The document discusses various regulatory and quality events in the pharmaceutical sector, particularly focusing on a trip by FDA officials to China aimed at improving drug safety and regulatory collaboration. It highlights significant recalls of medications due to manufacturing deviations, as well as positive Phase III trial results for a diabetes treatment involving dapagliflozin, saxagliptin, and metformin. Additionally, Mylan is expanding a recall of select injectable products due to visible particulate matter, emphasizing the potential health risks associated with their use.

1. VOLUME: 16 - ISSUE: JUL 2015 |
PHARMA UPTODAY

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Inside this issue
3 News Uptoday
59 New Guidance
72 Audit Findings
483 Observations
EU Non Compliance Report
- Polydrug Laboratories PVT. LTD., Ambernath, Maharashtra,
India
- ZHUHAI UNITED LABORATORIES CO., LTD, China
Health Canada Non Compliance Report
- Pharmax Limited, Ontario Canada.
78 Warning Letters
- VUAB Pharma a.s., Czech Republic
- Attix Pharmaceuticals, Canada
80 Regulations of the Month
- Sec. 211.22 Responsibilities of quality control unit

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News Uptoday
China‘s Pharmaceutical Future – Both Complex and Growing
A visit to any one of the cities we visited on this trip – Shanghai, Nanjing and Beijing – would
leave anyone marveling at the scale and trajectory of modern China. But it‘s not just the sheer
size of the population we were struck by. Rather, it was the seemingly tireless dedication to
modernity that provided an almost palpable affirmation of what we already knew: that China —
its skylines dotted with construction cranes and landscapes crisscrossed by high speed bullet
trains — is inextricably connected with our own country‘s economy, and increasingly with our
agency‘s ever-expanding regulatory mission.
Howard Sklamberg, FDA‘s Deputy Commissioner for Global Regulatory Operations and Policy
We traveled to China for a few reasons. First, we wanted to gain more on-the-ground insight
into how its drug industry works. We also wanted to offer some helpful perspective to Chinese
regulators and drug companies about the Food and Drug Administration Safety and Innovation
Act (FDASIA), which passed three years ago and is in the process of being fully implemented.
In part, the law gave the FDA new authorities to ensure the safety of the global drug supply
chain, in which China plays an enormous part. How enormous? After the United States, China

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ranks second for the number of FDA-registered drug establishments that the agency regulates,
and is the sixth largest provider of drugs and biologics to the U.S.
Our itinerary also included a meeting with the Chinese Food and Drug Administration (CFDA)
and a tour of a Chinese pharmaceutical manufacturing plant. And if you asked us what the most
important by-product of our trip has been, it was these face-to-face conversations with our
Chinese counterparts.
Specifically, we discussed the responsibilities of firms in the global drug supply chain. These
days, the drugs we have in our medicine chests may seemingly come from one company, but
the ingredients in them may actually come from numerous companies and countries. China is a
major provider of many of the active ingredients in finished drug products Americans rely on
every day.
Richard Moscicki, M.D., FDA‘s Deputy Director, Center for Drug Evaluation and Research
We had productive discussions with the Chinese about how seriously we are committed to
making sure that everyone in the drug supply chain – from the companies that make the active
ingredients to those that provide the packaging –shares in this collective commitment to quality.
As we did when we spoke with our counterparts in India, we stressed that we apply the same

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quality and data integrity standards to all countries shipping drug ingredients into the United
States.
We delivered the same message to a huge crowd of students at an event hosted by China‘s
Pharmaceutical University in Nanjing. In our remarks, we set forth our expectations for the
delivery of drug quality, saying: ―…ideally, our approach will complement the baseline, legal
requirement of compliance with the higher bar of firms‘ self-interest in being recognized for
providing quality products and engaging in a different way with FDA.‖
While in Nanjing, we had productive discussions with students and stakeholders about FDASIA,
quality in contract manufacturing, inspections, regulatory science, and expedited approval
pathways that FDA is using to accelerate the process for making novel drugs available to
patients.
Additionally, we toured a Chinese pharmaceutical facility and met with CFDA to discuss the
revision of China‘s Drug Administration Law, our own FDASIA implementation, regulatory
science matters, as well as continued collaborative activities. We also had a productive
roundtable discussion with leaders from 17 prominent Chinese pharmaceutical companies. We
addressed pharmaceutical quality, data integrity, and the approval process for generic and
innovator drugs.

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Alonza Cruse, FDA‘s Acting Director, Pharmaceutical Quality Program, Office of Regulatory
Affairs
As China‘s role on the global stage expands, FDA has significantly increased drug and medical
device inspections there, but we need to continue to strengthen our efforts. The Office of
Regulatory Affairs and our China office have managed a large number of pharmaceutical
inspections. The FDA‘s office in China has also strengthened relationships with regulators and
helped expand the country‘s expertise in regulatory operations. And we have worked with
industry and academia to explain our regulations and analyze trends and events that might
affect the safety of FDA-regulated products exported from China to the U.S.
Given the volume of U.S. trade with China, we are working to expand our presence there to
significantly increase the number of inspections we conduct. Staffing increases will allow FDA
to enhance its training efforts and technical collaboration with Chinese regulators, industry and
others. In fact, in November 2014, we signed a Memorandum of Understanding with the
Chinese government that expands our cooperation and will facilitate those staffing increases.
FDA‘s priorities in China match its global priorities: we work to ensure the safety and efficacy of
FDA-regulated products. China‘s size and relentlessly expanding economy have an

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increasingly significant impact on the products that Americans consume, particularly
pharmaceuticals.
We trust our trip to China added to the growing collaboration between FDA and our counterpart
agencies there, ensuring the safety of the pharmaceutical products exchanged between our two
nations.
InBrief: ‗The Smallest Individual Saleable Unit‘ In The DSCSA
The U.S. Drug Supply Chain Security Act(DSCSA) requires manufacturers and repackagers to
place DSCSA-specific ―product identifiers‖ on all drug packages and homogeneous cases by
November 27, 2017 (2018 for repackagers). These product identifiers must include a
Standardized Numeric Identifier (SNI), which is composed of the drugs National Drug Code
(NDC) and a unique serial number (for more on DSCSA ―product identifiers‖, see ―The DSCSA
Product Identifier On Drug Packages―, for more on the SNI, see ―FDA Aligns with GS1 SGTIN
For SNDC―, and for more on the NDC, see ―Anatomy Of The National Drug Code―).
A common question is, what is the smallest level of packaging that must be serialized?. The
DSCSA text provides the answer.
This is an update to an essay I wrote back in 2013 about the same topic, but for the California
pedigree law (see ―InBrief: ‗The Smallest Package Or Immediate Container‘ In California―),
which was subsequently preempted by the DSCSA. The California pedigree law would have
required manufacturers to serialize the smallest package of drugs that will be bought by a
dispenser. The DSCSA is basically the same. For some manufacturers targeting the U.S.
market, that may require serialization at a lower unit of measure than they might have thought.
For products that manufacturers package into multi-packs and sell to wholesalers packaged
only that way, you might assume that your ―smallest individual saleable unit‖ is the multi-pack.
Think again.

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For pharmaceutical manufacturers with products in this category, I strongly suggest that you
poll your wholesaler customers and find out how often they break down your multi-pack today
and sell the individual packages inside to their dispensing customers.
The DSCSA defines the term ―Package‖ this way:
―(A) IN GENERAL.—The term ‗package‘ means the smallest individual saleable unit of product
for distribution by a manufacturer or repackager that is intended by the manufacturer for
ultimate sale to the dispenser of such product.
―(B) INDIVIDUAL SALEABLE UNIT.—For purposes of this paragraph, an ‗individual saleable
unit‘ is the smallest container of product introduced into commerce by the manufacturer or
repackager that is intended by the manufacturer or repackager for individual sale to a
dispenser. [DSCSA Section 581(11)]
Yes, you could probably say that your multi-pack–just like today–is the level of packaging that
you intend for ultimate sale to the dispenser and so that‘s all you will be required to serialize.
And theoretically, you would be right. But, if today, before serialization is required, wholesalers
routinely break your multi-pack down further as part of their friendly service to their customers,
they won‘t be able to do that once they begin operating under the serialization requirements of
the DSCSA–November 27, 2019.
After that date they will no longer be able to break any package down unless the components
within are also serialized by the manufacturer or repackager.
―So what?‖ you say? If your product is routinely broken down by the wholesaler today, that is
done to supply small pharmacies with a smaller amount of your product so they are able to

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dispense it before the expiration date. This has happened in the past with multi-packs of some
prefilled insulin syringes, some vials and similar products.
Admittedly, not many products fall into this category, but if yours is one that does, you should
think about what those small pharmacies might do if they will be forced to only buy your product
in the full multi-pack. Will the pharmacies decide to start buying your multi-pack, since that‘s
the only form available to them? Or will their wholesaler help them find some alternative drug
that is serialized at a lower unit of measure instead? Poll your customers, and their customers,
to find out before you establish your final serialization plan.
When you are ready to serialize the individual packages contained inside your multi-packs,
make sure you consult the GS1 Healthcare GTIN Allocation Rules to get theGTINs right. Then
consult my essay ―Anatomy Of An FDA SNI‖ to learn how to combine a GTIN with a serial
number to serialize them.
Two drugs manufactured by Wockhardt recalled in the US
Over 200 bottles of Captoprilused in treatment of blood pressure and
antibiotics Clarithromycin tablets manufactured by Wockhardt are being recalled in the US due
to deviations in current good manufacturing practice norms laid down by US health regulator.
According to information on the US Food and Drug Administration (USFDA) website, 166
bottles of Captopril tablets of 50 mg strength are being recalled in the US.
In case of Clarithromycin, the recall is for 50 bottles containing tablets of 500 mg strength.
The recall is made by Blenheim Pharmacal Inc, which packages and repackages Captopril and
Clarithromycin respectively.

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The USFDA said the reason for the recall is cGMP (current good manufacturing practice)
deviations and current good manufacturing practice.
In both the cases, the products are being recalled "in response to a recall notice from the
manufacturer, Wockhardt Ltd, following a FDA inspection which noted inadequate investigation
of market complaints, resulting in unsuccessful identification of root causes, and the
investigation not being expanded to prevent repeat failure", it added.
Both the recalls are classified as Class II, "a situation in which use of or exposure to a violative
product may cause temporary or medically reversible adverse health consequences or where
the probability of serious adverse health consequences is remote".
AstraZeneca presents new positive phase III data on triple therapy approach with
dapagliflozin, saxagliptin and metformin for the treatment of type 2 diabetes
Data in oral presentation demonstrate that the investigational combination of dapagliflozin,
saxagliptin and metformin resulted in statistically significant reductions in HbA1c in patients
uncontrolled on saxagliptin and metformin
AstraZeneca today announced positive results from a Phase III study comparing the efficacy
and safety of dapagliflozin versus placebo as an add-on to saxagliptin and metformin immediate
release (IR) in adults with type 2 diabetes who had inadequate glycaemic control (baseline
HbA1c 7% - 10.5%).1
The study met its primary endpoint, with patients receiving the
investigational triple combination of dapagliflozin 10 mg, saxagliptin 5 mg and metformin
achieving significantly greater mean reductions in HbA1c compared to those treated with
placebo, saxagliptin 5 mg and metformin at 24 weeks (–0.82% vs. -0.10%, respectively; p-
value<0.0001).1
The results were presented today as an oral presentation (#105-OR) at the
75th Scientific Sessions of the American Diabetes Association (ADA) in Boston.
―In this study, when dapagliflozin was added to saxagliptin and metformin, patients
demonstrated greater HbA1C reductions than those in the placebo and metformin group,‖ said

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lead investigator Chantal Mathieu, MD, PhD, Chair of Endocrinology at the University Hospital
Gasthuisberg Leuven, Belgium. ―With nearly 50% of type 2 diabetes patients estimated to be
uncontrolled on metformin, new treatment approaches are needed, and these data add to the
growing body of knowledge for combination therapies.‖
Among secondary endpoints, the dapagliflozin combination group achieved a significantly
greater adjusted mean reduction from baseline in two-hour postprandial glucose (-74 mg/dL vs -
38 mg/dL, respectively; p-value<0.0001)1
and fasting plasma glucose versus the placebo group
(-33 mg/dL vs -5 mg/dL, respectively; p-value<0.0001).1
More patients in the dapagliflozin
combination group also achieved a HbA1c level of less than 7% compared to patients in the
placebo group at week 24 (38% vs 12%, respectively, p-value<0.0001).1
In addition, patients in
the dapagliflozin combination group had a greater reduction in weight (mean -1.9 kg vs -0.4 kg,
respectively; p-value<0.0001)1
than those in the placebo group. Adverse events were similar
across treatment groups. The most common adverse events (≥ 5%) were headache, urinary
tract infection, influenza and genital infections. The rate of hypoglycaemia was 1.3% in the
dapagliflozin combination group and 0.0% in the placebo group.1
Elisabeth Björk, Vice President, Head of Cardiovascular and Metabolic Diseases, Global
Medicines Development, AstraZeneca, said: ―We are focused on investigating combination
therapies with complementary mechanisms of action and our broad diabetes portfolio positions
us well in this area.These positive results reinforce our belief that combination therapies have
the potential to be used as early add-on therapy to help patients with type 2 diabetes achieve
their treatment goals.‖
The study included an open-label lead-in period in which patients on metformin (baseline
HbA1c 8.0%–11.5%) received open-label saxagliptin 5 mg and metformin for 16 weeks, while
patients on metformin and any DPP-4 inhibitor (baseline HbA1c 7.5%–10.5%) received open-
label saxagliptin 5 mg and metformin for 8 weeks. Following the end of the open-label period,
patients with inadequate glycaemic control (HbA1c 7%–10.5%) were randomised to receive
either placebo or dapagliflozin 10 mg in addition to open-label saxagliptin and metformin.

