barriers on any country that
repeatedly exports poor quality medicine to America, the
authors suggested.
FDAs recent enforcement actions involving data
integrity received attention at a session of the PDA
annual meeting in San Antonio, Texas in April.
The session began with Sanofi Global Quality VP Edwin Rivera-Martinez, a former FDA compliance official and ICH
Q7 expert working group member, highlighting some of the
recent enforcement trends and setting up the data integrity discussions that followed. CDER Senior Policy Advisor
Karen Takahashi, who serves as a point person on integrity
issues at the drug compliance office, provided her offices
current thinking on data integrity and what FDA is lookingfor and finding during its inspections (see IPQ Monthly
Update, May 2012, pp 11-15 for the full text of a similar
presentation by Takahashi at the 2012 University of Georgia/FDA GMP conference).
A revealing presentation followed by Katherine Eban, a
journalist well known for her book on drug counterfeiting,
Dangerous Doses, and a recent article, Dirty Medicine,
which probes into the Ranbaxy case and Thakurs role as
whistleblower (see IPQ Monthly Update, July/August
2013, pp 2-8). Rounding out the session was Interpro QRA
Senior Consultant Douglas Campbell, a former CDER compliance official with expertise in the integrity arena.




The following is excerpted from a statement by Ranbaxy whistleblower Dinesh Thakur at a briefing on FDA,
India and Substandard Drugs, held on Capitol Hill in late February 26, 2014. Thakur outlined the problems
with substandard generic drugs and manufacturing processes in India, their causes, and what can be done
to solve them.
My name is Dinesh Thakur. I am the whistleblower in the case against Ranbaxy Laboratories, which was unsealed
last May where the company pleaded guilty to seven counts of felony in a US court and agreed to pay $500 million in
penalties. I am here today to speak about the risk we face as to public health with adulterated drugs resulting from a
globalized supply chain and what we are asking the US Congress to do to address this risk.
We have made tremendous progress in our understanding and oversight of the global supply chain that provides lifesaving medicines to patients in the US, [including through provisions in FDASIA,(see IPQ September 29, 2013)and
the Drug Quality and Security Act(see IPQ January 23, 2014).]
My case against Ranbaxy in India and what happened with heparin in China demonstrate that unscrupulous actors in
the global supply chain take advantage of gaps in our regulation for financial gain. Economically driven adulteration
has become a new category of fraud in the pharmaceutical industry.
While the U.S. FDA is making every effort to address this area of risk, based on my past experience, incentives need
to be aligned for pharmaceutical companies located overseas to play by our rules.
In order for the efforts made by the FDA to produce the desired results, we need an able and willing partner in the
overseas regulators. Unfortunately, their objectives are more aligned with promoting commercial interests of their
industry than focusing on public health. I wish regulators overseas were as capable and competent as the US FDA;
unfortunately, they are not. In fact, the Parliament of India has called the Indian regulator incompetent and corrupt.
As much as the FDA expands its footprint in countries like India and China, it cannot replace the role of a national
regulator whose job ought to be to protect public health by guaranteeing good quality medicines for its people. Data
confirm that one in five medicines that are manufactured and distributed in India are spurious. Recent news reports
say that antibiotics administered intravenously to infants in the state of Kashmir did not have any active ingredient in
it, leading to deaths of several hundred children.
Clearly, we need a competent and effective national regulator in countries which provide medicines for the US
marketplace to work collaboratively with ours. The FDA can educate, but it cannot enforce local standards, which vary
widely among countries that supply our medicines.
I am here today to ask you to consider three proposals that I think will help alleviate this problem to a large extent.
1. Incentivize the countries that supply our medicines to upgrade their skills, comply with our quality standards and
improve public health for their own citizens. The US Congress will have to take a carrot and a stick approach. As much
as it wants to educate and train foreign regulators, please also consider punitive action against repeat offenders.
2. Make the reporting of drug substitution (substituting a brand drug for a generic due to lack of effect) mandatory. We
just do not have enough data to really understand what impact generic substitutions have on our public health. While
lack of effect cases are reported to the FDA Medwatch, we need additional data to better understand whether the lack
of effect was due to a generic substitution.
3. Make the pharmaceutical industry monitor its supply chain for economically driven adulteration, especially from
sourcing ingredients to manufacturing the product. We need to complement the existing track and trace legislation
to make sure that the other half of the supply chain is also monitored continuously for risks from global sourcing and
manufacturing. After all, what good is it to track and trace a product that is adulterated in the first place?
There are, unfortunately, no quick fixes in the long road towards drug safety. However, if we work together and apply
the right mix of force, incentives and education, I am confident we can foster a much safer and more dependable
generic drug supply chain.




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A proactive approach to achieving and sustaining
compliance is ideal. But, if the unforeseen occurs,
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HS - Contract Pharma Ad_1_14_PRINT.pdf 1 1/7/2014 10:18:15 AM





NSF-DBA, NSF-Pharmalytica and

Becker & Associates are changing their
names to NSF Health Sciences
on January 1, 2014.





NSF Health Sciences

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Component Testing Gains Prominence in Drug Product GMP Warning Letters
as FDA Focus Intensifies on OTC Topicals and Upstream Supply Chain
Inadequate testing of incoming components is a leading
problem area being cited by FDA on finished drug product
GMP warning letters and is particularly prevalent in the
expanding number of those addressing compliance at
topical manufacturers worldwide.
FDA is expressing concern that each component is not being
tested by the dosage manufacturer for conformity with all
of its specifications and/or that specific identification tests
are not being conducted on components that have been
accepted based on the suppliers certificate of analysis
(CoA), as required by CFR 211.84.
IPQs analysis of drug product GMP warning letters issued
from 2012 through the first quarter of 2014 shows that
over one in three of those addressing finished product
manufacturing (20 of 56) have highlighted non-compliance
with 211.84. Among warning letters addressing topical
manufacturing, the percentage soars to three in four (16 of
Topical manufacturing, meanwhile, emerges as the
leading target of drug GMP warning letters during
the past two years.
The 21 topical warning letters issued since the beginning
of 2012 represent 37% of those addressing dosage form
manufacturing exceeding the number issued to injectable
manufacturers (17) and oral dosage firms (13). Topical letters
also outpaced those addressing API manufacturing (15).
The finding is dramatic in that in the five years prior to 2012,
topical firms received only about one third as many letters
as oral manufacturers which led the warning letter totals
during that timeframe and significantly fewer than either
injectable or API operations.
It is clear that topical OTC manufacturing is getting more
attention as FDAs GMP enforcement efforts intensify in the
global arena. Also clear is the concern around how topical
firms are handling their component evaluation process and
that the agency will not be tolerant when the requirements
in this area are not being met.

making them unapproved new drugs.

Without the driver from the new drug application approval
process, OTC manufacturing has not received as much
inspection attention from FDA particularly overseas
where the majority of the topical warning letter recipients
are located. In this context, it is not surprising that when
the agency does visit these firms, it uncovers compliance
problems that reach actionable significance.
From 2012 to Q1 2014, eight warning letters were issued
addressing OTC oral dosage form manufacturing a few
of the facilities were also making prescription products.
Three of these highlighted component testing among
the GMP problem areas. Adding in topicals, 24 of the 56
warning letters issued to dosage manufacturers during this
timeframe involved OTCs.
Prompting FDA to get to more of the OTC
manufacturers is its ongoing effort to get nonmonograph-compliant/unapproved drugs off the
market an effort that has been expanding abroad,
as the warning letter data underscores. CDERs
compliance office has indicated that unapproved
drugs will remain a priority in 2014 (see IPQ
Monthly Update January 2014, pp. 13-20).
Half of the OTC-oriented warning letters in the 2012-14
cohort (12 of 24) also reference compliance with the formulation and/or labeling requirements of the monograph
Another salient aspect of these OTC warning letters is
the number of repeat observations they contain. And
the problems referenced are not in the somewhat more
subjective realm of how well deviations are investigated,
but address basic direct threats to the quality and safety of
the products.

OTC GMP and Monograph Problems Intersect

Manufacturers that are not constrained by the drug approval

rules also appear immune to the GMP dictates, and they do
not readily change their behavior, the warning letter data
indicates. Clearly one inspection visit is not enough in
many cases to have an impact a reason why this arena is a
resource intensive one for FDA.

80% (17 of 21) of the topical operations addressed in the

2012-2014 warning letter cohort make OTC products. Most
of the OTC topical letters link GMP non-compliance with the
finding of products that are not in conformance with OTC
monographs for labeling and/or ingredients, effectively

The CGMP/drug approval nexus of problems takes

another form in the bolus of warning letters that
have gone out to injectable compounders in the first
quarter of 2014. Nine of the 11 drug GMP warnings
issued during the quarter went to compounders





(see story p. 36).
The letters followed in the wake of the agencys 2013
inspection blitz of high-volume sterile pharmacy
compounding operations nationwide and legislative
empowerment through the Drug Quality and Safety Act
(DQSA), signed into law in November.
The compounding provisions of DQSA clarified FDAs
ability to take enforcement action against the large-scale
compounders on both CGMP and drug approval noncompliance grounds (see IPQ Monthly Update Nov.,/
Dec. 2013, pp. 28-30). They also define a new category
of compounder called outsourcer, which will give
compounders that qualify relief from the drug approval and
labeling rules. However, they will have to meet relevant
drug GMP requirements to qualify.

Incoming Materials Need Policing

The problem of inadequate component testing was addressed
in 10 of 11 warning letters to topical manufacturing
facilities outside the US, and in six of seven to those issued
domestically. The other four letters referencing 211.84 went
to oral product manufacturers (including the one letter
addressing veterinary drug compliance).
Given the broad universe of GMPs and that ingredient
testing is part of the materials handling system, which is not
automatically covered in domestic inspections, the frequency
of its appearance on the warning letters is significant.
The prevalence of the concern with excipient and API testing
on the foreign finished product warning letters reflects, in
part, the broader review that investigators do when applying
FDAs system-based inspection approach overseas. Foreign
inspections generally cover all six systems.
A domestic inspection, on the other hand, may only focus
on the quality system and one of the other five, and not
necessarily the materials handling system addressed by
211.84. The not-infrequent appearance of the component
testing cite on the domestic warnings speaks to FDAs view
of its importance, accordingly.
Also noteworthy is the increased attention
component testing has been getting recently. 211.84
ranked as only the twelfth most frequent citation in
the 2009-2011 foreign warning letter cohort.
FDA is looking closely at how finished product manufacturers
and those making APIs as well are overseeing not only
their own production and controls, but also the reliability of
the materials that they are receiving from upstream.
The problems the agency is seeing in the upstream testing

and distribution practices including the lack of integrity

in testing, release, and CoAs at the supplier level are
prompting investigators to make sure during drug product
manufacturing inspections that the controls are in place
to catch substandard ingredients before they enter dosage
processes and undermine the quality of drugs on the
market. With good reason, the agency is looking to dosage
manufacturers to do more policing of the materials they are

Field Expert Thoma Highlights Component

In a presentation at the University of Georgia/FDA
International GMP Conference in Athens, GA in mid-March,
Office of Regulatory Affairs (ORA) National Pharmaceutical
Inspection Expert Sharon Thoma highlighted the attention
that both the laboratory and material handling systems are
now getting, particularly during foreign inspections.
She noted that her review of foreign drug product GMP
warning letters issued in FY 2012 and 2013 found that failure
to meet the component testing requirements in 211.84(d)(2)
was the second most frequent citation only exceeded in
the foreign letters by the potentially related finding that the
facility was not meeting the analytical methods validation
requirements in 211.165(e).
Reflecting its prevalence in warnings letters to topical
manufacturers, component testing was the fourth leading
cite across all drug product GMP warning letters issued
in 2013, Atlanta District compliance official Phil Campbell
reported at the Georgia conference.
Notably, component testing does not appear among the top
ten 483 cites in FDAs 2013 Turbo EIR database it is 12th on
the list indicating that when the agency does uncover the
problem, it is taken seriously.
The receipt and testing of raw materials is something
she looks at every time, Thoma stressed.
I look at raw materials and I say, how are you testing it?
Are you doing full monograph testing if the full monograph
is available in the USP, or are you using the certificate
of analysis in lieu of raw material testing and doing an
identification exam?
Firms doing the latter, she cautioned, need to remember that
if the ID testing has three components, they have to do all
three to demonstrate that the product is what it says it is.
She finds this a common area where people mess up.

