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VOLUME: 19 - ISSUE: OCT 2015 |
PHARMA UPTODAY
PHARMA UPTODAY
2
Inside this issue
3 News Uptoday
35 New Guidance
45 Audit Findings
483 Observations
- 483 of Millers of W...
PHARMA UPTODAY
3
News Uptoday
Fareva buys Merck & Co API plant in France and outlines plan to invest €25m
Fareva has bough...
PHARMA UPTODAY
4
Strides Arcolab stock price On September 03, 2015, Strides Arcolab closed at Rs 1201.90, up Rs
21.85, or ...
PHARMA UPTODAY
5
The drug is also used for healing of erosive esophagitis and pathological hypersecretory conditions.
Acco...
PHARMA UPTODAY
6
TGA approves Hospira's biosimilar InflectraRead
US drug giant Hospira recently announced that the biosimi...
PHARMA UPTODAY
7
MHRA uncovers $1m illegal ED drug haul
A UK man has been sentenced to 16 months in prison for smuggling i...
PHARMA UPTODAY
8
There are four new drugs approved to treat hepatitis C: Sovaldi and Harvoni, made by Gilead
Sciences; Vie...
PHARMA UPTODAY
9
How to become a QP for Europe
Both the ECA Academy and the European Qualified Person Association (EQPA) a...
PHARMA UPTODAY
10
 Pharmacology
 Pharmaceutical technology
 Toxicology
 Pharmacognosy (study of the composition and ef...
PHARMA UPTODAY
11
must be noted that this criterion has been incorporated with sufficient discussion and deliberation
with...
PHARMA UPTODAY
12
The company is acquiring InvaGen Pharmaceuticals
and Exelan Pharmaceuticals, which had combined
sales of...
PHARMA UPTODAY
13
Now those working in the pharmaceutical sector have admitted they too have suffered
breaches. The Crown ...
PHARMA UPTODAY
14
"The commerce ministry is planning to hold an open forum of pharma producers in Hyderabad during
the fou...
PHARMA UPTODAY
15
CDSCO launches IT enabled system for online submission of applications & monitoring of
clinical trials
T...
PHARMA UPTODAY
16
Slew of upcoming forward looking polices by Central govt to transform pharma industry:
DCGI
The Drugs Co...
PHARMA UPTODAY
17
listing out the SOPs to ensure minimum impediments. While these regulations would be tough to
ensure hig...
PHARMA UPTODAY
18
We have rigid Medical Council of India (MCI) regulations as to who can perform what procedure. If
we loo...
PHARMA UPTODAY
19
Technology can also massively impact how healthcare is delivered and funded. Eleven years ago we
concept...
PHARMA UPTODAY
20
India is the country's second-largest provider of "finished drug products," but its drug plants lead the...
PHARMA UPTODAY
21
According to officials, the Indian pharmaceutical industry, which is one of the most vibrant sectors of
...
PHARMA UPTODAY
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the country. We strongly believe that this can be achieved by overall understanding of the drug
regulato...
PHARMA UPTODAY
23
The plant was shuttered and put up for sale following a long-term viability assessment by Pfizer.
“There...
PHARMA UPTODAY
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“So because of that - and as consolidation continues both on our customers side as well [as us] -
they n...
PHARMA UPTODAY
25
Dr Appaji informed that the business meet which will be held on three days from September 22 to 24
in Hy...
PHARMA UPTODAY
26
There is no dedicated treatment for the virus, and infected patients are generally asked to rest, drink
...
PHARMA UPTODAY
27
The organisations will share information not known to the public about the safety, quality and efficacy
...
PHARMA UPTODAY
28
Analysts estimated modest sales of about $50 million annually from Elepsia XR.
SPARC had said it would p...
PHARMA UPTODAY
29
Income tax rebates on upgradation of the existing R&D facilities should be doubled to 400 per cent
from ...
PHARMA UPTODAY
30
only state in the country to first adopt this advanced governance modalities for better administrative
a...
PHARMA UPTODAY
31
maintain records indicating that it has met the FSVP requirements, and must present those records
to FDA...
PHARMA UPTODAY
32
The International Federation of Health Plans (IFHP) sifted through insurance data to compare pricing
for...
PHARMA UPTODAY
33
The National Sample Survey Office (NSSO) had asked the state governments to provide information
to arriv...
PHARMA UPTODAY
34
Terminology
Packaging component means any single part of a container closure system. Typical
components ...
PHARMA UPTODAY
35
New Guidance
Agency Information Collection Activities; Proposed Collection; Comment Request; Guidance
fo...
PHARMA UPTODAY
36
Source: https://www.federalregister.gov/articles/2015/08/28/2015-21383/nonproprietary-naming-of-
biologi...
PHARMA UPTODAY
37
Nonclinical Evaluation of Endocrine-Related Drug Toxicity Guidance for Industry
This guidance provides r...
PHARMA UPTODAY
38
6 Compositional guidelines added by TGA:
The following new guidelines have been published on the TGA web...
PHARMA UPTODAY
39
- a declaration from these manufacturers that they are willing to be inspected before and after
being gr...
PHARMA UPTODAY
40
and impurity profiles) of the relevant intermediate products and the final active ingredient is
not sign...
PHARMA UPTODAY
41
In-process revision to USP <1058> - Analytical Instrument Qualification (AIQ)
An in-process revision to ...
PHARMA UPTODAY
42
The draft guideline also covers the following topics:
 General, regulatory requirements
 INDs for phas...
PHARMA UPTODAY
43
New guidance to speed up development of antibiotics
EMA invites comments on its draft guideline on the u...
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015
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Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015

