VOLUME: 15 - ISSUE: JUN 2015 |

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Inside this issue

3 News Uptoday 21 New Guidance 27 Audit Findings 483 Observations

EU Non Compliance Report

- RELONCHEM LIMITED, UK

Health Canada Non Compliance Report

- Health Canada Non-Compliance Report: Xenex Laboratories Inc - Health Canada Non-Compliance Report : CanadaDrugs.Com LP - Health Canada Non Compliance Report: Smiths Medical Canada

Ltd 33 Warning Letters

- Warning letter Absolute Pharmacy, LLC 4/27/15 (FLA-15-21) - Warning letter Vann Healthcare Services Inc 4/29/15 (CIN-15-

449139-18) 35 Regulations of the Month

- § 211.198 Complaint files. 21 CFR 211.198(b) - § 211.204 Returned drug products - Sec. 211.208 Drug product salvaging - Sec. 211.22 Responsibilities of quality control unit

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News Uptoday Novo Nordisk begins construction of $223m manufacturing plant in Denmark

Danish pharmaceutical firm Novo Nordisk has started construction of a new 7,500m² haemophilia

treatment manufacturing facility in Kalundborg, Denmark.

The company is investing DKK1.5bn ($223m) in this new facility, which is designed to produce active

pharmaceutical ingredients for NovoSeven and future products to treat haemophilia.

With the investment, 100 new production and engineering jobs will be created in Kalundborg, where the

company currently employs more than 2,800 people.

Novo Nordisk Product Supply executive vice-president Henrik Wulff said: "The investment in Kalundborg

underscores our long-term ambition to create and maintain jobs in Denmark.

"This year alone we expect Novo Nordisk will create about 250 new jobs in Kalundborg, and we are

always on the lookout for capable and highly skilled employees."

The new manufacturing facility is expected to be approved and fully operational in 2020.

Haemophilia is a bleeding disorder and people with it have either decreased, defective or absent

production of blood clotting protein.

For people with haemophilia, bleeds often occur in the joints, particularly knees and ankles, while they

can also occur in the muscles, soft tissues, gastrointestinal tract or even the brain.

FINAL WARNING FROM NPPA TO 59 PHARMA COMPANIES TO REGISTER ON IPDMS

The National Pharmaceutical Pricing Authority (NPPA) has developed in collaboration with the National

Informatics Centre, the Integrated Pharmaceutical Database Management System (IPDMS). The IPDMS

appears to be fully operational on NPPA’s website along with guidance to manufacturers on loading their

product and pricing information into the database. Today (May 1, 2015), NPPA has issued yet another

―Notice‖ regarding IPDMS, this time specifically highlighting 59 out of the top 100 pharma companies

who have not registered in the database while also informing Pharma Associations and their members

of their intention to launch the database shortly.

The idea behind the IPDMS is to facilitate on-line submission of pricing and other information that is

required to be submitted under Schedule II of the Drug Price Control Order, 2013 (DPCO 2013) Forms I

– V. With more timely information available via an online database, NPPA would be able to better

monitor price movements in the market and ensure companies’ compliance with the DPCO 2013. In

addition, NPPA may be able to lessen its reliance on third party databases such as IMS and Pharma

Trac that have come under criticism by companies for lacking complete information.

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The IPDMS was publicly announced on September 18, 2014 with registration open until October 31,

2014. One day before registration was to close, NPPA issued an extension for registration through

November 30, 2014. Another extension was granted on December 2, 2014 through December 31, 2014,

but this time the Notice made it clear that this would be the last extension. On December 30, 2014, the

Indian Drug Manufacturers Association (IDMA) submitted a letter to NPPA seeking another extension

and expressing concerns on loading voluminous amounts of data from excel sheets. This request was

also summarily denied on January 6, 2015. Notably, the January 6, 2015 communication to IDMA by

NPPA noted that 300 companies had already registered, which covered more than 20,000 formulation

packs that are currently under price control.

On May 1, 2015, the NPPA issued another Notice addressed to all ―Pharma Associations‖ giving a stern

warning to immediately register with the IPDMS. In this Notice, the NPPA states that out of the top 100

companies, 59 of them have not registered and the Notice lists these companies. Many of these 59

companies are household names in India and around the world such as Biocon, Alkem, Dr. Reddy’s,

Zydus Cadila, MSD Pharmaceuticals, Solvay, Janssen, Parke Davis, Sanofi, etc. The May

1st Notice also points out for the first time that NPPA will take appropriate action under provisions of

both the DPCO and its underlying source legislation, the Essential Commodities Act, 1955, as amended

without any further ―reference in the matter‖.

Without doubt, more than 59 companies throughout India have not registered with IPDMS. As of

January 2015, only 300 companies had registered. A recently issued report by the Parliamentary

Steering Committee (PSC) on Chemicals & Fertilizers, in its ―Demand for Grants‖ for the Department of

Pharmaceuticals noted that as of February 2015, 351 pharma companies have already registered and

449 pharma companies are in the process of registering with IPDMS, for a total of 800 companies.

Earlier in that same report, the PSC had stated that about 8,000 pharmaceuticals companies were

operating in India. Thus, only about 800 out of 8,000 pharma companies (or 10 percent) have registered

or are in the process of registering. Without all companies registering, irrespective of their overall market

share, the benefits of the IPDMS will be limited since price controls are calculated on all market prices.

So, why did NPPA single out these 59 companies? Is NPPA wishing to make an example of them,

thereby sending a message to the smaller and medium size companies? If so, will NPPA exercise its

authority under the DPCO 2013 and Essential Commodities Act?

If the NPPA decides to exercise its authority, what is the basis of its authority? Is the allegation that

companies have not complied with an Order issued under the DPCO 2013? Will NPPA be hard pressed

to use this as the grounds for a challenge since the original September 18, 2014 announcement of the

IPDMS was in the form of a ―Notice‖ and not an ―Order‖? Also, what will be the harm that NPPA is able

to demonstrate by lack of compliance by companies failing to register? If companies continue to provide

information in hard-copy form, will there be any harm, but for the cost of manual review by NPPA?

If recent history reveals anything, we can anticipate some type of administrative and/or court challenge

to the requirement for registration with IPDMS if NPPA decides to exercise the penalty provisions of the

Essential Commodities Act against companies failing to register with the system. Notably, the penalty

provisions allow for imprisonment in addition to fines.

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Perrigo takes over Mexican operations of Patheon for $34m

Irish over-the-counter (OTC) firm Perrigo has acquired the Mexican operations of US-based contract

pharmaceutical services company Patheon for $34m.

The acquisition further strengthens Perrigo's supply chain capabilities with the addition of softgel

manufacturing technology.

The transaction will also further solidify Perrigo's store brand leadership position in Mexico.

Perrigo chairman, president and CEO Joseph Papa said: "Perrigo has long desired to be a prime

manufacturer of softgel products and we believe the acquisition of Patheon's Mexican operations serves

as an ideal entry point into the space.

"Additionally, and importantly, we believe Perrigo is uniquely positioned to maximize the potential of the

business by leveraging our own Mexican operations to drive growth and value for our customers and

shareholders.

"This acquisition serves as yet another example of Perrigo's unwavering commitment to provide Quality

Affordable Healthcare Products to consumers around the world, and we look forward to further

executing on this mission."

The acquisition will broaden Perrigo's presence, product portfolio and customer network in Mexico.

Perrigo is also engaged in producing branded OTC products, generic extended topical prescription

products and receives royalties from multiple sclerosis drug Tysabri.

Baxter buys Sigma-Tau cancer drugs in $900m deal

Baxter International is shelling out $900 million on Sigma-Tau’s Oncaspar (pegaspargase) product

portfolio, in a move designed to strengthen its commercial foothold in the global oncology market.

Oncaspar is a first-line biologic used as part of a multi-agent chemotherapy regimen to treat the blood

cancer acute lymphoblastic leukaemia (ALL), currently pulling in sales of around $100 million a year.

The terms see Baxter gain access to the drug, as well as the investigational biologic calaspargase

pegol, which is also being developed for ALL, and an established oncology infrastructure with clinical

and sales resources.

The transaction shoud close in the third quarter, at which point the drugs will come under the reign of

Baxter’s biopharmaceuticals segment, expected to be spun out as Baxalta Incorporated by mid-year.

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Pfizer takes stake in AM-Pharma with takeover option

Pfizer has picked up a minority equity interest in AM-Pharma alongside an exclusive option to buy up the

remaining equity in the firm, in a deal potentially worth up to $600 million.

Pfizer can exercise its option on completion of a Phase II trial of AM-Pharma’s recAP, a potential first-in-

class therapy for Acute Kidney Injury (AKI) related to sepsis, results of which are expected in the second

half of next year.