Supplier CoAs Need Validating

Another common aspect of the problem is not validating the




- MA
authenticity of a suppliers certificates of analysis.
I do not know how many times I go into firms and they are
not doing this, the ORA expert investigator said. They will
get a certificate of analysis in, they will do an identification
exam, but they do not validate the authenticity of that
suppliers CoA.
What is needed according to the GMPs, she explained, is
doing the full monograph testing at least annually. You
have to validate them for giving you a good CoA, not a
bogus one, she stressed, adding that the most difficult test
is the one suppliers are going to fudge on the most.
A reduced component testing approach can be
employed, Thoma said, if you have a solid scientific
basis for how you are doing that.
She would not want a firm that gets 10 or 20 raw materials
from the same supplier to test only one of them, even if the
supplier is a trusted one with reliable CoAs.
I would want you to have some reasoning as to why you
do or do not test it, and then I would expect it to be on some
type of rotating basis where, overall, you are looking at all
of these. Thoma would not expect you to test every single
thing that comes in the door, but to have a procedure for
justifying why you are doing the testing you are doing.
She would want to see if a firm is either doing full
monograph testing, or ID testing and using the validation
of the authenticity of that suppliers CoA. She reminded
the conference attendees that for components that are
difficult to test, it may be in the firms best interest to do full
monograph testing, because if something goes wrong with
that API or that excipient, it is going to be your end product
that is majorly effected by that.

Monograph Compliance Also at Issue

The most recent of the warning letters issued to an OTC
topical manufacturer to Goleta, California-based Recsei
Labs in January incorporates the characteristic elements.
The OTC monograph and unapproved drug sections of the
letter point to one of Recseis products labeled for use as an
anti-itch and topical analgesic drug product, which combines
hydrocortisone and diphenhydramine HCl a combination
not generally recognized as safe and effective by the
relevant tentative final monograph for the labeled use.
The letter proceeds to cite the main CGMP deviations found
during an inspection six months earlier. Not establishing
the reliability of your component suppliers analyses
through appropriate validation of the suppliers test results
as required by 21 CFR 211.84(d)(2) tops the list.

The letter expresses further concern with Recseis not

reexamining or retesting its components to show continued
suitability after being kept in storage for long periods of
time or exposure to conditions that may adversely affect the
components, as required by 21 CFR 211.87.
The other problems cited are also frequently in the
OTC topical mix not establishing and following
adequate procedures for stability (166(a)) and for
equipment cleaning and maintenance (67(b)).
In turn, FDAs Los Angeles District Acting Director
Steven Porter notes in the letter that the corrective action
commitments the firm made in response to the inspection
lacked detail and implementation timeframes. Porter also
commented on the repeat nature of the CGMP issues found
during the inspection a not infrequent entry on OTC topical
warning letters as warranting the firms getting the help of
a third party GMP expert to assess its compliance.

Water Quality of Concern for Topicals

The warning letter received in December 2013 by Paterson,
New Jersey-based Ameriderm Labs, which focused on the
production of its topical products AmeriWash, DermaFix,
Instaclean and PeriShield, is similar in: citing component
testing first in the CGMP deviation list including equipment
cleaning, and highlighting the repeat nature of the various
deviations found.
As an example of not meeting 211.84(d)(2), NJ District
Director Diana Amador-Toro points to the inspection finding
that Ameriderm had not tested the water used in product
manufacturing to ensure the absence of objectionable
microorganisms since 2006. FDAs concern was heightened
in finding several microorganisms, including Pseudomonas,
Cronobacter, Burkholderia and Acinetobacter, in the water
samples the investigators collected during the inspection.
The firms response to the inspection concern was
inadequate in that the firm had not sufficiently
increased its water sampling and had not
investigated the root cause of the unsatisfactory
microbial control of its water system.
The district director emphasized the importance of
Ameriderms manufacturing and testing standards,
including microbial controls, for its topical products, in view
of their use in hospital or nursing home settings, and their
application on broken skin. As such, these products should
be consistently manufactured to minimize bioburden and be
free of objectionable microorganisms, the agency stresses.
The letter notes that the 211.84(d)(2) observation was also
made at the previous inspection in June 2011.




Regarding cleaning procedures (211.67(b)), the firm was
found to lack detailed instructions and logs regarding the
cleaning and sanitization of non-dedicated equipment,
including mixing kettles and tanks.
Ameriderms response to the inspection findings, in turn, was
inadequate because the revised procedure provided lacked
sufficient details including cleaning agent concentrations,
equipment disassembly instructions, cleaning frequency,
rinse times and water temperatures, and the firm did not
provide any information describing how the cleaning
process will be documented and monitored, or your method
for determining cleaning effectiveness.
FDA also found the lab operations inadequate for
testing components, in-process materials and finished
products, and for not deploying scientificallyjustified finished product specifications.
As in other of the OTC warning letters, the agency expressed
dissatisfaction with the relationship with the contract lab on
which Ameriderm was relying. FDA found that the assay
methods at the contract lab for testing its finished products
for release were not validated.
Process validation was also lacking (211.100(a)). The firm
had not identified the component attributes (e.g., solubility
and viscosity) and the process parameters (e.g., mixing
time, blending speed, and temperature) that are important
to produce the topical gel, cream and ointment products
under review with consistent quality. Concern was
also expressed with Ameriderms deviation investigation
procedures (211.100(b)).

CoAs Need to be Confirmed

The warning letter issued to Madrid, Spain-based Jabones
Pardo in August 2013 exemplifies FDAs underlying concern
that incoming materials are being accepted based on CoAs
Like several other of the OTC topical producers in the 20122104 warning letter cohort, the firm was found not to have
established the reliability of the component suppliers
analysis through appropriate validation of the suppliers test
results at appropriate intervals, and failing to conduct at
least one specific identify test on a component when relying
on the suppliers analysis.
The letter to the Spanish firm also fits the usual model in which
the incoming component testing shortfall is accompanied by
inadequate product release testing, including evaluating
the identity and strength of all of the active ingredients and
having validated methods as required by 211.165(a).
FDA is finding that the lab work at these firms is not

assuring the quality of the ingredients at either side of the

production process. And, as at Jabones Pardo, the stability
testing program is usually also deficient.

Expectations for Incoming Material Testing

What CDER Office of Manufacturing and Product Quality Acting Director Michael Smedley requested from Jabones Pardo in responding to
the letter is instructive on FDAs overall expectations for incoming material testing. Drug
manufacturers, and topical firms in particular,
should make sure that they can provide FDA investigators with the same information to forestall enforcement problems.
Describe procedures for conducting at least one specific identity test for each incoming lot of components
before releasing it for use in your finished products.
Include a description of your sampling procedure for
raw materials and the number of samples tested for each
incoming lot.
Provide documentation that demonstrates your firm
has performed method validation for each test method.
Provide test results of your reserve samples, within retention period, of each lot of API that you used in the
manufacture of finished drug products distributed to the
U.S. market.
Additionally, include your API supplier qualification procedures and results.

The warning letters issued in 2013 to topical

manufacturers Kanebo Cosmetics of Kanagawa,
Japan, Peking Medicine of Hong Kong, and
Cornelius, North Carolina-based V-SAB are among
those following the same model citing 165(a)
on methods validation and 166(a) on the stability
testing program along with 84(d)(2).
A similar nexus of GMP problems is referenced in warning
letters sent to OTC oral dosage manufacturers since 2012
usually also accompanied by concerns about monograph

Fabricated CoA Results Found in India

The reason for FDA concern with nave reliance on CoAs is
writ large in a warning letter the agency issued at the end
of February to Canton Labs regarding its API facility in
Vadodara, India.
Topping the warning letter was the finding during
an inspection last April that Canton was reporting
on its CoAs that batches were meeting microbial




- MA
and metal impurities limits without actually doing
the testing or having any supporting data.
Further, FDA had already found similar documentation
problems in its 2008 inspection of the firm, and stressed in
the warning letter its concern that proper actions had not
been taken to address the underlying issues.
Making the lack of integrity in the API firms CoAs even
more disturbing was FDAs findings of the lack of cleaning
validation in non-dedicated equipment, on which apparent
product residue was observed.
The warning letter goes on to cite a laundry list of other
GMP and documentation deviations that further undermine
the credibility of Cantons CoA reports that its APIs
conform to specs and that compromise the quality and
accountability of its API in the supply chain.
Following the warning letter, Canton was placed on FDAs
import alert list, banning all of the products made at the
Vadodara facility from entering the U.S.

API Relabeling Practices in Scope

A warning letter at t e end of January addressing practices
at the Hong Kong and Tempe, Arizona facilities of API
relabeler/repackager CBSCHEM shows FDAs concerns
extending a step further down the component distribution
chain. The findings again shed light on why the agency is
paying close attention to incoming material review at dosage
The letter from CDER Office of Manufacturing and Product
Quality (OMPQ) Director Steve Lynn explains what the
FDAs expectations are for the repacking/relabeling facet of
the API supply chain, how the firms practices were deficient,
and what was needed regarding their correction.

Lynn explained that the firms response to the 483 did

not provide sufficient detail regarding how the firm
would maintain and control appropriate supply chain
reconcilability of your APIs. He pointed to ICHs API GMP
guideline Q7 for a detailed description of the records that
are needed to ensure product traceability.
Moving downstream in the firms operations, the
letter cites the failure of CBSCHEM to transfer all
quality or regulatory information received from
the API manufacturer to its customers.
The firms CoAs were found to lack the identity of the
original API manufacturer and the actual testing facility.
Lynn added that it is essential that a CoA include batch
or lot codes, laboratory testing information, expiry or retest
dates, and other relevant information.
The CDER official asked that the repacker/relabeler respond
by providing written procedures for the transfer of quality
and regulatory information to customers. CBSCHEM
needed to explain how it would ensure the information
is accurate and complete. The firm was asked to provide
specific details of the information you will transfer, and
how you will transfer it to your customers, most notably
through creating an adequate CoA.
The other two entries in the Hong Kong section
address CGMP deficiencies in the repacking/
relabeling and holding operations themselves.
The operations were not controlled sufficiently to avoid mixups and loss of API identity, FDA maintained for example,
storing unlabeled APIs in inadequately labeled totes, and
storing returned APIs in the same shelves as incoming APIs
without clear separation or identification.

A mid-2013 inspection of CBSCHEMs Hong Kong

operations revealed that records were not being
retained allowing for the complete traceability of
the APIs it was handling.

The facility was also found not to have a quality unit that
would be responsible for reviewing and approving CGMP
documents and procedures and assuring product quality. In
the response to the letter, Lynn asked for written quality unit
procedures that would assure that the CGMP requirements
were met (see box below).

Records on about two dozen API lots were found not to

contain the batch numbers, manufacturing dates, and
expiration or retest dates. Also observed were inconsistent
record retention practices with regard to the original
manufacturing, including the manufacturers identity,
address, batch number, purchase, receipt, transportation,
distribution, and certificates of analysis.

On CBSCHEMs Tempe, AZ inspection, the

warning letter highlighted the findings that a
container labeled as an excipient was tested by
FDA and found to actually contain several different
APIs a mislabeling incident that could pose a
severe hazard to consumers.

The facilitys inventory records were also found to contain

insufficient information, such as invoice numbers, to identify
and track the APIs received and distributed by CBSCHEM.

Also highlighted was the Tempe facilitys inability to provide

basic documents that must be retained, including those
with the identity and address of the original manufacturer,
such as CoAs and other records with critical information
regarding the ingredient(s).





Quality Unit Oversight at API
In the warning letter to CBSCHEM, CDER compliance
official Steve Lynn lists the following as the oversight
activities expected to be performed by a quality unit at
a repacking/ relabeling facility in the API distribution
approving or rejecting all APIs, packaging and labeling materials
reviewing completed batch and lab control records before determining if an API lot can be released
ensuring that discrepancies, complaints, returns, and failures
are investigated and resolved
approving all specifications
approving all procedures affecting the quality of APIs
approving raw material vendors, API contract manufacturers,
contract labs, and other outsourced activities
approving changes that potentially affect API quality for their
making sure that materials are appropriately tested and the results are reported
making sure that there is stability data to support retest or
expiry dates and storage conditions of APIs

As in other recent warning letters, FDA strongly

recommended that CBSCHEMs executive management
immediately undertake a comprehensive evaluation of
[its] global operations to ensure compliance with CGMP
requirements, and engage a third party consultant with
appropriate CGMP expertise to assess your firms facility,
procedures, processes, and systems.
The letter goes on to point out the potential consequences of
the non-compliance at the repackaging/relabeling stage to
the downstream purchasers underscoring the importance
of drug manufacturers paying close attention to how the
materials they are using are being handled throughout the
distribution chain.
The letter warns that until all corrections have been
completed and FDA has confirmed corrections of the
violations and your firms compliance with CGMP, FDA may
withhold approval of any new applications or supplements
listing your firm as an API labeler/relabeler. The letter adds
that the failure to correct the deficiencies may result in FDA
continuing to refuse admission to the US of materials from
the Hong Kong facility.

Incoming Material Testing Also Cited at API


foreign API inspections as well.

