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VOLUME: 18 - ISSUE: SEP 2015 |
PHARMA UPTODAY
PHARMA UPTODAY
2
Inside this issue
3 News Uptoday
37 New Guidance
42 Audit Findings
483 Observations
- 483 of PharMEDium S...
PHARMA UPTODAY
3
News Uptoday
OpposingViewsonFDACompleteResponseLetters
Recently, the British Medical Journal published an...
PHARMA UPTODAY
4
MHRA enforces European Commission decision to suspend medicines for which
authorisation based on clinical...
PHARMA UPTODAY
5
Sidley Austin noted the CFDA also requires a locked database consistent with the original data as
well as...
PHARMA UPTODAY
6
 The majority of site assessment activities can be conducted not just at the same time as, but prior to,...
PHARMA UPTODAY
7
Topic Number of Comments Average Rating
Food 46 3.28
Medical Devices N/A N/A
Radiation-Emitting Products ...
PHARMA UPTODAY
8
Regulatory Planning for FDA FY 2016
Regulatory Planning for FDA FY 2016
The FDA operates on a Federal Fis...
PHARMA UPTODAY
9
revised formulations. Device companies will notice a small increase in the filing fee, now up to
$3,872, ...
PHARMA UPTODAY
10
spaces of different purity classes, no precautions to avoid contamination during the transfer of the
ste...
PHARMA UPTODAY
11
WHO Technical Report - GMP for Biological Products Revision
The World Health Organization (WHO) provides...
PHARMA UPTODAY
12
In a first, drug using 3D printing technology gets FDA nod
The U.S. Food and Drug Administration has, fo...
PHARMA UPTODAY
13
Although the government notice didn‘t address the data manipulations cited by the French
regulators, it ...
PHARMA UPTODAY
14
more challenging regulatory environment as well. In aggregate, this has caused an elongation of the
star...
PHARMA UPTODAY
15
Applications (INDs), and Abbreviated New Drug Applications (ANDAs), as appropriate for
immediate-release...
PHARMA UPTODAY
16
Activities Report of the Generic Drug Program (FY 2015)
GDUFA
YEAR/Actions This
Month
14-
Oct
14-
Nov
14...
PHARMA UPTODAY
17
GDUFA YEAR/
(Receipts)Amendment
s
14-
Oct
14-
Nov
14-
Dec
15-Jan 15-
Feb
15-
Mar
15-
Apr
15-
May
15-
Jun...
PHARMA UPTODAY
18
FY15) Unsolicited
PAS Supplements
(FY15) Administrative
1 6 3 7 2 7
PAS Supplements
(FY15) Tier 1
0 0 0 ...
PHARMA UPTODAY
19
++ = Starting FY15 ANDA Original Receipts are reported as raw receipts (versus filed receipts).
+++ = FY...
PHARMA UPTODAY
20
Guidance for Entities Considering Whether To Register as Outsourcing Facilities
The Food and Drug Admini...
PHARMA UPTODAY
21
FDA Warning for Kim Kardashian
A Lesson in paid and un-paid user testimonials
It is a bit of a surprise ...
PHARMA UPTODAY
22
Delhi government bans over the counter sale of NSAIDS without prescription
Delhi government today banned...
PHARMA UPTODAY
23
India sources over 70 per cent of its requirement of bulk drugs (ingredients) from Chinese
pharmaceutica...
PHARMA UPTODAY
24
Chinese plant banned by EU, getting compliance help from NJ company
Italian regulators came down hard re...
PHARMA UPTODAY
25
Political Bureau of CPC Central Committee and Party Secretary of Shanghai. He also accompanied
Premier L...
PHARMA UPTODAY
26
The British Pharmacopoeia's new website - setting the standards
The launch of the new integrated British...
PHARMA UPTODAY
27
Pfizer Receives FTC Clearance for Hospira Acquisition
Pfizer announced on Aug. 24, 2015 that the US Fede...
PHARMA UPTODAY
28
about what was a ―reporting establishment‖ and how CMOs could report metrics on a facility making
drugs ...
PHARMA UPTODAY
29
Data governance is an integral part of the pharmaceutical quality system
Trial (injections) and error
Th...
PHARMA UPTODAY
30
(including system stability check samples) should be reported. Importantly, a sample of the product
batc...
PHARMA UPTODAY
31
10 repetitions of the test. For additional security, parts of a validation batch can be inspected as wel...
PHARMA UPTODAY
32
914). They are even hopeful of the state‘s sex ratio improving drastically as a result. At least 17 stat...
PHARMA UPTODAY
33
Teneligliptin, a new third generation oral anti-diabetic agent, is used for the management of Type
2 Dia...
PHARMA UPTODAY
34
a GS1 Global Trade Item Number(GTIN) will be accepted as a valid product code, although it also
appears ...
PHARMA UPTODAY
35
two-dimensional barcode [except] the two-dimensional barcode carrying the unique identifier for the
purp...
PHARMA UPTODAY
36
Terminology
CLEAN AREA
An area with defined environmental control of particulate and microbial contamina...
PHARMA UPTODAY
37
New Guidance
Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage
Form...
PHARMA UPTODAY
38
Over-the-Counter Pediatric Oral Liquid Drug Products Containing Acetaminophen: Guidance
for Industry
Thi...
PHARMA UPTODAY
39
ICH guideline Q7 on good manufacturing practice for active pharmaceutical ingredients –
questions and an...
PHARMA UPTODAY
40
Application of the principles of the ICH M7 guideline to calculation of compound-specific
acceptable int...
PHARMA UPTODAY
41
Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM458484....
PHARMA UPTODAY
42
AUDIT FINDINGS - 483 Observations
Firm Name 483 Observation
Diamond Pharmacy, LLC - May
15, 2015
Batch p...
PHARMA UPTODAY
43
Cardinal Health - May 8, 2015 Your firm lacks adequate production and process controls to
ensure the con...
PHARMA UPTODAY
44
control unit are not fully followed.
Modern Products, Inc. - May 13,
2015
The identity of each component...
PHARMA UPTODAY
45
Acino Products, LLC - March 5,
2014
Laboratory controls do not include the establishment of
scientifical...
PHARMA UPTODAY
46
11. The labels and containers of your outsourcing facility's drug products do not include information
re...
Pharma Uptoday Monthly Magazine - Volume 18; Issue: Sep 2015
Pharma Uptoday Monthly Magazine - Volume 18; Issue: Sep 2015
Pharma Uptoday Monthly Magazine - Volume 18; Issue: Sep 2015
Pharma Uptoday Monthly Magazine - Volume 18; Issue: Sep 2015
Pharma Uptoday Monthly Magazine - Volume 18; Issue: Sep 2015
Pharma Uptoday Monthly Magazine - Volume 18; Issue: Sep 2015
Pharma Uptoday Monthly Magazine - Volume 18; Issue: Sep 2015
Pharma Uptoday Monthly Magazine - Volume 18; Issue: Sep 2015
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Pharma Uptoday Monthly Magazine - Volume 18; Issue: Sep 2015

