Pharma Uptoday Monthly Magazine - Volume 20; Issue: Nov 2015

VOLUME: 20 - ISSUE: NOV 2015 |
PHARMA UPTODAY

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Inside this issue
3 News Uptoday
38 New Guidance
51 Audit Findings
483 Observations
- Pernix Receives Form 483 for cGMP Violations
- FDA Hits Pfizer Subsidiary With Second Form 483 in Five Years
- Galena Hit With 10-Item Form 483 Over Unresolved Issues
55 Warning Letters
- Warning letter: Unimark Remedies Ltd., Mumbai, India
- Warning letter: SSM Health Care St. Louis DBA SSM St. Clare
Health Center
58 Health Canada Non Compliance Report
- Non Compliance Report: Unilever Canada Inc.
60 EMA Non-Compliance Report
- GlaxoSmithKline (Tianjin) Company Limited (Teda), China
- CARGILL FRANCE
63 Regulations of the Month
- Sec. 211.42 Design and construction features (c)(5) to (c)(10)
- Sec. 211.44 Lighting

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News Uptoday
India says EU ban on generic drugs 'unwarranted'
The European Union's ban on Indian generic drugs is "unwarranted" and an obstacle to moving
trade talks forward, India's foreign secretary said on Monday.
Subrahmanyam Jaishankar said EU restrictions on more than 700 generic drugs were unfair.
"It's our hope that this matter would be looked at fairly and sensibly and would hopefully not be an
impediment to the free trade deal," he told journalists after German Chancellor Angela Merkel met
with Prime Minister Narendra Modi during a visit to New Delhi.
India and Germany pledged on Monday to revive efforts to reach an Indo-European free trade pact
after talks fell apart this year.
The Union health ministry henceforth will not insist on repeat pre-clinical or toxicity studies on
animals for permission for a new drug or clinical trial if authentic data on animal toxicology has been
submitted with the technical data.
The health ministry's action in this regard comes in the backdrop of the fact that the Union minister
for women and child development Maneka Gandhi had written to the Union minister of health and
family welfare regarding pre-clinical/toxicity studies on animals under Schedule Y of the Drugs and
Cosmetics Rules, 1945.
In her letter, the minister stated that India being signatory of OECD (Organization for Economic
Cooperation and Development) Council Act related to mutual acceptance of data is under obligation
to respect the data generated by other country regarding pre-clinical/toxicity studies and therefore
there is no need for CDSCO to undertake further studies.
The molecules of interest have been those that are approved by multiple regulatory agencies and
have been through many animal studies which have been made available on sites and published in
scientific journals. Under the current regulations of item 4, Appendix-I of Schedule Y of Drugs and
Cosmetics Act, 1940, additional tests on animals are then ordered.
As the issue was related to pre-clinical or toxicity studies on animals under Appendix I and Appendix
III of Schedule Y, the matter was placed before the Investigational New drug (IND) Committee of the
Union health ministry.
The committee in its meeting held on August 6, 2015 deliberated and agreed with the statement
mentioning that, for drugs approved in other countries where complete toxicological data generated
in GLP certified laboratory and in alignment with the requirements prescribed under Drugs and
Cosmetics Act, 1940 and Rules, 1945 (Schedule Y), further toxicity study may not be required if

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complete data as per prescribed requirements is submitted during application for new drug
approval.
It may also be explored, in line with international practices, to encourage the use of other alternative
methods than animal studies, wherever such robust validated methods are available for small or
large animals, the IND committee further recommended.
The IND committee recommendations were then sent to the Drugs Technical Advisory Board
(DTAB), the highest authority under the Union health ministry on technical matters.
The issue came up for discussion in the DTAB meeting held on August 18, 2015. After deliberations,
the DTAB agreed to the recommendations of the IND committee and further recommended that
under item 4, Appendix I of Schedule Y, it may be mentioned that if authentic data on animal
toxicology as per requirements of annexure III has been submitted with the technical data, then
repeat animal testing for permission for a new drug or clinical trial is not necessary.
Brazil Suspends Pharma Serialization And Tracing Requirements
Last week, Brazil’s pharma industry regulatory agency, the National Agency of Sanitary
Surveillance (ANVISA), announced that they were ―suspending‖ at least part of RDC-54/2013, the
declaration that mandated drug serialization and tracing, until further notice. Thank you to all who
forwarded the link to the official announcement. I was able to translate and read it on Thursday, and
I submitted a comment on my own last essay, ―Pharma Serialization Deadlines In Flux―, to include
the link. Apparently shortly after that essay was published, ANVISA publicly announced the
suspension.
However, the ANVISA website was in accessible in the United States Sunday afternoon when I
normally write RxTrace essays so I was unable to finish this essay until Monday morning. Now that I
can access the site, here are the details.
According to a translation of a news article published on the ANVISA website, what they have done
is to suspend item II of Article 23 of RDC 54/2013. That’s the section the mandates the 3-lot pilot by
each registration holder that was to be completed by December 10 of this year. Apparently ANVISA
will publish a new RDC that will officially revoke that requirement ―in the coming days‖.
In addition, it appears that the entire regulation will be reviewed and the design of the mandated
solution potentially reconsidered.
In my view, RDC 54/2013 mandated data exchanges that were excessive and duplicative, but the
worst part about that regulation is that it makes registration holders responsible for collecting tracing
data from all downstream trading partners. The article indicates that the board members nodded in
agreement with the centralized tracing model, but it is unclear if that indicates support for a simplified
centralized model, a semi-centralized model (see ―The Viability of Global Track & Trace Models―), or

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the one they current have as defined in RDC 54/2013 (which is more of a convoluted hybrid model,
in my opinion).
Also unclear is whether this action changes the deadline for full serialization and tracing, previously
specified by RDC 54/2013 as December 10, 2016. The article only mentions the suspension of the
pilots but others have indicated that they expect, or they believe, that the 2016 deadline is, or will be,
suspended as part of the review and reconsideration. Treat this as more rumor until it is confirmed
by an official announcement. Hopefully that will come soon, so stay tuned.
Teva Acquires Rimsa to Accelerate its Emerging Markets Growth Strategy
Teva Pharmaceutical Industries has entered into definitive agreements under which the company will
acquire Representaciones e Investigaciones Médicas, S.A. de C.V. (Rimsa), pharmaceutical
manufacturing and distribution company in Mexico, along with a portfolio of products and companies,
intellectual property, assets and pharmaceutical patents in Latin America and Europe in a debt-free,
cash free set of transactions, for an aggregate of $2.3 billion. Through this acquisition, Teva will
become a leading pharmaceutical company in Mexico, the second largest market in Latin America
and one of the top five emerging markets globally. Teva expects the deal will yield substantial and
achievable synergies and offer a platform for growth in the region.
―This acquisition delivers on our strategy of increasing our presence in key emerging markets in
order to position Teva for long-term growth in these markets. Rimsa will provide Teva with a
significant platform for growth by combining the strong Rimsa brand, licensed portfolio of
differentiated, patent-protected products, promising pipeline, significant relationships with physicians,
patients and healthcare providers and its strong commercial presence,‖ said Erez Vigodman,
President and CEO of Teva. "The combination of our companies lays the foundation for a leadership
position and high long-term, profitable and sustainable growth in the region and further reinforces our
commitment to innovation, quality and improving the health of people worldwide."
Rimsa had revenue in 2014 of $227 million with an annual growth, year over year of 10.6% since
2011. The company has an extensive portfolio of specialty products, including fixed-dose
combination products which have fueled its growth. Rimsa’s well-established sales footprint is
expected to provide a platform for additional Teva products.
―For 45 years, Rimsa has operated as a leading pharmaceutical company in Mexico, the second
largest healthcare market in Latin America, with a high growth, unique and diversified business
model. We share Teva’s focus on providing quality healthcare and we are excited to become a part
of Teva in meeting the needs of a population of 120 million,‖ said Luis Jorge Pérez Juárez, CEO of
Rimsa.‖

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―In addition to this unique portfolio of patent-protected products, Rimsa differentiates itself as a
leading provider of branded specialty drugs, including fixed-dose combinations, which increase
adherence and reduce overall costs to patients,‖ stated Siggi Olafsson, President and CEO of Teva
Global Generic Medicines. ―We will build on their brand reputation, successful sales force model,
well-established commercial footprint and loyal customer base to introduce additional specialty and
generic Teva medicines to patients in Mexico and across the region.‖
The acquisition was unanimously approved by Teva's Board of Directors, led by the Chairman, Prof.
Yitzhak Peterburg.
Teva expects to close these transactions by early first quarter, 2016. The acquisition is not expected
to impact 2016 non-GAAP earnings and is expected to be accretive starting Q1 2017. The
transactions will be funded through a combination of cash on hand and lines of credit.
UK and India regulators agree deal for closer collaboration to improve public safety
The Medicines and Healthcare products Regulatory Agency (MHRA) has today (5 October 2015)
signed a Memorandum of Understanding (MOU) with its counterpart body in India. This agreement
will increase collaboration between the 2 countries in the area of medicines and medical devices with
the aim of further improving public safety in the 2 countries.
This is the first MOU agreed with the Central Drugs Standard Control Organisation (CDSCO), part of
the Ministry of Health and Family Welfare of Republic of India and was signed by Dr Gyanendra
Nath Singh, India’s Drugs Controller General, and MHRA Chairman, Professor Sir Michael Rawlins.
It provides a formal agreement between the 2 organisations, and strengthens relations between the
UK and Indian governments.
The central understandings of the agreement include promotion of each other’s regulatory
frameworks, requirements and processes. Significant outcomes will include the facilitation and
exchange of information and opportunities for technical cooperation of mutual benefit, helping to
ensure the regulators are better equipped to protect the health of their respective publics.
MHRA Chairman, Professor Sir Michael Rawlins said:
We are committed to protecting the health of UK citizens and that’s why we are continuing to
formalise our collaborative efforts with key partners like India.
We operate in a global environment and agreements such as these serve to further strengthen our
ability to promote good practices and we look forward to working even closer with our Indian
counterparts.
Dr Gyanendra Nath Singh commented:
The MoU signed between MHRA and CDSCO is going to create a new platform where patients will
be given utmost importance. Quality medicine, affordability and transparency will be the tools for
making medicines available to the people of the two nations.

