Pharma - Behavioural Issues

USFDA finds procedural lapses at Wockhardt's U.S. facility

The U.S. Food and Drug Administration has found as many as 12 procedural lapses in Wockhardt’s U.S. facility in Illinois.

The inspection, which was carried out by the FDA officials between January 22 and March 26, pointed out that the responsibilities and procedures applicable to the quality control unit were not in writing and fully followed.

“There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or the batch has already been distributed,” the report said in one of the observations.

The quality control unit lacked authority to review production records to assure no errors occurred and fully investigate errors that had occurred, it further said.

The FDA has already issued warning letters to two of the Wockhardt’s plants in India. In November last, the FDA issued an import alert, effectively a ban, against Wockhardt’s Chikalthana plant in western India.

The FDA had imposed a ban on the company’s Waluj plant in May. Wockhardt’s Managing Director Murtaza Khorakiwala recently told analysts that the FDA had in March inspected the company’s Chicago-based Morton Grove Pharmaceuticals unit, which accounts for more than 50 per cent of its sales in the United States.

When contacted, a company spokesperson declined to comment.

USFDA asks Indian pharma leaders to make quality their top priority

Top management of drugmaking companies must make quality control their top priority, said a senior US Food and Drug Administration (FDA) official at Hyderabad kicking off a series of FDA- Drug Controller General of India workshops to be held this year for Indian pharma companies to help them comply better to the US prescribed standards.

"Companies must ensure that they are saying what they do and they do what they say and demonstrate that they did it" said Leslie Ball, deputy director, office of international program, FDA. Since the beginning of last year, there's been a spike in "violations" at India based drug plants, according to data from FDA's Centre for Drug Evaluation and Research, the US drug safety office. The sites of leading drugmakers such as Ranbaxy Laboratories, Wockhardt, Strides Arcolab and Sun Pharma are on the list. Many of these allegations relate to 'data-fudging'.

This regulatory workshop in tie-up with Indian Pharma Alliance, a grouping of leading domestic drugmakers would be followed by 16 more of such meetings across India, which would be attended by 350 delegates from Indian pharma companies and 40 representative from central and state drug regulators' offices.

Howard Sklamberg, deputy commissioner, global regulatory operations and policy, (FDA) said in video message that leadership is all about choices and senior management in the companies must commit to pro-active rather than reactive approach to quality control and allocate adequate resources for managing quality. Every time the top executives see a slippage happen, they should follow it through with a sound internal investigation, he said.

At a time when leading Indian pharmaceutical companies have been cited for infringements by the US drug regulator, its chief Margaret Hamburg made her first visit to India in February this year. During her visit to India Hamburg had told ET "While some Indian companies operate state-of-the-art facilities and meet CGMPs (current good manufacturing practices), others do encounter problems and operational challenges. Staff from the FDA's India office will work with these companies to identify the problems and will take the necessary steps to self-correct".

An ET analysis showed that India-based drug manufacturing sites, including those of multinationals, accounted for over half of warning letters sent out globally by the US drug safety office in 2013. This is seen as high especially when compared with warnings letters that India received over the last three and half years, which were just a tenth of all warning letters sent out by the US drug safety office.

"Indian companies, which account for 40% of drug master files to date and 37% of Abbreviated New Drug Applications in 2012, accounted for 12% of US FDA warning letters," said DG Shah, secretary general of the Indian Pharmaceutical Alliance, a grouping of leading domestic drugmakers. Shah said he conducted a quantitative analysis of the FDA's enforcement actions from 2010 to June this year. India is the second largest supplier of over-the-counter and prescription drugs to the United States. Industry must effect a cultural change in attitude and implement processes vertically and horizontally across the company to keep up with a changing regulatory landscape of increased scrutiny worldwide, said Shah. He however expects the regulators to shift their role from just policing to training and communicating the rationale of prescribed processes, for companies to better appreciate those that can mitigate risks related to drug safety. "When a student slips in performance, the teacher also has to partake responsibility for it and take measures to help the student" he said, drawing a parallel between regulators and teachers.

During her visit early this year, when Hamburg was asked whether FDA is being too stringent with Indian drugmakers as believed in a section of the government, she had said, "It's because of our commitment to protecting the health of the American public that we've been focused on increasing our collaborative efforts and risk-based inspectional activity in India for a number of years already. And the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 does require the FDA to achieve the same inspectional schedule for foreign and domestic drug manufacturing facilities .FDASIA also requires the FDA to clear the backlog of applications by the end of the first five-year user-fee authorisation period". Because of these new requirements and additional resources, the FDA will increase the number of risk-based generic drug inspections conducted both in the US and abroad, including in India, she had added.

USFDA cities torn records, unclean toilets for banning Sun Pharma's Gujarat plant

Torn documents, partially destroyed raw data showing undesirable results and unclean toilets were among the reasons cited by the US drug regulator for the ban it imposed last month on a Gujarat-based facility of Sun Pharma, the largest Indian drugmaker by market capitalisation.

"Drug products failing to meet established specifications and quality control criteria are not rejected," said a form 483 issued to the company, which spelt out violations as observed by US investigators at the Karkhadi facility during their audit in November 2013. This plant, which manufactures the antibiotic Cephalosporin, accounts for less than 1% of the company's sales.

Analysts had pointed out that the import alert by the US Food and Drug Administration (FDA) on the facility was unlikely to cause any significant financial impact but said they awaited clarifications on the nature of violations.

"We identified multiple torn/partially destroyed raw data cGMP (current good manufacturing practices) manufacturing and quality records. Our review of these records identified the practice of maintaining duplicate versions of cGMP raw data records. Undesirable data was found to be changed in the official versions in order to meet specifications," said the FDA inspection report that ET has reviewed.

"We have sent our response to the FDA and given that the facility now has an import alert, it's clear that the FDA does not agree with our view. In this process, we have learnt and have resolved to work on further strengthening our systems and controls," a spokesperson told ET.

With regard to the torn documents and partially destroyed data, the company said it has put remedial measures in place. "The applicable SOP (standard operating procedure) in this case was not adhered to for which appropriate corrective action has been taken," Sun said in an email.

"The reason this was not detected as part of our internal compliance checks is due to the equipment not being CFR (code of federal regulation) compliant. We are now replacing this with CFR compliant equipment.

In addition, we are ensuring that equipment at all locations is CFR compliant. Also appropriate disciplinary action has been taken." The report, which makes 11 observations on deviations from USprescribed quality standards, said the toilet for manufacturing operators at the plant was in "total disrepair" and lists concerns about poor housekeeping.

"The two urinals present in the washing and toilet facility provided for quality control laboratory male employees were found to drain directly onto the floor. Urine was found to be collected in and around an open drain. A strong smell of urine was observed throughout your firm's quality control environment," said the report signed off by FDA investigators Peter Baker and Dipesh Shah.

The poor washing and toilet facilities have been fixed, Sun said. They also spotted a garbage dump in the perimeter of the manufacturing area, apart from various forms of infestation. "Buildings used in the manufacture, processing, packing or holding of drug products are not free of infestation by rodents, birds, insects and other vermin," the report said.

Sun has also addressed these issue, it said: "The observations are related primarily to the surroundings and supporting areas of the referred buildings. However, we have taken further corrective measures in this regard."

"While the poor maintenance issues can be sorted out, the gravity of charges on data destruction and tinkering with records cannot be undermined and is usually taken seriously by US FDA," said a former senior quality control executive at a rival firm, who reviewed the observations. He spoke on condition of anonymity.

He, however, didn't want to hazard a guess as to whether it could prompt more surprise inspections by the FDA at other sites of Sun, which has maintained a clean record till now. The bar on its plant last month was the first ever faced by the company in any of its Indiabased facilities and triggered a 5% intra-day dip in share price.

Prashant Nair of Citi Research dubbed the stock reaction "overdone". He said in a note: "This is a very small cephalosporins facility, with limited sales into the US. Besides its overseas manufacturing assets... Sun's plant at Halol (Gujarat) is the major feeder for its US business."

ssSun had earlier faced an import alert on a US-based facility belonging to subsidiary Caraco and a warning letter over unit Taro's Canadian plant but both were successfully resolved. Facilities of many top India-based drug firms, including Ranbaxy Labs and Wockhardt, were blacklisted by the US regulator last year.

Govt mulls USFDA-like checks to keep MNC drug makers on toes

Concerned by increasing regulatory action against domestic drug makers in the United States and Europe, the government is planning to initiate a similar system of checks on pharma manufacturers, including multi-national firms operating out of India.

