VOLUME: 19 - ISSUE: OCT 2015 |

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Inside this issue

3 News Uptoday 35 New Guidance 45 Audit Findings 483 Observations

- 483 of Millers of Wyckoff, Inc., NJ, - Producer of Sterile Drugs - 483 of InvaGen Pharmaceuticals, Inc., NY

49 Warning Letters

- Warning letter: Pan Drugs Ltd., India - Warning letter: Jaychem Industries Ltd, New Zealand

50 Health Canada Non Compliance Report

- Non Compliance Report: MS Pharma, Inc, Canada. 52 WHO Notice of Concern (NOC)Report

- Notice of Concern (NOC) - Svizera Labs Private Limited, India 53 Article of the Month

- Warning Signs of a Weak Quality Culture

54 Regulations of the Month

- Sec. 211.42 Design and construction features (c)(1) to (c)(4)

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News Uptoday

Fareva buys Merck & Co API plant in France and outlines plan to invest €25m

Fareva has bought an API plant in France from Merck & Co. and outlined plans to turn it into a

high-potency actives site.

The firm said that acquiring the facility in La Vallée, Haute-Loire – which has total reactor capacity of

128,000 litres - has nearly doubled its active pharmaceutical ingredient (API) production capabilities.

At present the contract manufacturing organisation‘s (CMO) API capacity is split between sites

operated by its Valdepharma and Fareva Romainville subsidiaries in France and its Excella division

in Germany.

Fareva said it plans to spend €25m ($28m) to bring the facility up to operational exposure (OEB) 4

standards – which are required for the handling of toxic and highly potent APIs – and predicted that

the work will be completed in mid-2017.

Merck & Co – known as MSD outside North America – announced its intention to seek a buyer for

the facility in 2013 as part of extensive cuts following its acquisition of Schering-Plough in 2009.

Last month, the US drugmaker revealed that restructuring since 2013 – which involved the sale of

other manufacturing sites and the elimination of 7,290 positions – has cost $2.7bn and predicted that

the total cost of the programme would reach $3bn by the end of 2015.

Strides completes acquisition of Aspen's generic biz in Aus

Pharmaceuticals firm Strides Arcolab on Monday said it has completed the Rs 1,910-crore

acquisition of Aspen Pharmacare's generic pharmaceutical business and related assets in Australia.

The transaction has now achieved closure on completion of closing conditions and statutory and

regulatory approvals, Strides Arcolab said in a BSE filing. "The acquired business will be integrated

and consolidated with Strides effective September 1, 2015," it added. In May this year, Strides

Arcolab had announced signing of agreements to acquire a generic pharmaceutical business in

Australia and certain branded pharmaceutical assets from Aspen. The deal marks re-entry of Strides

in the Australian market. The acquisition included access to the product pipeline that was under

development by Aspen and a number of major product launches slated for the next six months. The

portfolio of Aspen's 130 products in Australia comprises generic pharmaceutical business together

with certain branded pharmaceutical assets. The acquired products had sales of 120 million

Australian dollars in the fiscal year ended June 2014. In 2012, Strides Arcolab had sold its entire

stake in Australian subsidiary Ascent Pharmahealth to Watson Pharmaceuticals for 375 million

Australian dollars. The business will operate under Arrow Pharmaceutical brand. Strides Arcolab

shares were trading 2.42 percent up at Rs 1,216 apiece during pre-close session on the BSE.

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Strides Arcolab stock price On September 03, 2015, Strides Arcolab closed at Rs 1201.90, up Rs

21.85, or 1.85 percent. The 52-week high of the share was Rs 1373.00 and the 52-week low was Rs

625.10. The company's trailing 12-month (TTM) EPS was at Rs 92.84 per share as per the quarter

ended June 2015. The stock's price-to-earnings (P/E) ratio was 12.95. The latest book value of the

company is Rs 247.28 per share. At current value, the price-to-book value of the company is 4.86.

Aurobindo Pharma gets USFDA nod for hepatitis B drug Entecavir

Aurobindo Pharma has received approval from the US health regulator to market generic Entecavir

tablets, used to treat hepatitis B, in the American market.

The company has received final approval from the US Food and Drug Administration (USFDA) to

manufacture and market Entecavir tablets in strengths of 0.5mg and 1mg, Aurobindo Pharma said in

a statement.

The Hyderabad-based firm's approved abbreviated new drug application (ANDA) is therapeutically

equivalent to Bristol-Myers Squibb's Baraclude tablets.

Entecavir tablets are indicated for treatment of chronic hepatitis B virus infection of the liver.

According to IMS data, the product has an estimated market size of USD 294 million for the 12

months ending June 2015.

"This is the 44th ANDA to be approved out of Unit VII formulation facility in Hyderabad for

manufacturing oral non-antibiotic products," the company said.

The company has now a total of 209 ANDA approvals from the USFDA.

Aurobindo Pharma shares were trading at Rs 744 apiece on BSE, up 2.90 per cent from previous

close.

Lupin gets USFDA nod for generic ulcer drug

Drug firm Lupin has received approval from US health regulator USFDA to market generic

Omeprazole delayed-release capsules, used to treat ulcer, in the American market.

The company has received final approval for its Omeprazole delayed-release capsules (40 mg) from

theUnited States Food and Drugs Administration (USFDA),Lupin Ltd said in a statement.

The Mumbai-based company's Omeprazole delayed-release capsules are the generic equivalent of

AstraZeneca's Prilosec delayed-release capsules, which are indicated for the treatment of duodenal

ulcer, gastric ulcer and gastro esophageal reflux disease (GERD).

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The drug is also used for healing of erosive esophagitis and pathological hypersecretory conditions.

According to IMS MAT June data, Prilosec had annual US sales of $185 million.

Lupin shares today ended at Rs 1,898.50 apiece on the BSE, up 4.79 per cent from previous close.

Two Novartis drugs get first in class EU approvals

The European Commission has approved Revolade for severe aplastic anaemia, and the

combination of Tafinlar and Mekinist for patients with an aggressive form of melanoma.

Revolade (eltrombopag) is the first therapy approved in the EU for adults with severe aplastic

anaemia (SAA) who failed to respond to standard treatments. The combination of Tafinlar

(dabrafenib) and Mekinist (trametinib) is the first targeted therapy combination approved in the EU to

treat adults with the most aggressive form of skin cancer, unresectable or metastatic melanoma with

a BRAF V600 mutation.

Revolade was originally produced by GSK, and was acquired by Novartis as part of its $16 billion

purchase of GSK‘s oncology portfolio last year, as part of an asset-swap agreement.

Its approval gives people with SAA who were either refractory to prior immunosuppressive therapy or

heavily pre-treated and unsuitable for hematopoietic stem cell transplant, another treatment option

for the rare blood disorder, in which the bone marrow does not make enough red and white blood

cells or platelets. Two in every one million people in Europe are diagnosed with aplastic anaemia

every year.

The European Commission approved Revolade based on the results of a pivotal open-label Phase II

study and two supporting Phase II studies conducted by the National Heart, Lung and Blood Institute

(NHLBI) at the National Institutes of Health (NIH).

Alessandro Riva, global head, Novartis Oncology development and medical sffairs, welcomed the

Commission‘s approval, saying: "[It] is important news for adults in the EU with severe aplastic

anaemia, who now have an alternative to standard therapies that have not provided sufficient

benefit," Revolade helps address an unmet need in this community and underscores our

commitment to patients affected by rare diseases."

While the skin cancer combination approval is based on results from the Phase III COMBI-d and

COMBI-v studies, in which the Tafinlar/Mekinist combination demonstrated overall survival benefit

compared to Tafinlar and Roche‘s Zelboraf (vemurafenib) alone.

"We look forward to making the Tafinlar and Mekinist targeted combination treatment, which

demonstrated a significant overall survival benefit in two robust clinical trials, available across

Europe as soon as possible," said Bruno Strigini, president of Novartis Oncology. "Today's EU

approval further demonstrates our ongoing commitment to deliver medicines that can further

enhance outcomes for patients with metastatic melanoma."

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TGA approves Hospira's biosimilar InflectraRead

US drug giant Hospira recently announced that the biosimilar Inflectra (infliximab) has been

registered as a therapy in Australia. Inflectra is an artificial compound that is biologicaly similar to

Remicade (infliximab). As a biosimilar, Inflectra has been developed to mimic the high standards of

biologic manufacturing to treat the same disease as the original product. The drug can be used to

treat a total of eight inflammatory conditions can be treated with Inflectra, including rheumatoid

arthritis, psoriatic arthritis, ankylosing spondylitis (AS), adult and pediatric Crohn's disease, refractory

fistulising Crohn's disease, adult and pediatric ulcerative colitis, and plaque psoriasis. Mr Wayne

Lee, associate director of Medical Affairs at Hospira, said, "Registration of Inflectra by the TGA

shows that they support the fundamental principles of data extrapolation which allows patients and

healthcare professionals to access the full suite of indications. This is an important development for

patients, prescribers and payers." During the next five years, the Australian government expects that

the market of biosimilar medicines will expand due expiry of patents on original products. This

growth is estimated to deliver $880 million in Pharmaceutical Benefits Scheme (PBS) savings.

Health ministry aims to expand Japan’s pharmaceutical industry

The health ministry has compiled an outline of its comprehensive strategy for the country‘s

pharmaceutical industry, underlining the need for discussions on an expansion of the industry

through mergers and acquisitions.

In the outline released Monday, the ministry also said that it will consider raising government-set

drug prices to facilitate the development of innovative drugs.

The outline said makers that have been failing to create new drugs should change their business

lines. It urged them to promote the spread of low-cost generic drugs instead of depending heavily on

off-patent drugs.

The government aims to increase the share of generic drugs in all drugs used in the country to 80

percent or more by fiscal 2020, against 46.9 percent for fiscal 2013.

On generic drugmakers, the outline said that they should be consolidated to strengthen their

business foundations. It also underscored the need to consider lowering generic drug prices to

reduce the public costs.

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MHRA uncovers $1m illegal ED drug haul

A UK man has been sentenced to 16 months in prison for smuggling illegal erectile

dysfunction drugs following an MHRA investigation.

Sundeep Amin, 57, pled guilty to 21 counts of importing, possessing and supplying unlicensed

medicines.

Officers from the UK medicines regulator seized nearly £900,000 ($1.4m) of unlicensed medicines

from addresses linked to the man, who is from Romford, Essex, in southeast England.

The MHRA (Medicines and Healthcare products Regulatory Agency) discovered Amin was

registered as the owner of several companies and had rented a number of storage facilities across

Essex.

Law enforcement seized ―several large quantities‖ of erectile dysfunction drugs en route from India to

these addresses as they arrived in the UK, including one haul worth £100,000 ($155,000), seized at

London‘s Heathrow Airport.

The drugs were intended for UK and European customers.

As well as illegal importation, Amin admitted possession of a large amount of the Class C, Schedule

II benzodiazepine Phenazepam, and to laundering money from his crimes.

Public health

Alastair Jeffrey, head of enforcement at MHRA, said, ―Mr Amin had no medical qualifications and

was dealing in unlicensed medicines, which is a lethal combination and a serious risk to public

health.

―His operation ran for several years and it is further proof that if you buy medication from an illicit

source, you are handing over money to a criminal who has no regard for your well-being.

Costly Hepatitis C Drugs for Everyone?

New drugs to treat hepatitis C are tremendously effective — and tremendously costly — raising fears

that the high prices might outstrip the ability of public and private insurers to pay. Fortunately,

competitive market forces and hard-nosed bargaining by insurers for big discounts are going a long

way toward resolving the problem.

The drugs are sorely needed. The hepatitis C virus caused nearly 20,000 deaths in the United States

in 2013, many in patients who were also infected with H.I.V., the human immunodeficiency virus that

causes AIDS, a double whammy that triples their risk of liver disease.

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There are four new drugs approved to treat hepatitis C: Sovaldi and Harvoni, made by Gilead

Sciences; Viekira Pak, made by AbbVie; and Daklinza, made by Bristol-Myers Squibb. The cost for

Sovaldi is $84,000 for a standard 12-week course of treatment, which breaks down to about $1,000

for each pill, taken daily. State Medicaid programs typically obtain discounts, but prices still generally

exceed $600 a pill. Harvoni is even more expensive, with a list price of about $95,000 for a 12-week

course of treatment without a discount.

