Helping Indian and European Drugs Enter the US Market

VOLUME: 9 - ISSUE: DEC 2014 |
PHARMA UPTODAY
For feedback, suggestions & queries write
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Inside this issue
3 News Uptoday
22 New Guidance
28 Audit Findings
483 Observations
- Caraco Pharmaceutical Laboratories
- Hospira Inc
- Novartis Consumer Health
- McNeil Consumer Healthcare
Warning Letters
- Hikma Farmaceutica, (Portugal) S.A.
- Cadila Pharmaceuticals Limited
- Sharp Global Limited
- Wells Pharmacy Network LLC
EMA Non-Compliance Reports
- Taishan City Chemical Pharmaceutical Co. Ltd., China
- Zhejiang Apeloa Kangyu Bio-Pharmaceutical Co. Ltd., China
- MANUEL RIESGO S.A., Spain
- Ranbaxy Laboratories Limited, Dewas, India
36 Regulations of the Month
§ 211.186 Master production and control records
§ 211.188 Batch production and control records

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News Uptoday
Changes in titles to come for the 9th Edition PhEur
The European Pharmacopoeia released the latest version of its ‘Style Guide’ in August this year. In this
Guide, its new policy regarding monograph titles for hydrates was announced. The word ‘anhydrous’
will be deleted from the titles of a number of monographs. These changes in title will be implemented
for the 9th Edition and will come into force on 1 January 2017.
The list of concerned monographs and the latest version of the style guide is enclosed.
Professor Sir Michael Rawlins appointed Chair of Medicines and Healthcare Products Regulatory
Agency (MHRA):
The Medicines and Healthcare Products Regulatory Agency today announced the appointment of
Professor Sir Michael Rawlins as its new Chair. He will take up post formally from 01 December 2014
and his appointment will be for three years.
Professor Sir Michael will take over from Sir Gordon Duff who announced his intention to step down
earlier this year, following his election as Principal of St Hilda’s College, Oxford.
Professor Sir Michael Rawlins was until recently Chair of the National Institute of Health & Clinical
Excellence (NICE), a role from which he stood down in 2013. He is also currently Chairman of Biobank.
Professor Sir Michael Rawlins said:
“It will be a tremendous honour to take up the agency’s chair, whose vital work as the UK’s regulator of
medicines and medical devices is underpinned by first-class science and research carried out at each of
the agency’s centres; the Clinical Practice Research Datalink (CPRD), the National Institute for Biological
Standards and Control (NIBSC) and MHRA.
“Sir Gordon has overseen a very successful and crucial period of major change in the agency’s history
and I am looking forward to taking that on, as we seek to provide an innovative, transparent and cost-
efficient service to further protect and improve public health.”
Sir Gordon Duff said: “I am delighted at the appointment of Sir Michael Rawlins as agency Chair. In Sir
Michael, the agency is getting an experienced, highly respected and influential public health expert who
will prove a real asset in meeting the challenges to come. “I am proud of what the agency has achieved
in the last two years, not least in the ongoing day-to-day regulation of medicines and medical products
but also through the leading role the agency plays, both at home and on the global stage. I wish Sir
Michael and all agency staff every success as they continue their invaluable work.”
Chief Medical Officer, Prof Dame Sally C Davies said:
“I am delighted at Sir Michael Rawlins’ appointment as agency Chair. He will bring a wealth of
experience to the Board and will play a key role in the leadership of our national regulator who will
continue to focus on excellence and innovation.

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“I would also like to thank Professor Sir Gordon Duff for his considerable contribution as chairman. Sir
Gordon successfully led the agency through a period of organisational change and growth where the
agency took on substantial additional responsibilities, including NIBSC. I wish Sir Gordon all the best in
his new role as Principal of St Hilda’s College, Oxford.”
Although not regulated by the Commissioner for Public Appointment’s Code of Practice, this
appointment has been made in accordance with the Code. The appointment was made on merit and
political activity played no part in the selection process. However, in accordance with the original Nolan
recommendations, there is a requirement for appointees’ political activity (if any declared) to be made
public. Professor Sir Michael Rawlins has not declared any political activity and does not hold any other
Ministerial appointments
Source: www.mhra.gov.
MHRA publishes notice on "Medicines distribution in the maritime sector".
This notice sets out MHRA’s expectations for the supply of human medicine to the maritime (marine
shipping) sector.
The complete document is enclosed.
Source: http://www.mhra.gov.uk/Howweregulate/Medicines/Medicinesregulatorynews/CON473634
FDA Listing of Authorized Generics
This list of authorized generic drugs (AGs) was created from a manual review of FDA’s database of
annual reports submitted to the FDA since January 1, 1999 by sponsors of new drug applications
(NDAs). Because the annual reports seldom indicate the date an AG initially entered the market, the
column headed “Date Authorized Generic Entered Market” reflects the period covered by the annual
report in which the AG was first reported. Subsequent marketing dates by the same firm or other firms
are not included in this listing. As noted, in many cases FDA does not have information on whether the
AG is still marketed and, if not still marketed, the date marketing ceased. Although attempts have been
made to ensure that this list is as accurate as possible, given the volume of data reviewed and the
possibility of database limitations or errors, users of this list are cautioned to independently verify the
information on the list. We welcome comments on and suggested changes (e.g., additions and
deletions) to the list, but the list may include only information that is included in an annual report.
Please send suggested changes to the list, along with any supporting documentation
to:AuthorizedGenerics@FDA.HHS.GOV
The complete list is enclosed.
Source: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/uc
m126391.htm

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First time ANDA (Generic) Drug Approvals
To find all Generic Approvals and Tentative Approvals, you can search Drugs@FDA, using the "Drug
Approval Reports by Month" feature. On the Drug Approval Reports page, select:
 "Original Abbreviated New Drug Approvals (ANDAs) by Month" for Generic Approvals
 "Tentative Approvals by Month" for Tentative Approvals
New approvals and tentative approvals are added to Drugs@FDA Reports on a daily basis, so you can
run the reports every day to find the latest approvals.
First-Time Generic Drug Approvals - October 2014
Generic Drug Name Generic
Manufacturer
Brand Name Tentative
Approval
Date
Approval
Date
1 MARAVIROC TABLETS, 150 MG
AND 300 MG
HETERO LABS LTD. SELZENTRY
TABLETS
10/28/2014
2 TREPROSTINIL INJECTION, 1
MG/ML, 2.5 MG/ML, 5 MG/ML,
AND 10 MG/ML
SANDOZ, INC. REMODULIN
INJECTION
10/31/2014
3 OLOPATADINE HYDROCHLORIDE
NASAL SOLUTION (NASAL
SPRAY), 665 MCG/SPRAY
APOTEX INC. PATANASE
NASAL SPRAY
10/8/2014
4 METHYLPHENIDATE
HYDROCHLORIDE EXTENDED-
RELEASE CAPSULES, 10 MG
TEVA
PHARMACEUTICALS
USA
RITALIN LA 10/17/2014
5 IVERMECTIN TABLETS USP, 3
MG
EDENBRIDGE
PHARMACEUTICALS,
LLC
STROMECTOL
TABLETS
10/24/2014
6 SIROLIMUS TABLETS, 1 MG AND 2
MG
DR. REDDY'S
LABORATORIES
LIMITED
RAPAMUNE
TABLETS
10/27/2014
7 HYDROCODONE BITARTRATE AND
PSEUDOEPHEDRINE
HYDROCHLORIDE ORAL
SOLUTION, 5 MG/60 MG PER 5
ML
TRIS PHARMA, INC. REZIRA ORAL
SOLUTION
10/28/2014
8 LAMIVUDINE ORAL SOLUTION
USP, 10 MG/ML
SILARX
PHARMACEUTICALS,
INC.
EPIVIR ORAL
SOLUTION
10/31/2014