The Drug Controller General of India is set to start a system of sudden inspections of manufacturing facilities of pharma companies, including those of multi-national companies and will take stringent action against any violations.

“There has to be a level playing field. If foreign regulators can make surprise checks on Indian pharma companies, we can do the same for both domestic as well as foreign drug makers,” said GN Singh, Drug Controller General of India (DCGI).

At present, teams from the DCGI and state drug control officers conduct checks but firms are usually notified in advance of such visits. In case of any violations, the facilities are given at least a 45 day window to comply with norms that can be increased on a case-by-case basis.

The move comes soon after the US Food and Drug Administration (USFDA) banned Ranbaxy’s fourth unit at Toansa last Friday.

Although the DCGI is also set to inspect the facility to check for manufacturing violations, sources said there is increasing concern in the government over the regulatory action that Indian drug makers are facing abroad.

“Nearly 30 per cent of the generic medicines consumed in the US is manufactured by Indian drug makers. This is not a new phenomena but this has been the same for the last 10 years,” pointed out a senior government official.

Over the past few years, a number of Indian drug makers have been hauled up by the USFDA over issues relating to violation of good manufacturing practices. Pharma firms including Wockhardt, Fresenius Kabi, RPG Life Sciences have got warning letters from the USFDA earlier while others including Ranbaxy, Dr Reddy’s Labs, Sun Pharma, Cadila, Aurobindo Pharma and Glenmark have faced action for non-compliance with various US regulations.

Also, the UK Medicines and Healthcare Products Regulatory Agency had earlier issued a precautionary recall for sixteen medicines made by Wockhardt’s Waluj facility. With an estimated size of over Rs 72,000 crore in 2013, the Indian pharmaceutical industry is one of the largest exporters of generic drugs in the world.

The United States is the top market for Indian pharma exports, accounting for 26 per cent of all exports in 2012, followed by the United Kingdom (4 per cent) and Germany and Russia (3 per cent each).

USFDA slaps import alert on Sun Pharma's Karkhadi plant

In yet another blow, US Food and Drug Administration (FDA) issued an import alert on pharmaceutical company Sun Pharma for all products manufactured at its Karkhadi unit. The unit makes active pharmaceutical ingredients (API) and formulations. Speaking to CNBC-TV18, pharma analyst at Prabhudas Lilladher Surajit Pal said import alert generally means stalling of revenue for a year or two from the plant under vigilance. "But we need to see the quantum of revenue it generates from the plant and the kind of cost they saved by producing API from there because we also know that they supply API to their Caraco unit and they also enjoy the low cost API from Indian plant." Earlier in the week, the pharma major had recalled 2,528 bottles of its generic version of diabetes drug Glumetza from US-based Santarus Inc after it received a customer complaint. The company's subsidiary Caraco on Wednesday had received approval from US Food and Drug Administration (FDA) for making Risperidone oral tablets. Risperidone is used to treat schizophrenia. Earlier Ranbaxy and Wockhardt had come under USFDA scanner. Discussing the turn of events, Nilesh Shah of Envision Capital told CNBC-TV18 that the penalty on Karkhadi unit is reminiscent of the way Ranbaxy was examined by the USFDA. 'It started with import alert on one plant, but gradually the rest of it came under scrutiny."

India warns USFDA of false whistles

India has called for a review of the US whistleblower policy as it feels that the generous incentives offered by the US drug regulator to employees for revealing malpractices in their companies may encourage disgruntled executives to tamper with data to use against their employers.We feel the whistleblower policy may be suitably reviewed to avoid a possible misuse of it just to earn high rewards, said a government official.The government has,in a non-paper issued to the US Food and Drug Administration,said some aggrieved employees may fudge data in the hope of reaping huge rewards.A non-paper is an informal paper to discuss sensitive issues without elevating it to a formal or final position.Under the False Claims Act of the US federal law,whistleblowers stand to receive as much as 15-25 % of the recovered damages that go to the federal government.

US Food and Drug regulator to deploy more inspectors in India

The US Food and Drug regulator said on Tuesday that it will increase the number of its inspection staff in India.

Currently, the FDA deploys 12 officials in India, which the regulatory body plans to increase by 19, said Margret Hamburg, Commissioner, US Food and Drug Administration in the course of an interaction in Mumbai.

Hamburg is visiting India at a time when local drug makers are under intense scrutiny by the US regulator.

The manufacturing sites of several Indian companies have been banned from importing drugs to the US, because of quality issues. USFDA had banned exports from all the Indian facilities of RanbaxyBSE 3.43 % and WockhardtBSE 1.57 %.

Hamburg said the FDA does not base its action on popular opinion.

"We don't take regulatory action based on public opinion. What you see reflects the fact that our presence in India has increased and it is not surprising, given that role of Indian pharmaceutical manufacturers in providing drugs to US. So, we have legal and regulatory responsibilities to ensure safety, quality and efficacy of drugs that are used by American consumers within our border", she stressed.

In her one week visit to India, Hamburg has also focussed on the need for upholding the quality of spices, sea food and drugs coming from India. India is the eight largest exporters of food products to US and 40% of the drugs consumed in US come from India. "We are two great democracies and we have lot of shared commitments to science and research and also in my world shared commitments to improving and protecting public health," Hamburg said.

She further added that the drug controller general of India, GN Singh, expressed interest in working with the US regulator. Hamburg also said that Indian regulators needed to engage more with their international counterparts.

"We come together as a coalition of international regulators, we work together to harmonise standards and approaches and share information and often at those meetings India is not represented and India is such an important player on the global scene, so really hope they will join us on the table, so it will benefit them and also benefit rest of us", Hamburg said.

Innovator or generic, building quality will build reputation: Margaret Hamburg

US Food and Drug Administration Commissioner Margaret Hamburg is currently in India on her first official visit to the country, at a time when local drug makers are under increased scrutiny in the US over quality issues.

In an e-mail interview with ET, Hamburg says because of new US rules and the additional resources that the FDA now has, the regulator would step up generic drug inspections both in the US and abroad, including in India. Excerpts:

India accounts for half the warning letters the US FDA's drug safety office sent out globally in 2013. Doesn't that indicate a higher rate of violations here?

Margaret Hamburg: The problems encountered by FDA investigators in India are similar to those seen around the world in manufacturing. These 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.

While some Indian companies operate state-of-the-art facilities and meet CGMPs (current good manufacturing practices), others do encounter problems and operational challenges. Staff from the FDA's India office will work with these companies to identify the problems and will take the necessary steps to self-correct. The FDA has chosen to make quality one of our highest priorities in 2014. Whether innovator or generic, building quality is how companies must build their reputation and why patients and healthcare professionals will trust their products.

At least some quarters within the Indian government feel that the increased US FDA vigilance in India has been an indirect result of campaigning by top pharma MNCs against the Indian industry. Would you like to comment?

Margaret Hamburg: It's because of our commitment to protecting and promoting the health of the American public that we've been focused on increasing our collaborative efforts and risk-based inspectional activity in India for a number of years already. And the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 does require the FDA to achieve the same inspectional schedule for foreign and domestic drug manufacturing facilities.

FDASIA also requires the FDA to clear the backlog of applications by the end of the first five-year user-fee authorisation period. Because of these new requirements and additional resources, the FDA will increase the number of riskbased generic drug inspections conducted both in the US and abroad, including in India.

How would the US drug market be without India-made drugs?

Margaret Hamburg: India is the second largest supplier of over-the-counter and prescription drugs to the United States, and is an essential partner in ensuring the health and safety of American and Indian consumers. As two of the largest democracies in the world, our countries have enjoyed an enduring partnership and commitment to collaborate on initiatives designed to enhance both our economies and the lives of the people in our respective countries.

The FDA's India office will continue to engage and partner with our Indian counterpart regulatory authorities to ensure the safety and quality of FDA-regulated products being exported to the US.

While some believe that Indian drug firms will emerge stronger after the initial pain because of the FDA action, others think that many companies may get wiped out.

Margaret Hamburg: As I indicated earlier, many Indian firms understand good manufacturing practices and use them, and this commitment to quality manufacturing must be accepted from the topdown throughout the industry. To ensure that consumers have access to safe and highquality products, the agency will take appropriate action against any company distributing products to the US market that don't meet certain requirements.

The FDA is committed to working closely with Indian firms and our regulatory partners in India to resolve any issues. I'm confident that the essential partnership between our two nations will only be strengthened in the coming years, and that the industry as a whole will benefit.

Can we hope for globally harmonised guidelines for quality of drugs?

