VOLUME: 20 - ISSUE: NOV 2015 |

PHARMA UPTODAY

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Inside this issue

3 News Uptoday 38 New Guidance 51 Audit Findings 483 Observations

- Pernix Receives Form 483 for cGMP Violations - FDA Hits Pfizer Subsidiary With Second Form 483 in Five Years - Galena Hit With 10-Item Form 483 Over Unresolved Issues

55 Warning Letters

- Warning letter: Unimark Remedies Ltd., Mumbai, India - Warning letter: SSM Health Care St. Louis DBA SSM St. Clare

Health Center 58 Health Canada Non Compliance Report

- Non Compliance Report: Unilever Canada Inc. 60 EMA Non-Compliance Report

- GlaxoSmithKline (Tianjin) Company Limited (Teda), China - CARGILL FRANCE

63 Regulations of the Month

- Sec. 211.42 Design and construction features (c)(5) to (c)(10) - Sec. 211.44 Lighting

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News Uptoday

India says EU ban on generic drugs 'unwarranted'

The European Union's ban on Indian generic drugs is "unwarranted" and an obstacle to moving

trade talks forward, India's foreign secretary said on Monday.

Subrahmanyam Jaishankar said EU restrictions on more than 700 generic drugs were unfair.

"It's our hope that this matter would be looked at fairly and sensibly and would hopefully not be an

impediment to the free trade deal," he told journalists after German Chancellor Angela Merkel met

with Prime Minister Narendra Modi during a visit to New Delhi.

India and Germany pledged on Monday to revive efforts to reach an Indo-European free trade pact

after talks fell apart this year.

The Union health ministry henceforth will not insist on repeat pre-clinical or toxicity studies on

animals for permission for a new drug or clinical trial if authentic data on animal toxicology has been

submitted with the technical data.

The health ministry's action in this regard comes in the backdrop of the fact that the Union minister

for women and child development Maneka Gandhi had written to the Union minister of health and

family welfare regarding pre-clinical/toxicity studies on animals under Schedule Y of the Drugs and

Cosmetics Rules, 1945.

In her letter, the minister stated that India being signatory of OECD (Organization for Economic

Cooperation and Development) Council Act related to mutual acceptance of data is under obligation

to respect the data generated by other country regarding pre-clinical/toxicity studies and therefore

there is no need for CDSCO to undertake further studies.

The molecules of interest have been those that are approved by multiple regulatory agencies and

have been through many animal studies which have been made available on sites and published in

scientific journals. Under the current regulations of item 4, Appendix-I of Schedule Y of Drugs and

Cosmetics Act, 1940, additional tests on animals are then ordered.

As the issue was related to pre-clinical or toxicity studies on animals under Appendix I and Appendix

III of Schedule Y, the matter was placed before the Investigational New drug (IND) Committee of the

Union health ministry.

The committee in its meeting held on August 6, 2015 deliberated and agreed with the statement

mentioning that, for drugs approved in other countries where complete toxicological data generated

in GLP certified laboratory and in alignment with the requirements prescribed under Drugs and

Cosmetics Act, 1940 and Rules, 1945 (Schedule Y), further toxicity study may not be required if

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complete data as per prescribed requirements is submitted during application for new drug

approval.

It may also be explored, in line with international practices, to encourage the use of other alternative

methods than animal studies, wherever such robust validated methods are available for small or

large animals, the IND committee further recommended.

The IND committee recommendations were then sent to the Drugs Technical Advisory Board

(DTAB), the highest authority under the Union health ministry on technical matters.

The issue came up for discussion in the DTAB meeting held on August 18, 2015. After deliberations,

the DTAB agreed to the recommendations of the IND committee and further recommended that

under item 4, Appendix I of Schedule Y, it may be mentioned that if authentic data on animal

toxicology as per requirements of annexure III has been submitted with the technical data, then

repeat animal testing for permission for a new drug or clinical trial is not necessary.

Brazil Suspends Pharma Serialization And Tracing Requirements

Last week, Brazil’s pharma industry regulatory agency, the National Agency of Sanitary

Surveillance (ANVISA), announced that they were ―suspending‖ at least part of RDC-54/2013, the

declaration that mandated drug serialization and tracing, until further notice. Thank you to all who

forwarded the link to the official announcement. I was able to translate and read it on Thursday, and

I submitted a comment on my own last essay, ―Pharma Serialization Deadlines In Flux―, to include

the link. Apparently shortly after that essay was published, ANVISA publicly announced the

suspension.

However, the ANVISA website was in accessible in the United States Sunday afternoon when I

normally write RxTrace essays so I was unable to finish this essay until Monday morning. Now that I

can access the site, here are the details.

According to a translation of a news article published on the ANVISA website, what they have done

is to suspend item II of Article 23 of RDC 54/2013. That’s the section the mandates the 3-lot pilot by

each registration holder that was to be completed by December 10 of this year. Apparently ANVISA

will publish a new RDC that will officially revoke that requirement ―in the coming days‖.

In addition, it appears that the entire regulation will be reviewed and the design of the mandated

solution potentially reconsidered.

In my view, RDC 54/2013 mandated data exchanges that were excessive and duplicative, but the

worst part about that regulation is that it makes registration holders responsible for collecting tracing

data from all downstream trading partners. The article indicates that the board members nodded in

agreement with the centralized tracing model, but it is unclear if that indicates support for a simplified

centralized model, a semi-centralized model (see ―The Viability of Global Track & Trace Models―), or

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the one they current have as defined in RDC 54/2013 (which is more of a convoluted hybrid model,

in my opinion).

Also unclear is whether this action changes the deadline for full serialization and tracing, previously

specified by RDC 54/2013 as December 10, 2016. The article only mentions the suspension of the

pilots but others have indicated that they expect, or they believe, that the 2016 deadline is, or will be,

suspended as part of the review and reconsideration. Treat this as more rumor until it is confirmed

by an official announcement. Hopefully that will come soon, so stay tuned.

Teva Acquires Rimsa to Accelerate its Emerging Markets Growth Strategy

Teva Pharmaceutical Industries has entered into definitive agreements under which the company will

acquire Representaciones e Investigaciones Médicas, S.A. de C.V. (Rimsa), pharmaceutical

manufacturing and distribution company in Mexico, along with a portfolio of products and companies,

intellectual property, assets and pharmaceutical patents in Latin America and Europe in a debt-free,

cash free set of transactions, for an aggregate of $2.3 billion. Through this acquisition, Teva will

become a leading pharmaceutical company in Mexico, the second largest market in Latin America

and one of the top five emerging markets globally. Teva expects the deal will yield substantial and

achievable synergies and offer a platform for growth in the region.

―This acquisition delivers on our strategy of increasing our presence in key emerging markets in

order to position Teva for long-term growth in these markets. Rimsa will provide Teva with a

significant platform for growth by combining the strong Rimsa brand, licensed portfolio of

differentiated, patent-protected products, promising pipeline, significant relationships with physicians,

patients and healthcare providers and its strong commercial presence,‖ said Erez Vigodman,

President and CEO of Teva. "The combination of our companies lays the foundation for a leadership

position and high long-term, profitable and sustainable growth in the region and further reinforces our

commitment to innovation, quality and improving the health of people worldwide."

Rimsa had revenue in 2014 of $227 million with an annual growth, year over year of 10.6% since

2011. The company has an extensive portfolio of specialty products, including fixed-dose

combination products which have fueled its growth. Rimsa’s well-established sales footprint is

expected to provide a platform for additional Teva products.

―For 45 years, Rimsa has operated as a leading pharmaceutical company in Mexico, the second

largest healthcare market in Latin America, with a high growth, unique and diversified business

model. We share Teva’s focus on providing quality healthcare and we are excited to become a part

of Teva in meeting the needs of a population of 120 million,‖ said Luis Jorge Pérez Juárez, CEO of

Rimsa.‖

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―In addition to this unique portfolio of patent-protected products, Rimsa differentiates itself as a

leading provider of branded specialty drugs, including fixed-dose combinations, which increase

adherence and reduce overall costs to patients,‖ stated Siggi Olafsson, President and CEO of Teva

Global Generic Medicines. ―We will build on their brand reputation, successful sales force model,

well-established commercial footprint and loyal customer base to introduce additional specialty and

generic Teva medicines to patients in Mexico and across the region.‖

The acquisition was unanimously approved by Teva's Board of Directors, led by the Chairman, Prof.

Yitzhak Peterburg.

Teva expects to close these transactions by early first quarter, 2016. The acquisition is not expected

to impact 2016 non-GAAP earnings and is expected to be accretive starting Q1 2017. The

transactions will be funded through a combination of cash on hand and lines of credit.

UK and India regulators agree deal for closer collaboration to improve public safety

The Medicines and Healthcare products Regulatory Agency (MHRA) has today (5 October 2015)

signed a Memorandum of Understanding (MOU) with its counterpart body in India. This agreement

will increase collaboration between the 2 countries in the area of medicines and medical devices with

the aim of further improving public safety in the 2 countries.

This is the first MOU agreed with the Central Drugs Standard Control Organisation (CDSCO), part of

the Ministry of Health and Family Welfare of Republic of India and was signed by Dr Gyanendra

Nath Singh, India’s Drugs Controller General, and MHRA Chairman, Professor Sir Michael Rawlins.

It provides a formal agreement between the 2 organisations, and strengthens relations between the

UK and Indian governments.

The central understandings of the agreement include promotion of each other’s regulatory

frameworks, requirements and processes. Significant outcomes will include the facilitation and

exchange of information and opportunities for technical cooperation of mutual benefit, helping to

ensure the regulators are better equipped to protect the health of their respective publics.

MHRA Chairman, Professor Sir Michael Rawlins said:

We are committed to protecting the health of UK citizens and that’s why we are continuing to

formalise our collaborative efforts with key partners like India.

We operate in a global environment and agreements such as these serve to further strengthen our

ability to promote good practices and we look forward to working even closer with our Indian

counterparts.

Dr Gyanendra Nath Singh commented:

The MoU signed between MHRA and CDSCO is going to create a new platform where patients will

be given utmost importance. Quality medicine, affordability and transparency will be the tools for

making medicines available to the people of the two nations.

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In 2014, MHRA carried out more than 550 inspections in the UK and 125 in non-EU countries, 49 of

which were in India. The India Brand Equity Foundation states that the Indian pharma sector

accounts for about 2.4% of the global pharma industry and is the 3rd largest in terms of volume.

Approximately 25% of UK medicines are made in India and each batch is tested on importation to

ensure it is safe, of good quality and effective and it is important that MHRA assessors continue to

inspect Indian sites to ensure Good Manufacturing Practice – a globally recognised regulatory

framework.

Sir Michael Rawlins added: ―It’s essential that the commitment to good quality manufacturing comes

right down from the top levels of management to those on the factory floor, and throughout the entire

industry.

―Indian firms already accept and understand this, and the MOU is part of a concerted effort to ensure

the UK and wider global public continue to have access to quality and safe medicines.‖

The signing of the MOU took place at CDSCO’s headquarters in New Delhi and was followed by a

series of meetings to discuss next steps.

The agreement is similar to those already in place between MHRA and other counterpart bodies in

China and America, although it is a standalone bilateral document in its own right.

FTC Approves Endo’s Acquisition of Par

The FTC has cleared the way for Endo Pharmaceuticals to acquire Par Pharmaceuticals, pending

the divestiture of two of its generic drugs.

To resolve anticompetitive concerns, Endo will sell the rights and assets to glycopyrrolate and

methimazole tablets to Rising Pharmaceuticals in New Jersey. Used to treat ulcers and

overproduction of thyroid hormone, the medications are not commonly produced and, if the

drugmakers were allowed to keep them in their post-deal portfolio, costs would likely have been

raised, the FTC said last week.

Under the FTC settlement, Endo will supply Rising Pharmaceuticals with the drugs for two years

while it arranges for a third-party manufacturer.

The $8 billion deal, announced in May, will place Endo among the top five firms in the U.S. generics

market, adding more than 100 new drugs and more than 200 ANDAs to its offerings.

The Par acquisition follows several large Endo purchases in recent years, the most recent being

Auxilium for $2.6 billion last October.

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Sun Pharma Recalls Over 216,000 Bottles of Blood Pressure, Antidepressant Drugs

Sun Pharma is recalling more than 216,000 bottles of felodipine blood pressure tablets and the

antidepressant imipramine because the varnish on labels is leaching a chemical into the containers.

The news comes on the heels of a July recall of bupropion hydrochloride tablets made at Sun’s

Halol, Gujarat, India, plant.

The products, produced by Sun’s Mutual Pharmaceutical subsidiary, include 187,106 bottles of

felodipine extended-release tablets and 29,660 bottles of imipramine.

The problem was detected in stability results, which found trace amounts of benzophenone in the

drugs. Sun says the impurity occurs naturally and is unlikely to cause any significant adverse events,

and that the recall was initiated as a precaution.

The products were distributed between February 2014 and April of this year. The FDA has

designated the recalls Class III, the least worrisome rating.

The July recall of bupropion hydrochloride followed one in March involving eye solutions, continuing

a string of recalls of product made at that site. Those recalls followed 2014 recalls by the Halol

facility and Detroit-based Caraco Pharmaceutical Laboratories, which distributes drugs for Sun in the

U.S.

US FDA Activities Report of the Generic Drug Program (FY 2015)

GDUFA

YEAR/Actions

This Month

14-Oct 14-

Nov

14-

Dec

15-

Jan

15-

Feb

15-

Mar

15-

Apr

15-

May

15-Jun 15-

Jul

15-

Aug

15-

Sep

FY-

2015

Refuse to

Receive (RTR)

+

12 11 15 30 27 13 11 15 20 13 19 186

Withdrawals 6 12 2 11 7 13 23 11 21 16 18 140

Approvals 45 28 29 25 27 19 49 47 57 47 58 431

Tentative

Approvals

10 7 5 5 13 6 19 13 10 12 6 106

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Complete

Responses

(CR) +

43 76 96 104 108 94 115 97 116 134 96 1079

Drug Master

File

Completeness

Assessment

(DMF CA)

124 55 71 92 86 55 76 62 65 54 35 775

GDUFA YEAR

(Receipts)Submissions

This Month

14-

Oct

14-

Nov

14-

Dec

15-

Jan

15-

Feb

15-

Mar

15-

Apr

15-

May

15-

Jun

15-

Jul

15-

Aug

15-

Sep

FY-

2015

Abbreviated New Drug

Applications (ANDA) ++

50 27 43 27 29 57 58 49 39 52 431

CBE Supplements + 473 385 434 411 420 439 413 474 472 425 4346

PAS Supplements + 45 22 51 33 37 55 38 48 37 41 407

GDUFA YEAR/

(Receipts)Amendments

14-

Oct

14-

Nov

14-

Dec

15-

Jan

15-

Feb

15-

Mar

15-

Apr

15-

May

15-

Jun

15-

Jul

15-

Aug

15-

Sep

FY-

2015

Originals (Pre FY15)

Administrative

119 228 388 339 429 372

Originals (Pre FY15) Solicited

(CR, ECD/IR)

86 80 178 320 582 503

Originals (Pre FY15)

Unsolicited

398 229 108 118 84 130

Originals (FY15) Administrative 1 21 20 30 21 23

Originals (FY15) Tier 1 0 0 0 0 0 1

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Originals (FY15) Tier 2 0 0 0 0 0 1

Originals (FY15) Tier 3 0 0 0 0 0 0

Originals (FY15) ECD/IR 0 7 4 43 37 54

PAS Supplements (Pre FY15)

Administrative

5 21 15 18 14 9

PAS Supplements (Pre FY15)

Solicited (CR, ECD/IR)

47 35 88 45 42 53

PAS Supplements (Pre FY15)

Unsolicited

43 21 11 11 10 9

PAS Supplements (FY15)

Administrative

1 6 3 7 2 7

PAS Supplements (FY15) Tier

1

0 0 0 0 0 1

PAS Supplements (FY15) Tier

2

0 0 0 0 1 0

PAS Supplements (FY15) Tier

3

0 0 0 0 0 0

PAS Supplements (FY15)

ECD/IR

0 0 3 4 11 28

CBE Amendments (all years

together)

61 34 29 72 71 101

GDUFA YEAR

(Receipts)

14-

Oct

14-

Nov

14-

Dec

15-

Jan

15-

Feb

15-

Mar

15-

Apr

15-May 15-

Jun

15-

Jul

15-

Aug

15-

Sep

FY-

2015

Controls +++ 112 86 111 115 104 140 136 124 141 170 1239

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GDUFA Post CR

Meeting Requests ++++

84 89 96 105 113 123 129 132 134 137 1142

Post CR Meeting

Requests This month

0 5 7 9 8 10 6 3 2 3 53

+ = Revised to reflect more accurate counting by the GDRP. For example RTRs revised to include

both RTR due to failure to pay user fees and RTR due to technical reasons.