The benefits of these new drugs are undeniable. They can essentially cure the infection in eight to

24 weeks. Older medications are not nearly as effective and often produce disabling side effects.

Curing the patient decreases by more than 80 percent the risk of liver cancer, liver failure and the

need for a liver transplant, thus saving money in the long run. Successful treatment can also greatly

reduce the number of new cases of hepatitis C by preventing transmission of the virus through

needle-sharing among drug addicts infected with H.I.V.

After Gilead announced this year that it would give an average discount of 46 percent off the list

prices of its two drugs, the Institute for Clinical and Economic Review, previously a skeptic,

estimated that a likely course of treatment with Harvoni would make it a high value for individual

patients and for most health care systems.

Unfortunately, most state Medicaid programs, in an effort to control costs, have placed restrictions

on making the drugs widely available. These include requiring that patients have advanced liver

disease before they can get the drug, requiring patients to abstain from alcohol or illicit drugs for at

least a year before treatment, and requiring that the drugs be prescribed only by specialists like

infectious disease experts or gastroenterologists.

The restrictions run counter to guidelines published by the Infectious Diseases Society of America

and the American Association for the Study of Liver Diseases, which recommend treating all patients

infected with the hepatitis C virus except those who have a life expectancy of less than a year

because of some other disease. A June 9 letter to President Obama from the Presidential Advisory

Council on H.I.V./AIDS called for eliminating such ―unreasonable‖ restrictions. It said that increased

competition had ―dramatically reduced‖ the cost of treatment.

Even so, there is probably room to drive prices down even further. With these and other high-priced

drugs, the manufacturers typically charge what the market will bear. The public and private insurers

that pay for hepatitis C drugs should press for even bigger discounts.

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How to become a QP for Europe

Both the ECA Academy and the European Qualified Person Association (EQPA) are often contacted

by people who would like to become a Qualified Person (QP according the EU Directives) in a

Member State of the European Union or outside the EU to release products for the EU market.

Questions are for example:

"Can I become a QP and live and work outside the EU?"

"I work for an American company that would like to export medicinal product to the EU. How

can we hire a QP here in the U.S.?"

"I am an Irish Citizen living and working in Australia. I am thinking of studying a course by

distance learning, which also meets the requirement for persons seeking to become a QP. Is

that possible?"

"I'm a Spanish pharmacist working in Switzerland. I'm wondering how to proceed to become a

Qualified Person. Which is the training that I have to follow to become QP in Europe?"

Unfortunately this is not as easy as one would think. To become a QP there are a few things that

need to be considered:

1. The European Qualified Person is linked to a European Manufacturing authorization and licence

(EU/ECC).

2. A QP is registered by the authority of the respective EU member state (or MRA-State). The

requirements might differ from member state to member state.

In Article 49 of Directive 2001/83 (for veterinary medicinal products, please read Article 53 of

Directive 2001/82), the qualification level as well as the necessary experience of a QP is defined:

(2) "A qualified person shall be in possession of a diploma, certificate or other evidence of formal

qualifications awarded on completion of a university course of study, or a course recognized as

equivalent by the Member State concerned, extending over a period of at least four years of

theoretical and practical study in one of the following scientific disciplines: pharmacy, medicine,

veterinary medicine, chemistry, pharmaceutical chemistry and technology, biology (…). The course

shall include theoretical and practical study bearing upon at least the following basic subjects:

Applied physics

General and inorganic chemistry

Organic chemistry

Analytical chemistry

Pharmaceutical chemistry including analysis of medicinal products

General and applied biochemistry (medical)

Physiology

Microbiology

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Pharmacology

Pharmaceutical technology

Toxicology

Pharmacognosy (study of the composition and effects of the natural active substances of

plant and animal origin).

In so far as certain diplomas, certificates or other evidence of formal qualifications mentioned in the

first subparagraph do not fulfil the criteria laid down in this paragraph, the competent authority of the

Member State shall ensure that the person concerned provides evidence of adequate knowledge of

the subjects involved."

So, to act as a QP as defined in the EU Directives, you have to work in an EU Member State and

fulfil the requirements of the directives. These requirements have to be transferred to national law in

each EU Member State. However, there are a number of differences in the EU Member States due

to the fact that each Member can implement the directives into national law with slight modifications.

More information can also be found on the website of the European QP Association.

IDMA urges DGFT to make provision for parent child relationship between secondary &

tertiary packaging optional

Indian Drug Manufacturers' Association (IDMA) has urged the Directorate General of Foreign Trade

(DGFT) to make the provision of maintaining of data in the parent child relationship between

secondary and tertiary packaging optional or to keep in abeyance as it is difficult for the

manufacturers or exporters to provide all the infrastructure to create or upload all the data on DAVA

(Drug Authentication and Verification Application) portal till October.

The suggestion was made after the DGFT amended Para 2.89 A of Handbook of Procedure, 2015-

20, as notified on Public Notice No. 4/2015-20 dated 01.04.2015. As per Para 2.98 A (ii), the

manufacturer or exporter shall maintain the data in the parent-child relationship for three levels of

packaging i.e. primary, secondary and tertiary packaging and their movement in its supply chain.

However, maintenance of parent-child relationship between primary and secondary packaging is

optional.

Para 2.98 A(iii) states that the data shall be uploaded on the central portal of the government of India

by the manufacturer or exporter or its designated agency before release of the drug formulations for

sale or distribution.

S V Veerramani. president of IDMA says, ―The requirement of maintenance of data in parent-child

relationship between secondary and tertiary packaging has however not been made optional and it

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must be noted that this criterion has been incorporated with sufficient discussion and deliberation

with the industry. It does not add value at the moment from the standpoint of authentication by the

end user, as the 2 D barcode on the carton when decoded will surely confirm the authenticity or

otherwise of the pack.‖

He further adds, ―Having known that it does not serve the purpose of authentication or that of supply

chain verification when the market place is not ready, insisting on having this requirement will

discourage the SMEs from following the requirements, since even before they have managed to

come to terms with barcoding of tertiary and secondary packs, investing time and money in an

aggregation unit and additional scanners that will be required for the parent child relationship will

burden them with no added advantage. Besides, since the cartons would need to be scanned in the

shipper after packing, the activity will be offline and manual thereby reducing the output by more

than 20 per cent.‖

He also explained that since the onus of uploading the data on the DAVA portal is on the

manufacturer or exporter would not be aware about the end point sale of his products if they are not

properly tracked and the information uploaded on his server. Consequently, how is a manufacturer

or exporter supposed to upload the data in time ensuring that it is complete and correct? As the

manufacturer or exporter will be dependent on the supply chain for correctness of the data so every

link in supply chain, whether local or global, will also need to be held mandatorily responsible to

provide the correct/complete data to the manufacturer or exporter in a fixed time so that the

manufacturer or exporter can further upload the same on the central portal in time to ensure that the

data uploaded is truly authentic.

IDMA has also suggested the DGFT to make Pharmexcil as nominee for obtaining permission to

avail the option of printing the barcode in exporter's format, so that it reduces the burden on DCGI.

As per the provision under clause 2 (V) which states ―Where the government of the importing country

has mandated or formally notified its intention to mandate a specific requirement and the exporter

intends to avail the option of printing the barcodes in their format after duly obtaining the permission

of DCGI or its nominee.‖ So the IDMA suggested Pharmexcil, with their experience in regulatory

requirements of all countries be assigned with this responsibility for avoiding delays.

Cipla to buy two US pharmaceutical firms for $550m

Indian pharmaceutical and biotechnology firm Cipla has agreed to acquire two US-based companies

in all-cash deals worth $550m in order to expand its presence in the world's largest generics market.

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The company is acquiring InvaGen Pharmaceuticals

and Exelan Pharmaceuticals, which had combined

sales of more than $225m in the twelve months to June

2015.

InvaGen develops, manufactures, markets and

distributes generic pharmaceuticals with focus on

several therapeutic areas such as cardiovascular, anti-

infective, CNS, anti-inflammatory, anti-diabetic and anti-

depressants.

The company has drug product development and commercial operations at three different facilities in

Hauppauge, New York.

The deal with InvaGen brings Cipla around 40 approved abbreviated new drug applications, 32

marketed products and 30 pipeline products that are anticipated to be approved in the next four

years.

Exelan focuses on the sales and marketing of generic pharmaceuticals for the government and

institutional market.

Through Exelan, Cipla gains access to the government and institutional market in the US.

Cipla MD and global CEO Subhanu Saxena said: "This investment is in line with Cipla's strategy to

grow Cipla's share in the US pharmaceutical market. We see InvaGen as a strong strategic fit with a

relevant diverse portfolio as well as a strong market and customer presence.

"With a local manufacturing facility, Cipla can strengthen its presence and commitment to serve

patients in the country."

Extent of data breaches in pharmaceutical sector revealed

The extent of data breaches in the pharmaceutical sector has been unravelled by a survey that

reveals 60% have lost important data and almost one quarter have been hacked.

The Crown Records Management/Censuswide Survey of IT decision makers at UK

companies with more than 200 employees revealed some shocking results as companies

battle to keep information safe.

Data breaches are already big news following a cyber-attack on Carphone Warehouse

which put the personal information of up to 2.4m customers at risk – while the Ashley

Madison infidelity dating website made front page headlines when the data of subscribers

was stolen and then published by hackers.

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Now those working in the pharmaceutical sector have admitted they too have suffered

breaches. The Crown Records Management Survey revealed:

60% of IT decision makers in the pharmaceutical sector said their company had lost

important data

12% had done so between seven and nine times – and 8% between 13 and 15 times

24% reported their company had suffered a hack

Survey results should be a “wake-up call” for the pharmaceutical sector

Ann Sellar, Business Development Manager at Crown Records Management, a global

information management expert, said, ―These survey results should be a wake-up call for

UK businesses, and especially those in the pharmaceutical sector, because the importance

of protecting customer data is higher than ever. Not only because of potential fines for data

breaches (which will soon increase when the EU General Data Protection Regulation is

ratified) but also because of growing public awareness.

―It takes on average 20 years to build a reputation but just five minutes to ruin it with a data breach

and then up to two years to rebuild it. So businesses need to look at the way they protect their

information, understand where the threats are and start putting robust processes in place to protect

their customers. If they don‘t I can only see the number of data breaches increasing in the next few

years.‖

Drug companies may be told to upgrade facilities to meet PICS standards

India is looking at persuading thousands of drug makers to upgrade their manufacturing facilities to

help the country meet PICS standards, which will allow local companies access 45 export markets.

Geneva-based PICS (Pharmaceutical Inspection Convention and Pharmaceutical Inspection

Cooperation Scheme) has been insisting that India join the league so that exporters can avoid

multiple regulatory checks on drugs and manufacturing facilities. The member countries of PICS

procure drugs from the facilities of fellow member countries without duplicating inspections on the

drugs and facilities, helping exporters substantially save on time and money.

India's commerce ministry, which had earlier advised its drug makers to consider joining PICS, is

now planning to host comprehensive meetings with trade bodies along with a technical session this

month to decide on a timeframe for compliance.

The prescribed standards of the PICS alliance, comprising the US and European countries, include

good clinical practice (GCP) and good pharmaco-vigilance practice (GPP), apart from good

manufacturing practice (GMP).

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"The commerce ministry is planning to hold an open forum of pharma producers in Hyderabad during

the fourth week of this month for an initial round of awareness creation on the advantages of joining

the PICS league," a senior commerce ministry bureaucrat told ET, requesting anonymity. "We will

take it forward with another round of detailed talks with the trade bodies sometime during next month

or so."

He, however, admitted that many small and medium pharma firms, especially those focussing solely

on the domestic market, were averse to India joining the league given the costs involved in

upgrading their facilities.

"It costs at least Rs 5 crore per unit to upgrade manufacturing standards to comply with PICS

specifications, proving it an unwarranted burden on SMEs focussing only on the domestic market,"

said a senior executive of a mid-size drug maker based out of Hyderabad. "Joining PICS league will

of course be of significant benefit to the exporters."