Under the terms of the deal, the private Dutch biotech has bagged an $87.5-million upfront payment for

the minority equity interest and exclusive option, but stands to receive additional potential payments of

up to $512.5 million for the remaining equity and potential launch of any product resulting from the

agreement.

Further terms of the deal were not revealed.

Teva Completes Acquisition of Auspex Pharmaceuticals

Strengthens core CNS specialty business with high promise in movement disorder treatments; expected

to provide short and long-term value for Teva shareholders

Teva Pharmaceutical Industries Ltd., (NYSE:TEVA) announced today that the acquisition of Auspex

Pharmaceuticals, Inc. (NASDAQ: ASPX) has been completed through the successful tender offer for all

of the outstanding shares of common stock of Auspex at $101.00 per share in cash, representing total

consideration of approximately $3.2 billion in enterprise value and approximately $3.5 billion in equity

value. The acquisition is expected to enhance Teva’s revenue and earnings growth profile and

strengthen its core central nervous system franchise.

Auspex is an innovative biopharmaceutical company specializing in applying deuterium chemistry to

known molecules to create novel therapies with the potential for improved safety and efficacy profiles. Its

lead compound is SD-809 (deutetrabenazine) for the potential treatment of chorea associated with

Huntington’s disease, tardive dyskinesia, and Tourette syndrome. ―We believe that combining the

Auspex portfolio with our strong research and commercialization capabilities will unlock significant value

for Teva’s shareholders,‖ said Erez Vigodman, President and CEO of Teva. ―We are proud and excited

to continue to work to bring innovative treatments to the underserved movement disorder markets.‖

In April, data were presented on topline results of a Phase III study of SD-809 in Huntington’s in a

platform presentation at the American Academy of Neurology’s Annual Meeting. The compound has

been granted orphan drug status by the U.S. Food and Drug Administration and the NDA is expected to

be submitted in the second quarter of this year.

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―The opportunity to bring relief to the many patients who face the debilitating effects of movement

disorders and suffer from the effects of conditions such as chorea and tardive dyskinesia is greatly

needed and humbling,‖ said Michael Hayden, MD, PhD, Teva’s President of Global R&D and Chief

Scientific Officer. ―We are eager to continue the exciting work that the Auspex team has started, and

believe the portfolio is a natural fit for our development programs.‖

―Within Global Specialty Medicines, we have a rich history in building relationships with patients and

physicians to match treatments to those affected with CNS disorders,‖ said Rob Koremans, MD,

President and CEO of Global Specialty Medicines at Teva. ―People living with movement disorders and

those around them often need support and services beyond medication. We have the infrastructure,

existing strong relationships with neurologists, therapeutic expertise in CNS and passion in place to

assist them.‖

The tender offer expired at 12:01 a.m., Eastern Time, today, May 5, 2015. The depositary for the offer

advised Teva that, as of the expiration of the tender offer, a total of 24,889,292 shares were validly

tendered into and not validly withdrawn (not including 613,455 shares tendered pursuant to notices of

guaranteed delivery), representing approximately 77.7% of Auspex’s outstanding shares. The condition

to the tender offer that at least a majority of the outstanding shares of Auspex’s common stock be validly

tendered and not validly withdrawn prior to the expiration of the tender offer was thus satisfied and,

accordingly, all such validly tendered shares were accepted for payment. Teva will promptly pay for all

such shares in accordance with the terms of the tender offer.

Following the completion of the tender offer, Teva completed the acquisition of Auspex through a merger

effected under Section 251(h) of the General Corporation Law of the State of Delaware. As a result of

the merger, each share of Auspex that was not validly tendered in the tender offer (other than shares

held by any stockholder of Auspex who properly demanded appraisal of such shares under the

applicable provisions of Delaware law) was cancelled and converted into the right to receive the

same $101.00 per share in cash that will be paid in the tender offer. Also as a result of the merger,

Auspex became a wholly owned subsidiary of Teva, and shares of Auspex will cease to be traded on

the NASDAQ Global Market, effective later today.

About Teva

Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) is a leading global pharmaceutical

company that delivers high-quality, patient-centric healthcare solutions to millions of patients every day.

Headquartered in Israel, Teva is the world’s largest generic medicines producer, leveraging its portfolio

of more than 1,000 molecules to produce a wide range of generic products in nearly every therapeutic

area. In specialty medicines, Teva has a world-leading position in innovative treatments for disorders of

the central nervous system, including pain, as well as a strong portfolio of respiratory products. Teva

integrates its generics and specialty capabilities in its global research and development division to

create new ways of addressing unmet patient needs by combining drug development capabilities with

devices, services and technologies. Teva's net revenues in 2014 amounted to $20.3 billion. For more

information, visit www.tevapharm.com.

Teva's Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995:

This release contains forward-looking statements, which are based on management’s current beliefs

and expectations and involve a number of known and unknown risks and uncertainties that could cause

our future results, performance or achievements to differ significantly from the results, performance or

achievements expressed or implied by such forward-looking statements. Important factors that could

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cause or contribute to such differences include risks relating to: our ability to successfully integrate

Auspex and its lead product, SD-809, into our business; the possibility that we may not realize the

expected benefits and synergies from our acquisition of Auspex, including the transaction’s impact on

our revenue, earnings-growth profile and CNS franchise; future results of on-going or later clinical trials

for Auspex’s product candidates, including SD-809; our ability to develop and commercialize additional

pharmaceutical products; competition for our innovative products, especially Copaxone®(including

competition from orally-administered alternatives, as well as from potential purported generic

equivalents) and our ability to migrate users to our 40 mg/mL version; the possibility of material fines,

penalties and other sanctions and other adverse consequences arising out of our ongoing FCPA

investigations and related matters; our ability to achieve expected results from the research and

development efforts invested in our pipeline of specialty and other products; our ability to reduce

operating expenses to the extent and during the timeframe intended by our cost reduction program; our

ability to identify and successfully bid for suitable acquisition targets or licensing opportunities, or to

consummate and integrate acquisitions; the extent to which any manufacturing or quality control

problems damage our reputation for quality production and require costly remediation; increased

government scrutiny in both the U.S. and Europe of our patent settlement agreements; our exposure to

currency fluctuations and restrictions as well as credit risks; the effectiveness of our patents,

confidentiality agreements and other measures to protect the intellectual property rights of our specialty

medicines; the effects of reforms in healthcare regulation and pharmaceutical pricing, reimbursement

and coverage; governmental investigations into sales and marketing practices, particularly for our

specialty pharmaceutical products; adverse effects of political or economic instability, major hostilities or

acts of terrorism on our significant worldwide operations; interruptions in our supply chain or problems

with internal or third-party information technology systems that adversely affect our complex

manufacturing processes; significant disruptions of our information technology systems or breaches of

our data security; competition for our generic products, both from other pharmaceutical companies and

as a result of increased governmental pricing pressures; competition for our specialty pharmaceutical

businesses from companies with greater resources and capabilities; the impact of continuing

consolidation of our distributors and customers; decreased opportunities to obtain U.S. market

exclusivity for significant new generic products; potential liability in the U.S., Europe and other markets

for sales of generic products prior to a final resolution of outstanding patent litigation; our potential

exposure to product liability claims that are not covered by insurance; any failure to recruit or retain key

personnel, or to attract additional executive and managerial talent; any failures to comply with

complex Medicare and Medicaid reporting and payment obligations; significant impairment charges

relating to intangible assets, goodwill and property, plant and equipment; the effects of increased

leverage and our resulting reliance on access to the capital markets; potentially significant increases in

tax liabilities; the effect on our overall effective tax rate of the termination or expiration of governmental

programs or tax benefits, or of a change in our business; variations in patent laws that may adversely

affect our ability to manufacture our products in the most efficient manner; environmental risks; and

other factors that are discussed in our Annual Report on Form 20-F for the year ended December 31,

2014 and in our other filings with the U.S. Securities and Exchange Commission. Forward-looking

statements speak only as of the date on which they are made and we assume no obligation to update or

revise any forward-looking statement, whether as a result of new information, future events or otherwise.

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Torrent to acquire 100% stake in Zyg Pharma

Torrent Pharmaceuticals Limited (―Torrent‖) announced that it has signed a share purchase agreement

to acquire 100% stake in Zyg Pharma Private Limited (―Zyg Pharma‖), a company engaged in

manufacturing various dermatological formulations like creams, ointments, gels, lotions, solutions.

Zyg Pharma is part of the Encore Group, promoted by the Merchant family and is engaged into specialty

pharmaceutical business for over 50 years. The manufacturing facility is located at Pithampur, (Indore)

and is approved by various regulatory authorities including US FDA, TGA Australia. The company has

capabilities for on site development, analytical method development and QC laboratory with separate

areas for chemical, instrumental and micro sections.

