VOLUME: 18 - ISSUE: SEP 2015 |

PHARMA UPTODAY

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Inside this issue

3 News Uptoday 37 New Guidance 42 Audit Findings 483 Observations

- 483 of PharMEDium Services, LLC (Outsourcing facility) - 483 of "Walgreens Home Care, Inc. dba Walgreens Infusion

Services EU Non Compliance Report

- EU Non-Compliance Report: TXCELL - BESANCON, France

45 Warning Letters

- Warning letter : Sipra Labs Limited, Hyderabad - Warning letter : Mylan Laboratories Limited, India

50 Health Canada Non Compliance Report

- Procter & Gamble Inc., Canada. 53 Regulations of the Month

- Sec. 211.28 Personnel responsibilities (b) & (c) - Sec. 211.42 Design and construction features (a) & (b)

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News Uptoday

Opposing Views on FDA Complete Response Letters

Recently, the British Medical Journal published analysis on how pharmaceutical companies publicly

address Complete Response Letters (CRL) from the FDA, specifically the center for drug evaluation

and research (CEDR). While the EMA publishes data from refusal assessment reports, the FDA

does not fully disclose information with Complete Response Letters because of privacy rules around

unapproved applications. As a result there is a public debate as to whether there is a common good

for learning from the information should change this. We think change is in order—not only to

advance patient care, but to improve clinical trial operations.

There are several ways companies handle a complete response letter, ranging from full

disclosure to no disclosure. Unfortunately, only 93 of 687 (14%) FDA statements within complete

response letters from August 2008 to June 2013 were publicly shared in press releases from the

sponsoring company.

Not receiving approval for a new drug application is a challenging time for any pharmaceutical

company. These decisions should be made without pressure from competitors. But valuable

scientific and clinical information on a given drug class lies within the complete response letters. For

instance, 341 of 687 (49.6%) statements within complete response letters pertained to issues of

safety and efficacy. This information can be helpful not only to patients and prescribing physicians,

but also to trial operations practitioners. Of note, 32 of the 61 total (52.5%) complete response

letters called for a new clinical trial.

It‘s easy for those of us outside the sponsor to list off the benefits to publishing this data: scientific

understanding, patient and physician information access, and knowledge advancement for clinical

trial operations to name a few. Of course, immediate publishing of such information has the potential

to harm the individual pharmaceutical companies working on a specific cure.

So what‘s to be done? There is a third option to allow for delayed release of information within the

complete response letter, possibly 5 years following the issuing of a CRL. This would permit

collective learning on any given pharmaceutical subject and provide clear insight into the FDA

process, while protecting the individual drug company during the critical decisions that come

following an non-approval. Such an approach would also reduce hearsay common to clinical

operations professionals about what actually affects approval outcomes, allowing them to make the

right choices for their trials.

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MHRA enforces European Commission decision to suspend medicines for which

authorisation based on clinical studies conducted at GVK Biosciences

In accordance with the European Commission‘s decision (16 July 2015), MHRAhas suspended a number of products deemed non-critical to continuity of supply to the UK market (see attached Table 1). Products necessary to maintain continuity of supplies (Table 2) and those non-critical products for which further data in support of the marketing authorisation has been provided, have not been suspended at this time. The European Commission endorsed the recommendation of the European Medicines Agency‘s Committee for Medicinal Products for Human Use (CHMP) to suspend a number of licences for generic medicines, for which authorisation was based on clinical studies conducted at GVK Biosciences‘ site in Hyderabad, India. This action is being taken as a precautionary measure. There is no evidence of safety concerns or loss of efficacy with these products. People should continue to take their medicines as prescribed. Only generic medicines are affected, therefore alternatives to all suspended medicines are readily available and people should not experience any difficulty getting the medicines they need. If anyone has any questions about their medication they should speak to their doctor or pharmacist.

For more details : https://www.gov.uk/government/publications/mhra-enforces-european-

commission-decision-to-suspend-medicines-for-which-authorisation-based-on-clinical-studies-

conducted-at-gvk-biosciences

China FDA wants signed internal audits on clinical trial applications this month

China's FDA has issued a deadline for all drugmakers to submit signed internally audited data for

clinical trial applications by late August, as it warns the information could prompt unannounced

inspections and the prospect of having to withdraw filings if discrepancies to submissions already

made pop up.

The deadline of Aug. 25 outlined in a CFDA release last week says applicants must submit an

electronic version of the inspection report to the State Food and Drug Administration Food and Drug

audit identification centers, along with a scanned copy of the clinical trials contract, names of the

research team members and other key personnel as well as notarized signatures.

In a July 28 blog post, Law firm Sidley Austin said the new rule had "far-reaching" implications for

"the 1,622 pending drug registration applications that cover imported and local drugs" and has

caught firms by surprise.

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Sidley Austin noted the CFDA also requires a locked database consistent with the original data as

well as related statistical analysis and summary reports, among other comparisons across

maintenance of biological sample analysis and data records.

"CFDA will conduct further verification, including on-site inspections without notice, based on the

self-inspection reports and may impose penalties on manufacturers, clinical trial institutions and

clinical research organizations in case false, inauthentic or incomplete data are found," the Sidley

Austin blog said.

"In particular, companies that have submitted such data may be banned from filing any drug

registration applications with CFDA for a period of three years."

Multinational drugmakers in particular are also eyeing the announcement for any implications for

approval delays and for the use of multiregional clinical trials in applications.

In a hopeful sign for companies that use the MCRT pathway, CFDA has joined the International

Coalition of Medicines Regulatory Authorities as part of efforts to harmonize its regulation efforts as

companies seek to increase the number of Chinese patients in global trials.

Also in July, in a separate notice, CFDA also announced it would conduct surprise inspections of

drug manufacturing sites starting in September by inspectors who will digitally record the

investigations.

Australia looks to speed clinical trial start-up times

Australia’s National Health and Medical Research Council (NHMRC) is getting pragmatic with

increasingly long clinical trial timelines and is now looking to streamline the research

governance process in order to reduce delays in trial commencement.

More specifically, the council has released a Good Practice Process to streamline the site assessment and site authorization of trials. According to the NHMRC, two key improvements that will reduce the time taken to begin trials have been proposed by the council‘s development group:

An increased commitment to planning, preparation and ongoing support for clinical trials

within institutions where trials are conducted; and

A change to the order in which the activities within the assessment and authorization process

are conducted, whereby key assessment activities occur much earlier. Pharma companies, clinical researchers and CROs (contract research organizations) have raised concerns about the length of time taken to commence clinical trials in Australia, and particularly about the time taken to complete research governance, the council says. ―The proposed order in which activities can be completed in the Good Practice Process represents a paradigm shift from the way in which the site assessment and authorisation process has traditionally been conducted,‖ the NHMRC says. The new guidance offers three main differences between the proposed process and previous methodology:

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The majority of site assessment activities can be conducted not just at the same time as, but prior to,

ethical reviews being undertaken;

Many of these activities can be conducted in parallel instead of sequentially; and

Some key site assessment activities can be substantively completed in the feasibility assessment

stage and then formalized in documentation rather than be delayed until all documentation is

submitted.

FDA Basics Metrics: July 2015

Overview

Number of Visitors 284, 292

Average Rating 2.42

Statistics By Topic

Topic Number of Comments Average Rating

FDA Fundamentals 45 2.25

Animal & Veterinary 2 1.00

Cosmetics 2 5.00

Dietary Supplements 9 3.70

Drugs 17 3.45

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Topic Number of Comments Average Rating

Food 46 3.28

Medical Devices N/A N/A

Radiation-Emitting Products N/A N/A

Tobacco Products 6 2.75

Vaccines, Blood, and

Biologics

5 5.20

Children's Health N/A N/A

Top Accessed Pages

Rank Page Visits

1 FDA Basics Main 11,502

2 What does FDA regulate? 9,271

3 Did you know a store can sell food past the expiration date? 5,820

4 Whatis the meaning of "natural" on the label of food? 5,283

5 FDA Fundamentals 4,293

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Regulatory Planning for FDA FY 2016

Regulatory Planning for FDA FY 2016

The FDA operates on a Federal Fiscal Year rather than a calendar year. The FY runs from October

1 through September 30. The new FY brings fee increases, expiration of registrations and statuses

like the Small Business Decision, and a call for registration renewals. Regulatory Planning for FDA

FY 2016 varies depending on if you are an existing company or a new company and whether you

are a facility with food, dietary supplements, drugs, devices, or cosmetics. Below is an overview on

regulatory planning for FDA FY 2016.

Regulatory Planning for FDA FY 2016 – New Medical Device Companies

The FDA requires medical device facility registration within 30-days of entering the market. For

facilities with Class I Exempt devices or just receiving their device approval (510(k), PMA, de novo)

this time of year poses a challenge. Any registration occurring at this time is only valid until Sept. 30.

From October 1 – December 31 the registration must be renewed. That means two filing fees within

the span of a couple of months. Regulatory planning for FDA FY 2016 in this case may mean

delaying market entrance until mid-September or registering now, but waiting until December to pay

the renewal fee.

Many new device companies may have also applied for a Small Business Qualification Certification

to reduce FDA filing fees. Small Business Determinations expire with the FY on September 30. If you

have applied for a SBD or received a SBD number and not filed your pre-market application (510(k),

513(g), PMA etc.), then a second SBD application may be in order. Regulatory planning for FDA FY

2016 for a company in this scenario would involve assessing the time needed to complete the

submission. There is no reason to rush a submission to claim FY 2015 SBD. Applying for FY 2016

SBD will involve the same steps and only add thee to four weeks to the time-frame.

Regulatory Planning for FDA FY 2016 – Existing Drug and Device Companies

Regulatory planning for FDA FY 2016 is more mundane for existing drug and device companies with

no planned submission. Those companies must renew their registrations with the FDA between Oct.

1 and Dec. 31. Drug companies should use this opportunity to list any new drug products added or

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revised formulations. Device companies will notice a small increase in the filing fee, now up to

$3,872, but otherwise be unaffected by the countdown to the new FY.

Regulatory Planning for FDA FY 2016 – Food and Dietary Supplement Companies

Regulatory planning for FDA FY 2016 is different for food and dietary supplement companies. All

facilities registered with the Center for Food Safety and Applied Nutrition (CFSAN) are subject to a

bi-annual registration based on the FDA fiscal year. New companies will need to register prior to

entering the market, but renewals are not due this year. The last renewal period was between Oct. 1

– Dec. 31, 2014 and the next will be Oct. 1 – Dec. 31, 2016.