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Former Ranbaxy execs build NJ startup to help Indian, European drugs enter U.S. market
A cadre of former execs at Indian generic drugmaker Ranbaxy’s US branch quit last month and have
launched a startup in New Jersey. Called Bion Pharma, it will help Indian and European drugmakers
expand receive regulatory clearance and distribution rights in the world’s largest drug market – the
USA.
The ex-Ranbaxy team will build on its experience of handling the many regulatory setbacks that the
Indian generics maker faced in America.
“The core team collectively possesses more than 10 decades of varied experience and has navigated
through some very excruciating circumstances, including enforcement actions, import alerts and other
similar hurdles,” CEO Krishnan told ET.
Bear in mind:
Over the past eight years, all but one of Ranbaxy’s plants were barred from importing medicines to the
US and the company had to pay hundreds of millions of dollars as fines as it pleaded guilty to
manufacturing malpractices and other misdemeanours. Amid all its woes, the company also managed
to launch the generic version of two blockbuster drugs — Pfizer’s Lipitor and Novartis’ Diovan — under
a six-month exclusivity window and operations at the US plant remained functional.
“We will be discriminating in our choice of partners and will only take on players who are willing to
follow the rules and meet the expectations of the US market,” CEO Krishnan told the Economic Times.
“Our strategy is to have partners with whom we can work on a portfolio of products rather than pick
and choose products.”
The top team of Bion Pharma, the new venture, includes former Ranbaxy US unit CEO Venkat Krishnan,
its ex-CFO Gaurav Mehrotra, sales head Bill Winter, legal head Lavesh Samtani and supply chain head
Phanindranath Punji. The venture will be based in Princeton, New Jersey, where Ranbaxy’s
headquarters too are situated.
FDA Accepts Actavis' Bipolar Drug sNDA
Actavis announced that the U.S. Food and Drug Administration (FDA) has accepted for filing Actavis'
Supplemental New Drug Application (sNDA) for SAPHRIS (asenapine) for the acute treatment of manic
or mixed episodes associated with bipolar I disorder in pediatric patients 10 to 17 years of age. Actavis'
sNDA for saphris has been granted priority review status by the FDA.
"The sNDA filing of saphris speaks to our commitment to ongoing research and development of our
mental health portfolio," said C. David Nicholson, PhD, Senior Vice President, Actavis Global Brands

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R&D. "We are pleased that the FDA has accepted this sNDA, marking the first step towards our goal of
bringing this important antipsychotic treatment option to pediatric patients."
Actavis expects the Prescription Drug User Fee Act (PDUFA) date to be in Q1 2015. The sNDA submission
for asenapine is based on the results of a 3-week monotherapy trial in 403 pediatric patients (10 to 17
years of age), of whom 302 received asenapine. In the trial, asenapine was shown to be statistically
superior to placebo in the reductions of both the Young Mania Rating Scale (YMRS) total score and
Clinical Global Impression-Bipolar (CGI-BP) score at fixed doses of 2.5 mg, 5 mg and 10 mg twice daily.
The most commonly observed adverse reactions were somnolence, dizziness, dysgeusia, oral
hypoesthesia, oral paresthesia, nausea, increased appetite, fatigue and increased weight.
Source: http://www.dddmag.com/
Top-selling 100 drugs to get cheaper soon
New Delhi: Top selling medicine brands for stress, hypertension, HIV, pain and pneumonia may soon
become cheaper. The drug price regulator National Pharmaceutical Pricing Authority (NPPA) is set to
bring in at least 100 new drugs under price control to include combinations, dosages and strengths that
are commonly prescribed by doctors and sold by pharmacists.
For instance, currently only one strength of Paracetamol is under price control, whereas NPPA has
proposed to cap prices of all brands of the medicine as listed in the Indian Pharmacopeia. Similarly, in
case of Nelfinavir and Ritonavir, commonly used antiretrovirals in treatment of HIV, the regulator plans
to fix prices of tablets along with capsules.
The move is significant because this is the second time NPPA has attempted to slash prices of drugs that
are outside the National List of Essential Medicines (NLEM), 2011. In May, the pricing authority had
invoked a public interest clause to reduce prices of 108 medicines. However, it had to withdraw the
guidelines after companies approached court and the law ministry opined that using the clause may be
out of context.
However, official sources say, this time there is political consensus on the issue, mainly ahead of
upcoming assembly elections in some states.
Currently, the government regulates prices of only 348 medicine formulations or 652 packs as listed in
the NLEM. However, the list includes only specific dosages, strengths and combinations of medicine
formulation. The regulator is of the view that this loophole does not ensure price regulation of all life
saving and essential medicines of mass consumption.
The latest move of NPPA is aimed at expanding the span of price control to include medicines dosages,
strengths and combinations which are commonly used and have high market share in terms of sales.
Recently, the pricing authority conducted a detailed study that revealed presence of certain "anomalies
or discrepancies" in specification or description in the NLEM 2011. Following the findings of the study
conducted across the country, the NPPA has proposed rectification in the NLEM.
The move has created a stir among pharmaceutical companies who are concerned about stressed
margins as well as instability promoted through such periodic price changes. "Mass consumption is not
a criterion for NLEM. It would be desirable that the selection of drugs is left to the core committee of
experts as per the established criteria. The role of the NPPA is to implement the policy in letter and

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spirit and not create confusion leading to instability," says D G Shah, secretary general, Indian
Pharmaceutical Alliance.
According to a senior official in the department of pharma, the proposal for changes in the list of
essential medicines has been sent to the health ministry which has the ultimate authority to revise the
same. Besides, NPPA has also sought comments from other stakeholders such as patient groups and
drug manufacturers.
Source: http://economictimes.indiatimes.com/
Sun Pharma recalls 68,194 bottles of anti-depression drug in US:
Product Detail
Product Description Venlafaxine Hydrochloride Extended-Release Tablets, 37.5 mg, 30-
count bottles and 90-count bottles, RX only, Manufactured for Sun
Pharma Global Inc. Dubai, United Arab Emirates by Sun Pharmaceutical
Industries Limited, Halol, India
Recall Number D-0236-2015
Classification Class II
Code Info Batch Number: JKM3855A Mfg. Date: 06/25/2013 Exp. Date: 05/31/2015
Batch Number: JKM3855B Mfg. Date: 06/25/2013 Exp. Date: 05/31/2015
Batch Number: JKM7265A Mfg. Date: 12/25/2013 Exp. Date: 11/30/2015
Batch Number: JKM7265B Mfg. Date: 12/25/2013 Exp. Date: 11/30/2015
Product Distributed Qty 68194
Reason For Recall Failed Dissolution Specification; 12 month stability timepoint
Event Detail
Event Id 69370
Product Type Drugs
Status Ongoing
Recalling Firm Sun Pharma Global Inc.
City Dubai
State
Country AE
Voluntary / Mandated Voluntary: Firm Initiated
Recall Initiation Date 2014-09-26
Initial Firm Notification of
Consignee or Public
Two or more of the following: Email, Fax, Letter, Press Release,
Telephone, Visit
Distribution Pattern Nationwide and Puerto Rico

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Recap of the three possible District Decision conclusions based on FDA’s review of the inspection
results:
 NAI - No Action Indicated (either minor or no objectionable conditions)
 VAI - Voluntary Action Indicated (only minor objectionable conditions)
 OAI - Official Action Indicated (significant objectionable conditions that warrant FDA sanctions)
Using The SOFIETM System for Regulatory Intelligence, we investigated the frequency of occurrence for
each of these conclusions for the years 2009-2013, for Outside US (OUS) and US inspections. These are
inspections of all FDA-regulated industries including drugs, devices, biologics, veterinary, food and
cosmetics.
The two charts below show the number of facility inspections for OUS and US:

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As we might expect, it’s clear that the FDA conducts many more inspections within the US by a factor of
10. But we also see that while the number of inspections in the US peaked in 2011, for OUS the number
has increased significantly in the past three years. This could reflect an increasing number of foreign
manufacturing facilities, or perhaps increased resources dedicated to OUS inspections, or both.
Now let’s look at the percentage of inspections with each of the three conclusions for both OUS and US.

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We can see a couple of things from these charts:
 The rate of inspections deemed OAI is considerably higher OUS
 Inspection results for both OUS and US are improving over time
 There is a higher ratio of VAI to NAI for OUS
Indian Government to rollout bulk drug pharma policy within 15 days
NEW DELHI: Government today said it will rollout a new pharma policy for bulk drugs in 10-15 days
which will help the sector grow manifold over the next 5-7 years.
"The government is working on industry friendly bulk drug pharma policy. It is likely to be rolled out by
the Prime Minister in next 10-15 days." Pharmaceuticals Secretary V K Subburaj said at an event
organised the PHD Chamber of Commerce and Industry.
The committee and task force set up by the government for preparing the policy have finalised their
recommendations which have been sent to the Prime Minister's Office, he said.
The policy will have various concessions for all stakeholders of the pharmaceuticals sector so that it is
put on the growth trajectory, he said.
"With this policy, the pharma sector which is of Rs 1.8 lakh crore in size at present, is likely to grow by 4-
5 times in next 5-7 years with both its domestic production and exports rising phenomenally," Subburaj
added.
Drug Controller General G N Singh said the regulator is addressing all the pending issues to liberate the
pharma sector and to simplify export regulations which will be reflected in the forthcoming policy.
Source: www.economictimes.indiatimes.com