The issue was raised, for example, in a warning
letter to API manufacturer Asada Milling Company
of Gunma, Japan, issued in March 2013, which
stemmed from an inspection conducted the previous
As part of the weakness in Asadas quality oversight and
procedures outlined in the letter, the firm was cited for
not routinely performing identity testing on incoming
raw materials to be used in its API manufacturing and
not verifying the reliability of CoAs for these materials at
appropriate intervals.
The letter also points out that Asada did not have established
procedures that describe the receipt, identification, quarantine,
or storage of raw materials, nor had it established specs for
the raw materials or finished APIs.
Other concerns at Asada involved: inadequate equipment
and facility cleaning incomplete batch records and not
assigning of unique batch identification numbers not
meeting the stability program and expiry/retest assignment
requirements, and not performing process validation for
critical manufacturing parameters. Regarding the latter,
FDA asked the firm to submit validation protocols for all
of its APIs, a timeline for execution, and a description of
how a continued process verification program would be
implemented that will verify that your API manufacturing
processes remain in an ongoing state of control.
As in other foreign API warning letters, the Asada letter
states that FDA would continue to refuse admission of APIs
manufactured at the firm, and may withhold any new drug
applications or supplements listing the firm as a supplier,
until all the corrections were confirmed.
A warning letter issued to Hyderabad, India-based
Posh Chemicals in August 2013 demonstrates that
FDA is also looking at whether the methods that
are being used to assess incoming raw materials are
Along with significant concerns about the integrity of Poshs
lab data and related controls, the letter cites the inspection
findings that the lab was using non-validated assays for
testing of key starting materials and for an intermediate
used in API production.
FDA asks the firm to submit reports demonstrating the
scientific validity of these methods, along with a review
of the validation status of all other non-compendial
analytical methods used in your laboratory and a timeline
for completing the validation activities.

The review of incoming materials is being looked at during




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GAMS292F _ 2014-1

- MA
Wave of FDA Warning Letters to Injectable Compounders in Q1 2014 Follows
2013 Inspection Blitz and Legislative Empowerment; Recipients Among Those
Applying for Outsourcing Status
A bolus of FDA warning letters to injectable compounding
operations in the first quarter of 2014 has followed in the
wake of the agencys 2013 inspection blitz of high-volume
sterile pharmacy compounding operations nationwide and
legislative empowerment through the Drug Quality and
Safety Act (DQSA), signed into law in November.
Nine of the 11 drug GMP warning letters issued in 2014
that were posted by FDA through March went to injectable
The 2014 warning letters contain similar language
explaining the regulatory policy environment
that compounders are operating in, given the new
authorities granted to FDA in DQSA(see IPQ
Monthly Update Nov./Dec. 2013, pp. 28-30).
The agency explains in the letters that at the time the
recipients were inspected in 2013 prior to DQSAs passage,
there were conflicting judicial decisions regarding the
applicability of section 503A of the FDCA [21 U.S.C.
353a], which exempts compounded drugs from several key
statutory requirements if certain conditions are met. Title
I of DQSA referred to as the Compounding Quality Act
(CQA) the agency notes, amended that section of the Act
by eliminating the advertising restrictions that had been the
basis for the judicial conflicts.

FDA Transparent on Compounding

On December 4, a week after the law was signed, FDA
issued three draft guidances and three companion Federal
Register (FR) notices related to the implementation of the
compounding provisions of the act(ibid.)
The draft guidances and FR notices drew a wide array of
comments that reflect the complexity of the factors and the
various stakeholders that need to be considered in advancing
the regulatory processes for compounding (see story on p.
A draft guidance on the fees required for inspections and reinspections of outsourcing facilities was released on April 1
with a comment period extending through May.
The speed at which the agency is moving in the acts
implementation reflects the central place that compounding
operations have occupied on FDAs inspection and health
protection radar screen since the fall 2012 meningitis outbreak
caused by fungus-contaminated injectable methylpredisone

produced by NECC(see IPQ Special Report November,

In addition to speed, FDA is also exhibiting a high
degree of transparency in its enforcement actions
related to compounders.
The agency has assembled a comprehensive public database
that is updated in nearly real time and contains a list of
all compounding firms that have been inspected since
FDAs inspection blitz began in the wake of the meningitis
outbreak(see IPQ Monthly Update March 2013, pp. 1134) 82 as of the end of March with links to related: 483s
(issued to all 82 of the inspected facilities) warning letters
(34) recall notices (26) FDA and company press releases
(12), and referral letters to state boards of pharmacy with
recommended follow-up actions (7).
Included in the 34 warning letters are 15 citing GMP concerns
and 19 from 2008 to 2012 primarily addressing misbranded
and unapproved drugs and label claims. Also listed with
links are 483s given in 2012 and 2013 to five contract testing
laboratories used by compounders.

Outsourcing Rules and Fees Clarified

FDA is also being transparent on the firms that are registering
as outsourcers a new category of compounder provided
for in DQSA to allow a middle ground between a traditional
pharmaceutical manufacturer and a traditional pharmacy
compounder in recognition of the larger-scale interstate
hospital supply operations that have expanded in the US.
Under section 503B of the new act, an outsourcing facility:
is engaged in the compounding of sterile drugs has elected
to register as an outsourcing facility complies with all of
the requirements of section 503B is not required to be a
licensed pharmacy, but compounding must be by or under
the direct supervision of a licensed pharmacist, and may
or may not obtain prescriptions for identified individual
FDAs draft guidance explains that compounders registering
as outsourcers will be inspected by FDA according to a
risk-based schedule. Along with complying with the drug
product CGMPs, they must meet certain other requirements,
including reporting adverse events and providing FDA with
certain information about the products they compound(see
IPQ Monthly Update Nov./Dec. 2013, pp. 28-30).
The registration process is a voluntary one. Once




recognized as meeting the requirements, outsourcers
qualify for exemptions from the new drug application and
labeling requirements, and are able to offer the assurance
to hospitals and other health care providers that their
operations were subject to federal CGMP oversight.
Registration, the draft guidance points out, indicates that all
the required paperwork has been submitted to the agency,
but does not imply that the firms have been granted the
outsourcing status. Follow-up inspections, payment of fees,
and other conditions must be met for the firms to become
exempt from the approval and labeling requirements as set
forth in DQSA.
The new user fee draft guidance proposes a $15,000
annual establishment fee for outsourcers, or $5,000
if the firm qualifies as a small business as defined
in the draft. Should a re-inspection be required, the
cost would be $15,000, independent of the size of
the business.

Of the 38 registered firms, five have received GMP warning

letters: Avella of Deer Valley (Phoenix, AZ) Olympia
Pharmacy (Orlando, FL) Triangle Compounding Pharmacy
(Cary, NC) Medi-Fare Drug & Home Health Center
(Blacksburg, SC) and Allergy Laboratories (Oklahoma
City, OK) a registered drug manufacturer and BLA holder
that produces sterile products.
Of the remaining 33 registered firms, 15 have received
483s and may be subject to other further compliance
actions, 17 have not yet been inspected, and one Unique
Pharmaceuticals in Temple, TX was inspected in May 2004,
and no 483 was issued.
Three of the registered firms have conducted recalls
due to the FDA inspections.

The guidance explains that outsourcing facilities that register

prior to October 1, 2014 the end of the governments 2014
fiscal year (FY) will not have to pay a fee for FY 2014. They
will, however, need to pay the fee for FY 2015. Payments are
due by the end of the calendar year and are not pro-rated.
Failure to pay a user fee will result in the facility losing its
status as an outsourcing facility, the draft explains.

Warning Letters, Recalls do not Preclude

As of the beginning of April, 38 firms had registered with
FDA as outsourcers.

These include two that have received warning letters:

Olympia Pharmacy, which conducted a multi-state recall
in May 2013 of all sterile products compounded between
December 2012 and March 2013 due to concerns about sterility
assurance, and Avella of Deer Valley, which conducted a
nationwide recall of two medications due to concerns with
sterility testing at the contracted lab in September 2013. A
third registered oursourcer, JCB Laboratories,of North
Wichita, KS, recalled six drug product lots for the same
reason as Avella.
Additionally, 19 other recalls were performed by 14
compounders in 2013 the majority due to FDA findings of
a lack of sterility assurance. Including Avella and Olympia,
four of the 14 recalling firms received warning letters. The
remaining 10 received FDA 483s.

Key Concerns in Compounding Warning Letters

The following chart includes the CGMP concerns, recalls, and outsourcer registrations
among the 15 compounders that received GMP warning letters since 2012.











Custom Compound




Balanced Soluons


Green Valley


Stewart Compound












Total Pharmacy


Village Ferlity










- MA
2014 Warning Letters Show Commonalities
In addition to the common language in the majority of
the 2014 warning letters explaining FDAs new regulatory
authorities granted under the DQSA, six of the nine letters
cited the manufacturing and distributing of products without
valid prescriptions for individually-identified patients. The
agency explains that as these products are not the subject of
approved applications, they are rendered unapproved new
drugs and misbranded.
The majority of the letters contain a series of sections that
address: compounded drugs under the FDCA violations
of the FDCA unapproved new drug products misbranded
drug products adulteration charges the section in which
the main GMP concerns are explicated corrective actions,
and the agencys conclusions.
Each of the warning letters cited insanitary conditions or
serious deficiencies in aseptic practices in the compounding
of products that were intended or expected to be sterile,
which put patients at risk.
Along with Avella and Olympia, other recipients of the
warning letters were: Nora Apothecary and Alternative
Therapies (Indianapolis, IN) Pallimed Solutions (Woburn,
MA) Pentec Health (Boothwyn, PA) Total Pharmacy
Services (Houma, LA) Triangle Village Fertility Pharmacy
(Waltham, MA), and Wedgewood Village Pharmacy
(Swedesboro, NJ).
In the letters to Pallimed, Pentec, and Village Fertility
Pharmacy, the focus was primarily on unsanitary conditions
observed during the inspection, including aseptic breaches.
No reference was made to the agencys new authorities or
valid prescriptions. None of these three firms has applied
for outsourcer status.
In each of the nine letters, FDA strongly
recommended that the firms management
under-take a comprehensive assessment of
its manufacturing operations, including facility
design, procedures, personnel, processes, materials,
and systems.
In particular, the letters note, the review should assess
the acceptability of the aseptic processing operations. It is
advised that a third party consultant with relevant sterile
drug manufacturing expertise could be useful in conducting
this comprehensive evaluation.
As with most domestic GMP warning letters, this cohort
was signed by the director of the FDA district in which the
receiving facility is located.
At the University of Georgia/FDA International
GMP Conference in March, Atlanta District

Supervisory Consumer Safety Officer Philip

Campbell reviewed enforcement data from 2013,
including the agencys compounding pharmacy
inspection effort.
In his review of the compounding warning letters issed dur
ng the year, Campbell noted that a few trends popped up
ped up immediately.
Environmental monitoring (EM) and potential microbial
contamination were cited in all seven letters. Gowning was
addressed in six, and stability testing in five.
An analysis of the nine warning letters issued to compounders
in the first quarter of 2014 shows a similar pattern. All
nine were cited for EM and contamination concerns, eight
for gowning, and four for stability testing[see box at right
containing this analysis for all 15 GMP warning letters
issued to compounders since 2012].
A comparison of IPQs analysis of the initial results
of FDAs 2013 sterile compounding inspection
initiative(see IPQ Monthly Update March 2013,
pp. 30-34)with the top 2014 warning letter citations
reveals a significant overlap.
The top citations in the first 14 483s issued under the
initiative in order of occurrence were: gowning personnel
practices EM sterility/endotoxin testing media fills
investigations, and validation of sterilization.
A subsequent analysis by IPQ of seven compounders that
conducted recalls between March and May 2013 showed
the most prominent 483 observations in that cohort to also
include aseptic personnel practices, contamination control,
gowning, and sterilization validation(see IPQ Monthly
Update May 2013, pp. 34-41).
Comparing the top concerns raised in the 483s with
those in the 2014 warning letters shows the prevalence of
environmental monitoring and gowning in both. In turn, the
microbial contamination potential mentioned in the warning
letters in most cases resulted from the personnel practices
and/or lack of validation of sterilization cited in the initial

Inspection Crackdown Results in One Consent

So far, one consent decree has been signed in the wake of the
FDAs inspection crackdown on compounders with Med
Prep Consulting of Tinton Falls, New Jersey, in June.
Med Prep received a warning letter in July 2010 highlighting
concerns over the firms practice of repackaging sterile
products without registering with the agency as a repackager.