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In 2014, MHRA carried out more than 550 inspections in the UK and 125 in non-EU countries, 49 of
which were in India. The India Brand Equity Foundation states that the Indian pharma sector
accounts for about 2.4% of the global pharma industry and is the 3rd largest in terms of volume.
Approximately 25% of UK medicines are made in India and each batch is tested on importation to
ensure it is safe, of good quality and effective and it is important that MHRA assessors continue to
inspect Indian sites to ensure Good Manufacturing Practice – a globally recognised regulatory
framework.
Sir Michael Rawlins added: ―It’s essential that the commitment to good quality manufacturing comes
right down from the top levels of management to those on the factory floor, and throughout the entire
industry.
―Indian firms already accept and understand this, and the MOU is part of a concerted effort to ensure
the UK and wider global public continue to have access to quality and safe medicines.‖
The signing of the MOU took place at CDSCO’s headquarters in New Delhi and was followed by a
series of meetings to discuss next steps.
The agreement is similar to those already in place between MHRA and other counterpart bodies in
China and America, although it is a standalone bilateral document in its own right.
FTC Approves Endo’s Acquisition of Par
The FTC has cleared the way for Endo Pharmaceuticals to acquire Par Pharmaceuticals, pending
the divestiture of two of its generic drugs.
To resolve anticompetitive concerns, Endo will sell the rights and assets to glycopyrrolate and
methimazole tablets to Rising Pharmaceuticals in New Jersey. Used to treat ulcers and
overproduction of thyroid hormone, the medications are not commonly produced and, if the
drugmakers were allowed to keep them in their post-deal portfolio, costs would likely have been
raised, the FTC said last week.
Under the FTC settlement, Endo will supply Rising Pharmaceuticals with the drugs for two years
while it arranges for a third-party manufacturer.
The $8 billion deal, announced in May, will place Endo among the top five firms in the U.S. generics
market, adding more than 100 new drugs and more than 200 ANDAs to its offerings.
The Par acquisition follows several large Endo purchases in recent years, the most recent being
Auxilium for $2.6 billion last October.

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Sun Pharma Recalls Over 216,000 Bottles of Blood Pressure, Antidepressant Drugs
Sun Pharma is recalling more than 216,000 bottles of felodipine blood pressure tablets and the
antidepressant imipramine because the varnish on labels is leaching a chemical into the containers.
The news comes on the heels of a July recall of bupropion hydrochloride tablets made at Sun’s
Halol, Gujarat, India, plant.
The products, produced by Sun’s Mutual Pharmaceutical subsidiary, include 187,106 bottles of
felodipine extended-release tablets and 29,660 bottles of imipramine.
The problem was detected in stability results, which found trace amounts of benzophenone in the
drugs. Sun says the impurity occurs naturally and is unlikely to cause any significant adverse events,
and that the recall was initiated as a precaution.
The products were distributed between February 2014 and April of this year. The FDA has
designated the recalls Class III, the least worrisome rating.
The July recall of bupropion hydrochloride followed one in March involving eye solutions, continuing
a string of recalls of product made at that site. Those recalls followed 2014 recalls by the Halol
facility and Detroit-based Caraco Pharmaceutical Laboratories, which distributes drugs for Sun in the
U.S.
US FDA Activities Report of the Generic Drug Program (FY 2015)
GDUFA
YEAR/Actions
This Month
14-Oct 14-
Nov
14-
Dec
15-
Jan
15-
Feb
15-
Mar
15-
Apr
15-
May
15-Jun 15-
Jul
15-
Aug
15-
Sep
FY-
2015
Refuse to
Receive (RTR)
+
12 11 15 30 27 13 11 15 20 13 19 186
Withdrawals 6 12 2 11 7 13 23 11 21 16 18 140
Approvals 45 28 29 25 27 19 49 47 57 47 58 431
Tentative
Approvals
10 7 5 5 13 6 19 13 10 12 6 106

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Complete
Responses
(CR) +
43 76 96 104 108 94 115 97 116 134 96 1079
Drug Master
File
Completeness
Assessment
(DMF CA)
124 55 71 92 86 55 76 62 65 54 35 775
GDUFA YEAR
(Receipts)Submissions
This Month
14-
Oct
14-
Nov
14-
Dec
15-
Jan
15-
Feb
15-
Mar
15-
Apr
15-
May
15-
Jun
15-
Jul
15-
Aug
15-
Sep
FY-
2015
Abbreviated New Drug
Applications (ANDA) ++
50 27 43 27 29 57 58 49 39 52 431
CBE Supplements + 473 385 434 411 420 439 413 474 472 425 4346
PAS Supplements + 45 22 51 33 37 55 38 48 37 41 407
GDUFA YEAR/
(Receipts)Amendments
14-
Oct
14-
Nov
14-
Dec
15-
Jan
15-
Feb
15-
Mar
15-
Apr
15-
May
15-
Jun
15-
Jul
15-
Aug
15-
Sep
FY-
2015
Originals (Pre FY15)
Administrative
119 228 388 339 429 372
Originals (Pre FY15) Solicited
(CR, ECD/IR)
86 80 178 320 582 503
Originals (Pre FY15)
Unsolicited
398 229 108 118 84 130
Originals (FY15) Administrative 1 21 20 30 21 23
Originals (FY15) Tier 1 0 0 0 0 0 1

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Originals (FY15) ECD/IR 0 7 4 43 37 54
PAS Supplements (Pre FY15)
Administrative
5 21 15 18 14 9
Solicited (CR, ECD/IR)
47 35 88 45 42 53
Unsolicited
43 21 11 11 10 9
PAS Supplements (FY15)
Administrative
1 6 3 7 2 7
PAS Supplements (FY15) Tier
1
0 0 0 0 0 1
2
0 0 0 0 1 0
3
0 0 0 0 0 0
PAS Supplements (FY15)
ECD/IR
0 0 3 4 11 28
CBE Amendments (all years
together)
61 34 29 72 71 101
GDUFA YEAR
(Receipts)
14-
Oct
14-
Nov
14-
Dec
15-
Jan
15-
Feb
15-
Mar
15-
Apr
15-May 15-
Jun
15-
Jul
15-
Aug
15-
Sep
FY-
2015
Controls +++ 112 86 111 115 104 140 136 124 141 170 1239

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GDUFA Post CR
Meeting Requests ++++
84 89 96 105 113 123 129 132 134 137 1142
Post CR Meeting
Requests This month
0 5 7 9 8 10 6 3 2 3 53
+ = Revised to reflect more accurate counting by the GDRP. For example RTRs revised to include
both RTR due to failure to pay user fees and RTR due to technical reasons.
++ = Starting FY15 ANDA Original Receipts are reported as raw receipts (versus filed receipts).
+++ = FY 15 Controls have been revised to count only those requests appropriate for a control.
++++ = Cumulative and NOT specific to the month. DMF raw receipts have been eliminated since
DMF Completeness Assessments present a more accurate indication of workload.
Numbers are rounded and do not reflect actual numbers for Congressional reporting purposes.
Note: Amendment metrics for April, May and June will be forthcoming
Source: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandAppro
ved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm375079.htm
FDA Reassures Industry on Use of Quality Metrics
The FDA is trying to reassure drug companies by making it clear that the agency won’t use its quality
metrics collection to spur 483s, warning letters and other enforcement actions.
The quality metrics effort is not an enforcement program; it is a surveillance program, explained
Russell Wesdyk, acting director of the Office of Pharmaceutical Quality’s Office of Surveillance.
Submission of metrics will be used to determine a firm’s risk score in the selection model used to
prioritize scheduling of routine surveillance inspections, he said.
To encourage data submission, sites with more metrics could see a greater reduction of score,
Wesdyk, said, adding ―more information is better than less information.‖
For example, a drugmaker may worry that high recall or batch failure rates will mean they’ll get
inspected more. In fact, it could be just the opposite, as the numbers could be in line with other like
manufacturers, Wesdyk said.
In fact, a manufacturer that submits fewer data or data showing a very low recall or failure rate could
draw more agency scrutiny, he added. He spoke at a session last week at the FDA/PQRI
Conference on Advancing Product Quality in Bethesda, Md.
Wesdyk said he is also surprised by the amount of feedback from industry groups questioning the
agency’s authority to collect quality metrics. He said the FDA is trying to help industry and is not the
―boogeyman hiding behind trees.‖

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Meanwhile, ISPE said it is nearly halfway through the data submission and collection phase of its
quality metrics pilot program, which is continuing despite differences in its metrics and those the FDA
has targeted. Three of the four quality metrics the FDA plans to collect — lot acceptance rate,
product quality complaint rate and invalidated out-of-specification rate — are accounted for in the
eight quality metrics ISPE is collecting.
ISPE has collected data from 21 companies covering 88 sites so far. Data collected by Oct. 30 will
be analyzed for inclusion in ISPE’s comments on the FDA’s draft guidance on quality metrics, which
are due Nov. 27, said Máiréad Goetz, co-chair of ISPE’s quality metrics team.
The final deadline for collecting data under ISPE’s pilot program is Nov. 30. The totality of data will
be analyzed for ISPE’s final report, expected next February or March, Goetz said.
FDA’s Team-Based Inspection Program Taking Shape
The FDA’s new team-based inspection program is starting to take shape with a steering committee
led by high-ranking FDA officials and three subgroups.
The three subgroups are the Pre-Approval Inspection group, the Surveillance Inspection group and
the tentatively named For-Cause Inspection group. Tentative scoring systems, investigator training,
IT systems and investigator questions have been drafted for the first two groups, while the for-cause
group’s functions are being developed, said Russell Wesdyk, acting director of OPQ’s Office of
Surveillance.
Wesdyk spoke during a session last week at the FDA/Product Quality Research Institute Conference
on Advancing Product Quality in Bethesda, Md.
The PAI and Surveillance groups have conducted pilot inspections, and more are planned, Wesdyk
said. At this time, there are no plans for the for-cause group to conduct pilot inspections, as the pilots
for the other two groups may be enough, he said. The pilot program is also testing a new IT system
to support investigators while on site.
Once fully implemented, PAI will be tasked with performing inspections whose observations inform
premarket review decisions. The surveillance group will observe the state of quality in a facility to
determine quality risk and perform routine inspections, Lawrence Yu, deputy director of the Office of
Pharmaceutical Quality, said. The for-cause inspections will be handled by ORA and look for
evidence of cGMP violations to support enforcement actions.
Observations made in the PAI or surveillance inspections could trigger escalation or transition into
for-cause inspections, Yu said.
The New Inspection Protocol Project Steering Committee is co-chaired by Theresa Mullin, director of
CDER’s Office of Strategic Operations, and Ellen Morrison, assistant commissioner for operations in
the FDA’s Office of Regulatory Affairs.