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Apotex claims Health Canada’s ban on its drugs made in India is ‘unlawful’
Drug maker alleges in a lawsuit that the regulator’s decision to ban the import of drugs produced in
Bangalore was politically motivated.
Reeling from lost sales and fleeing customers, Toronto drug giant Apotex is lashing out at Health
Canada, alleging in a lawsuit that the regulator’s recent ban of drugs from its Indian factories was illegal
and politically motivated.
Apotex alleges Health Minister Rona Ambrose acted with “malice” toward the company and buckled
under political pressure after a series of Star articles exposed widespread problems in the company’s
Bangalore facilities.
The company is asking a federal court to quash the Health Canada ban blocking many of its India-made
products from reaching Canadian consumers.
“The minister’s decision to implement the import ban was politically motivated and, in particular, was
calculated to deflect public and parliamentary criticism of the minister as a result of the Toronto Star
articles,” Apotex alleges in a lawsuit filed in Toronto on Oct. 29.
An earlier Star investigation found Health Canada so lax that it allowed the import of Apotex drugs and
pharmaceutical ingredients that are banned from the United States because the adulterated
medications are potentially unsafe.
Inspectors from the U.S. Food and Drug Administration (FDA) had found that staff at Apotex plants in
Bangalore manipulated data, destroyed records and retested samples until they got favourable results,
the Star articles revealed.
Apotex’s president previously told the Star that “compliance is a journey” and the firm was working to
fix “procedural lapses” flagged by inspectors.
The fallout was swift and loud, as critics lambasted Canada’s drug regulator as “feeble, inadequate and
incompetent.”
Less than two weeks later, Ambrose declared the trust between Apotex and the regulator was “broken”
and announced the ban that affected more than 60 drugs and drug ingredients — including a generic
form of Viagra and popular treatments for hypertension, dementia and high blood pressure.
Apotex, which says it employs nearly 6,000 Canadians and makes drugs that fill about one of every five
prescriptions in this country, alleges it was blindsided by the unnecessary and unfair ban.
“The (Health) Minister has acted in an unlawful and discriminatory manner for improper purposes
against Apotex,” the suit alleges.
After U.S. agents found serious problems during inspections of Apotex’s India facilities, the company
said it kept Health Canada informed on a “voluntary basis” of the FDA concerns, which the firm says had
nothing to do with product quality.
(In its lawsuit, the company claims the FDA’s foreign plant inspection procedure is “discriminatory” and
a “breach” of fair trade agreements.)
Nevertheless, as Apotex continued to share information with the regulator throughout the summer, the
company alleges it never received any indication the regulator had serious concerns about its India
facilities.
In fact, in September, Health Canada inspectors gave one of the Bangalore plants a compliant rating, the
lawsuit says.

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Then, on Sept. 30, the company alleges, Health Canada suddenly banned products from Apotex’s India
plants without giving the firm detailed reasons or an opportunity to address the regulator’s concerns.
What the Star found and reported earlier this year was that Health Canada, concerned about U.S.
inspection results showing suspect drug ingredients were made by Apotex in India, twice asked the firm
to “stop sale and cease imports” from this Bangalore facility. Health Canada said at the time that the
company refused.
The Star has also learned from new FDA records that Apotex recently recalled more than 60,000 bottles
of blood pressure tablets — a medication called candesartan cilexetil — because of impurities. The
tablets were made at one of Apotex’s Bangalore factories.
An Apotex spokesperson did not answer several questions from the Star about the lawsuit and the
recent recall. “Apotex prides itself on a long legacy for providing our customers with the highest quality
medicines, care and service,” he said. “Our products are safe and effective. We cannot, per company
policy, discuss any proprietary commercial information or offer comment regarding ongoing litigation.”
In its lawsuit, Apotex has demanded reversals, retractions and reimbursements. It wants the court,
among other things, to order Ambrose to retract her online statements justifying the import ban as well
as release all Apotex products “unlawfully seized” by the government.
“Apotex is taking the shotgun approach for every grievance it has with the health minister. It smacks of
a desperate and hurt company rather than one who is using the courts in an ordinary way,” said Amir
Attaran, a University of Ottawa law professor who researches drug policy.
“The pleading has the flavour of a lover’s tiff, almost as if Apotex was spurned and had its feelings hurt
because the minister decided to deal with a public safety issue — perish the thought — in public.”
Ambrose did not answer the Star’s questions about the lawsuit. Earlier this month, in announcing new
drug safety legislation, Ambrose said an unnamed drug company was taking her to court.
“I’m being sued right now by a pharmaceutical company that’s not happy with action that we took.
That’s part of the business but it’s not going to stop me from taking action,” she said.
The lawsuit provides a behind-the-scenes look at the day of the ban and the tense aftermath.
On Sept. 30, Health Canada informed the company in a phone call that border agents had been
“instructed to restrict importation” of products from the two India facilities.
That kicked off a month of urgent discussions between top regulatory officials and Apotex, it was
demanding a justification for the ban.
Apotex alleges that on the evening of Oct. 28, a senior Health Canada official phoned the company’s
president to say her recommendation that the import ban be lifted was rejected by “unidentified
persons.” The official said one of the reasons against lifting the ban was concern over how Ambrose
would explain such an apparent flip-flop to the public, Apotex alleges. It’s not the first time Apotex has
complained about what it calls unfair and costly regulatory sanctions. In 2012, Apotex
complained before an international trade tribunal that a U.S. ban on its imports unfairly punished the
Canadian firm and decimated its U.S. sales. In August, the tribunal unanimously rejected Apotex’s claim
and ordered it to pay $1.2 million in legal fees to the U.S. government to cover the cost of the litigation.
In a letter to the court requesting an expedited hearing, an Apotex lawyer said Ambrose’s actions have
severely affected the company’s business. “Apotex has lost sales and, more importantly and irreparably,
it is losing customers.”

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Dr Reddy’s Lab’s Visakhapatnam unit comes under USFDA lens
The US Food and Drug Administration (USFDA) is conducting a surprise inspection of Dr Reddy’s
Laboratories’ Visakhapatnam plant. The inspection, which started on Tuesday, is expected to continue
till the end of the week. The surprise check by the regulator is at the chemical technical operation (CTO)
unit VI, which manufactures both active pharmaceutical ingredients (APIs) and bulk drugs.
When contacted, a DRL spokesperson confirmed the developments: “We are still awaiting the report
from USFDA and cannot comment on any issues,” the spokesperson said, without explaining the
reasons for the sudden inspection on the unit.
“The inspection may continue till the end of the week and we are confident that we have maintained
high quality standards including strict compliance,” sources in the know said. The unit, set up in 1990,
has a reaction volume capacity of over 570 KL, and is USFDA-inspected and ISO-9001 certified.
Source: http://indianexpress.com/
US court overturns Ranbaxy bid to block launch of rival generic drugs
NEW DELHI: A US court has turned down Indian drugmaker Ranbaxy Laboratories' request to block
competitors from launching copies of Roche's antiviral Valcyte. In a petition filed at the District Court of
Columbia last week, Ranbaxy had contended that the US Food and Drug Administration had
overstepped its jurisdiction by revoking approvals it granted to the company six years back.
The original approvals had given the Indian company the right to exclusively sell the generic version in
the US for the first six months of its launch - US law gives that right to the first successful generic
challenger of a patented drug. Ranbaxy had also sought an immediate restraining order to stop Indian
rival Dr Reddy's Laboratories and US firm Endo International from launching generics of Valcyte. A
Ranbaxy spokesperson refused to comment on the matter. Ranbaxy and the FDA have until November
21 to submit a schedule for further proceedings in the case in the US court.
Actavis to Buy Allergan for $66 Billion in ‘Transformative Deal’
Specialty and generic drug maker Actavis has agreed to buy Botox manufacturer Allergan for $66 billion
in a move analysts say could help transform Actavis into a major pharma giant.
The deal, unveiled last week, means Actavis’ annual branded sales in 2016 will more than double from
$7.8 billion to $16.6 billion, according to an estimate from Lawrence Biegelsen of Wells Fargo. Actavis’
generic business, meanwhile, is expected to account for a significantly lower percentage of overall
revenue, down to 27 percent from the current 42 percent, he said.
“This would take Actavis’ branded business to an entirely different level than Actavis’ specialty pharma
competitors, and put the drugmaker close to major pharma territory (for example, Bristol-Myers Squibb
[has brand sales] at $17.3 billion and Lilly at $22 billion),” Biegelsen said in a research note.
The deal comes with access to Allergan brand drugs in ophthalmology such as Restasis (cyclosporine
ophthalmic emulsion) and Lumigan (bimatoprost ophthalmic solution), in addition to the blockbuster