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Data further detailing this lead-in period was accepted as a late-breaker poster (#133-LB) on
display in Poster Hall B on Sunday, June 7 from noon to 2 p.m. EST.2
AstraZeneca has filed a New Drug Application (NDA) with the US Food and Drug
Administration (FDA) for the approval of an investigational fixed-dose combination of saxagliptin
and dapagliflozin for the treatment of type 2 diabetes and the Prescription Drug User Fee Act
(PDUFA) goal date will be in the fourth quarter of 2015.
Mylan is Expanding its Voluntary Nationwide Recall of Select Lots of Injectable Products
Due to the Presence of Particulate Matter
Mylan N.V. (Nasdaq: MYL) today announced that its U.S.-based Mylan Institutional business is
expanding its voluntary nationwide recall to the hospital/user level of select lots of the following
injectable products due to the presence of visible foreign particulate matter observed during
testing of retention samples.
Administration of a sterile injectable that has foreign particulates has the potential of severe
health consequences. Intrathecal administration could result in a life threatening adverse event
or result in permanent impairment of a body function. Intravenous administration has the
potential to damage and/or obstruct blood vessels which could induce emboli, particularly in the
lungs. If a right to left cardiac shunt is present, the particulate may lead to arterial emboli and
result in stroke, myocardial infarction, respiratory failure, and loss of renal and hepatic function
or tissue necrosis. Other adverse effects associated with intravenous injection of particulate
matter include local inflammation, phlebitis, allergic response and/or embolization in the body
and infection. Intra-arterial administration could result in damage to blood vessels in the distal
extremities or organs. Intramuscular administration could result in foreign-body inflammatory
response, with local pain, swelling and possible long term granuloma formation. To date, Mylan
has not received any reports of adverse events related to this recall.

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0069-3857-
10
Gemcitabine for Injection, USP 200 mg 10 mL 7801084 07/2015
0069-3857-
10
Gemcitabine for Injection, USP 200 mg 10 mL 7801110 08/2015
67457-463-
02
Gemcitabine for Injection, USP 2 g 100 mL 7801221 03/2016
67457-464-
20
Gemcitabine for Injection, USP 200 mg 10 mL 7801398 08/2016
67457-464-
20
Gemcitabine for Injection, USP 200 mg 10 mL 7801406 08/2016
67457-464-
20
Gemcitabine for Injection, USP 200 mg 10 mL 7801427 09/2016
67457-462-
01
Gemcitabine for Injection, USP 1 g 50 mL 7801284 05/2016
67457-467-
99
Methotrexate Injection, USP 50 mg/2 mL
(25 mg/mL)
5x2 mL 7801421 09/2016
Gemcitabine for Injection, USP is an intravenously administered product indicated for the
treatment of ovarian cancer, breast cancer, non-small cell lung cancer and pancreatic cancer.
These lots were distributed in the U.S. between January 8, 2014, and February 10, 2015, and

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were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot
7801084 and 7801110 are packaged with a Pfizer Injectable label.
Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously,
intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis
and adult rheumatoid arthritis. The lot was distributed in the U.S. between December 8, 2014,
and December 19, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan
company.
Mylan is notifying its distributors and customers by letter and is arranging for return of all
recalled products. Distributors, retailers, hospitals, clinics, and physicians that have these
products which are being recalled should stop use and return to place of purchase.
Centralised procedures and use of the common repository
From 1 July 2015, MHRA will fully adopt use of the common repository for centralised
procedures.
From that date, centralised applications submitted to the common repository do not need to be
sent separately to MHRA. Any centralised submission received directly by the MHRA after this
date will not be processed and will be disposed of securely.
Along with other national competent authorities (NCAs,) we intend to make this change
mandatory. This is in line with the EU roadmap, which has been progressed in consultation with
industry, trade bodies and other NCAs and made public for some time now on the European
Medicines Agency website
Medicines and vaccines post-market vigilance - statistics for 2014
The Therapeutic Goods Administration (TGA) is responsible for regulating medicines, vaccines
and biologicals, including monitoring the ongoing safety, quality and efficacy of these products
once they have been included on theAustralian Register of Therapeutic Goods (ARTG)(link is
external) through product vigilance activities.

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On an annual basis, the TGA's Post-market Surveillance Branch prepares a report for
incorporation into the Department of Health publication Australian Statistics on Medicines(link is
external).
Australian Statistics on Medicines(link is external) is produced by the Drug Utilisation Sub-
Committee (DUSC) of the Pharmaceutical Benefits Advisory Committee (PBAC) and is aimed
at providing comprehensive and valid statistics on the Australian use of medicines and vaccines
in the public domain to allow access by all interested parties.
This report from the Post-market Surveillance Branch includes a brief overview on the following
aspects of post-market monitoring of medicines and vaccines in Australia:
 Adverse event reporting statistics for 2014
 Processing and use of adverse event reports
 Database of Adverse Event Notifications
 'Safety through reporting' online learning modules developed for health professionals
 Reporting adverse events
 Expert advisory committees
 Medicines Safety Update
 Product vigilance
Adverse event reporting statistics for 2014
The TGA's reporting system for adverse events began in the late 1960s with the computerised
database dating back to the early 1970s. By the end of 2014 there were approximately 295,000
reports of suspected adverse events in the database.

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Figure 1: Origin of medicine and vaccine adverse events received by the TGA (2010-14)
In 2014 the TGA received approximately 16,500 reports of adverse events. As shown in Figure
1, the majority of reports made in 2014 were by sponsors. The number of reports made by
sponsors has significantly increased over the past five years, from 5612 in 2010 to 8359 in
2014. However, there was a slight decrease in 2014, from the peak of 9563 sponsor reports
received in 2013. This change is believed to be due to factors including a focus on provision of
better quality reports, following on from a strong rise the previous year after the release of new
pharmacovigilance guidelines. Approximately 51% (8359) of adverse event reports received by
the TGA in 2014 were from sponsors, 16% (2672) from State and Territory Health Departments
(reports of adverse events following immunisation), 13% (2184) from hospitals and hospital
pharmacists, 8% (1351) from community pharmacists, 5% (735) from general practitioners
(GPs), 3% (565) from consumers and 3% (441) from other sources.
The numbers of reports made by sources other than sponsors in 2014 were generally similar to
those received in 2013, with reports from State and Territory Health Departments decreasing
slightly (from 3011 in 2013 to 2672 in 2014) and those from hospitals and hospital pharmacists
increasing (from 1794 in 2013 to 2184 in 2014).

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While health professionals are encouraged to report suspected adverse events directly to the
TGA, they can also report to the sponsor or manufacturer.
Processing and use of adverse event reports
The Post-market Surveillance Branch assessed adverse event reports submitted to the TGA by
checking for the presence of 'minimum' details, including an individual patient, an adverse
event, at least one (suspected) medicine or vaccine, and an identifiable reporter. The specific
adverse event terms are identified along with the suspected, interacting or 'other' therapeutic
products and these are entered into the database.
The Post-market Surveillance Branch assesses causality of adverse event(s) and in some
cases requests further clinical or laboratory information from the reporter. Medical officers
review serious reports and Post-market Surveillance Branch staff regularly analyse reporting
data to identify potential safety signals.
Reports are forwarded to the Uppsala Monitoring Centre in Sweden, which administers the
World Health Organization Collaborating Centre for International Drug Monitoring. This global
database began in 1968 as a pilot program involving 10 nations, including Australia, and now
receives reports from more than 80 nations.
Database of Adverse Event Notifications
Information in the publicly searchable Database of Adverse Event Notifications (DAEN) comes
from reports made to the TGA by a wide range of sources, including members of the public,
general practitioners, nurses, other health professionals and the therapeutic goods industry.
Reports in this database start from 1 January 1971 up to three months prior to the date of
access. The TGA uses this three-month period to investigate each adverse event report.
The DAEN, which was launched in 2012, was created to support better health outcomes by
providing access to the information that the TGA gathers while monitoring medicine and
vaccine safety in Australia.

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'Safety through reporting' online learning modules developed for health professionals
The TGA and NPS MedicineWise worked together to create two interactive online learning
modules designed to improve adverse event reporting by health professionals and these tools
were launched in December 2014.
The 'Safety through reporting' modules were developed to increase health professionals'
existing knowledge around reporting adverse events associated with therapeutic products.
Some of the key features include:
 the importance of reporting adverse events
 sharing the responsibility of reporting
 how to build reporting into practice
 what happens to reports once they are submitted to the TGA.
Health professionals who complete the modules are eligible for continuing professional
development points from the relevant accrediting health professional bodies.
Reporting adverse events
The TGA encourages the reporting of all suspected adverse events to medicines and vaccines
available in Australia, including prescription medicines, over the counter and complementary
medicines. The reporting of seemingly insignificant or common adverse events can contribute
to the TGA's investigation of a potential safety signal.
The TGA particularly encourages reporting of:
 suspected adverse events involving new medicines and vaccines
 suspected medicine and vaccine interactions
 unexplained adverse events (adverse events that are not described in the Product
Information)
 serious adverse events, such as those suspected of causing:
o inability to work

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o admission to hospital
o prolongation of hospitalisation
o increased investigation or treatment costs
o danger to life
o birth defects
o death.
For further information about reporting suspected adverse events, visit the TGA website (click
on 'Report a Problem').
Sponsors of all medicines and vaccines on the ARTG have mandatory reporting
requirements regarding adverse events.
Expert advisory committees
Advisory Committee on the Safety of Medicines
The Advisory Committee on the Safety of Medicines (ACSOM) was established in January
2010 to provide expert advice to the TGA about safety issues under investigation and the
appropriateness of Risk Management Plans (RMPs). RMPs outline sponsors' plans to monitor
and communicate risks, and are evaluated as part of the registration process for new
medicines. RMPs accompany applications for registration of high risk medicines, such as new
chemical entities. RMPs characterise and pro-actively manage risks relating to a medicine over
its entire life cycle. ACSOM also provides advice to the TGA on other matters related to
pharmacovigilance, including the detection, assessment, understanding and prevention of
adverse events. ACSOM meeting statements are published on the TGA website.
Advisory Committee on the Safety of Vaccines
Following a recommendation from the government's Review of the management of adverse
events associated with Panvax and Fluvax in 2012 'to consider the current governance
arrangements for monitoring and responding to vaccine safety issues in Australia and make
recommendations for an improved system of governance for vaccine safety monitoring', the
Advisory Committee on the Safety of Vaccines (ACSOV) was established in the Therapeutic

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Goods Regulations. The functions of ACSOV are to provide advice and make
recommendations to the Minister for Health, the TGA and the Office of Health Protection on the
safety, risk assessment and risk management of vaccines. ACSOV meeting statements are
published on the TGA website.
Medicines Safety Update
The Medicines Safety Update was published six times during 2014. It was published within the
Australian Prescriber magazine, as well as on the TGA website. Medicines Safety
Update replaced the Australian Adverse Drug Reactions Bulletin in 2010.
The following articles were published in Medicines Safety Update during 2014:
 Quetiapine and QT prolongation
 bioCSL Fluvax - not for children under 5 years
 How you can play a vital role in medicine regulation
 Olmesartan and sprue-like enteropathy
 Codeine use in children after tonsillectomy and/or adenoidectomy
 Methoxyflurane and occupational exposure
 Bexsero meningococcal B vaccine - enhanced monitoring
 Strontium ranelate and cardiovascular and venous thromboembolic risks
 Complex regional pain syndrome and vaccines
 Azathioprine and cytomegalovirus reactivation
 Measles, mumps, rubella, varicella vaccine
 Fentanyl patches and accidental exposure in children
 Zolpidem and next day impairment
 Diclofenac and arteriothrombotic events
 Bupropion and serious cardiovascular adverse events
 Methylphenidate and priapism
 Propranolol - prescribing to patients who may be at risk of self-harm
 Valproate - fetal exposure and cognitive impairment
 Medicine shortages information resource

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 Epoetin alfa (Eprex) and increased risk of pure red cell aplasia with subcutaneous
administration
 Pregabalin and suicidality
 Online reporting form for consumers
 Topiramate and visual field defects
 Combined oral contraceptives and hormone replacement therapy - inflammatory bowel
disease
 Metoclopramide and neurological adverse events
 Publication changes for Medicines Safety Update.
Product vigilance
The TGA applies a risk management approach to ensure therapeutic goods supplied in
Australia meet acceptable standards of quality, safety and efficacy. Once a therapeutic product
is approved, the TGA continues to monitor the product in the market through therapeutic
product vigilance activities.
The aim of therapeutic product vigilance is to continually monitor and evaluate the safety and
efficacy (performance) profile of therapeutic goods and to manage any risks associated with
individual products over their life cycle. The TGA's therapeutic product vigilance framework is
available on the TGA website atTherapeutic product vigilance.
The maintenance and improvement of health and safety is a shared responsibility. In addition to
government and industry, health professionals, consumers and their respective associations
play an important role in reporting safety related issues.
Sponsors have the primary responsibility for the safety of any therapeutic products they import
into, supply in or export from Australia. Sponsors must comply with legislative requirements for
therapeutic product vigilance under the Therapeutic Goods Act 1989 (the Act) and there are
applicable offences and penalties under the Act for not complying. The legislative requirements
for therapeutic product vigilance vary depending on the type of therapeutic good.

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The TGA maintains up-to-date safety information on therapeutic products that is communicated
through a variety of means to consumers and health professionals. The TGA is committed to
advancing public health through market authorisation of beneficial, innovative therapeutic goods
and by providing timely, evidence-based and authoritative information to allow consumers and
health professionals to make informed decisions.
The TGA defines therapeutic product vigilance tools as tools designed to facilitate the collection
and evaluation of information pertaining to the benefits and risks associated with the use of
therapeutic products. The main product vigilance tools used by the Post-market Surveillance
Branch are adverse event reports, RMPs and Periodic Safety Update Reports (PSURs).
Adverse event reports are reports of any unwanted and sometimes harmful occurrences from
using medicines, vaccines or medical devices (collectively known as therapeutic goods).
Importantly, adverse events related to the use of a therapeutic good are not always caused by
the therapeutic good itself.
RMPs provide a summary of the known important safety information about the therapeutic
product, plans to identify and characterise known or potential safety concerns and plans to
minimise any identified or potential safety risk. A full outline of the scope of RMPs is above (see
'Expert advisory committee'). PSURs give an annual overview of the safety of the product,
including adverse events, a summary of its registration status world-wide, actions taken for
safety reasons, the world-wide usage of the product and an analysis of safety requirements.
Sponsors must submit PSURs to the TGA for at least three years after registration of a product.
An important aspect of product vigilance is ensuring there are mechanisms to communicate
safety information to both consumers and health professionals. To achieve this, the TGA
publishes Australian Public Assessment Reports (AusPARs) about recently registered
prescription medicines and vaccines on the TGA website. AusPARs outline the findings of the
TGA's evaluation of a product including important effectiveness and safety information.
Each adverse event report the TGA receives is entered into a database, which is continually
analysed by TGA staff to identify potential emerging problems for detailed investigation.