Margaret Hamburg: The FDA is transforming into a modern public health regulatory agency fully prepared for a complex globalised regulatory environment. The agency is sharpening and focusing its planning for enhanced alignment of FDA and international standards, and this remains an ongoing process. The FDA's presence in India has allowed us to more effectively focus our harmonisation efforts there through collaboration with our Indian regulatory counterparts.

This enables us to leverage our combined resources, ensure standards consistency and increase regulatory capacity, which includes information sharing, exchange programmes and specialty training.

Bitter pill: US issues alert on Ranbaxy again, shares fall 5%

Ranbaxy Laboratories, India’s largest drugmaker by sales, is under US health regulator scanner once again, now for it’s plant at Toansa in Punjab. The news sent the company’s shares down 5.4% on the BSE.

“On January 11, 2014, Ranbaxy received the form 483 with certain observations,” the company said in the press statement.

The USFDA Form 483 is issued to company managements at the conclusion of an inspection when an investigator observes any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic Act and related Acts. “The company is assessing the observations, and will respond to the US FDA in accordance with the agency’s procedure to resolve the concerns at the earliest.”

The failure to address these concerns would result in the FDA banning all exports to the US from the factory.

All of other Ranbaxy’s Indiabased factories are currently banned by the regulator from exporting medicines to the US.

The plant is estimated to manufacture around 70-75% of its active pharmaceuticals ingredient (API) requirements.

“With this plant under scanner, it would have impact on the operations of the company in the US, unless it can compensate for the same at the earliest and mange a smooth supply of key raw material,” said Sarabjit Kour Nangra, an analyst at Angel Broking. “We await more clarity from the company on the exact impact on the financials.”

Last September, the USFDA imposed an import ban on Ranbaxy’s factory in Mohali, saying it had not met “good manufacturing practices.”

US FDA to continue focus on India's pharma companies

The US health regu­lator — Food and Drug Administration — which cracked the whip against many Indian pharmaceutical companies in the year gone by including Ranbaxy Laboratories and Wockhardt, will continue to focus its attention on non-compliant companies.

“We will continue to focus our attention on non-compliant companies and facilities that are engaging in unacceptable quality and data integrity practices,” Christopher C Kelly, spokesperson, USFDA told HT via e-mail. “We will use all available enforcement tools to bring these facilities into compliance to ensure the public health is protected.”

The FDA’s concern is understandable, considering that nearly 40% of the generic drugs and over-the-counter products sold in the US come from India.

The regulator expects Ranbaxy to pull up its socks and address its concerns. “Once the agency is satisfied that Ranbaxy has addressed its manufacturing issues at the Mohali facility, the company will be permitted to resume manufacturing and distribution of FDA-regulated drugs (from Mohali),” Kelly said.

The FDA plans to follow in India the same system of facility inspections as in the US and other developed countries. “India has become a priority location for the FDA as it houses the largest number of FDA-approved drug manufacturing plants outside the US,” said Hitesh Sharma, national leader, life sciences, Ernst & Young. “It is also emerging as the largest exporter of generic drugs to that country.”

UK patients are not overconcerned about Indian drugs quality: Gerald Heddell

Indian companies are by and large good suppliers of generic drugs, but some bad apples might spoil the reputation of the entire industry, says Gerald W Heddell, director - Inspection, Enforcement and Standards Division of UK's Medicines and Healthcare Products Regulatory Agency (MHRA). In an interview to Divya Rajagopal, Heddell who was in India last week, spoke about some Indian generic drug makers' issues with compliance, the import alert on Wockhardt and what Indian drug makers need to do to keep up with regulatory changes. Edited excerpts:

What's the issue with Wockhardt? Why did you ban their products?

The issue, the biggest single issue that we are concerned about, is the degree to which we can trust, their data which they produce. There are other GMP non-compliances, but the thing that concerns us the most, at the top of the list is, that can we trust data from this company? I think the company is committed to correct the issue. And you really have to ask the senior management from Wockhardt to comment on this. They have met us.

Do you think Indian companies disguise facts in order to please authorities and get approvals?

There have been cases. We have seen that documents get damaged, things get spilled, or machine goes on to it and damages it. So what they do is rewrite documents so that they have nice clean copies. That may be very well intentioned but is misinformed. You cannot do that. You have to retain original records. So it went on from just being wanting to please to actually changing some of the data. It was not just the Wockhardt case, but an earlier case. So yes, there is an element of wanting to please. But the best way to please us is to recognise that there is an issue, to deal with it, and to prevent it from recurring and make sure everybody has confidence on those documents.

You allowed Wockhardt to supply some drugs post the ban, what is the status?

There were about 90 products that were involved. And approximately 60 of them we recalled from the market and we stopped the import. The remaining products we determined that risks to patients not getting the products is bigger than risk associated with compliance and quality issues so we allowed the company to supply. So, there is major risk of patients if they don't get these medicines.

Ranbaxy became a turning point on how not only regulators but also patients look at drugs manufactured out of India. Has there been any fallout of that in UK, where patients are worried about taking drugs coming from India?

The honest answer is no there hasn't been any (fallout/ loss of confidence) but I fear there might be. And one of the things that I would really want to avoid is any loss of confidence in Indian products. Patients should be able to take the product which is dispensed from pharmacy and regardless of its source they should have the same confidence in its quality. At the moment, patients in the UK are not over concerned about the quality of Indian products, but it could change if this is publicised in a wrong way and misunderstood.

Hopefully we do not get any more incidents like this. Part of this mission is to make sure that people deal with it openly and honestly, don't just tell us what we want to see. Recognise the issue and deal with them and prevent them from happening again, then we all will be happy.

What's your view on Ranbaxy?

Ranbaxy is an interesting case, in which US took action and no other authority decided to take similar action. It was not because US was not correct, but we could not find sufficient evidence to take action. So we considered it, and on the basis of evidence we had, we did not take action.

Couple of months ago when the Ranbaxy issue happened, we asked the USFDA about the Indian regulatory scene. I want to ask the same question to you, what is your view of the Indian drug regulatory system?

India is generally a good supplier of quality generic medicines to the world. And what we said today doesn't change that position. We conduct close to 50 inspections in a year, and the majority of inspections that we conduct, there is no issue. But certainly the small minority of that, may be less than 10 % is a major concern. So it is not all of Indian industry that is subject to this criticism.

Is there a need for companies to update themselves with the current quality norms of regulated markets?

Clearly those are which we have revealed the critical non-compliance divisions, clearly those companies have to revisit the way they behave and the attitude throughout the companies. They need to make sure that things are done correctly.

BIG BROTHER IS WATCHING

Then, there are the increasing instances of global drug regulators such as the US Food and Drug Administration issuing warning letters and restricting export of drugs from specific facilities. For instance, the total number of warning letters issued by the US regulator increased from 620 in 2010 to 749 by 2012.

Indian companies have been facing the heat of regulatory tightening. The recent regulatory action on Wockhardt’s Waluj facility which was issued a warning letter is an instance. The company was charged with withholding truthful information thereby delaying and limiting inspection.

During interactions with the production head, it came to light that unofficial data entries were being used for internal visual inspection; which were not shared with the inspector.

In addition to this, the regulator also claimed non-conformance to good manufacturing practices. Export of drugs to the US from this facility has been banned since late May 2013. The stock price tumbled over 78 per cent, post the ban, to Rs 381 currently.

Though import alerts and warning letters are quite common among pharma companies, investors may consider investments in companies with a good compliance track record.

While pharma majors such as Sun Pharma (for its Cranbury facility in New Jersey, US), Lupin (Mandideep, Madhya Pradesh) and Zydus Cadila (Moraiyya, Gujarat) have received warning letters in the past, they have succeeded in resolving the issues within a reasonable period of time.

And these companies have since stepped up efforts to ensure better regulatory compliance.

Heading India Like Scaling Everest for US FDA's Lal

The US drug regulator’s new India chief, Altaf Ahmed Lal, has expressed his intent to work closely with Indian pharmaceutical companies and sector regulators to minimize quality control lapses in manufacturing.

“I want a manufacturer to ask – and be able to answer – the questions, why are we failing inspections? And what specific controls do we still need to put into place on a 24*7 basis so that on the next FDA inspection we will pass?” he wrote on ‘FDA blog’ on Wednesday.

Lal, who took over as director of the US FDA India Office in June, is currently on a US tour. To a colleague likening his new role to scaling Mount Everest, Lal wrote, “I am fond of trekking and climbing.” He dubbed his new role in India as “a daunting challenge”.

ET had reported last month that the US drug safety office has issued warning letters to six Inia-based drugmaking facilities since end of May. India-based drug manufacturing sites, including those of multinationals, accounted for over 60% of all warning letters sent out globally by the US drug safety office, Centre for Drug Evaluation and Research (CDER), during the period.