The above are a few of the ways the close of a federal fiscal year will impact regulatory planning. Be

sure to consider registrations and submissions as the fiscal year winds down and the new fiscal year

begins.

Indian and Chinese API Manufacturers in the Focus of European Authorities

The EudraGMP database was originally launched in April 2007 and is used to exchange information

on compliance with the Good Manufacturing Practices (GMP) between the relevant regulatory

authorities of the EU Member States - including Iceland, Liechtenstein and Norway. Since January

2011 the data of all national authorities can be accessed. Further, since April 2013 the database also

contains information about GDP, why it is referred to as Eudra GMDP database now.

The database comprising the reports about deficiencies found in inspections by the European

authorities - the "non-compliance reports" or, officially, "statement of non-compliance with GMP" -

was extended by three reports last week: two of these reports related to Chinese firms, one report to

a company in India. The inspections were conducted by inspectors of the Italian authority.

The inspection of the Indian site (antibiotic APIs) revealed that samples, materials and documents

were stored improperly. The falsification of data and documents was found. At one of the two

Chinese manufacturers who also produces an antibiotic API, inspectors were also not allowed to

access an apparently uncontrolled storage area of raw material and finished products - which they

estimated as high risk in terms of data falsification. In the second inspected Chinese manufacturing

facility (sterile active ingredient manufacture) inspectors objected to especially high risks with regard

to contamination (inadequate clothing of workers, no monitoring of the differential pressure between

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spaces of different purity classes, no precautions to avoid contamination during the transfer of the

sterile active substance between different containers etc.).

As a consequence of the inspection results, the competent authorities were prompted to check in all

three cases whether the manufacturer must be removed from the relevant registration documents. In

this case, the marketing authorisation holders have to look for alternative API suppliers.

Furthermore, the regulatory authorities are urged not to approve new applications in which these

manufacturers are listed. The corresponding CEPs for the Indian and for one of the Chinese

manufacturers were suspended respectively withdrawn.

The Eudra GMDP database so far contains a total of 7 non-compliance reports on inspections at API

manufacturers in China (3), India (2), United States (1) and the United Kingdom (1).

Updating of the HMPC-Guideline on the use of the CTD Format in the Registration of

Traditional Herbal Medicinal Products

Compared to herbal medicinal products (HMPs) there is a simplified registration procedure for

traditional herbal medicinal products (THMP).

EMA's HMPC (Committee on Herbal Medicinal Products) published the draft of revision 2 on the use

of the CTD format in the preparation of a registration application for traditional herbal medicinal

products on 10 March 2015.

This guideline contains instructions on how to prepare a CTD for a registration application of

traditional herbal medicinal products.

Now, there is a new annex 2 with a mock-up which shows by means of a concrete example where

and to what extent information should be given on traditional herbal medicinal products in the

dossier.

Appendix 1 is a best practice guide for module 3 on quality. For further information please see the complete draft revision 2 of the "Guideline on the use of the

CTD format in the preparation of a registration application for traditional herbal medicinal products"

comprising more than 151 pages together with all annexes (!).

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WHO Technical Report - GMP for Biological Products Revision

The World Health Organization (WHO) provides a Technical Report Series on their website with

guidance documents comprising general recommendations for biological products.

The current document "Good Manufacturing Practices for biological products; Adopted 1991, TRS no

822, Annex 1" is now supposed to be revised. Thus the Expert Committee on Biological Products

published a proposed replacement of this document. This draft was developed based on the

outcomes and consensus of the WHO informal consultation convened

in July 2014 with participants from national regulatory authorities, national control laboratories, manu

facturers and academia researchers. It is furthermore supposed to include comments from the public

consultation on the WHO website. Additional comments can be submitted to the WHO until 14

September 2015.

The document is supposed to serve as a basis and reference/guide for the generation of

appropriate/suitable national guidelines. Possibly there will be modifications/changes necessary in

comparison with this document, based on a risk/benefit assessment and legal considerations of the

respective national authority.

The scope of this guidance document is defined as follows:

"These guidelines apply to the commercial manufacture, control and testing of biological products

from starting materials and preparations, including seed lots, cell banks and intermediates, through

to the finished products. Manufacturing procedures within the scope of these guidelines include:

growth of strains of microorganisms and eukaryotic cells

extraction of substances from biological tissues, including human, animal and plant tissues

and fungi

recombinant DNA (rDNA) techniques

hybridoma techniques and

propagation of microorganisms in embryos or animals"

The complete text and contact data for the submission of comments can be found at WHO GMP for Biological Products - Proposed replacement of: TRS 822, Annex 1.

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In a first, drug using 3D printing technology gets FDA nod

The U.S. Food and Drug Administration has, for the first time, approved a drug that uses 3D printing

technology, paving the way for potential customization of drugs to suit patients' needs.

The drug, made by privately held Aprecia Pharmaceuticals Co, was approved for oral use as a

prescription adjunctive therapy in the treatment of epilepsy, the company said on Monday.

Spritam uses Aprecia's "ZipDose" technology, a delivery system that creates premeasured doses

which disintegrate in the mouth with a sip of liquid.

3D printing could help companies make products "to the specifications of an individual patient rather

than (take a) one-size-fits-all kind of approach," Wedbush Securities analyst Tao Levy said.

3D printers help make products by layering material until a three-dimensional object is created.

In the healthcare industry, these printers are used by dentists to create replicas of jaws and teeth as

well as some finished dental implants and orthopedic surgeons have tested them to make

customized hip replacements. British scientists have also used 3D printing to create personalized replica models of cancerous

parts of the body to allow doctors to target tumors more precisely.

Indian government suspends EU trade talks over spat with GVK Biosciences

The Government of India will now defer EU trade negotiations as part of its effort to support

local CRO GVK Biosciences, which was accused of data manipulation by the EMA (European

Medicines Agency).

The proposal from India to defer the talks on Aug. 28 between the chief negotiators of India and the EU as part of the Broadbased Investment and Trade Agreement comes as the European Commission has officially banned the sale of more than 700 drugs tied to clinical trials run by GVK. The ban followed inspections by French regulators that revealed data manipulations of electrocardiograms (ECGs) during the conduct of some studies of generic medicines for more than five years, according to the EMA. In a statement, the Indian government said it‘s ―disappointed and concerned by the action of EU in imposing legally binding ban on the sale of around 700 pharma products clinically tested by GVK Biosciences, Hyderabad. The Government has engaged on the issue with various EU regulators over past 8 months.‖

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Although the government notice didn‘t address the data manipulations cited by the French regulators, it did point out: ―It is pertinent to mention that most of these drugs are already in EU market for many years without any adverse pharmacovigilance report from any member state.‖ EMA‘s Committee for Medicinal Products for Human Use (CHMP) previously said there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Biosciences at Hyderabad. Some of these medicines may remain on the market in some countries if they are of critical importance for patients because alternatives cannot meet patients‘ needs.

Parexel looks to accelerate margin growth with low-cost labor

CRO Parexel’s staffing numbers took center stage during its earnings call Thursday as the

company re-iterated plans to lay off as many as 850 employees – mostly in higher-cost

countries -- to increase its margins.

―What we're trying to accomplish with the Margin Acceleration Program is addressing from a payroll perspective, a reduction in managerial overhead,‖ COO Ingo Bank told investors. And although the company has already begun to investigate who will be laid off at one facility in North Carolina, Parexel actually added 3,100 employees over the course of the fiscal year, including the net addition of approximately 950 employees from the recent acquisition of India-based QSI . ―We have opportunities to organize ourselves more efficiently,‖ Bank explained, noting that the company is looking to accelerate ―the shift of activities into low cost countries, and that sometimes indeed means that you run for a little while with a sort of mirror organization to phase activities from one part of the world into another part of the world. And once that is done, you have the ability to reduce the personnel and then you benefit from the wage arbitration that you basically have by doing so.” Overall Market Beyond the margin acceleration program, company executives remained upbeat about where Parexel is headed.

―Our strategic partnerships are well on track and we have a promising pipeline of partnership

opportunities. Our BioPharm Unit is successfully addressing the market opportunity with small and

emerging biopharmas and we are well positioned to capitalize on emerging eClinical technology

trends,‖ CEO Josef von Rickenbach said.

Parexel is also seeing more diversity among its clients as its largest client represented approximately

12% of revenue, compared to 17% in the same quarter last year. The concentration of the top five

clients also declined by 3% to 44%.

And although he didn‘t get into the specifics, von Rickenbach noted that ―several important‖

countries have strengthened their regulatory requirements for study start-ups, which is creating ―a

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more challenging regulatory environment as well. In aggregate, this has caused an elongation of the

start-up stage.‖ Citi Research analyst Garen Sarafian still thinks Parexel will thrive in such a situation, noting:

"Despite lengthier start-ups, we think PRXL is well positioned to benefit from an increasingly

specialized trial market where we see regulatory expertise and a global footprint as key

differentiators. Although such complex trials take longer to convert into revenue, we believe the

increase in trials moving from the start-up phase to fully ramped over the course of the year will be

enough to drive the burn-rate higher."

Aurobindo gains FDA approval for alprazolam tablets

Aurobindo Pharma Limited on Tuesday received approval from the Food and Drug Administration for

its alprazolam tablets, a generic version of Xanax. The FDA approved Aurobindo‘s alprazolam

tablets in 0.25- 0.5-, 1- and 2-mg dosage strengths.

Alprazolam is used to treat anxiety disorders, panic disorders and anxiety caused by depression. As

a benzodiazepine, it slows down the movement of chemicals in the brain that may become

unbalanced, resulting in a reduction in nervous tension.

The product has an estimated market size of $102.7MM for the 12 months ending in June 2015,

according to IMS Health data.

Indian bio-pharma views US FDA’s dissolution test norms to a more simple process, ensuring

higher efficiency

Indian bio-pharma industry, which is now eyeing markets of the developed world with its range of

biosimilars and biopharmaceuticals, is now keen to ensure that the recent US FDA draft guidelines

on Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms

Containing Biopharmaceutics Classification System Class 1 and 3 drugs will be able to go through

the final stages of approval. The guidelines are viewed vital for the industry because it is seen to be

far more simpler to adopt and ensures higher efficiency.