In line with its strategy to diversify into new therapy segments, the acquisition will help Torrent to

strengthen its position in niche dermatological segment especially in the developed markets like US and

Europe. The company has been a manufacturing partner to several international companies in India and

it has also build a successful international business through partners in regulated markets as well as in

emerging markets.

Torrent would fund the acquisition through internal accruals.

The transaction has been approved by the Boards of Directors of both companies. The financial terms of

the transaction are confidential. The transaction closure is subject to customary closing conditions and

requisite regulatory and other approvals, and is expected to close by August 2015.

About Torrent Pharma

Torrent Pharma, with an annual turnover of over Rs.4200 crores is the flagship Company of the Torrent

Group. With many of its products ranking among the top 200 brands, Torrent continues to be at the

forefront of the Indian pharmaceutical industry. Torrent has a fully equipped Research Center,

employing almost 600 scientists, to support the company’s operations and product pipeline for both

domestic and overseas markets. The company’s manufacturing plants located at Indrad, Baddi & Sikkim

have facilities to produce Formulations and Bulk drugs. The plants are approved by authorities from

various regulated and semi regulated markets like US, UK, Brazil, Germany, Australia and South Africa.

High Level EU Document Calls for Better Supply Chain Oversight and Data Integrity Controls

The HMA (Heads of Medicines Agencies) and the EMA (European Medicines Agency) have issued a

high level EU document in order to plan the strategy of the EU regulators for the upcoming 5 years. On

27 March 2015 a consultation draft entitled "EU Medicines Agencies Network Strategy to 2020" has

been published. This document comprises a lot of information about potential improvement in marketing

authorisation procedures and controls but also contains some interesting GMP information.

HMA and EMA recognize the need for a tight control of suppliers located outside the EU. Today 80% of

the APIs used for the manufacture of medicinal products in Europe are manufactured at production sites

outside the EU (a majority in Asia, e.g. India and China). In addition the two regulatory bodies are

concerned about out of compliance situations as found in several sites in Asia. Especially failures to

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establish a system and to maintain the data integrity of GMP information is critical for patient safety. The

report says: "The complexity of international supply chains present risks of errors and occasionally

counterfeits or product diversion. Key to ensuring supply chain integrity is to make sure that all steps in

the supply chain are adequately controlled and monitored, both at an individual company level and

through appropriate regulatory oversight including inspections and audits.....Closely linked to these

challenges is the need to ensure the integrity of the data on which regulatory decisions about medicines

are based."

According to the report the HMA and EMA "will ensure that all suspicions of problems with data integrity

are thoroughly investigated working closely with other international partners where these data may have

been generated or used."

In parallel initiatives have been introduced by Member State authorities as well. For example the MHRA

just recently published their expectation on GMP Data Integrity. It is likely that other agencies in Europe

will follow this approach. Also US FDA intends to define their expectation on Data Integrity in a Guideline

(please read more about the new FDA inspection focus on data integrity)

Generic drugs to be available at rates fixed by state goverment: Surjit Kumar Jayani

Essential and generic drugs will be available in Punjab only at rates fixed by the government, state

Health Minister Surjit Kumar Jayani today said.

Jayani directed drug inspectors and chemists to ensure the availability of essential and generic dugs

only at the rates fixed by the government, an official spokesman said here.

Issuing fresh guidelines to the drug inspectors, the Minister said that various steps have been taken by

the Punjab government to improve health services and to check the ever increasing prices of the generic

medicines.

He reiterated the strong resolve of the government to ensure quality healthcare system.

Jayani directed the chemists to make the essential medicines available according to the guidelines of

the National Pharmaceutical Pricing Authority (NPPA) which has recently issued notification fixing the

uniform prices of the generic and essential medicines across the country.

According to the latest guidelines the prices of the medicines would be reduced to upto 50 per cent, the

minister said.

He asked the drug inspectors to conduct surprise checks on drug retailers and wholesalers to ensure

the accessibility of essential medicines according to the laid down guidelines of the NPPA.

The minister said that regarding price control of drugs a nexus between drug manufacturers, drug

inspectors, chemists, medical representatives and doctors was essential to be broken.

He termed the fleecing of the patients by the chemists in the name of expensive medicines, a "daylight

robbery of poor patients by some large scale and small scale manufacturers, especially by non-

scheduled generic drug manufacturers."

He said that unfortunately the manufacturers have made it a habit to display an inflated MRP on the

labels of the generic drugs, blown up by several times more than their original costs.

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Safety monitoring of medicines: EMA to screen medical literature for 400 active

substance groups

New service will improve safety monitoring of medicines and simplify

pharmacovigilance activities for companies

The European Medicines Agency (EMA) has published the list of active substances and a reference to

the journals that will be covered by its new medical literature monitoringservice. This service will start

with a limited number of active substances on 1 July 2015 and will be fully rolled out in September 2015.

A guide, a training video and a document detailing the inclusion and exclusion criteria to be used when

screening the literature are also available on a dedicated webpage.

Medical literature is an important source of information on suspected adverse reactions reported on

medicines. The European Union's (EU) pharmacovigilance legislation has given EMA responsibility for

the monitoring of selected medical literature for a defined list of active substances used in medicines

and for entering identified reports of suspected adverse reactions in EudraVigilance, the EU adverse

drug reaction collection and management system.

This initiative aims to improve the safety monitoring of medicines by enhancing the quality and

consistency of data reported in EudraVigilance. It is provided as a service to industry which, for the

active substances and literature covered by the EMA activities, will no longer be obliged to enter the

information on suspected adverse reactions intoEudraVigilance. Individual cases of suspected adverse

reactions found in the literature will be made available to marketing-authorisation holders so they can

include them in their safety databases and meet their reporting obligations outside the European

Economic Area.

A total of 400 active substance groups will be monitored by EMA, in particular substances that are

contained in a high number of medicinal products, and over 4,000 companies will benefit.

Following a public procurement procedure, EMA has selected a contractor to support the Agency in the

operation of this service.

Companies should consult the documents published today to find out whether their products are

included in the service.

As of 1 July 2015, the service will cover the top 50 chemical active substance groups (ID 1 to ID 50)

which are listed in the document published today. Companies with medicines containing one of these

active substances will benefit from the EMA service from 1 July and will need to adapt their processes

by that date. All the other substances, including the herbal active substances that are listed, will be

included in the EMA service as of September 2015.

EMA will send updates on the implementation of its medical literature monitoring service to the qualified

persons for pharmacovigilance as well as to pharmaceutical industry organisations.

The dedicated webpage will also be regularly updated.

FDA Initiates OpenFDA Challenge to Bolster Public Health

The FDA is inviting web developers to tap into publicly available data on adverse drug events, recalls

and labeling and assess their impact for drug research.

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The OpenFDA Developer Challenge, announced Tuesday, offers a choice of two options: to determine if

an algorithm could be used to automatically identify spikes in adverse events or to develop a model to

categorize adverse event language in the warning sections of structured product labeling.

Developers are encouraged to Tweet @openFDA with their proposal using #openFDAchallenge, and

then submit a link at www.reddit.com/r/openfda when they are ready to share their solution. The public

will be able to vote and comment on their favorites.

A second Consumer Challenge is scheduled to kick off the week of May 25.

OpenFDA was launched in June 2014 to facilitate public access to reports on adverse drug events and

medication errors.

Information on the challenge is available at https://open.fda.gov/. — Jonathon Shacat

Judge Dismisses Four of Five Drugmakers From Chicago Opioid Lawsuit

A federal judge has dismissed Teva, Johnson & Johnson, Endo Health Solutions and Actavis from a

lawsuit filed by the city of Chicago alleging use of deceptive marketing to sell opioid-based drugs. Two

complaints against a fifth company, Purdue Pharma, will proceed.

The four drugmakers, however, may not be in the clear, as Judge Jorge L. Alonso gave the city 30 days

to amend the dismissed claims. If it fails to do so, those claims will be dismissed with prejudice.

The claims against Purdue, maker of Oxycontin (oxycodone) and Dilaudid (hydromorphone), stem from

charges in 2005 that the drugmaker made misstatements about opioids on its websites to persuade

Chicago doctors to prescribe the drugs and consumers to take them. Purdue attorney Richard Silbert

says the company is pleased that Alonso dismissed nine of the 11 claims against the company.

Chicago’s suit, City of Chicago v. Purdue Pharma, et al, alleges that the five companies created,

supported and directed a network of front groups to promote the treatment of chronic pain using opioids

over other alternatives.