A 483 followed after a March 15 to April 3, 2013 inspection,
during which all of the firms sterile compounded drugs
were recalled due to the potential for mold contamination.
In addition to compounding products without
a patient-specific prescription and distributing
products across state lines, the 483 and consent
decree cited insanitary conditions and numerous
other GMP violations.
FDA analyses of product samples taken during the inspection
found mold in injectable drug products labeled as sterile,

and revealed that some of the products were sub-potent,

the consent decree noted. Med Prep has not registered for
outsourcer status.
FDA compounding enforcement database (con
taining 483s, warning letters, recall notices, press
releases, and FDA referral letters to state boards of
FDA draft guidance on outsourcing user fees

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- MA
Comments on FDAs Draft Compounding Guidances Reflect Complex Factors
and Varied Stakeholders Involved
Draft guidances and Federal Register (FR) notices issued
by FDA in December to help implement the compounding
provisions in the Drug Quality and Safety Act (DQSA)
drew a wide array of comments that reflect the complexity
of the factors that need to be considered in advancing the
regulatory processes for compounding.
The three draft guidances and three FR notices that
were issued in early December(see IPQ Monthly
Update Nov./Dec. 2013, pp. 28-30)received
significant numbers of comments from across the
broad spectrum of stakeholders impacted.
The draft guidances cover: overarching rules for what
constitutes pharmacy compounding and how enforcement
for violations may be applied a definition of a new category
of compounder created by the DQSA an outsourcing
facility and the registration requirements, and interim
requirements for ongoing reporting of information to FDA
by the outsourcers on their products and services.
One of the FR notices requests nominations for difficult-tocompound drugs. The other two provide instructions and
a template for completing the nominations. The comment
periods ended in early February for the draft guidances and
early March for the FR notices.

37 Stakeholders Comment on Umbrella

The umbrella guidance received comments from 37 stakeholders, 34 of which have been posted. The 34 comments
were submitted by 20 associations, nine pharmacies, and
five individuals.
Some common themes include: concerns that FDA may be
restricting the practice of compounding drugs for office use
without individual prescriptions the need for clarification
of key terms, and requests for clarification regarding FDAs
intent to establish memoranda of understanding (MOU)
with the states that will address the interstate distribution
of inordinate amounts of compounded drug products.
The International Academy of Compounding
Pharmacists (IACP) and the American Pharmacists
Association (APhA) weighed in on the ability of
pharmacies to compound products for office use
rather than to specific prescriptions.
Each commented that they understood FDA will be drafting
additional guidance regarding office use of compounded
products, but expressed concerns regarding the agencys
thinking in light of a December 3 stakeholder call in which

CDER Office of Regulatory Policy (ORP) Associate Director

Jane Axelrad responded to several questions regarding
office use in a fashion that seemed to imply that FDA does
not intend to allow it.
IACP stated that it is very concerned that FDA does not
intend to allow a pathway in which health care professionals,
hospitals, and other health facilities may purchase
compounded drugs from pharmacists without prescriptions
in order to administer the compounded medications within
the health care facility under 503A.
The association maintained that the Congressional
intent was to leave the issue of providing compounding
medications by pharmacists for a prescribers administration
to, or treatment of, a patient, within their practice to the
A request for clarification of key terms was made
by several commenters, including the Patient,
Consumer, and Public Health Coalition (PCPHC),
the Biotechnology Industry Organization (BIO),
and IACP.
PCPHC voiced general support for the umbrella guidance,
but requested clarification of the terms limited quantities,
inordinate amounts, and valid certificate of analysis.
BIO echoed a request for clarification on limited quantities
along with essentially copies of commercial drug products,
and regularly.
IACP requested clarification on inordinate amounts and
maintained that since the most recently passed legislation
was not accompanied by a Committee Report, it is essential
when defining inordinate amounts to look back at the Senate
Committee Report for the Food and Drug Administration
Modernization Act of 1997.
The 1997 report offers guidance to FDA and defines
inordinate quantities as the amounts typically associated
with ordinary commercial drug manufacturing. Taking
this definition into account, IACP would strongly oppose
any attempt by FDA to impose an arbitrary percentage
or quantity limitation on the amount of compounded
medications that may be distributed interstate.

MOUs Should be Publicly Available

The guidance statement in the umbrella guidance that MOUs
with the states will be drafted that will address the interstate
distribution of inordinate amounts of compounded drug
products drew comments from compounder PharMEDium,




the associations BIO and APhA, and Pew Charitable Trusts.
PharMEDium suggested that in the interest of transparency,
and ultimately public safety, that information displaying the
state-negotiated MOUs and any enforcement actions taken
for violations of its terms appear on the FDA website.
It maintained that making the information publicly available
will help ensure that those pharmacy compounding
operations that are not operating within the contours of
section S03A of the Act, but rather are operating more like
a 503B Outsourcing Facility, be categorized and regulated
under the appropriate regulatory framework (i.e., section
BIO echoed PharMEDiums request that the MOUs
be publicly available, and requested that FDA act as
expeditiously as possible to establish the state coordination
and MOU process.
In its comments, APhA strongly encouraged FDA to
promulgate the draft MOU subject to comment, to provide
an opportunity for all stakeholders, including but not limited
to the National Association of Boards of Pharmacy (NABP),
State boards of pharmacy, and pharmacists to offer input.
The association also attached the comments it had provided
to a draft MOU that FDA released in 1999.
Pew Charitable Trusts provided suggestions on
what it feels should be covered in an MOU between
FDA and the states.
Pew encouraged FDA to consider including alternate
parameters in the MOU to address high-volume, high-risk
compounding. It suggested the agency include a focus on:
compounders that primarily produce office stock products
or compound in anticipation of prescriptions at a large scale
compounders that sell to another dispensing entity rather
than dispensing drugs directly to patients, and sterile
versus non-sterile compounding.
Pew also maintained that MOUs should ensure states share
information with the FDA on known and potential violations
of federal statute and serious adverse events. It pointed out
that Section 105 of DQSA requires FDA to establish a process
for the agency and states to share information on identified
violations of 503A as well as any actions taken against
compounders, but that the information-sharing is voluntary
for states
MOUs should require states to provide this information
to the FDA, and should additionally require the sharing of
information on potential violations of 503A to help direct
FDA oversight, as well as serious adverse events related to
compounded products, Pew commented.

Outsourcing Guidance Prompts Sterility

Prominent among the comments on FDAs draft guidance
on registration as a compounding outsourcing facility were
questions regarding why only sterile product compounders
are in scope, and a provision allowing firms other than
licensed pharmacies to register. Seven organizations
submitted comments, including one association and six
Westlake Village, California-based Sinus Dynamics
Pharmacy and IACP questioned whether nonsterile compounding facilities are in fact covered
by the guidance.
IACP commented that while DQSA section 503B only allows
facilities in the practice of sterile compounding to register,
the draft guidance states that an outsourcing facility must
notify FDA whether the outsourcing facility compounds
sterile drugs.
The association stated that it is confused as to whether
other facilities that do not compound sterile compounds
are allowed to register, noting that if only facilities that
compound sterile drugs are allowed to register, then the
requirement of notification to FDA that one compounds
sterile drugs seems redundant.
IACP also expressed strong concerns with a
statement in the draft guidance that allows an
outsourcing facility not to be a licensed pharmacy.
The draft states that the outsourcing facility is not required
to be a licensed pharmacy, and may or may not obtain
prescriptions for individual patients.
The association asked for further guidance on whether this
language would allow a non-pharmacy to fill prescriptions.
It also requested clarification on whether FDA interprets the
statement to mean that FDA has the authority to regulate
both dispensing and compounding within a 503B registered
Allergy Laboratories of Oklahoma City, OK is an
example of a firm that registered as an outsourcer
but is not a compounding pharmacy.
Allergy is a registered drug manufacturer and BLA holder
that produces sterile products. The firm was among five
firms that have registered that have received a warning letter
addressing GMP issues since the end of March. (see p. 36 for
more on the results of FDAs inspection crackdown in the




- MA
sterile pharmacy compounding arena.)

Interim Reporting Requirements Questioned

FDAs draft guidance on interim reporting requirements
for registered outsourcers received comments from seven
Among them were questions regarding the timing
of report submissions to the agency and assertions
that the new requirements will not decrease the
likelihood of the issues that led to the pharmacy
compounding crisis that precipitated the renewed
compounding focus.
PharMEDium pointed out that the draft requires each
registrant to submit a product report to FDA in June and
December of each year, while it also specifies that the report
must identify all drugs compounded during the previous
six-month period.
Taken together, the compounder asserts, the statements
place a burden on the compounder if the reports are expected
to be inclusive of materials compounded during the month
the report is submitted. It suggests that the agency allow a
minimum of 30 days to compile and audit the information
prior to submission. It further suggests that the reporting
be aligned with annual business processes and Drug
Enforcement Agency (DEA) reporting.
PharMEDium further suggested that the date a compounded
drug is shipped out of the outsourcing facility is the most
appropriate date to report to the agency as the compounding
date to accurately reflect the production and consumption
The Academy of Managed Care Pharmacy (AMCP)
asserted that the outsourcer registration guidance
does not provide assurances to the public and
would not have likely prevented the tragedies in
AMCP commented that it has consistently maintained that
the FDA had the authority to address the fungal meningitis
outbreak and that additional authority was not necessary.
It asserted that the passage of DQSA created confusion
by creating a new, unnecessary outsourcing facility that
represents only an administrative registration requirement
with no further assurances of safety and efficacy of
compounded products.
The association further maintained that DQSA creates a
dual regulatory scheme, under which some pharmacies
will be licensed entities under state law and also registered
under federal law. Other non-pharmacy entities may seek

registration, but the public is not adequately informed of the

companys business practices or pharmacy status.
AMCP concluded that it believes this regulatory
infrastructure will create complications in administration
and that issues of responsibility and accountability will
undoubtedly continue to occur.

Comments Also Heavy on Difficult-toCompound List

FDAs December FR notice requesting nominations for a
list of products that present demonstrable difficulties for
compounding that may result in an adverse effect or the
safety or effectiveness of the product the risks the so-called
difficult-to-compound list received comments from 32
different organizations and individuals.
The submissions included nominations of
particular compounds as well as suggestions for
alternative approaches to determine which products
are difficult to compound as opposed to producing
a finite list.
Substances that were nominated for the list (and the submitting
firm) include: hyaluronidase for injection and hyaluronidase
injection (Halozyme) Collagenase SANTYL Ointment
(Smith & Nephew) dimethyl fumarate (Biogen Idec)
deoxycholic acid and its salts (Kythera Biopharmaceuticals)
methylprednisolone for epidural injection (Arachnoiditis
Society for Awareness and Prevention) injectable erectile
dysfunction drug combinations containing papaverine
(Auxilium Pharmaceuticals), and atropine, heparin, and
azithromycin reconstitution as a powder for IV infusion
(Nephron Compounding Center).
In its comments, BIO asserted that all biologicals should be
included on the list. The association requested that FDA
formally state that biological products subject to FDA
approval under section 351 of the PHSA are not covered
by the limited new drug application exemptions found in
FFDCA sections 503A and 503B, and thus compounding
these products without an approved BLA is prohibited and
would constitute illegal manufacturing.
The American Society of Health-System Pharmacists
(ASHP) and PharMEDium suggested some general
approaches to determining what products are
difficult to compound rather than submitting
specific examples.
ASHP commented that it supports FDAs approach of
evaluating candidates for the list on a case-by-case basis
using its stated criteria as well as other factors that may
emerge depending on the array of agents or formulations




proposed for the list.
The association maintained that, in general, the criteria
for factors that present demonstrable difficulties for
compounding proposed by FDA represent a reasonable
approach. It requested that the agency clarify the terms
sophisticated, complex, and significant, and explain
how the degree to which these apply may vary according
to the availability of newer compounding techniques or
PharMEDium suggested that the agency base its
determination of difficult-to-compound products in the
sterile arena on the increasing risk levels involved in the
continuum of sterile compounding, from, on the one hand,
producing a final sterile product combining only FDAapproved finished sterile drugs, to the higher risk start of
the compounding process using non-sterile bulk substances
to creating sterility in the final product. It pointed out that
as compounding risk increases, the procedures, processes
and training required to demonstrate competency in
compounding should increase as well.