++ = Starting FY15 ANDA Original Receipts are reported as raw receipts (versus filed receipts).

+++ = FY 15 Controls have been revised to count only those requests appropriate for a control.

++++ = Cumulative and NOT specific to the month. DMF raw receipts have been eliminated since

DMF Completeness Assessments present a more accurate indication of workload.

Numbers are rounded and do not reflect actual numbers for Congressional reporting purposes.

Note: Amendment metrics for April, May and June will be forthcoming

Source: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandAppro

ved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm375079.htm

FDA Reassures Industry on Use of Quality Metrics

The FDA is trying to reassure drug companies by making it clear that the agency won’t use its quality

metrics collection to spur 483s, warning letters and other enforcement actions.

The quality metrics effort is not an enforcement program; it is a surveillance program, explained

Russell Wesdyk, acting director of the Office of Pharmaceutical Quality’s Office of Surveillance.

Submission of metrics will be used to determine a firm’s risk score in the selection model used to

prioritize scheduling of routine surveillance inspections, he said.

To encourage data submission, sites with more metrics could see a greater reduction of score,

Wesdyk, said, adding ―more information is better than less information.‖

For example, a drugmaker may worry that high recall or batch failure rates will mean they’ll get

inspected more. In fact, it could be just the opposite, as the numbers could be in line with other like

manufacturers, Wesdyk said.

In fact, a manufacturer that submits fewer data or data showing a very low recall or failure rate could

draw more agency scrutiny, he added. He spoke at a session last week at the FDA/PQRI

Conference on Advancing Product Quality in Bethesda, Md.

Wesdyk said he is also surprised by the amount of feedback from industry groups questioning the

agency’s authority to collect quality metrics. He said the FDA is trying to help industry and is not the

―boogeyman hiding behind trees.‖

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Meanwhile, ISPE said it is nearly halfway through the data submission and collection phase of its

quality metrics pilot program, which is continuing despite differences in its metrics and those the FDA

has targeted. Three of the four quality metrics the FDA plans to collect — lot acceptance rate,

product quality complaint rate and invalidated out-of-specification rate — are accounted for in the

eight quality metrics ISPE is collecting.

ISPE has collected data from 21 companies covering 88 sites so far. Data collected by Oct. 30 will

be analyzed for inclusion in ISPE’s comments on the FDA’s draft guidance on quality metrics, which

are due Nov. 27, said Máiréad Goetz, co-chair of ISPE’s quality metrics team.

The final deadline for collecting data under ISPE’s pilot program is Nov. 30. The totality of data will

be analyzed for ISPE’s final report, expected next February or March, Goetz said.

FDA’s Team-Based Inspection Program Taking Shape

The FDA’s new team-based inspection program is starting to take shape with a steering committee

led by high-ranking FDA officials and three subgroups.

The three subgroups are the Pre-Approval Inspection group, the Surveillance Inspection group and

the tentatively named For-Cause Inspection group. Tentative scoring systems, investigator training,

IT systems and investigator questions have been drafted for the first two groups, while the for-cause

group’s functions are being developed, said Russell Wesdyk, acting director of OPQ’s Office of

Surveillance.

Wesdyk spoke during a session last week at the FDA/Product Quality Research Institute Conference

on Advancing Product Quality in Bethesda, Md.

The PAI and Surveillance groups have conducted pilot inspections, and more are planned, Wesdyk

said. At this time, there are no plans for the for-cause group to conduct pilot inspections, as the pilots

for the other two groups may be enough, he said. The pilot program is also testing a new IT system

to support investigators while on site.

Once fully implemented, PAI will be tasked with performing inspections whose observations inform

premarket review decisions. The surveillance group will observe the state of quality in a facility to

determine quality risk and perform routine inspections, Lawrence Yu, deputy director of the Office of

Pharmaceutical Quality, said. The for-cause inspections will be handled by ORA and look for

evidence of cGMP violations to support enforcement actions.

Observations made in the PAI or surveillance inspections could trigger escalation or transition into

for-cause inspections, Yu said.

The New Inspection Protocol Project Steering Committee is co-chaired by Theresa Mullin, director of

CDER’s Office of Strategic Operations, and Ellen Morrison, assistant commissioner for operations in

the FDA’s Office of Regulatory Affairs.

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EMA Report Shows 350 GMP Inspections in First Half of 2015

The European Medicines Agency conducted 350 good manufacturing practices inspections in the

first half of this year — roughly 50 percent more than in the same period a year ago, a new report

shows.

The number of GMP inspections nearly reached the annual forecast for the entire year, causing the

agency to revise its 2015 forecast from 390 to 425. By comparison, inspections totaled 235 for the

first half of 2014.

The EMA also met its half-year target of conducting 10 percent of routine GMP reinspections of

manufacturing sites using an exchange of information with international partners.

The EMA’s mid-year report, released last week, also shows pharmacovigilance monitoring running

even with 2014, with 10 inspections, while the number of good laboratory practice inspections

increased from zero to one and good clinical practice audits edged up to 35, from 33 a year ago.

Indian pharma majors get 113 ANDAs approval from US FDA in Jan-Sept 2015

Major Indian pharmaceutical companies and their subsidiaries have set to get higher Abbreviated

New Drug Application (ANDAs) approvals during 2015 with rising investment in research and

development. Indian companies already secured final approvals for 113 ANDAs from US FDA during

the first nine months ended September 2015 and 32 tentative approvals. This worked out to over 30

per cent of the total approvals by US FDA. The US FDA has approved total 372 final ANDAs during

January-September 2015 and 102 tentative ANDAs.

The overall approval rate of US FDA during 2015 will be higher as compared to full year 2014. In

2014, it approved 416 ANDAs of which Indian companies secured 122 final ANDA approvals.

Aurobindo Pharma and Lupin received highest number of 21 ANDA approvals each during the first

nine months ended September 2015, followed by 8 ANDA approvals each by Alembic

Pharmaceuticals, Glenmark Pharmaceuticals and Hetero Laboratories. Jubilant Life Sciences,

Macleods Pharma and Sun Pharmaceuticals grabbed 6 ANDA approvals each during first nine

months of 2015. Torrent Pharmaceuticals and Orchid Chemicals and Pharmaceuticals got 4 and 5

ANDA approvals each.

The higher approvals shows that Indian companies are well set to stepped up their presence in the

highly regulated market like US, Europe and also in emerging markets by offering new generic

products. Patent expiration in coming years may generate higher demand for these products.

Aurobindo Pharma, which secured approval for 21 ANDAs between January-September 2015, has

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incurred an R&D expenditure of Rs.359.88 crore during the year ended March 2015 as

against Rs.270.80 crore in the previous year. The company has filed 192 DMFs and 376 ANDAs

with the US FDA upto March 2015 and it received 193 ANDA approvals and 183 ANDA approvals

are awaiting.

Lupin's R&D expenditure moved up by 16.7 per cent to Rs.1,118.54 crore during the year ended

March 2015 from Rs.958.28 crore in the previous year. It filed 18 ANDAs for the US market during

2014-15 and its cumulative total reached at 210 ANDAs. Currently it has 99 ANDAs pending for

approval. It has 15 exclusive first-to-file ANDAs addressing a market size of US$ 2.5 billion. It also

filed 435 patent applications including 97 new inventions taking the cumulative total of 2,197 patents

filed.

Sun Pharmaceutical, after acquisition of Ranbaxy Laboratories, pushed its consolidated R&D

expenditure at Rs.1,955 crore during the fiscal year ended March 2015 as compared to Rs.1,042

crore in the previous year. Its five major R&D centres are located in India, Israel, Canada and USA

and strengthening the speciailty pipeline including patented products and complex generics. Sun's

cumulative filings of ANDAs reached at 597 and it received cumulative approvals for 438 ANDAs till

March 2015. The company and Taro Pharma received final approval for 8 ANDAs during January-

September 2015 and 2 tentative approvals.

Besides above pharma majors, Ajanta Pharma, Dr Reddy's Laboratories, Emcure Pharma, Granules

India, Natco Pharma, Strides Arcolab, Wockhardt, Zydus Pharma received approvals for ANDAs.

FDA Inspections at API Manufacturers - current Warning Letter Trends

Taking a look at the Warning Letters the FDA issued after inspections of activesubstance

manufacturers in the 2015 fiscal year, which ended on 30 September 2015, it is first of all striking

that only non-American companies are among the addressees. Almost half of them are Indian

companies. Overall the numbers look like this: India (3 WLs); China (2 WLs); Canada (1 WL);

Thailand (1 WL); Czech Republic (1 WL).

The top issue in the Warning Letters is the non-GMP compliant handling of electronic data or

missing data integrity. Each of the 8 warning letters contains the following comment in the same

wording:

"Failure to prevent unauthorized access or changes to data and to provide adequate controls to

prevent omission of data."

The lack of access control on electronic (raw) data is an issue the FDA investigators have been

observing for a long time, especially during inspections in pharmaceutical companies. In this as well

as in the last fiscal year there were significant deficiencies in several companies - medicinal product

as well as API manufacturers - as the comments in the appropriate Warning Letters show. For more

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information also see the GMP news Another FDA Warning Letter with Focus on "Data

Integrity" and FDA Warning Letter on Data Integrity.

Ultimately these deficiencies can be traced back to a failure of the quality assurance unit which also

affects other areas. In the Warning Letters, the following examples can be found for this:

"Failure of your quality unit to ensure that materials are appropriately tested and the results

are reported."

"Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured at

your facility are in compliance with CGMP, and meet established specifications for quality and

purity."

Data were manipulated by laboratory staff (change of the file name), to fake results from

identity tests in batches which in reality were not performed. Quality assurance was not able

to uncover this manipulation.

Despite an unknown peak in the examination for residual solvents the relevant batches were

released. Upon receipt of a complaint regarding this peak an examination was conducted with

the result that the contamination originated in the production process itself. Preventive control

measures to avoid this contamination were not established.

"Failure to adequately investigate complaints and extend the investigations to other batches

that may have been affected."

As a result of a complaint (bad smell), a cause study was initiated which was completed prior

to implementation of the preventive measures again. The CAPA measures subsequently

carried out were obviously not associated with the reason for the complaint.

"Failure to have appropriate controls for issuance of batch records".

The use of document templates for batch records is out of control. These can be printed out

from the production staff's personal computers. Although there is an SOP for the control of

batch records there are no appropriate training records.

"Failure to have appropriate documentation and record controls."

Data for tracing raw materials are not available. Log entries are without date/visa and partly

corrected with Tippex. There is an SOP prohibiting the use of correction fluid, however this

was not trained.

"Failure to record activities at the time they are performed and destruction of original records."

Original records of critical process data on uncontrolled memos were transferred

subsequently in new report templates (after batch approvals) and then destroyed.

This selection of examples shows the lack of fundamental GMP principles which leads to a blatant

misconduct of staff and ultimately to quality defects in the final product. The main responsibility

usually has the quality unit, which task it actually would be to ensure a thorough training in

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production and quality control and to monitor compliance with the appropriate regulations. These

examples of non-GMP-compliant behavior are not limited to active ingredient manufacturers; there

are very similar findings in Warning Letters issued to medicinal product manufacturers.

USP wants to considerably expand the Monograph for Ophthalmic Preparations <771>

The considerably expanded draft monograph <771> in the American pharmacopeia includes topical

ophthalmic products like eye drops as well as ophthalmic preparations for injection purposes. These

products are manufactured using terminal sterilisation, sterile filtration and aseptic filtration. An

overview lists and describes the different pharmaceutical forms in more detail: solutions,

suspensions, ointments, gels, emulsions, strips, injections, inserts and implants. However, the part

on product quality is particularly interesting, especially the general tests. According to this, all

ophthalmic preparations are to undergo a test to determine the integrity of the packaging and to test

for visible particles. A 100% test is only mentioned for ophthalmic preparations for injections in

transparent containers. If this is not possible due to the characteristics of the containers, reference is

made to random sample tests in monograph <790>. The requirements with regard to subvisible

particles are depending on the route of adminstration: According to the draft, products for intraocular

use are to correspond with the the monograph Particulate Matter in Ophthalmic Solutions <789>,

products for extraocular use should comply with the monograph Particulate Matter in Injections

<788>.

The inclusion of a limit value for invisible particles in ophthalmic preparations is currently being

discussed in Europe, too. You can find information on the discussion of expanding monograph 1163

on the EDQM homepage.

Further sections in the USP monograph discuss sterility, preservatives and endotoxins (in injectable

products). The requirements described for leachables/extractables that may come from the

packaging are also new. It is pointed out that a risk assessment of leachables/extractables is not

easy to perform, as there is little data about substances that can be absorbed via the eye. Therefore,

data that has been determined for other routes of administration can be used for the risk analysis.

Furthermore, the special tests that may be relevant for ophthalmic preparations are listed, such as

viscosity, particle size distribution (in suspensions/emulsions) and drop size.

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GDP certification by accredited bodies and GDP audit by QPs - dangerous

misunderstandings

With the publication of the new GDP Guideline in the year 2013 the legal requirements concerning

the Good Distribution Practice have increased significantly. This has manifold consequences

because now compliance with the quality requirements is controlled throughout the complete

distribution chain until the final release to the patient. This is the objective at least.

The competent supervisory authorities carry out GDP inspections of companies that undertake tasks

requiring GDP in the course of distribution. And this is where the problem already starts. Since the

date of availability of the new GDP Guideline each company which comes into contact with the

supply chain of medicinal products tries to receive a GDP certificate. After all, it is the declared

objective of the EU to guarantee GDP compliance throughout the complete supply chain. The GDP

certificates are listed throughout Europe in a central database called EudraGMDP. Here, the GDP

non-compliance reports are also recorded. So what could be more natural than to attempt to be

listed there in order to demonstrate GMP compliance to the customers?