Leading bio-pharma companies in the country including Biocon, Dr. Reddy‘s Labs, Intas among

others are eyeing to garner a fair share of the biosimilar pie in the US markets.

In this regard, the recent draft guidance is developed to provide manufacturers with

recommendations for submission of New Drug Applications (NDAs), Investigational New Drug

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Applications (INDs), and Abbreviated New Drug Applications (ANDAs), as appropriate for

immediate-release (IR) tablets and capsules that contain highly soluble drug substances.

The guidance also applies to solid orally-administered immediate release dosage forms, such as

tablets and capsules that are meant to be swallowed. It does not include chewable tablets, and does

not apply to orally disintegrating tablets.

The draft norms highlight the requirements for a standard release test. It also details the

requirements of drug absorption from a solid dosage form after oral administration. In addition, it also

addresses the dissolution of the drug under physiological conditions, and the permeation across the

gastrointestinal membrane.

The NDAs and ANDAs submitted to FDA contain bioavailability (BA) or bioequivalence (BE) data

and in vitro dissolution data that, together with chemistry, manufacturing, and controls (CMC) data,

characterize the quality and performance of the drug product. In vitro dissolution data are generally

obtained from batches that have been used in pivotal clinical and BA/BE studies. Knowledge about

the solubility, permeability, dissolution, and pharmacokinetics of a drug product is considered when

defining dissolution test specifications for the drug approval process, stated the regulator in its

guidelines.

The Biopharmaceutics Classification System (BCS) is a scientific framework for classifying drug

substances based on their aqueous solubility and intestinal permeability. The definitions of high and

low solubility and high and low permeability are used in the BCS guidance. The different

classifications are: Class 1: High Solubility - High Permeability Drugs, Class 2: Low Solubility - High

Permeability Drugs, Class 3: High Solubility - Low Permeability Drugs, Class 4: Low Solubility - Low

Permeability Drugs.

The classification can be used as a basis to determine when in-vivo BA and BE studies are needed.

The availability of these standards facilitate the rapid development of dissolution methodology and

related specifications for these classes during drug development and application review, according

to the regulatory authority.

According to Prema Desai, pharma consultant, the availability of these standards will facilitate the

rapid development of dissolution methodology and related specifications for these classes during

drug development and application review. For drug products in both BCS Classes 1 and 3, USP

disintegration testing can be used in lieu of the dissolution test if the product meets a dissolution

criterion which is Q=80 per cent in 15 minutes.

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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

Withdrawals 6 12 2 11 7 13 23 11 21

Approvals 45 28 29 25 27 19 49 47 57

Tentative Approvals 10 7 5 5 13 6 19 13 10

Complete Responses

(CR) +

43 76 96 104 108 94 115 97 116

Drug Master File

Completeness

Assessment (DMF CA)

124 55 71 92 86 55 76 62 65

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

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

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

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GDUFA YEAR/

(Receipts)Amendment

s

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-

15

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

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 43 21 11 11 10 9

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FY15) Unsolicited

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

GDUFA Post CR

Meeting Requests

++++

84 89 96 105 113 123 129 132 134

Post CR Meeting

Requests This

month

0 5 7 9 8 10 6 3 2

+ = 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.

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++ = 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

GSK closes North Carolina plant after Legionnaires' bacteria found

Drugmaker GlaxoSmithKline closed its North Carolina factory on Tuesday after testing at a cooling

tower found bacteria that causes deadly Legionnaire's disease, a company spokeswoman said.

The Legionella bacteria was discovered during routine inspections at the site in Zebulon, N.C., GSK

spokeswoman Jenni Brewer Ligday said.

GSK is a healthcare company that researches and develops pharmaceuticals, vaccines and

consumer healthcare products. The Zebulon site employs more than 4,400 manufacturing, research

and development, and sales and marketing staff, GSK said on its website.

The site will reopen when the situation is remedied, Ligday said. The tower is a stand-alone structure

that does not come in contact with any products, she said.

Ligday said 600 workers were sent home or told not to come in while the towers were being cleaned

and retested.

City and state officials said the discovery did not warrant a public health alert and that no threat was

posed to city drinking water but it was being tested as a precaution, according to a report in the

Charlotte News and Observer newspaper.

The bacteria is found naturally in warm water and thrives in environments such as hot tubs, cooling

towers, water tanks, large plumbing systems and fountains, according to the U.S. Centers for

Disease Control and Prevention.

Legionnaire's disease, a severe kind of pneumonia, is contracted by breathing in mist containing the

bacteria. It is not contagious, according to the CDC.

Last week, New York City's Department of Health ordered the inspection and cleaning of all cooling

towers in the city in response to an outbreak of Legionnaires' disease that has claimed 12 lives.

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Guidance for Entities Considering Whether To Register as Outsourcing Facilities

The Food and Drug Administration (FDA) is announcing the availability of a final guidance entitled

―Guidance for Entities Considering Whether to Register as Outsourcing Facilities Under Section

503B of the Federal Food, Drug, and Cosmetic Act.‖ This guidance is intended to inform entities that

are considering registering as outsourcing facilities under section 503B of the Federal Food, Drug,

and Cosmetic Act (the FD&C Act), as added by the Drug Quality and Security Act (DQSA), of the

regulatory implications of registration as an outsourcing facility.

FDA is announcing the availability of a final guidance for industry entitled ―Guidance for Entities

Considering Whether to Register as Outsourcing Facilities Under Section 503B of the Federal Food,

Drug, and Cosmetic Act.‖ On November 27, 2013, President Obama signed the DQSA (Pub. L.

113-54) into law. The DQSA added a new section 503B to the FD&C Act that created a category of

entities called ―outsourcing facilities.‖ Section 503B(d)(4) of the FD&C Act (21 U.S.C. 353b(d)(4))

defines an outsourcing facility, in part, as a facility that complies with all of the requirements of

section 503B, including registering with FDA as an outsourcing facility and paying associated fees.

If the conditions outlined in section 503B(a) of the FD&C Act are satisfied, a drug compounded by

or under the direct supervision of a licensed pharmacist in an outsourcing facility is exempt from

certain sections of the FD&C Act, including section 502(f)(1) (21 U.S.C. 352(f)(1)) (concerning the

labeling of drugs with adequate directions for use) and section 505 (21 U.S.C. 355) (concerning the

approval of human drug products under new drug applications (NDAs) or abbreviated new drug

applications (ANDAs)). Drugs compounded in outsourcing facilities are not exempt from the

requirements of section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)) (concerning current

good manufacturing practice for drugs).

FDA has received questions about whether entities engaged in various types of activities (e.g., a

facility that is compounding only non-sterile drugs or only repackaging biological products) should

register as an outsourcing facility. Because entities that register as outsourcing facilities must pay a

registration fee and FDA has determined that fees paid pursuant to sections 503B and 744K of the

FD&C Act will not be refunded, FDA is issuing this guidance to answer some of these questions and

to provide potential registrants additional information about the regulatory impact of registering as an

outsourcing facility.

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FDA Warning for Kim Kardashian

A Lesson in paid and un-paid user testimonials

It is a bit of a surprise to write about Kim Kardashian on a FDA regulatory blog. For clients it is often

equally surprising to discover the FDA monitors and enforces social media posts among other

mediums of marketing. If you are one of Mrs. Kardashian‘s 42 million followers on Instagram you‘ve

likely heard about her recent post to promote the morning sickness drug Diclegis. The Guardian

provided a full write-up on the Instagram post today.

The FDA sent a letter to the drug‘s maker requesting the Instagram post be removed and warning

statements on the risks associated with the drug be given. The FDA found the promotion ―false and

misleading‖ in large part because it omitted the risks of using the drug to treat morning sickness.

Yes, the FDA is holding the Duchesnay, Inc. the maker of Diclegis responsible for Mrs. Kardshian‘s

Instagram. There are a couple of reasons for this. First, the concept of ―label‖ and ―labeling‖ is

incredibly broad. Previous posts discussed how the concept expands beyond the product packaging

to social media, SEO, and customer testimonials. The test developed under case law is whether an

item ―supplements‖ or ―explains‖ a FDA regulated product. If it does, then it is a ―label‖ or ―labeling‖

subject to the misbranding provisions of the Food Drug and Cosmetic Act. Kim Kardashian‘s post

could be viewed as any other customer testimonial, but typically those testimonials that are included

in a company‘s social media page. Instead it appears Duchesnay paid Mrs. Kardashian to post the

endorsement to her legions of followers. This may be the more likely trigger for the FDA response.

Drug marketing is closely regulated. In particular the need for prescription drugs to list side effects. It

was not enough for the Instagram post to include a link to the safety information, the full side effects

were not disclosed.

Whether your using customer testimonials or celebrity endorsements always review the regulations.

This applies to medical devices, drugs, supplements, foods, and cosmetics.

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Delhi government bans over the counter sale of NSAIDS without prescription

Delhi government today banned over-the-counter sale of non-steroidal anti-inflammatory drugs

( NSAIDs) like Aspirin, Dispirin, Brufen, Voveran, without medical prescription as the use of these

may pose a threat to dengue patients, Health Minister Satyender Jain said.

"NSAIDs drugs (Aspirin, Dispirin, Brufen, Voveran, etc.) will be banned for over-the-counter (OTC)

sale by chemists. It will be sold only on the basis of prescription by a qualified doctor," Jain said.

According to senior officials, during this season cases of Dengue are on the rise and drugs

like Aspirin and Ibuprofen further cause destruction of platelets in human blood.

These drugs may add to the haemorrhage symptoms and can cause death in dengue patients,

official said.

Health department will take action against any retail chemist found flouting this advice.

"Chemists have also been advised to keep the records of stocks of such pain-killer drugs like Aspirin,

Ibuprofen and Diclofenac group of medicines. Stringent action will be taken if anyone is found selling

medicine without prescription," official said.

Health department has also directed all hospitals in the city to procure NS1 Antigen detection kits

and also arrange for adequate number of beds during the peak dengue season.

In a bid to spread awareness, schoolchildren will be told about the life cycle of the Aedes mosquito,

which transmits dengue, and be engaged in dengue-control activities.

Health department has also asked for pictorial pamphlets to be prepared containing Dos and Don'ts,

including symptoms described in easily understandable terms, mode of transmission, habits and

habitats of mosquitoes.

In order to make people aware about seasonal diseases and not to take certain medicines,

Government of Delhi, through the Drugs Control Department, has issued an advisory in public

interest.