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Botox (onabotulinumtoxinA). The products will complement Actavis’ existing portfolio of specialty drugs
such as osteoporosis treatment Actonel (risedronate) and dementia drug Namenda (memantine HCl).
Actavis also will get access to Allergan’s 15 dermatology, urology, neurology and ophthalmology
products currently in near- and mid-term development stages.
Company leaders singled out the financial potential of DARPin (abicipar pegol), an experimental
treatment for the eye condition wet age-related macular degeneration (AMD) expected to start Phase
III trials next year. The drug is intended to have a longer duration of action and therefore require fewer
injections into the eye than other AMD treatments, Allergan has said.
“If we can reduce the injection burden for patients then we can really have a potential blockbuster,”
Brent Saunders, current Actavis CEO and the leader of the new company, said in a conference call.
The new company also remains committed to generics and will work to extend Botox to other markets,
Saunders added.
The $66 billion cash and stock deal is 23 percent more than the $50.8 billion original bid from Valeant
Pharmaceuticals. The Canadian-based drugmaker relentlessly pursued a takeover of Allergan since April,
but Allergan resisted the overtures due to concerns with Valeant’s acquisition-heavy business model.
Valeant said that the $219-a-share price Actavis paid for Allergan was too steep.
Biegelsen noted that this is the second “transformative deal” in less than a year for Actavis after it
acquired Forest Labs in February 2014 for $25 billion.
The Actavis-Allergan deal is expected to close by spring 2015 and must still be approved by both
companies’ shareholders.
Apellis Pharmaceuticals to acquire Potentia Pharmaceuticals
Apellis Pharmaceuticals announced that it entered into an agreement to acquire Potentia
Pharmaceuticals.
As part of the acquisition agreement, Apellis obtained the necessary intellectual property rights to
develop its complement inhibitor drug compound (APL-2) in ophthalmology and plans its first clinical
trial in dry age-related macular degeneration (dry AMD).
Complement inhibition is the only mechanism thus far to show reductions in the growth of dry AMD.
Potentia was the first company to develop a complement inhibitor for the treatment of AMD.
APL-2 has the same mechanism of action as Potentia's original drug compound but has a significantly
improved half-life in the eye. APL-2 is in late preclinical development in ophthalmology and is expected
to enter Phase II clinical testing in patients with AMD by the middle of 2015.
Cedric Francois, MD, PhD and CEO of Apellis commented, "We are delighted to be back in retinal drug
development. Ophthalmology is a unique therapeutic area that is very dear to us. We have learned
much about complement since our first venture in this area a decade ago, and have great hopes that
complement inhibition will be the first effective treatment for patients with dry AMD."
Phil Rosenfeld, MD, a retinal specialist at Bascom Palmer and advisor to Apellis, added: "There's
overwhelming scientific and clinical evidence to suggest that complement inhibition should slow the
progression of dry AMD. I'm optimistic that based on its mechanism of action and its target within the
complement cascade, APL-2 offers us the best chance to help our AMD patients."

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AMAG Pharmaceuticals acquires Lumara Health's Maternal Health Business
AMAG Pharmaceuticals, announced that it has completed the acquisition of Lumara Health, a specialty
pharmaceutical company with a particular focus on maternal health.
The transaction was announced on September 29, 2014 and included upfront consideration of $600
million in cash and 3,209,971 shares of AMAG common stock, and additional contingent consideration
of up to $350 million based on the achievement of sales milestones.
Lumara Health is the exclusive marketer of Makena(R) (hydroxyprogesterone caproate injection), the
only U.S. Food and Drug Administration (FDA)-approved product indicated to reduce the risk of preterm
birth in women who are pregnant with one baby and who have delivered one preterm baby
spontaneously in the past. Lumara Health is committed to contributing to the fight against prematurity
in a meaningful way.
The company's focus includes helping to ensure that cost is not a barrier for patients. Its customer
support center, the Makena Care Connection, has helped tens of thousands of women in the past year
alone, providing insurance benefits and financial assistance, including assistance with commercial
insurance copayments and providing the drug at no cost to eligible uninsured women.
"I am looking forward to building on the progress that Lumara Health has made and is making to reduce
preterm birth. The emotional and economic toll of preterm births is enormous, and we'll continue to
work hard to ensure that every at-risk mother has access to Makena therapy," said William Heiden,
president and chief executive officer of AMAG.
"I believe that this acquisition also provides a significant opportunity for us to strengthen Lumara
Health's patient-centric model with additional products and services, and through even stronger
collaboration with healthcare providers and the broader maternal health community."
Lumara Health executive Ken Wilson will lead the new maternal health division within AMAG and will
report to Mr. Heiden.
"Becoming a part of AMAG provides the ideal environment for us to strengthen our fight against
preterm birth," said Ken Wilson, who will be president of AMAG's Lumara Health maternal health
division. "Bill Heiden has challenged the Lumara Health team to find innovative ways to help mothers at
risk for preterm birth and to enhance our collaborative efforts with the maternal health community."
Mr. Wilson brings over 25 years of experience in the healthcare industry and, specifically, in the
women's health space. Prior to joining Lumara Health as executive vice president of the company's
maternal health division, Mr. Wilson held various leadership roles at Alere Health, Inc. (formerly Matria
Healthcare), and has many accomplishments in women's health, including physician practice
enhancement programs, maternity and neonatal intensive-care unit (NICU) care management solutions
for both Medicaid and commercial health plans, as well as pediatric experience for medically fragile
children.
Mr. Wilson also has experience in planning, directing, and developing marketing, sales, and managed
care strategies.
In connection with the completion of this transaction, AMAG has closed on a $340 million term loan,
which will be used to fund part of the cash consideration for the acquisition of Lumara Health.
The facility has a six-year term, except that the term loans will mature on September 30, 2018 if (a)
more than $25 million in aggregate principal amount of AMAG's 2.50% Convertible Senior Notes due
2019 remain outstanding (and are not converted to common stock or refinanced and replaced with

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debt that matures following, and has no amortization prior to, the date that is six and one half years
following the closing of the transaction), and (b) the aggregate principal amount of all term loans,
including all undrawn incremental commitments, is greater than $50 million on and as of such date.
The facility bears interest at LIBOR plus 6.25% and is subject to a LIBOR floor of 1%. For a complete set
of terms of the financing, please refer to the Form 8-K filed today with the Securities & Exchange
Commission.
"The acquisition of Lumara Health accelerates AMAG's transformation into a profitable specialty
biopharmaceutical company and provides a strong operating and financial platform for future growth.
Our integration plans are well underway, and we are already hard at work preparing to issue our
combined 2015 financial guidance in early January," said Frank Thomas, executive vice president and
chief operating officer at AMAG.
Prior to AMAG's acquisition of Lumara Health, Lumara Health completed its previously announced
disposition of a portfolio of women's healthcare products to a third party, including through licenses
and sublicenses of certain intellectual property rights associated with those products.
Aurobindo Pharma USA, Inc. Issues Voluntary Nationwide Recall of Northstar Label Gabapentin
Capsules, USP 300 mg Due to Complaints of Empty Capsules
FOR IMMEDIATE RELEASE — November 21, 2014 – Dayton, NJ, Aurobindo Pharma USA is voluntarily
recalling lot GESB14011-A of Gabapentin Capsules, USP 300 mg 100-count bottles to the consumer
level. The product lot has been found to contain some empty capsules.
Empty capsules could result in missed dose(s) of gabapentin resulting in adverse health consequences
that could range from no effect, short term reduction in efficacy, short term withdrawal effect, or status
epilepticus (long period seizures) that could be life-threatening. Aurobindo Pharma USA, Inc. has not
received any reports of adverse events related to this recall to date, but has received four complaints
for empty capsules.
Gabapentin is used as in the treatment of epilepsy and for the management of postherpetic neuralgia
(pain after shingles). The affected Gabapentin lot is GESB14011-A, Expiration 12/2015 and is packaged
in 100-count bottles, NDC 16714-662-01. The product can be identified by the imprint D on yellow cap
and 03 on yellow body with black edible ink. Product was distributed through Northstar label to retail
outlets nationwide.
Aurobindo Pharma USA, Inc. is notifying its distributors and customers by recall letters and is arranging
for return of all recalled product. Consumers, distributors, and retailers that have product which is
being recalled should stop using, distributing, or dispensing the affected lot and return to place of
purchase.
Source: http://www.fda.gov/Safety/Recalls/ucm424470.htm
Baxter Initiates Voluntary Recall Of One Lot Of Highly Concentrated Potassium Chloride Injection In
The U.S. Due To Mislabeled Overpouch
FOR IMMEDIATE RELEASE — November 20, 2014, DEERFIELD, Ill. — Baxter International Inc. is
voluntarily recalling one lot of Highly Concentrated Potassium Chloride Injection, 10 mEq per 100 mL to