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If the TGA identifies a safety concern relating to a medicine or vaccine, we can take regulatory
action. This can include:
 informing health professionals and consumers via safety alerts, Early Warning
System monitoring communications and Medicines Safety Update, which provide information
and recommendations about therapeutic goods
 updating the Product Information, Consumer Medicine Information and/or product
labelling with new adverse effects, precautions or warnings
 requiring post-marketing studies
 imposing limits on their use
 investigating manufacturing sites
 recalling products from the market
 suspending or cancelling products.
When a product is cancelled, details are published on the TGA website.
Version history
Version Description of
change
Author Effective date
V1.0 Original
publication
Post-market Surveillance Branch 12 May 2015
Exporting to Brazil? ANVISA is tough and hands-on, says Kemwell
Site audits by Brazilian pharma regulator ANVISA are ―exactly the opposite‖ to the US
FDA‘s, says CMO Kemwell as it prepares to export to Brazil for Johnson & Johnson.

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ANVISA passed Kemwell‘s manufacturing facility for oral solids in Bangalore, India following a
recent inspection. The site will now be allowed to manufacture J&J‘s TB drug Sirturo
(bedaquiline) for the Brazilian market. The facility already makes drugs for the EU, US, Canada,
South Africa, and Australia.
―The [US] FDA is tough but ANVISA is considered the toughest regulatory agency with respect
to audits,‖ Ashok Hegde, Kemwell‘s VP, Pharmaceutical Operations, told this publication.
―Every inspector has its own methodology of auditing. The FDA mostly concentrates on the
documentation part. If an audit lasts five days, four of those will be spent on documentation.
―But ANVISA is exactly the opposite – it spends most of its time focusing on the facility and live
operations. They will ask you to demonstrate things about the manufacturing procedure.
―They want to be on the ‗shop floor‘ when manufacturing is going on – to see how you do
granulation or a tabletting procedure. They want to witness everything.‖
Brazilian market
The US and Brazilian agencies also differ in their warning notice. Since the FDA opened
several offices in India in the last four years, around 12 inspectors have been based in the
country and can schedule inspections at short notice. ―They will call you on Friday and say
they‘re coming on Monday,‖ said Hegde. ANVISA typically gives four weeks‘ warning, he
said. Brazil has historically had tight rules about pharmaceutical imports. Hegde said few
foreign manufacturers are approved by ANVISA, and the region prefers home-made products
or drugs imported in bulk and then packaged for consumers in Brazil.
But the country is growing as a market for complex, high-quality drugs. Hegde pinpointed
injectables, especially biologics, and third-generation antibiotics like cephalosporin as ―the next
segments where demand is going to pick up.‖

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Data Protection: Council agrees on a general approach
On 15 June 2015, the Council reached a general approach on the general data protection
regulation that establishes rules adapted to the digital era. The twin aims of this regulation are
to enhance the level of personal data protection for individuals and to increase business
opportunities in the Digital Single Market.
Latvia's minister for justice Dzintars Rasnačs said: "Today we have moved a great step
closer to modernised and harmonised data protection framework for the European Union.
I am very content that after more than 3 years of negotiations we have finally found a
compromise on the text. The new data protection regulation, adapted to the needs of the digital
age, will strengthen individual rights of our citizens and ensure a high standard of
protection."
A general approach means that the Council has a political agreement on the basis of which it
can now begin negotiations with the European Parliament with a view to reaching overall
agreement on new EU data protection rules. A first trilogue with the Parliament is planned
for 24 June 2015.
"I salute the readiness of the European Parliament to start the trilogue negotiations already
next week. Hopefully we will come to the final agreement rapidly so that our citizens can enjoy
the benefits of the reform as soon as possible", said Latvia's minister for justice Dzintars
Rasnačs.
The incoming Luxembourg Presidency indicated that, in parallel to the negotiations on the
regulation, works on the data protection directive in the law enforcement area would be
accelerated with the aim to find a general approach in October.
Main elements of the agreement
An enhanced level of data protection
Personal data must be collected and processed lawfully under strict conditions and for a
legitimate purpose. Data controllers (those responsible for the processing of data) must
respect specific rules, such as the requirement for unambiguous consent by the data
subject (the individual whose personal data is being processed), in order to be allowed to
process personal data.
Strengthened data protection rights give data subjects more control over their personal data:

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 easier access to their data.
 more detailed information about what happens to their personal data once they decide to
share it: data controllers must be more transparent about how personal data is handled,
for example by informing individuals about their privacy policy in clear and plain
language.
 a right to erasure of personal data and "to be forgotten", enabling anyone for
example to require that a service provider remove, without delay, personal data collected
when that individual was a child.
 a right to portability enabling easier transmission of personal data from one service
provider, for instance a social network, to another. This will also increase competition
among service providers.
 limits to the use of 'profiling', i.e. automated processing of personal data to assess
personal aspects, such as performance at work, economic situation, health, personal
preferences etc.
To ensure improved legal redress, data subjects will be able to have any decision of their data
protection authority reviewed by their national court, irrespective of the member state in which
the data controller is established.
Increased business opportunities in the Digital Single Market
A single set of rules, valid across the EU and applicable both to European and non European
companies offering their on-line services in the EU will prevent conflicting national data
protection rules from disrupting cross-border exchanges of data. Moreover, increased
cooperation between the supervisory authorities in the member states will ensure coherent
application of those rules throughout the EU. This will create fair competition and encourage
companies, especially small and medium-sized enterprises, to get the most out of the Digital
Single Market.
To reduce costs and provide legal certainty, in important transnational cases where several
national supervisory authorities are involved, a single supervisory decision will be taken.
This one-stop-shop mechanism will allow a company with subsidiaries in several member
states to limit its contacts to the data protection authority in the member state where it is
established.

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In order to reduce compliance costs, data controllers can, on the basis of an assessment of the
risk involved in their processing of personal data, define risk levels and put in place measures in
line with those levels.
More and better tools to enforce compliance with the data protection rules
Increasing responsibility and accountability of data controllers will improve compliance with the
new data protection rules. Data controllers must implement appropriate security
measures and provide, without undue delay, notification of personal data breaches to the
supervisory authority as well as to those significantly affected by the breach. Controllers and
processors may designate data protection officers in their organisation. Moreover, Union or
national law can require them to do so.
Data subjects, as well as, under certain conditions, data protection organisations can lodge
a complaint with a supervisory authority or seek judicial remedy in cases where data protection
rules are not respected. Furthermore, when such cases are confirmed,data controllers face
fines of up to €1 million or 2% of their global annual turnover.
Guarantees regarding transfers of personal data outside the EU
The protection of transfers of personal data to third countries and international organisations is
ensured through adequacy decisions. The Commission, with the involvement of member
states and the European Parliament, is competent to decide whether the level of data protection
offered by a third country or an international organization is adequate. In cases where no such
decision has been taken, the transfer of personal data may only take place if the appropriate
safeguards (standard data protection clauses, binding corporate rules, contractual clauses) are
in place.
General data protection regulation - general approach
Data protection reform
Kerala lacks efficient quality control system for drug testing: Dr Satheesh Kumar
Even as the state of Kerala consumes about 10 per cent of the medicines marketed in the
country per year, the quality control system of the drugs control department continues to be
weak and incompetent. Hence, a public-private-partnership (PPP) scheme may be developed

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to improve the quality control testing of drugs, according to Dr C S Satheesh Kumar, former
drugs controller of Kerala and vice-president, operations, of the Kochi based Agappe
Diagnostics.
In a telephonic interview with Pharmabiz, the former DC said a major quantity of the drugs
supplied to the government hospitals are found at higher rate of substandard quality. Even ten
percent of the total supply cannot be tested at state laboratories.
He said Kerala government is getting around Rs. 300 crore per annum towards sales tax from
the drugs market; but the drugs control department remains as a service department with poor
financial assistance from the government. The law enforcement authority is unable to assure
the quality of drugs marketed in the state from other states. Less than one percent of the drugs
sold in Kerala are manufactured by local companies.
―Very few number of drugs marketed and distributed in various places in Kerala is taken for
analysis. Out of the 2,50,000 odd batches of drugs moving in the market per annum, less than 2
percent is taken for analysis. This should be above 10 per cent for satisfactory sampling. For
this, new mechanism has to be developed by joint partnership of private and public agencies‖,
he suggested.
According to him, measures should be made to ensure hundred percent sampling, and it should
be made compulsory for government procurement. For better quality criteria, modification is
required in the tender process and the lowest rate (L1) quotation system has to be avoided.
Government should procure a lion portion of the requirement from the local manufacturers and
price preferences and other incentives should be given to them.
Regarding efficiency of the drugs testing lab (DTL) under the department, Dr Satheesh added
that the government laboratory at Thiruvananthapruam is not functioning in full capacity. The
second regional drugs testing lab established at Ernakulam has not started functioning fully due
to non-cooperation of senior officials in the department. He alleged that the rude and distorted
attitudes of lab authorities spoil the whole system of the quality control, leaving all options of
quality assurance.

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As a suggestion to improve the quality control system, he said if the lab facilities at the
pharmacy colleges can be utilized for sample analysis, majority of the drugs distributed in the
state can be tested. There are 25 pharmacy colleges working in Kerala. All these colleges
altogether can contribute a minimum rate of 15000-18000 samples per year provided one
college is able to do analysis of 50-70 samples per month in survey sample analysis.
WHO approves China flu vaccine, lauds growing industry
The World Health Organization (WHO) has approved a Chinese influenza vaccine as being
safe and effective, only the second Chinese vaccine to receive such status reflecting the
growing clout of the country's drug makers.
The WHO said in a statement on Friday that it had "prequalified" a vaccine made by Hualan
Biological Bacterin Corp, a subsidiary of Hualan Biological Engineering Inc.
The approval involved stringent lab tests and a site inspection.
The other made-in-China vaccine to achieve WHO prequalification was a drug against
Japanese encephalitis in 2013, the WHO said.
"WHO prequalification of the Hualan vaccine is another feather in the cap of China's growing
vaccine manufacturing industry," Bernhard Schwartländer, WHO representative in China, said
in a statement.
The development "shows that the country is set to become one of the preeminent vaccine
manufacturers globally," he added.
Chinese drug makers saw sales growth speed up and margins widen at the start of the year, in
a sign that the world's second-largest pharmaceuticals market may be rebounding from a
crackdown on corruption and high prices.
China is increasingly flexing its scientific muscle in drug development, approving a new polio
vaccine in January a month after local authorities gave the green light for a home-grown Ebola
vaccine.

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India scraps import duties on AIDS drugs to battle shortage
India has scrapped customs import duties for drugs and test kits used to treat AIDS in an effort
to cut prices across the country, as it struggles to cope with an ongoing shortage in its national
program to fight the disease.
More than a third of India's 2.1 million HIV/AIDS patients depend on getting their daily
antiretrovirals for free from state-run distribution centers, but many of them have been facing
shortages or stock outs for months.
The notice put out by the Central Board of Excise and Customs this week intends to make it
cheaper to import raw materials that are used to make antiretrovirals under the national
program, BB Rewari of the National AIDS Control Organisation (NACO) told Reuters.
Currently, U.S. firm Mylan Inc and India's Aurobindo Pharma supply AIDS drugs to the
government program.
The exemption applies to certain first-line and second-line antiretroviral drugs used to treat
adults and children, as well as to certain diagnostic kits and equipment that are used by NACO,
Rewari said.
He added the drugs under exemption make up roughly 95 percent of the antiretrovirals used by
India's AIDS patients under the national program.
The exemption, which will remain in effect until March 2016, is the national AIDS control
department's latest effort to deal with a chronic shortage of HIV/AIDS drugs at home, even
though Indian companies are some of the world's major suppliers of AIDS drugs. Local firm
Cipla Ltd made headlines in 2001 by making antiretrovirals for Africa for under $1 a day.
The AIDS control program has been in disarray for months after the government changed the
way over $1.3 billion in federal funds were distributed, according to data and letters seen by
Reuters.
Construction of clinics in rural areas has been delayed and many health workers have quit.
Government officials have previously told Reuters of a lack of participation by local drugmakers
in the tenders floated by the National AIDS Control Organisation (NACO) to procure drugs.
Industry insiders, meanwhile, cite delayed tender approvals, supply bottlenecks and late
payments, as well as poor coordination between the central and state governments.

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AIDS drugs sold on the open market are expensive, so in an effort to make those more
affordable, the government is likely to add more AIDS drugs under price control by including
them in the national list of essential medicines, people involved in the process told Reuters in
April.
Soon, doctors to write prescriptions in capital letters
Fear of misinterpretation due to doctor's illegible handwriting may soon be a thing of the past as
government is set to make it a norm for physicians to prescribe medicines "preferably" in capital
letters.
The Union Health Ministry will come out with a gazette notification under the
Indian MCIRegulations which will mandate doctors to prescribe medicines in capital letters in a
"legible" manner and also mention the generic names of the drugs.
"The Health Ministry will come out with gazette notification under the MCI regulations. Under
this, the prescription should be legible and preferably written in capital letters along with the
names of the generic drug prescribed," a senior Union Health Ministry official told PTI.
Sources said that the notification is likely to be issued by the Ministry within a week's time.
Health Ministry officials said that once the prescription is written in capital letters and is legible,
it would be hugely benefit patients as well as chemists who would have a clarity of the drug and
it would take away the fear of misinterpretation.
However, the senior health ministry official said that there would no penalties or punishment for
the doctor as such for not writing in capital letters.
"Like all other MCI regulations, this too will govern the doctors," the official said.
Health Minister J P Nadda last year in Parliament had agreed with concerns of some MPs that
illegible prescription by doctors may lead to serious implications and even death in certain
cases.
"The central government has approved to amend Indian Medical Council Regulations, 2002,
providing therein that every physician should prescribe drugs with generic names in legible and
capital latter and he/she shall ensure that there is a rational prescription and use of drugs,"
Nadda said.

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K K Aggarwal of Indian Medical Association (IMA) said this will help decrease prescription
errors and it is a cheaper alternative to electronic health records.
"Prescription errors will decrease. It will become uniform. One drug has 10 odd brands. The
patients will be now able to know whether the drug is generic or not," Aggarwal told PTI.
"In US alone, 100,000 prescription errors occur every year. India does not have any data on
this. This is a cheaper alternative to electronic health records. It will take some time for doctors
to get used to it," he said.
US FDA upgrades Jubilant Life's US plant status
Drug firm Jubilant Life Sciences today said the US health regulator has upgraded the status of
its US subsidiary's manufacturing facility at Spokane to Voluntary Action Indicated.
"The company's subsidiary, Jubilant HollisterStier, has been informed by the US Food and Drug
Administration (USFDA) that its pharmaceutical sterile manufacturing facility in Spokane,
Washington ( USA), has been upgraded to the status of Voluntary Action Indicated (VAI),"
Jubilant Life Sciences said.
In a filing to BSE, the company said Spokane site's latest establishment inspection report
indicates successful conclusion of inspections in April and December last year.
This upgradation by the USFDA from Official Action Indicated (OAI) to VAI is "indicative of the
current good manufacturing practice (cGMP) status at the facility" since receiving the warning
letter in 2013, the drug maker added.
Jubilant Life Sciences Chairman Shyam S Bhartia and Co-Chairman & MD Hari S Bhartiasaid:
"We consider this development as another step towards building a reliable and sustainable
pharmaceutical business."
According to FDA, a VAI inspection classification is issued when objectionable conditions or
practices were found that do not meet the threshold of regulatory significance.
The company currently has 10 manufacturing facilities in India, the US and Canada with 6,200
as global headcount.
The stock of Jubilant Life Sciences was today trading at Rs 173 on BSE, up 3.69 per cent.