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To recap the August 2015 month's pharma highlights to Pharma Uptoday members, Monthly magazine Volume 18 has been released with the following content.
News Uptoday
New Guidance
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 Warning Letters
- Warning letter : Sipra Labs Limited, Hyderabad
- Warning letter : Mylan Laboratories Limited, India
Health Canada Non Compliance Report
- Procter & Gamble Inc., Canada.
Regulations of the Month
- Sec. 211.28 Personnel responsibilities (b) & (c)
- Sec. 211.42 Design and construction features (a) & (b)

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Pharma Uptoday Monthly Magazine - Volume 18; Issue: Sep 2015

  1. 1. VOLUME: 18 - ISSUE: SEP 2015 | PHARMA UPTODAY
  2. 2. PHARMA UPTODAY 2 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)
  3. 3. PHARMA UPTODAY 3 News Uptoday OpposingViewsonFDACompleteResponseLetters 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.
  4. 4. PHARMA UPTODAY 4 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.
  5. 5. PHARMA UPTODAY 5 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:
  6. 6. PHARMA UPTODAY 6  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
  7. 7. PHARMA UPTODAY 7 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
  8. 8. PHARMA UPTODAY 8 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
  9. 9. PHARMA UPTODAY 9 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
  10. 10. PHARMA UPTODAY 10 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 (!).
  11. 11. PHARMA UPTODAY 11 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.
  12. 12. PHARMA UPTODAY 12 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.‖
  13. 13. PHARMA UPTODAY 13 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
  14. 14. PHARMA UPTODAY 14 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
  15. 15. PHARMA UPTODAY 15 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.
  16. 16. PHARMA UPTODAY 16 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
  17. 17. PHARMA UPTODAY 17 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
  18. 18. PHARMA UPTODAY 18 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.
  19. 19. PHARMA UPTODAY 19 ++ = 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.
  20. 20. PHARMA UPTODAY 20 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.
  21. 21. PHARMA UPTODAY 21 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.
  22. 22. PHARMA UPTODAY 22 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.
  23. 23. PHARMA UPTODAY 23 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.
  24. 24. PHARMA UPTODAY 24 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
  25. 25. PHARMA UPTODAY 25 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
  26. 26. PHARMA UPTODAY 26 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/
  27. 27. PHARMA UPTODAY 27 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
  28. 28. PHARMA UPTODAY 28 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.
  29. 29. PHARMA UPTODAY 29 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
  30. 30. PHARMA UPTODAY 30 (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
  31. 31. PHARMA UPTODAY 31 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
  32. 32. PHARMA UPTODAY 32 914). 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.
  33. 33. PHARMA UPTODAY 33 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
  34. 34. PHARMA UPTODAY 34 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
  35. 35. PHARMA UPTODAY 35 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
  36. 36. PHARMA UPTODAY 36 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.
  37. 37. PHARMA UPTODAY 37 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
  38. 38. PHARMA UPTODAY 38 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
  39. 39. PHARMA UPTODAY 39 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
  40. 40. PHARMA UPTODAY 40 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.
  41. 41. PHARMA UPTODAY 41 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
  42. 42. PHARMA UPTODAY 42 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.
  43. 43. PHARMA UPTODAY 43 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
  44. 44. PHARMA UPTODAY 44 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.
  45. 45. PHARMA UPTODAY 45 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.
  46. 46. PHARMA UPTODAY 46 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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