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the user level due to a complaint of mislabeling of the overpouch. The inability to detect this overpouch
mislabeling at the point of care may result in the administration of a dose lower than intended. In the
high-risk patient population – patients prone to severe electrolyte imbalance – this hazardous situation
may lead to serious, life-threatening adverse health consequences. There have been no reported
adverse events associated with this issue to date.
Potassium Chloride is indicated for treatment of potassium deficiency and administered intravenously.
Some containers of Product Code 2B0826, Highly Concentrated Potassium Chloride Injection, 10 mEq
per 100 mL, Lot Number P319160, Exp. 06/30/2015, NDC 0338-0709-48 were incorrectly labeled on the
overpouch as Highly Concentrated Potassium Chloride Injection, 20 mEq per 100 mL. Products were
distributed to customers in the U.S. between June 23, 2014 and October 2, 2014. Unaffected lot
numbers can continue to be used according to the instructions for use.
Baxter has notified customers, who are being directed not to use product from the recalled lot. Recalled
product should be returned to Baxter for credit by contacting Baxter Healthcare Center for Service at 1-
888-229-0001, Monday through Friday, between the hours of 7:00 a.m. and 6:00 p.m., Central Time.
Unaffected lots of product are available for replacement.
Source: http://www.fda.gov/Safety/Recalls/ucm424248.htm
Ban on plastic bottles may hike drug prices
MUMBAI: Prices of certain drugs meant for children, women and senior citizens are set to rise following
a government restrictions on use of Polyethylene Terephthalate (PET) containers. The government has
banned use of plastic ( PTA) containers as primary packaging in liquid oral formulations for paediatric,
geriatric and reproductive healthcare use from FY16.
Confirming the move, SV Veeramani, president, Indian Drug Manufacturers Association (IDMA) said,
"There would be estimated 25-30% cost increase per bottle as the alternative for PET is glass. Using
glass will increase the cost of medicines."
One lakh metric tonnes of PET used in pharmaceuticals market will have to be replaced by 9 lakh metric
tonnes of glass per year. Veeramani added that this may lead to shortage of liquid medicines because of
shortage of glass containers. Transportation will also go up by 50% as only 90,000 glass bottles can be
transported in a container compared to 1.5 lakh PET bottles.
"Due to increased demand for glass bottles, the prices of glass bottles will shoot up as demand will be
more than supply, which will lead to further shortages as small and medium pharma firms may not be
able to purchase glass bottles at increased prices," said IDMA in its representation to the health
ministry.
Plastic Convertors Manufacturers Association (PCMA), an association of plastics convertors believes that
proposed ban on use of plastic bottles for packing of drug formulations proposed by the erstwhile
health minister is likely to lead to a steep increase in the prices of such drugs.
"Direct cost increase on one to one basis between glass bottles and plastic bottles will be between 10%
and 15%. Further cost of outer packaging would go up by 20% minimum due to need of thicker cartons
to avoid breakages in transit. Other big cost increases would be on account of lesser loadability of

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heavier glass packaging and due to increased down time on filling line breakages and these range from
15 % to 30 %, with maximum disadvantages for supplies to remote and hilly areas," said Udit Seth,
member PCMA.
Source: http://economictimes.indiatimes.com/
US FDA issues norms to pharma industry on specification of Unique Facility Identifier or Drug
Establishment Registration
US FDA has issued the latest guidance on the specification of the Unique Facility Identifier (UFI) System
for Drug Establishment Registration . The preferred UFI for a drug establishment is the Data Universal
Numbering System D-U-N-S (DUNS) number, assigned and managed by Dun and Bradstreet.
The objective of the directive dated November 2014 is to ensure registration of the pharmaceutical
production facility across the world. This will provide transparency of the operations and status of each
production plant.
According to Kaushik Desai, pharma consultant, Hon General Secretary, Indian Pharmaceutical
Association and Chairperson, Industrial Pharmacy Section, Federation of Asian Pharmaceutical
Associations (FAPA), this is a step in the right direction and positive one because it enables streamlining
and identifying manufacturing facilities globally.
The regulator stated that this guidance specifies the unique facility identifier system for registration of
domestic and foreign drug establishments. It is intended to address provisions set forth in section 510
of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360), as amended by the Food and
Drug Administration Safety and Innovation Act (FDASIA) (Public Law 112-144), regarding the
specification of the UFI system.
In July 2012, FDASIA was signed into law. Sections 701 and 702 of FDASIA directed the Secretary of
Health and Human Services (Secretary) to specify the UFI system for registration of domestic and
foreign drug establishments. Once the UFI system is specified, section 510 of the FD&C Act, as
amended, requires that each initial and annual drug establishment registration include a UFI (21 U.S.C.
360(b), (c), and (i)).
The guidance, according to US FDA is intended solely to address sections 701 and 702 of FDASIA to
specify the UFI system for registration of domestic and foreign drug establishments. The guidance
reflects current thinking in light of data standards, information technology, and information
management resources. As these variables change over time, FDA may revisit this guidance and the
specification made in section III of this guidance.
For drug establishment registration, FDA is specifying a preferred UFI for a drug establishment is the
Data Universal Numbering System D-U-N-S (DUNS) number, assigned and managed by Dun and
Bradstreet.

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FDA has been using the DUNS number as a registration number for drug establishments since the
implementation of electronic drug registration and listing for information on the electronic submission
of registration and listing data.
Currently, FDA finds the DUNS number appropriate to meet Agency needs for a data standard for drug
establishment registration UFI. The DUNS number is available free of charge to all drug establishments,
and further information is available on the FDA web site aid the regulatory authority.
Prescription drug recalls triple in less than 10 years: ‘This is a threat to every Canadian’s life’
The number of recalls and alerts for defective prescription drugs in Canada has soared over the last nine
years, often highlighting problems that could put patients in significant danger, a new, British-led study
reports.
The annual volume of faulty medicines disclosed by
Health Canada more than tripled to 143 last year
from 42 in 2005, according to the research, just
published in the journal BMJ Open. Less than half as
many cases came to light in the U.K. over the same
period, the team reported.
The most common Canadian defects were related to
stability — drugs that degraded before their time,
possibly undermining their effectiveness — and
contamination by foreign substances or microbes.
“If you inject something that is not sterile, that can be
life-threatening,” said Imti Choonara, a clinical
pharmacologist at the University of Nottingham and
one of the authors. “This is an issue that’s not going
to go away … [But] most health professionals are
unaware of the issue. I would imagine that most
people in Canada are unaware of the issue.”
He said he wanted to avoid scaremongering, but
suggested patients and parents of patients keep the
problem in mind if they find that medicines are not
working or causing unexpected side effects.
One expert not involved in the study said it is limited
by the fact Health Canada – unlike U.S. regulators –
does not make public details of its interactions with
manufacturers that have quality problems, leaving
the reason for the trend unclear. But the nature of
the defects alone is worrisome, said Amir Attaran, a

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health-policy expert at the University of Ottawa.
“What we now know, more often than not, is that when Health Canada warns about problems, it is
because the drug is unstable, contaminated or defective … which can kill you,” he said. “This is a threat
to every Canadian’s life.”
What we now know, more often than not, is that when Health Canada warns about problems, it is
because the drug is unstable, contaminated or defective … which can kill you
In 2008, in fact, U.S. authorities linked the deaths of 81 patients to contamination found in shipments of
the blood thinner Heparin made in China.
It is unclear whether the increase in alerts and recalls is due to a growing problem or, possibly, more
vigilant regulation, said Stephane Shank, a Health Canada spokesman. Regardless, Canada has one of
the most rigorous drug-safety systems in the world, he said, augmented with a new law that allows the
government for the first time to order a medicine recalled, even if its maker does not consent.
“Having said that, it is true that the global drug-supply chain has become more complex and stretches
far beyond Canadian borders,” he said.
Source: http://news.nationalpost.com/
Computer system:
Computer hardware components assembled to perform in conjunction with
a set of software programmes, which are collectively designed to perform a
specific function or group of functions.
Computerised system:
a computer system plus the controlled function that it operates. Includes
hardware, software, peripheral devices, personnel, and documentation; e.g.,
manuals and Standard Operating Procedures (SOPs).
Validation of computerised systems:
The validation of computerised systems means the documented evidence
that, with a high probability, the sys-tem functions as it is supposed to
function in a reproducible manner.