Categories Approach Suggested

Public Citizen and GlasoSmithKline (GSK) recommended
in their comments that FDA use categories of compounds
rather than a discreet list and provided their rationale and
GSK suggested the following categories:
respiratory drugs modified-release drugs
certain drugs and drug products, including but
not limited to those subject to Risk Evaluation and
Mitigation Strategies (REMS), and drugs that are
characterized by narrow margins between their
effective and toxic doses.
The firm pointed out that respiratory products often
incorporate sophisticated drug delivery systems, such as
dry powder or metered dose inhalers, which are precisely
engineered and tightly controlled to deliver their active
ingredients to local sites of action within the body.
In addition to their device components, the formulations
of respiratory medicines are often complex, using
active and inactive ingredients with defined particle size
profiles and other qualities that are intended to interact
with those components in specific ways. It asserted that
the manufacturing of respiratory products requires
sophisticated facilities and equipment, and highly trained
personnel, beyond the capabilities of drug compounding
Modified release products including delayed, sustained,

and extended release tablets and capsules are generally

manufactured using complex, often patent-protected,
technologies, GSK stressed. The failure of a drug
compounding operation to understand, have access to,
and utilize these technologies appropriately could result
in products with poor dosing accuracy, bioavailability, or
product-to-product uniformity any of which may affect
safety or effectiveness.
The category that includes certain drugs and drug products,
including but not limited to those subject to Risk Evaluation
and Mitigation Strategies (REMS), the pharma firm
maintained, present increased risks. Adequate mitigation
of these risks requires careful and consistent manufacturing,
enhanced labeling and risk communications, and even
restricted distribution.
The fourth category that encompasses drugs characterized
by narrow margins between their effective and toxic doses
also includes others that require careful dose selection and
titration. For drugs in this category, even small differences
in dose or bioavailability can have clinical consequences
for patients, GSK maintained, citing anti-epileptic drugs
(AEDs) as perhaps the most well-known of such products.
Public Citizen expressed a concern that the FDA
intends to develop and publish a single list of drug
products and categories of drug products that cannot
be compounded because they present demonstrable
difficulties for compounding, and recommended
using product categories instead.
Like GSK, Public Citizen recommended dry powder
inhaler and modified release or time-released dosage form
categories. It recommended four other categories, including:
non-sterile-to-sterile compounding metered dose inhaler
(MDI) products transdermal delivery systems (TDSs), and
enteric-coated preparations.
Non-sterile-to-sterile compounding, the consumer advocacy
organization asserted, requires sophisticated facilities and
equipment that must be maintained to exacting standards,
rigorous training of the personnel performing the operations,
and appropriately-conducted sterility assurance testing. It
further referenced the problems found during FDAs 2013
inspection blitz of sterile compounders (FISH) as evidence
that this category of product deserves special attention.
Public Citizen recommended an MDI category because the
drug delivery systems are sophisticated and require
extensive development to ensure dosing accuracy and
reproducibility. In addition, precise formulation of the
drug product is required to ensure the dosing accuracy
and reproducibility, and product-to-product uniformity is
critical, and is usually difficult to achieve. Also cited was




- MA
the difficulty in achieving reproducible bioavailability of the
compounded drug.
In recommending a TDS category, Public Citizen cited an
FDA concept paper from 2000 that recommended TDS
products be identified as presenting demonstrable
difficulties in compounding. Similarly to MDI products,
TDSs are complex products that require extensive
development to ensure dosing accuracy and reproducibility,
and precise formulation of the drug product is required to
achieving reproducible bioavailability.
An enteric-coated preparations category was recommended
because improperly formulated enteric-coated preparations
could impact bioavailability, potentially reducing the drugs
efficacy or increasing safety risks. Public Citizen stressed
that clinical testing is necessary to prevent these problems,

but such testing is not required under the new compounding

Dockets for draft guidances (including comments):
Umbrella guidance on pharmacy compounding of human drug products
Registration for human drug compounding outsourcing facilities
Interim product reporting for human drug compounding outsourcing facilities
Dockets for draft guidances (including comments):
Drug products that present demonstrable difficulties for compounding


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Compounding Drivers and Problems Dissected by Merck Pharmacy Expert at
April PDA Annual Meeting
Root causes of the problems in the pharmacy compounding
arena range from the absence of training in pharmacy
schools to commercial pressures that prompt established
pharmaceutical firms to leave the market and force hospitals
to rely on less qualified providers to fill their immediate
patient needs, Merck Engineering BioSterile Validation
Director Chris Smalley commented at the April PDA annual
meeting held in San Antonio, Texas.
Smalleys insightful analysis of the current high-profile
issues in the compounding arena was informed by both
his extensive pharma experience as well as by the first two
decades of his career, which was spent in the U.S. military as
a licensed pharmacist performing hospital compounding.
As a hospital pharmacist, Smalley prepared IVs and total
parenteral nutritional (TPN) packages. He explained that his
training in pharmacy school in the 1970s included laboratory
courses that taught various types of compounding and
evaluated the students ability to perform them.
I couldnt pass compounding lab until I could make
capsules, Smalley commented. We made suppositories. We
made powder. And we made sterile products, including
hand-filling ampules with syringes. I learned about aseptic
Over the intervening three decades, the pharmacy
school curriculum has shifted towards clinical
pharmacy focused on drug/patient issues and
hands-on pharmacy compounding is no longer
usually taught, he pointed out.
Smalley commented during the Q&A after his presentation
that pharmacists and those inspecting them especially at
the state level generally have not had the training or the
skills to either perform compounding or evaluate those who
The New England Compounding Center (NECC) was
inspected by the Massachusetts State Board of Pharmacy
several times, he pointed out, and it continued to
Pharmacists have a role in healthcare, but they are not
being taught compounding pharmacy anymore. And yet a
pharmacist goes out and gets a license and is entitled to do
things like making TPN solutions and do compounding. It is
a real concern of mine.
Smalley explained that the American Society of Healthcare
Pharmacists published a book that provides instructions

on how to perform various types of compounding. I dont

think reading a book would help you manufacture sterile
products in your facility. They might have book knowledge,
but it has a lot to do with skills.

USP Forum Also Stresses Training Concerns

At a two-day forum on microbiology that took place at USP
headquarters in Rockville, Maryland in March, 2013, a panel
of experts that was convened to review compounding issues
also pointed to training in pharmacy compounding as a key
driver of the sterility issues that have been surfacing(see
IPQ Monthly Update May 2013, pp. 23-33).
In focus during the session were the aseptic practice, training,
laboratory and regulatory concerns that have surfaced
among sterile compounders in the US and how the 2008
version of USPs sterile compounding chapter <797> should
be refined to help address them.
A basic message that emerged is that, compared
to pharmaceutical manufacturers, the technicians
doing sterile pharmacy compounding have a much
harder job with generally much less training and
expertise to accomplish it.
Participating on the panel were two members of USPs
Sterile Compounding Committee, Keith St. John and Erik
Kastango, and two members of the USP Microbiology
Expert Committee to which it reports, Jim Agallaco and Russ
Madsen. Kastango is heading the committee that is looking
at revising USP <797>.
Pharmacy schools do not train pharmacists on aseptic
processing or control or sterility assurance, Kastango
commented. All of that stuff is tribal lore. It is verbal
tradition. So it is going to be, I go to my new tribe. I go
to my new facility. And I am going to get trained by Keith.
And I am now here. Keith leaves and Russ gets hired and so
now I am going to train Russ. So you have this rotation over
time of what people understand.
Madsen supported the training observation with
data from a Wall Street Journal article that reported
on a study looking at contamination rates in
pharmacy compounding operations.
The study showed that pharmacists who were doing media
fills in compounding had a contamination rate of about 4%.
For technicians in the same pharmacies, the contamination
rate was about 8%. Compare and contrast that with what
we see in the pharmaceutical industry for aseptic processing.




- MA
It is down around 0.1% or better, Madsen emphasized.
So we see orders of magnitude differences. And I relate
this to training and skill, and trying without the benefit
of scale-up, without the benefit of process development,
working with a very wide variety of materials and products
to produce sterile compounded products. It is very difficult
on its face.

Cost Pressures, Shortages Drive Compounding

During the Q&A at the April PDA meeting, Smalley also
pointed to changes that have taken place in the pharmaceutical
industry over time that have driven the growth in pharmacy
compounding, including less pharmacist presence, an
increasing focus on costs and profits, and the resulting drug
shortage problems.
In the 1970s as a newly-graduated pharmacist, Smalley had
the opportunity to tour pharmaceutical plants. At that time,
the head of packaging was a pharmacist. The manager of
production was a pharmacist. The manager of quality was
a pharmacist. There used to be a very nice interconnection
between industry and pharmacy. It has become very
separated. It has become difficult for us to talk.
At that time, Smalley recounted, Parke Davis and Eli
Lilly were the two largest pharmaceutical manufacturers.
They made everything. I could buy ammonium chloride
in perchlorate tablets, taken by people with tuberculosis
to improve their airflow. I am sure that it was not a big
contributor to the bottom line. But that was the focus of
pharmaceutical companies like Parke Davis and Eli Lilly to
make product available that met the need of patients.
In most pharma companies today, Smalley maintained,
the focus has shifted to the financial contribution of products
to the companys bottom line, with products periodically
dropped that meet patient needs but are not profitable.
Compounding pharmacies step in to fill the gaps when these
products that patients need are not commercially available.
The decreased profits from products with thin
margins and those about to go off patent can also
play out in drug shortages, Smalley explained.
Referencing the narcotic drug oxycontin, currently in short
supply, Smalley commented that if oxycontin was a big
moneymaker, there would be no shortage. There would be
some manufacturer out there pulling their hair out to make
sure that the product was on the market because they were
making a good buck.
Existing products and those going generic that have very thin
margins and do not contribute a lot to the bottom lines of the

companies wind up having this problem like oxycontin.

There is little financial incentive for industry to resolve the
drug shortage issue with these products, the Merck official
Smalley recounted an experience he had at Wyeth
regarding an oral antibiotic that went off patent and
the companys actions at the time that inadvertently
led to a shortage of the drug.
The day the product went off patent, he explained,
Wyeth did not wait to see what the sales were going to be
or how much it was going to earn. They closed the plant, laid
everyone off, and began deconstructing the plant, because
they knew it was not going to be a big profit contributor.
Because the generic firms had not yet geared up production
and did not anticipate that Wyeth would immediately leave
the market, a significant shortage situation resulted that
lasted for about six or nine months. That happens a lot.
Drug shortages are driving a lot of our compounding
right now, Smalley stressed. The increasing amount of
drug shortages is accelerating the need and demand for

Voluntary Outsourcing Registration of Concern

During the Q&A after his presentation, Smalley also
expressed concern regarding the voluntary approach that has
been written into the Drug Quality and Safety Act (DQSA) for
pharmacy compounders registering as outsourcers,(see
IPQ Monthly Update Nov./Dec. 2013, pp. 28-30)noting
the potential for abuse of the system.
FDA recognizes that some drug availability is going to have
to be managed by compounding pharmacies as provided for
in DQSA and the follow-up outsourcing registration draft
In exchange, facilities are supposed to voluntarily enroll so
that they can be inspected to assure that they meet relevant
CGMP requirements one of the qualification criteria for
the outsourcer status. But the key word is voluntary,
Smalley said. So, in the end, who do you think is going to
enroll? The ones that really need the help? Or the ones that
are in pretty good shape?
The comment drew a question from a participant,
who asked whether a hospital would be more likely
to source compounded products from an FDAregistered facility, and whether they would face
any liability if there were issues with a product that
had been obtained from a compounder that was not




Smalley responded with an analogy to demonstrate the two
facets of the issue: Whether people are aware of registration
or accreditation programs, and if so, whether they perceive
them to provide any value.
He pointed to USPs program for accreditation of nutritional
supplements. A manufacturer can enroll in the USP program
and get a symbol on their product that says that it meets
USP standards for their nutritional product, he explained.
Maybe it has not been publicized enough, so maybe it is a
matter of awareness. But are people willing to pay 20% more
to pick a bottle off the shelf that has that label that so-called
seal of approval?
If someone purchases an electric product in the U.S., Smalley
maintained, that person would probably be unwilling to buy
a product that did not have an underwriters laboratory label
on it. The fact of the matter is that about 20% of the electrical
products in the United States are illegally imported from
countries like China, and the UL label has been counterfeited
onto that product, he commented.

While there should be a willingness to pay a little bit more

to assure product quality, ultimately Smalley suspects that
the ability to provide the desired product reliably, in a timely
manner, and at a reasonable cost, would be the primary
deciding factors for a hospital pharmacy director making
sourcing decisions. Whether the firm is enrolled in the FDA
program would likely be a secondary consideration.
Smalley also expressed concern that there will be
compounders that do not enroll as outsourcers and
try to fly below the radar.
There are going to be thresholds for detection, he
commented, such as whether products are introduced into
interstate commerce or exceed a certain volume. There
are going to be people out there who are going to say, I
understand what that threshold is and I am going to stay
below that threshold, because of a perception that meeting
the FDA requirements would be cost-prohibitive.
It scares me, he emphasized, the whole concept of
having thresholds is just a struggle.