But the EU GDP Guide defines the group of companies which are subject to supervision very strict.

This means that many of the actors in the supply chain are not under supervision but must

implement GDP nevertheless. The competent authority for GDP will normally not carry out GDP

inspections at transport companies (shipping companies) or at airport hubs.

This gap is now filled by a number of service providers that grant GDP certificates. Some accredited

or non accredited bodies have started to offer GDP certificates for shipping companies or even

airports. An auditor of the (accredited) body carries out an audit and at the end a GDP certificate

beckons which will then be advertised in the internet and in company brochures. And here a big

misunderstanding arises. Because these commercial certificates cannot be compared to the GDP

certificates issued by the supervisory authority. But many actors in the supply chain are not aware of

this fact. The GDP certificate might be a marketing instrument such as the ISO 9001 certificate or a

certificate certifying compliance with environmental standards. But it does not confirm GDP

compliance within the meaning of an official GDP certificate. This can only be done by the competent

supervisory authority.

One also hears more and more about so-called QP audits carried out by independent consultants

who allegedly confirm GDP compliance by means of a GDP Certificate. As QPs play a central role in

the pharmaceutical law it is assumed by some companies that these "QP certificates" have a

particularly high significance and that they could virtually serve as substitute for the GDP certificate

of the supervisory authority. But this is not the case - as has already been explained for the GDP

certificates issued by accredited companies. A QP who actually works as part of the supplier

qualification for a pharmaceutical company will never issue a GDP certificate or written confirmation.

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What should companies do that would like to have a GDP certificate but will not be inspected by the

authority? It is important that each of these companies implements GDP. The requirements can be

checked in the GDP Guideline. A further certificate is not required. The key is an internal quality

management system for establishing GDP requirements with sufficiently qualified personnel. In the

case of a new customer/supplier relationship, for instance, the external auditor will want to see the

concrete implementation of GDP - regardless of a GDP certificate of any organisation.

FDA Clears Impax of Issues from 2011 Warning Letter

Impax Laboratories says the FDA has inspected its Hayward, Calif., manufacturing plant and cleared

it of all issues raised in a 2011 warning letter, paving the way for the launch of new drug products.

The pipeline consists of 33 pending ANDAs, with 25 developed internally and eight developed

through external partnerships, CEO and President Fred Wilkinson said.

Of the 17 ANDAs developed at the Hayward plant, two could launch later this year and eight in 2016.

The applications include generics of Sanofi's kidney disease drug Renvela (sevelamer carbonate),

Daiichi Sankyo's and Genzyme's diabetes and cholesterol drug Welchol (colesevelam HCI), Teva's

ADHD drug Adderall XR and Purdue Pharma's OxyContin TR.

The FDA issued the warning letter in May 2011 for manufacturing violations related to finished

pharmaceuticals identified during a Dec. 13, 2010, to Jan. 21, 2011, inspection.

The inspection found deviations in sampling and testing of in-process materials and drug products

and lapses in production record reviews. For example, Impax couldn't demonstrate that the

manufacturing process for fenofibrate capsules was capable of controlling weight variations and

didn't have data to support the temperature range used during the granulation process of colestipol

hydrochloride tablets, according to the warning letter.

The letter followed a Form 483 that triggered a voluntary recall of fenofibrate capsules in March

2011.

Wilkinson did not say how the company resolved the items in the warning letter.

FDA Bans Imports From Major Indian API Manufacturer

The US Food and Drug Administration (FDA) on Wednesday added Indian active pharmaceutical

ingredient (API) manufacturer Megafine Pharma's Nashik site in Maharashtra, India, to a list of

foreign manufacturing sites banned from sending products to the US.

Megafine, which was hit with an FDA Form 483 back in May at the site, produces 24 APIs for the US

market, including for drugs intended to treat Alzheimer's disease, depression, schizophrenia, multiple

sclerosis and overactive bladders. The company also produces the same number of APIs for the EU

market, as well as a number of other products for Canada, Australia, Brazil, Mexico and South

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Korea. The Nashik site, according to the company, has been inspected and approved by regulators

including the European Medicines Agency, Japan's Pharmaceutical and Medical Devices Agency,

the WHO and others.

The notice on Megafine does not indicate the specific issues that caused the import alert and does

not indicate if the company's other manufacturing site in Vapi, India will be impacted.

Form 483

According to a heavily redacted 13-page Form 483, the company was cited for manipulating lab

tests, as well as unjustified and unrecorded deviations from written lab mechanisms. The 483 notes

that one of the company's quality control (QC) analysts "manipulated" a test chromatogram "by

removing the unwanted peak out of the chromatogram and passed off the passing chromatogram as

the valid result."

In addition, the FDA inspector found that the QC management could not explain the "wide variation

between" an initial test result and a retest result, though, ―It is believed that the initial OOS [out of

specification] assay was switched with old passing sample vials and retested to obtain the passing

test results."

Another QC analyst was cited for manipulating high-performance liquid chromatography software "to

obtain passing test results."

In addition, FDA found that no "investigation reports were initiated after identification of non-cGMP

[current good manufacturing practice] practices within the production and quality control

department."

Companies on the import alert list that would like to request removal, according to FDA, "should

provide information to FDA to adequately demonstrate that the manufacturer has resolved the

conditions that gave rise to the appearance of the violation, so that the agency will have confidence

that future entries will be in compliance. This may include a letter detailing its corrective actions,

accompanied by documentation."

Forty-five other Indian pharmaceutical and API manufacturers are currently included on the import

alert list, including Ranbaxy, Wockhardt and Ipca Laboratories.

Megafine did not respond to a request for comment. For more details

browse: http://www.accessdata.fda.gov/cms_ia/importalert_189.html?source=govdelivery&utm_medi

um=email&utm_source=govdelivery

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Register of brokers authorised to deal in human medicines

MHRA (Medicines and Healthcare products Regulatory Agency) publishes current listing of UK

brokers authorised to broker human medicines, including company name, registration and address.

Source: https://www.gov.uk/government/publications/register-of-brokers-authorised-to-deal-in-

human-medicines

EU Court Clarifies When Drug Patents Expire

A ruling by the Court of Justice of the European Union has clarified when drug patents expire, in a

decision that could prove lucrative for drugmakers even though it adds only a few days of patent

protection.

The case, Seattle Genetics Inc. v. Austrian Patent Office, deals with a specific aspect of European

patent law known as a supplementary protection certificate, which extends the duration of certain

rights associated with a patent. SPCs take effect after the general patent expires and typically last

for five years. The combined exclusivity from the patent and SPC is normally capped at 15 years

from the time the product first receives marketing authorization.

The Austrian Patent Office granted an SPC to Seattle Genetics on Oct. 25, 2012, and set the

expiration date as Oct. 25, 2027. Seattle Genetics challenged that date, arguing the 15 years of

protection should start when the company was notified of the authorization, thereby pushing back the

expiration until Oct. 30, 2027.

In its Oct. 6 ruling, the CJEU agreed with the drugmaker, saying the term of an SPC begins on the

date when the innovator is notified of marketing authorization, not the date when authorities decided

to grant that authorization.

The case involved Seattle Genetics’ lymphoma therapy Adcetris (brentuximab vedotin).

Karnataka’s 27,000 chemists shut stores, KCDA submits memorandum to state health

minister to ban all online pharmacy websites

Karnataka Chemists & Druggists Association (KCDA) have stated that all the 27,000 chemists shops

across the state have brought the shutters down and the strike is a total success. The Association

also submitted to Karnataka health and family welfare minister UT Khader a memorandum to ban all

online pharmacy websites because it violates the Drugs & Cosmetics Act & Rules.

―Our memorandum was also accepted by Karnataka drugs controller Raghurama Bhandary, said V

Harikrishnan, president Karnataka Chemists & Druggists Association and the Bangalore District

Chemists and Druggists Association.

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―We are confident that the state government has comprehended the issue and will make efforts to

arrive at solution at the earliest,‖ he added.

The chemists and druggists across the state took out protest marches at various places. In

Bengaluru 2,500 chemists carried out peaceful protests at the Freedom Park to fight the cause of

online pharmacy players operating in the absence of a set of norms.

A dedicated committee for the creation of online pharmacy guidelines led by Maharashtra FDA

commissioner Harshadeep Kamble has Karnataka drugs controller Raghurama Bhandary, Odisha

drugs controller H Mahapatra, CDCSO assistant drugs controller Atul Kumar Nasa, FDA Goa

director Salim A Velijee, Madhya Pradesh State Licensing Authority Pankaj Agarwal and CDSCO

joint drugs controller Dr Eshwara Reddy as its members. The committee is now awaiting the

comments of the stakeholders covering druggists, chemists and the related associations before the

month end.

The online pharmacy retailers in the country have formed an association, the Indian Internet

Pharmacy Association (IIPA), to promote and protect the public health by ensuring that its members

operate in accordance with the existing Drugs & Cosmetics Rules read with Sections 4 & 5 of

Information Technology Act, 2008, and Pharmacy Practice Regulations, 2015 issued by government

of India through PCI.

―We strongly object to online pharmacy which is currently an unethical mode of doing business. It is

heartening to note that the state government is looking into the issue and keen to help us,‖

Harikrishnan told.

Both Karnataka Chemists & Druggists Association and the Bangalore District Chemists and

Druggists Association have exempted the hospital pharmacies in this 24-hour bandh. This ensured

the public and patients have had access to drugs from these outlets.

According to a section of people who gathered at pharmacy outlets in the government hospitals of

Victoria and Sri Jayadeva Institute of Cardiology, with an increased awareness about the nationwide

strike call on October 14, the drugs have been purchased well in advance to offset any immediate

emergencies. However, it is the outpatients and in-patients medicines which constituted the usual

and major chunk of sales today at the hospital pharmacies in most hospitals.

India risks missing boat as biosimilars shake up drug industry

India, which has dominated the generic drugs industry for decades, is falling behind in the race to

make copies of complex biotech drugs, which are expected to generate tens of billions of dollars in

sales in the coming years.

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While Indian firms have launched a few such products on the domestic market, where regulatory

barriers are relatively low, they are being overtaken by European, American and South Korean firms

in the race to supply lucrative Western markets.

Just three Indian groups - Biocon Ltd, Dr Reddy's Laboratories Ltd and Intas Pharamceuticals Ltd -

are working with partners on so-called biosimilars aimed at the United States and Europe.

Biotech drugs, which require genetic engineering, account for a growing share of new drugs and the

future sales of copycat products will also switch to this category of pharmaceuticals from simple

small-molecule pills like aspirin.

The global biosimilars market is predicted to have sales of $25 billion by 2020, according to a 2014

Thomson Reuters report.

"Biosimilars is a big opportunity," said Sujay Shetty, leader of the life sciences practice at PwC India.

"But unlike generics, it is not yet an opportunity (for Indian companies) in the U.S."

Copying chemical-based drugs has long been the bedrock of India's $15 billion pharmaceuticals

industry. Biotech drugs, however, are more difficult to make and cannot be replicated exactly, which

is why regulators have come up with the notion of versions that are similar enough to do the job.

That also means regulators will be eagle-eyed on quality, posing a challenge to Indian companies,

which have been distracted in recent years by manufacturing problems that have led to some drugs

being barred from key overseas markets.

Many, including the country's biggest drugmaker Sun Pharmaceutical Industries Ltd, are still

struggling to fix issues at their generic drug factories.

"FAR BEHIND"

Biosimilars have been available in India since the early 2000s, well before their 2006 arrival in

Europe and the recent introduction of a regulatory pathway in the United States, where the first

biosimilar was launched only last month.

But India's experience has not been problem-free. Intas, for example, recently received reports of

some patients on its biosimilar version of Roche's eye drug Lucentis developing inflammation barely

two months after the drug's launch.

An Intas spokesman said the problem was found to be in the drug's "cold chain logistics" distribution

channel and has restricted supply of the drug.

Arun Chandavarkar, the chief executive of Biocon, seen by analysts as the front-runner among

Indian firms developing biosimilars, believes the cost and complexity of developing biosimilars will be

a deterrent for many Indian players.

"At this time, there can't be too many companies willing to put in that much effort and investment," he

said.

The three Indian companies that have stated plans to make biosimilars for the United States and

Europe are all partnered with larger Western firms.

Biocon has a tie-up with Mylan Inc and is testing four molecules in global Phase III trials, for which it

plans to seek approvals in the United States and Europe starting in fiscal 2017, Chandavarkar said.

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Dr Reddy's is developing biosimilars such as rituximab and pegfilgrastim for use in cancer treatment

under a pact with Germany's Merck KGaA and said it plans to launch its first biosimilar in the United

States by 2018.

A spokesman at Intas, which developed pegfilgrastim in partnership with Canada's Apotex Inc, told

Reuters the company was considering partnering with a Swiss drugmaker to launch the product in

the United States. It declined to name the firm.

Chandru Chawla, head of Cipla Ltd's new ventures unit, said India's "fundamental disadvantage"

over United States, Europe and South Korea was that biotechnology never evolved in India to the

extent that chemistry did.

"In terms of having the right knowledge ecosystem and the pools of talent, India is far behind," he

said.

Globally, Western pharmaceutical firms such as Novartis AG; Pfizer Inc, in partnership with South

Korea's Celltrion Inc; and Merck & Co with partner Samsung Bioepis, are leading in the race to

dominate the Western biosimilars market.

"South Korea has made very significant strides in a very short period of time," said Cartikeya Reddy,

Dr Reddy's executive vice president for biologics. "In this regard they have indeed pulled ahead of

Indian companies."

Indian drug retailers protest against e-pharmacies

Indian drug retailers shut up shop for the day on Wednesday to protest against the country's growing

online pharmacy industry, and threatened to close indefinitely if the federal government did not shut

down e-pharmacies.

The nationwide protest was widely supported, with as many as 850,000 chemists closing their doors,

leaving patients waiting in long queues at any pharmacies that were open. "I have been to 7-8 shops

that were closed. My son has fever, and he needs medicine urgently," said Sukanti Bhoi, 55, as she

waited for her turn at a government hospital pharmacy in the eastern state of Odisha.

Shops inside and around hospitals as well as 24-hour pharmacies did not join in the one-day strike.

Online pharmacies are a relatively new phenomenon in India, where mom-and-pop stores have long

dispensed drugs. But online retailers pose a threat to their bricks-and-mortar peers in a market IMS

Health estimates is worth about $13 billion. Companies including Zigy and Sequoia Capital-backed

1mg have set up e-pharmacies over the past couple of years. Healthcare company Apollo Hospitals

Enterprise plans to start online sales if the government regulates the business.

Drug retailers are worried.

"It is a matter of our livelihoods, we must be prepared for a fight," said pharmacist Satish Vij, who

traveled from northern Haryana state to take part in a protest in New Delhi, where about 1,000

people, mostly pharmacists, wore black arm bands, held placards and shouted slogans against e-

pharmacies.

"We will struggle if multinationals enter this business," he said.