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CDSCO drug inspectors soon to get online training on cGMP
Aimed at empowering the central drug regulators with the similar regulatory knowledge as
offered to the US FDA officials, the Central Drugs Standard Control Organization (CDSCO) will
soon equip its drug inspectors with relevant areas of current Good Manufacturing Practices
(cGMP) through an online training module.
The US-based global leader in safety science Underwriters Laboratories (UL) will train around
15 officers from the CDSCO West Zone on critical areas including Good Manufacturing
Practices (GMP), Good Clinical Practices (GCP), audit-readiness and remedial training. UL
offers about 1,200 courses globally and has trained around 38,000 US FDA inspectors till date.
"Drug inspectors in the CDSCO western region require training on relevant areas of GMP and
cGMP. The online training module is going to start in a couple of months time," informed an
official associated with the development.
UL has recently signed up as a knowledge partner with the CDSCO West Zone. UL
EduNeering, the compliance education and training services business division of UL Life &
Health, will lead this initiative. UL also will build custom training modules for the CDSCO West
Zone that suit the learning needs of their investigators. In the first phase, 10 investigators will be
trained on 40 online modules.
CDSCO West Zone comprises the states of Maharashtra, Goa, Gujarat, Madhya Pradesh,
Chhattisgarh and Union Territories of Daman & Diu and Silvassa.
―UL's focus on quality is based on the expertise we have garnered from more than a century of
testing, certifying products and developing standards. Through this association we will be
training CDSCO inspectors across western region on what is essential in the inspection and
standardisation process. This association is another extension of the MoU, we recently signed
with the Gujarat government. We are happy to see the increase in quality awareness amongst

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the pharmaceutical industry across the region. We will further continue our focus on the sector
and expand our presence in industry and across regulators,‖ said Suresh Sugavanam,
managing director and vice president of UL South Asia.
Considering the fact that certain Indian companies have got critical global attention due to
certain evasions, violations and avoidances during US FDA inspections in the last couple of
years, government regulatory agencies have started emphasising the need to ensure consistent
quality of drugs manufactured in India. The drugs standardisation compliance and regulatory
requirements need to be at par with the international regulations, including the US FDA,
allowing drug manufacturers to maintain competitive advantage.
―UL EduNeering is a leader in providing regulatory and compliance learning solutions to the life
science industry. Our CFR 21 Part 11 validated platform is used globally by top pharma and
medical device companies. We partner with organisations to help them build an effective quality
and compliance training programme that best suits their needs,‖ stated Scott Barnard, vice
president, Life Sciences at UL EduNeering.
Out of the 700 courses offered through e-learning mode, 150 courses were also made available
in Gujarat FDCA for the state regulators on relevant areas of GMP, GDP and validation
protocols.
USFDA wants closer cooperation with Indian drug regulators
The United States Food and Drug Administration (USFDA) has sought closer cooperation with
its Indian counterpart Central Drugs Standard Control Organization (CDSCO) and Drug
Controller General of India (DCGI) in a wide ranging issues such as "good manufacturing
practices", "good clinical practices" and regulating spurious drugs.
Sources told Bloomberg TV India that USFDA wants Indian drug inspectors to assist them on
surprise visits.
The move assumes importance as India is drawing up a 7-point vision to double pharma output
to Rs 4 lakh crore by 2019 as part of the Make in India initiative but it has to step up regulations
and inspection to global standards.

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The USDFA officials visited India in March 2015 and had frank ranging discussions on the
regulatory issues in both nations.
As a follow-up to the visit, sources said that USFDA has written to the Indian government
appreciating the transparency in discussion on the Narendra Modi government's plans to
strengthen the regulatory systems and infrastructure.
The USFDA wanted collaboration on inspection for inspection of "good manufacturing
practices", "good clinical practices" and medical devices.
The US drug regulator also wants to collaborate on inspection to weed out sub-standard,
spurious, falsely labeled and counterfeit medical products, sources said.
The USFDA will hold joint common training workshops for drug inspectors in India in
September. The training workshops will focus to resolving issues pertaining to quality
management, risk management and data integration.
In China, Illegal Drugs Are Sold Online in an Unbridled Market
SHANGHAI — Ordering illegal drugs from China is as easy as typing on a keyboard.
On guidechem.com, more than 150 Chinese companies sell alpha-PVP, also known as flakka,
a dangerous stimulant that is illegal in the United States but not in China, and was blamed
for 18 recent deaths in one Florida county.
The e-commerce portal Qinjiayuan sells air-conditioners, trampolines anda banned
hallucinogen known as spice, which set off a devastating spike in United States emergency
room visits in April.
The stimulant mephedrone, sometimes sold as ―bath salts,‖ is banned in China but readily for
sale at the Nanjing Takanobu Chemical Company for about $1,400 a pound.
―I can handle this for you legally or illegally,‖ a company salesman said by phone when asked
about shipping the product overseas from the company‘s headquarters in coastal Jiangsu
Province. ―How much do you want?‖
The English-language website of China Enriching Chemistry, a Shanghai company, is a
veritable Amazon of synthetic drugs.

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While China says it has made thousands of arrests and ―joined hands‖ with foreign law
enforcement agencies, officials from several countries say Chinese authorities have shown little
interest in seriously combating what they see as the drug problems of other countries.
―They just didn‘t see what was in it for them to look into their own industries exporting these
chemicals,‖ said Jorge Guajardo, the former Mexican ambassador to China.
China‘s chemical factories and drug traffickers have exploited this opportunity, turning the
nation into a leading producer and exporter of synthetic drugs, including methamphetamine, as
well as the compounds used to manufacture them, according to seizure and trafficking route
data compiled by American and international law enforcement agencies.
China is now the source of a majority of the ingredients needed to manufacture
methamphetamine by Mexican drug traffickers, who produce 90 percent of the meth consumed
in the United States, according to theDrug Enforcement Administration.
As governments around the world have stepped up regulation of these so-called precursor
chemicals, the Mexican cartels have increasingly turned to Chinese chemical factories.
Mr. Guajardo, Mexico‘s ambassador from 2007 to 2013, said his efforts to persuade Chinese
authorities to restrict the export of these chemicals, which are banned in Mexico, came to
naught. Instead, he said, Chinese officials said the problem was best handled by Mexican
customs agents or claimed that Mexico‘s written requests for assistance had used the incorrect
typeface or were improperly translated into Chinese.
―In all my time there, the Chinese never showed any willingness to cooperate on stemming the
flow of precursors into Mexico,‖ he said in a telephone interview.
At the same time, clandestine Chinese labs manufacture and export their own meth and other
synthetic drugs around the world. In 2013, the police dismantled nearly 390 meth labs in China,
more than in any other country in the region, according to a United Nations report released in
May.
These manufacturers have flourished in part because the country‘s huge chemical industry is
weakly regulated and poorly monitored, officials say, making it easy for criminal syndicates to
divert chemicals with legitimate uses in making medicine, fertilizer and pesticides into the
production of new and dangerous drugs.

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The labs have also figured out how to stay one step ahead of laws banning illicit synthetic drugs
simply by tweaking a few molecules, creating new and not-yet-illegal drugs.
Since 2008, the number of new psychoactive substances reported to the United Nations Office
on Drugs and Crime has soared more than eightfold to 541, far outpacing the 244 drugs
controlled under global conventions. Often sold as ―legal highs‖ and ―research chemicals,‖
these drugs are designed specifically to exploit an outdated international legal framework.
Some countries, including the United States, have banned whole ranges of chemicals that
mimic illegal drugs, but many nations do not. The European Union in particular, with its open
borders and disparate drug laws, provides ample opportunity for smuggling contraband.
―Drug traffickers take advantage of this,‖ said Soren Pedersen, a spokesman for the European
police agency Europol. ―As soon as a substance becomes illegal in Germany, they can just
divert it to Denmark, Sweden or Austria.‖
Several American officials said China was the primary source for new synthetic drugs.
―Hands down China is No. 1,‖ said a federal law enforcement official, who was not authorized to
speak publicly.
―I know prosecutors in Arizona, Virginia, Minnesota,‖ said Carla Freedman, an assistant district
attorney in New York who in 2013 prosecuted a ring trafficking drugs from Shanghai. ―We‘re
seeing cases nationwide and ground zero always seems to be China.‖
According to the Australian Crime Commission‘s latest Illicit Drugs Report, released last month,
China was the primary source of illicit amphetamine-type drugs detected at the Australian
border in 2013 to 2014.
In 2013, the Australian police made their largest methamphetamine seizure ever, 1,300 pounds
discovered in a shipping container from China with a street value of $450 million. Since then,
Australian authorities have found meth in Chinese shipments of garden hoses, handbags,
lamps, aquarium pebbles, metal shafts, kayaks and 70 porcelain toilets.
―We‘ve seen it all,‖ said Detective Superintendent Scott Cook, who commands the Organized
Crime Squad in the state of New South Wales, which includes Sydney. ―There‘s absolutely no
limit in terms of how far they go to import drugs. They‘re ingenious.‖
Chinese officials say the government is committed to international cooperation against drug
traffickers.

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―We aim to help and support other countries in any way we can,‖ Liu Yuejin, the assistant
minister of public security, has said publicly.
In response to faxed questions, the Chinese Foreign Ministry denied any problems in law
enforcement cooperation with Mexico.
But Hao Wei, a member of the ministry‘s Committee for Prevention of Synthetic Drug Abuse,
said traffickers would always find loopholes.
―I really don‘t think only governments should be blamed for this,‖ he said in a telephone
interview. ―Instead of pointing fingers at each other, we should confront the problem and deal
with it in a comprehensive and balanced way.‖
Dr Reddy's Laboratories working on 18 new drug applications
HYDERABAD: Drugmaker Dr Reddy's Laboratories Limited is working on 18 new drug
applications, including the three NDAs it has already filed with the US Food and Drug
Administration, and expects 2 more drugs to go for approvals before 2018.
According to a filing with Securities and Exchanges Commission, DRL said the company
follows a hybrid research and development model, both in-house and virtual (operations are
outsourced, subject to supervision of strategic and project management functions).
"As of March 31, 2015, we had 18 active products in our Proprietary Products development
pipeline in various stages of development.
"We have filed 3 NDAs for products from this pipeline, two in March, 2015 and one in April,
2015, all under section 505 (b)(2) of the US Federal Food, Drug and Cosmetic Act," the filing
said.
The three NDAs it filed with FDA -- DFD-01, DFD-09, DFN-11 -- are focussed on developing
and commercialising therapies in dermatology and neurology.
DFD-01 is intended for the treatment of patients suffering from psoriasis and DFD-09 is for the
treatment of rosacea.
DFN-11 is a drug device combination product intended to treat acute migraine episodes.

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DFN-02 (for treatment of migraines, with or without aura) is expected to go for approval from
US FDA in 2018, DFD-06 which is being developed for treatment of moderate psoriasis
affecting up to 20 per cent of the body surface area in patients 18 years of age or older may
seek approval from the US regulator by next year, the company said.
"Our principal research laboratory is based in Hyderabad, India. As of March 31, 2015, we
employed a total of 152 scientists, including 30 scientists who held Ph.D. degrees, across all of
this segment's locations.
"Our research strategy focuses on discovery of new molecular targets, designing of screening
assays to screen promising molecules and developing novel formulations of currently marketed
drugs or combinations thereof to address unmet medical needs," it further said.
While the company continues to seek licensing and development opportunities with third parties
to further develop product pipeline, it also conducts clinical development of some candidate
drugs in-house.
CDSCO to upgrade manpower to enhance GMP compliance and quality of drugs
The Central Drug Standards Control Organization (CDSCO) would soon appoint 147 drug
inspectors by the end of 2015 to ensure quality of drugs on par with global standards in line with
current Good Manufacturing Practices (cGMP). The process for the appointments has already
started, says a senior CDSCO official.
A total of additional 1195 posts have been sanctioned for the upgradation of manpower and
labs under the 12th five year plan. Central government has allocated Rs.900 crore for
enhancing manpower and capacities of minilabs at port offices and mobile labs at CDSCO
level.
According to informed sources, ―CDSCO expects to double the manpower and enhance the lab
infrastructure both at the centre and states by the end of 2017. CDSCO has also conducted 17

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training programmes to train drug inspectors on carrying out GMP inspections in the year 2013-
14 to ensure quality of drugs supplied to over 200 countries from India‖.
Talking about the increasing global requirement for evolving regulatory compliance in regulated
and unregulated markets, an official stressed on the need for uniformity of GMP inspections for
supplying quality drugs globally. "The practice of deputing drug inspectors as observers through
joint inspections has been able to help draw suggestions and feedback from our global
regulatory counterparts on continuing good manufacturing practices. It will help manufacturers
in adopting global practices followed in other countries where our medicines are consumed.
Similar kinds of inspections have also been carried from India to other importing countries for
the sake of ensuring quality and consistency. Countries globally are concerned about safe and
efficacy of medicines to be supplied for the sake of patient safety," he added.
CDSCO had earlier started deputing drug inspectors as observers to carry out joint inspections
on an event of inspection from an international regulator.
The exercise done in coordination with state drug regulators was meant to monitor
manufacturing plants on GMPs and equip drug inspectors on enforcing its compliance across
the country. Following which, around 80 drug inspectors have been recruited at the CDSCO last
year.
It has been learnt that US FDA's workshops on GMP and CGMP compliance for the first time in
four cities of India in partnership with CDSCO earlier this year has been well received as over
60 pharma companies participated in the workshop.
The US FDA-CDSCO workshops held in Hyderabad, Goa, Chandigarh and Ahmedabad in May
last year covered relevant topics for US FDA regulatory requirements like process validation,
enforcements and computer system validation based on specific information.