Confirming the preparations of the commerce ministry on PICS compliance, Pharmaceuticals Export

Promotion Council Director-General PV Appaji said the government is aware of the apprehensions of

SME drug makers. It will go ahead with PICS compliance only after convincing all the stakeholders,

he told ET. "The proposed awareness conclaves and talks with trade bodies were aimed at this

purpose."

India, the third largest global pharma producer, has nearly 10,000 drug units with less than a sixth of

them, mostly exporters, certified with WHO-GMP standards. The government's decision to join the

PICS league will make more than 8,600 units to invest sizeable amounts on upgrading their facilities.

India currently exports over Rs 94,000 crore worth of medicines and more than two-thirds of the

products go to PICS member countries.

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CDSCO launches IT enabled system for online submission of applications & monitoring of

clinical trials

The Central Drugs Standard Control Organisation (CDSCO) has launched an IT enabled system for

the online submission of applications and monitoring of clinical trials in the country. The new system

is expected to improve transparency, accountability and efficiency in processing of trials of clinical

trial applications and its monitoring in the country. However, the online submission of clinical trial

application has not been made mandatory at present.

―In order to improve transparency, accountability and efficiency in processing of trials of clinical trial

applications and it‘s monitoring, CDSCO with the approval of ministry of health and family welfare,

government of India has taken initiative to create an IT enabled system for online submission of

applications and monitoring of clinical trials in the country,‖ the CDSCO in a notice said.

The clinical trials on the new drugs are regulated under the provisions of the Drugs & Cosmetic

Rules, 1945, amended from time to time.

All the information related to four major domain of clinical trial i.e. sponsor/CRO, investigator, ethics

committee and clinical trial subjects are captured in the system through online in an organised

manner which will result in efficient monitoring of clinical trials in the country for protection of right,

safety and well being of trial subjects and authenticity of the data generated. In the first phase, an IT

enabled system for online submission of applications of clinical trial has been created and made

accessible to the stakeholder throughhttp://octams.gov.in.

Applicants wishing to submit their clinical trial application online, can do so

through http://octams.gov.in.

Although the online submission is presently not mandatory, the applicants are encouraged to avail

the system which will enable CDSCO to process the application in an efficient and expedited

manner.

If any applicant faces any difficulty or problem during the process of online submission, the same

can be brought to the notice of CDSCO through email at dci@nic.in or phone at 01123236965 for

addressing the issues in consultation with NIC, the CDSCO notice said.

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Slew of upcoming forward looking polices by Central govt to transform pharma industry:

DCGI

The Drugs Controller General of India (DCGI) has indicated that a slew of forward looking polices by

the Union government that are expected in the next few weeks is set to transform the pharma

industry and the start-ups landscape in doing business.

Specifically adopting the e:governance model, this would cover easy issue of licenses, faster export

clearances for projects and speedy drug import approvals, among others. In principle, the

government has increased its fund allocation to the Central Drugs Standard Control Organisation

(CDSCO) by 25 per cent. Earlier this department worked in isolation and now the Prime Minister‘s

office (PMO) has insisted on a unified system of single window clearance regulatory approvals.

Some of these are new standard operating procedures (SOPs) interfacing CDSCO and state drugs

control departments and use of information technology (IT) like internet and electronically networked

systems would simplify the process to bring in complete transparency during drug approvals and

issue of license.

The multiple systems of complexity that prevailed in doing business which impacted the pharma

industry is now expected to witness a sea change as there would now be a huge difference in the

functioning of the CDSCO, said Dr G N Singh, DCGI who was in Bengaluru recently.

―We are now in the final leg to put in place a process of working out the modalities that would

support the pharma industry to market drugs either for domestic or international markets. Although

we do not expect too much time for the last leg of approvals from the Union government, yet the wait

would be worthwhile for the pharma industry,‖ Dr. Singh told Pharmabiz.

Now the office of the DCGI is the face of the pharma industry for clearing the regulatory hurdles. This

is why we felt that only a significant transformation in the functioning of CDSCO could stall

unnecessary delays which could mar the progress of pharma industry. The government has

recognised the need for faster clearances and went on to allocate Rs.1,800 crore to the CDSCO. For

the first time there is a dedicated allocation ofRs.750 crore to the state regulatory departments and

this is a big boost to efficient functioning of these departments, he added.

The PMO has categorically asked the CDSCO to come out of the ambit of inspector raj era where

cumbersome process led to inordinate delays. To this effect, the DCGI office made a presentation to

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listing out the SOPs to ensure minimum impediments. While these regulations would be tough to

ensure high quality drugs are in the market, the use of IT would streamline the process of drug

approvals and issue of licenses to bring in complete transparency, Dr Singh said.

―Further, there would be minimum interface and lucid interpretation of official notification and this

would see the Indian pharma industry strengthen its global footprint. Currently, stringent regulated

markets are recognising India as the pharmacy of the world and we need to sustain this image.

Therefore a positive environment is on the anvil. Just like the IT, pharmaceuticals will drive the

knowledge economy,‖ pointed out Dr. Singh.

―But unlike IT, for pharma the return on investment is insignificant. Now in order to accelerate the

government‘s commitment, we would look to encourage small-medium pharma entrepreneurs

together encourage the start-ups in this sector to increase the upfront investments in sector,‖ he

said.

How to fix India’s broken healthcare system without spending big money

India's infant mortality and maternal mortality rates are worse than in sub-Saharan Africa. Every 10

minutes a young woman dies during childbirth. Three lakh children die the day they are born and 1.2

million die before celebrating their first birthday.

Policy makers believe we can address the crisis by increasing budgetary allocation on healthcare.

The truth is that even if we increase it from the current 1.1 per cent to 10 per cent of GDP, maternal

and infant mortality in India will not come down because we do not have the skilled manpower to

address the crisis.

According to information from the health ministry the shortage of medical specialists in community

health centres - where the majority of children are born in rural India - is close to 75 per cent. Every

year 26 million babies are born in India; at least 5.2 million require caesarean sections. To perform

these we need at least two lakh gynaecologists. We only have 30,000; nearly half of them do not

practice obstetrics. We need two lakh anaesthetists for the pregnancies alone and we have less than

20,000.

Predominantly the shortfall is because even though we produce 50,000 doctors a year, there are

only 14,000 PG seats for them to become specialists. Because of the acute shortage of seats, young

MBBS students spend two to five years in coaching classes swotting up multiple choice questions in

Kerala and Kota instead of taking care of patients.

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We have rigid Medical Council of India (MCI) regulations as to who can perform what procedure. If

we look at the top causes of death in India - heart disease, liver failure, psychiatric illness, accidents,

pneumonia and TB - doctors without postgraduate qualifications cannot treat any of these cases.

How do we expect the death rate to come down?

Today, when it costs close to Rs 400-500 crore to start a medical college, state governments are

reluctant to get involved. I can't also think of a single trust with the honourable intention of building a

medical college that would spend Rs 500 crore and not expect anything in return. As a result, it is

people with ill-gotten wealth who build medical colleges and medical education has become

extremely expensive.

With the stroke of a pen India can equalise undergraduate and postgraduate seats in medical

colleges. This can happen without billions of dollars in investment or a long wait. Worldwide, higher

medical education happens in non-medical college hospitals which are centres for excellence.

One of the issues raised by various councils is the shortage of faculty. But who is allowed to teach?

According to MCI neither Naresh Trehan of Medanta Hospital nor Ramakanta Panda of the Asian

Heart Institute - both recognised as pioneers of cardiac surgery - are allowed to teach cardiac

surgery in India. Clearly, there is fundamentally something wrong with how we conduct medical

education.

Across the world, medical education is an integral part of healthcare delivery. By converting jobs

available in rural India to part of the training programme, we can bring talented doctors to these

difficult areas. But we seem to have consciously avoided using medical education as a tool.

Few would have heard of the College of Physicians and Surgeons based in Mumbai. The oldest

medical university in this part of the world, it was established 105 years ago and gave diploma

degrees in gynaecology, anaesthesia, paediatrics and radiology, to address the needs of rural India.

Unfortunately, a few years ago their degree was de-recognised.

But their training programme can happen at any government hospital, which would convert all MBBS

doctors in government sectors to medical specialists in two years, addressing 75 per cent of the

shortage of specialists in the government sector. All it requires is a simple instruction from the health

ministry.

Worldwide, nurse practitioners or physician assistants provide primary healthcare. Unfortunately,

here we have never created a legal framework for them to dispense basic medicines. We also have

close to six lakh Ayush doctors who are graduates from the same universities that gave medical

doctors their MBBS degrees. They just need a six-month bridge course to prescribe 47 basic drugs

in primary health centres. This could address absenteeism of MBBS doctors and ensure quality

healthcare to rural India. In spite of several meetings and expert opinions, nothing has changed. We

just need the political will to make it happen.

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Technology can also massively impact how healthcare is delivered and funded. Eleven years ago we

conceptualised a micro health insurance scheme, Yeshasvini, launched by Karnataka's department

of cooperation. In the first year 1.7 million farmers paid Rs 5 per month as a premium and the state

government became the reinsurer. Today over 4 million farmers pay Rs 10 per month and close to

10 lakh farmers have had surgery. Close to one lakh farmers had heart surgeries in one of 476

network hospitals.

We can scale up. Today, India has close to 900 million mobile phone subscribers, who spend at

least Rs 150 per month for basic services. If we create a regulation to get even Rs 20 from each

subscriber, we can cover surgical costs for all 900 million. It is not rocket science.

We have the opportunity to become the first country to prove that a nation's wealth has nothing to do

with the quality of healthcare its citizens can enjoy.

Strides Acrolab gains on Sun Pharma's divestment plan

The agreement involves transfer of two marketing divisions 'Solus' and 'Solus Care', along with

employees to Strides Acrolab

Shares of drug maker Strides Acrola have gained 3% to quote at Rs 1,180.60 on the BSE after,

India‘s largest drug maker, Sun Pharma sold the central nervous system (CNS) product business of

erstwhile Ranbaxy to Strides Arcolab for an amount of Rs 165 crore.

Sun Pharma and Strides have entered into a definitive agreement related to erstwhile Ranbaxy's

'Solus' and 'Solus Care' divisions operating in the central nervous system (CNS) segment in India,

Sun Pharma said in a statement.

The agreement involves transfer of these two marketing divisions, along with employees to Strides

for a consideration of Rs 165 crore, it added.

Earlier, Sun Pharma had completed the $3.2 billion acquisition of Ranbaxy Laboratories in March to

create the world‘s fifth-biggest generic pharmaceutical company by revenue.

Indian Drug Plants Are Freaking Out the FDA

The United States has issued its 42nd import alert on an Indian pharmaceutical plant since 2010,

shedding light on how globalized the drug supply chain has become. The Food and Drug

Administration issues these alerts to recommend that drug products from these plants be "detained

without physical inspection."

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India is the country's second-largest provider of "finished drug products," but its drug plants lead the

way in American import alerts, according to a VICE News/MedPage Today analysis of 114 plant

alerts across 29 countries since 2010.

"The problems encountered by FDA investigators in India are similar to those seen around the world

in manufacturing," said Food and Drug Administration spokesperson Christopher Kelly. "Common

issues include inadequate or poor quality systems implementation, data integrity issues, inadequate

validation of various processes used in manufacturing or testing, and product adulteration or

contamination."

Health ministry begins process of strengthening of drug regulatory systems in states

with Rs. 850 cr fund

The Union health ministry has started the process of strengthening of the drug regulatory systems in

the states which play a vital role in implementing the provisions of the Drugs & Cosmetics Act in the

length and breadth of the country. The ministry has now prepared a format of memorandum of

understanding, that is required to be signed by the respective state government and government of

India for implementation of theRs.850 crore proposal of strengthening the states drug regulatory

system.

Earlier on August 12, 2015, the Cabinet Committee on Economic Affairs had approved the proposal

for strengthening of drug regulatory system both at the central and the state levels at a total cost

of Rs.1,750 crore. Out of the total amount of Rs. 1,750 crore, an amount of Rs.900 crore will be

spent on strengthening central structures and Rs.850 crore will be made available to the state

governments, after signing a memorandum of understanding. Accordingly, the ministry has now

prepared the format of memorandum of understanding.