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J.S. Shinde, president of the All India Organization of Chemists and Druggists which called the

protest, said the retailers' trade group will consider an indefinite strike if the government does not

stop online drug sales within two months.

The dispute pits drug retailers, many of whom belong to the middle-class voter-base of Prime

Minister Narendra Modi's Bharatiya Janata Party, against the leader's push to encourage tech and

digital entrepreneurship in India.

Late on Tuesday, in a last-minute attempt to get pharmacies to stay open, Modi's Health Ministry

said it was studying several representations on how the online pharmacy business should be

regulated. It said the views of all stakeholders will be considered.

A Health Ministry spokeswoman could not immediately be reached for comment on Wednesday.

But retailers do not even want the government to consider online pharmacies as a legitimate

business. They say online sales will lead to more cases of drug abuse as medicines will be sold

without proper verification.

E-pharmacies say they have safeguards in place. Prashant Tandon, president of the newly formed

group of e-pharmacies -- Indian Internet Pharmacy Association -- said the internet will also help

small drug stores grow faster.

Japan's drug regulator PMDA plans India office

Japan's drug regulator, the Pharmaceuticals and Medical Devices Agency ( PMDA), is set to open

an India office soon, amid concerns over an aging population and burgeoning healthcare costs in a

country dominated by branded drugs.

The move is expected to help Indian generic drug manufacturers, which have been seeking to

increase their presence in Japan either through exports or by forging joint ventures with partners in

that country. Japan's market is worth $110 billion.

Japan wants to lower healthcare costs by encouraging generic drugs. It's looking to double the share

of generics in its healthcare system to 60% by 2017-18 to ease the burden on public expenditure,

translating into an attractive op portunity for Indian firms. "Indian drug makers, which are known for

their skills in producing efficacious and affordable copycat medicines, couldn't make much headway

in the highly attractive but regulated Japanese market for decades," said a senior commerce ministry

official, who did not want to be named. "The Japanese drug regulator is of late showing interest to

collaborate with its Indian counterpart over the last few weeks."

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The FDA Could Earn Over $60 Million A Day From Enforcing The Law

Many clinical trials on medicines and devices are subject to a 2007 federal law that requires the

results to be publicly disclosed on a federally sponsored website within a year after the clinical

trial is over. The reason for this requirement is simple: to give doctors and patients full information

so that they can make educated decisions about a given treatment. If disappointing clinical trial

results remain hidden, while only the most positive results are published and presented in the

media, doctors and patients can be wildly misled.

Unfortunately, investigators have found that over half the time, clinical trial sponsors fail to abide

by the law, sometimes failing to disclose results even after five years have elapsed. Even more

unfortunately, the Food and Drug Administration (FDA) has never once imposed the legally

authorized $10,000-per-day fine for failure to disclose a clinical trial’s results.

Compliance With Reporting Requirements

The most recent investigation was published in the New England Journal of Medicine (NEJM) in

March 2015. The authors identified 13,327 clinical trials that were registered on ClinicalTrials.gov,

that were completed between 2008 and 2012, and that were subject to the 2007 federal law

requiring full disclosure. A mere 13.4 percent of the clinical trials actually disclosed their results

within the 12 months required by law, and even after up to four years had elapsed, only 50.5

percent had disclosed the results or asked for a delay (see Figure 2 in the NEJM article).

In a twist that ought to embarrass academics, industry-funded trials were more likely to disclose

results than the National Institutes of Health (NIH)-funded trials, which were in turn more likely to

disclose results than academic medical centers. The authors found 6,599 clinical trials that were

overdue on reporting results.

Increasing FDA Enforcement

If the FDA imposed a $10,000 per day fine on each of these 6,599 outstanding trials, clinical trial

sponsors would be responsible for $66 million in payments in the first day alone, adding up to

over $24 billion per year.

Although the $24 billion figure shows the size and scope of the problem, the collective fines would

never reach that amount because as soon as the FDA actually begins enforcing the law, the

researchers who conducted these 6,599 trials would finally be incentivized to report the trials’

results.

Why doesn’t the FDA enforce the law? Some have argued that ClinicalTrials.gov is an antiquated

and difficult-to-use website. True enough, but given that 38 percent of trials do disclose their

results at some point, it is clearly not impossible to do so. This is not a reason to leave the federal

law completely unenforced.

The NEJM article states that one reason for lack of enforcement is that a new rule on clinical trial

report is still pending. But the 2007 law itself requires basic reporting of results; the only point of a

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new rule is toexpand the requirements to include other items, such as protocols. The mere fact

that a rule may be expanded in the future is no reason to leave the current requirements

unenforced. Yet another possibility is that the FDA does not want to get bogged down in lawsuits

from companies or universities that have a valid reason for delay. But this argument would

suggest, at most, that the FDA ought to levy a fine only when truly merited, not that the FDA

should never enforce the fine at all.

My proposal: as an experiment, the FDA should give the 30-day notice required by statute, and

then set aside a single week in which it will levy the $10,000-per-day fine on all overdue trials.

Assuming that there are around 6,600 overdue trials that don’t come into compliance within the

30-day grace period, the FDA would end up imposing over $460 million in fines within a week’s

time. In so doing, it would make a strong statement that disobeying the law and hiding clinical trial

results is no longer acceptable.

And within a week, compliance with the law would likely shoot up astronomically, and we would

have more complete knowledge about how well or how poorly drugs actually work. In turn, we

could all make better decisions about how to improve our nation’s health.

Source: http://healthaffairs.org/blog/2015/10/14/the-fda-could-earn-over-60-million-a-day-from-

enforcing-the-law/

Do fast drug approvals by FDA help or harm patients?

Two recent studies published by the British Journal of Medicine (BJM) raise concerns about the

speed with which the Food and Drug Administration approves drugs for market in the United States.

According to the FDA the stages of drug development and review necessary to gain marketing

approval include:

Pre-clinical Testing;

Investigational New Drug Application;

Phase 1 studies – Focused on safety. Seeks to identify frequent side effects, etc.;

Phase 2 studies – Focused on efficacy. Does the drug work on the condition or disease?;

Phase 3 studies – A larger pool of subjects is tested for safety and effectiveness of drug;

Review Meeting between the Drug maker and FDA;

New Drug Application (NDA) – The formal step the drug maker takes in submitting all testing

data to FDA for marketing approval.

When the NDA is submitted, the FDA has 60 days to decide whether to file the drug for review. The

testing phases are potentially the longest timeframes involved with the drug approval process as it

takes time to administer the drugs to the test subjects and gather safety and efficacy data. It can

take several years for a drug maker to gather sufficient information from testing phase.

Fast-track Approval Process Geared to Help Patients

There are four programs available that allow the agency to expedite the development and approval

process for new drugs: orphan drug- drugs used for diseases that affect very few people, fast track,

accelerated approval, and priority review.

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Regardless of the program used, expedited approvals are supposed to be reserved for drugs that

are considered first in class and innovative enough to treat serious life-threatening illnesses that lack

satisfactory treatments. However, when researchers from Brigham and Women’s Hospital and

Harvard Medical School examined the FDA’s expedited drug development and approval programs

between the years 1987 and 2014 they found quicker approvals were not necessarily granted to

drugs defined by that criteria.

In fact, researchers found a 2.6% increase per year in the number of expedited review and approval

programs during the timeframe studied. They noted these newly approved drugs did not always fit

the requirement of being considered first in class or innovative.

Lack of In-Depth Testing Information Can Increase Patient Risk

One reason for the increase in expedited review and approval of drugs might be the passage of the

Prescription Drug User Fee Act (PDUFA). This act was enacted in 1992 and authorizes the FDA to

collect fees from companies that produce certain drugs and biological products for humans.

At the same time that the FDA increased the amount of drugs it approved through the expedited

review process researchers with the Cambridge Health Alliance and Harvard Medical School

conducted a study to examine black-box warnings and market withdrawals. These researchers found

that drugs approved after the passage of the Prescription Drug User Fee Act were more likely to

have a black box warning or be withdrawn from the market. These two findings would suggest that

shorter approval times lack sufficient information to properly assess drug safety and efficacy and

increase a patient’s health risk.

Drug Injury Lawsuits

When pharmaceutical makers push for expedited development and approval of products, patient

safety could be compromised. Lawsuits have been filed against numerous drug makers who put

profits ahead of patients by failing to disclose safety and efficacy information gathered during trial

phases or failing to alert healthcare providers and the FDA of adverse events that occur once a drug

has market approval.

Source: http://www.lexology.com/library/detail.aspx?g=ea6f08cd-1127-4b8e-a2ec-8e41ecdfff1b

Daiichi Sankyo to Cut Thousands of U.S. Jobs

Daiichi Sankyo announced on Friday it plans to conduct another round of job cuts this year.

The Japanese drug-maker plans to eliminate an estimated 1,000 to 1,200 jobs primarily from its

commercial headquarters in Parsippany, New Jersey as well as reduce the headcount for its field

salesforce.

Ken Keller, the president of Daiichi Sankyo’s U.S. commercial business, said in a statement that this

restructuring would help the firm be better positioned to meet the needs of patients with more

complex healthcare needs.

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The Parsippany location lost 16 percent of its work force earlier this year as part of Daiichi’s

continued plan to shift resources away from primary care drugs to focus more on a portfolio of

specialty drugs.

Daiichi is about to lose patent protection for the lucrative blood pressure drug Benicar within the next

few months, according to FiercePharma.

Benicar brought in $2.6 billion in sales last year, which accounted for over one-quarter of the drug-

maker’s revenue for 2014, writes FiercePharma, which is why the firm is looking for a profitable

replacement.

Reports pegged the Food and Drug Administration (FDA) approved blood thinner Savaysa as a

potential alternative to Benicar.

However, Pharmalot’s Ed Silverman wrote that the sales potential for this drug remains unclear

because it comes with a boxed-warning that alerts prospective customers of serious side-effects in

some patients.

The FDA's website explains doctors should cautiously assess starting therapy with

Savaysa for atrial fibrillation patients with creatinine clearances greater than 95 millimeters per

minute. The drug is less effective in this group and can lead to an increased risk of stroke.

This new phase of downsizing will conclude by the end of March 2016.

Cipla gets FDA's nine observations and issues noticed memo for Indore unit

The US Food and Drug Administration has identified nine areas of concern that need correction at

Indian drug maker Cipla's manufacturing unit at Indore.

Cipla is among the few large domestic companies that has so far not faced any tough regulatory

action from the FDA.

As part of its observations made during an inspection of the plant in July and

August,FDA investigators Ademola Daramola and Nebil Oumer noted that the quality control unit

lacked the authority to review production records to ensure that no errors have occurred and to

investigate any mistakes made.

They said that although one batch of levalbuterol inhalation solution was recalled from the US in May

2015, "the investigation did not extend into other strengths of the product to determine the product's

quality, safety and stability."

In another observation, they said a failure related to a leakage was documented 35 times but no

study was initiated to identify problems that could potentially affect product safety and quality.

The FDA officials faulted Cipla's Indore unit for facility and equipment systems and noted that the

aseptic processing areas were deficient in monitoring environmental conditions.

In an observation related to quality parameters, the FDA staff noted that the sterile filling lines were

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frequently opened in order to complete manual interventions. "In the packaging hall, sterile product

vials exiting the filling line were handled with ungloved and unsanitised hands by packaging line

employees," the inspectors said.

India maintains GVK Bio’s drug ban issue must be resolved for trade talks with EU

India is not ready to play ball yet as Brussels has not made any attempt to sort out the issue of the

ban placed on generic drugs tested by Hyderabad-based GVK Biosciences. This is despite leaders

such as German Chancellor Angela Merkel pushing for resumption of the proposed India-EU free

trade agreement (FTA) talks.

―We have been asking the EU to resolve the matter. We have said that we are even ready for re-

testing of the banned medicines. But there is no official response from the bloc on the matter. We will

not re-start FTA negotiations till there is some concrete movement on resolution of our problem,‖ a

Commerce Ministry official told.

EU ban on 700 generics

In July this year, the EU had announced a ban on marketing of 700 generics (copied versions of off-

patent drugs) tested at GVK Biosciences. Charges of manipulation of clinical trials for bio-

equivalence testing (test to prove that generic or copied drugs are as effective as the ones whose

patents have expired) of these drugs were made against the lab by a French standards agency

ANSM. The ban was implemented on August 21.

In protest against the ban, India had called off the talks scheduled in July-end with EU to re-start the

FTA negotiations that had not seen movement for more than two years.

Merkel, during her recent visit to India, raised the issue of resumption of FTA talks in her meeting

with Prime Minister Narendra Modi, but it failed to make an impression on New Delhi.

―The ban on the 700 drugs was implemented despite all our efforts to convince the European

Medicines Agency (EMA) that there was nothing wrong with the data. Now that we are prepared for

re-tests to be run, the EU is not showing any interest. If the EU can be so stubborn, why should we

relent?‖ the official asked.

With slowdown gripping the EU, the 27-member bloc is keen to have better access to the Indian

markets for its goods, which an FTA can provide. ―If the EU is interested enough in the FTA, we

believe it will be more sensitive towards our concerns,‖ the official said.

Six-member panel

Last month, the Commerce Ministry set up a six-member panel consisting of experts from various

departments, including drug regulators and cardiologists, to look into allegations made by ANSM

against GVK for manipulation of data related to electrocardiograms (ECGs). The panel confirmed

GVK’s assertion that there were no irregularities in the data.

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―We feel that the EU may be slow in reacting because of pressure from big pharma companies who

benefit if generics are out of the market. Since generics are several times cheaper than the patented

variants, the profits of MNCs get dented,‖ the official said.

Pharma companies team up to clean industry’s image

For the first time ever, some of India's biggest pharmaceutical companies, cutting across their

respective associations and representing nearly half the Rs 93,000 crore market, have come

together to push for ethical marketing practices to clean up the industry's image.

The forum, comprising of 40 to 50 domestic and MNC firms, had its first closed-door meeting on

October 14. It has made a "voluntary and moral commitment" to follow ethical marketing practices in

"letter and spirit", and will work with the regulatory mechanism to facilitate the exercise.

Earlier attempts at bringing about a code acceptable to the entire industry had failed, as the

associations the Indian Pharmaceutical Alliance (representing domestic firms), MNCs-led

Organisation of Pharmaceutical Producers of India (OPPI) and the Indian Drug Manufacturers'

Association (IDMA) were at loggerheads.

This comes even as the government has already expressed its intention to make the 'Uniform Code

of Pharmaceutical Marketing Practices' mandatory from next year. The code banning cruise tickets,

freebies and paid vacations for doctors sponsored by drug companies is voluntary at present. But in

light of rampant violations, the government plans to make it binding on companies.

The group which includes top MNCs like Novartis, MSD and Abbott, and domestic firms Sun

Pharma, Zydus Cadila and Dr Reddy's among others wants to start a movement and build pressure

on those who are not following ethical practices. A "voluntary" coming together out of sheer "moral

commitment carries greater weightage" than guidelines being thrust on them, said an expert, who is

part of the forum. "We have come together voluntarily to push for ethical marketing practices," IPA

director general D G Shah said. "Over the years, our industry has been maligned."