As per ET’s analysis, this is a sharp contrast to the number of warning letters that drug manufacturing plants in India received about 10 warning letters from CDER between 2010 and 2012, making for less than a tenth of over 130 warning letters that the US drug safety office sent out globally in the last three and half years.

Besides domestic firms Wockhardt and RPG Life sciences, Promed and Posh Chemicals, India-based facilities of foreign firms - US-headquartered Hospira and Germany-based Fresenius Kabi - also drew the USFDA's ire during the period. Since last month, two more warning letters have been issued to Indian drugmaking facilities-those of Bengaluru headquartered Strides Arcolab and API player Aarati Drugs, according to FDA’s website.

Ranbaxy's latest state of art facility at Mohali, on which the company had pinned hopes to overcome its prolonged regulatory troubles, has attracted an import alert, which bars exports from the plant to US.

The rise in detection of fault is partly because US FDA is increasing its activities and manpower in India.

Nine drugmakers have been fined a total of 146 million euros

U antitrust regulators fined nine drugmakers a total of 146 million euros on Wednesday for blocking the supply of cheaper medicines on the market, with a penalty of 94 million euros imposed on Denmark's Lundbeck.

The punishments follow a 2009 report by the European Commission on the pharmaceutical sector, which said "pay-for-delay" deals lead to consumers paying as much as 20 percent more for their medicines.

The European Commission, which acts as competition regulator across the 27-member European Union, imposed a 21.4 million euro fine on Germany's Merck KGaA and another 7.77 million euros on it jointly with former subsidiary Generics UK, which is now owned by US generic drugmaker Mylan .

The other penalised companies were Arrow, Resolution Chemicals, Xellia Pharmaceuticals, Alpharma - which is now part of Zoetis Products LLC, AL Industrier and India's No 1 pharmaceutical company Ranbaxy .

Reuters flagged the EU fines on June 3.

"Agreements of this type directly harm patients and national health systems, which are already under tight budgetary constraints," EU Competition Commissioner Joaquin Almunia said in a statement.

"The Commission will not tolerate such anticompetitive practices."

Interview with Mr. Arun Sawhney, MD&CEO. Ranbaxy Laboratories Ltd

The Indian pharma sector has in the recent past faced a slew of allegations and pessimism . Ranbaxy , one of India's pharma majors, has been the harbinger of this negativity. The company has faced and eight year long civil and criminal probe in the United States, four year long import ban on its manufacturing facilities in India for supplies to the US, admissions to felony charges, a USD 500 million settlement fine and a very strict consent decree.

Speaking to CNBC-TV18, Arun Sawhney, managing director and chief executive officer of Ranbaxy says the company has taken all measures to make sure that an epsiode like this does not recur in the future. He says the USFDA's ban on its products is due to different definitions of what is 'adulterated' in the US and in India.

"The drugs that were put on the market in the US at that time based on delayed testing of stability samples data were described as adulterated. Does that make that drug in the US substandard or contaminated or spurious? The clear answer is no. The definition of the world adulterated in the US context is very different from the definition of a drug as adulterated in the Indian context," adds Sawhney in an interview to CNBC-TV18.

Below is edited transcript of Sawhney's interview to CNBC-TV18.

Q: Are the troubles over for Ranbaxy here? We understand there is fresh probe that has been ordered by the Drug Controller General of India in the manufacturing facilities for Ranbaxy. What are the sort of dialogues are you having with the drug controller now?

A: I recognise that there were issues in the past. I can assure you that Ranbaxy Laboratories has taken all measures to make sure that they do not recur again the future. We have invested more than USD 300 million since 2009 in upgrading our facilities, making sure that there are good systems and procedures in place, training people, hiring the best consultants in the world to build skill sets at Ranbaxy. I am not aware of any probe being ordered by local authorities on Ranbaxy.

Q: But we understand they are in constant dialogue with the company and they have an initiated a probe.

A: I have regular meetings with all the stakeholders including the government. We are cooperating with them. We provide all information that is requested of us. We will be happy to provide all information that any government agency is seeking from us.

Q: If we go back to the settlement that you have signed with US Food and Drugs Administration (USFDA), you have agreed that you issued adulterated drugs between 2005 and 2006 in the US. You have agreed that one of these drugs Sotret had failed accelerated dissolution stability test but you continued selling it for another 13 months. You have accepted that Gabapentin in 2007 certain batches for testing out a specifications had unknown impurities and would not maintain shelf life. These were also some of the drugs that were sold in India that point in time. How would Ranbaxy claim and with what certainty that the drugs that were sold in India were not adulterated and substandard as you have accepted in the US?

A: A pharmaceutical company is expected to operate under CGMP conditions. CGMP stands for Current Good Manufacturing Practices. In Ranbaxy’s context, the delayed testing of stability data was a non-GMP activity. So, the data that was generated out of delayed stability testing was a non-GMP data. The drugs that were put on the market in the US at that time based on delayed testing of stability samples data were described as adulterated. Does that make that drug in the US substandard or contaminated or spurious? The clear answer is no. The definition of the world adulterated in the US context is very different from the definition of a drug as adulterated in the Indian context.

Q: In the press release of Department of Justice (DoJ) they have said that when company sell adulterated drug, they undermine the integrity of FDA’s approval process and may cause patients to take drugs that are substandard, ineffective or unsafe?

A: In Ranbaxy context the adulteration was because of the data that was generated on delayed testing of stability samples. That was the context relevant to Ranbaxy.

Q: You have accepted that you were selling drugs which had failed stability testing, which were testing out of specification had unknown impurities, doesn’t that lead two drugs which would eventually may not be harmful or unsafe but maybe ineffective?

A: We have on record FDA advising the patients in the US to continue taking Ranbaxy drugs because they discovered Ranbaxy drugs were of good quality. So, there was nothing wrong with the quality of drugs in the US. The expression adulterated has a definite meaning in the US context which is not the same as in India or anywhere else in the world.

Q: In 2008 press release FDA had mentioned that while this does not involve removing products from the market, FDA has no evidence to date, that Ranbaxy has shipped defective products. So, at that point in time, to date they did not have enough evidence and in 2013 when you signed the settlement, in that meantime they had come across all the issues that have been highlighted in the current press release?

A: Yes, it is the delayed testing on the stability samples and delayed information that was provided to FDA. That was it. Since 2008, we have not shipped any product from Dewas or Paonta to the US.

In 2008 FDA has gone on record telling that Ranbaxy drugs are safe, there is no issue with the quality of the drugs. We have taken all measures since then to ensure that the issues that we were facing way back in 2004-05 are not faced again.

Q: There has been a case of outright fraud by the company at that point in time which you have agreed in your statements to the USFDA and the DoJ. That is the story for the US. The same plants were supplying those drugs in India and continue to supply drugs in India, how do you convince the consumers here in India? You have a Public Interest Litigation (PIL) filed against Ranbaxy. You have hospitals which are taking independent action advising their doctors to take caution before they advice Ranbaxy drugs?

A: We have signed consent decree with FDA. We have settled with US DoJ. In case of FDA we will go through the consent decree process and once we go through the consent decree process we will be back in business from Dewas and Paonta in the future.

In case of DoJ we provided in 2011 and took a big knock in 2011. 2012 we performed ahead of expectations. In 2013 we are performing as per our target and we remain firm on our guidance of Rs 120 billion in 2013.

We have very aggressive growth plans for Ranbaxy also in the US. In India, we have key markets, key therapeutic areas. We have continued to make investments in our manufacturing. We have very exciting portfolio in R&D and above all I also have a team that will execute on all these plants. So, this is the implication of the DoJ and FDA.

Now, coming to the point on hospitals, by and large in India all hospitals are prescribing Ranbaxy drugs. I respect internal processes of all the hospitals. I will provide continuously information that they seek to build confidence in Ranbaxy drugs and Ranbaxy medicines and I am sure that they will continue to prescribe Ranbaxy medicines as they have been doing up till now.

Q: You have also admitted that false, fictitious and fraudulent statements were given to FDA in the annual reports of 2006 and 2007 regarding the dates of stability testing at Dewas for certain products. Has this sort of fraud, this part of fraud being taken care at Ranbaxy? Have you been able to identify and pin down the specific departments who were involved, the specific employees who were involved and have you been able to oust that entire bit out of the company?

A: I am assuring that we have taken all corrective measures to ensure that the same is not repeated again. We have strengthened our quality department, we have staffed appropriately, so it is no longer understaffed. We have improved the infrastructure in our quality department. All the issues that we faced in the past I assure you will not be the issues the company will not face in the future.