The strengthening of the state drug regulatory system is important as under the provisions of the

Drugs & Cosmetics Act, 1940 and the Drugs & Cosmetics Rules, 1945, the manufacture, sale and

distribution of drugs and cosmetics are regulated by the state drugs control authorities appointed by

the state governments. Even sale of imported drugs after having been permitted by the Central

Drugs Standard Control Organisation (CDSCO) is monitored and regulated by state drug control

departments.

Presently, the drug regulatory systems in most of the states are faced with major concerns such as

inadequate or weak drug control infrastructure at the state level; inadequate drug testing facilities;

non-uniformity of enforcement of law and rules; lack of training to regulatory officials; lack of data

base; and inadequate IT services.

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According to officials, the Indian pharmaceutical industry, which is one of the most vibrant sectors of

Indian economy, has been growing at the rate of 10-12 per cent per annum. It is the 3rd largest in

the world by volume and 10th by value. The total size of the Indian pharmaceutical industry is

about Rs.2 lakh crore, out of which exports account for nearly 55 per cent. To ensure the quality,

safety and efficacy of medicines both for domestic use and for exports, the states regulatory system

is required to be strengthened.

Pharmexcil to organise interactive meeting with govt & top drug regulatory officials in

Hyderabad

In a move to bring in better clarity over the Indian drug regulatory norms, and deliberate the issues of

the exporters and international buyers alike, the Pharmaceuticals Export Promotion Council of India

(Pharmexcil) is organising an interactive meeting with the government and top drug regulatory

officials of the country in Hyderabad. This move is aimed at boosting the confidence of the Indian

exporters by providing them with a platform to duly interact with the regulators on key issues

affecting exports.

The meeting, which will be held from September 22 to 24, will see the presence of senior officials

from the commerce ministry including Sudhanshu Pandey, joint secretary; Drug Controller General

of India (DCGI) Dr G N Singh along with state drug controllers from across the country. Dr P V

Appaji, director general of Pharmexcil informed that several technical and regulatory information will

be shared during this meet, with special focus on data integrity issues, which is a burning topic

affecting the industry at present.

He further informed that this meeting is strategically important for the stakeholders to attend, as

Pandey will be giving detailed information of not only various government schemes and incentives

available for the exporters, but also interact with the stakeholders to gauge and understand their

requirements and issues.

Most importantly, the members from the UN and WHO will also be part of this meet wherein they will

sensitize the exporters on procedures to participate for pre-qualification bids in the WHO and various

UN agencies. Deliberations will also be made on the pharma exporters' long standing demand of

making India a member country of Pharmaceutical Inspection Cooperation Scheme (PICS) which will

enable and help the exporters to overcome the export hurdles to several less explored countries.

―We have organised this meet keeping in mind the current requirements and market dynamics of the

industry. Pharmexcil is always striving hard to initiate steps that will help in boosting the exports from

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the country. We strongly believe that this can be achieved by overall understanding of the drug

regulatory system of the country as well as the exporting countries. The purpose of this meeting is to

provide guidance and useful tools that will assist in the process of boosting the exports by opening

up window of unique opportunity for manufacturers to learn more about the regulations and

procedures used in globally,‖ he added.

Drug Goes From $13.50 a Tablet to $750, Overnight

Specialists in infectious disease are protesting a gigantic overnight increase in the price of a 62-year-

old drug that is the standard of care for treating a life-threatening parasitic infection.

The drug, called Daraprim, was acquired in August by Turing Pharmaceuticals, a start-up run by a

former hedge fund manager. Turing immediately raised the price to $750 a tablet from $13.50,

bringing the annual cost of treatment for some patients to hundreds of thousands of dollars.

―What is it that they are doing differently that has led to this dramatic increase?‖ said Dr. Judith

Aberg, the chief of the division of infectious diseases at the Icahn School of Medicine at Mount Sinai.

She said the price increase could force hospitals to use ―alternative therapies that may not have the

same efficacy.‖

Pfizer to sell Mumbai manufacturing plant for $27m

Pfizer has agreed to sell a manufacturing facility in India to Vidhi Research and Development

for around $27m.

In July , Pfizer announced it would close or sell its Thane, Mumbai manufacturing facility with effect

from September 16. Today, the Big Pharma firm revealed it has found a buyer.

“Pfizer Limited has announced that it has entered into a Business Transfer Agreement (BTA) for the

transfer of the company’s business at the Thane plant as a going concern to Vidhi Research and

Development,” the firm said in a statement sent to in-Pharmatechnologist.

“Upon the conclusion of the BTA, all current workmen at the plant shall be transferred to the buyer

so as to facilitate manufacturing operations.”

Gujarat-based company Vidhi is a relatively new entrant in the Indian pharma industry and will pay a

lump sum of 1.78bn rupees ($27m) for the site, located in the Maharashtra region of India.

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The plant was shuttered and put up for sale following a long-term viability assessment by Pfizer.

“There has practically been no production activity at this plant since 2013, and the closure will not

impact the supply of any of the Company's medicines to patients,” the firm said in the July filing.

And spokesperson Trupti Wagh added the company remains committed to India, telling this

publication Pfizer continues to “manufacture its products at its facility in Goa and at several partner

facilities across the country.”

A reliable supply chain has never been more important, says Mylan CEO

Drugmakers need more certainty and reliabilty around their supply chain in light of increased

regulatory vigilance says Mylan, itself carrying out remediation across several Indian

facilities.

Last month , generic drug and API maker Mylan received a US Food and Drug Administration (FDA)

warning letter citing a lack of protection against contamination across three of its Indian

manufacturing facilities, two of which the firm acquired when it bought Agila from Strides Arcolab in

2013 .

Speaking at the Morgan Stanley Global Healthcare Conference in New York last week, CEO

Heather Bresch said the firm is on-track with its remediation plan to bring the ex-Agila plants up to

standard.

“As we inherit facilities, as we do acquisitions, we take the time that we need to invest to bring those

standards up,” she told investors.

“In some cases just the yardstick changes, FDA changes kind of their thinking or philosophy about

what they wanted standard to move to,” she continued. “So obviously we are in constant dialogue as

changes are happening or as standards are improving, to make sure that we are doing everything

we can to meet them if not exceed them.”

Despite the regulatory setback, she said the injectables business was a huge growth driver and

Mylan is on the way to “really be a leader in the space.”

Supply Chain Stability

She told investors there has been growing demand from Mylan‘s customers for a reliable, high

quality global supply chain

“As we continue to live through the FDA transformation as far as inspection and facilities, the need

for quality reliable supply chain has probably never been higher,” she said.

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“So because of that - and as consolidation continues both on our customers side as well [as us] -

they need more volume and more certainty and reliability around this volume.”

This has helped drive Mylan‘s M&A strategy, she continued, as its growing portfolio reassures supply

chain stability among its customers.

“When you take because of the breadth of our portfolio, we are able to really kind of manage the

entire portfolio and not just the one off by our customers. That again helps bring that stability

because of the supply we are able to reliably give and the quality around the portfolio of product that

we are offering.”

Pharmexcil to organise international meet focused on promoting API exports

Keen to push the exports of APIs from the country, the Pharmaceutical Export Promotion Council of

India (Pharmexcil) is strategically planning to organise an international meet specifically focused on

promoting the API sector along with generic formulations. The Pharmexcil‘s increased focus on APIs

stems from the fact that API exports from the country is not growing properly as desired, coupled

with the assumption that the iphex expo is seen as an expo for generic formulations than for APIs.

Interestingly, this meet will be organised as a part of the 11th general meet along with host of other

strategic export promotional activities to attract investment opportunities to the country. Dr P V

Appaji director general of Pharmexcil informed that since APIs make up a large bulk of business for

the country with its huge potential, there is an urgent need to further explore and push this segment.

It is with this vision that the Pharmexcil has initiated this move to increase its focus on this sector.

However he stressed that generic formulation will also be on the table during this event.

The chief of drug procurement agency of Ecuador from the Latin American region is also expected to

come for the meet. The main aim behind this visit is to understand and interact with the Indian

suppliers and regulators and get an idea about the Indian pharma industry in detail. This is a

strategic development especially since the chief will be accompanied by six strong buyers of

formulations from Ecuador. It is important to note that there is a huge requirement for generic

formulations from Ecuador and thus this visit could pave way to lot of export promotion for the

country.

It is understood that 80 delegates from 25 different countries will be making a beeline to attend this

meet including countries like Azerbaijan, Bangladesh, Chile, Colombia, El Salvador, Ethiopia,

Ghana, Hungary, Iran, Indonesia, Japan, Jordan Kenya, Mauritius, Nigeria, Paraguay, Peru,

Philippines, Peru, Poland, Russia, South Korea, Sri Lanka Tanzania, Thailand, Ukraine, UAE, UK,

Uruguay, Vietnam, etc, to name a few.

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Dr Appaji informed that the business meet which will be held on three days from September 22 to 24

in Hyderabad will also see the giving away of 15 to 20 export awards for various categories of

pharma exporters along with 15 awards for those companies who have secured ‗granted patents‘

during current financial year. There will also be a CEO conclave chaired by Satish Reddy, board

member of Pharmexcil and chairman of Dr Reddy‘s Lab wherein experts will deliberate and discuss

new strategies and way ahead to push pharma exports.

Asia's biggest vaccine maker to seek fast-track nod for dengue drug in India

Asia's largest vaccine maker, Serum Institute of India, plans to file for fast-track approval to launch a

dengue treatment in India, its chief executive said, potentially becoming the first company globally to

launch a drug for the mosquito-borne virus.

Serum's plans come as India battles soaring death rates from dengue and its capital New Delhi

faces the worst outbreak of the virus in five years, exposing inadequate public health measures to

combat the disease.

Dengue is common in India and cases generally peak in October, after the monsoon rains. It is one

of the biggest causes of hospitalization and death among children in India.

Serum bought exclusive rights from U.S. biotech Visterra to sell its innovative monoclonal antibody,

VIS513, as a treatment for dengue in the Indian subcontinent in a deal worth up to $39 million, both

companies said earlier this month.

Serum, owned by the billionaire Cyrus Poonawalla, has sought the Indian government's approval to

import the antibody and conduct clinical trials in India, its Chief Executive Adar Poonawalla said in an

interview.

Visterra has tested the antibody on animals so far.

"Once you inject this into a patient who has dengue, they should show a result within three or four

days, or even sooner," he said. "It won't be a normal vaccine trial that needs to go into thousands of

thousands of patients to prove its safety and efficacy."

Approvals to launch new drugs generally take about three to four years in India, Poonawalla said.

"We are trying to make that into a year or maximum a year and a half if we can get quickly the

permissions and do a trial to prove that the virus is being neutralized in humans."

Except for a dip in 2011, the number of dengue cases in the country has been steadily rising since

2007, according to the World Health Organization.

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There is no dedicated treatment for the virus, and infected patients are generally asked to rest, drink

fluids, and take paracetamol to bring down fever and reduce joint pains.

"We would have to wait to see how the drug reacts in humans, as it has only been tested in animals

so far," said a senior virologist with a government research institute, declining to be named.

"There are other companies globally developing therapeutic antibodies."

There is no vaccine for dengue available in the market, but there are some undergoing clinical trials.

French drugmaker Sanofi SA hopes to win approval for the world's first dengue vaccine soon.

FDA streams $19m into rare disease programmes

The US Food and Drug Administration has awarded 18 new research grants worth more than $19

million to encourage and accelerate the development of products for patients with rare diseases.

The cash will flow into projects targeting 17 different therapeutic areas - including HPV-related

oropharyngeal cancer, Prader Willi Syndrome and familial dysautonomia - all of which represent high

areas of unmet need with little or no existing therapies.

Ten of the 18 awards fund studies that enrol children as young as newborns, while two are related to

sickle cell disease, specifically focusing on the extreme pain that patients suffer from, which is also a

leading cause of hospitalisations in this group.

The grants are awarded through the FDA‘s Orphan Products Grants Program, which is designed to

encourage clinical development of drugs, biologics, medical devices, or medical foods for use in rare

diseases by helping to fund studies that could underpin their approval.