The 'Forum of Pharmaceutical Ethical Marketing Practices' will draw a core working group from the

firms to decide the modalities of taking the "movement" forward, and is in favour of a body similar to

the Advertising Council of India which is not a statutory body, to regulate the code. A final proposal

will be drawn up soon. Even after the code kicked in this year, complaints continued, with many

saying it existed only on paper, as firms try to influence prescriptions. "We plan to seek clarifications

from the government so that it (the code) is tweaked into a more practical and implementable code,"

said Ranjana Smetacek, director general, OPPI.

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CDSCO begins Induction Programme for assistant drug inspectors to upgrade technical,

professional & other functional skills

To train the regulatory officers to enable them to devise strategies for optimum utilisation of available

resources and to upgrade their technical, professional and other functional skills, the Central Drugs

Standard Control Organisation (CDSCO) has begun the Induction Programme for assistant drug

inspectors, which is a three-month long training programme from October 5 to December 31, 2015.

Major focus of the training, which is being held at National Institute of Biologicals, Noida, will be on

technical and regulatory framework in India such as Drugs and Cosmetics Act and Rules, Drugs and

Magic Remedies Act, and Narcotic Drugs and Psychotropic Substances Act; legal and administrative

issues; managerial and ethical issues; and IT and communication skills. Besides, there will be basic

introduction to GMP, GLP, GCP, etc.

The CDSCO has roped in a team of high level resource personnel for this programme. To begin

with, CDSCO will engage faculty drawn from regulatory agencies, administrative and police services,

pharmaceutical industry, management institutes and colleges and also training modules adopted by

other regulators.

The faculty would comprise retired /current drug regulatory personnel; experts from outside for

personality development; officials from CBI, IB, legal departments, subject experts from academic

institutions like NIPER, IIT, IISc, etc; subject experts and professionals from industry on GMP, GCP,

GLP etc; experts from international organisations including WHO etc; and retired/current senior

government officials.

The technical areas which will be covered in the programme include good manufacturing practices;

good laboratory practices; good clinical practices; good distribution and storage practices; principles

of product development and pre-formulation studies; new drug approval process; clinical trials

including BA/BE studies; pharmacovigillance; quality audits and inspections – planning, procedures,

report writing; and quality assurance and safety aspects in blood and blood products.

Besides, the programme will cover special feature of manufacture and quality assurance in vaccines

and sera, r-DNA products, active pharmaceutical ingredients, medical devices, stem cells,

monoclonal antibodies, antimicrobial resistance etc; advances in biotechnology and immunology;

drug discovery and development; and international regulatory framework including WHO.

The legal areas of the programme include in-depth knowledge of drug laws – Drugs and Cosmetics

Act and Rules; Narcotic Drugs and Psychotropic Substances Act; Drugs Price Control Order; Drugs

and Magic Remedies Act; Intellectual Property Rights; and Patent Act.

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It will also cover principles of jurisprudence, and principles of natural justice; principles of

interpretation; applicability of code of Criminal Procedure Code in investigations and trials under drug

laws; fundamentals of Evidence Act; investigation techniques including gathering of intelligence and

making proper use of such intelligence; and launching of prosecutions.

According to senior officials in the CDSCO, there is a constant need for such training programmes

as the drug regulatory system needs to keep itself abreast of the fast-changing scientific innovations,

evolving international regulatory framework and other developments. The central role of the Indian

pharma industry and globalisation necessitate that the regulatory framework has to constantly evolve

by integrating new developments. It is, therefore imperative for the present and future drug control

officials to continuously upgrade their skills and knowledge, and gain expertise in a variety of

subjects to meet with such functional requirements.

As the government has started recruiting a number of regulatory personnel, the need of the hour is

to train the regulatory officers to enable them to devise strategies for optimum utilisation of available

resources. Training that could constantly upgrade their technical, professional and other functional

skills would play an important role in their professional growth and diligent execution of their

responsibilities, officials said.

It is proposed to develop an extensive training programmes for various regulatory officials covering

all areas of functions of CDSCO including deputing the inspectors in various zonal offices, port, sub-

zonal offices for receiving practical experiences, hands-on training in the various regulatory functions

of CDSCO. It has also been decided that all regulatory personnel working in CDSCO will undergo

basic and advanced training programmes.

FDA Removes Warning Letter Issued to Pacira

The FDA has quietly removed a September 2014 warning letter issued to Pacira Pharmaceuticals for

touting unapproved uses of its analgesic Exparel. The removal comes after the drugmaker sued the

agency late last month claiming a First Amendment right to promote the drug for unproven uses.

The Sept. 22, 2014, warning letter cited problems with promotional materials for Exparel

(bupivacaine liposome injectable suspension), which is approved as a postsurgical analgesic for

bunion and hemorrhoid removal surgeries. According to the FDA, the promotional materials

suggested Exparel could be used in aparoscopic cholescystectomy, a procedure to remove

gallstones, and in open colectomy to remove part of a patient’s colon.

In Pacira Pharmaceuticals Inc., et. al v. Food and Drug Administration et. al, the company maintains

that the promotional material is truthful and should be allowed under the same ruling as Amarin

Pharma Inc., et. al v. Food and Drug Administration et. al.

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That ruling rejected the agency’s arguments to prevent off-label promotion, and Pacira said the

agency’s arguments are even less persuasive because its promotions met the standards of the

drug’s indications and usage section.

FDA spokesman Christopher Kelly said the agency cannot comment on the reasoning behind the

letter’s removal because it is a matter related to pending litigation.

India’s CDSCO Sets Up Three-Month Training Program

India’s drug regulatory authority has set up a three-month training program for assistant drug

inspectors that will run through the end of this year, as the agency works to ramp up their skill sets.

The Central Drugs Standard Control Organization developed an extensive training program for

regulatory officials covering all functions of the agency, focusing on technical and regulatory, legal

and administrative, managerial and ethical, and IT and communications skills.

The program will help bridge a ―huge gap‖ in regulatory science, practices and knowledge, says G.N.

Singh, India’s drugs controller general.

India’s prime minister approved a $270 million plan in August to strengthen the country’s drug

regulatory system, including a training academy for regulatory and drug testing officials.

R&D spending of 25 India pharma cos soar by 28.8% in 2014-15

Indian pharmaceutical companies have substantially stepped up investments in R&D during 2014-15

to overcome stiff competition and to create product pipeline and strengthen their presence in world

market. A Pharmabiz study of leading 25 companies shows that there is a 28.8 per cent growth in

R&D expenditure at Rs. 9,250 crore during the year ended March 2015 from Rs. 7,179 crore in the

previous year. These companies have spent almost seven per cent of their consolidated net sales in

2014-15, which is slightly higher from 6.6 per cent in the previous year.

These companies have created strong product pipeline by filing ANDAs, DMFs and patents in the

world market. With rising healthcare cost, several countries are undertaking cost cutting measures

and moving towards cost effective generics and biosimilars products. Indian companies are focusing

on novel drug discovery & development (NDDD), generics, biotechnology and biosimilars. These

companies are taking steps to strengthen intellectual property area to tap expiration of patent

opportunities.

Though the R&D investment by Indian companies moved up to Rs. 9,250 crore, it is negligible as

compared to major international pharma which are spending over 15 per cent of their net sales on

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R&D. Indian companies have successfully received higher approvals for ANDAs from the highly

regulated authorities. For the nine months ended September 2015, Indian companies received final

approval for 113 ANDAs from US FDA as against 122 final ANDAs approval during full year ended

December 2014 with Aurobindo Pharma, Lupin, Glenmark Pharmaceuticals, Alembic

Pharmaceuticals, Jubilant Life Sciences, Natco Pharma, Sun Pharmaceuticals, Hetero Labs, etc.,

received good number of approvals.

These companies are working towards creating niche and complex products through investments in

R&D. Despite high risk of success, gestation periods and uncertainty regarding returns on

investment, Indian companies are continuously investing higher funds in R&D efforts. These

companies are entering new tie-ups with major international players, universities, academicians and

absorbing new technologies. Indian pharma companies are engaged in contract manufacturing in a

big way and R&D investments are offering necessary support for these activities. Even these

companies are taking up clinical trials for MNCs.

Sun Pharmaceutical Industries, after merging Ranbaxy Laboratories during 2014-15, remained on

top in R&D spending. Its consolidated R&D expenditure increased almost 87 per cent to Rs. 1,856

crore from Rs. 993 crore in the previous year and enhanced its ability to invest further in R&D. Its

consolidated net sales also moved up by 71 per cent to Rs. 27,433 crore from Rs. 16,080 crore.

R&D spending as percentage of its consolidated net sales worked out to 6.8 per cent as compared

to 6.2 per cent in the previous year.

Sun has entered into an exclusive worldwide in-licensing agreement for Merck's investigational

therapeutic antibody candidate tidrakiziumab, (MK-3222) to treat chronic plaque psoriasis, a skin

aliment. It has setup a joint venture with Intrexon Corporation for developing gene-based therapies

for ocular diseases. Sun has strengthen Taro's R&D pipeline and Taro had a pipeline of 35 ANDAs

awaiting US FDA approval as at the end of 2014-15.

Dr Reddy's Laboratories has pushed its R&D spending by 33.4 per cent to Rs. 1,685 crore during

2014-15 from Rs.1,263 crore, and remained as second highest R&D spender. This was followed by

Lupin with R&D spending up by 16.8 per cent to Rs. 1,118 crore from Rs. 958 crore. The fourth

largest R&D spender, Cipla invested an amount of Rs. 844 crore in R&D as compared to Rs.518

crore in the previous year, a significant growth of over 63 per cent. Glenmark's R&D investment

remained almost same at Rs. 600 crore.

Further, Aurobindo Pharma, Biocon, Sun Pharmaceutical Advance Research Co (SPARC),

belonging to Sun Pharmaceutical and Ajanta Pharma registered noticeable growth of over 30 per

cent in R&D expenditure during 2014-15. Similarly, Ipca Laboratories and Natco Pharmaceuticals

also shown strong growth of over 25 per cent in R&D spending during 2014-15. However, the R&D

expenditure of Piramal Healthcare, Unichem Laboratories, Orchid Chemicals and Pharmaceuticals,

Jubilant Lifesciences, Panacea Biotec and Strides Arcolab declined during 2014-15.

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Lupin has intensify is research efforts to address opportunities in difficult-to-do generics,

dermatology, inhalation, complex injectables and the biosimilars space. It has undertaken

biotechnology development program with the help of 190 highly-qualified bio-technologists. Its

biosimilars pipeline includes 12 blockbuster molecules. Its two biosimilars are ready to launch in

India under the brand names Lupifil and Lupifil-P. Its cumulative ANDA filings with the US FDA

reached at 210 with 111 approvals received. Its cumulative DMF filings reached at 157 as at the end

of 2014-15.

Biocon is developing novel biologics and biosimilars for addressing chronic diseases like cancer

diabetes and autoimmune conditions for patients across the globe. Biocon, Asia's largest insulins

producer, has stepped up its R&D spending by over 50 per cent to Rs. 200 crore during 2014-15. Its

oral insulin under development has the potential to transform diabetes management the world over.

The company is setting up integrated insulins manufacturing facility at Malaysia. It is offering niche

services to multinational companies like Bristol Myers Squibb, Abbott and Baxter. Its subsidiary

Syngene has built a strong reputation of being the 'innovation partner' for many of its clients and well

positioned to tap global contract research organization opportunity. It filed over 1,150 patent

applications and holds over 530 patents. Syngene International, a leading contract research

organisation of Biocon, entered the capital market and now setting up a new manufacturing facility at

Mangalore SEZ and is in the process of acquiring 40 acres of land and obtaining necessary

approvals. The estimated expenditure for setting up the facility is US$ 100 million.

DRL's R&D expenditure increased sharply by 33.4 per cent to Rs. 1,685 crore during 2014-15, which

worked out to 11.5 per cent of its consolidated net sales. It filed 77 DMFs, taking the cumulative

number of DMF filings to 735 as at the end of March 2015. Similarly it filed 13 ANDAs with US FDA

and cumulatively 68 ANDAs pending approval. It has more than 2000 scientists across its

development centers in India, UK, US and Netherlands. The company launched 61 new products in

FY2015.

Aurobindo Pharma, which has set up a revenue target of US$ 3 billion by 2017-18, is moving ahead

strongly by investing in R&D activities. Its R&D expenditure increased by 33 per cent to Rs. 360

crore during 2014-15. The company has started investing in peptide technology and is building a

commercial facility with two modules commensurate with cGMP standards. It has developed

technologies for more than ten products. The company cumulatively filed 192 DMFs and 376

ANDAs. It received total 193 ANDA approvals and 183 ANDAs were under review.

Aurobind has developed and made penem filings for four products in injectable portfolio and it is

planning to launch products in Brazil and Mexico in current year. The company is now entering the

vaccines business with a joint venture for developing pneumococcal conjugate vaccine. The

company is also working on 15 oncology products.

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Glenmark's consolidated R&D spending remained almost stagnant at Rs. 600 crore during 2014-15.

It announced first clinical development candidate in oncology, GBR 1302, a bispecific antibody for

cancer treatments. The company is initiating a phase I clinical trial for GBR 1302 in Germany. It

another product GBR-900 is entering clinical development in current year and first t anti-OX40

monocional antibody has completed phase I and phase II studies in US and EU. The company is

moving fast in NCE front also and its mPGES-1 discovery program, GRC 27864 has moved forward

in human trials and is nearing completion of phase I. Currently it has 70 applications pending with

the US FDA, of which 33 are Paragraph IV applications.

Panacea Biotech's R&D expenditure declined sharply by over 47 per cent to Rs. 46.82 crore during

2014-15 from Rs. 88.88 crore due to heavy losses. It has set up four disciplinary R&D centers. at

Navi Mumbai, Lalru, Mohali and New Delhi for development of vaccine, biopharmaceuticals,

proteins, peptides, monoclonal antibodies, NDDS, etc., It invested 6.8 per cent of net turnover on

R&D during 2014-15. Its R&D center is focusing in the fields of oncology and organ transplantation.

The company has filed more than 1,500 patent applications worldwide including 230 patent

applications in India.

Thus, the rising investment in R&D will give necessary push to overall working and presence in

regulated and emerging market. Indian companies are pushing the boundaries of innovation to meet

niche unmet medical needs. These companies are focusing on R&D to develop new chemical or

molecular entities. Anti-cancer treatments and diabetes attract the large R&D investments. It is

expected that the new government may initiate steps to offer tax incentives or favorable tax

environment for investment in R&D in near future.

Source: http://pharmabiz.com/

ICH announces organisational changes

On its inaugural meeting on 23 October 2015 the International Council for Harmonisation (ICH),

formerly the International Conference on Harmonisation (ICH), announced organisational changes:

ICH emphasizes that it is a truly global initiative and more involvement of regulators around the world

is welcomed and expected, as they will be invited to join counterparts from Europe, Japan, USA,

Canada and Switzerland. This is aligned with the possibility of wider inclusion of global industry

sectors affected by ICH Harmonisation.

In addition, a more stable operating structure is achieved through the establishment of an ICH

association, a legal entity under Swiss law, which will facilitate future growth through the

participation of new members.

For further information please visit the ICH official website.