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To recap the previous month's pharma highlights, Monthly magazine Volume 19 has been released with the following content.

News Uptoday

New Guidance

Audit Findings
483 Observations (Millers of Wyckoff, Inc., NJ, - Producer of Sterile Drugs & InvaGen Pharmaceuticals, Inc., NY
Warning Letters (Pan Drugs Ltd., India & Jaychem Industries Ltd, New Zealand)
Health Canada Non Compliance Report (MS Pharma, Inc, Canada.)
WHO Notice of Concern (NOC)Report (Svizera Labs Private Limited, India)
Article of the Month - Warning Signs of a Weak Quality Culture

Regulations of the Month - Sec. 211.42 Design and construction features (c)(1) to (c)(4)

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Pharma Uptoday Monthly Magazine - Volume 19; issue: Oct 2015

  1. 1. VOLUME: 19 - ISSUE: OCT 2015 | PHARMA UPTODAY
  2. 2. PHARMA UPTODAY 2 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)
  3. 3. PHARMA UPTODAY 3 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.
  4. 4. PHARMA UPTODAY 4 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).
  5. 5. PHARMA UPTODAY 5 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."
  6. 6. PHARMA UPTODAY 6 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.
  7. 7. PHARMA UPTODAY 7 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.
  8. 8. PHARMA UPTODAY 8 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.
  9. 9. PHARMA UPTODAY 9 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
  10. 10. PHARMA UPTODAY 10  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
  11. 11. PHARMA UPTODAY 11 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.
  12. 12. PHARMA UPTODAY 12 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.
  13. 13. PHARMA UPTODAY 13 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).
  14. 14. PHARMA UPTODAY 14 "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.
  15. 15. PHARMA UPTODAY 15 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.
  16. 16. PHARMA UPTODAY 16 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
  17. 17. PHARMA UPTODAY 17 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.
  18. 18. PHARMA UPTODAY 18 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.
  19. 19. PHARMA UPTODAY 19 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."
  20. 20. PHARMA UPTODAY 20 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.
  21. 21. PHARMA UPTODAY 21 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
  22. 22. PHARMA UPTODAY 22 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.
  23. 23. PHARMA UPTODAY 23 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.
  24. 24. PHARMA UPTODAY 24 “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.
  25. 25. PHARMA UPTODAY 25 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.
  26. 26. PHARMA UPTODAY 26 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.
  27. 27. PHARMA UPTODAY 27 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.
  28. 28. PHARMA UPTODAY 28 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.
  29. 29. PHARMA UPTODAY 29 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
  30. 30. PHARMA UPTODAY 30 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
  31. 31. PHARMA UPTODAY 31 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.
  32. 32. PHARMA UPTODAY 32 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.
  33. 33. PHARMA UPTODAY 33 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.
  34. 34. PHARMA UPTODAY 34 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.
  35. 35. PHARMA UPTODAY 35 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.
  36. 36. PHARMA UPTODAY 36 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
  37. 37. PHARMA UPTODAY 37 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
  38. 38. PHARMA UPTODAY 38 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,
  39. 39. PHARMA UPTODAY 39 - 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
  40. 40. PHARMA UPTODAY 40 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.
  41. 41. PHARMA UPTODAY 41 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.
  42. 42. PHARMA UPTODAY 42 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).
  43. 43. PHARMA UPTODAY 43 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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