At the 2014 PDA annual meeting, Merck BioSterile Validation Engineering Director Chris Smalley reviewed
some of the more high-profile contamination events with compounded injectables and then discussed three
drivers for the increased reliance of healthcare practitioners on sterile compounding: the lack of commercially-available products drug shortages, and cost pressures.
I am going way back before NECC. In 2001, eleven people in Northern California developed bacterial infections from
injections with compounded betamethasone a steroid. Three died.
In 2002, seven people became ill and two died from fungal infections caused by contaminated methylprednisolone,
another steroid, made by a compounding pharmacy in South Carolina.
In 2011, contaminated steroids were injected into the eyes of patients in Florida for macular degeneration. There is a
product on the market for macular degeneration, but it is extremely expensive. What happens is, the price pressures
cause people to consider going to alternate products. There is, in fact, a product that is commercially made, but it
does not have as an indication the injection in the eye for macular degeneration. The manufacturer does not make that
claim. And compounding pharmacies have arisen that will make that product and will make that claim.
And here, thirteen people, instead of having the macular degeneration stopped since sometimes you are not curing
the macular degeneration but you are stopping the degradation got a contaminated steroid product that damaged
their eyes.
So maybe in 2001, and in 2011, you didnt hear about it because we have a threshold of how many deaths it takes
get our attention nationally. The New England Compounding Center probably hit that threshold with 50 deaths. And
what was the product? A steroid injection. And 720 additional people were injured.[Editors Note: For more on the
compounding problems and the regulatory environment that preceded the NECC crisis, seeIPQs November
2012 Special Report.]
Okay, 50 deaths probably hit our threshold. Now everyone is interested and everyone is excited. And what you noticed
is, every product that we have been talking is a steroid.




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What makes this popular? What makes this demand for compounding pharmacies? Physicians do not want to inject a
preservative-containing product, intrathecal into the spinal canal. So what is our root cause?

Lack of Commercially-Available Products

Our root cause is that we are not making commercially available products. There is a need, and the physicians are
demanding this from pharmacists. I can tell you, I have been standing in the pharmacy when the pharmacist has said,
thats not commercially available. I cant give you what you need.
And of course the pharmacist winds up first telling the nurse, because the nurse is the one who wants the product
to give to the patient. The nurse in turn tells the physician. The physician, in turn, calls the pharmacy and dances on
the pharmacists face and says, why cant you give me what I need? I am the captain of this ship. Physicians regard
themselves as being the captain of the ship. This is what I want. You are responsible as the pharmacist for giving me
what I want, for giving me the meds I need to treat my patient. Get it. There is a lot of pressure on the pharmacist.
So lets continue to talk about what drives some of these things. Sometimes products are commercially available as
they are listed in the catalogue, but they are not available at the time the pharmacist needs them.

Drug Shortages
These are recalls from us the pharmaceutical industry. [In December 2013] Baxter initiates a worldwide voluntary
recall of 5% dextrose injection and normal saline solution, 0.9% sodium chloride injection for IV solutions. Okay.
A doctor writes an order for a patient. What am I going to do? I am going to take 5% dextrose and I am going to
put enough sodium chloride in to get it up to 0.9%. I am going to start compounding, because the product is not
commercially available to me.
[Also in December 2013]Hospira issues a voluntary recall of one lot of Lidocaine injection of 2%, 5 ml in 5 ml vials
due to the presence of particulate matter. We receive an awful lot of particulate matter recalls. Recently there was
a recall where one company found a particle in a vial that was on stability, notified FDA, and wound up recalling the
whole lot.
That lot gets recalled. I need Lidocaine 2%. Now I probably have Lidocaine 50% on my shelf. So what am I going
to do? I am going to take Lidocaine 50% and dilute it and make up smaller vials. I am now compounding, because
commercially available products have been withdrawn from the market. These recalls creating drug shortages are
getting to be more and more of a problem.
Drug shortages are driving a lot of our compounding right now. Earlier I talked about how product simply wasnt
commercially available, and now I am talking about how the increasing amount of drug shortages is accelerating the
need and demand for compounding.
A Pfizer facility caused a drug shortage. [There] is an instruction to me as a pharmacist at a hospital from the director
of pharmacy to prepare these compounds because these compounds were no longer being made available. The one
I want to highlight for you is oxytocin, 10 units in a 500 ml normal saline solution bag. How many people know what
oxytocin is normally used for in a hospital? Wow. Didnt get a lot of hands raised.
It is crucial. If you have a doctor in the delivery room, if you have an OBGYN, and the delivery is scheduled, their hair
is going to be on fire if they dont have oxytocin available. That is the best way I can characterize it.
This is the instruction to the pharmacist: Currently, oxytocin 20 units of 100 and 1000 ml in normal saline solution must
still be made in the pharmacy and stocked in the Womens Care Unit. One of the reasons I point this out is because
earlier I said that prescriptions are made based upon the physicians order for a patient. This points out how we are
beginning to detach ourselves from that philosophy. Pharmacies in hospitals will compound these and stock them in
the nurses unit before the doctors order has been received, so that when the doctor wants the oxytocin it is there and
he can give it to the woman who is going to deliver.




So we begin to detach ourselves. No one is being evil. No one is being malicious. But philosophically we are beginning
to separate the concept of filling to an order. In fact now, even within the hospital, we are compounding to stockpile in
anticipation of that order.
So when we talk about these compounding pharmacies not filling to an order and in fact, this is what FDA has been
trying to achieve with the new law hospitals have been doing this for a while.

Cost Pressures
Cost remains a big concern. Everyone is on a tight budget. The Affordable Care Act (ACA) actually cuts reimbursements
further. For those of you who are not familiar with some of the things hospitals are struggling with in the ACA, if someone
is admitted to a hospital with one of three types of conditions, such as a heart attack, and they are discharged from
the hospital, if they need to be re-admitted to the hospital within a certain time-frame, the hospital will not be paid for
the re-admission. The hospital is being told that when it discharges that patient there have to be more effective aftercare activities that are taking place to ensure that the patient is not being re-admitted. And by the way, if you need to
re-admit the patient, you are not going to be reimbursed for your cost.
The cost demands are extreme on hospitals. I can tell you within the next three years you are probably going to 20%
of hospitals in the United States go out of business.
I want to talk more about this third factor. I actually have the article right here. US Medicine is a publication that
services healthcare providers in the military and also in the Veterans Administration. I continue to receive it, even
though I am now retired, as a courtesy.
It talks about how Walter Reed, one of the premier hospitals in the US military system, has saved $700,000. The gist
of the article is that by using a closed transfer device, they can now, on average, get ten doses out of nine single dose
vials. They know that there is over-filling in single dose vials. So by using a closed transfer system, they now know by
the time they open up nine vials, they have enough overfill to that they can get a tenth dose.
They are so proud of it that they published an article. [The pharmaceutical industry is] making single dose vials with
the intention that the single dose vial, obviously, will be used one time. Maybe you do it that way because you are able
to reduce or eliminate a preservative in that single dose vial. Remember earlier the demand for intrathecal use was
lets get the preservatives out. So now you want to use that single dose vial, and nine vials will be combined to give
ten doses, and they will save $700,000. It is that important to them. They do not realize the risk that they are putting
on the patients.
Between drug shortages, product not-available, plus savings, this is why as an industry we have to be interested in
compounding pharmacy.
For a pharmacist, I would tell you, whatever your role is, it is to ultimately meet the needs of the patient. You might
regard your customer as being the physician. You might regard your customer as being the healthcare system. But
ultimately the needs of the patient need to be met. All of these forces are impacting on what is causing more pharmacy
compounding skills, cost, and availability. But ultimately we have to ensure the patient is not being harmed.





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- MA

ICH Q8-11 Oriented Submission and GMP Expectations for Process
Validation and Other Quality Issues Taking Shape in Europe
The effort in Europe to update its expectations for process
validation (PV) to reflect the quality management principles
underpinning ICH Q8-11 moved closer to completion in
late February with the issuance of a final guideline on PV
submissions for medicinal products and a draft revision of
EU GMP Annex 15.
A draft of EMAs guideline on what should be submitted in
marketing dossiers regarding process validation for finished
products was put out for public comment in the spring of
2012(see IPQ Monthly Update May 2012, pp. 44-45). The
final guideline, modified to reflect the numerous comments
received on the draft, becomes effective in August.
Annex 15, which addresses the qualification and validation
of processes from a GMP vantage point, was last revised
in 2001. A concept paper explaining the motivations
for the revision was released by EMAs GMP/GDP
Inspectors Working Group (IWG) in late 2012(see IPQ
Monthly Update Jan./Feb 2013, pp. 24-30). Among them
are technology advances, changes to the EU GMPs, the
incorporation of ICH Q8-11 principles, and the rewrite of
the PV drug product submission guidance. Comments on
the Annex 15 revision are due by May 31.
A third EMA PV project is focused on biotech active
substances(ibid.). A concept paper on the need for a biotech
guideline was released for a three-month public consultation
in May 2011. Further industry input into the drafting
process was gathered at an agency/industry meeting at
EMA headquarters in London in mid-2013. Release of a
draft for comment is anticipated this year.
The biotech guide, being developed by EMAs Biologics
Working Party (BWP), will instruct assessors and industry
on submission expectations in key areas such as: clearance
of process and product-related impurities, such as host cell
proteins and DNA column and membrane sanitization
and life time hold times reprocessing pooling of
intermediates, and selection of batches to be included in
evaluation and validation batches.

Comments Prompt Revisions in PV Submission

EMA received more than 200 comments from 23 companies
and associations on the 2012 draft of its drug product PV
submission guideline.

Revised definitions, a new annex on non-standard

processes, and a new title were among the changes
made to the draft in the wake of the comments.
The comments reflected industry sensitivity to defining
process validation and submission requirements in a way that
necessitates regulator pre-clearance for any post-approval
adjustments effectively running counter to the continuous
improvement mandate in the ICH Q8-10/quality systems
paradigm.(Editors Note: The stories inIPQs Monthly
Update for Februaryprovide an in-depth review of the
problems that manufacturers face in trying to make process
and control adjustments, given the limitations, constraints,
and disconnects in the current CMC review processes.)
The redefinition of process validation as a lifecycle
continuum extending from development through postmarketing, as manifested in FDAs 2011 PV guidance, is an
effort to create better alignment with the evolving quality
management paradigm(IPQ Monthly Update February
2011, pp. 35-41).
In turn, a key focus of the comments on the EMA draft
was the perceived divergence from FDAs guidance in
particular, regarding the concepts of process design, process
qualification and continued process verification (see IPQ
Monthly Update Jan./Feb 2013, pp. 24-30).

Continuous is Different than Continued

One of the salient aspects of EMAs drug product PV
guideline is its inclusion of the concept of continuous
process verification as an alternative approach to
traditional process validation, in which manufacturing
process performance is continuously monitored and
evaluated using on-line or at-line controls.
EMA describes continuous process verification as applying
the principles of ICH Q8 and employing tools such as
process analytical technology (PAT), NIR, and multivariate
statistical process controls.
While the concept is congruent with the thrust
of FDAs PV guidance, potential terminology
concerns do surface when the two documents are
The FDA guidance does not specifically refer to
continuous process verification, and would view it as a




PV enhancement rather than an alternative approach.
The terminology divergence reflects EMAs more limited
application of the term process validation to refer to the
stage 2 qualification component in FDAs revised threestage PV approach.
FDA, in turn, uses the similar term continued process
verification to designate the third stage in the PV lifecycle
the ongoing assurance gained during routine production
that the process remains in a state of control.
In explaining its response to the comments on the
draft, EMA stressed that efforts were made in the
final version to harmonize the terminology with
EMA noted, in particular, that continued process verification is similarly labeled ongoing process verification in
its guideline, adding that to avoid confusion between both
terms, they have been spelled out in full, and acronyms have
been avoided. On-going process verification, the European
agency explained, is now considered to fall under GMP,
and is addressed in the update to Annex 15.
In response to comments pointing to the differences
between its PV guide and FDAs, EMA explained that its
document is aimed at assessors and deals with submission
information, whereas the FDA guidance is aimed at
industry and inspectors and focuses primarily on GMP
considerations. Regarding bringing the two closer together,
EMA emphasized that due to regional regulations, it is not
envisaged to align and harmonize approaches between EU
and FDA guidelines.
The concern about the differences may also indicate
a need for FDA to more clearly delineate the
relationships between the PV lifecycle expectations
as defined in its guidance and the related information
agency reviewers expect to see in applications.

dossier, unless otherwise justified. A partial list of nonstandard processes was provided, and the onus was placed
on the company to make the determination regarding its
The European Federation of Pharmaceutical Industries and
Associations (EFPIA) maintained that the list in the draft
may have had merit years ago. However, many of the
cited examples are now common processes supported by a
history of successful manufacture. Some examples include
lyophilization, suspensions, modified release, and aseptic
EFPIA further commented that making a decision whether a
process is non-standard is subjective and could be open to
In the final guideline, EMA moved most of the
content of section eight into a new Annex II. In
the annex, it removed the list EFPIA referred to as
outdated, and provided some additional clarification
on non-standard process determination.
The annex states, for instance, that all biological products
are considered to be non-standard. While the examples of
specific manufacturing technologies were deleted, the current
draft maintains the same general categories of products
or processes which could be considered as nonstandard
as appeared in the draft. These are: the manufacture of
specialized pharmaceutical dose forms the incorporation
of some new technology into a conventional process
highly specialized processes involving new technologies
or an established process known, or likely, to be complex
and therefore to require particular care, and non-standard
methods of sterilization.
Regarding PV submission requirements for these categories,
the final version changed might need to be provided to the
more definitive should be provided.