EC, EU and WHO share 'need to know' private drug data

European regulators and the WHO have begun sharing confidential information about drug

applications, quality, and inspections under a new agreement.

The European Commission, European Medicines Agency and World Health Organization said they

started to ―step up cooperation‖ on EU medicines to help protect global public health on September

1.

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The organisations will share information not known to the public about the safety, quality and efficacy

of on-the-market pharmaceuticals and drug candidates under review.

This includes post-authorisation pharmacovigilance data, especially adverse reactions and periodic

safety update reports. It will also cover information in new drug applications on scientific advice,

orphan medicine designation, marketing authorisation and post-authorisation activities of significant

public health interest.

The groups will also swap data related to inspections, manufacturing facilities and clinical research,

especially applications for clinical studies in children.

The collaboration will speed access to new medicines, avoid duplication of assessments and

improve the safety of medicines, the organisations said.

Trade secrets

In a letter to Marie-Paule Kieney, WHO Assistant-Director General, the heads of the EMA and EC

wrote that confidential information may be shared with people within each organisation ―who have a

need to know,‖ including staff at DG Santé, EMA, and WHO, as well as ―national experts on

secondment,‖ members of their scientific committees, European national regulators, and consultants.

The agreement does not overrule limits on information-sharing from ―specific interests‖ or ―legal

obligations,‖ said the letter, including ―commercial, industrial or professional secrecy.‖

―In some cases, exchange of information under this arrangement may be subject to prior

authorisation from third parties concerned, including the person and/or organisation from which the

information emanated,‖ wrote EC Health and Food Safety head Ladislav Miko and Deputy Executive

Director of the EMA, Andreas Pott.

FDA revokes approval for Sun Pharma's seizure drug over compliance issues

The U.S. Food and Drug Administration has revoked an approval issued in March to India's Sun

Pharma Advanced Research Company Ltd (SPARC) to launch a drug for seizures, citing

manufacturing quality problems at its production site.

The move comes as a setback to SPARC, the research arm of India's largest drugmaker, Sun

Pharmaceutical Industries Ltd. The drug, Elepsia XR, was its first to receive an FDA approval.

The company said in June it had been working "very aggressively" to find partners for the product. It

had had "some advanced discussions" and aimed to launch the drug by the second half of fiscal

2016.

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Analysts estimated modest sales of about $50 million annually from Elepsia XR.

SPARC had said it would produce the drug at Sun Pharma's Halol plant, in the western Indian state

of Gujarat, as an adjunct treatment for partial onset seizures in epilepsy patients of 12 years and

older.

Most analysts saw the approval as positive mainly because it came despite the FDA having

expressed concerns a year ago about manufacturing processes at the Halol plant.

Sun Pharma had been working on fixing the issues the FDA outlined and some analysts said the

approval allayed fears of a possible adverse FDA action at Halol.

On Saturday, SPARC said the FDA issued it a "Complete Response Letter" in which it said "the

compliance status of the manufacturing facility was not acceptable on the date of approval".

It said Sun Pharma "has taken several corrective measures" to fix problems at the plant.

Katoch panel makes sweeping recommendations for revival of API manufacturing including

15-year tax free status

The Katoch Committee on Active Pharmaceuticals Ingredients (APIs), constituted by the department

of pharmaceuticals (DoP), has made sweeping recommendations for revival of API manufacturing in

India including tax free status to cluster developers and cluster participants for 15 years.

Immediate financial investment will be required from the government for development of clusters

which may be in the form of a professionally managed dedicated equity fund for the promotion of

manufacture of APIs. All central and state duties, taxes, levies etc in creating the entire community

cluster infrastructure and individual unit infrastructure should be zero. If a unit promises more than

50 per cent capacity utilized for NLEM products then at least these benefits should be given, the

panel recommended.

The panel also recommended soft loans to the industry through interest subvention upto 7.5 per

cent, at least at par with interbank lending rates. Capex loan to the manufacturers of APIs for high

priority identified drugs, with a moratorium of 10 years for repayment was recommended.

Alternatively debt instruments should be long term ie 3+5 years for APIs/intermediates and 3+7

years duration for fermentation. Margin money for strategic projects should be cut down, preferably

to 15 per cent equity and 85 per cent debt.

To encourage foreign investment, the committee recommended that faster clearances, funding for

green field/brown field areas should be appropriately analyzed and support should be encouraged

for the brownfield technologies.

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Income tax rebates on upgradation of the existing R&D facilities should be doubled to 400 per cent

from existing 200 per cent so as to encourage new development. Income tax benefits should be

given for manufacturing companies for an initial period of 10 years for each product from the date of

launch of the product, the committee further recommended.

A long term strategy keeping a goal of strengthening API sector by involving ministry of commerce

as well as other regulatory authorities is required, the committee recommended and suggested

judicious and liberal use of measures like anti-dumping, safeguards/duties, reciprocation and

application of rules of origin.

The DoP has now asked the industry associations like IDMA, IPA, OPPI and BDMA to provide their

comments latest by October 12, 2015.

Delhi drug control dept to replicate Gujarat's e-governance model for better governance

The six-member team headed by Dr Mrinalini Darswal from the drugs control department of Delhi

recently visited the Gujarat FDCA office to discuss and deliberate over adopting the much renowned

e-governance initiative adopted in the state. Apart from getting first hand experience of the

regulatory mechanism adopted in the state, the senior officials from the Delhi drugs control

department is reported to be deeply impressed by the Gujarat‘s much accomplished and well

accepted e-governance programme.

The main aim behind this visit, which included two members each from the drugs and food

department along with a member from the administrative department, was to understand the

modalities and key requirements needed for replicating the same in Delhi. Dr Hemant G Koshia,

commissioner of Gujarat FDCA informed that they showed keen interest in understanding the self-

licensing software Xtended Licensing and Laboratory Note (XLN) and effectively adopting it in Delhi

to ensure good governance.

This software, an integral part of the e-governance programme adopted by the Gujarat drug authority

has been successful in regulating the sales and manufacturing aspects related to drugs, food and

cosmetics; issuance of licenses, etc. One of the most important features of this software is that it

enables the registration of all the pharmacists and chemists within the state, which prevents multiple

illegal enrollments of pharmacists, a grave issue that regulators have to tackle with today.

Dr Koshia added that apart from the XLN software, they were also equally intrigued by the online

application for granting product licenses called drug manufacturing license application (DMLA) that

enabled the regulators to deliver efficient paperless services on time, and the mobile food and drug

testing lab that was recently launched in the state. It is important to note that Gujarat has been the

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only state in the country to first adopt this advanced governance modalities for better administrative

and regulatory purpose.

―It is a matter of great pride that other regulators look upon us as inspiration to adopt and implement

our governance style. They were really impressed by our capabilities and expressed their full intent

to adopt the same in Delhi as well, which in itself is an achievement for us as it comes as a

testament to our commitment to safeguard the public health through such progressive initiatives,‖ Dr

Koshia expressed.

As of now nearly 14 states from across the country including Maharashtra, Goa, Karnataka, etc.

have adopted the e-governance initiative inspired by Gujarat FDCA.

Not surprisingly, in yet another recognition to their ongoing efforts at improving the regulatory

functions, the Gujarat FDCA was this week recognized with the Skoch award for being India‘s best

2015 in smart governance for its XLN software.

Preparing for FDA’s Final Ruling on the Foreign Supplier Verification Program (FSVP)

FDA plans to publish the final rule for the Foreign Supplier Verification Program (FSVP) on October

31, 2015under the Food Safety Modernization Act (FSMA). This rule will require U.S. food importers

to adopt an FSVP, verifying that the foods they import are safe and their foreign suppliers are

operating within the requirements of FDA‘s other substantive food safety regulations. Importers that

are not exempt from this rule will be required to comply within eighteen months of its publication

date. Hence, we advise importers to begin making preparations for it now!

Will Your Products Be Exempted?

Foods exempt from the FSVP rule include foods that are: subject to the seafood Hazard Analysis

and Critical Control Plan (HACCP), subject to juice HACCP, only for research or evaluation,

alcoholic beverages, transshipped, for personal use only, or imported under FDA‘s Import For Export

program. In addition, foods subject to the low-acid canned food and acidified food regulations

(LACF/AF) are exempt from addressing microbiological hazards under the FSVP rule, since those

hazards are covered under FDA‘s LACF/AF contols.

All other imported foods must be in compliance with the FSVP rule.

What Importers Should Know

Specifically, importers will be required to adopt an FSVP that identifies and addresses the risks and

hazards associated with each type of food product they import, and write a plan (similar to a HACCP

plan) for each imported food/foreign food suppler combination. Each importer will be required to

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maintain records indicating that it has met the FSVP requirements, and must present those records

to FDA upon its request.

The FSVP provision requires reviewing the compliance status of their imported foods and of their

foreign suppliers. Hence, importers should start checking into the regulatory history of their foreign

suppliers. Importers might begin by checking to see if any of their suppliers are on an import alert or

are subject to an FDA warning letter (posted on FDA‘s website), and other records of violations of

FDA regulations. As a word of caution, FDA‘s import alerts page represents only a ―snap shot‖ in

time. FDA‘s import alerts do not reflect the history of the firm – just its current status. (For a more

robust regulatory report, contact us at FDAImports.com). Food importers should also check their

suppliers‘ food safety performance history.

Under the revised proposed FSVP rule, importers will be required to determine any known or

reasonably foreseeable hazards of the foods they import and establish controls to minimize or

prevent those hazards. Before distributing the food, the importer must verify that the controls are

effective by performing a verification activity which may be conducting an onsite audit, sampling and

testing of the foods, or reviewing the foreign supplier‘s food safety records.

Also, importers will need to periodically reassess the effectiveness of their FSVPs by being aware of

any new information about the potential risks associated with the foods they import and their

suppliers, and they must revise any FSVPs that are inadequate. Remember, it is critical for

importers to make and maintain adequate records of all FSVP activities!

Where are the Gaps in your FSVP?

We strongly encourage all importers subject to the FSVP rule to begin preparing their FSVPs now

since they only have 18 months to comply once the rule is published! Start now by evaluating the

risks and hazards associated with the foods you import, checking your suppliers‘ compliance history

with FDA, reviewing current food safety plans and SOPs, and begin drafting the plans.

Position yourself ahead of your competition in the race for FSVP compliance. Contact us today for

help filling in the gaps in your existing plans.

How much more does the U.S. pay for drugs? Up to 10 times more, report says

Skyrocketing drug prices are triggering a firestorm of criticism, with lawmakers and the public calling

for new reforms. A common point: Drugs cost more in the U.S. than in other countries that use cost

assessments and price caps to keep a lid on costs.

Here's how much, according to a payer organization that studies relative pricing in an annual report.

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The International Federation of Health Plans (IFHP) sifted through insurance data to compare pricing

for prescription drugs in countries such as the U.S., Australia, Argentina, Spain and Canada. The

group found enormous differences between the U.S. and other countries, especially with specialty

meds such as Novartis' ($NVS) cancer fighter Gleevec and Teva Pharmaceutical Industries'

($TEVA) multiple sclerosis powerhouse Copaxone.

For example, the average price for Gleevec in the U.S. is $6,214, while the same drug costs $989 in

New Zealand, according to the IFHP research, based on 2013 numbers. And Copaxone runs at an

average price of $3,903 in the U.S. compared with $862 in England.

Sampling on spurious drugs from ports to conclude by September 30

Sampling of drugs imported into the country through its 9 notified ports under the national survey on

spurious and not-of-standard quality (NSQ) drugs is likely to conclude on September 30, 2015.

Conducted by National Institute of Biologicals (NIB) as per a statistical design, around 3200 APIs

and formulations have been collected till date.

Drug samplings done at ports in Delhi, Hyderabad, Ahmedabad, Chennai, Mumbai, Kolkata in

collaboration with Indian Statistical Institute (ISI), Hyderabad will cover 224 molecules under 15

therapeutic categories. The sampling at ports which was earlier scheduled to be a one-month

exercise got further extended to 3 months to accomplish collection of more drug samples in a

comprehensive manner.