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EMA Report Shows 350 GMP Inspections in First Half of 2015
The European Medicines Agency conducted 350 good manufacturing practices inspections in the
first half of this year — roughly 50 percent more than in the same period a year ago, a new report
shows.
The number of GMP inspections nearly reached the annual forecast for the entire year, causing the
agency to revise its 2015 forecast from 390 to 425. By comparison, inspections totaled 235 for the
first half of 2014.
The EMA also met its half-year target of conducting 10 percent of routine GMP reinspections of
manufacturing sites using an exchange of information with international partners.
The EMA’s mid-year report, released last week, also shows pharmacovigilance monitoring running
even with 2014, with 10 inspections, while the number of good laboratory practice inspections
increased from zero to one and good clinical practice audits edged up to 35, from 33 a year ago.
Indian pharma majors get 113 ANDAs approval from US FDA in Jan-Sept 2015
Major Indian pharmaceutical companies and their subsidiaries have set to get higher Abbreviated
New Drug Application (ANDAs) approvals during 2015 with rising investment in research and
development. Indian companies already secured final approvals for 113 ANDAs from US FDA during
the first nine months ended September 2015 and 32 tentative approvals. This worked out to over 30
per cent of the total approvals by US FDA. The US FDA has approved total 372 final ANDAs during
January-September 2015 and 102 tentative ANDAs.
The overall approval rate of US FDA during 2015 will be higher as compared to full year 2014. In
2014, it approved 416 ANDAs of which Indian companies secured 122 final ANDA approvals.
Aurobindo Pharma and Lupin received highest number of 21 ANDA approvals each during the first
nine months ended September 2015, followed by 8 ANDA approvals each by Alembic
Pharmaceuticals, Glenmark Pharmaceuticals and Hetero Laboratories. Jubilant Life Sciences,
Macleods Pharma and Sun Pharmaceuticals grabbed 6 ANDA approvals each during first nine
months of 2015. Torrent Pharmaceuticals and Orchid Chemicals and Pharmaceuticals got 4 and 5
ANDA approvals each.
The higher approvals shows that Indian companies are well set to stepped up their presence in the
highly regulated market like US, Europe and also in emerging markets by offering new generic
products. Patent expiration in coming years may generate higher demand for these products.
Aurobindo Pharma, which secured approval for 21 ANDAs between January-September 2015, has

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incurred an R&D expenditure of Rs.359.88 crore during the year ended March 2015 as
against Rs.270.80 crore in the previous year. The company has filed 192 DMFs and 376 ANDAs
with the US FDA upto March 2015 and it received 193 ANDA approvals and 183 ANDA approvals
are awaiting.
Lupin's R&D expenditure moved up by 16.7 per cent to Rs.1,118.54 crore during the year ended
March 2015 from Rs.958.28 crore in the previous year. It filed 18 ANDAs for the US market during
2014-15 and its cumulative total reached at 210 ANDAs. Currently it has 99 ANDAs pending for
approval. It has 15 exclusive first-to-file ANDAs addressing a market size of US$ 2.5 billion. It also
filed 435 patent applications including 97 new inventions taking the cumulative total of 2,197 patents
filed.
Sun Pharmaceutical, after acquisition of Ranbaxy Laboratories, pushed its consolidated R&D
expenditure at Rs.1,955 crore during the fiscal year ended March 2015 as compared to Rs.1,042
crore in the previous year. Its five major R&D centres are located in India, Israel, Canada and USA
and strengthening the speciailty pipeline including patented products and complex generics. Sun's
cumulative filings of ANDAs reached at 597 and it received cumulative approvals for 438 ANDAs till
March 2015. The company and Taro Pharma received final approval for 8 ANDAs during January-
September 2015 and 2 tentative approvals.
Besides above pharma majors, Ajanta Pharma, Dr Reddy's Laboratories, Emcure Pharma, Granules
India, Natco Pharma, Strides Arcolab, Wockhardt, Zydus Pharma received approvals for ANDAs.
FDA Inspections at API Manufacturers - current Warning Letter Trends
Taking a look at the Warning Letters the FDA issued after inspections of activesubstance
manufacturers in the 2015 fiscal year, which ended on 30 September 2015, it is first of all striking
that only non-American companies are among the addressees. Almost half of them are Indian
companies. Overall the numbers look like this: India (3 WLs); China (2 WLs); Canada (1 WL);
Thailand (1 WL); Czech Republic (1 WL).
The top issue in the Warning Letters is the non-GMP compliant handling of electronic data or
missing data integrity. Each of the 8 warning letters contains the following comment in the same
wording:
"Failure to prevent unauthorized access or changes to data and to provide adequate controls to
prevent omission of data."
The lack of access control on electronic (raw) data is an issue the FDA investigators have been
observing for a long time, especially during inspections in pharmaceutical companies. In this as well
as in the last fiscal year there were significant deficiencies in several companies - medicinal product
as well as API manufacturers - as the comments in the appropriate Warning Letters show. For more

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information also see the GMP news Another FDA Warning Letter with Focus on "Data
Integrity" and FDA Warning Letter on Data Integrity.
Ultimately these deficiencies can be traced back to a failure of the quality assurance unit which also
affects other areas. In the Warning Letters, the following examples can be found for this:
 "Failure of your quality unit to ensure that materials are appropriately tested and the results
are reported."
 "Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured at
your facility are in compliance with CGMP, and meet established specifications for quality and
purity."
Data were manipulated by laboratory staff (change of the file name), to fake results from
identity tests in batches which in reality were not performed. Quality assurance was not able
to uncover this manipulation.
 Despite an unknown peak in the examination for residual solvents the relevant batches were
released. Upon receipt of a complaint regarding this peak an examination was conducted with
the result that the contamination originated in the production process itself. Preventive control
measures to avoid this contamination were not established.
 "Failure to adequately investigate complaints and extend the investigations to other batches
that may have been affected."
As a result of a complaint (bad smell), a cause study was initiated which was completed prior
to implementation of the preventive measures again. The CAPA measures subsequently
carried out were obviously not associated with the reason for the complaint.
 "Failure to have appropriate controls for issuance of batch records".
The use of document templates for batch records is out of control. These can be printed out
from the production staff's personal computers. Although there is an SOP for the control of
batch records there are no appropriate training records.
 "Failure to have appropriate documentation and record controls."
Data for tracing raw materials are not available. Log entries are without date/visa and partly
corrected with Tippex. There is an SOP prohibiting the use of correction fluid, however this
was not trained.
 "Failure to record activities at the time they are performed and destruction of original records."
Original records of critical process data on uncontrolled memos were transferred
subsequently in new report templates (after batch approvals) and then destroyed.
This selection of examples shows the lack of fundamental GMP principles which leads to a blatant
misconduct of staff and ultimately to quality defects in the final product. The main responsibility
usually has the quality unit, which task it actually would be to ensure a thorough training in

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production and quality control and to monitor compliance with the appropriate regulations. These
examples of non-GMP-compliant behavior are not limited to active ingredient manufacturers; there
are very similar findings in Warning Letters issued to medicinal product manufacturers.
USP wants to considerably expand the Monograph for Ophthalmic Preparations <771>
The considerably expanded draft monograph <771> in the American pharmacopeia includes topical
ophthalmic products like eye drops as well as ophthalmic preparations for injection purposes. These
products are manufactured using terminal sterilisation, sterile filtration and aseptic filtration. An
overview lists and describes the different pharmaceutical forms in more detail: solutions,
suspensions, ointments, gels, emulsions, strips, injections, inserts and implants. However, the part
on product quality is particularly interesting, especially the general tests. According to this, all
ophthalmic preparations are to undergo a test to determine the integrity of the packaging and to test
for visible particles. A 100% test is only mentioned for ophthalmic preparations for injections in
transparent containers. If this is not possible due to the characteristics of the containers, reference is
made to random sample tests in monograph <790>. The requirements with regard to subvisible
particles are depending on the route of adminstration: According to the draft, products for intraocular
use are to correspond with the the monograph Particulate Matter in Ophthalmic Solutions <789>,
products for extraocular use should comply with the monograph Particulate Matter in Injections
<788>.
The inclusion of a limit value for invisible particles in ophthalmic preparations is currently being
discussed in Europe, too. You can find information on the discussion of expanding monograph 1163
on the EDQM homepage.
Further sections in the USP monograph discuss sterility, preservatives and endotoxins (in injectable
products). The requirements described for leachables/extractables that may come from the
packaging are also new. It is pointed out that a risk assessment of leachables/extractables is not
easy to perform, as there is little data about substances that can be absorbed via the eye. Therefore,
data that has been determined for other routes of administration can be used for the risk analysis.
Furthermore, the special tests that may be relevant for ophthalmic preparations are listed, such as
viscosity, particle size distribution (in suspensions/emulsions) and drop size.

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GDP certification by accredited bodies and GDP audit by QPs - dangerous
misunderstandings
With the publication of the new GDP Guideline in the year 2013 the legal requirements concerning
the Good Distribution Practice have increased significantly. This has manifold consequences
because now compliance with the quality requirements is controlled throughout the complete
distribution chain until the final release to the patient. This is the objective at least.
The competent supervisory authorities carry out GDP inspections of companies that undertake tasks
requiring GDP in the course of distribution. And this is where the problem already starts. Since the
date of availability of the new GDP Guideline each company which comes into contact with the
supply chain of medicinal products tries to receive a GDP certificate. After all, it is the declared
objective of the EU to guarantee GDP compliance throughout the complete supply chain. The GDP
certificates are listed throughout Europe in a central database called EudraGMDP. Here, the GDP
non-compliance reports are also recorded. So what could be more natural than to attempt to be
listed there in order to demonstrate GMP compliance to the customers?
But the EU GDP Guide defines the group of companies which are subject to supervision very strict.
This means that many of the actors in the supply chain are not under supervision but must
implement GDP nevertheless. The competent authority for GDP will normally not carry out GDP
inspections at transport companies (shipping companies) or at airport hubs.
This gap is now filled by a number of service providers that grant GDP certificates. Some accredited
or non accredited bodies have started to offer GDP certificates for shipping companies or even
airports. An auditor of the (accredited) body carries out an audit and at the end a GDP certificate
beckons which will then be advertised in the internet and in company brochures. And here a big
misunderstanding arises. Because these commercial certificates cannot be compared to the GDP
certificates issued by the supervisory authority. But many actors in the supply chain are not aware of
this fact. The GDP certificate might be a marketing instrument such as the ISO 9001 certificate or a
certificate certifying compliance with environmental standards. But it does not confirm GDP
compliance within the meaning of an official GDP certificate. This can only be done by the competent
supervisory authority.
One also hears more and more about so-called QP audits carried out by independent consultants
who allegedly confirm GDP compliance by means of a GDP Certificate. As QPs play a central role in
the pharmaceutical law it is assumed by some companies that these "QP certificates" have a
particularly high significance and that they could virtually serve as substitute for the GDP certificate
of the supervisory authority. But this is not the case - as has already been explained for the GDP
certificates issued by accredited companies. A QP who actually works as part of the supplier
qualification for a pharmaceutical company will never issue a GDP certificate or written confirmation.