Teva manufactures Actiq (fentanyl) and Fentora (fentanyl buccal tablets); J&J makes Duragesic

(fentanyl transdermal system) and Nucynta (tadentadol extended-release tablets); Endo makes Opana

(oxymorphone), Percodan (aspirin and oxycodone) and Percocet (acetaminophen and oxycodone); and

Actavis makes Kadian (morphine sulfate extended-release) and generic versions of Duragesic and

Opana.

Chicago provides prescription drug coverage to its employees under the city’s self-insurance health

plans.

The lawsuit also accuses the companies’ marketing campaigns of promoting doctors who favor opioid

use to treat chronic pain as experts. In return for their support of opioids, the doctors received money,

prestige, recognition, research funding and publishing opportunities which allowed them to exert even

more influence in the medical community, the complaint says.

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In dismissing claims against the four drugmakers, Alonzo said Chicago had failed to produce sufficient

information to go forward — specifically, that the city hadn’t named any doctor or consumer affected by

Actavis’ alleged misrepresentations and that it had not explained what editorial control Teva, Endo and

J&J had over materials they allegedly sponsored or funded.

EMA Will Monitor 400 Drug Substances for Adverse Reactions

The EMA plans to screen medical literature to identify suspected adverse reactions with 400 active

substances authorized in the EU.

The project will kick off July 1 with the monitoring of 50 substances and will be rolled out fully by

September. The 400 targeted substances were chosen because of the frequency with which they

appear in authorized medicines, the EMA says. Data gleaned from the effort will be entered in the

EudraVigilance database.

The project is expected to benefit more than 4,000 companies by relieving them of the job of monitoring

the medical literature for these 400 substances. They will, however, still need to monitor the literature for

side effects related to other drugs.

Other expected benefits of the project include enhancing the quality and consistency of adverse event

data, reducing the number of duplicate reports and conserving industry resources, the EMA says.

The project is in line with guidance from Good Pharmacovigilance Practices Module VI.

PDUFA Reauthorization Process Begins

Reauthorization of the Prescription Drug User Fee Act is officially underway with the FDA’s

announcement of a July 15 public meeting to assess the current PDUFA V.

In particular, the FDA wants to know how PDUFA might be tweaked to improve the efficiency and

effectiveness of the drug review process. Stakeholder presentations should focus on process

enhancements and funding issues, rather than policy issues, aFederal Register notice says.

PDUFA V is set to expire in September 2017, and the sixth iteration will set user fees and review goals

for fiscal years 2018 to 2022.

The meeting will be held at the FDA’s White Oak Campus. To register, go

tohttp://pdufapublicmeeting.eventbrite.com. The registration deadline is June 30.

Electronic comments may be submitted at www.regulations.gov through Aug. 15. Read the Federal

Register notice at www.fdanews.com/05-13-15-PDUFA.pdf.

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Why Does ANVISA Embrace GS1 Standards, Except The Serial Number?

In Brazil, the National Agency of Sanitary Surveillance(ANVISA) has built their pharma serialization

regulation around GS1 standards. They embrace the GS1 Datamatrixand GS1-128, both encoded

with GS1 Application Identifiers(AI) and using GS1 Human Readable Interpretation (HRI) (see my

previous essay, ―The ANVISA Unique Medicine Identifier (IUM) on Drug Packages‖, for my thoughts on

HRI), the GS1 Global Trade Item Number (GTIN) and the GS1 Serial Shipping Container Code (SSCC)

to be specific. But there is one GS1 standard they steer clear of: the GS1 serial number. Why is that?

I’m not sure, but I think I have a pretty good theory. See if you agree.

But first, let’s review how GS1’s serial numbers are defined (see the GS1 General Specifications for

more details and specifics). GS1 serial numbers can be any length, up to 20 characters. The allowed

character set includes 82 distinct characters, including digits 0-9, the upper and lower case English

alphabet, and a set of 20 symbols and punctuation characters. Most applications, trading partners and

regulations limit the serial numbers used within their closed domain to something shorter and often limit

the allowed character set by written agreement or guidance. But the feature of GS1 serial numbers

most pertinent to this discussion is that they must always refer to a specific GS1 GTIN. That is, any

reference to a GS1 serial number without including its associated GTIN is, by definition, totally

ambiguous and meaningless.

WHY DOES THAT NOT APPEAL TO ANVISA?

ANVISA wants the serial number (held within AI 21 in the barcode) to be unique across all GTINs

registered by the registrant, not just the one GTIN referenced along with it on the product. See the

difference? GS1 says the serial number must be unique only for that GTIN, but ANVISA says serial

numbers used in their supply chain must be unique to the manufacturer (more accurately,

the registration holder). That really complicates things for larger manufacturers, inside and outside

Brazil, because it means they have to coordinate the serial number assignment across all of their

products that are targeted for the Brazilian market. For large multi-national corporations, that could

involve dozens—perhaps hundreds—of packaging facilities around the globe and include a wide

diversity of products.

I originally thought this was just a simple mis-interpretation of GS1’s General Specifications by ANVISA,

but now that I better understand their regulation, it makes better sense. The serial number assigned to

the package is not relative to the GTIN, despite the use of AI 21. (Notice that the GTIN is not part

of the Unique Medication Identifier, or IUM.) Instead, the serial number (which is part of the IUM) is

relative to the holder of the ANVISA Medication Registry Number (AMRN) for the drug (also part of the

IUM).

The AMRN, by its definition, will indicate to ANVISA which company and product the serial number is

referencing, much like the GTIN would, but the company referenced in the registration might not be the

manufacturer. It could be an importer instead (see RDC No- 54, 10 December 2013, Chapter I, Article

2). And if ANVISA regulations allow, multiple importers might register and import the same product with

the same manufacturer’s GTIN. To keep straight which company is responsible for each set of imported

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packages, the serial number is unique across all products registered with ANVISA by the specific

registration-holder.

Of course, most multi-national companies import their own product so this will likely be a technical

hardship for those companies when assigning serial numbers to their drugs packaged for the Brazil

market. But, perhaps a bigger hardship for those companies might be that this technical approach

seems to enable parallel import of pharmaceuticals, if ANVISA regulations allow it.

New York Introduces Pharmaceutical Cost Transparency Bill

New York is the latest state to introduce a ―pharmaceutical cost transparency act,‖ following five

others—California, Oregon, Massachusetts, North Carolina, and Pennsylvania. Like the bills before it,

New York would require pharmaceutical manufacturers to submit a report to the state outlining the total

costs of the production of certain expensive drugs, with the information to be published on a public

website.

Much has been written in just the last few weeks about various state initiatives to require drug

manufacturers to detail the costs spent on high-priced products. A New York Times article

entitled Runaway Drug Prices, and an LA Times piece were just a number of recent examples, written

primarily in support of these laws. In fact, the introduction to the NY bill specifically references the New

York Times article as justification for drug cost transparency.

New York’s Pharmaceutical Cost Transparency Act of 2015

New York Senate Bill 5338 is sponsored by state senator Ruben Diaz (D) and introduced May 13. The

bill states that each manufacturer of a prescription drug, made available in New York, that has a

wholesale acquisition cost of $10,000 or more annually or per course of treatment would have to file a

report that includes:

The total costs of the production of the drug, including:

· (1) The total research and development costs paid by the manufacturer, and separately,

the total research and development costs paid by any predecessor in the development of the

drug.

· (2) The total costs of clinical trials and other regulatory costs paid by the manufacturer,

and separately, the costs paid by any predecessor in the development of the drug.

· (3) The total costs for materials, manufacturing, and administration attributable of the

drug.

· (4) The total costs paid by any entity other than the manufacturer of predecessor for

research and development, including any amount from federal, state, or other governmental

programs or any form of subsidies, grants, or other support.

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· (5) Any other costs to acquire the drug, including costs for the purchase of patents,

licensing or acquisition of any corporate entity owning any rights to the drug while in

development, or all of these.

· (6) The total marketing and advertising costs for the promotion of the drug directly to

consumers, including, but not limited to, costs associated with direct to consumer coupons and

amount redeemed, total marketing and advertising costs for promotion of the drug directly or

indirectly to prescribers, and any other advertising for the drug.

The report also must contain:

· A cumulative annual history of average wholesale price and wholesale acquisition cost

increases for the drug (expressed as percentages), including the months each increase in each

category, average wholesale price, and average wholesale acquisition cost took effect.

· The total profit attributable to the drug as represented in total dollars and represented as

a percentage of the total company profits that were derived from the sale of the drug.

· The total amount of financial assistance the manufacturer has provided through patient

prescription assistance programs, if available.

New York would require all the various pricing information be itemized and documented by the

manufacturer, and audited by a fully independent third-party auditor prior to filing May 1 of each year.