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New Guidance
Guidance for Industry: Specification of the UFI System for Drug Establishment Registration
This guidance specifies the unique facility identifier (UFI) system for registration of domestic and foreign
drug establishments. This guidance is intended to address provisions set forth in section 510 of the
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360), as amended by the Food and Drug
Administration Safety and Innovation Act (FDASIA) (Public Law 112-144), regarding the specification of
the UFI system.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested or recommended, but not required.
Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM421827.pdf
Ph.Eur Chapter 2.6.8. Pyrogens Revision open for Comments
Related to the current state of the art, Directive 2010/63/EU revising Directive 86/609/EEC on the
protection of animals used for scientific purposes was adopted on 22 September 2010. The Directive is
firmly based on the principle of the Three "Rs", to replace, reduce and refine the use of animals used for
scientific purposes. After a transition of two years, it should be implemented in the member states.
This directive effects the classic rabbit test used for pyrogen detection in medicinal products. In
accordance with the provisions of the European Convention for the Protection of Vertebrate Animals
used for Experimental and Other Scientific Purposes, tests must be carried out in such a way as to use
the minimum number of animals and to cause the least pain, suffering, distress or lasting harm.
Wherever possible and after product-specific validation, the pyrogen test is replaced by the monocyte-
activation test (2.6.30).
In Pharmeuropa Issue 26.4, the EDQM published the revised chapter 2.6.8. Pyrogens. It includes
information about selection of animals, animals quarters, materials, Thermometers, preliminary and
main tests and interpretation of results. The document is open for comments until 31. December 2014.
The complete revision is enclosed.
New FDA Inspection Guidance gives the Agency more Power
The U.S. Food and Drug Administration (FDA) is obliged to carry out inspections of facilities at
reasonable times, within reasonable limits and in a reasonable manner. However, sometimes the FDA is
not able to perform their tasks. Some companies delay or deny an inspection or even refuse the
inspector to enter.
Now, the FDA has published the final Guidance for Industry: Circumstances that Constitute Delaying,
Denying, Limiting, or Refusing a Drug Inspection. Based on the title, the document is divided into four
sections:

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 Delay of Inspection (not agreeing to an inspection start date or unreasonably delaying),
 Denial of Inspection (active behaviour by the owner or an operator to prevent an authorized
representative of FDA from conducting an inspection or to prevent FDA from completing an
inspection),
 Limiting of Inspection (for example denial to disclose or permit observation of the manufacturing
processes or unreasonably restricts entry to a particular facility without adequate justification),
 Refusal to Permit Entry (includes also passive behaviour and non-action preventing the FDA
representative to enter or inspect the facility.
In the case a drug that "has been manufactured, processed, packed, or held in any factory, warehouse,
or establishment and the owner, operator, or agent of such factory, warehouse, or establishment
delays, denies, or limits an inspection, or refuses to permit entry or inspection", it will be considered
adulterated. This would give the FDA much more power when dealing with uncooperative companies.
This would be also applicable during an inspection; if an inspector asks for records that FDA has the
right to review during a reasonable period of time and the records are not provided, the drug can be
considered adulterated!
The draft Guidance was published in July 2013. The final version contains a few examples for potentially
reasonable explanations that industry can have to avoid trouble:
 "A facility does not provide the FDA investigator access to aseptic processing areas until the
investigator accommodates the facility's documented gowning procedures.
 The FDA investigator requests translation of the records into English, and the translation is not
readily available.
 The records requested are not available at that time because they are being used for a
manufacturing operation that is in progress.
 The volume of the records requested is sufficiently large as to require reasonable time to
compile.
 At the beginning of an unannounced inspection, appropriate personnel are not immediately
available to accurately answer the FDA investigator's questions.
 The FDA investigator arrives for an unannounced inspection, but the facility is closed due to
scheduled maintenance.
 Training specified by the Occupational Safety and Health Administration is required before an
individual may enter a particular area of the facility, and the FDA investigator has not completed
such training.
 The chemical properties of products manufactured at the facility are such that taking
photographs would adversely affect product quality."
Source: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM360484.pdf

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ECA and PQG publish next chapter of the interpretation of the EU GDP Guide
The ECA Foundation Working Group on GDP and the Pharmaceutical Quality Group (PQG) have
published an additional chapter of the interpretation of the EU Good Distribution Practice (GDP
Guide). Working Group has released Chapter 5 Operations. The Chapter deals with a number of critical
GDP activities like qualification of suppliers and customers, receipt and storage of medicinal products,
picking, export to third countries and other elements. The Guidance document is structured in three
parts for each GDP requirement. The original text is mentioned and the Guidance documents provides
information on:
 what is the rationale for the point in the Guidance
 what are the risks and benefits associated with this aspect of the relevant aspect in the guidance
 how might this requirement be implemented/what does this mean
By this the Guidance the joint Working Group provides answers to readers of the EU GDP Guideline. For
example the issue of qualification of supplier raised a lot of questions by companies who are
implementing the GDP requirements. The ECA/PQG Guide provides more information and can serve as
a checklist to check for implementation.
TGA consults to comment on "Interim guideline on antimicrobial resistance risk data"
The TGA is seeking comments from interested parties on any part or all of the proposed Interim
guideline on antimicrobial resistance risk data. Documents released for consultation on Friday 7
November 2014. Interested parties should respond by close of business Friday 19 December 2014.
Source: http://www.tga.gov.au/consultation/consultation-interim-guideline-antimicrobial-resistance-
risk-data
FDA Guidance for Industry: Vaginal Microbicides: Development for the Prevention of HIV Infection:
This guidance provides recommendations for the development of vaginal microbicides regulated within
the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA) for the
prevention of human immunodeficiency virus (HIV) infection. Specifically, this guidance addresses the
FDA’s current thinking regarding the overall development program and clinical trial designs to support
the development of vaginal microbicide drug products.
Information in this guidance is also generally relevant for developing vaginal microbicides that are part
of a drug-device combination product. Guidance on development and testing of devices can be
obtained from the Center for Devices and Radiological Health (CDRH).
UCM328842.pdf

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FDA draft Guidance for Industry: Rare Pediatric Disease Priority Review Vouchers, Draft Guidance for
Industry:
This guidance provides information on the implementation of section 908 of the Food and Drug
Administration Safety and Innovation Act (FDASIA), which added section 529 to the Federal Food, Drug,
and Cosmetic Act (the FD&C Act). Under section 529, FDA will award priority review vouchers to
sponsors of certain rare pediatric disease product applications that meet the criteria specified in that
section.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The
use of the word should in Agency guidances means that something is suggested or recommended, but
not required.
Source: http://www.fda.gov/RegulatoryInformation/Guidances/ucm423313.htm
FDA publishes MAPP on INDs: Exception From Informed Consent Requirements for Emergency
Research:
 This MAPP describes policies and procedures for consistent review and administrative oversight
of an investigational new drug application (IND) for emergency research in which the clinical
investigation includes a request, pursuant to 21 CFR 50.24, for an exception from the requirement to
obtain informed consent from patients.
 This MAPP does not apply to emergency treatment of individual patients with investigational
drugs without informed consent by physicians carrying out medical care in a life-threatening situation as
provided under 21 CFR 50.23 (see also the definition of emergency use at 21 CFR 56.102(d)) or to an
emergency situation that does not allow time for submission of an IND as provided under 21 CFR
312.310(d) (i.e., “emergency procedures” for individual patients).
FDA New Guidance for Industry: Registration of Human Drug Compounding Outsourcing Facilities
Under Section 503B of the FD&C Act
This guidance is intended for facilities planning to register or renew registration as human drug
compounding outsourcing facilities (outsourcing facilities). A compounder can elect to register with FDA
as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act)
(21 U.S.C. 353b), as added by the Drug Quality and Security Act (DQSA), Pub. Law No. 113-54
(November 27, 2013). This guidance describes the process for electronic submission of establishment
registration information for outsourcing facilities. In certain rare cases, FDA may grant an entity a
waiver from submitting registration information electronically. This guidance also provides information
on how to obtain such a waiver.
FDA’s guidance documents, including this guidance, do not establish legally enforceable rights or
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The