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Terminology

data. Data means all original records and certified true copies of original records, including source data and metadata and all subsequent transformations and reports of this data, which are recorded at the time of the GxP activity and allow full and complete reconstruction and evaluation of the GxP activity. Data should be accurately recorded by permanent means at the time of the activity. Data may be contained in paper records (such as worksheets and logbooks), electronic records and audit trails, photographs, microfilm or microfiche, audio- or video-files or any other media whereby information related to GxP activities is recorded. data governance. The sum total of arrangements to ensure that data, irrespective of the format in which it is generated, are recorded, processed, retained and used to ensure a complete, consistent and accurate record throughout the data lifecycle. data integrity. Data integrity is the degree to which a collection of data is complete, consistent and accurate throughout the data lifecycle. The collected data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate. Assuring data integrity requires appropriate quality and risk management systems, including adherence to sound scientific principles and good documentation practices. data lifecycle. A planned approach to assessing and managing risks to data in a manner commensurate with potential impact on patient safety, product quality and/or the reliability of the decisions made throughout all phases of the process by which data is created, processed, reviewed, analyzed and reported, transferred, stored and retrieved, and continuously monitored until retired. metadata. Metadata are data about data that provide the contextual information required to understand those data. Typically, these are data that describe the structure, data elements, interrelationships and other characteristics of data. They also permit data to be attributable to an individual. For example, in weighing the number 8 is meaningless without metadata, i.e. the unit, mg. Other examples of metadata may include the time/date stamp of the activity, the operator ID of the person who performed the activity, the instrument ID used, processing parameters, sequence files, audit trails and other data required to understand data and reconstruct activities. Ref: GUIDANCE ON GOOD DATA AND RECORD MANAGEMENT PRACTICES - WHO

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New Guidance Acceptability of Draft Labeling to Support Abbreviated New Drug Application Approval;

Guidance for Industry

This guidance provides recommendations and information related to the submission of proposed

labeling with abbreviated new drug applications (ANDAs) under section 505(j)(2)(A)(v) of the Federal

Food, Drug, and Cosmetic Act (the Act) and FDA’s implementing regulations (21 CFR 314.94(a)(8)).

This guidance is intended to assist applicants submitting ANDAs under section 505(j) of the Act to

the Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research (CDER). It

explains FDA’s interpretation of the regulatory provision related to the submission of copies of

applicants’ proposed labeling in ANDAs and clarifies that OGD will accept draft labeling and does not

require the submission of final printed labeling (FPL) in order to approve an ANDA.

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

s/UCM465628.pdf

FDA Provides New Guidelines for Cleaning Duodenoscopes

Following the outbreak of infections related to a deadly superbug, the FDA has provided new

guidelines to help healthcare facilities ensure their duodenoscopes are cleaned adequately.

Duodenoscopes gained intense media scrutiny after reports of antibiotic-resistant infections in

Chicago, Pittsburgh, Seattle and Los Angeles. Earlier this year, the FDA revealed that between

January 2013 and December 2014, it had received 75 reports involving about 135 patients suffering

from carbapenem-resistant Enterobacteriaceae transmissions linked to these devices.

The FDA acknowledges that the duodenoscope's unique design is useful for performing endoscopic

retrograde cholangiopancreatography procedures. This utility has its drawbacks, however, as the

device has small working parts, including a moveable elevator mechanism with tiny crevices. This

elevator is particularly difficult to clean and disinfect properly, even if a healthcare professional

adheres to a manufacturer's instructions for use.

"Meticulous adherence to the manufacturer's reprocessing instructions is labor-intensive and prone

to human error," according to the agency.

To combat the threat of infection transmission, the FDA is recommending facilities adopt the

following supplemental measures: microbiological culturing; ethylene oxide sterilization; use of a

liquid chemical sterilant processing system; and repeat high-level disinfection.

"We recognize that not all healthcare facilities can implement one or more of these measures, which

require specific resources, training, and expertise," the FDA said. While this may be the case, it is

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still critical that those professionals in charge of reprocessing the devices have instructions for use at

hand and remain proficient in performing all reprocessing steps.

In addition to the supplemental measures, the agency is urging healthcare facilities to adopt the

following best practices:

Meticulously clean the elevator mechanism and recesses surrounding it by hand;

Implement a comprehensive quality control program for reprocessing duodenoscopes;

Review reprocessing recommendations from a consensus document from the

American Society for Gastrointestinal Endoscopy and the Society for Healthcare

Epidemiology of America.

The FDA notes that it is monitoring the situation and evaluating information from the healthcare

community, adverse events reports and other sources. It also is partnering with The Joint

Commission, the nation's largest hospital accreditation body, and the Centers for Medicare &

Medicaid Services to bolster hospitals' adherence to duodenoscope cleaning instructions. In

addition, the agency says it is working with industry as it modifies and validates instructions for

cleaning duodenoscopes.

EMA Guidance Explains How Drugmakers Can Hasten Antibiotics Development

The European Medicines Agency has released draft guidance explaining how drugmakers can use

pharmacodynamic and pharmacokinetic analyses to hasten the development and review of new

antibiobics.

According to the EMA, PD and PK data can replace or supplement human dosing studies, speeding

access of badly needed drugs to market. It can also aid in identifying differences and dealing with

dose variations for specific demographics, such as children and seniors, the obese and patients with

liver and kidney failure, the agency says.

Cellular analyses can also bolster drug candidates whose development has been held back by a

lack of appropriate trial participants or other feasibility issues, the EMA says.

The guideline, which would update 15-year-old recommendations, covers both antibacterial and

antifungal treatments.

To be most effective, drugmakers should gather specific microbiologic data on:

The time it takes to kill a particular pathogen;

Pathogen distribution markers;

How those markers react to resistance mechanisms when the drug is administered;

Intracellular biologic responses to the bacteria;

Post-drug effects; and

Which bacterial microorganisms are more- or less-resistant.

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The EMA prefers in vitro studies such as chemostat over in vivo — often mice — trials for preclinical

analysis. Animal models using blood samples and treatments based off earlier data are also allowed,

but researchers should provide reasoning behind the chosen strategy.

The EMA asks that sponsors document enough data on exposure-response relationships.

Manual of Policies and Procedures (MAPP) 4657.11 Rev.1 Religious Compensatory Time

This MAPP outlines the policies and procedures within the Center for Drug Evaluation and Research

(CDER) for earning and using religious compensatory time (RCT) for religious observances. All

civilian employees regardless of exempt/non-exempt status or grade, are permitted to use RCT for

religious observances. Experts, consultants, and Commissioned Corps Officers are not permitted to

earn and use RCT.

Source: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobac

co/CDER/ManualofPoliciesProcedures/UCM466670.pdf

Final Guidance for Compounders Clarifies “Unexpected Event” in AE Reporting

Serious adverse events associated with compounded drugs whose labeling doesn’t include any

adverse experiences should be considered unexpected and reported to the FDA within 15 days, the

agency clarifies in final guidance released last week.

Reports should include four key elements: an identifiable patient, an identifiable reporter, a suspect

drug and a serious adverse event. If a facility isn’t able to include all four data points, it should keep

records of the due diligence it took to try to obtain them — for example, dates of discussions with a

reporter to determine how many patients experienced a particular event, the FDA says.

Defining an ―unexpected‖ event was a major sticking point in comments from compounding facilities

on the FDA’s Feb. 13 draft guidance on adverse event reporting.

The final guidance also stipulates that for compounded drug products with multiple components —

such as excipients and drug substances — each component and its manufacturer should be listed, if

known. Further, as part of each adverse event report, outsourcing facilities should submit a copy of

the current labeling for the affected product.

Also new in the final guidance, the FDA puts compounders on notice that adverse event reports may

trigger an inspection of the outsourcing facility or manufacturer of a component of the compounded

drug.

The agency notes that adverse event reports can help to distinguish between issues with

outsourcing facilities and issues with active pharmaceutical ingredients manufacturers. While

multiple adverse event reports from the same compounder may signal a quality issue with that

facility, multiple adverse event reports from various outsourcing facilities may suggest a quality

problem with the APIs used in those compounded drugs.

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The new APIC Guidance on Handling of Insoluble Matter and Foreign Particles in the

Manufacture of Active Pharmaceutical Ingredients

Foreign particles in APIs or medicinal preparations are undesirable and sometimes lead to a recall of

the batches concerned. Depending on the type of particles their presence in active pharmaceutical

ingredients may be harmless; in many cases they are inevitable. In any case the manufacturer must

find an adequate way how to handle those impurities visible to the human eye. The search for a

guideline or another official document in the relevant regulations is in vain. Visible particles or fibres

are only mentioned in the USP chapter <790>, in chapter 2.9.20 of the European Pharmacopoeia as

well as in the United States Food, Drug and Cosmetic Act (FD&C Act).

In order to remedy this lack of guidance or recommendations a group of experts within APIC has

drawn up a guidance on the handling of foreign particles. This "Guidance on Handling of insoluble

Matter and Foreign Particles in APIs" describes in detail

the types of particles which can often occur during the manufacture of APIs, API

intermediates and raw materials (including packaging materials),

suitable measures to minimize the presence of particles or to remove them,

how to determine them analytically

how to identify the source and to carry out subsequent CAPA measures and an adequate risk

management.

This APIC guidance offers valuable assistance for all API manufacturers that are confronted with the

problem of the occurrence of foreign particles in their products, intermediates or raw materials. The

implementation of the very concrete and practicable recommendations in this guidance offers also

valuable supporting arguments for GMP inspections or audits and can help to avoid unpleasant

surprises.

Finally published: new Annex 16 on QP Certification and Batch Release

The European Commission has published the final version of the revised EU-GMP Guideline Annex

16 "Certification by a Qualified Person and Batch Release". Deadline for coming into operation is 15

April 2016.

As one important topic, it has been pointed out that the major task of a Qualified Person (QP) is the

certification of a batch for its release. In this context, the QP must personally ensure the

responsibilities listed in chapter 1.6 are fulfilled. In chapter 1.7 a lot of additional responsibilities are

listed which need to be secured by the QP. The work can be delegated and the QP can rely on the

respective Quality Management Systems. However "the QP should have on-going assurance that

this reliance is well founded" (1.7). Amongst these twenty-one tasks are for example:

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Starting materials comply and the supply chain is secured, including GMP assessments by

third parties

The necessary audits have been performed and the audit reports are available

Manufacturing and testing performance are compliant with the MA

Manufacturing and testing processes are validated

Changes have been evaluated and investigations completed

It is important to mention in this context that "the ultimate responsibility for the performance of an

authorised medicinal product over its lifetime; its safety, quality and efficacy lies with the marketing

authorisation holder (MAH). However "the QP is responsible for ensuring that each individual batch

has been manufactured and checked in compliance with laws in force (…), in accordance with the

requirements of the marketing authorisation (MA) and with Good Manufacturing Practice (GMP)"

(see General Principles).

In the case that the QP has to rely on the correct functioning of the quality management system of

other sites, the QP "should ensure that a written final assessment and approval of third party audit

reports has been made". The QP should also "be aware of the outcome of an audit with critical

impact on the product quality before certifying the relevant batches."

Another important section clarifies the role of the QP when it comes to deviations, implementing

main features of the EMA Position Paper on QP Discretion (which was issued in February 2006 and

updated January 2008). Chapter 3 of the draft describes the "handling of unexpected deviations". A

batch with an unexpected deviation from details contained within the Marketing Authorisation and/or

GMP may be certified if a risk assessment is performed, evaluating a "potential impact of the

deviation on quality, safety or efficacy of the batch(es) concerned and conclusion that the impact is

negligible." Depending on the outcome of the investigation and the root cause, the submission of a

variation to the MA for the continued manufacture of the product might be required.

During the consultation phase, stakeholders expressed their concerns regarding the sampling of

imported products. Now the new annex is clear on this: "Samples may either be taken after arrival in

the EU, or be taken at the manufacturing site in the third country in accordance with a technically

justified approach which is documented within the company's quality system. (…) Any samples taken

outside the EU should be shipped under equivalent transport conditions as the batch that they

represent."

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New FDA Guidance for Industry released:

Product Development Under the Animal Rule Guidance for Industry

This guidance provides information and recommendations on drug and biological product

development when human efficacy studies are not ethical or feasible. The regulations that set forth

the pathway for approval of these products under 21 CFR 314.600 through 314.650 (drugs) or 21

CFR 601.90 through 601.95 (biological products) are commonly referred to as the Animal Rule.

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

s/UCM399217.pdf

Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for

Administration by an Alternate Route Guidance for Industry and Review Staff Good Review

Practice

This guidance provides recommendations for the nonclinical evaluation of previously approved drug

substances when a new formulation or a new route of administration for a previously approved

formulation is proposed by the sponsor. This guidance is intended for sponsors and review staff in

the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA)

involved in the development and review of new formulations of previously approved drug substances

and proposals for existing formulations to be used by a new route of administration.

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

s/UCM079245.pdf

Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the

Federal Food, Drug, and Cosmetic Act

This guidance sets forth the Food and Drug Administration’s (FDA or Agency) interim regulatory

policy concerning compounding using bulk drug substances under section 503A of the Federal Food,

Drug, and Cosmetic Act (FD&C Act or Act). Section 503A of the FD&C Act includes certain

restrictions on the bulk drug substances that can be used in compounding and directs the FDA to

develop a list of bulk drug substances that can be used in compounding under that section. FDA is

developing this list of bulk drug substances (the 503A bulks list), and this guidance describes FDA’s

interim regulatory policy for licensed pharmacists in State-licensed pharmacies and Federal facilities,

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and for licensed physicians that compound human drug products using bulk drug substances while

the list is being developed

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

s/UCM469120.pdf

Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the

Federal Food, Drug, and Cosmetic Act

This guidance sets forth the Food and Drug Administration’s (FDA or the Agency) interim regulatory

policy concerning compounding by outsourcing facilities registered under section 503B of the

Federal Food, Drug, and Cosmetic Act (FD&C Act or Act) using bulk drug substances. Section 503B

of the FD&C Act includes certain restrictions on the bulk drug substances that outsourcing facilities

can use in compounding and directs FDA to develop a list of bulk drug substances that can be used

in compounding under that section. FDA is developing that list of bulk drug substances (the 503B

bulks list), and this guidance describes FDA’s interim regulatory policy regarding outsourcing

facilities that compound human drug products using bulk drug substances while the list is being

developed.

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

s/UCM469122.pdf

Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal

Food, Drug, and Cosmetic Act Guidance

This guidance announces FDA’s intention with regard to enforcement of section 503A of the Federal

Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 353a) to regulate entities that compound

drugs, now that section 503A has been amended by Congress to remove the advertising and

solicitation provisions that were held unconstitutional by the U.S. Supreme Court in 2002 (see

section II below). Several parts of section 503A require rulemaking and consultation with a

Pharmacy Compounding Advisory Committee to implement. This guidance explains how the

provisions will be applied pending those consultations and rulemaking. This guidance also describes

some of the possible enforcement actions FDA can bring against individuals or firms that compound

drugs in violation of the FD&C Act.

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

s/UCM469119.pdf

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Manual of Policies and Procedures (MAPP) 5241.2 Consolidation of ANDAs by the Office of

Generic Drugs

This MAPP describes the process for reviewing and approving or denying requests to consolidate

previously approved abbreviated new drug applications (ANDAs) submitted by an ANDA applicant.