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What should companies do that would like to have a GDP certificate but will not be inspected by the
authority? It is important that each of these companies implements GDP. The requirements can be
checked in the GDP Guideline. A further certificate is not required. The key is an internal quality
management system for establishing GDP requirements with sufficiently qualified personnel. In the
case of a new customer/supplier relationship, for instance, the external auditor will want to see the
concrete implementation of GDP - regardless of a GDP certificate of any organisation.
FDA Clears Impax of Issues from 2011 Warning Letter
Impax Laboratories says the FDA has inspected its Hayward, Calif., manufacturing plant and cleared
it of all issues raised in a 2011 warning letter, paving the way for the launch of new drug products.
The pipeline consists of 33 pending ANDAs, with 25 developed internally and eight developed
through external partnerships, CEO and President Fred Wilkinson said.
Of the 17 ANDAs developed at the Hayward plant, two could launch later this year and eight in 2016.
The applications include generics of Sanofi's kidney disease drug Renvela (sevelamer carbonate),
Daiichi Sankyo's and Genzyme's diabetes and cholesterol drug Welchol (colesevelam HCI), Teva's
ADHD drug Adderall XR and Purdue Pharma's OxyContin TR.
The FDA issued the warning letter in May 2011 for manufacturing violations related to finished
pharmaceuticals identified during a Dec. 13, 2010, to Jan. 21, 2011, inspection.
The inspection found deviations in sampling and testing of in-process materials and drug products
and lapses in production record reviews. For example, Impax couldn't demonstrate that the
manufacturing process for fenofibrate capsules was capable of controlling weight variations and
didn't have data to support the temperature range used during the granulation process of colestipol
hydrochloride tablets, according to the warning letter.
The letter followed a Form 483 that triggered a voluntary recall of fenofibrate capsules in March
2011.
Wilkinson did not say how the company resolved the items in the warning letter.
FDA Bans Imports From Major Indian API Manufacturer
The US Food and Drug Administration (FDA) on Wednesday added Indian active pharmaceutical
ingredient (API) manufacturer Megafine Pharma's Nashik site in Maharashtra, India, to a list of
foreign manufacturing sites banned from sending products to the US.
Megafine, which was hit with an FDA Form 483 back in May at the site, produces 24 APIs for the US
market, including for drugs intended to treat Alzheimer's disease, depression, schizophrenia, multiple
sclerosis and overactive bladders. The company also produces the same number of APIs for the EU
market, as well as a number of other products for Canada, Australia, Brazil, Mexico and South

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Korea. The Nashik site, according to the company, has been inspected and approved by regulators
including the European Medicines Agency, Japan's Pharmaceutical and Medical Devices Agency,
the WHO and others.
The notice on Megafine does not indicate the specific issues that caused the import alert and does
not indicate if the company's other manufacturing site in Vapi, India will be impacted.
Form 483
According to a heavily redacted 13-page Form 483, the company was cited for manipulating lab
tests, as well as unjustified and unrecorded deviations from written lab mechanisms. The 483 notes
that one of the company's quality control (QC) analysts "manipulated" a test chromatogram "by
removing the unwanted peak out of the chromatogram and passed off the passing chromatogram as
the valid result."
In addition, the FDA inspector found that the QC management could not explain the "wide variation
between" an initial test result and a retest result, though, ―It is believed that the initial OOS [out of
specification] assay was switched with old passing sample vials and retested to obtain the passing
test results."
Another QC analyst was cited for manipulating high-performance liquid chromatography software "to
obtain passing test results."
In addition, FDA found that no "investigation reports were initiated after identification of non-cGMP
[current good manufacturing practice] practices within the production and quality control
department."
Companies on the import alert list that would like to request removal, according to FDA, "should
provide information to FDA to adequately demonstrate that the manufacturer has resolved the
conditions that gave rise to the appearance of the violation, so that the agency will have confidence
that future entries will be in compliance. This may include a letter detailing its corrective actions,
accompanied by documentation."
Forty-five other Indian pharmaceutical and API manufacturers are currently included on the import
alert list, including Ranbaxy, Wockhardt and Ipca Laboratories.
Megafine did not respond to a request for comment. For more details
browse: http://www.accessdata.fda.gov/cms_ia/importalert_189.html?source=govdelivery&utm_medi
um=email&utm_source=govdelivery

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Register of brokers authorised to deal in human medicines
MHRA (Medicines and Healthcare products Regulatory Agency) publishes current listing of UK
brokers authorised to broker human medicines, including company name, registration and address.
Source: https://www.gov.uk/government/publications/register-of-brokers-authorised-to-deal-in-
human-medicines
EU Court Clarifies When Drug Patents Expire
A ruling by the Court of Justice of the European Union has clarified when drug patents expire, in a
decision that could prove lucrative for drugmakers even though it adds only a few days of patent
protection.
The case, Seattle Genetics Inc. v. Austrian Patent Office, deals with a specific aspect of European
patent law known as a supplementary protection certificate, which extends the duration of certain
rights associated with a patent. SPCs take effect after the general patent expires and typically last
for five years. The combined exclusivity from the patent and SPC is normally capped at 15 years
from the time the product first receives marketing authorization.
The Austrian Patent Office granted an SPC to Seattle Genetics on Oct. 25, 2012, and set the
expiration date as Oct. 25, 2027. Seattle Genetics challenged that date, arguing the 15 years of
protection should start when the company was notified of the authorization, thereby pushing back the
expiration until Oct. 30, 2027.
In its Oct. 6 ruling, the CJEU agreed with the drugmaker, saying the term of an SPC begins on the
date when the innovator is notified of marketing authorization, not the date when authorities decided
to grant that authorization.
The case involved Seattle Genetics’ lymphoma therapy Adcetris (brentuximab vedotin).
Karnataka’s 27,000 chemists shut stores, KCDA submits memorandum to state health
minister to ban all online pharmacy websites
Karnataka Chemists & Druggists Association (KCDA) have stated that all the 27,000 chemists shops
across the state have brought the shutters down and the strike is a total success. The Association
also submitted to Karnataka health and family welfare minister UT Khader a memorandum to ban all
online pharmacy websites because it violates the Drugs & Cosmetics Act & Rules.
―Our memorandum was also accepted by Karnataka drugs controller Raghurama Bhandary, said V
Harikrishnan, president Karnataka Chemists & Druggists Association and the Bangalore District
Chemists and Druggists Association.

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―We are confident that the state government has comprehended the issue and will make efforts to
arrive at solution at the earliest,‖ he added.
The chemists and druggists across the state took out protest marches at various places. In
Bengaluru 2,500 chemists carried out peaceful protests at the Freedom Park to fight the cause of
online pharmacy players operating in the absence of a set of norms.
A dedicated committee for the creation of online pharmacy guidelines led by Maharashtra FDA
commissioner Harshadeep Kamble has Karnataka drugs controller Raghurama Bhandary, Odisha
drugs controller H Mahapatra, CDCSO assistant drugs controller Atul Kumar Nasa, FDA Goa
director Salim A Velijee, Madhya Pradesh State Licensing Authority Pankaj Agarwal and CDSCO
joint drugs controller Dr Eshwara Reddy as its members. The committee is now awaiting the
comments of the stakeholders covering druggists, chemists and the related associations before the
month end.
The online pharmacy retailers in the country have formed an association, the Indian Internet
Pharmacy Association (IIPA), to promote and protect the public health by ensuring that its members
operate in accordance with the existing Drugs & Cosmetics Rules read with Sections 4 & 5 of
Information Technology Act, 2008, and Pharmacy Practice Regulations, 2015 issued by government
of India through PCI.
―We strongly object to online pharmacy which is currently an unethical mode of doing business. It is
heartening to note that the state government is looking into the issue and keen to help us,‖
Harikrishnan told.
Both Karnataka Chemists & Druggists Association and the Bangalore District Chemists and
Druggists Association have exempted the hospital pharmacies in this 24-hour bandh. This ensured
the public and patients have had access to drugs from these outlets.
According to a section of people who gathered at pharmacy outlets in the government hospitals of
Victoria and Sri Jayadeva Institute of Cardiology, with an increased awareness about the nationwide
strike call on October 14, the drugs have been purchased well in advance to offset any immediate
emergencies. However, it is the outpatients and in-patients medicines which constituted the usual
and major chunk of sales today at the hospital pharmacies in most hospitals.
India risks missing boat as biosimilars shake up drug industry
India, which has dominated the generic drugs industry for decades, is falling behind in the race to
make copies of complex biotech drugs, which are expected to generate tens of billions of dollars in
sales in the coming years.