Q: Basically, people involved in that aspect of the business have been moved out of the company?

A: None of the people who occupy critical positions way back in that time are working with Ranbaxy today. It is altogether a new company, the board of Ranbaxy is newly constituted, the executive team at Ranbaxy is newly constituted, and the executives in critical positions are completely new.

US FDA wants RPG Life Sciences for violation of manufacturing norms

The US Food and Drug Administration (USFDA) has issued a warning letter to RPG Life Sciences for violation of current good manufacturing practices (CGMP) norms at its two plants at Ankleshwar and Mumbai.

Source: PTI

The US Food and Drug Administration (USFDA) has issued a warning letter to RPG Life Sciences for violation of current good manufacturing practices (CGMP) norms at its two plants at Ankleshwar and Mumbai.

"During our November 20, 2012 through November 24, 2012 inspection of your pharmaceutical manufacturing facility, MS Ankleshwar, investigator(s) from the FDA identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals," the health regulator said in a letter posted on its website.

Likewise, during an inspection of the pharmaceutical manufacturing facility, at Navi Mumbai, investigators from the FDA identified significant deviations from CGMP for the manufacture of active pharmaceutical ingredients (APIs), it added.

"These violations cause your APIs and drug products to be adulterated ...the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP," USFDA said.

When contacted, a company spokesperson declined to comment. The US health regulator said that it has conducted a detailed review of RPG Life Sciences' responses dated December 11, 2012 and February 19, 2013 and "note that they lack sufficient corrective actions".

"Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm's compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer," USFDA said.

USFDA further warned that the failure on the part of the company's management to correct the violations may result in banning of import of drugs manufactured at the company's facilities at Ankleshwar and Navi Mumbai, into the United States.

Shantha Biotech

For Shantha Biotech, choppy waters may calm down soon. It's been three years since Shan-5, its 5-in-1 vaccine, was disqualified by the WHO on quality concerns, but the vaccine is now up for reassesment. CNBC-TV18’s Archana Shukla reports.

A single vaccine to protect infants against five diseases -- diptheria, pertusis, Hep-B, tetanus, and a bacterium causing pnemonia and meningitis -- was a major factor in Sanofi buying Shantha Biotech for USD 800 million in 2009.

But the vaccine was disqualified by the WHO, and Sanofi's big plans came to naught. But now, there is a glimmer of hope, with the World Health Organisation preparing for a re-inspection of Shantha's facilities that manufacture the vaccine.

Nata Menabde, India representative, WHO says “We are preparing for a re-inspection along with some other international regulators.”

But the three-year ban on the vaccine, which came after the WHO found white sediments sticking to the vaccine's glass vials, has cost Shantha a pretty penny.

The first to go was the USD 340 million supply contract with the WHO. This led to the removal of the drug from the global markets, causing Shantha's annual sales of nearly Rs 500 crore to fall to Rs 100 crore.

The disqualification meant Shantha had to revamp its management cadre and go back to the drawing board. With the drug in redevelopment, Shantha also missed out on participating in the 2013-15 UNICEF contract. But now, Shantha says the redeveloped vaccine has completed Phase-3 clinical trials, and is ready for safety studies.

Sanofi also has a lot riding on this reassessment starting with its plans to make Shantha its vaccine hub for emerging markets. But the French drugmaker is confident that Shan5 will return, bringing with it a significant contribution to the company's Hepatitis-B coverage, and becoming the stepping stone to the next version - Shan6.

Dr Reddy's sued for 'infringing' thyroid injection patent

The US Drug maker requested the court to pass an order to restrain Dr Reddy's Labs from commercially manufacturing, using, offering for sale, selling, marketing, distributing, or importing DRL's generic paricalcitol injectable products prior to the expiration of said patents.

Source: PTI

US-based drug maker AbbVie Inc, the spun-off entity of Abbott, has dragged Dr Reddy's Lab to court for allegedly infringing the former's patented drug Zemplar on six counts concerning three patents.

"DRL committed an act of infringement by filing an ANDA (Abbreviated New Drug Application) with a Paragraph IV Certification that seeks FDA-marketing approval for DRL generic versions of AbbVie's paricalcitol injection products prior to expiration of the patents-in-suit," according to a petition filed by AbbVie along with Wisconsin Alumni Research Foundation in the US District Court for the District of Delaware.

The US Drug maker requested the court to pass an order to restrain DRL from commercially manufacturing, using, offering for sale, selling, marketing, distributing, or importing DRL's generic paricalcitol injectable products prior
to the expiration of said patents.

Dr Reddy's filed an ANDA with the US Food and Drug Administration, seeking approval to sell a generic copy of US drug maker's Zemplar injectable products in 2 microgram/ml and 5 microgram/ml formulations, prior to the expiration of the
patents owned by and exclusively licensed to the complainants, the petition said.

Dr Reddy's Lab refused to comment on the issue. Zemplar (Paricalcitol) is a drug used for the prevention and treatment of secondary hyperparathyroidism (excessive secretion of parathyroid hormone) associated with chronic
renal failure.

AbbVie, in its annual report 2012, said it cloaked USD 383 million from Zemplar sales including USD 230 from the US. Two patents (799 and 758) originally belonged to Abbott and subsequently transferred to AbbVie. These two patents will expire on April 8, 2018. Wisconsin Alumni research foundation holds the rights for patent no. 815, which will expire on July 13, 215, AbbVie informed the court in the petition.

On or about May 20, 2013, AbbVie and WARF received letters dated May 17, 2013, from DRL notifying that the India drug maker had filed an ANDA containing a Paragraph IV Certification for paricalcitol injection.

The letter also stated that, in DRL's opinion, the patents-in-suit are invalid, unenforceable, or will not be infringed by the commercial manufacture, use, or sale of the generic paricalcitol injection products, the petitioners said.

"DRL has committed and will commit acts of infringement of the patents-in-suit that create a justiciable case or controversy between plaintiffs and DRL," the petitioners alleged.

Wockhardt Story

Wockhardt Story : UK drug regulator MHRA (Medicines and Healthcare Products Regulatory Authority) said on Thursday that pharmacies, dispensing clinics and wholesalers have been asked to return 16 prescription only medicines made by Wockhardt following a precatuionary recall.

The recall follows manufacturing deficiencies it has identified at the pharma company's plant at Waluj near Aurangabad in Maharashtra, MHRA said.

"The deficiencies identified during a routine inspection in March included a low risk of cross-contamination because of poor cleaning practices and defects in building fabric and the ventilation systems at the site. There was also evidence of forged documents relating to staff training records that had been rewritten," it said.

The medicines affected by the precautionary recall include those used for the treatment of infections, high blood pressure, diabetes, epilepsy, depression, schizophrenia, Parkinson’s disease, dementia in Alzheimer’s patients and thyroid conditions, it added.

However, this is only a precautionary recall and there is no evidence that medicines made by Wockhardt are defective and so people should continue taking the medicines as per prescription, said Gerald Heddell, MHRA's director of inspection, enforcement and standards.

Wockhardt shares ended at Rs 939.35 on NSE on Thursday, down 2.3 perce

Frensenius Kabi Oncology

Fresenius Kabi Oncology in Friday said it has received a warning letter from the US health regulator asking for more information and implementation of additional corrective and preventive measures regarding GMP non-conformities.

"The company has received a warning letter from US Food and Drug Administration (USFDA), inter-alia, asking for certain other information and implementation of more corrective and preventive measures so as to avoid recurrence of deviations," Fresenius Kabi Oncology said in a BSE filing.

On February 26, in a routine inspection at the company's API plant located at Kalyani, West Bengal, USFDA had made observations relating to GMP non-conformities in respect of manufacturing, documentation practises and product testing, it added.

"The company has immediately taken steps to implement remedial measures and has voluntarily put the production on hold," it said.

Shares of Fresenius Kabi Oncology on Friday closed at Rs 106.55 per scrip on BSE, down 0.65 percent from its previous close.