At issue is where the CMC/review and GMP/inspection

boundaries lie and where they intersect, and what role
each should play in moving toward a more risk-based,
improvement-friendly quality regulatory paradigm.

The revised section eight in the final guideline

focuses specifically on how a firms experience with
the manufacture of specialized products can be used
to justify providing less PV data in a submission.

Non-Standard Processes Clarified

For specialized products validated using traditional methods,

section eight indicates that requests to provide less than full
production-scale validation data will be reviewed on a caseby-case basis. A justification that takes into account the risk
to the patient of failure of the product or process should
be provided for each manufacturing site(see box on next

Also drawing industry comment in the EU 2012 draft were

the differing submission requirements for non-standard
processes and how a firm makes a determination of whether
a process is non-standard.
In the draft, section eight on standard vs. non-standard
methods of manufacture stated that, for non-standard
processes, production scale validation data might need
to be provided in the marketing authorization application

A change to the title of the PV submission guideline also

resulted from consideration of a comment made to the 2012




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ISPE commented that the title of the document be adjusted
to more closely reflect its purpose. It suggested that the
Guideline on Process Validation be changed to Guideline
on Process Validation Information to be Included in
Regulatory Submissions, which EMA adopted.

MHRA Expectations for Data Integrity

Self Auditing
The following expectations regarding self inspections by pharma firms were announced by
the UKs MHRA in December, 2013:
The MHRA is setting an expectation that pharmaceutical manufacturers, importers and contract laboratories,
as part of their self-inspection program, must review the
effectiveness of their governance systems to ensure data
integrity and traceability.
This aspect will be covered during inspections from the
start of 2014, when reviewing the adequacy of self inspection programs in accordance with Chapter 9 of EU
It is also expected that in addition to having their own
governance systems, companies outsourcing activities
should verify the adequacy of comparable systems at the
contract acceptor.
MHRA invites companies that identify data integrity
issues to contact them by email at:

version. Also noteworthy is the elimination of any mention

Annex 15 Rewrite Reflects QbD

In addition to aligning Annex 15 with the PV guideline
and ICH Q8-11 principles, the GMP/GDP IWG noted in its
late-2012 concept paper that changes to GMPs since 2001
create the need to update the annex specifically regarding:
change control the implication for product quality reviews
revisions to Chapters 3 and 5 on dedicated facilities, and
revisions to Annex 11 on computerized systems.
A comparison of the tables of contents of the 2001 and 2014
versions of the Annex 15 shows where the most updates
were made in response to the PV guidance revision and the
ICH Q8-11 specifically, the addition under the process
validation heading of continuous and ongoing process
validation, and new sections focusing on validation of
transportation, packaging, utilities, and test methods(see
box at right). None of these topics was addressed in the 2001

of retrospective validation.
Also reflected in the Annex 15 revision are updates
made to Chapter 1 of the EU GMPs to align with ICH
Q10 change management expectations, expanding
the change control section from two paragraphs
to seven. The Chapter 1 revision became effective
in January 2013.
The Annex 15 draft now includes more detail regarding
change management systems and how they need to be
handled as part of the firms quality system. Incorporated
are the quality-by-design principles of risk management and
design space.
The draft notes that where design space is used, the impact
on changes to the design space should be considered
against the registered design space within the marketing
authorization and the need for any regulatory actions





the context of the complaints and recalls chapter.

The changes that the IWG made to Annex 15

regarding the implications for product quality
reviews and the changes related to Chapters 3 and 5
and Annex 11 were minimal.

A revision of Chapter 2 on personnel came into effect

in February, 2014. The chapter was amended to
incorporate the senior management responsibilities
described in ICH Q10.

The draft notes that ongoing process verification should

be used to support the validated status of the product in
the product quality review, along with a reminder that
incremental changes over time should also be considered
and the need for any additional actions (e.g. enhanced
sampling) should be assessed.

Also emerging from the EMA GMP pipeline in November

2012 was a concept paper proposing the revision of Annex
17 on parametric release. A redraft of the Annex is expected
in 2014.

The use of dedicated equipment is recommended when

cleaning validation has shown to be ineffective or is not

Annex 1 on the manufacture of sterile products and Annex

16 on the qualified person (QP) and batch release are two
other current EU GMP focal points.

Regarding computerized systems, Annex 15 points to Annex

11: Computerized systems used for the manufacture of
medicinal products should be validated according to the
requirements of Annex 11. The relevant concepts and
guidance presented in ICH Q8, Q10 and Q11 should also be
taken into account.

Other EU GMP Chapters Under Revision

EMA is working on revising several other chapters and
annexes of the EU GMPs. These revisions will clarify the
expectations regarding current compliance focal points,
such as supply chain oversight, shared facilities, starting
materials, lab method transfers, and investigating and
reporting quality defects(see IPQ Monthly Update Jan./
Feb 2013, pp. 31-41).
In early 2013, EMA released draft revisions of four
of its GMP chapters for a six-month consultation
period: Chapter 3, Premises and Equipment
Chapter 5, Production Chapter 6, Quality
Control, and Chapter 8, Complaints, Quality
Defects and Product Recalls.
EMA noted that the revised Chapters 3 and 5 should be
read in conjunction with a draft EMA guideline on setting
health-based exposure limits for use in risk identification in
the manufacture of different medicinal products in shared
facilities, which was released just prior to the chapter
Chapters 3, 5, 6, and 8 are slated to be finalized in 2014,
according to the GMP/GDP Inspectors Working Group
(IWG) work plan. Specifically, Chapter 6 will now include
identification of minimal requirements for the transfer
of analytical methods, and Chapter 8 will incorporate
requirements for product shortage notifications and
introduce specific quality risk management concepts within

Sterile Product and QP Annexes Also in Focus

The 2008 revision of Annex 1 proved controversial

when it was issued and industry concerns about the
revision have continued.(Editors Note: TheJan./
Feb. 2009issue of IPQ provides an extended analysis
of: the changes made to Annex 1 by the rewrite
the concerns regarding its interpretation and
implementation, and the broader implications for
aseptic processing regulation.)
The EMA GMP IWG has been considering whether to again
revise the annex or address the concerns through Q&As(see
IPQ Monthly Update Jan./Feb 2013, pp. 31-41).
The discussions on the best way to move forward on Annex
1 were essentially tabled with the bolus of work the IWG
faced in the wake of the Falsified Medicines Directive (FMD).
However, Annex 1 is included on the agenda in the IWGs
work plan for 2014. It calls for the IWG to work with PIC/S to
arrive at the best approach to dealing with recurring issues
on the interpretation of this annex and whether guidance is
needed on biofilms.
The EU GMPs form the basis for PIC/S GMPs, and the
international pharmaceutical inspection group is actively
involved in EMA GMP modification discussions accordingly.
With its expert circle on sterile products, PIC/S will provide
important input into the Annex 1 debate.
A concept paper on revising Annex 16 was issued
by the IWG in 2011(see IPQ Monthly Update June
2011, pp. 9-19). A revision of the annex, reflecting
the concept paper and the ensuing comments and
discussions around it, was released for public
comment in July 2013(see IPQ Monthly Update
July/August 2013, pp. 22-30).
Drivers for the revision were identified by the EMA as
including: the globalization of the supply chain, which is
putting more distance between QPs and the manufacturing




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operations for which they are ultimately responsible the
introduction of new quality control strategies such as realtime release the implications of the FMD and the refining
of the GDPs in Europe the principles embedded in ICH
Q8-10 a new manufacturing and import authorization
(MIA) interpretation document, and differences between
member states in interpreting the existing Annex 16.
Among the significant changes EMA incorporated into the
2013 revision were a clearer distinction between the release
of a batch and its certification by the QP, directions for what
responsibilities the QP can share and how, and a template for
use by a QP to sign off on a subset of manufacturing steps.
The comments that came in on the revision have
been reviewed by the IWG and a revision is being
drafted, with a release anticipated in 2014.
In its 17-page comment letter, EFPIA expressed appreciation
for the efforts made in revising the annex to foster
harmonization of the requirements and their interpretations
throughout the EU. However, the association cautioned
that more attention would be needed to assure that those
objectives are achieved.
EFPIAs concern was specifically relevant to duties that have
to be performed by a QP and those that can be delegated.
The association stressed that allowing the QP to rely on the
company or site-based pharmaceutical quality systems as
given in ICH Q10 is a key aspect to ensure that requirements
laid down in this annex are being fulfilled.
Europes QP Association joined EFPIA in expressing concern
with the practical implementation of some of the provisions
and terminology in the revised draft.

IWG has Full Agenda for 2014

EMAs GMP/GDP IWG includes senior representatives from
the inspectorate of the European Economic Area member
states and the European Commission (EC), along with
observers from EDQM, the inspectorates of the countries
accessing to the EU, and MRA partner countries. Under the
groups purview are GMP and GDP inspection procedures
and guidance, MRAs, legislation impacting GMP inspection
activity, and inspection harmonization.
Also prominent on the IWG agenda for 2014 is
continued work on developing procedures and
coordinating inspections related to centrally
authorized products and to master files for plasma
and vaccine antigens.
The plan calls for EMA to build upon its commitment to
making best use of EU inspection resources by leveraging
information from international regulatory authority partners

wherever possible.
Other aspects of the international component of the IWG
responsibilities are also targeted for attention, including
simplifying all operational aspects of the EU mutual
recognition agreements and encouraging the use by MRA
partners of the EudraGMDP database to replace the paper
exchange of GMP certificates. Specifically targeted are
managing the Health Canada audits of new EU member
states, and extending the scope of the MRA with Japan.
The IWG will continue its dialogue with EDQM, WHO,
PIC/S, and other international regulators paying particular
attention to supporting collaborative activities aimed at
optimizing the use of inspection resources and capacity
buildingthrough existing international platforms.
Similarly to the workload facing FDAs drug
compliance office in implementing the FDA Safety
and Innovation Act (FDASIA) and the Drug Quality
and Security Act (DQSA)(see IPQ Monthly
Update January 2014, pp. 13-20), the EMA IWG will
have its plate full in implementing the EU Falsified
Medicines Directive (FMD)(see IPQ Monthly
Update July/August 2013, pp. 16-21).
Included under the FMD umbrella are refining the procedures
for coordinating third country inspections and dealing with
serious GDP non-compliance. Other FMD topics that will
be receiving attention are the GMP and GDP principles
and guidelines for active substances, and finalizing the risk
assessment guideline regarding excipient GMPs.
The IWG will continue its focus on the implementation of the
rules for API importation under the directive and the effort
to avoid product shortages when written confirmations are
not available from exporting third country authorities(ibid.).
The plan also calls for IWG involvement in implementing an
improved procedure for managing GMP non-compliance
linking to processes under development to manage
EMAs recent description of the IWG explains that
there is increasing awareness of the importance
of interactions between GMP inspectors and
IWG meets with the Quality Working Party at least once
a year, and contributes along with the QWP and Biologics
Working Party (BWP) to EMAs PAT team. Among the joint
projects with the QWP was a workshop on QbD held at the
end of January in London, which was coordinated by PDA
The IWG and QWP will be working with EDQM on issues
related to reverse osmosis for production of water for




injection (WFI) and to biological indicators for monitoring/
control of sterilization.

QWPs 2014 CMC Plate Also Full

The Quality Working Party is set up to: advise and support
EMAs committees for human and veterinary medicinal
products (CHMP/CVMP) on the broad range of issues
related to the CMC component of the review process
develop relevant harmonized standards and guidance, and
liaise with other EU groups involved with or impacted by
quality regulation and with international organizations and
On the QWP radar screen are training of quality assessors,
and industry workshops. The agenda includes working with
the EU PAT team on new CMC approaches and with EDQM
on European Pharmacopeia monographs and general
methods, terminology, certification, and impurities.

The QWP will be helping in implementing ICH M7 on

genotoxic impurities and Q3D on metal impurities. It will
also be participating in the ICH discussions on the common
technical document (M4), and developing a Veterinary ICH
(VICH) guideline on bioequivalence and revising GL3 on
veterinary API and product stability testing.
QWPs collaborative projects with EDQM during 2014
will include reviewing the existing qualification and limits
of impurities on approved medicinal products in the EU
and their presentation in the EP general chapters and


Comments on Annex 16
EMA GMP/GDP IWG 2014 work plan
EMA QWP 2014 work plan


The following are the guidance efforts that the EMAs GMP/GDP Inspectors Working Group (IWG) and the
CHMP/CVMP Quality Working Party (QWP) have on their respective agendas in 2014. In the IWG section, the
documents being worked on are followed by a brief description of the work plan goals. The QWP guidance
initiatives pertain to human (H) and/or veterinary (V) medicinal products as indicated.