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While Indian firms have launched a few such products on the domestic market, where regulatory
barriers are relatively low, they are being overtaken by European, American and South Korean firms
in the race to supply lucrative Western markets.
Just three Indian groups - Biocon Ltd, Dr Reddy's Laboratories Ltd and Intas Pharamceuticals Ltd -
are working with partners on so-called biosimilars aimed at the United States and Europe.
Biotech drugs, which require genetic engineering, account for a growing share of new drugs and the
future sales of copycat products will also switch to this category of pharmaceuticals from simple
small-molecule pills like aspirin.
The global biosimilars market is predicted to have sales of $25 billion by 2020, according to a 2014
Thomson Reuters report.
"Biosimilars is a big opportunity," said Sujay Shetty, leader of the life sciences practice at PwC India.
"But unlike generics, it is not yet an opportunity (for Indian companies) in the U.S."
Copying chemical-based drugs has long been the bedrock of India's $15 billion pharmaceuticals
industry. Biotech drugs, however, are more difficult to make and cannot be replicated exactly, which
is why regulators have come up with the notion of versions that are similar enough to do the job.
That also means regulators will be eagle-eyed on quality, posing a challenge to Indian companies,
which have been distracted in recent years by manufacturing problems that have led to some drugs
being barred from key overseas markets.
Many, including the country's biggest drugmaker Sun Pharmaceutical Industries Ltd, are still
struggling to fix issues at their generic drug factories.
"FAR BEHIND"
Biosimilars have been available in India since the early 2000s, well before their 2006 arrival in
Europe and the recent introduction of a regulatory pathway in the United States, where the first
biosimilar was launched only last month.
But India's experience has not been problem-free. Intas, for example, recently received reports of
some patients on its biosimilar version of Roche's eye drug Lucentis developing inflammation barely
two months after the drug's launch.
An Intas spokesman said the problem was found to be in the drug's "cold chain logistics" distribution
channel and has restricted supply of the drug.
Arun Chandavarkar, the chief executive of Biocon, seen by analysts as the front-runner among
Indian firms developing biosimilars, believes the cost and complexity of developing biosimilars will be
a deterrent for many Indian players.
"At this time, there can't be too many companies willing to put in that much effort and investment," he
said.
The three Indian companies that have stated plans to make biosimilars for the United States and
Europe are all partnered with larger Western firms.
Biocon has a tie-up with Mylan Inc and is testing four molecules in global Phase III trials, for which it
plans to seek approvals in the United States and Europe starting in fiscal 2017, Chandavarkar said.

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Dr Reddy's is developing biosimilars such as rituximab and pegfilgrastim for use in cancer treatment
under a pact with Germany's Merck KGaA and said it plans to launch its first biosimilar in the United
States by 2018.
A spokesman at Intas, which developed pegfilgrastim in partnership with Canada's Apotex Inc, told
Reuters the company was considering partnering with a Swiss drugmaker to launch the product in
the United States. It declined to name the firm.
Chandru Chawla, head of Cipla Ltd's new ventures unit, said India's "fundamental disadvantage"
over United States, Europe and South Korea was that biotechnology never evolved in India to the
extent that chemistry did.
"In terms of having the right knowledge ecosystem and the pools of talent, India is far behind," he
said.
Globally, Western pharmaceutical firms such as Novartis AG; Pfizer Inc, in partnership with South
Korea's Celltrion Inc; and Merck & Co with partner Samsung Bioepis, are leading in the race to
dominate the Western biosimilars market.
"South Korea has made very significant strides in a very short period of time," said Cartikeya Reddy,
Dr Reddy's executive vice president for biologics. "In this regard they have indeed pulled ahead of
Indian companies."
Indian drug retailers protest against e-pharmacies
Indian drug retailers shut up shop for the day on Wednesday to protest against the country's growing
online pharmacy industry, and threatened to close indefinitely if the federal government did not shut
down e-pharmacies.
The nationwide protest was widely supported, with as many as 850,000 chemists closing their doors,
leaving patients waiting in long queues at any pharmacies that were open. "I have been to 7-8 shops
that were closed. My son has fever, and he needs medicine urgently," said Sukanti Bhoi, 55, as she
waited for her turn at a government hospital pharmacy in the eastern state of Odisha.
Shops inside and around hospitals as well as 24-hour pharmacies did not join in the one-day strike.
Online pharmacies are a relatively new phenomenon in India, where mom-and-pop stores have long
dispensed drugs. But online retailers pose a threat to their bricks-and-mortar peers in a market IMS
Health estimates is worth about $13 billion. Companies including Zigy and Sequoia Capital-backed
1mg have set up e-pharmacies over the past couple of years. Healthcare company Apollo Hospitals
Enterprise plans to start online sales if the government regulates the business.
Drug retailers are worried.
"It is a matter of our livelihoods, we must be prepared for a fight," said pharmacist Satish Vij, who
traveled from northern Haryana state to take part in a protest in New Delhi, where about 1,000
people, mostly pharmacists, wore black arm bands, held placards and shouted slogans against e-
pharmacies.
"We will struggle if multinationals enter this business," he said.

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J.S. Shinde, president of the All India Organization of Chemists and Druggists which called the
protest, said the retailers' trade group will consider an indefinite strike if the government does not
stop online drug sales within two months.
The dispute pits drug retailers, many of whom belong to the middle-class voter-base of Prime
Minister Narendra Modi's Bharatiya Janata Party, against the leader's push to encourage tech and
digital entrepreneurship in India.
Late on Tuesday, in a last-minute attempt to get pharmacies to stay open, Modi's Health Ministry
said it was studying several representations on how the online pharmacy business should be
regulated. It said the views of all stakeholders will be considered.
A Health Ministry spokeswoman could not immediately be reached for comment on Wednesday.
But retailers do not even want the government to consider online pharmacies as a legitimate
business. They say online sales will lead to more cases of drug abuse as medicines will be sold
without proper verification.
E-pharmacies say they have safeguards in place. Prashant Tandon, president of the newly formed
group of e-pharmacies -- Indian Internet Pharmacy Association -- said the internet will also help
small drug stores grow faster.
Japan's drug regulator PMDA plans India office
Japan's drug regulator, the Pharmaceuticals and Medical Devices Agency ( PMDA), is set to open
an India office soon, amid concerns over an aging population and burgeoning healthcare costs in a
country dominated by branded drugs.
The move is expected to help Indian generic drug manufacturers, which have been seeking to
increase their presence in Japan either through exports or by forging joint ventures with partners in
that country. Japan's market is worth $110 billion.
Japan wants to lower healthcare costs by encouraging generic drugs. It's looking to double the share
of generics in its healthcare system to 60% by 2017-18 to ease the burden on public expenditure,
translating into an attractive op portunity for Indian firms. "Indian drug makers, which are known for
their skills in producing efficacious and affordable copycat medicines, couldn't make much headway
in the highly attractive but regulated Japanese market for decades," said a senior commerce ministry
official, who did not want to be named. "The Japanese drug regulator is of late showing interest to
collaborate with its Indian counterpart over the last few weeks."

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The FDA Could Earn Over $60 Million A Day From Enforcing The Law
Many clinical trials on medicines and devices are subject to a 2007 federal law that requires the
results to be publicly disclosed on a federally sponsored website within a year after the clinical
trial is over. The reason for this requirement is simple: to give doctors and patients full information
so that they can make educated decisions about a given treatment. If disappointing clinical trial
results remain hidden, while only the most positive results are published and presented in the
media, doctors and patients can be wildly misled.
Unfortunately, investigators have found that over half the time, clinical trial sponsors fail to abide
by the law, sometimes failing to disclose results even after five years have elapsed. Even more
unfortunately, the Food and Drug Administration (FDA) has never once imposed the legally
authorized $10,000-per-day fine for failure to disclose a clinical trial’s results.
Compliance With Reporting Requirements
The most recent investigation was published in the New England Journal of Medicine (NEJM) in
March 2015. The authors identified 13,327 clinical trials that were registered on ClinicalTrials.gov,
that were completed between 2008 and 2012, and that were subject to the 2007 federal law
requiring full disclosure. A mere 13.4 percent of the clinical trials actually disclosed their results
within the 12 months required by law, and even after up to four years had elapsed, only 50.5
percent had disclosed the results or asked for a delay (see Figure 2 in the NEJM article).
In a twist that ought to embarrass academics, industry-funded trials were more likely to disclose
results than the National Institutes of Health (NIH)-funded trials, which were in turn more likely to
disclose results than academic medical centers. The authors found 6,599 clinical trials that were
overdue on reporting results.
Increasing FDA Enforcement
If the FDA imposed a $10,000 per day fine on each of these 6,599 outstanding trials, clinical trial
sponsors would be responsible for $66 million in payments in the first day alone, adding up to
over $24 billion per year.
Although the $24 billion figure shows the size and scope of the problem, the collective fines would
never reach that amount because as soon as the FDA actually begins enforcing the law, the
researchers who conducted these 6,599 trials would finally be incentivized to report the trials’
results.
Why doesn’t the FDA enforce the law? Some have argued that ClinicalTrials.gov is an antiquated
and difficult-to-use website. True enough, but given that 38 percent of trials do disclose their
results at some point, it is clearly not impossible to do so. This is not a reason to leave the federal
law completely unenforced.
The NEJM article states that one reason for lack of enforcement is that a new rule on clinical trial
report is still pending. But the 2007 law itself requires basic reporting of results; the only point of a

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new rule is toexpand the requirements to include other items, such as protocols. The mere fact
that a rule may be expanded in the future is no reason to leave the current requirements
unenforced. Yet another possibility is that the FDA does not want to get bogged down in lawsuits
from companies or universities that have a valid reason for delay. But this argument would
suggest, at most, that the FDA ought to levy a fine only when truly merited, not that the FDA
should never enforce the fine at all.
My proposal: as an experiment, the FDA should give the 30-day notice required by statute, and
then set aside a single week in which it will levy the $10,000-per-day fine on all overdue trials.
Assuming that there are around 6,600 overdue trials that don’t come into compliance within the
30-day grace period, the FDA would end up imposing over $460 million in fines within a week’s
time. In so doing, it would make a strong statement that disobeying the law and hiding clinical trial
results is no longer acceptable.
And within a week, compliance with the law would likely shoot up astronomically, and we would
have more complete knowledge about how well or how poorly drugs actually work. In turn, we
could all make better decisions about how to improve our nation’s health.
Source: http://healthaffairs.org/blog/2015/10/14/the-fda-could-earn-over-60-million-a-day-from-
enforcing-the-law/
Do fast drug approvals by FDA help or harm patients?
Two recent studies published by the British Journal of Medicine (BJM) raise concerns about the
speed with which the Food and Drug Administration approves drugs for market in the United States.
According to the FDA the stages of drug development and review necessary to gain marketing
approval include:
 Pre-clinical Testing;
 Investigational New Drug Application;
 Phase 1 studies – Focused on safety. Seeks to identify frequent side effects, etc.;
 Phase 2 studies – Focused on efficacy. Does the drug work on the condition or disease?;
 Phase 3 studies – A larger pool of subjects is tested for safety and effectiveness of drug;
 Review Meeting between the Drug maker and FDA;
 New Drug Application (NDA) – The formal step the drug maker takes in submitting all testing
data to FDA for marketing approval.
When the NDA is submitted, the FDA has 60 days to decide whether to file the drug for review. The
testing phases are potentially the longest timeframes involved with the drug approval process as it
takes time to administer the drugs to the test subjects and gather safety and efficacy data. It can
take several years for a drug maker to gather sufficient information from testing phase.
Fast-track Approval Process Geared to Help Patients
There are four programs available that allow the agency to expedite the development and approval
process for new drugs: orphan drug- drugs used for diseases that affect very few people, fast track,
accelerated approval, and priority review.