India woos Italian bulk drug makers to cut dependency on Chinese APIs

The government is looking to promote domestic pharma companies' tieups with bulk drug makers in

Italy to cut dependence on China for pharmaceutical ingredients.

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India sources over 70 per cent of its requirement of bulk drugs (ingredients) from Chinese

pharmaceutical companies.

A senior commerce ministry official said the government, which will unveil a new bulk drug policy

soon, is preparing schemes aimed at wooing Italian drug makers with attractive incentives as a part

of its 'Make in India' initiative.

"The ministry is asking Italian drug makers to forge alliances with Indian pharmaceutical firms to set

up joint ventures in India," PV Appaji, director general of Pharmaceuticals Export Promotion

Council (Pharmexcil), told ET. "The move is primarily aimed at reducing the dependence on China,

even while encouraging domestic pharmaceutical firms towards backward integration that ensures

greater cost efficiencies and quality control."

Appaji said the proposed new bulk drugs policy is being given final touches to include attractive

incentives to lure global bulk drug manufacturers in general, and Italian firms in particular, given their

technological strength in manufacture of crucial bulk drugs for life-saving medicines.

At present, India depends largely on China for common essential bulk drugs such as

Paracetamol, Metformin, Pen-G, 6-APA, Aspirin, Erythromycin Thiocinate, Sartans, Ofloxacin,

Levofloxacin and Vitamin C for intermediates, and Metronidazole, Vitamin C, Ofloxacin and

Levofloxacin for active pharmaceutical ingredients (APIs). While India produced about $10 billion

worth of APIs last year, its export of APIs remained flat at $3.6 billion. As against this, the

subcontinent imports around $3.5 billion worth of APIs every year, mostly from China.

The top 100 Indian medicine manufacturers depend on China for at least half of their API

requirement, and at least 150 medicines classified under the National List of Essential Medicines

(NLEM) depend on Chinese imported bulk drugs.

Italy is the world's third largest API producer with about $4 billion and exports more than three

fourths of its production, mostly to the US market. Among the prominent Italian API producers are

FIS (Fabbrica Italiana sintetici), Angelini Pharmaceuticals and Trifarma.

According to Pharmexcil's director general, since some Italian firms have shown interest in forging

alliances with Indian drugmakers, the commerce ministry plans to hold another dialogue with Italian

drug makers in October.

Increased cost of production and other European economy related constraints had led to several

local drug makers shutting down their unviable units.

"Technology transfer agreements from Italian drug makers is also being actively pursued," Appaji

said. Jayant Tagore, president of India's Bulk Drug Manufacturers' Association (BDMA), said

overdependence on a few suppliers for key bulk drugs is turning alarming. The factors working

against domestic bulk drug makers include fragmented capacities, high cost of land and power,

absence of adequate incentives and reservation of certain products for the small scale industry, he

said.

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Chinese plant banned by EU, getting compliance help from NJ company

Italian regulators came down hard recently on Chinese drugmaker Jinan Jida after an inspection

found issues that led the European Directorate for the Quality of Medicines (EDQM) to suspend its

certificate of suitability for the antibiotic nitrofurantoin. But the company is responding quickly, having

turned to a U.S. company to help it fix its problems and regain its place in the E.U. API market.

The API maker has hired New Jersey-based ChemWerth to help it get its processes up to E.U. standards and hopes to reapply for its certificate within a year. ChemWerth is a generic API development and supply specialist that also offers regulatory support. The two already had a business relationship and extended that to include its nitrofurantoin manufacturing. "We are pleased to announce Jinan Jinda has entered into a 5-year service agreement with ChemWerth with the goal being to correct Jinda's quality system and GMP compliance conditions," Cheng Yushui, general manager of the Shandong-based company, said in a statement. "Our commitment to be a qualified supplier for the E.U. and U.S. regulatory markets has never changed." The suspension was recommended to the European Directorate for the Quality of Medicines by Italian inspectors, who recorded 18 deficiencies at the plant, one which was classified as critical and 6 as major. They were most concerned about raw supplies and finished products they discovered behind a barred door. Inspectors "concluded there was a serious risk of data falsification" related to the ingredients in room, the door of which had been screwed shut by employees, and the possibility that the company was not being forthright about the data for them. In June the EDQM banned a number of the sterile products made by China's Zhuhai United Laboratories after inspectors from Romania uncovered shortcomings in the company's aseptic manufacturing in a plant in Guangdong, China.

USP Strengthens Relationship with China to Improve Quality of Medicines and Food

Many of the drug ingredients used in generic medicines around the world are produced in China, and the Chinese government has consistently expressed a desire to help promote quality medicines for the Chinese people as well as for the world at large, which impacts public health at a global level. In fact, according to the U.S. Food and Drug Administration (FDA), as much as 80 percent of active pharmaceutical ingredients (APIs) in drugs marketed in the United States (U.S.) come from other countries, primarily India and China. In recent years, there is also a trend that indicates more and more Chinese companies are exporting drug products to the U.S. market. Not only are more pharmaceutical ingredients in medicines exported from China today, but food ingredients from this country are also prominent in the U.S. market. USP-China is working collaboratively with China‘s local governments and other key stakeholders to advance the quality of medicines and food in China and globally. Meeting National Leaders

On August 6, USP-China was fortunate to have Dr. Ron Piervincenzi and Dr. Koduru Surendra Nath meet with Mr. Zheng Han, one of the top 25 leaders in China. Mr. Han is a member of the

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Political Bureau of CPC Central Committee and Party Secretary of Shanghai. He also accompanied Premier Li on his visit to USP-China in September 2014. Several topics were covered in the meeting with Mr. Han: the benefits of the Free Trade Zone (FTZ) policies to foreign organizations like USP, standards-setting activities for herbal medicines and drugs, government efforts in promoting innovation and R&D, and food quality and global impact. Dr. Piervincenzi talked about our USP-China‘s new Global Center of Excellence for Food and related initiatives. USP is the publisher of the Food Chemicals Codex (FCC) and currently all R&D work in FCC food ingredients is centered in USP-China laboratories. However, USP-China wants to do more and because one of the Chinese government‘s priority is food safety, we hosted discussions on the possibility of future projects in capacity building, training in international standards, joint research projects as well as the use of vulnerability assessments for food fraud, an area where USP has made significant progress in the past two years. Mr. Han highly praised USP‘s efforts in food and drug standards-setting activities and showed great interest in our work in the herbal medicines area. At the end of the meeting, Mr. Han presented a silk book, The Art of War by Sun Tzu, while Dr. Piervincenzi gave him the Chinese translated edition of the Food Chemicals Codex. Meeting with Wei Zhang (ChP)

On the same day, the USP-China site hosted a meeting with Mr. Wei Zhang, Secretary General of the Chinese Pharmacopoeia Commission (ChP). ChP is a member of the USP Convention. Dr. Piervincenzi and Mr. Zhang(pictured together at right) held a USP-ChP summit to exchange ideas on bilateral collaboration and future action plans. As a key outcome, USP will closely collaborate with ChP to support the upcoming 6th WHO World Pharmacopeias Meeting and ChP Annual Scientific Conference in Suzhou in September 2015. Meetings with Chinese Media

The week‘s activities ended with a full media event and a wonderful opportunity to establish USP-China as a prominent player in the region. USP-China hosted a media event organized by the Ministry of Commerce. Key state media, such as People‘s Daily, China Daily, Xinhua News Agency, China Business News TV, andInternational Business Journal were present to ask questions about USP and USP-China. Dr. Koduru Surendra Nath, Stephen Gardner, Diana Zhang and I answered their questions. USP-China has doubled its project output in the food and drug standards in the two years since moving to FTZ and has laid a solid foundation in Shanghai, with potential of collaborations all over China. The media were impressed by USP-China‘s achievements. They were also interested in how USP could help China‘s manufacturers increase their exports globally. I sincerely hope that USP-China continues to grow and play an important role in China‘s food and medicines quality. As USP approaches its 200th anniversary as a standards-setting organization, I‘m very confident that USP-China will increase its activities to meet our stakeholders‘ expectations.

Source: http://qualitymatters.usp.org/usp-strengthens-relationship-china-improve-quality-medicines-

and-food

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The British Pharmacopoeia's new website - setting the standards

The launch of the new integrated British Pharmacopoeia website this week presents a great

opportunity to explore this other group within the Inspection, Enforcement & Standards Division of

MHRA.

The British Pharmacopoeia (BP) makes an important contribution to the role of MHRA in protecting

public health by providing authoritative quality standards for UK pharmaceutical substances and

medicinal products. Celebrating its 150th anniversary last year, the British Pharmacopoeia &

Laboratory Services group has been establishing standards since 1864 and continues to play an

important role in the standard-setting process worldwide. Now used in over 100 countries, the BP

remains an essential reference for all individuals and organisations working within pharmaceutical

research and development, manufacture and testing around the globe.

New integrated website Just this week the new website has been launched bringing together the online BP publication, the

British Pharmacopoeia Chemical Reference Substances (BPCRS) catalogue and sales making it

easier for users to find what they need quickly and easily. As it is smartphone and tablet compatible

the new site is easier to use whether you are in the office, at the lab bench or on the go.

BP, BP (Vet), European Pharmacopoeia (Ph. Eur.) and updated Ph. Eur. texts are highlighted with

different colours so that it is easy to see the source of the text and whether it has been updated

through the Ph. Eur. in-year supplements. New improved functionality means that users can easily

add BPCRS to their shopping carts or view draft and revised monographs or example test results

related to a monograph by simply switching tabs. There is also a new timeline feature allowing users

to quickly jump between different publications and updates of a monograph or text.

For more information:

https://www.youtube.com/watch?v=dTUgiC5pF3I & https://www.pharmacopoeia.com/

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Pfizer Receives FTC Clearance for Hospira Acquisition

Pfizer announced on Aug. 24, 2015 that the US Federal Trade Commission terminated the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended, with respect to Pfizer‘s pending acquisition of Hospira, contingent upon Pfizer‘s commitment to divest four US sterile injectable assets, including acetylcysteine, clindamycin, voriconazole, and melphalan. Pfizer also announced that Brazil‘s Superintendency-General of CADE has published its unconditional clearance decision. In a press statement, Pfizer reported an anticipated transaction close in early September. Industry Responds to FDA Metrics Program

After nearly three years of workshops, white papers, and pilot tests, one might expect some

agreement between FDA and manufacturers of drugs and biologics on how to measure the quality

and reliability of production systems and resulting products. A draft Request for Quality

Metrics guidance published July 28, 2015 by the Center for Drug Evaluation and Research (CDER)

and Center for Biologics Evaluation and Research (CBER) outlines an initial set of metrics that the

regulators believe will help field inspectors assess the ability of an operation to produce high quality

medicines on a reliable basis.