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21st Century Cures would extend exclusivity for 15% of drugs
A six-month extension of marketing exclusivity proposed in the 21st Century Cures Act(H.R.
6) for drugs repurposed for Orphan indications would delay generic or biosimilar competition for
about 15% of brand name drugs expected to lose exclusivity from 2016-25, according to an
estimate released Tuesday by the Congressional Budget Office. The extension would cost the
federal government about $869 million, according to the CBO. The estimate implies that the
bill's provision would trigger a surge in new Orphan drug indications for approved drugs.
The CBO estimated the full cost of H.R. 6 at $106.4 billion from 2016-2020, including $97 billion
to reauthorize NIH for three years. The estimate includes an increase in NIH funding by $1.5
billion annually, as well as $8 billion for an NIH Innovation Fund. The CBO estimated that FDA's
provisions in the bill would cost $872 million, including a $550 million Cures Innovation Fund for
the agency.
According to the CBO, the bill would reduce direct spending by a net $11.9 billion over the five-
year period, based on budget offsets that were passed by the House Energy & Commerce
Committee, including sales from the Strategic Petroleum Reserve, cash flow management for
Medicare prescription drug programs, and cost savings from limiting Medicaid reimbursement
for durable medical devices. These offsets may be changed, however, when the bill moves to
the House floor
India to open drugs database to global regulators
Drug regulators and retailers across the world will soon be able to access a large database that
India is building on domestic pharmaceutical manufacturers. India has decided to throw open
the database to global stakeholders following concerns over spurious drugs emanating from the
country.
The government had earlier introduced barcoding on export consignments of medicines to help
trace their point of origin.
Now it has mandated all drug exporters to adhere to labelling of prescribed manufacturing data
on various levels of packaging from October 1 while temporarily exempting barcode labelling on
primary packaging.

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A senior commerce ministry official said a pilot project will begin at the end of this month for
uploading data provided by some select medicine exporters, even as an expert group will
recommend technologies for the socalled track and trace system within four months.
India had exported medicines worth $15.2 billion (about Rs 97,000 crore) in 2014-15, an
increase of 5% over the previous year's figure.
PV Appaji, director general of Indian Pharmaceuticals Export Promotion Council (Pharmexcil),
said the medicine exporters will upload data pertaining to the parent-child relationship for all the
three levels of packaging — primary, secondary and tertiary — along with the movement of
goods in the supply chain.
Sun Pharma, Wockhardt and Unichem are among the medicine exporters that have come
forward to upload their barcoding data on the central server of National Informatics Centre,
Appaji said. "We are talking to a few more top exporters including Dr Reddy's Laboratories,
Mylan Labs, Sandoz and Aurobindo Pharma to take part in the pilot project," he said.
Appaji is the member secretary of the expert group on technology that comprises the commerce
ministry's joint secretary Sudhanshu Pandey, pharmaceuticals department's joint
secretary Sudhansh Pant and the Drug Controller General of India. He is also a member
secretary of the expert committee group set up for finding the right technology for
implementation of the track and trace system for export of drug formulations.
Indian Drug Manufacturers' Association president SV Veeramani said the industry players were
waiting for clarity on technologies and guidelines for uploading the manufacturing data and its
data security features. "India is the first country to implement the barcode system in the world.
We are in principle willing to participate while incurring additional expenditure to comply with the
new mandatory process, but we are not sure of its benefits."
Appaji said the commerce ministry is scheduled to organise a meeting on Friday in Mumbai to
providing clarity to various stakeholders.

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IPA wants Regulatory Affairs Science as academic discipline for higher education in
pharmacy
The Regulatory Affairs Division (RAD) of the Indian Pharmaceutical Association (IPA) wants
Regulatory Affairs Science as an academic discipline and a research topic as part of higher
education in pharmacy.
In respect of this field of study, RAD is conceiving ideas from experienced drug regulatory
officers, expert leaders of industry and prominent academicians, said Dr Subhash Mandal,
chairman of RAD of IPA.
He said PG and research programmes in Regulatory Affairs Sciences have developed in some
western countries and several universities offer higher level academic programmes in the
subject. In India, discussions are going on among experts to justify its status as an independent
academic discipline in the pharmacy education. RAD will apprise the Union government and the
office of the Drugs Controller General of India (DCGI) of the necessity of introducing Regulatory
Affairs as an academic discipline.
He pointed out that in today‘s world when crores of rupees worth drugs are consumed everyday
by people in the country and the industry manufactures millions of rupees worth drugs for
domestic and international sale, regulatory professionals of the central and state agencies need
to learn and acquire specialized knowledge and practical skill about regulatory aspects of
pharmaceuticals, neutraceuticals, cosmetics, biotechnology, medical devices, food, herbal
drugs and other life-science industries. Pharmaceutical Regulatory Affairs professionals are
responsible for developing, compiling and filing documentation required to support the licensing
and approval of pharmaceutical products.
Dr Mandal said that with an aim to bring up this science into the pharmacy academic domain,
last year RAD had organised seminars and workshops on the concept and importance of
regulatory affairs in various pharmacy colleges, and discussions held among academic groups,
research groups and industries. The residuary work will be carried out this year. He said once
the subject becomes an academic discipline, it will provide the students with the knowledge and

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skills required to fulfill vital roles in assuring adherence with the complex regulations necessary
for the development, delivery and marketing of safe and effective health-care products.
For an international level progress of the subject, RAD will contact regulatory authorities in
foreign countries such as USFDA (USA), MHRA (UK), TGA (Australia), Health Canada
(Canada), MCC (South Africa), ANVISA (Brazil), EMEA (European Union), SFDA (China),
NAFDAC (Nigeria), MEDSAFE (New Zealand), MHLW (Japan), MCAZ (Zimbabwe),
SWISSMEDIC (Switzerland), KFDA (Korea), MoH (Sri Lanka), etc.
Regulatory Science is the science of developing new tools, standards, and approaches to
assess the safety, efficacy, quality, and performance of all regulated products. The course on
the subject will have several disciplines like operational regulatory affairs, strategic regulatory
affairs, clinical research regulatory affairs, international regulatory affairs, regulatory
compliance, and general regulatory affairs, said Dr Subhash Mandal.
Health Canada requests quarantine of drug products from Polydrug Labs due to data
integrity concerns
Drug regulatory authority of Health Canada has requested that Canadian importers voluntarily
quarantine drug products with active pharmaceutical ingredients (APIs) manufactured or tested
by an Indian drug maker, Polydrug Laboratories, based in Ambernath, Maharashtra state, due
to data integrity concerns.
Health Canada is taking this interim precautionary measure to help mitigate any potential risk in
light of recent findings from trusted regulatory partners that raised concerns about the reliability
of data generated at this site.
At this time there is no identified risk to health, and Health Canada is not requesting a recall of
any products with API from Polydrug Laboratories currently available at Canadian market.
APIs are used to make finished drug products that are sold to consumers. A quarantine will

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mean that Canadian importers and distributors will stop distributing products in Canada with
APIs linked to this site.
Health Canada continues to review information from the trusted regulatory partners and from
Canadian importers. Canadians will be updated about the list of products affected by the
requested quarantine through updates on the Inspection Tracker.
Canadians should not make any changes to their medication without consulting with a
healthcare professional, said an official release.
Health Canada will continue to work with international partners and Canadian importers to
gather and assess information regarding the situation and take action as necessary to help
protect Canadians.
Health authority will also engage the provinces and territories to share information about the
situation.
HMPC Document on the systematic Review of Monographs Herbal Medicinal Products
updated
On 28 January 2015 the EMA's HMPC (Committee on Herbal Medicinal Products) has updated
the procedure which defines the systematic review of the monographs for herbal medicinal
products of the European Union and the list entries of the European Union as well as their
supporting documentation.
The legal basis for this is the EMA/HMPC reflection paper about the reasons and time periods
for the revision of monographs and list entries. Every 5 years it has to be checked whether a
monograph or a list entry is still up-to-date.
The HMPC review document deals with the following aspects:
 Scope of the revisions
 Timelines
 Documentation of the review / revision

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With regard to the last point it is mentioned that the extent of the changes made in each
document must be transparent.
For more information please see the complete Rev 1 document Procedure for the systematic
review of European Union herbal monographs and/or European Union list entries and
supporting documents.
Better training tools recommended to support patients using adrenaline auto-injectors
Training device and audio-visual material expected to promote appropriate use of auto-
injectors
The European Medicines Agency (EMA) has recommended several measures, including the
introduction of more effective educational material, to ensure that patients and carers use
adrenaline auto-injectors successfully. Adrenaline auto-injectors are potentially life-saving
treatments for anaphylaxis (severe allergic reactions) while the patient waits for emergency
medical assistance.
EMA carried out a review of adrenaline auto-injectors following concerns that currently available
devices may deliver adrenaline under the skin instead of into a muscle, and this may delay
response to treatment.
Having assessed all the available data, EMA‘s Committee for Medicinal Products for Human
Use (CHMP) acknowledged that giving the medicine by injection into the muscle is the
preferred way to obtain a rapid response in anaphylaxis. However, the CHMP noted that
several factors may affect whether adrenaline is actually delivered into a muscle; these include
needle length, the thickness of fat under the skin, the way the auto-injector works (e.g. if it is
spring loaded or not), the angle at which the device is placed on the skin and the force used to
activate the device as well as how well the user follows the instructions for injection.
The CHMP concluded that training of the user is of paramount importance. The companies that
market adrenaline auto-injectors will therefore be asked to develop more effective educational
material for patients, as well as for healthcare professionals, to ensure their optimal use. This

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will include a training device with which patients can practise; audio-visual material to show in
detail how the device is to be used; and a checklist for prescribers to ensure that sufficient
information is given to the patient before they use the auto-injector. The product information of
adrenaline auto-injectors will also be updated with further warnings and precautions, including a
recommendation that patients should be prescribed two auto-injectors which they should carry
at all times and a recommendation for family members, carers or teachers to be trained on how
to use the auto-injector.
The CHMP also concluded that further data should be generated to better understand how
adrenaline penetrates body tissues when given with each of the different auto-injectors.
The CHMP recommendation will now be sent to the European Commission for a legally binding
decision that will be valid throughout the EU.
Information for patients
 Adrenaline auto-injectors are used to treat severe allergic reactions, while the patient awaits
emergency medical assistance. They are designed so that they can be easily used by the
patient themselves or a carer.
 The review of adrenaline auto-injectors showed that patients could benefit from further training
to use the auto-injector successfully.
 You will receive training from your doctor or nurse on how to use your adrenaline auto-injector.
A training device will also be developed so that you can practise with it before you need the
auto-injector in an emergency. A training video will be produced to show you in detail how to
use the injector properly.
 It is important that you use the auto-injector correctly so that the adrenaline is delivered into
your muscles and works as quickly as possible.
 If you have been prescribed an adrenaline auto-injector because you are at risk of severe
allergic reactions, you should ensure you are familiar with it and carry it with you at all times.
 It is likely that your doctor will recommend that you carry 2 injectors, in case a second dose is
needed while you wait for emergency assistance.

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 Your family members, carers or teachers should also be instructed in the correct use of the
auto-injector.
 If you have any question or concern, speak with your doctor or pharmacist.
Information for healthcare professionals
 The review of adrenaline auto-injectors confirmed that intramuscular injection is the preferred
route of administration in the treatment of anaphylaxis in order to obtain a rapid response.
 Several factors may affect whether adrenaline reaches the muscle layer. These include: needle
length, the skin-to-muscle depth, the way the auto-injector works (e.g. if it is spring loaded or
not), the angle of placement on the skin and the force used to activate the device.
 Because of the uncertainties over drug delivery from adrenaline auto-injectors and the
consequent uncertainties around the onset of pharmacodynamic response, it is recommended
that healthcare professionals prescribe 2 auto-injectors, which patients should carry at all times.
 Educational material will be developed to ensure that patients or carers use adrenaline auto-
injectors successfully. This will include a training device that patients can practise with, audio-
visual material and a prescriber checklist.
 A study in 2013 by Brown et al. showed that 15% of the mothers were unable to use the auto-
injector successfully in their children. This supports the introduction of proper training and
comprehensive educational material for patients and healthcare professionals.
 The companies that market adrenaline auto-injectors will be asked to carry out a
pharmacokinetic/pharmacodynamic study to better understand how adrenaline penetrates body
tissues when given through an auto-injector.
More about the medicine
Adrenaline (epinephrine) auto-injectors are given to people who are at risk of anaphylaxis
(severe allergic reaction) or have had a previous episode of anaphylaxis, to use as a first-aid
measure in case of emergencies while waiting for emergency medical assistance.

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Anaphylaxis is a life-threatening reaction that causes a drop in blood pressure and breathing
difficulties. An injection of adrenaline helps to relieve the symptoms of anaphylaxis quickly by
narrowing the blood vessels (thereby increasing the blood pressure) and opening up the
airways to help with the breathing.
Adrenaline auto-injectors have been approved through national procedures in all the EU
Member States.
More about the procedure
The review of adrenaline auto-injectors was initiated at the request of the United Kingdom in
April 2014, under Article 31 of Directive 2001/83/EC. This followed a national review of all
adrenaline auto-injector products approved in the UK, which concluded that there was no robust
evidence that the devices deliver adrenaline into a muscle for all patients.
The review has been carried out by the Committee for Medicinal Products for Human Use
(CHMP), responsible for questions concerning medicines for human use, which has adopted
the Agency‘s final opinion. The CHMP opinion will now be forwarded to the European
Commission, which will issue a final legally binding decision applicable in all EU Member
States.
Source: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2015/06/WC5
00188786.pdf
Pharmaceuticals regulator set for revamp
India‘s drug regulator Central Drug Standard Control Organisation (CDSCO) is all set to be
revamped into a world-class body.
With the rise in import alerts from the US Food and Drug Administration (USFDA), the
government has geared up to increase the efficiency and quality of the pharma sector.