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Regardless of the program used, expedited approvals are supposed to be reserved for drugs that
are considered first in class and innovative enough to treat serious life-threatening illnesses that lack
satisfactory treatments. However, when researchers from Brigham and Women’s Hospital and
Harvard Medical School examined the FDA’s expedited drug development and approval programs
between the years 1987 and 2014 they found quicker approvals were not necessarily granted to
drugs defined by that criteria.
In fact, researchers found a 2.6% increase per year in the number of expedited review and approval
programs during the timeframe studied. They noted these newly approved drugs did not always fit
the requirement of being considered first in class or innovative.
Lack of In-Depth Testing Information Can Increase Patient Risk
One reason for the increase in expedited review and approval of drugs might be the passage of the
Prescription Drug User Fee Act (PDUFA). This act was enacted in 1992 and authorizes the FDA to
collect fees from companies that produce certain drugs and biological products for humans.
At the same time that the FDA increased the amount of drugs it approved through the expedited
review process researchers with the Cambridge Health Alliance and Harvard Medical School
conducted a study to examine black-box warnings and market withdrawals. These researchers found
that drugs approved after the passage of the Prescription Drug User Fee Act were more likely to
have a black box warning or be withdrawn from the market. These two findings would suggest that
shorter approval times lack sufficient information to properly assess drug safety and efficacy and
increase a patient’s health risk.
Drug Injury Lawsuits
When pharmaceutical makers push for expedited development and approval of products, patient
safety could be compromised. Lawsuits have been filed against numerous drug makers who put
profits ahead of patients by failing to disclose safety and efficacy information gathered during trial
phases or failing to alert healthcare providers and the FDA of adverse events that occur once a drug
has market approval.
Source: http://www.lexology.com/library/detail.aspx?g=ea6f08cd-1127-4b8e-a2ec-8e41ecdfff1b
Daiichi Sankyo to Cut Thousands of U.S. Jobs
Daiichi Sankyo announced on Friday it plans to conduct another round of job cuts this year.
The Japanese drug-maker plans to eliminate an estimated 1,000 to 1,200 jobs primarily from its
commercial headquarters in Parsippany, New Jersey as well as reduce the headcount for its field
salesforce.
Ken Keller, the president of Daiichi Sankyo’s U.S. commercial business, said in a statement that this
restructuring would help the firm be better positioned to meet the needs of patients with more
complex healthcare needs.

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The Parsippany location lost 16 percent of its work force earlier this year as part of Daiichi’s
continued plan to shift resources away from primary care drugs to focus more on a portfolio of
specialty drugs.
Daiichi is about to lose patent protection for the lucrative blood pressure drug Benicar within the next
few months, according to FiercePharma.
Benicar brought in $2.6 billion in sales last year, which accounted for over one-quarter of the drug-
maker’s revenue for 2014, writes FiercePharma, which is why the firm is looking for a profitable
replacement.
Reports pegged the Food and Drug Administration (FDA) approved blood thinner Savaysa as a
potential alternative to Benicar.
However, Pharmalot’s Ed Silverman wrote that the sales potential for this drug remains unclear
because it comes with a boxed-warning that alerts prospective customers of serious side-effects in
some patients.
The FDA's website explains doctors should cautiously assess starting therapy with
Savaysa for atrial fibrillation patients with creatinine clearances greater than 95 millimeters per
minute. The drug is less effective in this group and can lead to an increased risk of stroke.
This new phase of downsizing will conclude by the end of March 2016.
Cipla gets FDA's nine observations and issues noticed memo for Indore unit
The US Food and Drug Administration has identified nine areas of concern that need correction at
Indian drug maker Cipla's manufacturing unit at Indore.
Cipla is among the few large domestic companies that has so far not faced any tough regulatory
action from the FDA.
As part of its observations made during an inspection of the plant in July and
August,FDA investigators Ademola Daramola and Nebil Oumer noted that the quality control unit
lacked the authority to review production records to ensure that no errors have occurred and to
investigate any mistakes made.
They said that although one batch of levalbuterol inhalation solution was recalled from the US in May
2015, "the investigation did not extend into other strengths of the product to determine the product's
quality, safety and stability."
In another observation, they said a failure related to a leakage was documented 35 times but no
study was initiated to identify problems that could potentially affect product safety and quality.
The FDA officials faulted Cipla's Indore unit for facility and equipment systems and noted that the
aseptic processing areas were deficient in monitoring environmental conditions.
In an observation related to quality parameters, the FDA staff noted that the sterile filling lines were

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frequently opened in order to complete manual interventions. "In the packaging hall, sterile product
vials exiting the filling line were handled with ungloved and unsanitised hands by packaging line
employees," the inspectors said.
India maintains GVK Bio’s drug ban issue must be resolved for trade talks with EU
India is not ready to play ball yet as Brussels has not made any attempt to sort out the issue of the
ban placed on generic drugs tested by Hyderabad-based GVK Biosciences. This is despite leaders
such as German Chancellor Angela Merkel pushing for resumption of the proposed India-EU free
trade agreement (FTA) talks.
―We have been asking the EU to resolve the matter. We have said that we are even ready for re-
testing of the banned medicines. But there is no official response from the bloc on the matter. We will
not re-start FTA negotiations till there is some concrete movement on resolution of our problem,‖ a
Commerce Ministry official told.
EU ban on 700 generics
In July this year, the EU had announced a ban on marketing of 700 generics (copied versions of off-
patent drugs) tested at GVK Biosciences. Charges of manipulation of clinical trials for bio-
equivalence testing (test to prove that generic or copied drugs are as effective as the ones whose
patents have expired) of these drugs were made against the lab by a French standards agency
ANSM. The ban was implemented on August 21.
In protest against the ban, India had called off the talks scheduled in July-end with EU to re-start the
FTA negotiations that had not seen movement for more than two years.
Merkel, during her recent visit to India, raised the issue of resumption of FTA talks in her meeting
with Prime Minister Narendra Modi, but it failed to make an impression on New Delhi.
―The ban on the 700 drugs was implemented despite all our efforts to convince the European
Medicines Agency (EMA) that there was nothing wrong with the data. Now that we are prepared for
re-tests to be run, the EU is not showing any interest. If the EU can be so stubborn, why should we
relent?‖ the official asked.
With slowdown gripping the EU, the 27-member bloc is keen to have better access to the Indian
markets for its goods, which an FTA can provide. ―If the EU is interested enough in the FTA, we
believe it will be more sensitive towards our concerns,‖ the official said.
Six-member panel
Last month, the Commerce Ministry set up a six-member panel consisting of experts from various
departments, including drug regulators and cardiologists, to look into allegations made by ANSM
against GVK for manipulation of data related to electrocardiograms (ECGs). The panel confirmed
GVK’s assertion that there were no irregularities in the data.

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―We feel that the EU may be slow in reacting because of pressure from big pharma companies who
benefit if generics are out of the market. Since generics are several times cheaper than the patented
variants, the profits of MNCs get dented,‖ the official said.
Pharma companies team up to clean industry’s image
For the first time ever, some of India's biggest pharmaceutical companies, cutting across their
respective associations and representing nearly half the Rs 93,000 crore market, have come
together to push for ethical marketing practices to clean up the industry's image.
The forum, comprising of 40 to 50 domestic and MNC firms, had its first closed-door meeting on
October 14. It has made a "voluntary and moral commitment" to follow ethical marketing practices in
"letter and spirit", and will work with the regulatory mechanism to facilitate the exercise.
Earlier attempts at bringing about a code acceptable to the entire industry had failed, as the
associations the Indian Pharmaceutical Alliance (representing domestic firms), MNCs-led
Organisation of Pharmaceutical Producers of India (OPPI) and the Indian Drug Manufacturers'
Association (IDMA) were at loggerheads.
This comes even as the government has already expressed its intention to make the 'Uniform Code
of Pharmaceutical Marketing Practices' mandatory from next year. The code banning cruise tickets,
freebies and paid vacations for doctors sponsored by drug companies is voluntary at present. But in
light of rampant violations, the government plans to make it binding on companies.
The group which includes top MNCs like Novartis, MSD and Abbott, and domestic firms Sun
Pharma, Zydus Cadila and Dr Reddy's among others wants to start a movement and build pressure
on those who are not following ethical practices. A "voluntary" coming together out of sheer "moral
commitment carries greater weightage" than guidelines being thrust on them, said an expert, who is
part of the forum. "We have come together voluntarily to push for ethical marketing practices," IPA
director general D G Shah said. "Over the years, our industry has been maligned."
The 'Forum of Pharmaceutical Ethical Marketing Practices' will draw a core working group from the
firms to decide the modalities of taking the "movement" forward, and is in favour of a body similar to
the Advertising Council of India which is not a statutory body, to regulate the code. A final proposal
will be drawn up soon. Even after the code kicked in this year, complaints continued, with many
saying it existed only on paper, as firms try to influence prescriptions. "We plan to seek clarifications
from the government so that it (the code) is tweaked into a more practical and implementable code,"
said Ranjana Smetacek, director general, OPPI.