As part of the national drug survey, around 43000 field data or samples have already been collected

from 665 of the total 676 districts of the country based on a statistical design encompassing all the

retail drug stores including government medical stores, CHCs and PHCs. These 43000 samples

have also further been sent to 7 central drug testing labs and 3 state drug testing labs of the country.

Aimed at identifying geographical areas where spurious drugs are available, around 1000 drug

inspectors from across the country were trained for the pan-India initiative. Based on this broad-

based survey, a focused monitoring can be done by the concerned authorities in these geographical

areas for eliminating the menace of spurious drugs. A similar survey in 2009 had revealed that the

extent of drugs found spurious was 0.046 per cent only.

In order to assess the extent of spurious drugs and NSQ drugs in a comprehensive manner, the drug

regulatory authority - Central Drugs Standard Control Organisation (CDSCO) formulated the survey

plan in consultation with NIB for conducting the study. The survey which is a part of the co-ordinated

efforts between Centre and the states will help project a clear statistics on spurious drugs, thus

clarifying India‘s stand on the same with scientific evidence.

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The National Sample Survey Office (NSSO) had asked the state governments to provide information

to arrive at a statistical design for the survey like information such as the number of retail outlets

(district-wise); information regarding the maximum prescription of drugs under each of the 15

categories including their trade name district wise; number of civil hospital stores (district-wise);

number of central medical store (state-wise); and number of Central Government Health Scheme

(CGHS) dispensaries throughout the country. NSSO is an organisation under the ministry of

statistics of the government of India which conducts regular socio-economic surveys in the country.

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Terminology

Packaging component means any single part of a container closure system. Typical

components are containers (e.g., ampules, vials, bottles), container liners (e.g., tube liners),

closures (e.g., screw caps, stoppers), closure liners, stopper overseals, container inner seals,

administration ports (e.g., on large-volume parenterals (LVPs)), overwraps, administration

accessories, and container labels.

Primary packaging component means a packaging component that is or may be in direct

contact with the dosage form.

Secondary packaging component means a packaging component that is not and will not be in

direct contact with the dosage form.

Container closure system refers to the sum of packaging components that together contain

and protect the dosage form. This includes primary packaging components and secondary

packaging components, if the latter are intended to provide additional protection to the drug

product.

Packaging system is equivalent to a container closure system.

Package or market package refers to the container closure system and labeling, associated

components (e.g., dosing cups, droppers, spoons), and external packaging (e.g., cartons or

shrink wrap). A market package is the article provided to a pharmacist or retail customer upon

purchase and does not include packaging used solely for the purpose of shipping such articles.

Contract packager is a firm retained by the applicant to package a drug product. The

applicant remains responsible for the quality of the drug product during shipping, storage, and

packaging.

Re-packager is a firm that buys drug product from the drug product manufacturer or

distributor and repackages it for sale under a label different from that of the manufacturer.

The re-packager is responsible for ensuring the quality and stability of the repackaged drug

product.

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New Guidance Agency Information Collection Activities; Proposed Collection; Comment Request; Guidance

for Industry on Safety Labeling Changes-Implementation of Section 505(o)(4) of the Federal

Food, Drug, and Cosmetic Act

The Food and Drug Administration (FDA) is announcing an opportunity for public comment on the

proposed collection of certain information by the Agency. Under the Paperwork Reduction Act of

1995 (the PRA), Federal Agencies are required to publish notice in the Federal Register concerning

each proposed collection of information, including each proposed extension of an existing collection

of information, and to allow 60 days for public comment in response to the notice.

This notice solicits comments on the requirement to make safety related labeling changes based

upon new safety information that becomes available after the drug or biological product is approved

under the Federal Food, Drug, and Cosmetic Act (the FD&C Act) or the Public Health Service Act

(PHS Act.)

Source: https://www.federalregister.gov/articles/2015/09/02/2015-21645/agency-information-

collection-activities-proposed-collection-comment-request-guidance-for-industry

Nonproprietary Naming of Biological Products; Draft Guidance for Industry; Availability

The Food and Drug Administration (FDA, we, or the Agency) is announcing the availability of a draft

guidance for industry entitled ―Nonproprietary Naming of Biological Products.‖ The draft guidance

describes our current thinking on the need for biological products licensed under the Public Health

Service Act (PHS Act) to bear a nonproprietary name that includes an FDA-designated suffix. Our

current thinking is that shared nonproprietary names are not appropriate for all biological products.

There is a need to clearly identify biological products to improve pharmacovigilance, and, for the

purposes of safe use, to clearly differentiate among biological products that have not been

determined to be interchangeable. Accordingly, for biological products, we intend to designate a

nonproprietary name that includes a suffix composed of four lowercase letters.

Each suffix will be incorporated in the nonproprietary name of the product. This naming convention is

applicable to biological products previously licensed and newly licensed under the PHS Act. The

nonproprietary name designated for originator biological products, related biological products, and

biosimilars will include a unique suffix. However, FDA is considering whether the nonproprietary

name for an interchangeable product should include a unique suffix, or should share the same suffix

as its reference product. FDA invites comment on the draft guidance and solicits comments on ways

to improve active pharmacovigilance systems for the purposes of monitoring the safety of biological

products.

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Source: https://www.federalregister.gov/articles/2015/08/28/2015-21383/nonproprietary-naming-of-

biological-products-draft-guidance-for-industry-availability

EMA Guideline for good clinical practice E6(R2)

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing,

conducting, recording and reporting trials that involve the participation of human subjects.

Compliance with this standard provides public assurance that the rights, safety and well-being of trial

subjects are protected, consistent with the principles that have their origin in the Declaration of

Helsinki, and that the clinical trial data are credible.

Source: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/08/WC5

00191488.pdf

New guidance on good clinical practice

The European Medicines Agency (EMA) is consulting on a new International Conference on

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

guidance document on good clinical practice (GCP).

The aim of the guidance is to provide a unified standard for the European Union, Japan and the

United States so that there is consistency around clinical data requirements in these regions.

Source: https://www.gov.uk/government/news/new-guidance-on-good-clinical-practice

Formal Dispute Resolution: Appeals Above the Division Level Guidance for Industry and

Review Staff Good Review Practice

This guidance provides recommendations for industry and review staff on the procedures in the

Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and

Research (CBER) for resolving scientific and/or medical disputes that cannot be resolved at the

division level.

This guidance describes the formal dispute resolution (FDR) procedures for formally appealing

scientific and/or medical issues to the office or center level and provides a structured procedure for

resolving disputes.

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance

s/UCM343101.pdf

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Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry

This guidance provides recommendations to sponsors of investigational new drug applications, new

drug applications, and biologics license applications regulated by the Center for Drug Evaluation and

Research (CDER) regarding nonclinical studies intended to identify the potential for a drug to cause

endocrine-related toxicity.

The goals of this guidance are to:

Describe how endocrine-related toxicity is assessed using the standard battery of nonclinical

tests.

Identify situations in which additional studies should be considered to more fully characterize

the endocrine-related toxicity of a drug.

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance

s/UCM369043.pdf

US FDA releases Q3D Elemental Impurities - Guidance for Industry

Elemental impurities in drug products may arise from several sources; they may be residual catalysts

that were added intentionally in synthesis or may be present as impurities (e.g., through interactions

with processing equipment or container/closure systems or by being present in components of the

drug product).

Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the

drug product should be controlled within acceptable limits.

There are three parts of this guidance:

• the evaluation of the toxicity data for potential elemental impurities;

• the establishment of a permitted daily exposure (PDE) for each element of toxicological

concern;

• and application of a risk-based approach to control elemental impurities in drug products.

Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance

s/UCM371025.pdf

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6 Compositional guidelines added by TGA:

The following new guidelines have been published on the TGA website.

· Compositional guideline: Calcium pyruvate

<https://www.tga.gov.au/compositional-guideline-calcium-pyruvate>

· Compositional guideline: Choline dihydrogen citrate

<https://www.tga.gov.au/compositional-guideline-choline-dihydrogen-citrate>

· Compositional guideline: Dimethylglycine hydrochloride

<https://www.tga.gov.au/compositional-guideline-dimethylglycine-hydrochloride>

· Compositional guideline: Lepidium meyenii (dried tuber)

<https://www.tga.gov.au/compositional-guideline-lepidium-meyenii-dried-tuber>

· Compositional guideline: Magnesium pyruvate

<https://www.tga.gov.au/compositional-guideline-magnesium-pyruvate>

· Compositional guideline: Ribose

<https://www.tga.gov.au/compositional-guideline-ribose>

As of September 2015, updated Requirements apply to the Application of a CEP!

The EDQM recently published a revised version of its certification policy document titled "Content of

the dossier for chemical purity and microbiological quality". The revision takes into account the new

regulatory developments in Europe that are reflected in many revised and, to some extent, new

guidelines of the EMA, ICH as well as in some revised general chapters and monographs of the

European Pharmacopoeia (see the summary of these guidance documents under "References" at

the end of the policy document).

The aim of the policy document is to provide CEP applicants with a guideline for preparing the

authorisation dossier and for compiling all the documents required for this. The dossier is to be

divided into 3 modules:

Module 1: The authorisation history of the products is to be described which contain the active

ingredient for which a CEP application is submitted. The following declarations are also to be

submitted:

- a declaration of GMP conformity from all manufacturers involved in the manufacture

of intermediate products and the final active ingredient,

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- a declaration from these manufacturers that they are willing to be inspected before and after

being granted a certificate of suitability,

- a declaration of the CEP applicant/holder about the use/non-use of material of human or

animal origin. In cases where such material is used, compliance with the provisions of the

EDQM Guideline "Content of the dossier for a substance for TSE risk assessment

(PA/PH/CEP (06) 2)" should be demonstrated.

- a commitment to provide the EDQM, upon request, with samples of the final active

ingredient and/or its impurities,

- a declaration to acknowledge the provisions of the Certification procedure and to agree to

the exchange of assessment reports between the national competent authorities of the

European Member States as well as the EMA experts.

Module 2: Part of this module (analogous to the CTD structure) is the Quality Overall

Summary (QOS). The EDQM published a ready-to-use Word template for this. The template

can be accessed on the EDQM website "Submit a new application" which contains the most

important facts regarding the submission of a new application for a CEP together with links for

the relevant documents. With the description of the active ingredient in the QOS, evidence

must be provided that the pharmacopoeia monograph is suitable to control the quality of the

active ingredient, particularly with regard to the impurity profile of the substance. Plausible

justification is important for the cases where testing for possible impurities is omitted.

Module 3: Also this Module reflects the CTD structure, i.e. the content of subchapter 3.2.S.1

to 3.2.S.7 with further subdivisions corresponds to the content of a standard authorisation

application for a medicinal product. Here are some examples of important points that must be

considered in light of the regulatory developments:

- A CEP that covers different grades of active ingredient (different physical properties, such as

particle size or certain polymorphic forms) cannot be issued if these grades also have

different limits for impurities and if different analytical methods of determination are required

for their control. A CEP for different grades of freedom from pyrogens or bacterial endotoxins

is only possible when the relevant monograph foresees this. Otherwise, separate applications

must be submitted for grades of the active ingredient that do and do not contain pyrogens or

endotoxins ("General properties"; 3.2.S.1.3).

- Different production sites and manufacturing processes may only be described in one and

the same application if it can be proven in a plausible manner that the quality (specifications

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and impurity profiles) of the relevant intermediate products and the final active ingredient is

not significantly changed. Reprocessing steps are to be clearly described; reworking is not

normally accepted ("Description of the manufacturing process and process controls";

3.2.S.2.2).

- The selection of the starting material is to be justified as per the regulations of ICH Q11 and

the EMA Reflection Pager on Starting Materials (EMA/448443/2014). Single step synthesis is

generally not accepted unless the starting material itself has a CEP (see EDQM Guideline

"Use of a CEP to describe a starting material in an application for another CEP"). Testing for

impurities including solvents, catalysts and reactants and absence of a possible carryover into

the final product is to be described ("Control of materials"; 3.2.S.2.3).