But industry‘s initial response, as presented at an FDA public meeting held August 24, 2015, is that

the timeframe for reporting and specific data requests are ―not reasonable,‖ said David Gaugh,

senior vice-president of the Generic Pharmaceutical Association (GPhA). Genentech Vice-President

Diane Hagerty, representing the International Society for Pharmaceutical Engineering (ISPE),

advised FDA to ―start small, learn, and evolve‖ the metrics program. Manufacturers want FDA to

phase in the initiative, starting with higher-risk facilities and products, and to defer reporting on APIs

until later. Both FDA and industry need to understand the volume of data involved and how FDA will

use that information before specifics become final.

Furthermore, Camille Jackson of the Pharmaceutical Research and Manufacturers of America

(PhRMA) questioned whether FDA‘s use of guidance, as opposed to more formal notice-and-

comment rulemaking, provides sufficient authority for the agency to require metrics reporting in

advance of inspections, while Gaugh similarly speculated if FDA can require metrics reporting by

foreign companies; if not, that could encourage firms to shift drug production overseas.

Excipient makers objected to the idea of collecting metrics on ―high-risk‖ excipients, while API

makers raised a host of questions about how they could provide measures on products made for

multiple drug companies. Non-prescription drug firms want to limit initial metrics to high-risk

medicines, as opposed to hand creams. And contract manufacturers voiced a range of concerns

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about what was a ―reporting establishment‖ and how CMOs could report metrics on a facility making

drugs for multiple clients.

Richard Johnson, president of the Parenteral Drug Association (PDA), seemed more optimistic that

the FDA proposal is ―a good place to start,‖ and that regulatory relief in inspections and post-

approval changes are ―key to driving this program.‖ Johnson also cited challenges in assessing the

―quality culture‖ at companies and contradicted others on the basic issue of whether FDA should

collect quality metrics by establishment for products or for products by establishment.

FDA officials were disappointed by all the objections and acknowledged that it needs to clarify

definitions, how data will be used, and reporting relationships. The main aim of the program is to

assist FDA in inspection scheduling and in efforts to avoid supply disruptions, and issuing final

guidance ―is a high priority,‖ said Russell Wesdyk, acting director of the Office of Surveillance in the

Office of Pharmaceutical Quality. FDA wants to minimize the reporting burden of the program and

won‘t use metrics data in isolation to make regulatory decisions, he said, adding that a final guidance

will not appear this year.

Good Manufacturing Practice (GMP) data integrity: a new look at an old topic, part 3

Data integrity is fundamental in a pharmaceutical quality system which ensures that medicines are of

the required quality. A robust data governance approach will ensure that data is complete, consistent

and accurate, irrespective of the format in which data is generated, used or retained.

This is the last in a series of 3 blogs exploring the impact of organisational behaviour and procedures

on reliable, consistent and accurate data in medicines manufacture. The first blog looked at the

impact of organisational behaviour and the second blog discussed ways in which systems can be

designed to assure data quality and integrity.

The final blog in this series will look at the recurring problem of ‗trial analysis‘, and ways in which

organisations within the supply chain can take steps to build confidence and reliance on each other‘s

data.

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Data governance is an integral part of the pharmaceutical quality system

Trial (injections) and error

The use of ‗trial injections‘ in chromatographic tests to verify stability of the analytical set-up is a

recurrent theme reported as grounds for regulatory action. This practice is particularly concerning

where the ‗trial injection‘ is a product sample, whose results are then discarded or retained under a

different file structure to other results. In these circumstances, data integrity is undermined,

particularly if the result obtained from the trial injection failed to comply with specification. At the very

least it asks serious questions regarding analyst understanding of data integrity, quality system

design or managerial response to undesirable results.

In cases where analyses run over an extended period, it may be understandable that the analyst

would wish to verify that the analytical system is operating as expected before committing the full

system suitability and sample set. Where there is management agreement that verification of

analytical system stability is required prior to system suitability checks, there are some basic

considerations which can address the data integrity concerns.

The practice needs to be consistent with the company‘s data governance system. The system

stability check must be proceduralised as part of the approved method or standard operating

procedure (SOP), with corresponding guidance on the assessment of the results, and all data

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(including system stability check samples) should be reported. Importantly, a sample of the product

batch under test should not be used for the system stability check. An independent, well-

characterised sample or standard will fulfil the analytical requirement without raising data integrity

concerns relating to ‗testing into compliance‘. A robust laboratory data governance approach will also

include periodic reconciliation of analytical sample runs, to confirm that there are no concealed trial

injections or modified sample runs.

Supply chain

In the first blog of this series I described how omitting one aspect of the data lifecycle weakens the

effectiveness of other governance measures. The same principle applies to the supply chain. A

failure at one site weakens all sites downstream in the chain.

To keep the supply chain moving, organisations need to place reliance on summary reports – batch

records, analytical data, validation reports etc, especially in relation to outsourced services. It is

therefore important to use supplier audits as an opportunity to build confidence in these summaries

provided on a routine basis. What is the contractors organisational culture and maturity relating to

data governance? What systems do they have to ensure data integrity?

Conclusion

Data governance is an integral part of the pharmaceutical quality system, with effort and resource

being balanced in accordance with other risks to product quality. As such, manufacturers and

analytical laboratories are not expected to implement a forensic approach to data checking on a

routine basis, but instead design and operate a system which provides an acceptable state of control

based on data criticality and inherent risk.

Data integrity requirements apply equally to manual (paper) and electronic data. Reverting from

computerised to paper-based systems will not in itself remove the need for data integrity controls.

The implementation of effective behavioural, procedural and technical steps based on a clear

understanding of risk will ensure that the system will encourage the right behaviours, improve

compliance, and provide greater assurance of product quality.

Number of samples in PQ/validation of a fully automated 100% visual inspection system As a rule, in the PQ and even more so in the validation, the batch size typical of the future routine

production are expected. But does it make sense to compare the detection rates of humans and

machines based on complete batches with 20,000 vials, for example?

In the PQ/ validation of the system, the human-machine comparison is made by repeatedly testing

the Qualification Test Sets. This is a product-specific test set that contains the approximately 20%

defects that can occur in the real process. The ECA Best Practice Guide recommends a minimum of

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10 repetitions of the test. For additional security, parts of a validation batch can be inspected as well,

for example, 5000 units. It is also possible to combine samples from the three validation batches for

a total of 5000 units. However, this mixes up the batches and afterwards, the inspectetd units may

not be returned to their batches if they are intended for the market.

As part of revalidation, the 5000-unit test can be repeated regularly.

Drug testing labs at Rajasthan to recruit staff towards ensuring drug quality

The three drug testing laboratories at Udaipur, Jodhpur and Bikaner in Rajasthan established

recently are now in the process of recruiting highly skilled manpower required for the job. As per the

requirement, 12 lab personnel will be recruited for the purpose. Having a budget allocation of Rs. 18

crore, the labs will also be equipped with the state-of-the-art testing technologies and methods.

Currently, there is only one drug testing laboratory in the state which is located at Jaipur.With the

coming up of three state drug testing labs in Rajasthan, testing would be done in a mere 15 days

time and the capacity would gradually increase over a period of time. The enhancement in the

capacities will reduce the downtime significantly.

At present, the drug testing lab at Jaipur gets around 500 samples and testing of samples takes one

month to three months time.

According to a state drug control official, "The task of upgrading infrastructure will also entail

recruiting skilled technical personnel for the same. A request has been sent to the Rajasthan Public

Service Commission on the same." Around 60,000 brands of drugs are available in the market and

drug samples are collected based on the random survey. There are 60 drug control officers in the

state. There are around 20,000 retail establishments and 16,000 drug distribution counters in

government hospitals across the state which are closely monitored by the state drug regulators.

Rajasthan has a total of 17,298 healthcare institutions including primary health centres (PHCs),

community health centres (CHCs), sub centres and government hospitals. The state has also been

providing free medicines under the Rajasthan Free Drug Distribution Scheme since its launch on

October 2, 2011 through Rajasthan Medical Services Corporation (RMSC). The scheme has been

able to address issues like insufficient supply of drugs at several places and shortage of doctors,

para-medical staff and pharmacists mainly at the primary health centres in remote villages.

The scheme aims to provide essential medicines free to anyone walking into a government-run

health institute. RMSC, formed to implement the scheme and steer the state towards a Right to

Health, cites studies to point out that expenditure on medicines accounts for about 50 to 80 per cent

of the total cost of treatment in India. As per the WHO, 65 per cent of the Indian population lacks

regular access to essential medicines.

Officials say that since the scheme started, there has been a substantial increase in the number of

girl children in the state (from 921 in 2001 to 928 in 2011, with the rise in urban areas being 890 to

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914). They are even hopeful of the state‘s sex ratio improving drastically as a result. At least 17 state

governments and several countries including Nepal and Canada have also expressed interest in

replicating it.

India taking legal advice on EU's medicine ban: Commerce Secretary Rita Teaotia

India is seeking "legal advice" to deal with the recent ban imposed by the European Union on 700

medicines which were clinically tested by GVK Biosciences, a top official said.

"We are certainly exploring what are the options for India. We are taking legal advice... We will take

a call on this to move forward," Commerce Secretary Rita Teaotia told.

The largest EU-wide suspension of sales and distribution of generic drugs ordered by the European

Commission has already come into effect and will be applicable to all 28 member nations, according

to Germany's drug regulator, the Federal Institute for Medicines and Medical Products (BfArM).

Peeved at the move, India has already deferred talks with the European Union on the proposed free

trade agreement.

India-EU trade talks, which were launched in June 2007, remain stuck as both sides are not satisfied

with each other's offers.

Teaotia added that India also has the option to use global framework to resolve the issue.

The European Union has banned the marketing of around 700 generic medicines for alleged

manipulation of clinical trials conducted by the Hyderabad-based GVK Biosciences.