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31
CDSCO begins Induction Programme for assistant drug inspectors to upgrade technical,
professional & other functional skills
To train the regulatory officers to enable them to devise strategies for optimum utilisation of available
resources and to upgrade their technical, professional and other functional skills, the Central Drugs
Standard Control Organisation (CDSCO) has begun the Induction Programme for assistant drug
inspectors, which is a three-month long training programme from October 5 to December 31, 2015.
Major focus of the training, which is being held at National Institute of Biologicals, Noida, will be on
technical and regulatory framework in India such as Drugs and Cosmetics Act and Rules, Drugs and
Magic Remedies Act, and Narcotic Drugs and Psychotropic Substances Act; legal and administrative
issues; managerial and ethical issues; and IT and communication skills. Besides, there will be basic
introduction to GMP, GLP, GCP, etc.
The CDSCO has roped in a team of high level resource personnel for this programme. To begin
with, CDSCO will engage faculty drawn from regulatory agencies, administrative and police services,
pharmaceutical industry, management institutes and colleges and also training modules adopted by
other regulators.
The faculty would comprise retired /current drug regulatory personnel; experts from outside for
personality development; officials from CBI, IB, legal departments, subject experts from academic
institutions like NIPER, IIT, IISc, etc; subject experts and professionals from industry on GMP, GCP,
GLP etc; experts from international organisations including WHO etc; and retired/current senior
government officials.
The technical areas which will be covered in the programme include good manufacturing practices;
good laboratory practices; good clinical practices; good distribution and storage practices; principles
of product development and pre-formulation studies; new drug approval process; clinical trials
including BA/BE studies; pharmacovigillance; quality audits and inspections – planning, procedures,
report writing; and quality assurance and safety aspects in blood and blood products.
Besides, the programme will cover special feature of manufacture and quality assurance in vaccines
and sera, r-DNA products, active pharmaceutical ingredients, medical devices, stem cells,
monoclonal antibodies, antimicrobial resistance etc; advances in biotechnology and immunology;
drug discovery and development; and international regulatory framework including WHO.
The legal areas of the programme include in-depth knowledge of drug laws – Drugs and Cosmetics
Act and Rules; Narcotic Drugs and Psychotropic Substances Act; Drugs Price Control Order; Drugs
and Magic Remedies Act; Intellectual Property Rights; and Patent Act.

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It will also cover principles of jurisprudence, and principles of natural justice; principles of
interpretation; applicability of code of Criminal Procedure Code in investigations and trials under drug
laws; fundamentals of Evidence Act; investigation techniques including gathering of intelligence and
making proper use of such intelligence; and launching of prosecutions.
According to senior officials in the CDSCO, there is a constant need for such training programmes
as the drug regulatory system needs to keep itself abreast of the fast-changing scientific innovations,
evolving international regulatory framework and other developments. The central role of the Indian
pharma industry and globalisation necessitate that the regulatory framework has to constantly evolve
by integrating new developments. It is, therefore imperative for the present and future drug control
officials to continuously upgrade their skills and knowledge, and gain expertise in a variety of
subjects to meet with such functional requirements.
As the government has started recruiting a number of regulatory personnel, the need of the hour is
to train the regulatory officers to enable them to devise strategies for optimum utilisation of available
resources. Training that could constantly upgrade their technical, professional and other functional
skills would play an important role in their professional growth and diligent execution of their
responsibilities, officials said.
It is proposed to develop an extensive training programmes for various regulatory officials covering
all areas of functions of CDSCO including deputing the inspectors in various zonal offices, port, sub-
zonal offices for receiving practical experiences, hands-on training in the various regulatory functions
of CDSCO. It has also been decided that all regulatory personnel working in CDSCO will undergo
basic and advanced training programmes.
FDA Removes Warning Letter Issued to Pacira
The FDA has quietly removed a September 2014 warning letter issued to Pacira Pharmaceuticals for
touting unapproved uses of its analgesic Exparel. The removal comes after the drugmaker sued the
agency late last month claiming a First Amendment right to promote the drug for unproven uses.
The Sept. 22, 2014, warning letter cited problems with promotional materials for Exparel
(bupivacaine liposome injectable suspension), which is approved as a postsurgical analgesic for
bunion and hemorrhoid removal surgeries. According to the FDA, the promotional materials
suggested Exparel could be used in aparoscopic cholescystectomy, a procedure to remove
gallstones, and in open colectomy to remove part of a patient’s colon.
In Pacira Pharmaceuticals Inc., et. al v. Food and Drug Administration et. al, the company maintains
that the promotional material is truthful and should be allowed under the same ruling as Amarin
Pharma Inc., et. al v. Food and Drug Administration et. al.

PHARMA UPTODAY
33
That ruling rejected the agency’s arguments to prevent off-label promotion, and Pacira said the
agency’s arguments are even less persuasive because its promotions met the standards of the
drug’s indications and usage section.
FDA spokesman Christopher Kelly said the agency cannot comment on the reasoning behind the
letter’s removal because it is a matter related to pending litigation.
India’s CDSCO Sets Up Three-Month Training Program
India’s drug regulatory authority has set up a three-month training program for assistant drug
inspectors that will run through the end of this year, as the agency works to ramp up their skill sets.
The Central Drugs Standard Control Organization developed an extensive training program for
regulatory officials covering all functions of the agency, focusing on technical and regulatory, legal
and administrative, managerial and ethical, and IT and communications skills.
The program will help bridge a ―huge gap‖ in regulatory science, practices and knowledge, says G.N.
Singh, India’s drugs controller general.
India’s prime minister approved a $270 million plan in August to strengthen the country’s drug
regulatory system, including a training academy for regulatory and drug testing officials.
R&D spending of 25 India pharma cos soar by 28.8% in 2014-15
Indian pharmaceutical companies have substantially stepped up investments in R&D during 2014-15
to overcome stiff competition and to create product pipeline and strengthen their presence in world
market. A Pharmabiz study of leading 25 companies shows that there is a 28.8 per cent growth in
R&D expenditure at Rs. 9,250 crore during the year ended March 2015 from Rs. 7,179 crore in the
previous year. These companies have spent almost seven per cent of their consolidated net sales in
2014-15, which is slightly higher from 6.6 per cent in the previous year.
These companies have created strong product pipeline by filing ANDAs, DMFs and patents in the
world market. With rising healthcare cost, several countries are undertaking cost cutting measures
and moving towards cost effective generics and biosimilars products. Indian companies are focusing
on novel drug discovery & development (NDDD), generics, biotechnology and biosimilars. These
companies are taking steps to strengthen intellectual property area to tap expiration of patent
opportunities.
Though the R&D investment by Indian companies moved up to Rs. 9,250 crore, it is negligible as
compared to major international pharma which are spending over 15 per cent of their net sales on

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34
R&D. Indian companies have successfully received higher approvals for ANDAs from the highly
regulated authorities. For the nine months ended September 2015, Indian companies received final
approval for 113 ANDAs from US FDA as against 122 final ANDAs approval during full year ended
December 2014 with Aurobindo Pharma, Lupin, Glenmark Pharmaceuticals, Alembic
Pharmaceuticals, Jubilant Life Sciences, Natco Pharma, Sun Pharmaceuticals, Hetero Labs, etc.,
received good number of approvals.
These companies are working towards creating niche and complex products through investments in
R&D. Despite high risk of success, gestation periods and uncertainty regarding returns on
investment, Indian companies are continuously investing higher funds in R&D efforts. These
companies are entering new tie-ups with major international players, universities, academicians and
absorbing new technologies. Indian pharma companies are engaged in contract manufacturing in a
big way and R&D investments are offering necessary support for these activities. Even these
companies are taking up clinical trials for MNCs.
Sun Pharmaceutical Industries, after merging Ranbaxy Laboratories during 2014-15, remained on
top in R&D spending. Its consolidated R&D expenditure increased almost 87 per cent to Rs. 1,856
crore from Rs. 993 crore in the previous year and enhanced its ability to invest further in R&D. Its
consolidated net sales also moved up by 71 per cent to Rs. 27,433 crore from Rs. 16,080 crore.
R&D spending as percentage of its consolidated net sales worked out to 6.8 per cent as compared
to 6.2 per cent in the previous year.
Sun has entered into an exclusive worldwide in-licensing agreement for Merck's investigational
therapeutic antibody candidate tidrakiziumab, (MK-3222) to treat chronic plaque psoriasis, a skin
aliment. It has setup a joint venture with Intrexon Corporation for developing gene-based therapies
for ocular diseases. Sun has strengthen Taro's R&D pipeline and Taro had a pipeline of 35 ANDAs
awaiting US FDA approval as at the end of 2014-15.
Dr Reddy's Laboratories has pushed its R&D spending by 33.4 per cent to Rs. 1,685 crore during
2014-15 from Rs.1,263 crore, and remained as second highest R&D spender. This was followed by
Lupin with R&D spending up by 16.8 per cent to Rs. 1,118 crore from Rs. 958 crore. The fourth
largest R&D spender, Cipla invested an amount of Rs. 844 crore in R&D as compared to Rs.518
crore in the previous year, a significant growth of over 63 per cent. Glenmark's R&D investment
remained almost same at Rs. 600 crore.
Further, Aurobindo Pharma, Biocon, Sun Pharmaceutical Advance Research Co (SPARC),
belonging to Sun Pharmaceutical and Ajanta Pharma registered noticeable growth of over 30 per
cent in R&D expenditure during 2014-15. Similarly, Ipca Laboratories and Natco Pharmaceuticals
also shown strong growth of over 25 per cent in R&D spending during 2014-15. However, the R&D
expenditure of Piramal Healthcare, Unichem Laboratories, Orchid Chemicals and Pharmaceuticals,
Jubilant Lifesciences, Panacea Biotec and Strides Arcolab declined during 2014-15.