GVK Biosciences: European Medicines Agency confirms recommendation to suspend medicines

over flawed studies

Medicines considered critically important for patients to remain available

The European Medicines Agency (EMA) has confirmed its recommendation to suspend a number of

medicines for which authorisation in the European Union (EU) was primarily based on clinical studies

conducted at GVK Biosciences in Hyderabad, India. This is the outcome of a re-examination requested

by marketing authorisation holders for seven of the medicines concerned.

EMA’s Committee for Medicinal Products for Human Use (CHMP) had adopted its original

recommendation in January 2015 following an inspection of GVK Biosciences’ site at Hyderabad by the

French medicines agency (ANSM) that raised concerns about how GVK Biosciences conducted studies

at the site on behalf of marketing authorisation holders.

The inspection revealed data manipulations of electrocardiograms (ECGs) during the conduct of some

studies of generic medicines, which appeared to have taken place over a period of at least five years.

Their systematic nature, the extended period of time during which they took place and the number of

members of staff involved cast doubt on the integrity of the conduct of trials at the site generally and on

the reliability of data generated.

During the re-examination, the CHMP concluded that concerns about reliability of the clinical studies

remain and therefore maintained its recommendation of January 2015 to suspend medicines for which

no supporting data from other studies were available. This is with the exception of one medicine

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included in the re-examination for which concerns about studies were addressed. This medicine is now

no longer recommended for suspension.1

As a result of the CHMP’s January 2015 opinion and the re-examination, around 700 pharmaceutical

forms and strengths of medicines studied at the Hyderabad site remain recommended for suspension.

For around 300 other pharmaceutical forms and strengths, sufficient supporting data from other sources

had been provided; these medicines will therefore remain on the market in the EU.

The updated list of medicines for which the CHMP recommends suspension is available on the EMA

website.

The CHMP noted that there is no evidence of harm or lack of effectiveness linked to the conduct of

studies by GVK Biosciences at Hyderabad. Some of these medicines may remain on the market in

some countries if they are of critical importance for patients because alternatives cannot meet patients’

needs.

The decision on whether a medicine is critical for patients lies with the national authorities of EU

Member States depending on the situation in their country. For medicines that are considered critical,

companies are given 12 months to submit additional data.

EMA and national authorities work closely with international partners to ensure that studies underpinning

marketing authorisations in the EU are carried out to the highest standards and that the companies

involved comply fully with all aspects of Good Clinical Practice (GCP).

The CHMP’s recommendation will now be sent to the European Commission for a legally binding

decision. This decision will apply to all Member States irrespective of whether or not they have taken

interim measures to suspend medicines.

Information to patients and healthcare professionals

A number of medicines are being considered for suspension in EU countries following concerns about

how studies had been conducted at GVK Biosciences’ site in Hyderabad, India. Patients and healthcare

professionals are advised of the following:

There is no evidence of harm or lack of effectiveness with any of the medicines linked to studies

conducted by GVK Biosciences.

Some medicines considered critical for patients will remain on the market in some countries

pending the submission of new data.

National authorities in the EU will consider how critical individual medicines are in their countries

and make final decisions on whether to suspend or allow them to remain available, while new data

are generated.

Patients should continue to take their medicines as prescribed and contact their doctor or

pharmacist if they have any questions.

GMP clearance application process improvements

The TGA has experienced a significant increase in the total number of GMP Clearance Applications,

from approximately 2500 in 2010 to more than 4000 in 2014/2015. This has placed significant pressure

on TGA's existing resources, as a result of which we are currently not able to consistently meet our

target timelines.

To improve TGA's ability to meet demand we are reforming our processes. Our process reforms include

the collection of performance data which will enable us to better understand inefficiencies in our

processes. This information will be used to inform consultation with stakeholders.

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In the interim please ensure that all required information, as prescribed in the Australian Regulatory

Guidelines, Good Manufacturing Practice (GMP) Clearance for Overseas Manufacturers, 17th Edition, is

provided at time of lodgement, and can be easily identified.

Over the coming months we will be providing further updates on progress on this web site and through

the TGA Industry Working Group on GMP.

Source: http://www.tga.gov.au/

AMR a development challenge, not just a health security risk: India

India today said that the issue of anti-microbial resistance (AMR) should be seen holistically as a

"development challenge" instead of interpreting it narrowly as a health security risk.

"We believe that AMR should be seen from a broader perspective as a development challenge rather

than limiting it to a health security risk," India said during a debate on the draft global action plan on

AMR at the 68th World Health Assembly (WHA).

"Emphasis should be on raising awareness, infection prevention, promoting rational use of antibiotics

and addressing the needs of developing countries in strengthening access to health care facilities,

promoting availability and affordability of existing and new antibiotics, diagnostics and vaccines," India

said.

Developing countries and health activists have been concerned about resources for implementing AMR

plans particularly, affordable, point of care diagnostics to inform health practitioners and veterinarians of

the susceptibility of pathogens to available antibiotics.

The draft in its current form emphasises surveillance but doesn't mention any financial commitment

crucial for developing countries to implement the plans, they have argued.

AMR can develop in human and animal health as well as through food and agriculture sectors.

WHO has warned of a "post-antibiotic era" where common infections could become difficult to treat due

to the overuse or misuse of antibiotics and other microbial medicines.

All member states are expected to have in place, within two years of the endorsement of the draft action

plan by WHA, national action plans on AMR aligned with the global plan.

India also pointed out that there is not only a need to accelerate R&D for new antibiotics since no new

class of antibiotics has been developed in the last 30 years but also for the global health body to ensure

the affordability of new antibiotics.

Currently, most major pharmaceutical companies have stopped research in development of new

antibiotics; a situation described by WHO's Consultative Expert Working Group on Research and

Development, as a "serious market failure."

India had in January called for de-linking the cost of investment in R&D from the volume of sale. In the

same meeting, they had also indicated the role of pharmaceutical industries in unethical marketing

practices that may lead to overdose in antibiotics -- which the draft global action plan on AMR does not

address.

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"All five objectives identified in the AMR should be simultaneously pursued with equal emphasis and

priority," India stated and requested the Chair of the Assembly for further consultations before the

resolution is adopted.

The five objectives mentioned are "whole-of-society engagement, prevention first, access not excess,

sustainability, incremental targets for implementation."

In May 2014, the 67th WHA had adopted a resolution to draft a global action plan to combat anti-

microbial resistance, including antibiotic resistance, to be submitted in this WHA.

Australian eCTD submissions, version 3.0

We have finalised the specification for the Australian electronic Common Technical Document (eCTD)

format submissions.

In late 2014, the TGA commenced a pilot of electronic Common Technical Document (eCTD) format

submissions using Version 0.9 of the Australian eCTD Module 1 and Regional Specification. As a result

of experience gained during the pilot and feedback provided during the consultation, the TGA has

developed the final version of the Australian eCTD specification:

Australian eCTD specification: Module 1 and regional information, Version 3.0

Australian eCTD regional specification and validation criteria 3.0 (Microsoft Excel,5.74Mb)*

Timeline

Submissions in version 3.0 of the eCTD format will be valid from 1 June 2015 onwards.

Submissions in version 0.9 of the eCTD specification will be valid up until 31 December 2015. Applicants

submitting after this date must use version 3.0 of the specification as it will not validate.

Australian eCTD file downloads

The eCTD XML schema and related files are available from http://apps.tga.gov.au/downloads/(link is

external) and allow the possibility of automated access by eCTD publishing tools.

o Australian regional backbone schema for module 1 (xsd,12kb)

o Style sheet for Australian regional backbone (xsl,28kb)

o W3C schema for XLink1.1 (xsd,10kb)

o W3C schema for XML namespace (xsd,6kb)

o Style sheet for the code files (xsl,3kb)

o Codes and defined lists for Regulatory Activity Lead (xml,1kb)

o Codes and defined lists for Sequence Description (xml,4kb)

o Codes and defined lists for the Sequence Type (xml,6kb)

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Terminology

Quality – A measure of a product’s or service’s ability to satisfy the customer’s

stated or implied needs.

Quality Unit – A group organized within an organization to promote quality in

general practice.

Quality Assurance – Proactive and retrospective activities that provide confidence

that requirements are fulfilled.

Quality Control – The steps taken during the generation of a product or service to

ensure that it meets requirements and that the product or service is reproducible

Quality Management – Accountability for the successful implementation of the

quality system

Quality Objectives – Specific measurable activities or processes to meet the

intentions and directions as defined in the quality policy

Quality Plan – The documented result of quality planning that is disseminated to

all relevant levels of the organization

Quality Planning – A management activity that sets quality objectives and defines

the operational and/or quality system processes and the resources needed to fulfill

the objectives

Quality Policy – A statement of intentions and direction issued by the highest level

of the organization related to satisfying customer needs. It is similar to a strategic

direction that communicates quality expectations that the organization is striving to

achieve.