Ranbaxy Laboratories Ltd - 16th Sept. 2013

Ranbaxy Laboratories Ltd: The US Food and Drug Administration (USFDA) issued import alert on Ranbaxy Laboratories 's Mohali Unit - reports CNBC-TV18’s Ekta Batra. This could be an extreme negative for Ranbaxy and according to the analyst community Ranbaxy could be on its last legs for having a good strong base in the US. After the problems at Paonta Sahib and Dewas, the USFDA now has a problem per se with its unit at Mohali. Mahali being a new plant, manufacturing wasn’t at full scale but most of the new drugs by the company were slated to be actually manufactured there. There is yet more clarity required from the company itself in terms of what will happen to all of their big ticket drugs, which were expected to be launched especially in Q4 CY13. Key Points There was already Form 483, which was issued for Mohali. This means there were certain manufacturing practices which the US FDA had already pointed out and the company had time to comply to the problems US FDA had bought up. However, since Ranbaxy could not comply to with those issues the 483 has now converted to an import alert. product filings not hit' The question that needs to be resolved is what exactly is happening in terms of product filing and why is Ranbaxy saying that the product filings have not been impacted, says Vikas Dandekar, India Bureau Chief, PharmAsiaNews.Com. Vikas Dandekar, India Bureau Chief ,PharmAsia News.Com.

The US Food & Drug Administration (USFDA) issued an import alert on Ranbaxy ’s Mohali unit on September 13. The inspectional observation was made way back earlier this year, but was not revealed by Ranbaxy, says Vikas Dandekar, India Bureau Chief, PharmAsiaNews.Com. Whenever there is an import alert, the company needs to redo all its manufacturing practices, give a renewed submission and that is reviewed, he says. So, it is a long haul again and it is like a repeat of history which happened in 2008, he adds. Generally import alerts do not give deviations that have happened in the manufacturing system, but broadly it is a detention without any physical inspection, Dandekar says. The import alert was due to non compliance with drug good manufacturing practices (GMPs). The only recourse the company has now is to have site transfers of their product filings to Ohm Laboratories, he says. However, the Ranbaxy management has consistently maintained that it is doing its product filing and nothing has stopped so far as Mohali is concerned, says Dandekar. So, that question needs to be resolved as to what exactly is happening in terms of product filing and why is Ranbaxy saying that the product filings have not been impacted, he adds. Below is the verbatim transcript of Vikas Dandekar's interview on CNBC-TV18 Q: Explain to us the last note that the US FDA has carried on its website on Ranbaxy and what does it mean for the company? A: It is a September 13 notice. Generally import alerts do not give the deviations that have happened in the manufacturing system, but broadly it is a detention without any physical inspection. It follows inspectional observation which were made way back earlier this year which was not revealed by Ranbaxy but it came out and it had issues with product contaminations and filings were stopped at that point of time and that was also a result why Atorvastatin had stopped coming out from the Mohali site. So, in the natural course we would have expected a warning letter to come out of the FDA’s office after the inspectional observation but that did not happen, it came straight on import alert. Whenever there is an import alert we have a situation where the company needs to redo all its manufacturing practices, give a renewed submission and that is reviewed. So, it is a long haul again and it is like a repeat of history which has happened in 2008 which is a second time an import alert has been issued on Ranbaxy side. Q: In terms of earnings growth will it adversely impact its upcoming product launches like Diovan and Nexium or do you think the company can monetise all these three products from the Ohm Laboratories? A: That is the only recourse that the company will to have site transfers of their product filings to Ohm Laboratories and that’s exactly what saved Ranbaxy from losing its exclusivity on atorvastatin. The product filings will move or probably has already moved to Ohm Labs. However, both Diovan and Valcyte were in question. September 22, 2012, was when it was expected, but it’s almost over a year now that has not happened. So, it is a big question mark. The point which is curious is that the Ranbaxy management has consistently maintained that it is doing its product filing and nothing has stopped so far as Mohali is concerned. So, that question needs to be resolved as to what exactly is happening in terms of product filing and why is Ranbaxy saying that the product filings have not been impacted.

Strides Acrolab - 16th Sept, 2013

Strides Arcolab: Updates on USFDA inspections Strides Arcolab Ltd has informed that the Sterile Manufacturing Facility 2 (SFF) at Bangalore of Agila Specialties Private Limited, a wholly owned subsidiary of the Company, has received a warning letter from the United States Food and Drug Administration (US FDA).

Arcolab Ltd has informed BSE that the Sterile Manufacturing Facility 2 (SFF) at Bangalore of Agila Specialties Private Limited, a wholly owned subsidiary of the Company, has received a warning letter from the United States Food and Drug Administration (US FDA).The US FDA inspected SFF in the month of June 2013 and the inspection resulted in issuance of Form FDA 483 with observations. The Company responded to the 483 observations by implementing corrective actions.The Company is committed to work collaboratively and expeditiously with the US FDA to resolve concerns cited in the warning letter in the shortest possible time.Further, the Oncology facility at Bangalore of Agila Specialties Private Limited was also inspected recently by the US FDA and this facility has cleared the inspection with "Zero 483 status".The Company has 8 US FDA approved sterile manufacturing facilities. Source : BSE

Cipla shares fall after US FDA found deficiencies at Goa unit

Shares of pharmaceutical company Cipla Ltd declined as much as 6.6 per cent to Rs 522.90, the lowest since June 6. US FDA has found deficiencies in Cipla's batch production and control records after inspecting Goa unit. The unit's lab records did not include complete testing data and equipment used in manufacturing, processing and packing were not of appropriate design.

Cipla said the inspection was product specific, and observations are procedural and addressable in nature and that it has responded to the FDA, a CNBC TV18 report said

Reuters could not immediately reach Cipla for comment.

Dr Reddy's gets 4 observations from USFDA for Telangana plant

Drug major Dr Reddy's Laboratories today said the US health regulator had issued four observations after inspecting its active pharmaceutical ingredients (API) facility in Telangana

"The audit of our API Hyderabad plant 1 at Jinnaram Mandal, Medak district, Telangana, by the USFDA has been completed today. We have been issued a Form 483 with four observations which will be addressed comprehensively within stipulated time," Dr Reddy's said in a regulatory filing

As per the USFDA, a Form 483 is issued to a firm's management at the conclusion of an inspection when investigator has observed any conditions that in its judgement may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts.

It notifies the company's management of objectionable conditions.

Dr Reddy's shares were trading 1.71 per cent down at Rs 2145.95 on the BSE.

US FDA flags issues at Sun Pharma’s Halol plant

Sun Pharmaceutical Industries Ltd, India’s largest drug maker, on Friday said the US Food and Drug Administration (FDA) had made three observation after inspecting its factory at Halol in Gujarat, for failing to meet good manufacturing practice standards.

“The US FDA conducted a Good Manufacturing Practices (GMP) inspection of Sun Pharmaceuticals Industries Ltd’s Halol facility. At the conclusion of the inspection, the agency issued a Form 483 with three observations,” the drugmaker said in a regulatory filing. The inspection was conducted between 12 February and 23 February.

The shares ended 5.17% higher to close at Rs570.20 on the BSE on 23 February.

Sun Pharma’s US supplies were hit over the past year after the US FDA found violations of manufacturing practices at the company’s Halol manufacturing unit. US FDA conducted its first inspection of the facility in 2014 and another in December 2015. The company was given a warning letter with six observations, preventing it from making fresh filings of new drug applications.

In November-December 2016, Sun Pharma’s Halol plant was re- inspected and the US FDA issued Form 483 with nine observations. The FDA inspectors found the drugmaker’s testing programmes inadequate and said the company had failed to report potential contamination issues on time.

As per the US health regulator, observations are made in Form 483 when the investigators feel conditions or practices in a facility are such that products may become adulterated or could be injurious to health.

The facility at Halol, one of Sun Pharma’s biggest units, holds the key to its US formulation business. Sun Pharma gets about half of its revenue from the US market and the Halol unit contributes a majority of its drug filings.

Barred from new drug filings in the American market, the company’s US business has been severely impacted in last couple of years due to the US FDA’s observations on Halol.

Resolution of concerns at the Halol unit is therefore critical for the company’s US business. Sun Pharma has been struggling to fix quality control problems at the facility. Clearance from the FDA will unlock several complex generic filings and allow the company to bolster existing products.

“The company remains committed to working closely with the US FDA and continues to enhance its Good Manufacturing Practices compliance on an ongoing basis. The company is committed to addressing these observations and will submit a reply to the Food and Drug Administration within 15 days,” it said in the exchange filing.

Centrum Broking analyst Ranjit Kapadia said though the number of observations have come down to three from nine, it didn’t make any difference. “We still need details on these three observations. How serious they are before making any further comments. It is not known whether these observations are the same as earlier or new observations. The number of observations going down doesn’t matter.”

Purvi Shah, research analyst at Sharekhan said, “We view the development as a sentimentally positive read-thru for Sun Pharma and Sparc, as they have got only 3 observations as compared to earlier 9 observations in 2016-17 re-inspections. Closure of these observations with positive clearance from US FDA will remove long standing overhang on Sun Pharma and also for Sparc as it will help in acceleration of approvals from the plant. Currently, we have a ‘hold’ recommendation on the stock.”.