This MAPP applies to the Office of Generic Drugs’ (OGD) ANDA Consolidation Coordinator (ACC),

who coordinates requests for consolidation, makes the consolidation determination, and ensures

ANDAs are properly consolidated. This MAPP also applies to OGD regulatory project managers

(RPMs), who determine whether any of the ANDAs identified in the request for consolidation have

associated open issues or pending reviews and Document Room staff who send consolidation

requests to the OGD RPMs.

Source: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobac

co/CDER/ManualofPoliciesProcedures/UCM469249.pdf

Investigational Medicinal Products - Recent Changes in EC Guidance

As reported before in IMPs: Four new public consultations concerning GMP and GCP published the

implementation of the Clinical Trial Regulation 536/2014 resulted in four new public consultations

concerning good manufacturing practices and clinical trials for human medicinal products (opened

August 28, 2015) with closing date November 24, 2015.

As a consequence Annex 13 is expected to be deleted from EudraLex Vol 4 when the new

guidelines "Detailed Commission guidelines on GMP for IMPs for human use" become operational.

It carries over relevant principles of Annex 13.

Basically the ideas are the same. However there is more detail in regard of

the pharmaceutical quality system and handling deviations by CAPA

supplier approval

quality risk management principles

final certifying by the qualified person

the retaining period of batch records

reference and retention samples.

On the European QP Assocaition website you can find a Synopsis of Annex 13 / "Detailed

Commision guidelines for GMP for IMPs for human use". There you will also find a summary which

contains links to the most recent changes being published for consultation.

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Annex 15 and FDA Process Validation Guideline: Similarities/differences from the FDA

perspective

The "new" FDA Process Validation Guidance has been in force since January 2011. The revised

Annex 15 has been valid since 1 October 2015. At a Conference in September 2015 which was co-

sponsored by the FDA, Grace McNally, Senior FDA Official reported about similarities and

differences between the two documents from the perspective of the FDA.

First to the similarities: both documents address a process validation life cycle and quality risk

management across all stages of the life cycle. For Grace McNally there is also comparability with

regard to a science-based process development and to the development of process understanding

as the basis for stage 2 in accordance with the FDA Process Validation Guideline, resp. with the

actual process validation in the sense of Annex 15. Prospective validation is favoured in both

documents. Only in special cases one concurrent validation is possible, but is never favoured as a

routine procedure. The FDA also sees similarities between the Annex 15 and the FDA Process

Validation Guideline relative to the need for a rationale for determining the number of samples for

PPQ/process validation, as well as in determining the number of PPQ - / validation runs. And this

rationale should include, for example, the process variables and the complexity and experience with

the process. For the FDA there are further similarities with regard to statistical methods and analyses

as part of the process validation: mentioned are PAT, multivariate SPC, statistical methods regarding

variability and process capabilities, trend analyses and methods for measuring/evaluating process

stabilities and capabilities. Moreover, the authority considers stage 3 in the process validation life

cycle (continued/ongoing process verification) as comparable. An exception is mentioned below in

the differences. Finally, the requirements for change control in both FDA Process Validation

Guideline and the revised Annex 15 are also similar from the perspective of the FDA.

But what are now the differences between the FDA Process Validation Guidelines and the revised

Annex 15?

As one difference the Annex 15 asks to also list non-critical attributes and parameters in the

validation protocol. The FDA Process Validation Guideline only requires the specification of critical

quality attributes and critical process parameters. The FDA sees another difference in the number of

validation batches. Annex 15 refers to the minimum number of 3, whereas the FDA Process

Validation Guideline does not mention a number. For the FDA there is another difference in terms of

process validation approaches. In Annex 15 three approaches are mentioned (traditional, continuous

process verification, hybrid), while the FDA Process Validation Guideline makes no distinction.

Further, the requirements for statistics also differ in the two documents. This topic is emphasized

more in the FDA Process Validation Guideline. The FDA even recommends that a statistician should

create the data collection plans and should also be consulted with regard to the use of statistical

methods. This requirement goes beyond what is stated in the FDA Process Validation Guideline. It

"just" recommends someone with statistical knowledge. The FDA also sees differences regarding the

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subject of sampling in the stage 3 of the process validation life cycle (continued/ongoing

process verification). The FDA Guideline demands a higher number of samples (comparable to

stage 2) - at least until sufficient data exist to assess variability. There is no such demand for an

increased number of samples in the ongoing process verification in Annex 15. In addition, it

addresses transport, packaging operations and cleaning validation, while the FDA Guideline

addresses processes in general. Also, Annex 15 mentions more details with regard to transfer,

bracketing and qualification. However, the FDA Process Validation Guideline does not address the

qualification stages DQ IQ, OQ as such, but mentions similar requirements.

Conclusion

There is (gratifying) much conformity between the FDA Process Validation Guideline and the revised

Annex 15. A better match with the FDA Guideline was also one of the reasons for the revision of

Annex 15.

But there are also differences, and companies that want to operate both in the US market and in

Europe have to be aware of these differences. The recommendation that a statistician should create

the data collection plans and should be consulted with regard to the use of statistical methods is

somewhat surprising. This requirement goes beyond what is stated in the FDA Process Validation

Guideline. Here "just" someone with statistical knowledge is recommended. On the other hand this

emphasizes the FDA's increased focus on statistics in the field of process validation. Information on

knowledge of statistics cannot be found in Annex 15.

What are "complex manufacturing processes"? A recent reply from the EMA

The Variations Regulation (EC) no. 1234/2008 of the European Commission defines the procedure

for variations of existing marketing authorisations. The "detailed guidelines for the various categories

of variations", which were published in the consolidated version in August 2013 in the European

Official Journal, explain the interpretation and application of this Variations Regulation.

Although the "detailed guidelines" describe a number of scenarios of possible variations in some

detail, there are formulations in the Guideline text which require clarification due to their blur. The

EMA adopted such a case in a recent update of itsquestions and answers collection "Quality of

Medicines Questions and Answers: Part 1" to concretise the case through a statement.

It is about the term "complex manufacturing processes", which is used in two scenarios associated

with type II variations (found in the "detailed guidelines" p 40ff):

Replacement or addition of a manufacturing site for part or all of the manufacturing process of

the finished product (Guideline change code B.II.b.1)

...

c) Site where any manufacturing operation(s) take place, except batch release, batch control,

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and secondary packaging, for biological/immunological medicinal products, or for

pharmaceutical forms manufactured by complex manufacturing processes.

Change in the batch size (including batch size ranges) of the finished product (Guideline

change code B.II.b.4)

...

d) The change relates to all other pharmaceutical forms manufactured by complex

manufacturing processes .

The EMA now clarified this term as follows:

Guideline Change Code B.II.b.1: Complex manufacturing processes are given when the

understanding of the relation between quality characteristics of the product and its in vivo

efficacy is lacking. This is often the case in innovative medicines such as products of

nanomedicine.

Guideline Change Code B.II.b.4: Complex manufacturing processes are those which contain

one or more sub-steps, where a scale-up can lead to problems.

In both scenarios, the approving authority will decide on a case by case basis. If the applicant

submits the variation as a Type IB, he must provide a valid justification that the production process is

not "complex". However, in doubt the authority may upgrade the variation to a Type II. Therefore, the

EMA recommends that the applicant clarifies the situation with the authority before submitting the

variation.

Ph. Eur. Chapter 5.15. Functionality-related characteristics of excipients

A Draft of Ph. Eur. Chapter 5.15. "Functionality-Related Characteristics of Excipients" has been

published in Pharmeuropa 27.4.

The non-mandatory chapter has been completely reviewed to better align with ICH guideline Q8

Pharmaceutical Development. The chapter deals with the critical quality attributes (CQAs) of

excipients which are identified during pharmaceutical development work resulting in an excipient

quality specification.

It introduces the "quality by design" concept described in the ICH Q8 guideline to excipients which

requires a comprehensive understanding of the way their attributes interact in the formulation and

with manufacturing processes.

Additionally, the draft emphasizes a certain degree of regulatory flexibility based on the description

of the design space (Life Cycle Management).

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The draft is available for comments until 31 December 2015.

Following your registration on the Pharmeuropa website you can get to the complete Chapter 5.15.

"Functionality-Related Characteristics of Excipients".

WHO publishes draft guideline for HVAC systems for non-sterile pharmaceutical dosage

forms

Nearly all guidelines addressing the requirements with regard to HVAC systems or air qualities focus

on the manufacture of sterile medicinal products. This is especially true for the Annex 1 of the EU

GMP Guideline.

The WHO now published a revised working document of the guideline for public consultation which

specifically addresses the requirements for HVAC systems used during the manufacture of non-

sterile pharmaceutical dosage forms. The version valid so far dates back to 2011 and is contained in

the WHO Technical Report Series, No. 961 as Annex 5 (Supplementary guidelines on good

manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile

pharmaceutical dosage forms). The main changes are the integration of sample layouts (such as for

weighing and dispensing) in the chapter "Premises" and a revision of the chapter "Commissioning,

Qualification and Validation". Furthermore, a separate chapter now is devoted to maintenance.

You can find the current draft of the "Guideline Supplementary guidelines on GMPs for HVAC

systems for non-sterile pharmaceutical dosage forms" in the members' area of the ECA website.

Revised USP General Chapter <661> Containers-Plastics

The revised USP General Chapter <661> (Containers-Plastics) will be published in USP 39-NF34

with an official date of May 1, 2016.

Including Changes to the title of General Chapter <661> (new title: Plastic Pckaging Systems and

their Materials of Construction), sections of General Chapter <661> moved into new General

Chapters <661.1> (Plastic Materials of Construction) and <661.2> (Plastic Packaging Systems for

Pharmaceutical Use). The General Chapter <661.1> gives information on the comprehensive

characterization of a plastic material, while General Chapter <661.2> covers testing methods and

standards for packaging systems made of plastic.

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The Drafts of the above mentioned General Chapters were proposed for comment in Pharmacopeial

Forum 39(5) and 40(5).

All modifications will become official on May 1, 2016.

Additionally, a Draft of a new USP General Chapter <1661> (Evaluation of Plastic Packaging

Systems and their Materials of Construction with respect to their user safety impact) was proposed in

Pharmacopeial Forum 40(6).

Following your registration on the USP Pharmacopeial Forum website you can get to the

complete Drafts of USP General Chapters <661>, <661.1> ,<661.2> and <1661>.

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AUDIT FINDINGS - 483 Observations

Firm Name 483 Observation

Alfa Wassermann S.p.A. - July

3, 2015

Written procedures are lacking which describe in sufficient

detail the testing of components.

SeQuent Scientific, Ltd. - July 3,

2015

Employees are not given training in the particular operations

they perform as part of their function.

PETNET Solutions, Inc. - July

17, 2015

You did not take appropriate action to correct any identified

problems to prevent recurrence of a nonconforming product or

other quality problem.

Noven Pharmaceuticals, Inc. -

July 10, 2015

The accuracy, sensitivity, specificity and reproducibility of test

methods have not been established and documented.

Galena Biopharma, Inc. - Aug.

25, 2015

Adverse drug experience information has not been reported to

FDA.

Medical Products Laboratories,

Inc. - July 21, 2015

Written production and process control procedures are not

followed in the execution of production and process control

functions and documented at the time of performance.

Mutual Pharmaceutical Co., Inc. - July 17, 2015

Drug products failing to meet established standards,

specifications, and quality control criteria are not rejected.

Sentara Enterprises - July 23, 2015

Procedures designed to prevent microbiological contamination

of drug products purporting to be sterile are not established.

GlaxoSmithKline - July 24, 2015 The suitability of the reference standard used for the release

and stability testing of Drug Substance [REDACTED] has not

been adequately qualified.

Mayo Clinic - PET Radiochemistry Facility - Aug. 3, 2015

You did not notify facilities immediately when PET products

failed to meet a criterion for sterility nor did you complete an

investigation for all suspected sterility failures.

Chen Shwezin, Inc. - Sept. 11, 2015

Separate or defined areas to prevent contamination or mix-ups

are deficient regarding operations related to aseptic processing

of drug products.

Mana Products, Inc. - July 10, 2015

Equipment used in the manufacture, processing, packing

or holding of drug products is not of appropriate design to

facilitate operations for its intended use.

Hartley Medical Center Pharmacy, Inc. - July 8, 2015

Clothing of personnel engaged in the processing of drug

products is not appropriate for the duties they perform.

Washington Homeopathic Products, Inc. - March 31, 2014

Equipment and utensils are not cleaned at appropriate intervals

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to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.

Fareva Richmond, Inc. - March 7, 2014

Written production and process control procedures are not followed in the execution of production and process control functions.

Mylan Pharmaceuticals, Inc. - March 21, 2014

Laboratory records do not include complete records of all stability testing performed.

C-Care, LLC - March 12, 2014 Written procedures are not established and followed for evaluations conducted at least annually to review records associated with a representative number of batches, whether approved or rejected.

West-Ward Pharmaceutical Corp. - June 30, 2011

Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

Alliance Medical Products, Inc. - Aug. 21, 2015

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed.

Pacific Healthcare, Inc. - Aug. 18, 2015

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not followed.

Shine & Pretty USA Corp. - Aug. 12, 2015

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

Tris Pharma, Inc. - Aug. 12, 2015

Not all quarterly periodic adverse drug experience reports have been submitted within 30 days of the close of the quarter.

Downing Labs, LLC - Oct. 9, 2015

There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.

Pernix Receives Form 483 for cGMP Violations

Contract manufacturer Pernix Manufacturing received an 11-observation Form 483 for a litany of cGMP violations, including failing to investigate complaints about caterpillars and poppy seeds in vials of finished product. The company received four serious complaints regarding particulate matter in products, but didn't thoroughly investigate the incidents, according to the 483, which followed a March 10 to 21, 2014, inspection. The complaints cited lumps and sediments in solution, a caterpillar drawn into a syringe from a vial and poppy seeds and floating debris at the bottom of bottles. In all four instances, Pernix closed the investigation and determined there was no root cause, saying either that the problem was not due to the manufacturing process or that it did not perform a review of the manufacturing process.

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The company's investigations of adverse event reports also failed to determine root causes and didn't include corrective and preventive actions. The FDA investigator also cited Pernix for not maintaining trending data on deviations, out-of-specification results, change controls, aborted batches, rejected raw and in-process materials and finished products. Pernix was purchased by Houston-based Woodfield Pharmaceutical in April 2014, just weeks after

the failed inspection. Woodfield did not respond to a request for comment.

