VOLUME: 16 - ISSUE: JUL 2015 |

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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

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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??

Few Pharma Uptoday topics can be accessed from our website

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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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· Data Integrity II - Chromatography data system (CDS) in Pharma

· Good chromatographic practices

· HPLC - Peak integration for chromatography

· Good Laboratory Practices for Pharmaceutical Quality Control Laboratories

· Laboratory Errors

· Understand the importance of each step to minimise Laboratory errors

· Sample preparation techniques of solid dosage forms

· Investigating aberrant potency values in Pharma Analysis

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