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use of the word should in Agency guidances means that something is suggested or recommended, but
not required.
Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM377051.pdf
FDA New Guidance for Industry: Electronic Drug Product Reporting for Human Drug Compounding
Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act.”
This revised draft guidance explains how facilities that elect to register with FDA as outsourcing facilities
are to submit drug product reports, consistent with section 503B of the Food, Drug, and Cosmetic Act
(FD&C Act) (21 U.S.C. 353b). Section 503B of the FD&C Act provides that a facility that elects to register
with FDA as an outsourcing facility must report to FDA information about the drugs compounded at that
outsourcing facility in the form and manner that FDA may “prescribe by regulation or guidance.”
This guidance describes who must report and what information they must provide and explains that
drug compounding reports must be submitted in structured product labeling (SPL) format using FDA’s
electronic submissions system.
This guidance is a revision of the FDA draft guidance Interim Product Reporting for Human Drug
Compounding Outsourcing Facilities Under Section 503B of the FD&C Act. FDA has revised that draft
guidance to explain that outsourcing facilities are to report on compounded drugs using FDA’s updated
electronic submissions system. This draft revision supersedes the draft guidance Interim Product
Reporting for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act.
Source: http://www.fda.gov/downloads/Drugs/NewsEvents/UCM424303.pdf
FDA New Guidance for Industry: Fees for Human Drug Compounding Outsourcing Facilities Under
Sections 503B and 744K of the FD&C Act
This guidance is intended for entities that compound human drugs and elect to register as outsourcing
facilities under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act), which was added
by the Drug Quality and Security Act (DQSA). Once an entity has elected to register as an outsourcing
facility, it must pay certain fees to be registered as an outsourcing facility.
This guidance describes the types and amounts of fees that outsourcing facilities must pay, the
adjustments to fees required by law, how outsourcing facilities can submit payment to FDA, the
consequences of outsourcing facilities’ failure to pay fees, and how an outsourcing facility can qualify as
a small business to obtain a reduction in fees. FDA has issued separate guidances on registration and
reporting requirements for outsourcing facilities.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements are cited or otherwise
applicable. The use of the word should in FDA guidances means that something is suggested or
recommended, but not required.

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UCM391102.pdf
FDA New MAPP on Developing Indication-Specific Guidances
This MAPP describes the process to be used by office and review division staff within the Office of New
Drugs (OND) in the Center for Drug Evaluation and Research (CDER) when developing indication-specific
guidances for industry.
This MAPP applies to indication-specific guidances only. Policies and procedures for developing non-
indication-specific guidances can be found in MAPP 4000.2 Developing and Issuing Guidance.
Source: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacc
o/CDER/ManualofPoliciesProcedures/UCM073016.pdf
FDA New MAPP on Chemistry Review of Question-based Review (QbR) Submissions
This MAPP clarifies how drug substance and drug product reviewers in the Office of Pharmaceutical
Science (OPS) should assess new drug applications (NDAs), abbreviated new drug applications (ANDAs),
or Type II DMF submissions that follow a Question-based Review (QbR) format in conjunction with the
International Conference on Harmonisation (ICH) guidance M4Q: The CTD – Quality, (ICH M4Q) Module
The MAPP may also be used as a guide for the assessment of submissions that do not follow the QbR
format.

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AUDIT FINDINGS - 483 Observations
Firm Name 483 Observation
King Pharmaceuticals,
LLC
Equipment and utensils are not maintained at appropriate intervals to
prevent malfunctions and contamination that would alter the safety,
identity, strength, quality or purity of the drug product.
Regeneron
Pharmaceuticals, Inc.
The responsibilities and procedures applicable to the quality control unit
are not in writing and fully followed.
Vantage
Oleochemicals, Inc.
Testing and release of drug product for distribution does not include
appropriate laboratory determination of satisfactory conformance to the
final specifications and identity and strength of each active ingredient prior
to release.
Pharmaceutics
International, Inc.
Procedures for design control have not been established.
South Coast Specialty
Compounding, Inc.
Aseptic processing areas are deficient regarding the system for monitoring
environmental conditions.
Cumsee Enterprise Batch production and control records are not prepared for each batch of
drug product produced.
Nanophase
Technologies Corp.
The firm's procedures for performing investigations into deviations or non-
conformances do not require a root cause determination or an attempt to
find the underlying reason for the occurrence of the deviation or non-
conformity.
OSO
BioPharmaceuticals
Manufacturing, LLC
Procedures designed to prevent microbiological contamination of drug
products purporting to be sterile are not established.
Pharbest
Pharmaceuticals, Inc.
Written production and process control procedures are not followed in the
execution of production and process control functions.
Perry Drug, Inc. Procedures designed to prevent microbiological contamination of drug
products purporting to be sterile do not include validation of the
sterilization process.
L. Perrigo Co. There are no written procedures for production and process controls
designed to assure that the drug products have the identity, strength,
quality, and purity they purport or are represented to possess.
Hydrox Laboratories Written records of investigations into the failure of a batch or any of its
components to meet specifications do not always include the conclusions
and follow-up.

PHARMA UPTODAY
29
FDA Updates 483 of Caraco Pharmaceutical Laboratories, Ltd. (Inspection dates: 01/07/2013 -
01/11/2013) in its website:
1. Drug products are not stored under appropriate conditions of temperature and humidity so
that their identity, strength, quality and purity are not affected.
2. The responsibilities and procedures applicable to the quality control unit are not fully followed .
483 of Hospira Inc. (Mar-2013)
1. There are no written procedures for production and process controls designed to assure that the
drug products have the identity, strength, quality, and purity they purport or are represented to
possess.
2. Procedures designed to prevent microbiological contamination of drug products purporting to
be sterile are not established, written, and followed
3. The responsibilities and procedures applicable to the quality control unit are not in writing and
fully followed
4. Drug product production and control records, are not approved by the quality control unit to
determine compliance with all established, approved written procedures before a batch is
released or distributed.
5. There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or
any of its components to meet any of its specifications whether or not the batch has been
already distributed.
6. Aseptic processing areas are deficient regarding the system for monitoring environmental
conditions.
7. Equipment for adequate control over air pressure, humidity, and temperature is not provided
when appropriate for the manufacture, processing, packing or holding of a drug product.
8. Aseptic processing areas are deficient regarding humidity controls.
9. Testing and release of drug product for distribution do not include appropriate laboratory
determination of satisfactory conformance to the final specifications prior to release.
10. Written specifications for laboratory controls do not include a description of the testing
procedures used.
11. Laboratory records do not include complete data derived from all tests, examinations and assay
necessary to assure compliance with established specifications and standards.
12. Procedures designed to prevent microbiological contamination of drug products purporting to
be sterile do not include adequate validation of the sterilization process.
13. Rejected in-process materials are not identified and controlled under a quarantine system to
prevent their use in manufacturing or processing operations for which they are unsuitable.
14. Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the
room and equipment to produce aseptic conditions.
15. Employees engaged in the manufacture and processing of a drug product lack the training
required to perform their assigned functions.

PHARMA UPTODAY
30
16. Laboratory controls do not include the establishment of scientifically sound and appropriate
sampling plans and test procedures designed to assure that in-process materials and drug
products conform to appropriate standards of identity, strength, quality and purity.
17. Written production and process control procedures are not followed in the execution of
production and process control functions.
18. Equipment used in the manufacture, processing, packing or holding of drug products is not of
appropriate design to facilitate operations for its intended use.
19. Equipment and utensils are not cleaned, maintained, and sanitized at appropriate intervals to
prevent malfunctions and contamination that would alter the safety, identity, strength, quality
or purity of the drug product.
20. Buildings used in the manufacturing and processing of a drug product are not maintained in a
good state of repair.
483 of Novartis Consumer Health (Feb-2013):
1. Investigations of an unexplained discrepancy did not extend to other batches of the same drug
product and other drug products that may have been associated with the specific failure or
discrepancy.
2. Deviations from written production and process control procedures are not justified.
3. Written records of investigations into unexplained discrepancies do not always include the
conclusions and follow-up.
4. Written procedures are not followed for evaluations conducted at least annually to review
records associated with a representative number of batches, whether approved or rejected.
5. An NDA-Field Alert Report was not submitted within three working days of receipt of
information concerning a failure of one or more distributed batches of a drug to meet the
specifications established for it in the application.
6. Procedures describing the handling of written and oral complaints related to drug products are
not written or followed.
7. There is no written testing program designed to assess the stability characteristics of drug
products.
8. Container closure systems do not provide adequate protection against foreseeable external
factors in storage and use that can cause deterioration or contamination of the drug product.
9. The responsibilities and procedures applicable to the quality control unit are not fully followed.
483 of McNeil Consumer Healthcare:
1. Procedures describing the handling of written and oral complaints related to drug products are
deficiently written or followed.
2. Control procedures are not established which monitor the output and validate the performance
of those manufacturing processes that may be responsible for causing variability .in the
characteristics of in-process material and the drug product.