- Validation data for manufacturing sterile substances is to be submitted; the complete

validation data (protocols and reports) is to be presented for the sterilisation process. Part 2 of

the EU GMP guidelines applies to the manufacture of the active ingredient until immediately

before the sterilisation stage; sterilisation and aseptic processing should be carried out

according to Annex 1 of the guideline ("Process validation and/or evaluation" 3.2.S.2.5).

- Testing for all kinds of impurities (reagents, catalysts, solvents, by-products etc.) and their

potential sources are to be described, particularly if the monograph does not contain suitable

test methods. Analytical data and a minimum of significant validation data (incl. LOD/LOQ

values) are to be presented ("Impurities"; 3.2.S.3.2).

- Data from formal stability studies are not normally required for active ingredients. However,

when a retest period is requested to be mentioned on the certificate, these data must be

collected and submitted as per the guideline "Stability testing of existing active substances

and related finished products" and its Annexes ("Stability"; 3.2.S.7).

Overall the provisions of the new certification policy document are rather extensive. As mentioned at

the start, the pharmacopoeia authority has reacted to the increased requirements in the newly

published and revised ICH and EU guidelines.

The policy document is now applicable with no transition period, which means CEP applicants who

submitted their application without knowing about this document may receive from the EDQM a

particularly long list of deficiencies along with the request to submit the relevant information required.

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In-process revision to USP <1058> - Analytical Instrument Qualification (AIQ)

An in-process revision to USP <1058> on Analytical Instrument Qualification (AIQ) was issued for

public comment in the May-June 2015 issue of Pharmacopoeial Forum. What has changed in this

version of USP <1058>?

The introduction has been expanded and now includes mention of risk assessment and risk

management being essential to undertaking AIQ. The section on the instrument groups has been

brought forward to the introduction from the back of the current general chapter and the criteria

presented but in contrast with few examples are given as the group an instrument is in depends on

the intended use. In the sections on installation qualification and operational qualification there is the

requirement that purchased packages must be reviewed pre and post execution. An improvement is

that the OQ needs to be performed on the software configuration used for analysis to integrate

computer validation with instrument qualification. The instrument parameters to qualify are to be

found in the instrument specific general chapters of the USP. In the PQ phase there is a

requirement for periodic review of critical computerised systems.

From the software perspective, the reference to the FDA's guidance on general principles of

software validation has been replaced by GAMP 5 and the GAMP Lab Systems Guide 2nd Edition

which are far more pertinent to laboratory instruments and systems than the FDA's document. There

is mention of verification of instrument calculations and control of user defined programs that are

both missing in the current version of <1058>. There is increased granularity of software as <1058>

now considers configured and customised lab computerised systems but the section on standalone

software has been deleted from the proposed update.

Instead of definition of validation and qualification, there is now a glossary of 7 terms at the back of

the document.

New FDA Requirements for the Development of Herbal Medicinal Products

In August 2015, the FDA has published a draft of the guideline "Botanical Drug Development". This

guideline addresses issues arising from the particular nature of herbal medicinal products. After its

finalization it is supposed to replace the previous guideline from June 2004.

The general approach in the development of herbal medicinal products remained unchanged since

2004. But due to the better understanding of herbal medicinal products and the experience gained

during the review of the approval documents for herbals (NDAs/New Drug Applications and

INDs/Investigational New Drug Applications), specific recommendations could be adjusted. Still, new

sections will be supplemented to better address the late development phase.

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The draft guideline also covers the following topics:

General, regulatory requirements

INDs for phase 1-3 clinical trials

NDAs for herbal medicinal products

For further information please see the full FDA document 'Botanical Drug Development'.

Genotoxic impurities: the new ICH M7 addendum to calculation of compound-specific

acceptable intakes

The final document of the ICH-Guideline M7 was published in June 2014. It describes the procedure

for evaluating the genotoxic potential of impurities in medicinal products (see also our news Final

ICH M7 Guideline on Genotoxic Impurities published dated 23 July 2014).

An important approach to the risk characterisation of impurities is the TTC concept (TTC = threshold

of toxicological concern). According to this approach the exposure to a mutagenic impurity having

the concentration of 1.5 µg per adult person per day is considered to be associated with a negligible

risk. It can be used as default evaluation approach to most pharmaceuticals for long-term treatment

(> 10 years) and where no carcinogenicity data are available (classes 2 and 3). According to ICH M7

the TTC concept should not be used where sufficient carcinogenicity data exist. Instead the data

should be used to calculate or derive compound-specific acceptable intakes.

Now the ICH published an addendum to Guideline M7 with the title "Application of the principles of

the ICH M7 Guideline to calculation of compound-specific acceptable intakes" ("Addendum to ICH

M7"; short name "M7(R1)").

This addendum describes the basis for calculating the acceptable intakes for 15 substances in total

that are common and widespread in pharmaceutical manufacturing. These substances are known to

have mutagenic/carcinogenic potential (ICH M7(R1) contains comprehensive references on the

toxicology of these substances). The calculations of the AI (acceptable intake) or PDE (permitted

daily exposure) values are partly based on a linear extrapolation from the TD50 values as well as on

toxicological data on the non-linear dose-response curve of the relevant substances.

ICH M7(R1) has the status of a draft consensus guideline (step 2 document). The draft guideline

was published on the EMA "Scientific Guidelines" site as step 2b document on 4 August 2015 for

consultation (deadline for comments: 3 February 2016).

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New guidance to speed up development of antibiotics

EMA invites comments on its draft guideline on the use of pharmacokinetics and

pharmacodynamics analyses in the development of antibiotics

The European Medicines Agency (EMA) has released a draft guideline for public consultation on the

use of pharmacokinetics and pharmacodynamics analyses in the development of antibiotics. The

document provides guidance for the conduct of robust analyses to facilitate and speed up the

development of new antibiotics, in particular those targeting multi-drug resistant bacteria. Comments

on this draft guideline should be sent to IDWPsecretariat@ema.europa.eu using the form provided,

no later than 31 March 2016.

The increasing emergence of bacteria that have become resistant to a wide range of antibiotics is a

major and global public health issue. On the one hand it is essential to encourage the prudent use of

antibiotics so that development of antimicrobial resistance can be reduced to a minimum, on the

other hand new antibiotics are urgently needed for the treatment of serious infectious diseases, in

particular when patients have very limited or no remaining treatment options. A central pillar in

EMA‘s strategy to fight antimicrobial resistance is to offer an environment that stimulates and

facilitates development of innovative antibiotics.

Pharmacokinetics relates to the effect the body has on a medicine; in other words how the

medicine is absorbed by the body, distributed through the organs, transformed and finally excreted.

Pharmacodynamics refers to the effect a medicine has on the body or on microorganisms or

parasites; in the context of antibiotics, this relates to the ability of a medicine to kill or inhibit the

growth of bacteria at a given dose.

With the development of modelling and simulation methods, pharmacokinetics and

pharmacodynamics analyses, which are conducted prior to the start of clinical trials in humans and

throughout the clinical development, play an increasing role during the development of a new

antibiotic by providing evidence around the appropriateness of the dose and frequency of

administration that should be used in patients to achieve the optimal benefit-risk balance. If they are

conducted in a robust manner, these analyses have the potential to reduce the size of the clinical

development programme.

These analyses are particularly crucial in the development of new antibiotics that address unmet

medical needs or target multi-drug resistant bacteria since they contribute to streamlining and

accelerating the development using innovative data-gathering strategies, in line with the new

regulatory approach described in the EMA addendum to the guideline on the evaluation of medicines

for the treatment of bacterial infections.

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They also provide important data to inform the selection of dose regimens that may minimise the risk

of developing resistant bacteria.

The draft guideline reflects both the recent scientific advances and the regulatory experience in this

area. It provides guidance to medicine developers for the conduct of robust pharmacokinetics and

pharmacodynamics analyses and outlines the regulatory requirements regarding the type of data

that need to be collected, their analyses and interpretation, in view of a marketing

authorisation application.

EMA is organising a workshop on 12-13 November 2015 with a broad range of stakeholders,

including academia, regulatory agencies, industry as well as international and EU experts in the field,

to discuss the draft guideline. The discussions will inform the finalisation of the document.

Attendance at the workshop is by invitation only. However, the workshop will be broadcast live on

the EMA website.

Controlled Correspondence Related to Generic Drug Development; Guidance for Industry;

Availability

The Food and Drug Administration (FDA or Agency) is announcing the availability of a guidance for

industry entitled ―Controlled Correspondence Related to Generic Drug Development‖. The guidance

document provides information regarding the process by which human generic drug manufacturers

and related industry can submit correspondence to FDA requesting information on generic drug

development. This guidance also describes FDA's process for providing communications related to

such correspondence.

FDA is announcing the availability of a guidance for industry entitled ―Controlled Correspondence

Related to Generic Drug Development‖. The guidance document provides information regarding the

process by which human generic drug manufacturers and related industry can submit

correspondence to FDA requesting information on generic drug development. This guidance also

describes FDA's process for providing communications related to such correspondence.

Under the provisions of the Generic Drug User Fee Amendments of 2012 (GDUFA), FDA agreed to

certain obligations as laid out in the Generic Drug User Fee Act Program Performance Goals and

Procedures for fiscal years 2013 through 2017 (the GDUFA Commitment Letter) that accompanies

the legislation (Ref. 1). Among those obligations is FDA's commitment to performance metrics for its

responses to controlled correspondence for fiscal years 2015 through 2017.

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AUDIT FINDINGS - 483 Observations

Firm Name 483 Observation

KIK Custom Products - June 25,

2015

Buildings used in the manufacturing and processing of a drug

product are not maintained in a good state of repair.

Kirkman Laboratories, Inc. -

June 24, 2015

Control procedures are not established which monitor the output

and validate the performance of those manufacturing processes

that may be responsible for causing variability in the

characteristics of in-process material and the drug product.

Cardinal Health 414, LLC - June

17, 2015

When errors occurred or a production batch failed to meet

specifications, you did not determine the need for an investigation,

conduct an investigation, and take appropriate corrective actions

when necessary.

Lehigh Valley Technologies, Inc.

- June 17, 2015

Equipment used in the manufacture, processing, packing or

holding of drug products is not suitably located to facilitate

operations for its intended use.

Galephar Pharmaceutical

Research, Inc. - June 11, 2015

The responsibilities and procedures applicable to the quality

control unit are not fully followed.

Prime Enterprises, Inc. - June 8,

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.

Baxter Healthcare Corp. - May 26, 2015

The responsibilities and procedures applicable to the quality

control unit are not fully followed.

InfuScience, a subsidiary of Bioscrip - May 15, 2015

Procedures describing the handling of all written and oral

complaints regarding a drug product are not followed.

Ei, LLC - May 8, 2015 Investigations of an unexplained discrepancy did not extend to

other batches of the same drug product and other drug products

that may have been associated with the specific failure or

discrepancy.

Fujifilm Diosynth Biotechnologies - May 1, 2015

There were multiple instances of filters clogging during the ... drug

substance commercial manufacturing process.

Catalent Pharma Solutions, LLC - March 20, 2015

The responsibilities and procedures applicable to the quality

control unit are not fully followed.

7 Oaks Pharmaceuticals Corp. - March 10, 2015

The responsibilities and procedures applicable to the quality

control unit are not in writing.

John W. Hollis, Inc. dba John Hollis Pharmacy - March 21,

Procedures designed to prevent microbiological contamination of

drug products purporting to be sterile do not include validation of

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2014 the sterilization process.

Cosmetic Essence, Inc. - March 20, 2014

Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the prior to release.

Ohm Laboratories, Inc. - March 18, 2014

Deviations from written test procedures and laboratory mechanisms are not justified.

Sonar Products, Inc. - March 18, 2014

The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.

Neolpharma, Inc. - June 18, 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.

Geritrex Corp. - March 21, 2014 Results of stability testing are not used in determining expiration dates.

The Wellness Pharmacy, LLC - March 12, 2015

Each batch of drug product purporting to be sterile and pyrogen-free is not laboratory tested to determine conformance to such requirements.

Angelini Pharma, Inc. - March 17, 2015

Written procedures have not been developed for the surveillance, receipt, evaluation, and reporting to FDA of post marketing adverse drug experiences.