GMP/GDP Inspectors Working Group

EU GMP guide:
Chapters 3 and 5 (premises and equipment and production): To finalize all changes planned for these
Chapter 6 (quality control): To finalize the revision aimed at identifying minimal requirements for the transfer
of analytical methods.
Chapter 8 (complaints and product recall): To finalize the revision dealing with product shortage notifications
and to introduce specific quality risk management concepts within the context of this chapter.
Annex 1: To agree, in consultation with PIC/S, on the best approach to dealing with recurring issues on the
interpretation of this annex and whether guidance is needed on biofilms.
Annex 15 (validation): To finalize the revision to update guidance including any necessary changes to
maintain consistency with the new CHMP guideline on process validation in the light of ICH Q8, Q9, Q10.
Annex 16 (certification by a QP and batch release): To finalize the revision aimed at updating this annex.
Annex 17 (parametric release): To finalize the revision aimed at updating this annex.
Importation of medicinal products:To consider the need for specific guidance for importers
EudraGMDP database:To continue to fulfil the role of Telematics Implementation Group (TIG) for EudraGMDP
and to act upon the recommendations of the EudraGMDP IT subgroup formed to advise the TIG. To examine ways
that the planning module can be used as a common tool for international collaboration.
FMD Implementation:




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Finalize the guideline on GDP principles for active substances
Finalize the risk assessment guideline to establish appropriate GMPs for excipients
Revise the procedure for coordination of third country inspections
Finalize the procedure for dealing with serious GDP non-compliance

CHMP/CVMP Quality Working Party

New technologies and approaches to quality as described in ICH guidelines Q8 (pharmaceutical development),
Q9 (quality risk management), Q10 (pharmaceutical quality systems) and Q11 (development and manufacture of
drug substances):
Guidelines on the manufacture of the finished dosage form (CPMP/QWP/848/96 & EMEA/CVMP/126/95):
Guidelines on the chemistry of new active substances (CPMP/QWP/130/96-Rev1 & EMEA/CVMP/541/03):
Guideline on the chemistry of active substances (3AQ5a/1987): revision(H/V)
Guidance document on definition of starting materials(H/V)
Q & A document on QbD pilot(H/V)
Guidance on genotoxic impurities in veterinary medicinal products (multidisciplinary topic led by SWP):
contribution to the development(V)
Work on the development of an EU harmonized approach to application of quality risk management to the
assessment of applications(H/V)
Guideline on stability testing for applications for variations to a marketing authorization: finalize revision(H/V)
Reflection paper on definition of new active substances(H)
Reflection paper on the assessment of the quality of medicinal products containing existing/known active
substances: revision(H/V)
Reflection paper on the use of co-crystals and other solid state forms of active substances in other medicinal
Guidance on the quality aspects of biowaivers(H/V)
Reflection paper on quality aspects of medicines for older people(H)
Guidance on packaging(H/V)
Guideline on quality and bio-equivalence of topical products(H)
QWP questions/answers document (EMA website): maintenance(H/V)
Update, operation and maintenance of the QWP quality database, accessible to all quality assessors in the
member states, where harmonized decisions taken at QWP meetings are recorded(H/V)
Update, operation and maintenance of the QWP core team database, accessible to all quality assessors in the
member states, where decisions taken at QWP core team virtual meetings are recorded(H/V)
Review of applicability and adaptation of CPMP/CHMP guidelines to veterinary medicinal products(V)
Review of validity of existing human and veterinary quality guidelines and other QWP guidance documents(H/V)



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3/29/2012 8:46:01 AM


Updates in Brief
FDA Requests Comments on NDA/ANDA Processes
In late March, FDA put out a Federal Register announcement requesting public comment on its drug application processes that
could open the door for industry input on the CMC issues involved in expedited reviews and post-approval changes (see IPQ
Monthly Update February 2014). The agency is looking for potential simplifications or modifications that would make the review
process more efficient. Comments are due by May 23, 2014.
The Global Ingredient Archival System (GinAS) Progressing
A progress report on the Global Ingredient Archival System (GinAS) will be presented at the IPEC/ExcipientFest conference
in late April. The system is being developed through cooperation between NIH, FDA, and industry with the intent to provide a
consistent definition of substances globally, and a common identifier for all the substances used in marketed medicinal products
as well as active substances under clinical investigation.
FDA Issues New BA/BE Draft Guidance
An FDA draft guidance for establishing bioavailability/bioequivalence (BA/BE) was released in late March and is intended to
replace the existing 2003 BA/BE guidance. The guidance details the methods most suitable and accurate for the determination of
BA/BE, as required by FDA. An expanded section is included on in vitro studies and their applicability for different formulations.
Changes also include subsections on combination drug/device products, endogenous substances, and advice on excipients that
affect BA/BE.
FDA Releases Draft Guidance on Vial Overfills
FDA released a draft guidance in mid-March to better define acceptable practices regarding the overfilling of vials. The guidance,
open for comment until June 12, illustrates the best use of overfilling to achieve accurate doses, while preventing contamination.
FDA Finalizes Guidance on Interpreting Sameness of MAbs Under Orphan Drug Regs
In late April, FDA released a guideline on how to interpret sameness in the molecular structure of MAb products, antibody
conjugates, fusion protein products, and bio-specific antibodies. The guideline was released as a draft in 1999 in response to the
related language used in the 1992 orphan drug regulations. The final version remains similar in structure and wording with the
exception of reference to the Biologics Price Competition and Innovation Act of 2009.
ISPE Launches Quality Metrics Pilot Program
ISPE announced in mid-March that it will conduct the industrys first Quality Metrics Pilot Program designed to define standard
metrics reporting to FDA. The pilot will test a series of indicators that support an FDA risk-based inspection program. ISPE plans
to launch the pilot with workshops for industry education and input, involving FDA participation, during the 3rd Annual ISPEFDA CGMP Conference in Baltimore, MD, in early June 2014. The pilot will be open to a limited number of sites and product
types, and will represent branded, generic, and over-the-counter products, ensuring statistically meaningful findings.
CDER Seeks Mapping Capabilities
In mid-March, FDA issued a solicitation for software to aid in geo-spatial mapping data analysis. According to the FDA Statement
of Work, the focus [of the] pharmaceutical quality platform is to geo-map the facilities that manufacture drug products in case
of issues, to ensure the stability and quality of supply chain. By being able to map all facilities that manufacture drug products,
FDA will be able to quickly locate trouble spots and deploy resources.




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EMA to Launch Drug Approval Fast-track
EMA announced in mid-March that it will launch a fast-track for drug approval termed the adaptive licensing pilot project.
Like FDAs breakthrough therapy pathway (see IPQ Monthly Update September 2013, pp. 2-23), the program is intended to
grant early access for medicines meant to treat unmet needs. Companies who are interested in participating in the pilot are requested to submit ongoing drug development programs for consideration.
EMA Concept Paper Proposes a Guideline for the Selection of Sterilization Processes
In early April, EMA released a concept paper on developing a guideline for the selection of sterilization procedures that would
align EMAs advice with ICH Q8. The period for public consultation lasts until July 9, 2014.
EMA Finalizes Guideline on Stability Requirements for Variations
In mid-March, EMA published a revision to its 2005 guideline on stability testing for changes made to a marketing authorization.
The revision provides specific indications for a variety of Type II variations previously unaddressed. It clarifies that three months
of stability data is required for products known to be stable. For products known to be unstable or if there are changes to the quality characteristics of the active substance, the requirements increase to six months of data. The guideline also requires six months
of stability data following changes made to: excipients that may impact quality dosage forms batch size, or fill volume.
UK Begins Construction on Biologics Research Center
The groundbreaking of the National Biologics Manufacturing Centre in the UK took place in mid-April with completion estimated for 2015. The UK government is putting 38 mill. pounds into the NBMC to facilitate innovation in the field of biologics and
to help strengthen the UKs bio-pharma sector by reducing risks for companies involved in developing new biologic products.
MHRA Releases 2014-2015 Business Plan
The MHRA has released their business plan for 2014-2015 as of mid-April. The key strategic activities section of the plan shows
an emphasis on surveillance as well as on increasing collaboration with other regulators to better ensure the quality of medicinal
EC Reports on Advanced Therapy Regulatory Uncertainties
In late March, the EC published a report about currently unaddressed issues for advanced therapy medicinal products(ATMP),
such as gene therapy or tissue engineering. Of concern in the report is that only four ATMPs have been approved in Europe, despite numerous applications, and that different member states have come to different conclusions regarding the same ATMPs.
EMA Q&A Addresses Post-Authorization
In early April, EMA released the first installment of a Q&A intended to provide an overview of EMAs position on issues typically
discussed with marketing authorisation holders regarding post-authorization procedures. The Q&A is a running list and will be
updated as new questions and answers emerge.
EDQM Clarifies CEP Evaluation Policy
In late March, EDQM clarified its approach to assessing new applications for CEPs. The policy document explains that the process
is handled in two rounds: the evaluation of the original application, and if necessary, the evaluation of additional information upon request from EDQM. Following these two rounds, an application lacking the necessary data or response will be closed,
though the application may be resubmitted.updated as new questions and answers emerge.




EDQM Launches Anti-Counterfeiting Database
In late March, as part of its anti-counterfeiting activities, EDQM announced the launch of a new database called Know-X. The
database collates reports on counterfeit/falsified medical products that have been detected in European member states, and also
contains details on closed cases of counterfeit/falsified medical products, technical information on the testing performed, the
authorities involved, and what actions were taken. The information provided is gathered from various sources and is intended
to provide governments with decision aids for the management and prevention of specific risks.
EMA Revising Applications/Advice Procedures
In late March, EMA announced a revision to its procedures for application submission and for advice requests that reflects a
structural reorganization in September 2013. The changes, one of which relates to the EMA contact persons, will be implemented for new applications submitted as of April 1, 2014. For ongoing applications a transition plan has been put into place.
EMA Issues Concept Paper for Revised Immunogenicity Guideline
EMA issued a concept paper in late February revising its immunogenicity assessment guideline. The aim of the revision is to
clarify how immunogenicity data is presented, to introduce a risk-based approach, and to determine the appropriate studies
needed for different products. [For a discussion of the quality/immunogenicity relationship, see IPQ Monthly Update January 2014, pp. 21-31.]
EC Publishes Q&A on GDPs
In late March, the European Commission published a question and answers (Q&A) related to its new guideline on Good
Distribution Practice for medicinal products for human use, which went into effect in November 2013. The document contains 25
Q&As. The questions focus on: competence and training of personnel segregation of products temperature and environmental
control alarms and deviations qualification of customers verification of authorization for sale control of returned products
and recall procedure, and transport requirements, such as temperature and safety.
EC Revises EU GMP Chapter 6 on Quality Systems
In late March, the European Commission published a revision of Chapter 6 of the EU GMPs, which covers quality control. The
revision includes a new section on analytical methods transfer that calls for verifying application conformance and having a
transfer protocol. Other revisions involve: investigating OOS trends establishing a risk-based sampling plan culture media
and strains management, and sample management. [See story p. 50 for more on EU GMP revision initiatives.]

Brazil to Require Notice One Year Prior to Drug Withdrawal
A new mandate, approved by Brazils Anvisa in late March, requires drug manufacturers to provide a years notice prior to
removing a drug from the market if that withdrawal could lead to a shortage. If the withdrawal would not pose a risk of a
shortage, the notice can be given six months ahead rather than twelve. Additionally, there is a 72-hour requirement of notice if
sudden, previously unforeseen circumstances could lead to a drug shortage.




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EMA and TGA to Collaborate on Orphan Drugs
In a statement published in early April, EMA announced its collaboration with TGA on creating better access to orphan drugs.
In the statement, EMA noted that the two regulators have agreed to share the full assessment reports related to marketing
authorisations of orphan medicines. The statement goes on to note that this strengthens pre-exisiting collaborations, such as
those involved in GMPs.
FDA and EMA Extend QbD Pilot, Plan More QbD Guidance
In early March, FDA and EMA announced a two year extension of their pilot program for collaborative review of QbD applications
launched in 2011. FDA and EMA also indicated that additional QbD guidances are expected to be published in 2014. [See story
on p. 50 for more on EMAs 2014 quality initiatives.]
WHO Revising its Guideline on Hold Time
In late February, WHO published a revised draft of its guideline on best practices to follow when designing hold time studies. The
new draft adds the recommendation that manufacturers consider using a most probable rather than a worst case approach
to hold times.