PHARMA UPTODAY
31
3. There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or
any of its components to meet any of its specifications whether or not the batch has been
already distributed.
4. Records are not maintained so that-data therein can be reviewed at least annually to evaluate
the quality standards of each drug product to determine the need for changes in specifications
or manufacturing or control procedures.
5. Investigations of an unexplained discrepancy and a failure of a batch or any of its components to
meet any of its specifications did not extend to other batches of the same drug product and
other drug products that may have been associated with the specific failure or discrepancy.
6. Written records are not always made of investigations into unexplained discrepancies.
7. The responsibilities and procedures applicable to the quality control unit are not fully followed.
FDA Warning letters
FDA Warning letter: Hikma Farmaceutica, (Portugal) S.A.:
1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or
any of its components to meet any of its specifications, whether or not the batch has already
been distributed (21 CFR 211.192)
2. Your firm failed to establish adequate written procedures for production and process control
designed to assure that the drug products you manufacture have the identity, strength, quality,
and purity they purport or are represented to possess, and your firm’s quality control unit did
not review and approve those procedures, including any changes (21 CFR 211.100(a)).
Cadila Pharmaceuticals Limited 10/15/14 (WL: 320-15-02)
1. Failure to adequately investigate complaints and extend the investigations to other batches that
may have been affected.
2. Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured are in
compliance with CGMP, and meet established specifications for quality and purity.
3. Failure to prevent unauthorized access or changes to data and to provide adequate controls to
prevent omission of data.
Sharp Global Limited 10/15/14 (WL: 320-15-01)
Your firm failed to fulfill its registration obligations under Section 510(i)(1) of the Act and its listing
obligations under Sections 510(i)(2) and 510(j), which is prohibited under Section 301(p), 21 U.S.C.
360(i)(1) and (2), 360(j), and 331(p).

PHARMA UPTODAY
32
Warning letter of Wells Pharmacy Network LLC 11/10/14 (FLA-15-07):
FDA investigators also noted CGMP violations at your facility, causing the drug products for which you
have not obtained valid prescriptions for individually-identified patients to be adulterated under section
501(a)(2)(B) of the FDCA. The violations include, for example:
1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent
microbiological contamination of drug products purporting to be sterile, and that include validation of
all aseptic and sterilization processes (21 CFR 211.113(b)).
2. Your firm failed to establish and follow an adequate written testing program designed to assess the
stability characteristics of drug products and to use results of such stability testing to determine
appropriate storage conditions and expiration dates (21 CFR 211.166(a))
3. Your firm failed to establish an adequate system for cleaning and disinfecting the room and
equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).
4. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic
processing areas (21 CFR 211.42(c)(10)(iv))
5. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug
product from contamination (21 CFR 211.28(a)).
6. Your firm failed to establish adequate written procedures for production and process control
designed to assure that the drug products you manufacture have the identity, strength, quality, and
purity they purport or are represented to possess (21 CFR 211.100(a))

PHARMA UPTODAY
33
AUDIT FINDINGS - EMA Non Compliance Reports
Non-Compliance Report: Taishan City Chemical Pharmaceutical Co. Ltd., China
Nature of non-compliance:
Overall 24 deficiencies were observed, including 6 major deficiencies related to:
[Major 1] Numerous weaknesses in the quality management system (review of process validation data,
documentation, product quality review);
[Major 2] Insufficient securisation of the electronic raw data in the Quality Control laboratory (No
limitation of access levels, no restriction on the deleting of data, no audit trail, inadequate traceability
and archiving practises);
[Major 3] Inability of the Quality Control unit to conduct and manage HPLC tests appropriately (e.g. no
documentation and justification of deviations from analytical procedures, no detection of analysts
errors);
[Major 4] Multiple risks of contamination identified in the production areas of Ciclosporin (e.g. no
protection of clean equipment outlets, equipment under status “to be used for production” stored dirty
for several months, open parts of the final steps exposed in dirty surroundings);
[Major 5] Blending of Ciclosporin batch tails without adequate traceability and validation combined with
unsuitable sample representativity and traceability;
[Major 6] Inappropriate equipment and area qualification (e.g. no qualification for the automatic
temperature controllers at the fermentation warehouse, the strain centre for Ciclosporin and the cool
storage area for Ciclosporin).
Non-Compliance Report: Zhejiang Apeloa Kangyu Bio-Pharmaceutical Co. Ltd., China:
Nature of non-compliance:
The inspection identified one critical, no major and several minor deficiencies to EU GMP Guide Part II.
The critical deficiency was found during inspection of the quality control laboratories.
 The company failed to establish a procedure to identify and validate GMP-relevant
computerized systems in general.
 Two batch analysis reports for Colistin Sulfate proved to be manipulated.
 HPLC chromatograms had been copied from previous batches and renamed with different
batch and file names.
 Several electronically stored HPLC runs had not been entered into the equipment
logbooks.The nature of these data could not finally been clarified.
 Neither the individual workstation nor the central server had been adequately protected
against uncontrolled deletion or change of data.
 The transfer of data between workstations and server showed to be incomplete.

PHARMA UPTODAY
34
 No audit trail and no consistency checks had been implemented to prevent misuse of data.
Non-Compliance Report: MANUEL RIESGO S.A., Spain
Nature of non-compliance : During the inspection carried out to this repacker of APIs, the inspection
team observed 32 non-conformities to EU GMP Part II. One of these was rated as critical and eight were
categorised as major deficiencies.
Action taken/proposed by the NCA :
Prohibition of supply
-Prohibition of the supply of active substances (primary or secondary) packaged by this manufacturer.
The distribution of these active substances is restricted to Spanish market.
Others
-Suspension of manufacturing and distribution activities of active substances to be used as starting
materials in medicinal products for human use. -Removal of the authorisation holder from the Register
of manufacturers, importers and distributors of active substances published in AEMPS Web page
(http://www.aemps.gob.es/industria/principios-activos/RUESA.htm)
Additional comments :
Critical:
 Laboratory Controls. This repacker does not have laboratory facilities.
 It is not possible to ensure that APIs are in compliance to established standards of quality and
purity.
 No tests to verify the identity of a batch of material are conducted and original manufacturers
have not been evaluated and approved.
Major deficiencies (8):
 Weakness in the QA system and a significant risk of repackaging operations summarize these
deficiencies.
 This repacker has not established, documented and implemented an effective system of
managing quality to ensure confidence that the API will meet its intended specifications for
quality and purity.
 Subdividing operations are not conducted under appropriate environmental conditions to avoid
contamination and cross-contamination.
 Repackaging operations are conducted in a manner that will not prevent contamination
between APIs.
 Utensils are not cleaned and stored to prevent contamination.
 There are not an adequate number of personnel qualified by appropriate education, training and
experience to perform and supervise the manipulation of APIs.
 Buildings used in the manipulation of APIs are not properly maintained, repaired and kept in a
clean condition.

PHARMA UPTODAY
35
 HVAC systems are not qualified, appropriately monitored and actions are not taken when limits
are exceeded.
 Materials are not handled and stored in a manner to prevent degradation, contamination, and
cross-contamination.
 Deviations are not sufficiently investigated, documented and explained.
Non-Compliance Report: Ranbaxy Laboratories Limited, Dewas, India:
 Unsatisfactory investigations into media trials failures -- deficiencies concerning: - design and
operation of the clean rooms - controls for preparation (including sterilization) of components
and equipment - controls concerning aseptic filling.
Audit trails need to be available and convertible to a generally
intelligible form and regularly reviewed. (A11§9)
System Audit Trail
– shows changes to system objects and system policies
– details archive activity
– notes all changes to security (users, user types etc)
– documents all successful and unsuccessful logins
 you have a history of who was logged into the application at any
time
 you have information about system break in attempts
 includes the client the login/login attempt occurred at

PHARMA UPTODAY
36
Regulations of the Month
Subpart J--Records and Reports
§ 211.186 Master production and control records.
(b) Master production and control records shall include:
(5) A statement concerning any calculated excess of component;
(6) A statement of theoretical weight or measure at appropriate phases of processing;
(7) A statement of theoretical yield, including the maximum and minimum percentages of
theoretical yield beyond which investigation according to 211.192 is required.
(8) A description of the drug product containers, closures, and packaging materials, including a
specimen or copy of each label and all other labeling signed and dated by the person or persons
responsible for approval of such labeling.
(9) Complete manufacturing and control instructions, sampling and testing procedures,
specifications, special notations, and precautions to be followed.
§ 211.188 Batch production and control records.
Batch production and control records shall be prepared for each batch of drug product produced and
shall include complete information relating to the production and control of each batch. These records
shall include:
(a) An accurate reproduction of the appropriate master production or control record, checked
for accuracy, dated, and signed.
Batch production and control records shall be prepared for each batch of drug product produced
and shall include complete information relating to the production and control of each batch.
These records shall include:
(b) Documentation that each significant step in the manufacture, processing, packing, or holding
of the batch was accomplished, including:
(1) Dates;
(2) Identity of individual major equipment and lines used;
(3) Specific identification of each batch of component or in-process material used;

PHARMA UPTODAY
37
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