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CDSCO regulates quality standards of drugs and is also responsible for the approval of new
drugs. The ministry has floated the draft Cabinet note with an aim to upgrade the body at par
with the world‘s best health regulator, US Food and Drug Administration (US FDA).
―We have floated a Cabinet note on revamping CDSCO… For it to be upgraded into a world-
class health regulator. The regulator will also be renamed as Central Drug Administration,
which is as easy as Food and Drug Administration,‖ said a senior official of the health ministry.
―The Cabinet may take up the proposal within July.‖
The draft note also suggests that CDSCO should fall under the direct supervision of the health
ministry as currently it falls under the Directorate General of Health Services (DGHS).
―We have set USFDA as the standard to upgrade and revamp the entire health system.
Upgradation is a dynamic process and our aim is to adopt best international manufacturing
practices,‖ said GN Singh, drug controller general of India (DCGI), who heads CDSCO.
New CDSCO is likely to have six arms divided into categories — drugs, cosmetics, medical
devices, laboratories, new emerging areas and ayush.
The responsibilities of CDSCO include grants of import and export license, clinical trial
approvals and permissions for marketing and manufacturing. State Food and Drug
Administration (FDA) work with CDSCO in each state and is responsible for issuance of license
to manufacture similar biologic in India apart from regulating the drug quality.
Pharmacopoeia Commission mandates pharma cos to submit ADR reports to
Pharmacovigilance Programme
With a view to strengthen the quality assessment of all the drugs marketed in the country and to
reinforce the Pharmacovigilance Programme of India (PvPI), the Indian Pharmacopoeia
Commission (IPC), the national coordination centre for the programme, has issued an order
mandating all the pharmaceutical industries to submit adverse drugs reaction (ADR) reports of
their respective pharmaceutical products.
The order, signed by Dr G N Singh, secretary-cum-scientific-director of PvPI, has come into
force from June 1, this year.

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Last year, the IPC had issued a similar order asking all the hospitals to submit the ADRs in
particular formats to government of India. But the responses to the order are poor hitherto, said
a chief regulatory officer of a state.
The latest order, concerning submission of ADR reports by manufacturers, dated May 18, 2015,
states that pharma companies should submit the reports in XML-E2B format to PvPI. IPC office
hopes that the particular format will enable the authorities to hasten the process of uploading
Individual Case Safety Reports (ICSRs) to VigiFlow, a web-based database of the WHO–UMC
(World Health Organisation – Uppsala Monitoring Centre). This measure is also expected to
enhance the process of assessment and signal detection, says the order.
Following the IPC directive, a Coimbatore-based pharmacovigilance consulting company, Oviya
Medsafe, has informed Pharmabiz that they will provide support services for pharma companies
to submit the reports to PvPI.
The managing director of the company, Dr Vijay Venkataraman, claims that although
pharmaceutical companies in India collect suspected ADR reports from healthcare
professionals through their marketing teams, only a few of them have pharmacovigilance
departments and drug safety software databases to generate ADR reports in XML-E2B format.
Update From the Most Recent ICH Meeting
The International Conference on Harmonisation (ICH) Steering Committee (SC) and its Expert
Working Groups (EWGs) met in Fukuoka, Japan from June 5-11, 2015. The meeting was
hosted by the Ministry of Health, Labour and Welfare and the Japan Pharmaceutical
Manufacturers Association.
The SC agreed on the key issues relating to the reform of ICH in terms of the Articles of
Association, funding model and membership. An important part of the reform effort is
establishing a formal organisation with a new approach to membership, governance and shared
funding among ICH members. During a special session on June 10, Interested Parties were
updated on the future of ICH, including issues regarding membership and governance of the
new association. All participants welcomed the goals of the reform and recognised the intended

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roles of the Assembly as well as the Management Committee. Most participants indicated their
interest for becoming ICH members or observers and the different intended eligibility criteria
were discussed.
The new ICH Association under Swiss law is expected to be established over the coming
months with the aim of being operational starting in 2016.
Twelve working groups met in Fukuoka and achieved important progress towards their
respective objectives. The Question & Answer (Q&A) document on the Q7 Guideline on Good
Manufacturing Practices for Active Pharmaceutical Ingredients (APIs) has been signed off
at Step 4 in Fukuoka and is thus ready for implementation in the ICH regions.
In addition, two documents, the draft Addendum to the M7 Guideline on Assessment and
Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential
Carcinogenic Risk document and the draft Addendum to E6 on Good Clinical Practicehave
reached Step 2b and will be submitted to public consultation. More details on the progress
achieved by the different groups is provided hereunder.
Safety Guidelines Update
The M7 EWG reached agreement on the draft Addendum to the Guideline Assessment and
Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential
Carcinogenic Risk. The SC signed off the Step 2a/2b document in Fukuoka. thus releasing this
document for public consultation.
A new EWG, S5(R3), was created to revise the Guideline on Detection of Toxicity to
Reproduction for Medical Products and Toxicity to Male Fertility and met in Fukuoka for the first
time. This group made good progress in reviewing and revising the current guidance in
developmental and reproductive toxicity studies and expects to reach Step 2 by June 2017.
It was also the first meeting of the S11 EWG tasked to develop a new ICH Guideline
on Nonclinical Safety Testing in Support of Development of Paediatric Medicines.
Efficacy Guidelines Update
The EWG developing an Addendum to E6 on Good Clinical Practice to promote innovative
approaches to clinical trial design, management, oversight and conduct made good progress
and reached Step 2a/2b. The draft document that will take the format of an integrated
addendum will now be submitted to public consultation.

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The EWG developing an Addendum to E9 on Choosing the Appropriate Estimand and Defining
Sensitivity Analyses in Clinical Trials, met to focus on harmonising improved clinical trial
planning, conduct, analysis and interpretation.
The E11 EWG worked to develop an Addendum to the Guideline on Clinical Investigation of
Medicinal Products in the Pediatric Population and made good progress towards the draft Step
1 technical document. Step 2 for this topic is expected in December 2015.
The E14 Discussion Group (DG) met to develop a Concept Paper to revise the ICH E14
Guideline on the Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic
Potential for Non-Antiarrhythmic Drugs. During the meeting in Fukuoka, the SC endorsed the
Concept Paper on the revision of the Q&A 5.1 on Concentration-Response Modelling for
regulatory decision making thereby allowing experts to initiate this revision.
The group working on the development of the E17 Guideline on Multi-regional Clinical
Trials progressed towards developing the Step 1 technical document.
The E18 EWG on Genomic Sampling Methodologies for Future Use made progress towards
a Step 2 document which is expected in December 2015. This Guideline will clarify points to
consider in collecting genomic samples in clinical trials, resulting in further implementation of
genomic research for the benefit of all stakeholders.
Quality Guidelines Update
The Q7 Implementation Working Group (IWG) on Good Manufacturing Practices for
APIs reached agreement on the Step 3 Q&A document ahead of the Fukuoka meeting. The SC
approved this document for release by signing off Step 4 in Fukuoka.
The SC also signed-off on Step 2a/2b of the Q3C(R6) Guideline for Residual Solvents including
two solvents: Triethylamine and Methyl Isobutyl Ketone. The Q3C maintenance EWG had
reached agreement on this document ahead of the Fukuoka meeting
The Q12 EWG on Technical and Regulatory Considerations for Pharmaceutical Product
Lifecycle Management met for the second time in Fukuoka. This group is expected to finalise
its Step 1 technical document in June 2016.
The ICH SC approved an interim face-to face meeting of the Q11 IWG to develop Q&As on
Selection and Justification of Starting Materials for the Manufacture of Drug Substances in
September 2015.

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Multidisciplinary Guidelines Update
The M2 EWG on Electronic Standards for the Transfer of Regulatory Information (ESTRI) met
in Fukuoka, making progress on a variety of issues.
The M4E(R2) EWG working on the revision of the Common Technical Document (CTD)
Efficacy Guideline to provide greater specificity on the format and structure of benefit-risk
information also made progress to finalise a draft of its Step 1 technical document.
The M8 EWG on electronic Common Technical Document (eCTD) met in Fukuoka and the SC
signed-off at Step 4 of Version 1.27 of the eCTD Change Request Q&A document and
endorsed that the M8 would update the Granularity Document based on Q&A from CTD-Quality
and change requests M8 received. The M8 EWG reconciled all of the comments received on
the draft eCTD Implementation Guide v.4.0 during Step 3.
The next ICH meeting will be held in Jacksonville, Florida, USA on December 5 - 10, 2015.
Pharma industry's struggles to tighten standards paves way for M&A deals
Smaller generic drugmakers struggling to cope with a bruised reputation and tougher regulation
in the United States, are under pressure to consider branching out to new, less-profitable
markets or sell out to larger rivals.
Two years after its most high-profile regulatory setback to date in the United States - Ranbaxy's
$500 million U.S. fine for drug safety violations - India's $15 billion a year generic drug industry
is still rebuilding its image in its biggest market.
Many of its top firms are facing sanctions at some of their factories, as the U.S. Food and Drug
Administration (FDA) tightens checks and its approvals process.
Combined with government-mandated price controls on drugs at home, that is piling pressure
on smaller players.
"If they want to have a presence globally, they have to make investments. If they can't, then
they'll have to focus on other markets or scale back their ambition outside of India, and that's
probably what will happen," said Subhanu Saxena, CEO of Cipla, fourth-largest drugmaker by
revenue.

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Ashok Anand, president of Hikal Ltd, a Mumbai-based drugmaker with a market value of $167
million, said some peers were putting themselves on the block.
"If they cannot deal with the stricter regulations, they might just prefer to sell out," he said.
Pressure on U.S. sales has been felt across the industry, with all drugmakers hit by delays in
FDA approvals as the U.S. safety body overhauls its review process. Growth in U.S. revenue
for drugmakers slowed to 14 percent in the year to March 2015, less than half what it was in the
year to March 2012, according to brokerage Edelweiss.
But for larger players who want to plug gaps or, for the likes of Glenmark and Aurobindo who
aim to grow in the United States, this pressure has lowered prices and could pave the way for
attractive deals, bankers said.
"Now that some of the smaller companies are reeling under intensive regulatory scrutiny and
want to cash out on their investments, valuations would be much more realistic," said the head
of India M&A at a large European bank in Mumbai.
SPENDING SPREE
Manufacturers say they have spent millions in high-end testing equipment, improved training
and have hired larger teams in quality control since Ranbaxy was fined for manipulating clinical
data.
Some consultants estimate spending on compliance has more than doubled to reach about 6 to
7 percent of sales for the larger companies.
But while the number of U.S. export bans issued to Indian companies fell to eight in 2014 from
21 in 2013, according to FDA data, the agency continues to find manufacturing violations at the
plants of some of the biggest drugmakers in the country, an indication of the pervasiveness of
the problem.
Sun Pharmaceutical Industries, Wockhardt, Dr Reddy's Laboratories and Cadila Healthcare
have all faced FDA rebukes over the past year.
Smaller firms Ipca and Aarti Drugs faced FDA bans on their plants this year.
These failures - which executives blame on India's "quick fix" culture and consultants blame on

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a failure to prioritise compliance - have clouded short-term growth prospects and added to
pressure on smaller players, pushing some to look elsewhere.
"They can choose to be in lesser-regulated markets, such as Latin America, where there is a lot
of demand. But they will have to live with much thinner margins," said the finance director of a
small drugmaker, who did not want to be named. "It's survival of the fittest."
The 2015/16 business plan for the Medicines and Healthcare products Regulatory
Agency has been published
The plan highlights the key areas where we will focus our efforts this year, and supports the
delivery of our 2013/18 Corporate Plan. Our public health mission will remain at the core of
what we do.
Over the next year our focus will be on:
 supporting the cross-government innovation and growth agenda – including playing a key
part in the Accelerated Access Review
 implementing revised medical devices funding arrangements
 driving forward work on key EU negotiations and implementation relating to clinical trials,
falsified medicines and medical devices
 continuing to grow the Clinical Practice Research Datalink (CPRD) and increase uptake of
its services
 building closer and strong collaboration with the Department of Health and partners in the
health and care system, ensuring that we are working towards common goals around
public health and innovation and growth
 progressing the agency‘s efficiency programme
 being at the leading edge of digital devices and technology
 developing further our excellence in science, including developing the capabilities of the
National Institute for Biological Standards and Control (NIBSC) to ensure it remains a
global leader in standardisation and control of biological medicines

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 leading the further development of incident and safety reporting systems – including
embedding Yellow Card reporting into the National Health Service (NHS) and care system
 continuing to meet our aspiration as a world-class regulator that leads the way in best
practice
The agency‘s priorities feed into the Department of Health‘s goals and priorities, specifically:
 preventing people from dying prematurely
 making a step change in the way technology and information is used
 improving productivity and long term sustainability and ensuring value for money for the
taxpayer
 contributing to economic growth
The complete report is enclosed.
(Source: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/439779/
Agency_Business_Plan_2015-16__v1_1_.pdf)

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Terminology
Containers
A container for pharmaceutical use is an article which holds or is intended to contain
and protect a drug and is or may be in direct contact with it. The closure is a part of
the container. The container and its closure must not interact physically or chemically
with the substance within in any way that would alter its quality. The following terms
include general requirements for the permeability of containers:
• Well-closed containers must protect the contents from extraneous matter or
from loss of the substance under normal conditions of handling, shipment or storage.
• Tightly closed containers must protect the contents from extraneous matter,
from loss of the substance, and from efflorescence, deliquescence or evaporation
under normal conditions of handling, shipment or storage. If the container is
intended to be opened on several occasions, it must be designed to be airtight after
reclosure.
• Hermetically closed containers must protect the contents from extraneous
matter and from loss of the substance, and be impervious to air or any other gas
under normal conditions of handling, shipment or storage.