PHARMA UPTODAY
35
Lupin has intensify is research efforts to address opportunities in difficult-to-do generics,
dermatology, inhalation, complex injectables and the biosimilars space. It has undertaken
biotechnology development program with the help of 190 highly-qualified bio-technologists. Its
biosimilars pipeline includes 12 blockbuster molecules. Its two biosimilars are ready to launch in
India under the brand names Lupifil and Lupifil-P. Its cumulative ANDA filings with the US FDA
reached at 210 with 111 approvals received. Its cumulative DMF filings reached at 157 as at the end
of 2014-15.
Biocon is developing novel biologics and biosimilars for addressing chronic diseases like cancer
diabetes and autoimmune conditions for patients across the globe. Biocon, Asia's largest insulins
producer, has stepped up its R&D spending by over 50 per cent to Rs. 200 crore during 2014-15. Its
oral insulin under development has the potential to transform diabetes management the world over.
The company is setting up integrated insulins manufacturing facility at Malaysia. It is offering niche
services to multinational companies like Bristol Myers Squibb, Abbott and Baxter. Its subsidiary
Syngene has built a strong reputation of being the 'innovation partner' for many of its clients and well
positioned to tap global contract research organization opportunity. It filed over 1,150 patent
applications and holds over 530 patents. Syngene International, a leading contract research
organisation of Biocon, entered the capital market and now setting up a new manufacturing facility at
Mangalore SEZ and is in the process of acquiring 40 acres of land and obtaining necessary
approvals. The estimated expenditure for setting up the facility is US$ 100 million.
DRL's R&D expenditure increased sharply by 33.4 per cent to Rs. 1,685 crore during 2014-15, which
worked out to 11.5 per cent of its consolidated net sales. It filed 77 DMFs, taking the cumulative
number of DMF filings to 735 as at the end of March 2015. Similarly it filed 13 ANDAs with US FDA
and cumulatively 68 ANDAs pending approval. It has more than 2000 scientists across its
development centers in India, UK, US and Netherlands. The company launched 61 new products in
FY2015.
Aurobindo Pharma, which has set up a revenue target of US$ 3 billion by 2017-18, is moving ahead
strongly by investing in R&D activities. Its R&D expenditure increased by 33 per cent to Rs. 360
crore during 2014-15. The company has started investing in peptide technology and is building a
commercial facility with two modules commensurate with cGMP standards. It has developed
technologies for more than ten products. The company cumulatively filed 192 DMFs and 376
ANDAs. It received total 193 ANDA approvals and 183 ANDAs were under review.
Aurobind has developed and made penem filings for four products in injectable portfolio and it is
planning to launch products in Brazil and Mexico in current year. The company is now entering the
vaccines business with a joint venture for developing pneumococcal conjugate vaccine. The
company is also working on 15 oncology products.

PHARMA UPTODAY
36
Glenmark's consolidated R&D spending remained almost stagnant at Rs. 600 crore during 2014-15.
It announced first clinical development candidate in oncology, GBR 1302, a bispecific antibody for
cancer treatments. The company is initiating a phase I clinical trial for GBR 1302 in Germany. It
another product GBR-900 is entering clinical development in current year and first t anti-OX40
monocional antibody has completed phase I and phase II studies in US and EU. The company is
moving fast in NCE front also and its mPGES-1 discovery program, GRC 27864 has moved forward
in human trials and is nearing completion of phase I. Currently it has 70 applications pending with
the US FDA, of which 33 are Paragraph IV applications.
Panacea Biotech's R&D expenditure declined sharply by over 47 per cent to Rs. 46.82 crore during
2014-15 from Rs. 88.88 crore due to heavy losses. It has set up four disciplinary R&D centers. at
Navi Mumbai, Lalru, Mohali and New Delhi for development of vaccine, biopharmaceuticals,
proteins, peptides, monoclonal antibodies, NDDS, etc., It invested 6.8 per cent of net turnover on
R&D during 2014-15. Its R&D center is focusing in the fields of oncology and organ transplantation.
The company has filed more than 1,500 patent applications worldwide including 230 patent
applications in India.
Thus, the rising investment in R&D will give necessary push to overall working and presence in
regulated and emerging market. Indian companies are pushing the boundaries of innovation to meet
niche unmet medical needs. These companies are focusing on R&D to develop new chemical or
molecular entities. Anti-cancer treatments and diabetes attract the large R&D investments. It is
expected that the new government may initiate steps to offer tax incentives or favorable tax
environment for investment in R&D in near future.
Source: http://pharmabiz.com/
ICH announces organisational changes
On its inaugural meeting on 23 October 2015 the International Council for Harmonisation (ICH),
formerly the International Conference on Harmonisation (ICH), announced organisational changes:
ICH emphasizes that it is a truly global initiative and more involvement of regulators around the world
is welcomed and expected, as they will be invited to join counterparts from Europe, Japan, USA,
Canada and Switzerland. This is aligned with the possibility of wider inclusion of global industry
sectors affected by ICH Harmonisation.
In addition, a more stable operating structure is achieved through the establishment of an ICH
association, a legal entity under Swiss law, which will facilitate future growth through the
participation of new members.
For further information please visit the ICH official website.

PHARMA UPTODAY
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Terminology
data. Data means all original records and certified true copies of original records,
including source data and metadata and all subsequent transformations and reports of
this data, which are recorded at the time of the GxP activity and allow full and complete
reconstruction and evaluation of the GxP activity. Data should be accurately recorded by
permanent means at the time of the activity. Data may be contained in paper records
(such as worksheets and logbooks), electronic records and audit trails, photographs,
microfilm or microfiche, audio- or video-files or any other media whereby information
related to GxP activities is recorded.
data governance. The sum total of arrangements to ensure that data, irrespective of the
format in which it is generated, are recorded, processed, retained and used to ensure a
complete, consistent and accurate record throughout the data lifecycle.
data integrity. Data integrity is the degree to which a collection of data is complete,
consistent and accurate throughout the data lifecycle. The collected data should be
attributable, legible, contemporaneously recorded, original or a true copy, and accurate.
Assuring data integrity requires appropriate quality and risk management systems,
including adherence to sound scientific principles and good documentation practices.
data lifecycle. A planned approach to assessing and managing risks to data in a
manner commensurate with potential impact on patient safety, product quality and/or the
reliability of the decisions made throughout all phases of the process by which data is
created, processed, reviewed, analyzed and reported, transferred, stored and retrieved,
and continuously monitored until retired.
metadata. Metadata are data about data that provide the contextual information required
to understand those data. Typically, these are data that describe the structure, data
elements, interrelationships and other characteristics of data. They also permit data to be
attributable to an individual. For example, in weighing the number 8 is meaningless
without metadata, i.e. the unit, mg. Other examples of metadata may include the
time/date stamp of the activity, the operator ID of the person who performed the activity,
the instrument ID used, processing parameters, sequence files, audit trails and other
data required to understand data and reconstruct activities.
Ref: GUIDANCE ON GOOD DATA AND RECORD MANAGEMENT PRACTICES - WHO

PHARMA UPTODAY
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New Guidance
Acceptability of Draft Labeling to Support Abbreviated New Drug Application Approval;
Guidance for Industry
This guidance provides recommendations and information related to the submission of proposed
labeling with abbreviated new drug applications (ANDAs) under section 505(j)(2)(A)(v) of the Federal
Food, Drug, and Cosmetic Act (the Act) and FDA’s implementing regulations (21 CFR 314.94(a)(8)).
This guidance is intended to assist applicants submitting ANDAs under section 505(j) of the Act to
the Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research (CDER). It
explains FDA’s interpretation of the regulatory provision related to the submission of copies of
applicants’ proposed labeling in ANDAs and clarifies that OGD will accept draft labeling and does not
require the submission of final printed labeling (FPL) in order to approve an ANDA.
Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM465628.pdf
FDA Provides New Guidelines for Cleaning Duodenoscopes
Following the outbreak of infections related to a deadly superbug, the FDA has provided new
guidelines to help healthcare facilities ensure their duodenoscopes are cleaned adequately.
Duodenoscopes gained intense media scrutiny after reports of antibiotic-resistant infections in
Chicago, Pittsburgh, Seattle and Los Angeles. Earlier this year, the FDA revealed that between
January 2013 and December 2014, it had received 75 reports involving about 135 patients suffering
from carbapenem-resistant Enterobacteriaceae transmissions linked to these devices.
The FDA acknowledges that the duodenoscope's unique design is useful for performing endoscopic
retrograde cholangiopancreatography procedures. This utility has its drawbacks, however, as the
device has small working parts, including a moveable elevator mechanism with tiny crevices. This
elevator is particularly difficult to clean and disinfect properly, even if a healthcare professional
adheres to a manufacturer's instructions for use.
"Meticulous adherence to the manufacturer's reprocessing instructions is labor-intensive and prone
to human error," according to the agency.
To combat the threat of infection transmission, the FDA is recommending facilities adopt the
following supplemental measures: microbiological culturing; ethylene oxide sterilization; use of a
liquid chemical sterilant processing system; and repeat high-level disinfection.
"We recognize that not all healthcare facilities can implement one or more of these measures, which
require specific resources, training, and expertise," the FDA said. While this may be the case, it is

PHARMA UPTODAY
39
still critical that those professionals in charge of reprocessing the devices have instructions for use at
hand and remain proficient in performing all reprocessing steps.
In addition to the supplemental measures, the agency is urging healthcare facilities to adopt the
following best practices:
 Meticulously clean the elevator mechanism and recesses surrounding it by hand;
 Implement a comprehensive quality control program for reprocessing duodenoscopes;
 Review reprocessing recommendations from a consensus document from the
American Society for Gastrointestinal Endoscopy and the Society for Healthcare
Epidemiology of America.
The FDA notes that it is monitoring the situation and evaluating information from the healthcare
community, adverse events reports and other sources. It also is partnering with The Joint
Commission, the nation's largest hospital accreditation body, and the Centers for Medicare &
Medicaid Services to bolster hospitals' adherence to duodenoscope cleaning instructions. In
addition, the agency says it is working with industry as it modifies and validates instructions for
cleaning duodenoscopes.
EMA Guidance Explains How Drugmakers Can Hasten Antibiotics Development
The European Medicines Agency has released draft guidance explaining how drugmakers can use
pharmacodynamic and pharmacokinetic analyses to hasten the development and review of new
antibiobics.
According to the EMA, PD and PK data can replace or supplement human dosing studies, speeding
access of badly needed drugs to market. It can also aid in identifying differences and dealing with
dose variations for specific demographics, such as children and seniors, the obese and patients with
liver and kidney failure, the agency says.
Cellular analyses can also bolster drug candidates whose development has been held back by a
lack of appropriate trial participants or other feasibility issues, the EMA says.
The guideline, which would update 15-year-old recommendations, covers both antibacterial and
antifungal treatments.
To be most effective, drugmakers should gather specific microbiologic data on:
 The time it takes to kill a particular pathogen;
 Pathogen distribution markers;
 How those markers react to resistance mechanisms when the drug is administered;
 Intracellular biologic responses to the bacteria;
 Post-drug effects; and
 Which bacterial microorganisms are more- or less-resistant.

Pharma Uptoday Monthly Magazine - Volume 20; Issue: Nov 2015

Pharma Uptoday Monthly Magazine - Volume 20; Issue: Nov 2015

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