Quality System – Formalized business practices that define management

responsibilities for organizational structure, processes, procedures, and resources

needed to fulfill product/service requirements, customer satisfaction, and continual

improvement.

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New Guidance Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for

Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification

System Guidance for Industry

This guidance provides recommendations for sponsors of investigational new drug applications (INDs),

and applicants that submit new drug applications (NDAs), abbreviated new drug applications (ANDAs),

and supplements to these applications for immediate-release (IR) solid oral dosage forms, and who wish

to request a waiver of in vivo bioavailability (BA) and/or bioequivalence (BE) studies. These waivers are

intended to apply to: (1) subsequent in vivo BA or BE studies of formulations after the initial

establishment of the in vivo BA of IR dosage forms during the IND period, and (2) in vivo BE studies of

IR dosage forms in ANDAs.

Guidance for Industry: Providing Regulatory Submissions in Electronic Format —Certain Human

Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications

Guidance for Industry

Under section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), at least 24 months

after the issuance of a final guidance document in which the Food and Drug Administration (FDA) has

specified the electronic format for submitting submission types to the Agency, such content must be

submitted electronically and in the format specified by FDA.3 This guidance and the technical

specification documents it incorporates by reference4 describe how sponsors and applicants must

organize the content that they submit to the Agency electronically for all submission types under section

745A(a) of the FD&C Act. In addition to this guidance and existing technical specification documents,

further and more detailed technical instructions will be included in a separate eCTD technical

conformance guide.

ECA and PQG publish Chapter 6 of the interpretation of the EU GDP Guideline

The ECA Foundation and the Pharmaceutical Quality Group (PQG) have been working on the

interpretation of different chapters of the EU GDP Guideline. The interpretation of five chapters have

been published already. The following 5 Guidance chapters on the EU GDP Guideline are available:

Chapter 1: Quality Management

Chapter 9: Transportation (also contains a template for a Technical Agreement)

Chapter 7: Outsourced Activities

Chapter 2: Personnel

Chapter 5: Operations

Now the group has finalized the work on chapter 6 - Complaints, Returns, Suspected Falsified Medicinal

Products & Medicinal Product Recalls. Chapter 6 of the EU GDP Guideline requires that all complaints,

returns, suspected falsified medicinal products and recalls must be recorded and handled carefully

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according to written procedures. Some returned medicinal products might be released for resale. The

handling should be performed only after an assessment of the returned medicinal products. The

approval should be made by the Responsible Person (RP). Also complaints must be handled based on

a written procedure and all details of each complaint must be recorded. Finally, the identification and

handling of Falisified Medicinal Products are also defined in chapter 6. The ECA/PQG Guidance

document provides information on how to implement the requirements.

You will find chapter 6 and all other GDP Guidance chapters in the members area of the GDP Group

Webpage.

PIC/S takes over new Annex 15 on Validation/Qualification

Mid of April the Pharmaceutical Inspection Co-operation Scheme (PIC/S) has taken over the revised

Annex 15 of the EU GMP Guide on Validation and Qualification in their GMP Guide. We reported about

the Annex 15 revision in detail. The Annex 15 takeover by PIC/S was expected, but is yet interesting as

now the new requirements with regard to validation and qualification will also be applicable in non-EU

countries - for instance in Canada, Australia, Taiwan and Argentina.

Similar to the EU Annex 15 the document becomes effective on 1 October 2015.

Please see the PIC/S website for the Guide to Good Manufacturing Practice for Medicinal Products -

Annex 15.

Australian regulatory guidelines for complementary medicines (ARGCM)

The Australian regulatory guidelines for complementary medicines (ARGCM) provide information for

manufacturers, sponsors, healthcare professionals and the general public on the regulation of

complementary medicines in Australia.

If you want to supply a complementary medicine in Australia, you may choose to employ a regulatory

affairs consultant (for a list of consultants, refer to theComplementary Medicines Australia,(link is

external) the Australian Self Medication Industry(link is external) and the Association of Therapeutic

Goods Consultants(link is external)).

Contents

Introduction

Part A: General guidance on complementary medicine regulation in Australia

Part B: Listed complementary medicines

Part C: New complementary medicine substance evaluation

Part D: Registered complementary medicines

Additional guidance material

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EMA Issues New Guideline on Gene Therapy

The European Medicines Agency (EMA) is seeking feedback on a new draft guideline aimed at clarifying

the scientific evidence necessary to support the authorization of new gene therapies.

Background

Gene therapy works by modifying a patient's genes to correct for genetic issues. Researchers have

been studying gene therapy for the past 30 years, but few products have reached advanced stages of

development. Because so few gene therapies have been submitted for authorization, regulators haven't

yet worked out how best to assess them.

In Europe, gene therapies are regulated as advanced therapy medicinal products (ATMPs)

under Regulation (EC) No. 1394/2007, and are further defined in Part IV of Annex I to Directive

2001/83/EC. Thus far, EMA has only authorized a single gene therapy, Glybera, which treats a rare

condition called lipoprotein lipase deficiency (LPLD).

Regulatory Challenges

As the first authorized gene therapy, Glybera's regulatory path was fraught with challenges. Speaking

to Reuters, Tomas Salmonson, then acting chairman of EMA's Committee for Medicinal Products for

Human Use (CHMP) said EMA's "established ways of assessing the benefits and risks of Glybera were

challenged by … uncertainties associated with data provided."

Glybera was initially given a negative opinion by EMA's Committee on Advanced Therapies (CAT), but

after several reexaminations and a request for review by the European Commission (EC), it was

eventually authorized under "exceptional circumstances." To maintain Glybera's authorization, its

sponsor was required to provide EMA with follow-up data each year and establish a patient registry for

long-term monitoring.

Eventually, Amsterdam Molecular Therapeutics (AMT), Glybera's original developer, was liquidated and

its assets sold to another company, UniQure. In a circular sent to its shareholders, AMT cited "regulatory

setbacks" as a factor in its dissolution.

In April, Regulatory Focusreported that the German Federal Joint Committee (G-BA) had postponed its

benefit assessment of Glybera after EMA's rapporteur for Glybera said the therapy lacked efficacy.

Since then, CAT has maintained its positive opinion for Glybera, though G-BA announced today it found

the additional benefits of Glybera to be "unquantifiable."

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New Guideline

EMA's draft Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal

products is intended to answer questions that might arise during the development of a gene therapy.

EMA says it used the lessons learned from its recent experience reviewing gene therapies and providing

scientific advice for others in development to develop the draft guideline.

According to the agency, the guideline should help developers of gene therapies that are unfamiliar with

regulatory submissions to meet the agency's requirements. Additionally, the draft guideline follows the

order of the common technical document (CTD), which should make it easier for companies to follow

since they are required to use the CTD when submitting for marketing authorization.

The three main sections of the 42-page document outline considerations companies should take when

designing non-clinical and clinical programs, as well as quality considerations that should be made in

designing and manufacturing the product itself.

Because gene therapies rely on a biological vector (viral, bacterial, cellular), companies must carefully

consider the chosen vector's properties, and maintain "full documentation of the [vector's] origin …

history and biological characteristics." Additionally, EMA recommends vectors be "produced from well-

characterized bacterial or virus seeds and/or cell banks," which in turn should be qualified and controlled

to protect from contamination.

For non-clinical programs, companies should pay careful attention to "potential in vivo effects of the

transgene or recombinant nucleic acid sequences, the vector backbone … and of the excipients

including any carrier or support medical device employed." When designing non-clinical studies,

companies should also ensure they have selected suitable end-points and control groups.

While the same requirements as other medicinal products generally apply to the clinical development of

gene therapies, EMA recognizes that there may be cases where adhering to certain guidelines may be

impossible. In such cases, companies must be able to justify any deviation from existing clinical

requirements.

In place of pharmacokinetic studies, which are not relevant for many gene therapies, other studies

should be performed to address the excretion of gene therapies and the risk of them being transmitted

to others.

Because of differences in gene therapies compared to traditional pharmaceutical substances, classical

dose finding principles may not be applicable. In these cases, EMA says companies should instead

establish a "minimal effective dose and a maximum tolerable dose.‖

For gene therapies using viral vectors, companies should evaluate the chosen vector for complications

that may arise if patients have been previously exposed to the parent virus. Additionally, for therapies

that require multiple doses over time, the product should be evaluated for immune response as well to

ensure any developed response does not interfere with the product's therapeutic effect.