FDA Hits Pfizer Subsidiary With Second Form 483 in Five Years

A Pharmacia & Upjohn plant was slammed with its second FDA Form 483 in five years for GMP deficiencies ranging from quality systems, facilities and equipment to materials, production and laboratory systems. Major lapses uncovered during the June 23 to July 9 inspection included failure to investigate discrepancies and out-of-specifications results, inadequate annual product reviews, failure to follow written procedures for identifying, handling and storing containers, and inadequate documentation for cleaning procedures. The Kalamazoo, Mich., plant received a 10-item Form 483 following a September 2010 inspection for many of the same issues. Although drugmakers have received repeat 483 observations that have not resulted in further action such as warning letters, the agency will likely take a much harder stance toward companies with repeat observations under its new team-based inspectorate program. A team of four investigators descended upon the facility, including CDER Office of Manufacturing Quality Director Thomas Cosgrove, who participated as an observer. The FDA team noted, for instance, that nonconfirmed OOS investigations weren’t documented to prove that an adequate investigation was performed prior to batch release, and some laboratory investigation reports and lot results records were missing key information on the manufacturing process. Annual product reviews also were lacking a review of all appropriate data to evaluate quality characteristics such as content uniformity data, and investigators noted numerous examples of manufacturing equipment that was not designed for its intended use and missing cleaning logs for major equipment. The plant also failed to follow written procedures for identifying, handling and storing containers. According to the 483, containers that were torn, leaking and associated with rodent infestation were not placed in an area identified as rejected. Moreover, procedures to prevent microbiological contamination of sterile products weren’t written and followed. Pfizer spokeswoman Kim Bencker says the recent inspection was a routine GMP inspection, and the company is working closely with the FDA to address the concerns raised.

Observations: QUALITY SYSTEM: 1. Documented investigations into discrepancies and out-of-specification results are not fully investigated .

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2. Annual product reviews do not include a review of all appropriate data to evaluate quality characteristics indicative of potential trends FACILITIES & EQUIPMENT SYSTEM 3. Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use, cleaning, and maintenance 4. Individual logs for major equipment do not include written records of cleaning. MATERIALS SYSTEM: 5. Written procedures are not followed for identification, handling, and storage of components. PRODUCTION SYSTEM: 6. Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not written and followed. LABORATORY SYSTEM: 7. Acceptance criteria for the sampling and testing conducted by the quality control unit is not adequate to assure that batches of drug product meet appropriate statistical quality control criteria as a condition for their approval and release. 8. Drug products not required to be sterile are not examined to prevent objectionable microbiological contamination.

Galena Hit With 10-Item Form 483 Over Unresolved Issues (NDA holder)

The FDA handed Galena Biopharma a 10-item Form 483 for lapses in adverse drug event reporting — some of them repeat observations — following a reinspection of its Portland, Ore., facility.

During the Aug. 17 to 25 inspection, investigators found that ADE information was not reported to the FDA, including for a serious and unexpected incident involving Galena’s breakthrough cancer pain treatment Abstral (fentanyl). The firm also failed to conduct follow-up investigations on at least two ADEs related to the opioid drug.

Galena didn’t have written procedures on evaluating, processing and reporting ADEs until last December, and there’s no documentation that the firm retrospectively reviewed all events that are subject to 15-day alerts, the 483 says. The form notes that at least nine serious and unexpected ADEs were not reported in time.

The 483 also dings the drugmaker for failing to develop written procedures for reporting postmarketing ADEs to the FDA and for incomplete and inaccurate information in periodic safety update reports.

Further, investigators found several repeat observations from a November 2014 inspection related to the failure of Galena’s quality unit to ensure that written responsibilities and procedures for risk

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assessment, use of electronic signatures, annual product reviews and IND safety reporting were fully followed. The FDA issued a warning letter in April citing those and the ADE concerns.

Galena CEO Mark Schwartz saysthe firm ―has resolved the prior manufacturing issues, taken steps to ensure comprehensive reporting of AEs, and [is] working to address all aspects of our reporting systems.‖

Observations:

1. Adverse drug experience information has not been reported to FDA

2. Adverse drug experiences that were the subject of post marketing 15-day reports were not

investigated

3. Not all adverse drug experiences that are both serious and unexpected have been reported

to .FDA within 15 calendar days of initial receipt of the information.

4. Not all periodic adverse drug experience reports contained a narrative summary and

analysis of the information in the report.. an analysis of the post marketing 15-day Alert

reports submitted during the reporting interval, an index consisting of a line listing for all

individual case safety reports for serious, expected, and non-serious adverse drug

experiences.

5. Procedures describing the handling of written and oral complaints related to drug products

are deficiently written or followed.

6. The responsibilities and procedures applicable to the quality unit are not in writing and fully

followed.

7. lndividual ADEs which were not reported to FDA in a post marketing 15-day alert have not

been included in a periodic safety report.

8. Complaint records are deficient in that they do not document the reason and the individual

making the decision not to conduct a complaint investigation.

9. Written procedures have not been developed for the reporting to FDA of post marketing

adverse drug experiences.

10. Follow-up reports were not submitted within 15 calendar days of receipt of new

information concerning post marketing 15-day reports

FDA Warning letters

US FDA Warning letter: Unimark Remedies Ltd., Mumbai, India:

Observations:

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1. Failure to document production and analytical testing activities at the time they are

performed.

(a) The start and stop times and (b)(4) for Step #(b)(4) were not recorded or signed in the batch

record contemporaneously

(b) Products returned due to the presence of extraneous threads, the investigator found many

inconsistencies in your reprocessing batch records.

operators signed batch records for periods when they were not in your facility.

(c) Water testing records for sampling point (b)(4) on March 19, 2014, were incomplete, analyst did

not record observations at the time they were made.

2. Failure to prevent unauthorized access or changes to data and to provide adequate

controls to prevent omission of data.

Laboratory systems lacked access controls to prevent raw data from being deleted or altered

No unique usernames, passwords, or user access levels for analysts on multiple

laboratory systems.

All laboratory employees were granted full privileges to the computer systems

They could delete or alter chromatograms, methods, integration parameters, and

data acquisition date and time stamps

Multiple instruments had no audit trail functions to record data changes.

3. Failure to maintain complete data derived from all testing, and to ensure compliance with

established specifications and standards.

o you discarded necessary chromatographic information such as integration

parameters and injection sequences from test records, you relied on incomplete

records

o no procedures for manual integration or review of electronic and printed analytical

data for (b)(4) stability samples

o Electronic integration parameters were not saved or recorded manually, When the

next samples were analyzed, the previous parameters were overwritten during the

subsequent analyses.

o We found that some analytical testing data was inadequately maintained and

reviewed.

o computer files included raw data for undocumented (b)(4) stability samples

analyzed, but no indication of where these samples came from and why they were

tested.

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o In a data file folder created, 23 chromatograms were identified as stability

samples for(b)(4) lots (b)(4), and (b)(4). Results were not documented, the

acquisition date was more than six weeks after the samples were run.

o (b)(4) lots (b)(4) and (b)(4) were not in your stability study records at the time of

inspection. Additionally, there were no log notes of any samples from the three

lots removed from the stability chamber.

4. Failure to properly maintain buildings and facilities used in the manufacture of

intermediates and APIs in a clean condition

o Evidence of pests in your facility. o Manufacturing building was not sealed against pests. o There were significant gaps in the (b)(4) level, where piping entered from outside.

o A bird’s nest near the ceiling. o Bird feces on a rack and on a bag of (b)(4) in the general raw material warehouse. o A lizard in the general raw material warehouse

US FDA Warning letter: SSM Health Care St. Louis DBA SSM St. Clare Health Center

An FDA investigator noted CGMP violations at your facility, causing your drug products to be

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

example:

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

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

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

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

validation of all aseptic and sterilization processes (21 CFR § 211.113(b)).

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

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

4. Your firm has failed to prepare batch production and control records with complete information

relating to production and control of each batch of drug product (21 CFR § 211.188).

5. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet

its specifications whether or not the batch has already been distributed (21 CFR § 211.192).

For more details refer:

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm469126.htm

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Health Canada Non-Compliance Report

Health Canada Non-Compliance Report: Unilever Canada Inc.

GMP Inspection Report Card Summary

Establishment

Name

Reference

Number Inspection Start Date Type of Inspection Inspection Rating

Unilever Canada

Inc.

100585 2015-06-16 Good Manufacturing

Practices (GMP) -

Regular

Non-Compliant

Observation

Number Regulation Summary of Observation

1 C.02.015 - Quality

Control

Quality oversight was lacking resulting in significant GMP deficiencies.

2 C.02.028 - Stability Deficiencies were noted with the assessment of confirmed out-of-specification stability testing results.

No action taken when data shows that the products do not meet their specifications prior to the expiry date.

3 C.02.020 - Records Deficiencies were noted with record keeping practices. Deficiencies were noted with the investigation of a deviation from

procedures or instructions.

4 C.02.027 - Stability Deficiencies were noted with the determination by the importer of the stability of a drug prior to its marketing.

5 C.02.028 - Stability Lack of or inadequate continuing stability program. Deficiencies were noted with the inclusion of the relevant chemical

tests in the continuing stability program implemented by the distributor.

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Observation

Number Regulation Summary of Observation

6 C.02.019 - Finished

Product Testing

Failing confirmatory testing results were not investigated.

7 C.02.014 - Quality

Control

Deficiencies were noted with regards to the content of the provided certificate of manufacture.

8 C.02.018 - Finished

Product Testing

There was inadequate control of finished product testing requirements and certificates of analysis.

9 C.02.028 - Stability Deficiencies were noted with the implementation of a continuing stability program to ensure compliance with the approved shelf-life specifications.

10 C.02.015 - Quality

Control

Deficiencies were noted with customer complaint investigation and follow-up.

11 C.02.011 -

Manufacturing

Control

All critical production processes have not shown to produce consistent results.

12 C.02.012 -

Manufacturing

Control

Deficiencies were noted with the self-inspection program.

13 C.02.015 - Quality

Control

Deficiencies were noted with the change control system to assure that all changes were properly documented, evaluated and approved by the quality control department.

14 C.02.014 - Quality

Control

Deficiencies were noted with quality oversight of returned drugs placed back into inventory and made available for further sale.

15 C.02.015 - Quality Deficiencies were noted with the control of labels.

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Observation

Number Regulation Summary of Observation

Control

16 C.02.012 -

Manufacturing

Control

Deficiencies were noted with the capacity of distribution records to enable tracing of each drug product.

17 C.02.018 - Finished

Product Testing

Microbiological preparatory testing was not conducted.

18 C.02.020 - Records Deficiencies were noted with the maintenance of master production documents by the importer of a drug.

19 C.02.015 - Quality

Control

Inadequate evidence to demonstrate that storage and transportation conditions are appropriate.

20 C.02.011 -

Manufacturing

Control

Regular periodic quality reviews of all drugs were not done.

21 C.02.015 - Quality

Control

Deficiencies were noted with the written agreement among the parties involved that addressed responsibilities for the fabrication of drugs.

EMA Non-Compliance Report

EMA Non-Compliance Report : GlaxoSmithKline (Tianjin) Company Limited (Teda), China: Nature of non-compliance :

A critical deficiency was cited with regards system failures to ensure that the manufacture of medicinal products were fit for their intended use, complied with the requirements of the Marketing Authorisation and did not place patients at risk due to inadequate safety, quality or efficacy.

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• Since 2005, the company identified tablet discoloration in the stability samples during the stability trials which did not meet the shelf life specification. No action was taken to assess the risk of the remaining products in the markets. Adverse trends in stability-indicating attributes were observed but not investigated. • Product impact assessments failed to ensure that the defective product was not potentially supplied to the user. • Failure to notify competent authorities on the discovery of defective products. • Failure to address the root cause due to ineffective CAPA. Also delay in CAPA implementation. • Failure to escalate the incident and conduct effective investigations in a timely manner.

EMA Non-Compliance Report: CARGILL FRANCE: Nature of non-compliance : Overall, 14 observations were made, including 1 critical deficiency and 4 major deficiencies:

[Critical] The management of semi-finished batches and of the mixing operations was deficient and conformity of the final batches to specifications, notably Ph.Eur. specifications, could not be guaranted. [Major 1] The site had been manufacturing an active substance without ANSM authorisation. [Major 2] The change control related to the suppression of one filtration step in the active substance manufacturing process was deficient. [Major 3] The manufacturing of the active substance had not been made using master production instructions and no batch production records had been established. [Major 4] No review of batch production records of critical process steps had been done before release of the active substance for distribution. 7 observations are related to lack of traceability, risks of contamination induced by the absence of cleanliness in the production environment, very bad condition of the production equipment and insufficient equipment cleaning procedures. The inspection’s observations also apply to the manufacture of pharmaceutical excipients and starting materials that are intended to be used as ingredients in cosmetics and medical devices, which are manufactured under the same conditions as the active substance.

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For improvement ….

• Conduct “mock inspections” within the

department to help employees feel more

comfortable with the expectations of the

inspection process.

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Regulations of the Month

Subpart C--Buildings and Facilities

Sec. 211.42 Design and construction features.

(c) Operations shall be performed within specifically defined areas of adequate size. There shall be

separate or defined areas or such other control systems for the firm's operations as are necessary to

prevent contamination or mixups during the course of the following procedures:

(5) Manufacturing and processing operations;

(6) Packaging and labeling operations;

(7) Quarantine storage before release of drug products;

(8) Storage of drug products after release;

(9) Control and laboratory operations;

(10) Aseptic processing, which includes as appropriate: (i) Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable; (ii) Temperature and humidity controls; (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar; (iv) A system for monitoring environmental conditions; (v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions; (vi) A system for maintaining any equipment used to control the aseptic conditions.

(d) Operations relating to the manufacture, processing, and packing of penicillin shall be performed

in facilities separate from those used for other drug products for human use.

Sec. 211.44 Lighting.

Adequate lighting shall be provided in all areas.

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Top Presentations of Pharma Uptoday

· Presentation on data integrity in Pharmaceutical Industry

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

· Good chromatographic practices

· HPLC - Peak integration for chromatography

· Good Laboratory Practices for Pharmaceutical Quality Control Laboratories

· Laboratory Errors

· Understand the importance of each step to minimise Laboratory errors

· Sample preparation techniques of solid dosage forms

· Investigating aberrant potency values in Pharma Analysis

· All about Tablets (Pharma)

The module Consult Yourself.... “Know Regulation - No Observation” deals with most common

(top 20) basic CFR regulations having frequent violations and previous observations for better

understanding.

#1 "21 CFR 211.160" http://www.slideshare.net/skvemula/top-20-observation-series-1-21-cfr-211160

(Subpart I--Laboratory Controls: Sec. 211.160 General requirements.)

#2 "21 CFR 211.22" http://www.slideshare.net/skvemula/top-20-observation-series-2-21-cfr-21122

(Subpart B--Organization and Personnel: Sec. 211.22 Responsibilities of quality control unit)

#3 "21 CFR 211.192" http://www.slideshare.net/skvemula/top-20-observation-series-3-21-cfr-211192

(Subpart J--Records and Reports: Sec. 211.192 Production record review.)

#4 "21 CFR 211.67" http://www.slideshare.net/skvemula/top-20-observation-series-4-21-cfr-21167

(Subpart D—Equipment: Sec. 211.67 Equipment cleaning and maintenance)

PHARMA UPTODAY

65

#5 "21 CFR 211.100" http://www.slideshare.net/skvemula/top-20-observation-series-5-21-cfr-211100

(Subpart F- Production and Process Controls: Sec. 211.100 Written procedures; deviations.)

#6 "21 CFR 211.165" http://www.slideshare.net/skvemula/top-20-observation-series-6-21-cfr-211165

(Subpart I--Laboratory Controls: Sec. 211.165 Testing and release for distribution)

Few Pharma Uptoday topics can be accessed from our website

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Few Pharma Uptoday presentations can be accessed from our website

http://www.slideshare.net/skvemula

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