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New Guidance
FDA draft guidance seeks to address ‗lack of clarity‘ around CMC changes
The new draft guidance from the US FDA seeks to address the lack of clarity around when new
chemistry, manufacturing, and controls (CMC) information must be reported to the agency.
The guidance comes as FDA seeks to help companies understand what CMC changes require reporting
to the agency and what changes can be made solely under a company’s Pharmaceutical Quality System
(PQS).
“Clarification regarding which elements of the CMC information constitute established conditions and
where in an application these elements are generally expected to be described, should lead to a better
understanding that certain CMC changes can be made solely under the Pharmaceutical Quality System
(PQS) without the need to report to FDA,” the agency says.
FDA defines “established conditions” as the description of the product, manufacturing process, facilities
and equipment, and elements of a control strategy that assure process performance and quality of an
approved product. Changes to these conditions must be reported to the FDA.
“Although the reporting mechanism for many CMC changes is clear, FDA is concerned that there is
confusion regarding which elements of an application are considered to be established conditions. This
confusion could have a negative impact on change management activities and could discourage
continual improvement in product manufacturing processes, lead to unnecessary submission of post-
approval supplements to FDA for changes that could be managed solely by a manufacturer’s PQS, or,
upon inspection, lead to Form 483 observations for hanges that should have been reported to FDA,” the
agency says.
In terms of which elements of the control strategy that are submitted in an application and may be
considered established conditions, the FDA lists:

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 DS/DP (drug substance/drug product) manufacturing and testing facilities, including in-process
materials;
 Source of and specifications for starting materials for biological products;
 Process, including in-process tests and sequence of operations, equipment, and process parameters and
their ranges;
 Specifications, including the tests, analytical procedures and acceptance criteria, including specifications
for the DS, other components, in-process materials, and the DP;
 Container closure system, components, and specifications; and
 Maintenance strategy for chemometric and/or multivariate models (e.g., for models that may have a
high impact on product quality).
And in cases where the relevance of the established conditions will depend on manufacturing site
specific capabilities, such as on-line, real-time attribute monitoring, the FDA says “certain elements of
established conditions may need to be specific to a particular facility or facilities should the application
have multiple facilities approved for the same intended function.”
The applicant should also provide an updated summary of the established conditions and supportive
information (e.g., validation data, batch analysis) for any new or modified established conditions in a
manufacturing supplement or the next annual report, the agency adds.
Alternatively, if an established condition is no longer necessary to assure process performance and
quality, the applicant may remove such a condition by submitting a supplement or annual report, where
the submission type is based on the recommendations found in FDA regulations and post-approval
change guidance documents or in an approved protocol.
USP Chapter <1207>: Container Closure Integrity Testing
The USP Chapter <1207> on the integrity testing of primary containers of sterile dosage forms is
currently in the second round of review. After a first publication in the UPS-NF Pharmacopeial Forum in

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September/October 2014 the comments received are now evaluated by the USP Expert Committee.
This review process is supposed to be completed in 2015, and it is expected that the new Chapter will
become effective in 2016.
Different from the visual inspection, the leak testing of primary containers (so far) has not to be
performed to 100% (with the exception of ampoules). Chapter <1207> makes recommendations here,
which are - unlike the USP Chapters with numbers less than 1000 - not binding. So the Chapter is rather
similar to a guideline than to a pharmacopoeia monograph. For the USP the container / closure integrity
is comprised of a package integrity testing and a package leak testing. A simple microbiological
challenge test is not considered sufficient. The chapter furthermore lists various test methods, whereby
the USP now prefers deterministic methods rather than probabilistic methods. A probabilistic
procedure such as the bubble test or the blue bath method can serve well for locating a leak, though. As
deterministic methods are listed e.g.: high voltage leak detection (HVLD), laser Headspace analysis as
well as the pressure and vacuum decay methods.
For the validation of a method it will be important not only to build on the qualification of the testing
device, but to examine the different packaging/product combinations, for example with and without
defects.
The revised chapter will be applied to vials, ampoules, syringes and bags. But certain concepts are also
supposed to be transferable to active substances, as well as to intermediate or bulk materials in
storage.
WHO publishes interesting new Guidance for the Storage and Transport of
Pharmaceutical Products
During The 137th World Health Organisation (WHO) Executive Board (EB) meeting, the Report of the
49th meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations was
presented. With this report, a set of new guidances was adopted and recommended for use, in addition

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to certain monographs and general texts for inclusion in The International Pharmacopoeia. The report is
now available in the WHO Technical Report Series as No. 992.
For those working in the area of Good Distribution Practice (GDP) the following paper might be
interesting: Technical supplements to Model guidance for the storage and transport of time and
temperature-sensitive pharmaceutical products.
This series of technical supplements intends to give further guidance and more details to the
recommendations given in theModel guidance for the storage and transport of time- and temperature-
sensitive pharmaceutical products (WHO Technical Report Series, No. 961, 2011, Annex 9).This
document focuses on principal requirements for the safe storage and distribution of time- and
temperature sensitive pharmaceutical products (TTSPPs).
The additional material provided in these supplements links back to a specific clause or clauses in the
parent document mentioned above. All of the 16 single documents contain a reference section with
hyperlinks to relevant supporting materials. This gives a great overview on what is the current state of
the scientific and technical knowledge in this area.
Here are the links to the single documents:
 Supplement 1: Selecting sites for storage facilities
 Supplement 2: Design and procurement of storage facilities
 Supplement 3: Estimating the capacity of storage facilities
 Supplement 4: Building security and fire protection
 Supplement 5: Maintenance of storage facilities
 Supplement 6: Temperature and humidity monitoring systems for fixed storage areas
 Supplement 7: Qualification of temperature-controlled storage areas
 Supplement 8: Temperature mapping of storage areas
 Supplement 9: Maintenance of refrigeration equipment
 Supplement 10: Checking the accuracy of temperature control and monitoring devices
 Supplement 11: Qualification of refrigerated road vehicles
 Supplement 12: Temperature-controlled transport operations by road and by air

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 Supplement 13: Qualification of shipping containers
 Supplement 14: Transport route profiling qualification
 Supplement 15: Temperature and humidity monitoring systems for transport operations
 Supplement 16: Environmental management of refrigeration equipment
Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for
Treatment Guidance for Industry
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the treatment
of Duchenne muscular dystrophy (DMD) and related dystrophinopathies including Becker muscular
dystrophy (BMD), DMD-associated dilated cardiomyopathy (DCM), and symptomatic carrier states in
females. Specifically, this guidance addresses FDA’s current thinking regarding the clinical development
program and clinical trial designs for drugs to support an indication for the treatment of one or more of
these dystrophinopathies. The most prominent pathology in dystrophinopathies is degeneration of
skeletal and cardiac muscle leading to progressive loss of muscle function, respiratory and cardiac
failure, and premature death. This draft guidance is intended to serve as a focus for continued
discussions among the Division of Neurology Products, pharmaceutical sponsors, the academic
community, and the public. This guidance does not address the development of drugs to treat
secondary complications of muscle degeneration in dystrophinopathies (e.g., drugs specifically for heart
failure or for pulmonary infections).
Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM450627.pdf
Assessment of Male- Mediated Developmental Risk for Pharmaceuticals Guidance for
Industry
This guidance provides recommendations to sponsors for assessing risks to embryo/fetal development
resulting from administration of an investigational active pharmaceutical ingredient (API) to males,

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either through an effect on the male germ cell or from seminal transfer of an API that has been shown
to be genotoxic or a potent developmental toxicant when administered to pregnant animals or humans.
The guidance presents an overview of FDA’s current approach to assessing the following potential risks
associated with pharmaceutical use in male patients: Male-mediated developmental risk involving
effects of the API on the germ cell
Developmental toxicity in the conceptus associated with transfer of the API in seminal fluid to pregnant
partners
The guidance also applies to a new molecular entity for which the risk has not yet been assessed.
Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM450229.pdf
Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug
and Biological Products — Content and Format Guidance for Industry (Small Entity
Compliance Guide) :
This guidance is intended to help small businesses better understand and comply with the new content
and format requirements of the Pregnancy, Lactation, and Females and Males of Reproductive Potential
subsections of labeling for human prescription drug and biological products. On December 4, 2014, we
published the final rule “Content and Format of Labeling for Human Prescription Drug and Biological
Products; Requirements for Pregnancy and Lactation Labeling,” referred to as the “Pregnancy and
Lactation Labeling Rule” (PLLR, or final rule, 79 FR 72064). The final rule requires that the former
“Pregnancy,” “Labor and delivery,” and “Nursing mothers” subsections of the USE IN SPECIFIC
POPULATIONS section of the labeling for human prescription drug and biological products be replaced
by the three subsections entitled Pregnancy, Lactation, and Females and Males of Reproductive
Potential.
Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM450636.pdf

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Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological
Products Guidance for Industry
This guidance provides the pharmaceutical industry with the Center for Drug Evaluation and Research’s
(CDER’s) and the Center for Biologics Evaluation and Research’s (CBER’s) current thinking on allowable
excess volume and labeled vial fill size in injectable drug and biological products. It replaces the draft of
the same name that was published on March 14, 2014 (79 FR 20 14517). Specifically, the guidance
clarifies the FDA regulatory requirements and recommendations pertaining to allowable excess volume
in injectable vials and describes when justification is needed for a proposed excess volume in these
injectable drug products. This guidance also discusses the importance of appropriate fill volumes for
injectable drug products and recommends that labeled vial fill sizes be appropriate for the intended use
and dosing of the drug product.
Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM389069.pdf
WHO publishes final Guideline for Hold-Time Studies
After the World Health Organisation (WHO) had released the second draft of the guideline for the
design of hold-time studies in March already, it now released the final version as part of the Technical
Report Series 992 (TRS 992, Annex 4).
The GMP regulations require that raw materials, packaging materials, intermediate, bulk and finished
products need to be stored under suitable conditions. This also includes the definition of maximum
hold-times for intermediate and bulk products prior to their further processing. The definition of these
times should be justified on the basis of scientific data. This guideline aims at reflecting aspects that
may be important in the design of hold-time studies. Active substances and biological products are
explicitly excluded. According to WHO, hold-time studies can be part of the development or also be
carried out during the later Scale-Ups. In any case they should be confirmed during product validation,
though.

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With coated tablets as an example the guideline demonstrates at what points in the manufacturing
process samples can be taken and examined for durability. The number of batches to be examined is
supposed to be risk-based. The times, according to which the listed intermediates could be sampled and
examined are also mentioned exemplary. Whereas the original draft comprised propositions with
regard to combined hold times - meaning the impact of hold times of various intermediates among one
another - they are not part of the final guideline any more.
Product-Specific Recommendations for Generic Drug Development
To successfully develop and manufacture a generic drug product, an applicant should consider that their
product is expected to be: pharmaceutically equivalent to its reference listed drug (RLD), i.e., to have
the same active ingredient, dosage form, strength, and route of administration under the same
conditions of use, bioequivalent to the RLD, i.e., to show no significant difference in the rate and extent
of absorption of the active pharmaceutical ingredient; and, consequently, therapeutically equivalent,
i.e., to be substitutable for the RLD with the expectation that the generic product will have the same
safety and efficacy as its reference listed drug.
According 21 CFR 320.24, different types of evidence may be used to establish bioequivalence for
pharmaceutically equivalent drug products, including in vivo or in vitro testing, or both. The selection of
the method used to demonstrate bioequivalence depends upon the purpose of the study, the analytical
methods available, and the nature of the drug product. Under this regulation, applicants must conduct
bioequivalence testing using the most accurate, sensitive, and reproducible approach available among
those set forth in 21 CFR 320.24. As the initial step for selecting methodology for generic drug product
development, applicants are referred to the following draft guidance:
Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs
Submitted Under an Abbreviated New Drug Application (ANDA) (Dec. 2013)
To further facilitate generic drug product availability and to assist generic pharmaceutical industry with
identifying the most appropriate methodology for developing drugs and generating evidence needed to
support ANDA approval, FDA publishes product-specific recommendations describing the Agency’s

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current thinking and expectations on how to develop generic drug products therapeutically equivalent
to specific reference-listed drugs.
These recommendations are published in an incremental manner and listed below in alphabetical order
according to RLD’s name. The most recently published recommendations (new and revised) are listed
below.
The Agency is seeking feedback and considers comments to the docket on these recommendations. The
comments should be submitted to the Division of Dockets Management (DDM) under Docket FDA-2007-
D-0369-0015. For electronic comments, refer to the website http://www.regulations.gov OR mail your
written comments to DDM (HFA-305), FDA, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Please
contact the Regulations.gov Help Desk at 1-877-378-5457 (toll free) for assistance regarding
submissions.
For additional information on development of generic drug products refer
tohttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064964.htm
FDA‘s Latest ANDA Guidance: Patent Carve Outs Become a Guessing Game
In May 2015, the FDA released is Guidance (Revision 1) on Refuse-to-Receive Standards for Abbreviated
New Drug Application (ANDA) submissions, in response to the 2012 Generic Drug User Fee
Amendments (GDUFA) that required the FDA to “enhance” these rejection criteria. A refuse-to-receive
decision indicates that the ANDA is not sufficiently complete to permit a substantive review, and results
in the forfeiture of the GDUFA fee and potential 180 day exclusivity rights if the applicant is eligible for
“first to file” status. Under the new Guidance, a major deficiency will trigger a refuse-to-receive
decision, as will nine or fewer uncorrected minor deficiencies. In the case of nine or fewer minor
deficiencies, the applicant will have seven days to correct the application and, if not remedied within
that period of time, the FDA will issue a refuse-to-receive notice, although it may waive this
requirement for good cause shown.
In an Appendix to the Guidance, the FDA says that an incorrect section viii carve out will be considered a
minor deficiency. The FDA will reject a section viii statement if it determines that the Orange Book use

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code has not been properly carved out of the generic label. The Appendix goes on to say that the FDA
will not tell the ANDA applicant what specifically is the problem with the carve out nor will it offer
suggestions on how to fix it.
While the FDA has always taken precautions to stay clear of Orange Book patent disputes, this new
refuse-to-receive policy borders on the nonsensical. Under this Guidance, the section viii carve out
process can become a guessing game where the ANDA applicant is required to divine what the FDA
thinks is the infirmity in the proposed use code carve out and, if it guesses wrong within the seven day
window, it receives a refuse-to-receive notice that is exceedingly costly. One has to wonder whether
patent-phobia has finally pushed the FDA off the deep end.
Use Codes Play Important Role
Under Hatch-Waxman, the section viii review process was designed to function as a surrogate for
determining whether a generic drug might induce infringement of a method patent based on the brand
label. When the brand lists a use patent in the Orange Book it is required to draft a use code (240
characters maximum) that describes the language on the brand label that is protected by the patent.
Because the FDA operates only in a ministerial capacity when it comes to patent information submitted
for an Orange Book listing, it is required to accept the brand’s use code at face value. In theory, this
means that if the use code language is removed from the label the generic drug will not induce
infringement of the brand patent. The only regulatory limitation is that the omitted use code cannot
render the “skinny labeled” generic drug less safe or effective than the brand for all remaining
conditions of use. If it does, the FDA cannot approve the use code carve out and the generic must
certify as to the patent.
For simple use codes – e.g. “method of treating hives” – the section viii process is straightforward and
the FDA’s role is perfunctory. The generic label would be scrubbed of all references to treating hives
and the brand’s patent rights would be protected. But for use codes that are complex, the section viii
review process becomes more difficult, particularly where protected information appears throughout
the label.
Here, unpacking a complex use code from an even more complex label is not so easy for the FDA to
administer. In some cases, a section viii carve out will involve the removal of use code information from