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EMA Draft Guideline

Guidance for Industry: ANDA Submissions--Refuse-to-Receive Standards:

This guidance is intended to assist applicants preparing to submit to FDA abbreviated new drug

applications (ANDAs) and prior approval supplements (PASs) to ANDAs for which the applicant is

seeking approval of a new strength of the drug product. The guidance highlights deficiencies that may

cause FDA to refuse to receive an ANDA. A refuse-to-receive decision indicates that FDA determined

that an ANDA is not sufficiently complete to permit a substantive review.

This guidance is not meant to be a comprehensive list of the deficiencies that may or will lead to a

refuse-to-receive determination by FDA. Instead, this guidance identifies certain deficiencies and certain

recurrent deficiencies that in FDA’s experience have led FDA to refuse-to-receive an ANDA. This

guidance also describes how FDA will assess deficiencies identified during FDA’s filing review to

determine whether an ANDA should be received. We note that industry is aware of many of the

standards described in this guidance because FDA has historically applied many of these standards in

its refuse-to-receive determinations.

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U

CM370352.pdf

Guidance for Industry: Established Conditions: Reportable CMC Changes for Approved Drug

and Biologic Products

This guidance has been developed to address the lack of clarity with respect to what chemistry,

manufacturing, and controls (CMC) information in a marketing application constitutes an established

condition or a ―regulatory commitment‖ that, if changed following approval, requires reporting to FDA.

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. For those changes that do require reporting, a better

understanding of established conditions could allow for a more effective post-approval submission

strategy by the regulated industry

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U

CM448638.pdf

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Guidance for Industry: M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in

Pharmaceuticals to Limit Potential Carcinogenic Risk

The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents, catalysts,

and other processing aids. As a result of chemical synthesis or subsequent degradation, impurities

reside in all drug substances and associated drug products. While ICH Q3A Impurities in New Drug

Substances (Revision 2) (Q3A) and Q3B(R2) Impurities in New Drug Products (Q3B) (Refs. 1 and 2)

provide guidance for qualification and control for the majority of the impurities, limited guidance is

provided for those impurities that are DNA reactive. The purpose of this guidance is to provide a

practical framework that is applicable to the identification, categorization, qualification, and control of

these mutagenic impurities to limit potential carcinogenic risk. This guidance is intended to complement

ICH Q3A, Q3B (Note 1), and M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials

and Marketing Authorization for Pharmaceuticals

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U

CM347725.pdf

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AUDIT FINDINGS - 483 Observations

Firm Name 483 Observation

Alliance Packaging Group, Inc. -

Dec. 4, 2014

Control procedures are not established which validate the

performance of those manufacturing processes that may be

responsible for causing variability in the characteristics of in-

process material and the drug product.

Kremers Urban Pharmaceuticals,

Inc. - Dec. 16, 2014

Routine calibration of mechanical equipment is not performed

according to a written program designed to assure proper

performance.

J.M. Huber Corp. - Dec. 17, 2014 Laboratory controls do not include the establishment of

scientifically sound and appropriate specifications, standards,

sampling plans, and test procedures designed to assure that

components, and drug products conform to appropriate

standards of identity, strength, quality, and purity.

ForeverGreen International, LLC

- Feb. 4, 2015

There is no quality control unit.

Laboratoires Boiron - Jan. 20,

2015

Drug product production and control records are not

reviewed and approved by the quality control unit to

determine compliance with all established, approved written

procedures before a batch is released or distributed.

Pharmaceutica North America -

Jan. 6, 2015

The responsibilities and procedures applicable to the quality

control unit are not in writing and fully followed.

Kyowa Hakko Kirin Co., Ltd., Sakai Plant - Jan. 16, 2015

There is inadequate control over the use of "preconditioning"

injections during HPLC analyses in the QC laboratory.

Walgreens Infusion Services - Nov. 25, 2014

Adequate exhaust systems or other systems to control

contaminants are lacking in areas where air contamination

occurs during production.

Apotex Pharmachem, Inc. - Nov. 21, 2014

Computerized Systems do not have sufficient controls to

prevent unauthorized access or changes to data.

Golden Touch Mfg. - Nov. 5, 2104

There is no quality control unit.

Hospira Healthcare India Pvt. Ltd. - Feb. 4, 2015

Written records of investigations into unexplained

discrepancies do not include the conclusions and follow-up.

Spoonamore Drug Co., Inc. - Feb. 3, 2015

Aseptic processing areas are deficient regarding the system

for monitoring environmental conditions.

F. Hoffman - La Roche, Ltd. - Dec. 9, 2014

The Drug Product manufacturing process is not adequately

validated.

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EU Non-Compliance Report

RELONCHEM LIMITED, UK:

The company systems for investigating product that was potentially out of specification and not in compliance with the Market Authorisation were not robust and had allowed certification of potentially non-compliant product without appropriate investigation and product impact assessment. The Quality Management System had a number of issues including lack of robust product review, and lack of appropriate root cause investigation into deviations. The company had transported a large number of batches of product from the Manufacturing sites in India that were subject to temperature excursions during transport. These had not been adequately investigated, recorded or the impact of these excursions assessed.

Health Canada Non-Compliance Report

Health Canada Non-Compliance Report: Xenex Laboratories Inc.

1C.02.015 – Quality Control Department

The company did not demonstrate tracebility with respect to the active pharmaceutical supply chain.

Active Pharmaceutical Ingredients were sourced from companies for which GMP compliance information was not available.

There was no written agreement on the responsibilities related to the fabrication of drugs that was arranged among the parties involved.

2C.02.015 – Quality Control Department

Deficiencies were noted with procedures in place for various quality control operations. Required Standard Operating Procedures were not available, did not adequately describe key

operations, were out of date and/or were not being followed. The quality control department did not establish a change control system in order to assure a

continuing state of control of processes.

3C.02.011 – Manufacturing Control

Deficiencies were noted with control of the packaging operations. Packaging operations were not done according to comprehensive operating procedures.

4C.02.014 – Quality Control Department

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Deficiencies were noted with inclusion of all relevant factors in the assessment of finished products by the quality control department.

5C.02.017 - Packaging Material Testing

Each packaging material used in the packaging/labelling of a drug was not covered by specifications that had been approved and dated by the person in charge of the quality control department or a designated alternative who met the requirements.

Deficiencies were noted with the examination of labels on packaging materials following receipt of the packages on the premises of the person who packaged the drug.

6C.02.027 - Stability

Deficiencies were noted with the determination by the importer of the stability of a drug prior to its marketing.

7C.02.014 – Quality Control Department

Deficiencies were noted with the generation of in-house certificate of analysis.

8C.02.004 - Premises

Deficiencies were noted with the demonstration by packagers that the premises were designed such that the risk of cross-contamination between products was minimal.

Deficiencies were noted with the operational qualification of equipment used during the critical steps of packaging/labelling.

Deficiencies were noted with the monitoring of air-pressure differentials between production areas, intended to avoid contamination.

Deficiencies were noted with the control of temperature sufficient to safeguard materials.

9C.02.015 – Quality Control Department

The quality control department did not ensure that guidelines were in place for precautions, other than storage and transportation considerations, that were necessary to maintain the quality and safe distribution of a drug.

10C.02.015 – Quality Control Department

Deficiencies were noted with documentation regarding the assessment of the suitability of disinfecting agents.

Deficiencies were noted in the description in the sanitation program of the cleaning requirements for equipment used for processing.

11C.02.005 - Equipment

There was no system in place to ensure the respect of the calibration schedule of measuring devices.

Deficiencies were noted with the control and cleaning of measuring devices.

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12C.02.006 - Personnel

Deficiencies were noted with the training of personnel with respect to GMP principles, relevant standard operations procedures and/or their specific job duties.

Deficiencies were noted in the training program.

13C.02.020 - Records

The retention time for records required under Regulations maintained by the distributor was not established in writing.

The SOPs were not regularly reviewed and kept up to date by qualified personnel.

Health Canada Non-Compliance Report : CanadaDrugs.Com LP

1 C.02.015 - Quality Control Department

Deficiencies were noted with the transportation procedures to assure that transportation conditions would maintain the quality and safe distribution of a drug.

2 C.02.015 - Quality Control Department

Deficiencies were noted with the procedures for packaging finished drug product for shipping.

3 C.02.015 - Quality Control Department

Deficiencies were noted with temperature mapping of the refrigerator and warehouse to assure that labelled storage conditions can be maintained during storage of finished drug products.

4 C.02.012 - Manufacturing Control

Deficiencies were noted with validation of the software used to manage finished drug product inventory and to support drug product recalls.

5 C.02.015 - Quality Control Department

Deficiencies were noted with temperature records for monitoring of the warehouse and refrigerator used for finished drug product storage.