Industry body Pharmexcil pegs India's business loss from the EU ban at around $1.2 billion. The

pharmaceutical sector, which contributes over $20 billion in India, is facing a lot of regulatory issues

in several developed countries, including the US.

In 2014-15, India's pharmaceuticals exports grew 2.63 per cent to $15.34 billion.

Glenmark expecting USFDA nod for 4-6 products this fiscal

Glenmark Pharmaceuticals is expecting approvals for four to six new products during the fiscal from the US Food and Drug Administration (USFDA), a senior official said today. "We are expecting approvals for 4-6 products from the USFDA during this year," Glenmark Pharmaceuticals President and Head-India Business Sujesh Vasudevan told reporters here on the sidelines of launch of Teneligliptin in Telangana. The company had already got approvals for eight products this year, he added.

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Teneligliptin, a new third generation oral anti-diabetic agent, is used for the management of Type 2 Diabetes Mellitus.

Glenmark has launched this molecule under two brands, Ziten and Zita Plus, at Rs 19.90 per tablet. "... the launch of these two products will lower the daily cost of treatment for a diabetes patient on Gliptin therapy by approximately 55 per cent," Vasudevan said. Glenmark's diabetes segment is valued at around Rs 100 crore, Vasudevan said, adding it is growing at 20 per cent per annum.

Reacting to a query, he said, "The capex for this year is Rs 600 crore and majority of this will go for the plant in the US."

The ‘Unique Identifier’ in the EU Delegated Act

The European Commission published a discussion draft of the European Union Delegated

Act (EUDA) about two weeks ago (See ―Breaking News: The EC Has Published The Delegated

Act―). The EUDA was called for in the Falsified Medicines Directive (FMD) back in 2011 and is

primarily intended to define the ―safety features‖ that must appear on most drugs three years after it

is finalized. Assuming it gets finalized around the end of 2015, that means that manufacturers and

repackagers targeting the European pharmaceutical market will need to begin placing the specified

safety features on their drug packages near the end of 2018. EU Member States who already have

an operational drug tracing law, like Italy and a few others, get an additional six years for companies

to switch to the FMD and EUDA on drugs distributed there.

There are a lot of details about the operation of the drug tracing solution in the EUDA document. I

hope to cover different parts of it over several RxTrace essays. Be aware that we are referring to a

discussion draft, not the final version, so some things could change between now and then. I suspect

that the kind of things that will change are going to be minor so I feel comfortable discussing the

larger topics. However, if anything I write does end up changing, I will make the change retroactively

in that essay and I will also write a new essay about the change since it would probably be

significant.

This essay is about the ―unique identifier‖, which is one of two safety features that the EUDA

mandates. According to the text, a ―unique identifier‖ is a code consisting of:

The product code

This is ―a code allowing the identification of at least the name, the common name, the

pharmaceutical form, the strength, the package size and the package type of the medicinal product

bearing the unique identifier.‖ The EUDA does not say anything about GS1, but it appears clear that

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a GS1 Global Trade Item Number(GTIN) will be accepted as a valid product code, although it also

appears that it is not the only code that will be accepted;

A serial number

This is ―a numeric or alphanumeric sequence of maximum 20 characters, generated by a

deterministic or a non-deterministic randomization algorithm.‖ The definition appears to conform to

GS1‘s serial number that is associated with a GTIN. The randomization requirement goes beyond

GS1‘s specification but does not cause any conflict with it. Adding some clarification to the

randomization requirement, the text says that ―The probability that the serial number can be guessed

shall be negligible and in any case lower than one in ten thousand.‖ (For more on randomization of

GS1 serial numbers, see the five-part series starting with ―Randomization—An Interview with Ken

Traub—Part 1: GS1 Serial Number Considerations‖.);

A national reimbursement number

This is any number that an EU Member State where the product is intended to be placed on the

market may require. So far only a handful of Member States have their own national reimbursement

numbers. For drugs marketed in Member States that do not have their own, this data element will not

be present. Also, ―Where the national reimbursement number or other national number identifying

the medicinal product is contained in the product code, it is not required to be repeated within the

unique identifier.‖;

The batch number

This is sometimes referred to elsewhere as the ―Lot Number‖;

The expiry date.

Oddly, the EUDA does not require the batch number or the expiry date to appear on packages in

human readable form. If this is really true then it is one way to get around the problem of formatting

the date in a standard way (for more on human readable date formatting, see ―What The UDI Date

Format Says About FDA‘s Direction‖). According to the EUDA, only the product code, serial number

and national reimbursement number must appear in human readable form, subject to the size of the

package.

For the machine readable form, this unique identifier must be encoded in a Data Matrix

ECC200 barcode. The EUDA specifically allows companies to encode additional data within this

same barcode, where permitted. And importantly, the regulation does not allow ―…any other visible

PHARMA UPTODAY

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two-dimensional barcode [except] the two-dimensional barcode carrying the unique identifier for the

purpose of their identification and verification of their authenticity.‖

The second safety feature that must be on all drug packages is an anti-tampering device. No

additional details are provided about these devices in the text.

New fees calculator for initial marketing authorisation applications

Fees calculator to help companies calculate the fees for an initial application for a marketing

authorisation.

MHRA has developed a fees calculator to help companies calculate the fees they will be charged

when making an initial application for a marketing authorisation.

Many licence applications are invalidated because the correct fee has not been paid. This new

calculator will help companies avoid this problem.

More details on fee calculator : https://www.gov.uk/guidance/apply-for-a-licence-to-market-a-

medicine-in-the-uk#fees-calculator

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Terminology

CLEAN AREA

An area with defined environmental control of particulate and microbial contamination, constructed and

used in such a way as to reduce the introduction, generation and retention of contaminants within the

area.

Note The different degrees of environmental control are defined in the Supplementary Guidelines for

the Manufacture of sterile medicinal products.

CLEAN/CONTAINED AREA

An area constructed and operated in such a manner that will achieve the aims of both a clean area

and a contained area at the same time.

CONTAINED AREA

An area constructed and operated in such a manner (and equipped with appropriate air handling and

filtration) so as to prevent contamination of the external environment by biological agents from within

the area.

.

CONTROLLED AREA

An area constructed and operated in such a manner that some attempt is made to control the

introduction of potential contamination (an air supply approximating to grade D may be appropriate),

and the consequences of accidental release of living organisms. The level of control exercised should

reflect the nature of the organism employed in the process. At a minimum, the area should be

maintained at a pressure negative to the immediate external environment and allow for the efficient

removal of small quantities of airborne contaminants.

AIR-LOCK

An enclosed space with two or more doors, and which is interposed between two or more rooms, e.g.

of differing class of cleanliness, for the purpose of controlling the air-flow between those rooms when

they need to be entered. An air-lock is designed for and used by either people or goods.

PHARMA UPTODAY

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New Guidance Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage

Forms Containing Biopharmaceutics Classification System Class 1 and 3 Drugs Guidance for

Industry

This guidance is developed to provide manufacturers with recommendations for submission of new

drug applications (NDAs), investigational new drug applications (INDs), and/or abbreviated new drug

applications (ANDAs), as appropriate, for immediate-release (IR) tablets and capsules that contain

highly soluble drug substances. The guidance is intended to describe when a standard release test

and criteria may be used in lieu of extensive method development and specification-setting

exercises. When final, this guidance will supersede the guidance for industry on Dissolution Testing

of Immediate Release Solid Oral Dosage Forms (August 1997) for biopharmaceutics classification

system (BCS) class 1 and 3 drug substances in immediate-release drug products that meet the

criteria in this guidance. For class 2 and 4 drug substances, applicants should still refer to the August

1997 guidance mentioned above.

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

s/UCM456594.pdf

Fees for Human Drug Compounding Outsourcing Facilities Under Sections 503B and 744K of

the FD&C Act Guidance for Industry

This guidance is intended for entities that compound human drugs and elect to register as

outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act),

which was added by the Drug Quality and Security Act (DQSA). Once an entity has elected to

register as an outsourcing facility, it must pay certain fees to be registered as an outsourcing facility.

This guidance describes the types and amounts of fees that outsourcing facilities must pay, the

adjustments to fees required by law, how outsourcing facilities can submit payment to FDA, the

consequences of outsourcing facilities‘ failure to pay fees, and how an outsourcing facility can qualify

as a small business to obtain a reduction in fees. FDA has issued separate guidances on registration

and reporting requirements for outsourcing facilities.

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

s/UCM391102.pdf

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Over-the-Counter Pediatric Oral Liquid Drug Products Containing Acetaminophen: Guidance

for Industry

This guidance is intended to help drug manufacturers, packagers, and labelers minimize the risk to

consumers of acetaminophen-related liver damage associated with the use of nonprescription also

known as over-the-counter or OTCpediatric oral liquid acetaminophen drug products. Many of these

products are marketed under the OTC conditions stated in FDA‘s Tentative Final Monograph for

Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for OTC Human Use (the IAAA

TFM).

FDA plans to address portions of the tentative final monograph through the notice and comment

rulemaking process. In the meantime, however, to encourage safer use of these products, we are

providing recommendations regarding acetaminophen concentration, container labels, carton

labeling, and packaging of such products as well as for any associated delivery devices. FDA‘s

recommendations are designed to encourage safer use of these products by minimizing the potential

for acetaminophen overdosing due to medication errors or accidental ingestion. Unless otherwise

specified, these recommendations apply to both single-ingredient and combination-ingredient OTC

oral liquid drug products (such as suspensions, solutions, elixirs, and syrups) that are labeled for use

in children under 12 years of age and contain acetaminophen. This guidance does not address OTC

acetaminophen oral liquid drug products for use in both children and adults or for adults only.

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

s/UCM417568.pdf

Brief Summary and Adequate Directions for Use: Disclosing Risk Information in Consumer-

Directed Print Advertisements and Promotional Labeling for Prescription Drugs Guidance for

Industry

This revised draft guidance provides recommendations on the disclosure of risk information in

prescription drug product advertisements and promotional labeling in print media directed toward

consumers with respect to the brief summary requirement and the requirement that adequate

directions for use be included with promotional labeling.2 The recommendations describe an

alternative disclosure approach that FDA refers to as a consumer brief summary.

This revised draft guidance does not focus on the presentation of risk information in the main body of

promotional labeling or advertisements and does not apply to promotional materials directed toward

health care professionals.