Bell-More Laboratories, Inc. - March 13, 2015

Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

C.B. Fleet Co., Inc. - March 12, 2015

Employees engaged in the processing and packing of a drug product lack the training required to perform their assigned functions.

Hunter Holmes McGuire Veterans Admin Medical Center - March 11, 2015

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and written.

Afton Scientific, LLC - May 1, 2015

Drug products failing to meet established specifications are not rejected.

Elba, Inc. dba Elba Laboratories - April 1, 2014

Drug products failing to meet established specifications are not rejected.

Pharmakon Pharmaceuticals, Inc. - March 13, 2014

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed.

Americare Compounding, LLC - June 22, 2015

Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions.

Lotus Pharmaceutical Co. Ltd. - June 4, 2015

Your firm Quality Unit failed to fully follow the responsibilities of assuring that processes and procedures, among others, are approved in accordance to established specifications and using sound scientific rationales.

Bayer Health Care, LLC - July 30, 2015

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not written and followed.

Unifirst First Aid Corp. - July 13, Drug product expiration dates do not appear on the labeling in the

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2015 manner prescribed by regulations.

Central Solutions, Inc. - July 10, 2015

The number of qualified personnel is inadequate to supervise the manufacture, processing, packing, and holding of each drug product.

Steuart Laboratories - July 10, 2015

There is no written assessment of stability of homeopathic drug products based at least on marketing experience with the drug product to indicate that there is no degradation of the product for the normal or expected period of use.

Grant Industries, Inc. - July 15, 2015

The responsibilities and procedures applicable to Quality Unit are not fully followed.

Research Technologies, Inc. - March 18, 2014

GMP training is not conducted on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.

Pfeiffer Pharmaceuticals, Inc. - March 31, 2014

Written procedures are not followed for the identification, storage, and handling of drug product containers.

Morton Grove Pharmaceuticals, Inc. - March 26, 2014

The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.

BMC 1092, Inc. dba Solo Laboratories, Inc. - March 13, 2014

The responsibilities and procedures applicable to the quality control unit are not in writing.

KRS Global Biotechnology, Inc. - March 17, 2014

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.

Pharmacreams Corp. - March 6, 2014

There is no quality control unit.

Swiss Caps USA, Inc. - March 28, 2014

Your quality control personnel approved and released for distribution a batch of dietary supplement that did not meet established product specifications.

Tapemark Co. - March 25, 2014 Written procedures are not followed for evaluations conducted at least annually to review records associated with a representative number of batches, whether approved or rejected.

Upsher Smith Laboratories, Inc. - March 3, 2014

Employees are not given training in the particular operations they perform as part of their function.

Pharmacia & Upjohn Co., LLC - July 9, 2015

Documented investigations into discrepancies and out-of-specification results are not fully investigated.

Iso-Tex Diagnostics, Inc. - July 10, 2015

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.

Allergan Sales, LLC - July 10, 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.

The Dodge Co., Inc. - March 25, 2014

There is no quality control unit.

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Alza Corp. - Sept. 19, 2014 Written production and process control procedures are not followed in the execution of production and process control functions.

Qilu Tianhe Pharmaceutical Co., Ltd. - June 2, 2015

Batch manufacturing instructions are not followed.

FDA 483: Millers of Wyckoff, Inc., NJ, - Producer of Sterile Drugs:

1. Procedures designed to prevent microbiological contamination of drug products purporting to

be sterile are not established,written, and followed.

2. Drug products do not bear an expiration date determined by appropriate stability data to

assure they meet applicable standards of identity, strength, quality and purity at the time use.

3. Each batch of drug product purporting to be sterile is not laboratory tested to determine

conformance to such requirements.

4. Equipment and utensils are not maintained at appropriate intervals to prevent malfunctions

contamination that would alter the safety, identity, strength, quality or purity of drug product.

5. Employees are not given training in the particular operations they perform as part of their

function.

6. Aseptic processing areas are deficient regarding the system for monitoring environmental

conditions.

7. There is a failure to thoroughly review the failure of a batch or any its components meet any of

its specifications whether or not the batch has been already distributed.

8. Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the

equipment to produce aseptic conditions.

9. Testing and release of drug product for distribution do not include appropriate laboratory

determination satisfactory conformance to the final specifications prior to release.

10. Procedures designed to prevent microbiological contamination of drug products purporting be

sterile do not include adequate validation the sterilization process.

11. The responsibilities and procedures applicable to the quality control unit are not in writing and

fully followed.

12. The flow of components, drug product containers, in-process materials, and drug products

though the building is not designed to prevent contamination.

FDA 483: InvaGen Pharmaceuticals, Inc., NY

Observation: The responsibilities and procedures applicable to the quality control unit are not fully

followed.

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FDA Warning letters

Pan Drugs Ltd. 9/2/15, India

1. Failure to properly maintain, repair, and keep clean buildings used in the manufacture of APIs in a manner that prevents contamination where open equipment is used. For example,

a) Our investigator observed holes in the walls and roof which allowed pigeons access near production equipment in multiple manufacturing areas.

b) Gaps and holes in outside walls for piping and air ducts which allow contaminants to enter the building.

2. Failure to properly maintain equipment used in the manufacture of APIs and minimize the risk of contamination, where open equipment is used. For example,

a) Our investigator observed rust, dirt, lubrication leaks, and exposed insulation material on and around open drug manufacturing equipment.

3. Failure to maintain complete data derived from all testing and to ensure conformance with established specifications and standards.

a. No heavy metals analysis was performed

b. The name of the analyst who performed the residual solvents analysis was not included

c. No second person reviewed the documents for accuracy, completeness, and compliance with established standards

Source: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm462075.htm

Jaychem Industries Ltd 9/4/15, New Zealand

CGMP Violations

Our investigators observed specific violations during the inspections, including, but not limited to, the

following.

1. You failed to ensure the quality of components, including your (b)(4) active ingredients

from various suppliers (21 CFR 211.84(d)(1) and (2)).

2. You failed to establish adequate written control procedures to monitor (b)(4) during

manufacturing (21 CFR 211.110(a)). You stated that you released all (b)(4) lotions

regardless of (b)(4) results. The effectiveness of(b)(4) Lotion is (b)(4).

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3. You failed to test finished batches for the identity and strength of active ingredients (21

CFR 211.165(a)).

4. You have no data to demonstrate that the chemical and physical properties

of (b)(4) Lotion remain acceptable throughout its (b)(4) shelf life (21 CFR 211.166(a)).

Source: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm462371.htm

Health Canada Non-Compliance Report

Health Canada Non-Compliance Report: MS Pharma, Inc, Canada

GMP Inspection Report Card Summary

Establishment

Name

Reference

Number

Inspection

Start Date Type of Inspection

Inspection

Rating

MS Pharma

Inc.

101675 2015-07-22 Good Manufacturing

Practices (GMP) - Regular

Non-Compliant

Summary of Observations

Observation

Number Regulation Summary of Observation

1 C.02.015 -

Quality Control

In the case where an original out-of-specification result was valid, a complete investigation of the deviation from specifications was not done.

Out of specification test results were not investigated to determine the cause of the problem.

Deficiencies were noted with the invalidation and re-testing done in a case of an out-of-specification test result that was clearly identified as a laboratory error.

In the case where an out-of-specification test result was valid, a complete investigation of the deviation from

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Summary of Observations

Observation

Number Regulation Summary of Observation

specifications was not done. Out of specification test results were not investigated to

determine the cause of the problem. Deficiencies were noted with the invalidation and re-testing

done in a case of an out-of-specification test result that was clearly identified as a laboratory error.

2 C.02.015 -

Quality Control

Deficiencies were noted in the control of the IT equipment used for laboratory analysis.

3 C.02.015 -

Quality Control

Deficiencies were noted in the labratory record keeping. Deficiencies were noted with the preparation of reagents in

the laboratory according to written procedures.

4 C.02.005 -

Equipment

Deficiencies were noted with the calibration of equipment used for significant testing operations.

5 C.02.006 -

Personnel

Not all personnel received continuing training in GMP principles relevant to their responsibilities.

Deficiencies were noted with the appointment of qualified personnel to carry out the duties of key personnel when these key people were absent.

6 C.02.015 -

Quality Control

Deficiencies were found with the suitability of the laboratory control equipment for the testing procedures being done.

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WHO Notice of Concern (NOC)Report

WHO Notice of Concern (NOC) - Svizera Labs Private Limited, India:

1. The company failed to adequately perform dissolution tests and may have manipulated

dissolution test results.

2. The company failed to ensure the integrity of data

(a) Several analyses were seen without records of the analysis being made in the

instrument log book without being retrievable in official analytical reports.

(b) Data was found to be deleted for several runs.

(c) Instrument audit trails were not available except for login and logouts/password

entry.

(d) The original weighing measurement values were not available.

(e) The company was unable to demonstrate their ability to readily restore data that

was archived or backed-up for HPLC equipment.

3. The company failed to adequately conduct stability tests inline with stability protocols and

commitments.

4. The company failed to maintain adequate records of equipment usage and failed to ensure

data integrity in production.

5. The company failed to provide adequate controls of contamination and cross-

contamination of the product.

6. The company may have falsified analytical test data

7. The company failed to maintain adequate standards of housekeeping and hygiene

8. The company failed to maintain adequate and true records for in-process controls in

production

9. The company failed to package products under adequate conditions on blister packaging

lines.

10. The company failed to ensure cleanliness of the air supply to manufacturing areas where

the product may have been exposed.

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Check your area for ….

• Have internal audits and address items that

are identified as soon as possible.

It is much better to resolve issues internally

before a regulatory inspection takes place.

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Article of the Month

Warning Signs of a Weak Quality Culture Quality Culture: An environment in which each and every person understands and embraces their responsibility for protecting product quality and patient safety.

Reference: Culture of Quality (Forbes Insight)

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Regulations of the Month

Subpart C--Buildings and Facilities

Sec. 211.42 Design and construction features.

(c) Operations shall be performed within specifically defined areas of adequate size. There shall be

separate or defined areas or such other control systems for the firm's operations as are necessary to

prevent contamination or mixups during the course of the following procedures:

(1) Receipt, identification, storage, and withholding from use of components, drug product

containers, closures, and labeling, pending the appropriate sampling, testing, or

examination by the quality control unit before release for manufacturing or packaging;

(2) Holding rejected components, drug product containers, closures, and labeling before

disposition;

(3) Storage of released components, drug product containers, closures, and labeling;

(4) Storage of in-process materials

Top Presentations of Pharma Uptoday

· Presentation on data integrity in Pharmaceutical Industry

· 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

· All about Tablets (Pharma)

PHARMA UPTODAY

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The module Consult Yourself.... “Know Regulation - No Observation” deals with most common

(top 20) basic CFR regulations having frequent violations and previous observations for better

understanding.

#1 "21 CFR 211.160" http://www.slideshare.net/skvemula/top-20-observation-series-1-21-cfr-211160

(Subpart I--Laboratory Controls: Sec. 211.160 General requirements.)

#2 "21 CFR 211.22" http://www.slideshare.net/skvemula/top-20-observation-series-2-21-cfr-21122

(Subpart B--Organization and Personnel: Sec. 211.22 Responsibilities of quality control unit)

#3 "21 CFR 211.192" http://www.slideshare.net/skvemula/top-20-observation-series-3-21-cfr-211192

(Subpart J--Records and Reports: Sec. 211.192 Production record review.)

#4 "21 CFR 211.67" http://www.slideshare.net/skvemula/top-20-observation-series-4-21-cfr-21167

(Subpart D—Equipment: Sec. 211.67 Equipment cleaning and maintenance)

#5 "21 CFR 211.100" http://www.slideshare.net/skvemula/top-20-observation-series-5-21-cfr-211100

(Subpart F- Production and Process Controls: Sec. 211.100 Written procedures; deviations.)

#6 "21 CFR 211.165" http://www.slideshare.net/skvemula/top-20-observation-series-6-21-cfr-211165

(Subpart I--Laboratory Controls: Sec. 211.165 Testing and release for distribution)

Few Pharma Uptoday topics can be accessed from our website

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Few Pharma Uptoday presentations can be accessed from our website

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