USFDA issues 3 observations at Alembic Pharma’s Panelav facility

Alembic Pharma has reported that the USFDA has conducted an inspection at Alembic Pharmaceuticals Formulation Facility located at Panelav from 12th March, 2018 to 20th March, 2018.

This was a scheduled inspection and at the end of the inspection, the US FDA issued a Form 483 with 3 observations. Company has said that none of the observations are related to data integrity or repetitive in nature.

Panelav is a formulations facility. it has formulations facilities at Vadodara, Panelav and Baddi. The US generics business accounted 21% of its revenue in Q3FY18.

The Company is preparing the response to the observations, which will be submitted to the US FDA shortly. The stock should remain volatile, unless there is more clarity.

Indoco Remedies receives 8 USFDA observations for its Goa unit

Pharma company Indoco Remedies has informed that USFDA inspected its solid dosage plant in Goa (Unit I). At the end of the inspection, the plant has received 8 observations (483s). The filling indicates that all the observations are correctable and the company is in the process of preparing its response for the same.

Exports from Goa solid dosage plant constitute less than 10% of the Indoco’s total exports and less than 4% of the total sales.

This development might have a negative impact on the stock.

Previously, USFDA had inspected Indoco’s two drug manufacturing units (I&II) at Goa plant in 2016 and had issued 6 observations in Form 483. The company was issued a warning letter with respect to Ophthalmic Product leakage. Unit I had received clearance in 2015.

Company has manufacturing facilities located at Goa, Baddi, Waluj, Rabale and Patalganga.

In the last trading session, Indoco Remedies ended at Rs276.85, up by Rs3.35 or 1.22% from its previous closing of Rs273.5 on the BSE.

Dr Reddy’s to USFDA: Staff giving illogical answers not appropriate

After inspecting cancer drug manufacturing facility of Dr Reddy’s Laboratories (DRL) at Visakhapatnam for ten days last year, the two inspectors of USFDA (United States Food and Drug Administration) wrote in their Establishment Inspection Report (EIR) that employees in multiple departments provided them “false and misleading answers” repeatedly. In its written response to USFDA, the DRL stated that giving “answers that are not logical” is “not appropriate” and there is a “need for improvements in culture of discipline and compliance” in the company.

“Finally, a third action identified was the need for improvements in culture of discipline and compliance….Personnel have been reminded that failure to follow SOPs (standard operating procedures) does not make either CGMP (Current Good Manufacturing Practice) or business sense. Similarly, responding to questions with answers that are not logical or information that cannot be supported by actual facts or data is not appropriate. We regret that the FDA consequently interpreted such actions as ‘providing false and misleading information’,” the DRL stated in its 118-page response to the USFDA’s adverse observations.

While the third action is improvement in culture of compliance, the first and second action identified as “critical priorities” by the company are related to “investigation robustness” and “skill or capability building”.

DRL, one of India’s biggest pharmaceutical firms, earned approximately half of its revenues in 2016-17 from the US market. The Visakhapatnam facility was issued a warning letter by the USFDA in November 2015. Then, in 2017, it was inspected by the two USFDA inspectors from February 27 to March 8. On the last day of their inspection, the inspectors issued a Form 483 that contained 13 adverse observations. In response to these observations, the DRL sent the aforementioned 118-page response to the USFDA.

The US drug regulator issued the EIR to the DRL in November last year but it has not closed the inspection on Duvvada facility as yet. The company is expecting the Duvvada’s re-inspection to happen during 2018 only. In its EIR, the two USFDA inspectors stated: “Over multiple days in multiple departments we were provided false and misleading answers to the questions that we asked employees. We repeatedly expressed our concerns directly to the most responsible personnel present, Vikramkumar B Shukla, vice president of operations, and Manish Kumar Choube, vice president of quality, at the time of these incidents. We also expressed our concerns at the start of the day on numerous days. However, the pattern of providing false and misleading statements persisted throughout the inspection.”

According to a senior USFDA official, the US drug regulator received the company’s response at around March 29, 2017. The Indian Express has reviewed the DRL’s response to the USFDA. Replying to specific questions sent by The Indian Express, the DRL spokesperson stated: “The communication you have referred to between Dr. Reddy’s and the USFDA is not released by us. Our communication with USFDA is privileged and confidential. As the veracity of the information you have is clearly not established, we cannot comment on unauthorised and speculative information. Please refrain from publishing this as our response to the USFDA.”
Deleted files and a ‘fearful’ employee

During inspection, the two inspectors found evidence of deleted files in computers of few employees, who then gave “false and misleading answers” to inspectors on subsequent questioning. For example, a resource production manager working at this facility was found to be having no Word or Excel file in desktop or in networked drives or in Recycle Bin of his computer.

The inspectors then started questioning this employee but he repeatedly said that he did not delete the files on his computer. Later, when Shukla asked the employee to answer honestly, the employee admitted that he had deleted the files saved on his computer, emptied the Recycle Bin, and cleared his ‘Recent’ list. “I asked him why he had done this and why he had provided me different answers. He stated that he was “fearful” due to the inspection,” one of the inspectors wrote in the EIR.

In its written response, the DRL talked about “misleading” answers given by its employees on file deletion. It stated: “The different answers were not to mislead the investigator but were due to lack of understanding of the archival of data to network folder and deletion of data which is redundant. The questions asked by the investigators were not completely understood by the employees in some cases and when explained in vernacular language by the escort, the employee gave the appropriate information.”

The company further explained: “These general computers are used by multiple users with unique user login and pass words (Windows ID and Password) with common share folders to ensure the work management within the team in preparation of documents.” It also talked about its “ombudsman and quality helpline” where the “concerns can be reported fearlessly by employees”. The DRL further stated: “The company assures non-retaliation of any kind on concerns raised in good faith, and taken all reasonable efforts to correct the same. This is being used to build a stronger culture of quality.”
‘Unreliable’ biometric data

During inspection, one of the USFDA inspectors found that one company employee — a supervisor who has to sign the ‘checked by’ section of the form — was signing the forms at “many steps in many different areas over an amount of time that appeared unreasonable”. The inspector reviewed the attendance records and biometric access records that “appeared to demonstrate that the employee was not actually in that particular area at many of the times in which he had signed for in the batch record”.

When confronted, the employee repeatedly told the inspector that he was always present in the area with the operator who performed the task. Later, the inspector found more evidence of him “signing for steps when the biometric access data placed him in different parts of the facility.” The employee then “changed his previous answers and confirmed that sometimes he signed at a later time than what was indicated in the batch record”.

The DRL told the USFDA in its 118-page written response: “We would like to emphasise that the data in the biometric system is not reliable and hence no conclusions can be drawn from these data regarding the presence and absence of operator or supervisor at a specific time and location in the plant as the biometric data was never intended to be used as ‘Entry and Exit log’ to document presence of personnel in the plant.”
The DRL added that though there are several biometric access control points available, “evidence or few of the entries are not available” in the biometric data due to two reasons: first is “tailgating”, which means employees are entering a room behind an employee who unlocks the door with his/her biometric access. The company admitted that tailgating behind someone should never be permitted. Second reason, according to the DRL, is the practice of opening the door from the inside by an employee when he sees that another employee is unable to enter inside due to repeated failure of biometric system to recognise the latter’s fingerprint.

Alkem Laboratories falls 11% as USFDA issues 13 observations to Daman plant

Alkem Laboratories share price plunged as much as 11 percent in afternoon Wednesday after the US health regulator issued 13 observations to Daman facility and 1 to US plant.

The Mumbai-based pharma company informed exchanges that it has received a Form 483 with thirteen observations from US Food and Drug Administration (USFDA) for Daman facility.

The regulator had conducted an inspection at manufacturing facility located at Amaliya, Daman during March 19-27, 2018.

"The company will put together a detailed response with adequate corrective and preventive measures to address the US FDA observations and the same is proposed to be filed within the timeline stipulated by the USFDA," Alkem said.

Furthermore, the US FDA had also conducted an inspection at manufacturing facility in USA during March 12-16, 2018 and issued one Form 483 observation.

The company said it has submitted a detailed corrective and preventive action (CAPA) plan to the regulator within the stipulated timelines.
At 13:38 hours IST, the stock price was quoting at Rs 1,896.50, down Rs 195.80, or 9.36 percent on the BSE.