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

s/UCM069984.pdf

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ICH guideline Q7 on good manufacturing practice for active pharmaceutical ingredients –

questions and answers

Since the ICH Q7 guidance was finalized, experience with implementing the guidance worldwide has

given rise to requests for clarification of uncertainties due to the interpretation of certain sections.

This Question and Answer (Q&A) document is intended to respond to those requests.

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

00191492.pdf

Q3C (R6): Impurities: guideline for residual solvents

The proposed guideline will replace 'ICH Q3C (R5) Guideline to include a PDE for triethylamine and

revise the PDE of methylisobutylketone due to new toxicity data

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

500191491.pdf

Guideline for good clinical practice E6(R2)

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

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

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

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

Helsinki, and that the clinical trial data are credible.

The objective of this ICH GCP Guideline is to provide a unified standard for the European Union

(EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the

regulatory authorities in these jurisdictions.

The guideline was developed with consideration of the current good clinical practices of the

European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic

countries and the World Health Organization (WHO).

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

00191488.pdf

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Application of the principles of the ICH M7 guideline to calculation of compound-specific

acceptable intakes

The ICH M7 guideline discusses the derivation of acceptable intakes for mutagenic impurities with

positive carcinogenicity data, (section 7.2.1) and states: ―Compound-specific risk assessments to

derive acceptable intakes should be applied instead of the TTC-based [Threshold of Toxicological

Concern-based] acceptable intakes where sufficient carcinogenicity data exist. For a known

mutagenic carcinogen, a compound-specific acceptable intake can be calculated based on

carcinogenic potency and linear extrapolation as a default approach. Alternatively, other established

risk assessment practices such as those used by international regulatory bodies may be applied

either to calculate acceptable intakes or to use already existing values published by regulatory

authorities.‖

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

00191489.pdf

Qualification of Biomarker Total Kidney Volume in Studies for Treatment of Autosomal

Dominant Polycystic Kidney Disease Draft Guidance for Industry

This draft guidance provides a qualified context of use (COU) for the biomarker TKV in studies for

the treatment of autosomal dominant polycystic kidney disease (ADPKD). This draft guidance also

describes the experimental conditions and constraints for which this biomarker is qualified through

the CDER Biomarker Qualification Program. This biomarker can be used by drug developers for the

qualified COU in submissions of investigational new drug applications (INDs), new drug applications

(NDAs), and biologics license applications (BLAs) without the relevant CDER review group

reconsidering and reconfirming the suitability of the biomarker.

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

s/UCM458483.pdf

Botanical Drug Development: Guidance for Industry

This guidance describes the Center for Drug Evaluation and Research‘s (CDER‘s) current thinking on appropriate development plans for botanical drugs to be submitted in new drug applications (NDAs) and specific recommendations on submitting investigational new drug applications (INDs) in support of future NDA submissions for botanical drugs. In addition, this guidance provides general information on the over-the-counter (OTC) drug monograph system for botanical drugs. Although this guidance does not intend to provide recommendations specific to botanical drugs to be marketed under biologics license applications (BLAs), many scientific principles described in this guidance may also apply to these products.

PHARMA UPTODAY

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

s/UCM458484.pdf

Rare Diseases: Common Issues in Drug Development Guidance for Industry

This guidance assists sponsors of drug and biological products intended to treat or prevent rare diseases in conducting more efficient and successful development programs through a discussion of selected issues commonly encountered in rare disease drug development. Although similar issues are encountered in other drug development programs, they are frequently more difficult to address in the context of a rare disease with which there is often little medical experience. These issues are also more acute with increasing rarity of the disorder. A rare disease is defined by the Orphan Drug Act of 1983 as a disorder or condition that affects less than 200,000 persons in the United States. Most rare diseases, however, affect far fewer persons.

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

s/UCM458485.pdf

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AUDIT FINDINGS - 483 Observations

Firm Name 483 Observation

Diamond Pharmacy, LLC - May

15, 2015

Batch production and control records are not prepared for each

batch of drug product produced and do not include complete

information relating to the production and control of each batch.

Ajinomoto Althea, Inc. - May 18,

2015

Procedures designed to prevent microbiological contamination of

drug products purporting to be sterile are not written.

Genentech, Inc. - May 21, 2015 Your firm's Bulk Dispensing Unit (BDU), filling and packaging

operations for Active Pharmaceutical Ingredients (APIs) Actemra

SC and IV are deficient.

Alexza Pharmaceuticals, Inc. -

May 21, 2015

Investigations of an unexplained discrepancy did not extend to

other drug products that may have been associated with the

specific failure or discrepancy.

The Compounding Pharmacy of

America - May 21, 2015

Each batch of drug product purporting to be sterile and pyrogen-

free is not laboratory tested to determine conformance to such

requirements.

Amgen, Inc. - May 22, 2015 Written records of investigations into unexplained discrepancies

do not always include the conclusions and follow-up.

S&B Pharma, Inc. dba Norac Pharma - May 22, 2015

Materials are not re-evaluated as appropriate to determine their

suitabiity for use.

The Wellness Center Pharmacy, Inc. dba Designer Drugs - May 28, 2015

Procedures designed to prevent microbiological contamination of

drug products purponing to be sterile do not include adequate

validation of the sterilizalion process.

Lincare, Inc. - June 12, 2015 Aseptic processing areas are deficient regarding the system for

monitoring environmental conditions.

Care Fusion 213, LLC - June 25, 2015

Procedures designed to prevent objectionable microorganisms in

drug products not required to be sterile are not established and

followed

Colonial Dames Co., Ltd. - June 25, 2015

Procedures designed to prevent objectionable microorganisms in

drug products not required to be sterile are not established and

followed.

Pyramid Laboratories, Inc. - June 5, 2015

Aseptic processing areas are deficient regarding the system for

cleaning and disinfecting the room and equipment to produce

aseptic conditions.

Hamamatsu/Queen's PET Imaging Center, LLC - May 14, 2015

Your firm lacks adequate production and process controls to

ensure the consistent production of a PET drug that meets the

applicable standards of identity, strength, quality and purity.

Abrams Royal Pharmacy II, LLC - May 11, 2015

Your firm has not established appropriate testing and release procedures and controls to ensure finished drug products conform to satisfactory identity and strength prior to release.

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Cardinal Health - May 8, 2015 Your firm lacks adequate production and process controls to ensure the consistent production of a PET drug that meets the applicable standards of identity, strength, quality and purity.

Vista Biologicals Corp. - May 6, 2015

Your firm failed to complete the process validation of the intermediate API as specified in a written and approved protocol.

Home Intensive Care Pharmacy, LLC - May 5, 2015

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.

Specialty Compounding, LLC - May 5, 2015

Your firm has failed to establish adequate procedures for conducting appropriate media fill simulations.

Hawknad Manufacturing Industries, Inc. - April 23, 2015

The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.

Seattle Genetics, Inc. - June 9, 2015

Written records are not always made of investigations into unexplained discrepancies and the failure of a batch or any of its components to meet specifications.

Ricerca Biosciences, LLC - May 29, 2015

Written procedure 24-Q038 requires processes to be reviewed periodically to determine if revalidation is required.

Air Liquide Healthcare America Corp. - May 26, 2015

Out of specification (OOS) investigations are not thorough.

Liberty Drug & Surgical - May 22, 2015

The flow of components, drug product containers, closures, in-process materials and drug products through the building is not designed to prevent contamination.

IBA Molecular - May 15, 2015 The calibration range used for your depyrogenation oven does not include the temperature used for conducting depyrogenation of your finished product glassware.

Central Illinois Compounding, Inc. dba Preckshot Professiona - May 29, 2015

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.

McNeil Consumer Pharmaceutical Healthcare - May 6, 2015

Laboratory controls do not include determination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of drug products used in the manufacture, processing, packing or holding of drug products.

Mirror Pharmaceuticals, LLC - May 4, 2015

Not all quarterly periodic adverse drug experience reports have been submitted within 30 days of the close of the quarter.

Metalweld, Inc. - May 29, 2015 The calibration of instruments is not done at suitable intervals in accordance with an established written procedure.

VistaPharm, Inc. - May 28, 2015 There are not 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.

Essential Pharmacy Compounding - May 22, 2015

Procedures designed to prevent microbiological contamiation of drug products purporting to be sterile do not include adequate validation of the sterilization process.

Independent Nutrition Centers, Inc. - May 15, 2015

You did not hold cleaning compounds, sanitizing agents, pesticides, pesticide chemicals or other toxic materials in a manner that protects against contamination of components, dietary supplements or contact surfaces.

Tufco, L.P. - May 13, 2015 The responsibilities and procedures applicable to the quality

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control unit are not fully followed.

Modern Products, Inc. - May 13, 2015

The identity of each component of a drug product is not verified by conducting at least one test to verify the identity, using specific identity tests if they exist.

MedImmune UK Ltd. - May 13, 2015

The investigation conducted regarding Complaint 115043 lacks a comprehensive evaluation of the cumulative impact of all changes.

Montana Compounding Pharmacy and Wellness Center - May 8, 2015

Each lot of a drug component that is liable to microbiological contamination that is objectionable in view of its intended use is not subjected to microbiological tests before use.

Nesher Pharmaceuticals USA, LLC - May 7, 2015

Equipment for adequate control over humidity and temperature is not provided when appropriate for the manufacture, process, packing or holding of a drug product.

Dipharma Francis S.r.l. - May 6, 2015

For qualification of supplier, complete analyses of test items according to the supplier's certificate of analysis (COA) were not performed on at least three batches and at appropriate intervals.

Glaxo SmithKline (SmithKline Beecham, Ltd.) - May 1, 2015

Weight verification of the raw materials dispensed to production is not performed by a second person.

Nosch Labs Pvt. Ltd. - May 1, 2015

Drug products failing to meet established quality control criteria are not rejected.

Polysciences, Inc. - April 29, 2015

There are not 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.

The Medicines Co. - April 17, 2015

Design verification does not confirm that design output meets design input requirements.

Master Pharm, LLC - May 6, 2015

Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions.

Chartwell Pharmaceuticals, LLC - May 1, 2015

Written procedures have not been developed for the surveillance, receipt, evaluation, and reporting to FDA of post marketing adverse drug experiences.

Cerovene, Inc. - May 4, 2015 Acceptance criteria for the sampling and testing conducted by the quality control unit is not adequate to assure that batches of drug products meet appropriate statistical quality control critiera as a condition for their approval and release.