6 C.02.015 - Quality Control Department

Deficiencies were noted with follow-up action taken after investigation and evaluation of complaint(s) concerning potentially defective products.

7 C.02.015 - Quality Control Department

Changes to procedures were not properly evaluated,

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documented and approved by the quality control department.

8 C.02.012 - Manufacturing Control

Inventory records provided did not reflect the actual inventory at the facility in order to facilitate recall of finished drug products.

9 C.02.015 - Quality Control Department

Uncontrolled forms were used to document quality system procedures.

10 C.02.015 - Quality Control Department

Deficiencies were noted with the procedure for determining calibration dates for temperature m

Health Canada Non Compliance Report: Smiths Medical Canada Ltd.

1 C.02.015 - Quality Control Quality oversight was lacking resulting in significant GMP

deficiencies.J11I3I2:J9

2 C.02.014 - Quality Control Products made available for sale without approval of Quality

Control department.

The assessment of finished products by the quality control

department did not embrace all relevant factors.

3 C.02.027 - Stability Deficiencies were noted with the determination by the importer

of the stability of a drug prior to its marketing.

4 C.02.011 - Manufacturing Control

Deficiencies were noted with the report written on a deviation

from procedures or instructions.

A written report summarizing recorded results and conclusions

from validation studies of critical production processes was not

evaluated.

5 C.02.006 - Personnel Deficiencies were noted with the practical experience of the

individual in charge of the quality control department of the

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importer.

6 C.02.028 - Stability Deficiencies were noted with the implementation of a continuing

stability program to ensure compliance with the approved shelf-

life specifications.

The importer did not fulfill its responsibility to obtain up-to-date

records associated with the ongoin

7 C.02.014 - Quality Control Deficiencies were noted with the procedure to evaluate

deviations.

Deficiencies were noted with the procedures for recording,

handling, and tracking of deviations from standard processes.

8 C.02.015 - Quality Control Deficiencies were noted with the change control system to

assure that all changes were properly documented, evaluated

and approved by the quality control department.

9 C.02.006 - Personnel Deficiencies were noted for the training of key personnel in the

quality unit.

Deficiencies were noted in the training program.

10 C.02.019 - Finished Product Testing

Periodic complete confirmatory testing of finished products was

not done by the importer on at least one lot of finished product

per dosage form per fabricator.

11 C.02.012 - Manufacturing Control

Deficiencies were noted with the distribution records

maintained by the distributor of all sales of drugs as they

related to all operations in Canada including professional

samples.

12 C.02.015 - Quality Control Deficiencies were noted with the controls in place in the

warehouse to assure drug products are stored at the

recommended labelled conditions.

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13 C.02.011 - Manufacturing Control

Deficiencies were noted with the regular periodic quality

reviews of drugs.

14 C.02.012 - Manufacturing Control

Deficiencies were noted with the written agreement among

the parties involved that addressed responsibilities for the

fabrication of drugs.

FDA Warning letters

Warning letter Absolute Pharmacy, LLC 4/27/15 (FLA-15-21)

The FDA investigator noted CGMP violations at your facility, causing your drug product(s) to be

adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example:

1. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic

processing areas (21 CFR 211.42(c)(10)(iv)).

2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent

microbiological contamination of drug products purporting to be sterile, and that include validation of all

aseptic and sterilization processes (21 CFR 211.113(b)).

3. Your firm failed to clean and, where indicated by the nature of the drug, sterilize and process

container closures to remove pyrogenic properties to assure they are suitable for their intended use (21

CFR 211.94(c)).

4. Your firm failed to establish an adequate air supply filtered through high-efficiency particulate air

filters under positive pressure in the aseptic processing areas (21 CFR 211.42(c)(10)(iii)).

5. Your firm failed to establish time limits for the completion of each phase of production to assure the

quality of the drug product (21 CFR 211.111).

6. Your firm does not have, for each batch of drug product purporting to be sterile and/or pyrogen-

free, appropriate laboratory determination of satisfactory conformance to final specifications for the drug

product (21 CFR 211.167(a)).

7. Your firm does not have, for each batch of drug product, appropriate laboratory determination of

satisfactory conformance to final specifications for the drug product, including the identity and strength of

each active ingredient, prior to release (21 CFR 211.165(a)).

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Source: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm446540.htm

Warning letter Vann Healthcare Services Inc 4/29/15 (CIN-15-449139-18)

The FDA investigator observed CGMP violations at your facility, causing the drug products for which

you have not obtained valid prescriptions for individually-identified patients to be adulterated under

section 501(a)(2)(B) of the FDCA. The violations include, for example:

1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent

microbiological contamination of drug products purporting to be sterile, and that include validation of all

aseptic and sterilization processes (21 CFR 211.113(b)).

2. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug

product from contamination (21 CFR 211.28(a)).

3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic

processing areas (21 CFR 211.42(c)(10)(iv)).

4. Your firm failed to establish an adequate system for cleaning and disinfecting the room and

equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).

5. Your firm failed to clean and, where indicated by the nature of the drug, sterilize and process

container closures to remove pyrogenic properties to assure they are suitable for their intended use (21

CFR 211.94(c)).

6. Your firm does not have, for each batch of drug product purporting to be sterile and/or pyrogen-

free, appropriate laboratory determination of satisfactory conformance to final specifications for the drug

product (21 CFR 211.167(a)).

Source: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm446387.htm

Check your area for ….

• Do lab instruments clearly display calibration

status? Are instruments that are being repaired

or out of calibration clearly labeled to ensure

they are not used for GMP work?

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Regulations of the Month

§ 211.198 Complaint files. 21 CFR 211.198(b):

A written record of each complaint shall be maintained in a file designated for drug product complaints. The file regarding such drug product complaints shall be maintained at the establishment where the drug product involved was manufactured, processed, or packed, or such file may be maintained at another facility if the written records in such files are readily available for inspection at that other facility. Written records involving a drug product shall be maintained until at least 1 year after the expiration date of the drug product, or 1 year after the date that the complaint was received, whichever is longer. In the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption under 211.137, such written records shall be maintained for 3 years after distribution of the drug product.

(b) A written record of each complaint shall be maintained in a file designated for drug product complaints. The file regarding such drug product complaints shall be maintained at the establishment where the drug product involved was manufactured, processed, or packed, or such file may be maintained at another facility if the written records in such files are readily available for inspection at that other facility. Written records involving a drug product shall be maintained until at least 1 year after the expiration date of the drug product, or 1 year after the date that the complaint was received, whichever is longer. In the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption under 211.137, such written records shall be maintained for 3 years after distribution of the drug product.

(2) Where an investigation under 211.192 is conducted, the written record shall include the findings of the investigation and followup. The record or copy of the record of the investigation shall be maintained at the establishment where the investigation occurred in accordance with 211.180(c).

(3) Where an investigation under 211.192 is not conducted, the written record shall include the reason that an investigation was found not to be necessary and the name of the responsible person making such a determination.

§ 211.204 Returned drug products.

Returned drug products shall be identified as such and held. If the conditions under which returned drug products have been held, stored, or shipped before or during their return, or if the condition of the drug product, its container, carton, or labeling, as a result of storage or shipping, casts doubt on the safety, identity, strength, quality or purity of the drug product, the returned drug product shall be destroyed unless examination, testing, or other investigations prove the drug product meets appropriate standards of safety, identity, strength, quality, or purity.

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A drug product may be reprocessed provided the subsequent drug product meets appropriate standards, specifications, and characteristics. Records of returned drug products shall be maintained and shall include the name and label potency of the drug product dosage form, lot number (or control number or batch number), reason for the return, quantity returned, date of disposition, and ultimate disposition of the returned drug product. If the reason for a drug product being returned implicates associated batches, an appropriate investigation shall be conducted in accordance with the requirements of 211.192. Procedures for the holding, testing, and reprocessing of returned drug products shall be in writing and shall be followed.

Sec. 211.208 Drug product salvaging.

Drug products that have been subjected to improper storage conditions including extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures shall not be salvaged and returned to the marketplace. Whenever there is a question whether drug products have been subjected to such conditions, salvaging operations may be conducted only if there is

(a) evidence from laboratory tests and assays (including animal feeding studies where applicable) that the drug products meet all applicable standards of identity, strength, quality, and purity and

(b) evidence from inspection of the premises that the drug products and their associated packaging were not subjected to improper storage conditions as a result of the disaster or accident. Organoleptic examinations shall be acceptable only as supplemental evidence that the drug products meet appropriate standards of identity, strength, quality, and purity. Records including name, lot number, and disposition shall be maintained for drug products subject to this section.

Sec. 211.22 Responsibilities of quality control unit.

(a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.

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