Despite spending big on legal & professional consultants, FDA woes continue to haunt pharma companies

Sun Pharmaceutical Industries spent Rs 1,615 crore on professional, legal and consultancy services in 2017-18, the same as what four of its peers – Dr Reddy’s Laboratories (DRL), Cipla, Lupin and Cadila Healthcare – spent together during the financial year. The amount was also more than the profit earned by any of these peers.

Nonetheless, Sun Pharma’s Halol plant received four observations (albeit not of serious nature) three months after it received the clearance from the US Food and Drug Administration (FDA) that had ended a two-year import ban. Last week, FDA issued one observation on inspecting Lupin’s Tarapur plant. The company is yet to receive FDA clearance for its plants in Goa and Indore that had received warning letters from the drug regulator in November last year.

Besides, last month, Cadila Healthcare’s subsidiary received observations after FDA inspected its plant in Vadodara. In April, Cipla received observations on its Pithampur plant. In March, one of the formulation units of Aurobindo Pharma had received nine FDA observations. At around the same time, DRL had got five observations after FDA inspected its active ingredient facility.

Pharma companies spent more on legal and consultancy services than companies in any other industry. An analysis of legal costs of 67 companies from the BSE 100 index shows that six pharma companies together constituted a quarter of the total of Rs 3,597 crore incurred by these companies on legal expenses. Sun Pharma has been the top spending company in the country in three of the past four years.

Pharma companies incur costs on hiring consultants for FDA compliance, IPR litigation and M&A – areas that have seen increased action in recent years.

The total legal costs of six pharma companies show a sign of stabilising, after having peaked in 2015-16. However, continued adverse FDA observations for pharma companies imply that the costs of resolution of these issues are not coming down. The latest instance of Sun’s Halol plant shows that compliance with regulations is a continuous process and any lapse can result in observations.

Dr Reddy's gets 8 observations from USFDA for Duvvada plant

Dr Reddy's Laboratories said US health regulator has issued eight observations after inspecting its formulations plant at Duvvada, Visakhapatnam.

"The audit of our formulations manufacturing facility at Duvvada, Visakhapatnam, by the US Food and Drug Administration (USFDA), has been completed today. We have been issued a Form 483 with eight observations, which we are addressing," the company said in a regulatory filing.

As per the USFDA, a Form 483 is issued to a firm's management at the conclusion of an inspection when investigator has observed any conditions that in its judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts.

It notifies the company's management of objectionable conditions. The Hyderabad-based company's shares on October 30 ended 2.48 percent up at Rs 2,597.70 on the BSE.

USFDA issues warning letter for Cadila Healthcare's Moraiya facility

Drug maker Cadila Healthcare Ltd (Zydus Cadila) received a warning letter today from the US Food and Drugs Administration (USFDA) for its Moraiya formulation unit.

Contributing roughly $400 million (Rs 2,800 crore), or 45 per cent of the firm's US sales, the Moraiya plant saw its case escalate with the US regulator on getting an official action indicated (OAI) after inspection between April 22 and May 3.

A warning letter is an escalation of Form 483 (which notes adverse observations about quality and compliance of a facility that needs the manufacturer needs to address) by the USFDA. Exports from a facility stop if it is placed under an import alert, which is an escalation of a warning letter.

For now, the warning letter does not affect the company's existing business in the US and product supplies from Moraiya will continue, Cadila Healthcare Ltd informed exchanges in its filing on Monday.

"The company has taken multiple steps after the inspection to address the observations received from USFDA during the inspection. The Company will continue to take all necessary steps to ensure that the USFDA is fully satisfied with our remediation of the above facility. We are confident of responding to USFDA to address the observations within the statutory time permitted in the letter," it stated, while adding that it was committed to patient safety and meeting expectation of regulatory compliances.

Sticking with their buy recommendations for Cadila Healthcare, analysts too are not making much of it, as they found the warning letter along expected lines.

"This warning letter at Moraiya is as per our expectations as the facility already classified as OAI status (observations related to cleaning validation/OOS). We expect Cadila Healthcare to deliver muted growth in the US owing to pending regulatory issues," Krishnanath Munde, Senior Analyst (Pharma) of Reliance Securities said in a note.

According to Munde, the firm does not expect any new approval from Moraiya for Cadila Healthcare owing to the warning letter till the facility gets resolved from the US regulator. "We have already factored warning letter impact of lack of new approvals into our valuation model in Q1 of FY20 only. We note that the remediation efforts at Moraiya are not likely to have any significant impact on product supplies to the US, as per management," Munde added in the note.

So far in 2019, Indian pharma companies have received a dozen-odd warning letters from the US drug regulator - much more than the seven that came in all of 2018. This has resulted in major companies now de-risking their business by developing alternative sites for their key products.

For Cadila Healthcare, this comes in the form of its Liva facility which has seen the company initiate site transfer of approved injectable products from its Moraiya plant. The firm expects to complete the site transfer of these injectables by the end of FY20, Cadila Healthcare management told analysts in its Q1 earnings call, according to an Edelweiss Securities' note.

Meanwhile, this year after the inspection of the Moraiya unit, Cadila Healthcare successfully completed USFDA audits of its formulations facility at Baddi, and AP! manufacturing units at Ankleshwar and Dabhasa. On Monday, Cadila Healthcare's stock price shed 5.42 per cent to close at Rs 241.45 on the Bombay Stock Exchange.

Granules India scolded over truckloads of torn manufacturing documents after recent FDA inspection

From truckloads of torn documents to avian incursions in the production plant, Granules India’s recent manufacturing reprimand from the FDA is alarming no matter which way you look at it.

Earlier this month, Granules was slapped with a Form 483 from the FDA following an inspection of its Telangana facility in India that ran from Aug. 26 to Sept. 6. The FDA’s report cites six observations around poor quality control procedures, subpar cleaning, cross-contamination risks and more.

The FDA published the Form 483 on its website Tuesday.

Drugmakers are subject to Form 483s when FDA inspectors discover “objectionable conditions” at a facility that could result in potential manufacturing violations. The write-ups are often followed by the more serious consequence of a warning letter if the company at fault fails to clean up its operations.

One of Granules’ biggest offenses comes down to poor control over production records.

The FDA noted that on the first day of its inspection, investigators witnessed three trucks “full of scrap materials” attempting to depart Granules’ plant. Upon digging into these scraps, the FDA found remnants of signed and dated manufacturing documents such as analytical balance printouts, handwritten worksheets and a “large number” of “uncontrolled papers” that had been “torn into pieces and crumpled.”

When the FDA was doing a walk-through of Granules’ quality control laboratory, inspectors noticed cleaning personnel removing a large black “scrap bag” from the area. The bag, like the trucks, contained a “large number of torn and a few intact pieces of analytical balance printouts, pH meter printouts” and more, the FDA said in its write-up.

The FDA concluded Granules’ quality control unit had been dropping the ball by documenting manufacturing data on “uncontrolled white paper” and later disposing of the documents by tearing them into pieces and throwing them into trash bags.

Upon piecing together some of these scraps with the help of Granules’ employees, the FDA was told by the plant's quality unit management that the torn pieces contained records that “should not have been destroyed.”

Elsewhere, Granules struggled to keep its facility clean, free of pests and adequately guarded against cross-contamination incidents, the FDA said.

For one, Granules failed to clean equipment to effectively remove traces of drug substance from previous manufacturing runs, creating the potential for cross-contamination, FDA investigators noted in their report.

Further, the FDA observed a buildup of white to off-white powdery materials along with water droplets, wet surfaces and material hinting at potential bacterial, fungal and mold growth inside air purification units.

Upon inspecting the filters for some of these purification units, the FDA found they were “torn in many sections,” while Granules’ HEPA filters contained “apparent dust, powdery materials and wet surfaces.”

Investigators also found bird droppings and feathers on certain purification units and noted the walls surrounding some of Granules’ manufacturing equipment “were not secured enough to prevent birds from getting inside the facility.”

Granules isn’t the only company being written up by the FDA for its poor handling of data and quality issues.

In a separate Form 483 handed down to a Biocon Biologics plant in India this summer, the FDA noted that the company both failed to back up and overwrote manufacturing data predating April 25, 2024, hindering the agency’s investigation.

The FDA further chided Biocon for its failure to properly investigate batch discrepancies. The regulator pointed out that it found employees had “inappropriately changed set points for instruments” that affected monitoring alarms in a room used to produce a U.S.-bound drug product.

“The investigation found these inappropriate changes were made as a quick fix instead of addressing frequent maintenance issues,” the FDA explained in the Form 483.

The write-ups for Granules and Biocon come as part of a slew of Form 483s published on the FDA’s website this month.