Raining Rose, Inc. - June 11, 2015

Your cosmetic was prepared, packed, or held under unsanitary conditions whereby it may have been rendered injurious to health.

Tolmar, Inc. - June 18, 2015 Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variablity in the characteristics of in-process material and the drug product.

Novartis Vaccines & Diagnostics, Ltd. - June 11, 2015

The controls over the Fluvirin influenza vaccine manufacturing equipment cleaning, cleaning validation, sanitization processes and maintenance are inadequate.

InvaGen Pharmaceuticals, Inc. - May 26, 2015

The responsibilities and procedures applicable to the quality control unit are not fully followed.

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Acino Products, LLC - March 5, 2014

Laboratory controls do not include the establishment of scientifically sound and appropriate specifications designed to assure that incoming materials and drug products conform to appropriate standards of identity, strength, quality and purity.

Coats Aloe International, Inc. - March 4, 2014

The quality control unit lacks authority to fully investigate errors that have occurred.

CoreRx, Inc. - June 19, 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.

483 of PharMEDium Services, LLC (Outsourcing facility) - Observations:

1. There is a failure to thoroughly review 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.

2. Testing and release of drug product for distribution do not include appropriate laboratory

determination satisfactory conformance to the identity strength each active ingredient prior to

release.

3. Buildings used in the manufacture, processing, packing or holding of drug products are not

maintained in a clean and sanitary condition.

4. Procedures designed to prevent microbiological contamination of drug products purporting to be

sterile are not followed.

5. Procedures designed to prevent microbiological contamination of drug products purporting to be

sterile do not include validation of the sterilization process.

6. Laboratory controls do not include the establishment of scientifically sound and appropriate

specifications and test procedures designed to assure that drug products conform standards

identity, strength, quality and purity.

7. Aseptic processing areas are deficient regarding the system for monitoring environmental

conditions.

8. Each batch of drug product purporting to be sterile and pyrogen-free is not laboratory tested to

determine conformance to such requirements.

9. The written stability program for drug products does not include meaningful and specific test

methods.

10. Appropriate controls are not exercised over computers or related systems to assure that

changes in master production and control records or other records are instituted only by

authorized personnel.

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11. The labels and containers of your outsourcing facility's drug products do not include information

required by section 503B(a)(10)(A) and (B).

The FDA 483 of "Walgreens Home Care, Inc. dba Walgreens Infusion Services", TX

1. Buildings used in the manufacture, processing, packing or holding of drug products are not

maintained in a clean and sanitary condition and free of infestation by rodents, birds insects,

and other vermin .

2. Protective apparel is not worn as necessary to protect drug products from contamination.

3. Procedures designed to prevent microbiological contamination of drug products purporting be

sterile are not followed.

4. Aseptic processing areas are deficient regarding the system for monitoring environmental

conditions.

5. There is no written testing program designed to assess the stability characteristics of drug

products.

6. Aseptic processing areas are deficient regarding systems for maintaining any equipment used

to control the aseptic conditions.

EU Non-Compliance Report

EU Non-Compliance Report: TXCELL - BESANCON, France

Nature of non-compliance : Overall, 22 deficiencies were observed, including 7 major deficiencies on the following topics: 1. The pharmaceutical quality system was deficient as several deviations opened during the period 2014-2015 were overdue and still pending. Namely, 43 non conformities were related to environnemental deviations of which 30 were related to mould contamination during production of investigational batches and Media Process Test. Moreover, some investigational product batches were released whereas deviations cases were still opened. 2. Paper batch record and labels required in aseptic areas were not sterilised or passed into the area by a procedure which achieves the same objective of not introducing contamination. 3. Appropriate alert limits were not set for the results of microbiological monitoring of clean rooms.

FDA Warning letters

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Warning letter : Sipra Labs Limited, Hyderabad

1. Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods (21 CFR §211.165(e)).

a. Our inspection documented that only four of the fourteen analytical methods identified in the 2011 inspection have since been validated. Ten methods remain unvalidated. b. The FDA investigator found that you did not follow your established standard operating procedure (SOP) for validation activities.

2. Your firm failed to thoroughly investigate unexplained discrepancies or failures of a batch or its components to meet its specification, whether or not the batch has already been distributed (21 CFR §211.192).

written procedures do not adequately address the need to investigate anomalies,

unexpected events, or out-of-trend results

There was no documentation that the event was reviewed by your laboratory or reported

to your client manufacturing firm.

not have a validated practice for reusing HPLC/GC vials and stoppers

Warning letter : Mylan Laboratories Limited, India The U.S. Food and Drug Administration (FDA) inspected the following three pharmaceutical manufacturing facilities. A. February 6-13, 2015: Mylan Laboratories Limited OTL, Plot No. 284-B (19A) Bommasandra Jigani Link Road, Ind. Area, Anekal Taluk, Bangalore, 560 105 B. September 23, 2014 through October 3, 2014: Agila Specialties Private Ltd., Specialty Formulation Facility (SFF) 19A, Plot No. 284-B/1 Bommasandra Jigani Link Road, Anekal Taluk, Bangalore 560 105 C. August 1-8, 2014: Agila Specialties Private Ltd., Sterile Product Division, Opp II M, Bilekahalli, Bannerghatta Road, Bangalore, Karnataka, 560 076 At all three sites, we identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. A. Mylan Laboratories Limited OTL (FEI: 3007512701)

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1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). a. Non-integral (b)(4) gloves were used in Suites (b)(4) and (b)(4) for conducting aseptic processing operations b. There is a lack of assurance that you maintain your manufacturing environment in a state of control suitable for aseptic processing c. Aseptic garments worn in the filling area were also non-integral. 2. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)). a. You failed to follow your SOP MIA/007/R11 ―Monitoring of Water for Microbiological Quality‖ for collecting water samples. b. Your environmental monitoring data is not reliable because of the materials you use to conduct EM tests. 3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)). a. You do not have a scientific rationale for the environmental monitoring sampling locations in aseptic filling Suites b. During our inspection, we noted that you have no justification for two different action levels for finger dab results B. Agila Specialties Pvt Ltd (SFF) (FEI: 3007648351) 1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). Your process simulation (media fill) studies are inadequate a. During our review of several media fill batch records (MFBR), we documented that integral vials identified as ―jam rejects‖ or ―other rejects‖ were rejected without assignable causes, and not incubated. b. You have no smoke studies for the (b)(4) air flow units used to transfer sterilized material to manufacturing areas and aseptic fill rooms under dynamic conditions and during routine interventions. 2. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

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a. Your firm does not have a robust sampling plan as part of its environmental monitoring program. b. In your ISO-5 and ISO-7 environments, the building management system (BMS) monitoring differential pressure and the non-viable particle monitoring system (NVPMS) for non-viable particles appear to be out of control. c. Your firm failed to identify the source of gram-negative contamination in your ISO 7 area and to implement appropriate corrective actions and preventive actions 3. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel can change master production and control records, or other records (21 CFR 211.68(b)). C. Agila Specialties Pvt Ltd (SPD) (FEI: 3003813519) 1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). Your investigation was inadequate. You did not investigate this defect to determine the root cause You did not evaluate the qualitative attributes of the product to determine if discoloration 2. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)). a. You did not have settling plates located where the risk of product contamination was greatest 3. Your firm failed to 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)). a. We observed that operators moving in and out of the classified areas were not slow and deliberate during the set-up and filling of batch

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Health Canada Non-Compliance Report Health Canada Non-Compliance Report : Procter & Gamble Inc., Canada

GMP Inspection Report Card Summary

Establishment Name

Reference

Number

Inspection

Start Date Type of Inspection Inspection Rating

Procter & Gamble Inc. 100142 2015-05-19 Good Manufacturing

Practices (GMP) - Regular

Non-Compliant

Summary of Observations

Observation

Number Regulation Summary of Observation

1 C.02.015 - Quality

Control Deficient laboratory controls were noted which allowed trial

tests to be performed prior to the official testing of samples.

Deficiencies were noted with the reporting of all valid test

results, both passing and suspect.

Deficiencies were noted with the assessment of non-

conformances pertaining to testing that may have had an impact

on the quality of batches of finished products.

2 C.02.015 - Quality

Control Quality oversight was lacking resulting in significant GMP

deficiencies.

3 C.02.015 - Quality

Control Deficiencies were noted with documentation practices.

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Summary of Observations

Observation

Number Regulation Summary of Observation

4 C.02.015 - Quality

Control Deficiencies were noted with the procedures in place to describe

the steps to be taken as part of an out-of-specification

investigation.

5 C.02.005 - Equipment Deficiencies were noted with controls of computerized

laboratory testing equipment.

6 C.02.015 - Quality

Control Deficiencies were noted with the labelling of glassware and

samples.

7 C.02.015 - Quality

Control Deficiencies were noted with the availability of standard

operating procedures for organoleptic tests.

8 C.02.012 -

Manufacturing Control Deficiencies were noted with the self-inspection program.

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Check your area for ….

• Do methods and procedures accurately

reflect the way processes are actually being

done?

Be sure to update methods and procedures

as soon as possible when updates are

necessary.

You are expected to be doing what is written

in these documents; updating them as

needed isn’t just a good practice, it is a

necessity.

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Regulations of the Month

Subpart B--Organization and Personnel Sec. 211.28 Personnel responsibilities.

(b) Personnel shall practice good sanitation and health habits.

(c) Only personnel authorized by supervisory personnel shall enter those areas of the

buildings and facilities designated as limited-access areas.

Sec. 211.34 Consultants.

Consultants advising on the manufacture, processing, packing, or holding of drug products

shall have sufficient education, training, and experience, or any combination thereof, to advise

on the subject for which they are retained. Records shall be maintained stating the name,

address, and qualifications of any consultants and the type of service they provide.

Subpart C--Buildings and Facilities Sec. 211.42 Design and construction features.

(a) Any building or buildings used in the manufacture, processing, packing, or holding of a

drug product shall be of suitable size, construction and location to facilitate cleaning,

maintenance, and proper operations.

(b) Any such building shall have adequate space for the orderly placement of equipment and

materials to prevent mixups between different components, drug product containers, closures,

labeling, in-process materials, or drug products, and to prevent contamination. The flow of

components, drug product containers, closures, labeling, in-process materials, and drug

products through the building or buildings shall be designed to prevent contamination.

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· Presentation on data integrity in Pharmaceutical Industry

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