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multiple sections of the label including clinical studies, adverse drug reactions, warnings, medication
guides, etc. As a result, the FDA may approve a section viii carve out that appears to be complete only
to discover that the generic drug induces infringement of the brand patent, nonetheless. Because the
ANDA applicant is not required to notify the brand manufacturer or patent holder as to the section viii
carve out, there is no opportunity to litigate the labeling issue prior to launch; moreover, this can also
put the generic manufacturer unwittingly at risk of infringement.
This is essentially what happened in AstraZeneca v. Apotex, 633 F.3d 1042 (Fed. Cir. 2010), involving the
drug Pulmicort, where the generic tried to carve out label language suggesting once a day dosing but
was rebuffed by the FDA, which thought that the carve out went beyond the use code. The generic
drug was launched without notice, the brand manufacturer sued and the court enjoined generic
marketing based on a construction of the label that the court said “would inevitably lead patients to
infringe” the brand patent.
Still a Guessing Game
Thus, the FDA’s new Guidance seems to exacerbate an already challenging task by silencing the agency
staff and forcing generics to effectively guess what should be taken off the brand label. To confuse
matters further, this comes on the heels of the carve out decision involving the sedation drug Precedex,
where the FDA held that a “minor overlap” between a use code and a generic label is permissible in
some circumstances. Cf. Bayer Schering Pharma v. Lupin. Ltd., 676 F.3d 1316 (Fed. Cir. 2012). In the
Bayer Schering case, however, the Federal Circuit said that overlap between a use code and generic
label precluded the use of a section viii statement. Beyond the facts in the Precedex example, the FDA
offers no guidance as to the kinds of overlaps considered to be minor and those that are not – forcing
ANDA applicants to guess again as to what the FDA may be thinking.
And the use code issues do not stop just here. Earlier this year, the FDA released for public comment its
proposed rules implementing the 2003 Medicare Modernization Amendments (i.e. better late than
never), which, among other things, proposes a new policy to address patent use code disputes. Under
existing law, a use code may be questioned by an ANDA applicant and the FDA will ask the brand for
clarification but ultimately it is the brand’s call. See 21 CFR 314.94(a)(12)(vii). If the ANDA applicant
wants to challenge a use code appearing in the Orange Book it can do so by filing a counterclaim in a
Paragraph IV Hatch-Waxman litigation pursuant to the statutory procedure added by Congress in 2003

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specifically to address use code abuses. However, under the FDA’s proposed regulations, if an NDA
holder is asked to clarify the scope of an Orange Book patent and it fails to respond to the FDA’s
request, the ANDA (or 505(b)(2)) application can be reviewed by the FDA “with deference” to the
applicant’s interpretation of the scope of the brand patent (i.e. the use code).
Where do matters stand for now? An ANDA applicant submitting a section viii statement is required to
guess correctly on how to carve out a patent use code or risk the loss of GDUFA fees and possible 180
exclusivity rights. But a minor overlap of the generic label and use code may still be allowed by the FDA
under circumstances that are not altogether clear. In the future, if a brand is non-responsive to a
request for use code clarification, the FDA may accept the ANDA applicant’s carve out notwithstanding
the use code listed in the Orange Book.
DSCSA Implementation: Product Tracing Requirements for Dispensers — Compliance
Policy Guidance for Industry
This guidance addresses the readiness of dispensers in the pharmaceutical distribution supply chain to
comply with the provisions in section 582 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21
U.S.C. 360eee-1(d)(1)) related to the exchange of transaction information, transaction history, and
transaction statements (product tracing information). For dispensers, requirements for the tracing of
products through the pharmaceutical distribution supply chain under section 582(d)(1) of the FD&C Act
go into effect on July 1, 2015.2
This guidance announces the FDA’s intention with regard to enforcement of the product tracing
information requirements under section 582(d)(1) of the FD&C Act. As described below, FDA does not
intend to take action against dispensers who, prior to November 1, 2015, (1) accept ownership of
product without receiving product tracing information, prior to or at the time of a transaction, as
required by section 582(d)(1)(A)(i) of the FD&C Act, or (2) do not capture and maintain the product
tracing information, as required by section 582(d)(1)(A)(iii) of the FD&C Act. Section IV of this guidance
provides further detail about the scope of this compliance policy and FDA’s expectations for dispensers
and trading partners involved in transactions with dispensers.

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Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM453225.pdf
Guidance Document - Submission of Risk Management Plans and Follow-up
Commitments
Effective Date: June 26, 2015
Guidance documents are meant to provide assistance to industry and health care professionals
on how to comply with governing statutes and regulations. Guidance documents also provide assistance
to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair,
consistent and effective.
Guidance documents are administrative instruments not having force of law and, as such, allow for
flexibility in approach. Alternate approaches to the principles and practices described in this
document may be acceptable provided they are supported by adequate justification. Alternate
approaches should be discussed in advance with the relevant program area to avoid the possible finding
that applicable statutory or regulatory requirements have not been met.
As a corollary to the above, it is equally important to note that Health Canada reserves the right to
request information or material, or define conditions not specifically described in this document, in
order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic
product. Health Canada is committed to ensuring that such requests are justifiable and that decisions
are clearly documented.
This document should be read in conjunction with the accompanying notice and the relevant sections of
other applicable guidance documents.
The complete guide is enclosed. Source: http://www.hc-sc.gc.ca/dhp-mps/pubs/medeff/_guide/2015-
risk-risques_management-gestion_plans/index-eng.php

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AUDIT FINDINGS - 483 Observations
Firm Name 483 Observation
Deseret Laboratories, Inc. -
March 27, 2015
Written production and process control procedures are not
followed in the execution of production and process control
functions.
Aurobindo Pharma, Ltd. -
March 5, 2015
Batch records lack complete details for operations
performed.
Sciegen Pharmaceuticals, Inc.
- Jan. 9, 2015
The responsibilities and procedures applicable to the
quality control unit are not fully followed.
Mallinckrodt, Inc. - Jan. 8,
2015
Drug product production and control records, are not
reviewed and approved by the quality control unit to
determine compliance with all established, approved and
written procedures before a batch is released or distributed.
Tarmac Products, Inc. - Jan. 8,
2015
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.
Quality Animal Care Mfg., Inc.
- March 25, 2015
There is no quality control unit.
Product Quest Manufacturing
LLC - Feb. 18, 2015
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.
Pharmaceutical Manufacturing
Research Services, Inc. - Jan.
20, 2015
Acceptance criteria for the sampling and testing conducted
by the quality control unit is not adequate to assure that
batches of drug products meet each appropriate
specification and appropriate statistical quality control
criteria as a condition for their approval and release.
Ortho Biologics LLC - Jan. 16,
2015
Approved procedure was not followed as established during
the evaluation and approval of current supplier.
University of Texas MD
Anderson Cancer Center -
Jan. 16, 2015
Periodic reports of non-alert adverse drug experiences
have not been submitted quarterly for an application which
was approved less than three years ago.
Celsus Laboratories, Inc. -
Nov. 14, 2014
Your firm's investigation into complaint #52 for low potency
in Sodium Heparin (Anti-Factor IIa), lot PH79112 was not
complete.

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Care-Tech Laboratories, Inc. -
March 24, 2015
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.
Applied Laboratories, Inc. -
Feb. 20, 2015
Laboratory controls do not include the establishment of
scientifically sound and appropriate test procedures
designed to assure that drug products conform to
appropriate standards of identity, strength, quality and
purity.
DPT Lakewood LLC - Feb. 6,
2015
Laboratory controls do not include the establishment of
scientifically sound and appropriate specifications and test
procedures designed to assure that the drug product
conforms to appropriate standards of identity, quality and
purity.
Wood's Pharmacy, Inc. - Jan.
15, 2015
Testing and release of drug product for distribution do not
include appropriate laboratory determination of satisfactory
conformance to the identity and strength of each active
ingredient prior to release.
Right Value Drug Stores, Inc. -
Dec. 12, 2014
Clothing of personnel engaged in the manufacturing and
processing of drug products is not appropriate for the duties
they perform.
Meridian Medical Technologies
- March 23, 2015
Batch production and control records do not include
complete information relating to the production and control
for each batch.
D.R. Pharmacy, Inc. - March 6,
2015
Testing and release of drug product for distribution do not
include appropriate laboratory determination of satisfactory
conformance to the identity and strength of each active
ingredient prior to release.
B. Braun Medical, Inc. - March
3, 2015
An NDA-Field Alert Report was not submitted within three
working days of receipt of information concerning
bacteriological contamination and significant chemical,
physical, or other change or deterioration in a distributed
drug product.
Long Pharmaceuticals, LLC -
Feb. 26, 2015
Changes to written procedures are not drafted, reviewed
and approved by the appropriate organizational unit and
reviewed and approved by the quality control.
Westwood Laboratories - Feb.
25, 2015
Testing and release of drug product for distribution do not
include appropriate laboratory determination of satisfactory
conformance to the identity and strength of each active
ingredient prior to release.
Blue Naturals, LLC - Feb. 4,
2015
There is no quality control unit.
Amgen Manufacturing Ltd. - The current procedures for the monitoring of the

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Jan. 23, 2015 environmental conditions in the drug-product aseptic
production and the drug-substance production areas do not
always establish/include and/or require sample collections
which could provide a more accurate and/or more thorough
assessment on the microbiological quality and/or condition
of the aseptic-filling operation and drug-substance
production areas and/or surfaces that are monitored as part
of these procedures.
Abbey Color, Inc. - Jan. 20,
2015
Investigations (CAPA's) conducted by the firm in response
to Out of Specification (OOS) results are not always
complete.
EU Non-Compliance Report
Polydrug Laboratories PVT. LTD., Ambernath, Maharashtra, India
Nature of non-compliance : Overall, 17 deficiencies were found, of which 5 Major consisting in:
- Customer complaints deliberately unregistered in the official logbook
- Storage of quality documents in an uncontrolled location, involving staff from QC, QA, maintenance
and production
- Deficient management of paper documents
- Deficient management of the computerised system
- Failure to address risks of cross contamination for APIs sent out to micronisation subcontractor.
The combination of these major deficiencies represents a critical deficiency leading to a potential risk
for the patient.
ZHUHAI UNITED LABORATORIES CO., LTD, China
Nature of non-compliance :
The company was not operating its aseptic manufacture operations in compliance with EU GMP Annex
1. This was evident from by the high number of observations regarding the aseptic manufacturing
facilities design, equipment, operations, environment monitoring and media fill validation. However,
the QA system of the company failed to notice these problems and therefore was considered weak and
inappropriately implemented.

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Detailed list of critical and major deficiencies is included in regulatory risk assessment
Health Canada Non-Compliance Report
Health Canada Non-Compliance Report: Pharmax Limited, Ontario Canada
GMP Inspection Report Card Summary
Establishment
Name
Reference
Number
Inspection
Start Date Type of Inspection Inspection Rating
Pharmax Limited 100302 2015-04-07 Good Manufacturing
Practices (GMP) -
Regular
Non-Compliant
Observation
Number Regulation Summary of Observation
1 C.02.015 - Quality
Control
 Quality oversight was lacking resulting in significant
GMP deficiencies.
2 C.02.013 - Quality
Control
 Inadequate practices/precautions to minimize
contamination or prevent mix-ups.
3 C.02.027 - Stability
 The distributor did not determine the stability of the
drug prior to its marketing.

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Observation
Number Regulation Summary of Observation
4 C.02.005 -
Equipment
 Purified water system not maintained or operated to
provide water of adequate quality.
5 C.02.014 - Quality
Control
 Master production documents were not maintained
by the importer of a drug.
 The importer of a drug fabricated, packaged/labelled
and tested at a foreign site did not meet the
requirements described in the Health Canada
document entitled Drug GMP Compl
6 C.02.007 -
Sanitation
 Inadequate practices/precautions to minimize
contamination or prevent mix-ups.
7 C.02.015 - Quality
Control
 All critical production processes have not shown to
produce consistent results.
8 C.02.011 -
Manufacturing
Control
 Periodic self-inspections were not carried out for all
aspects of the operation. Repeat observation.
9 C.02.015 - Quality
Control
 Deficiencies were noted with the change control
system to assure that all changes were properly

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Observation
Number Regulation Summary of Observation
documented, evaluated and approved by the quality
control department. Repeat observation.
10 C.02.015 - Quality
Control
 Deficiencies were noted with customer complaint
investigation and follow-up.
Summary of Observations
11 C.02.012 - Manufacturing
Control
 Deficiencies were noted with the written agreements
among the parties involved that addressed responsibilities
for the fabrication, packaging, storage and transportation
conditions and testing activities of drugs.
12 C.02.006 - Personnel
 Deficiencies were noted in the training program.
13 C.02.009 - Raw Material
Testing
 Expired raw materials were observed in the warehouse.
14 C.02.020 - Records
 Deficiencies were noted with documentation practices.

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15 C.02.015 - Quality Control
 Deficiencies were noted with the implementation of
guidelines put in place by the quality control
department to ensure that storage conditions would
maintain the quality and safe distribution of a drug.
FDA Warning letters
VUAB Pharma a.s., Czech Republic (WL: 320-15-10):
1. Failure to adequately investigate and resolve all quality-related customer complaints, and to
investigate other batches that may have been associated with specific failures.
Your quality unit released API with objectionable microbial contamination into distribution.
2. Failure to prevent unauthorized access or changes to data and to provide adequate controls
preventing data omissions.
failed to have proper controls in place to prevent unauthorized manipulation of your laboratory’s raw
electronic data.
Source: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm448433.htm
Attix Pharmaceuticals, Canada
1. Failure to package beta-lactam drug products, (including penicillin and non-penicillin beta-lactams)
and other drug products under appropriate conditions to avoid potential cross-contamination.
a. Your firm failed to use separate facilities to manufacture penicillins, non-penicillin beta-lactams, and
non-beta-lactam APIs.
b. Your firm increased the risk of cross-contamination by allowing personnel and materials to move
freely between beta-lactam and non-beta-lactam manufacturing areas.
2. Failure to transfer expiry dates received from the API manufacturer to your customers.

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Check your area for ….
 Is lab software validated?
 Is it password protected, with each user having an
individual password that is not shared with other
analysts?
 Is data backed up and able to be restored?
 Is there a disaster recovery plan?
 Is an audit tail being used?
 Can files be overwritten?
 Do calculations performed by software conform to the
company’s rounding procedures??
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80. PHARMA UPTODAY
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Regulations of the Month
Sec. 211.22 Responsibilities of quality control unit.
(b) Adequate laboratory facilities for the testing and approval (or rejection) of
components, drug product containers, closures, packaging materials, in-process
materials, and drug products shall be available to the quality control unit.
(c) The quality control unit shall have the responsibility for approving or rejecting all
procedures or specifications impacting on the identity, strength, quality, and purity of the
drug product.
(d) The responsibilities and procedures applicable to the quality control unit shall be in
writing; such written procedures shall be followed.
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