Pharma Uptoday Monthly Magazine Volume 14 Issue May 2015

VOLUME: 14 - ISSUE: MAY 2015 |
PHARMA UPTODAY

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Inside this issue
3 News Uptoday
34 New Guidance
48 Audit Findings
483 Observations
- 483 of Amylin Pharmaceuticals Inc (Dec-2009)
49 Warning Letters
- Hospira Spa
- Yunnan Hande Bio-Tech. Co. Ltd., China
51 Regulations of the Month
- § 211.198 Complaint files

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News Uptoday
Ozonization of Pharmaceutical Water and the Biocidal Products Regulation
With the new biocidal products regulation from 2013 in-situ generated ozone now also falls into the
scope of this regulation. Ozone generation systems with a biocide application (such as disinfection of
pharma water) thus require an approval after the transitional period expires in the September 2017. We
already reported about the impact of the new Biocidal Products Regulation - please see the GMP News
"Pharmaceutical Water: Uncertainty caused by the New Biocidal Products Regulation" from 21 May
2014.
Admission will take place in two stages. In the first step, ozone is certified as an active ingredient and
registered in the list of active substances authorised in the EU. In the second step, the ozone generation
system is approved as a biocidal product. The major manufacturers of ozone generation systems have
joined forces for this in the ozone registration group (ORG). It aims at relieving users of ozone systems
from the registration procedure. That means the documents should be provided to the users. The
access to the marketing authorisation dossier is supposed to be assured through a Letter of Access
(LoA). One of the open questions seems to be resolved now: the question whether an authorisation
document will be required for each ozone precurser (i.e. water, oxygen or air). As this seems to be
unnecessary, only one authorisation document is currently being processed.
The question with regard to how reasonable it is to include ozone from pharmaceutical water systems in
the biocidal products regulation cannot be clarified at this point. The same is true with regard to the
question on who is supposed to control pharmaceutical companies and whether their ozone comes from
approved ozone systems.
Overview about API manufacturing for the European market
EudraGMDP provides some interesting information about the API manufacturing sites as well as about
importers, distributors of APIs to be used as starting material in Medicinal Products for human use in
Europe. Although the database is still not complete (not all competent authorities in Europe have
established a system to make sure that all registration data will be entered into EudraGMDP in a timely
manner) the current information is already very interesting.
Currently (as per 19 March 2015) the database counts 3.275 API manufacturing sites, importers or
distributors located outside Europe. On the other side 936 API manufacturing sites, importers or
distributors are located in EEA countries (EU Member states plus Norway, Liechtenstein and Iceland).
According to the database India counts for 1.473 companies and China for 1102 companies. The USA
only counts for 198 and Switzerland for 71 companies. Within the EEA the United Kingdom counts 138
countries while Italy counts for 71and Spain for 192. Still work is needed to put all information into the
database as France does not have a single entry and Germany only 3.
But the database is a good source to find some basic information about API manufacturers, importers
and distributors. Each company registration file is available and allows to check the date of issue of the
registration and the products concerned. However, it must be stated that a registration does not mean
that an inspection took place. A registration will be granted also without a prior inspection at the
company.
Source: API Registration in EudraGMDP

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FDA plans a new approach to facility inspections
The "FDA Voice" is a Blog which has been developed by the US Agency to post current initiatives,
presentation and views. In a recent post published on March 24, 2014 Howard Sklamberg (FDA‘s
Deputy Commissioner for Global Regulatory Operations and Policy) and Cynthia Schedar (Director of
the Office of Compliance at FDA‘s Center for Drug Evaluation and Research) discuss ideas to improve
the quality of inspections.
The two high level agency representatives discuss a new approach to facility inspections, "one that will
not only note problems, but will also allow our inspectors to document where a firm‘s quality
management system exceeds what would be required to meet regulatory compliance. To put it simply:
the inspections can yield also carrots, and not just sticks."
The new approach will consider the findings by using them to plan the frequency of FDA Inspections. In
addition, a good overall quality management system and culture might even lead to more flexibility for
post-approval manufacturing changes. This was also a goal of ICH Q10 but regulators did not implement
this idea yet. The new FDA proposal could be a starting point for providing regulatory flexibility to those
companies who do more than what is needed.
FDA is currently preparing a questionnaire to standardize inspections with the goal of "uniformly
harvesting the kind of data that supports accurate measures of quality." The authors go on by saying
"We believe that by improving the inspection process in this way, future ―metrics‖ that define quality will
be understood and aspired to by manufacturers — no matter where they are in the world."
The new inspection approach might complement the current initiative to develop a FDA Guideline on
Quality Metrics which is an intensively discussed initiative. Also other regulators around the world might
consider this idea. Just recently the MHRA has published an update on their risk based inspection
model. According to the MHRA approach to inspections questionnaires will be used to define the
frequency as well. But the MHRA intends also to use the questionnaire once between inspection cycles
to define the frequency.
Development, Commercialization of Antibacterial Drugs to Speed Up
The growing threat posed by multi-drug resistant gram-negative organisms (MDR-GNBs) is lending a
sense of urgency to the development of antibacterial drugs worldwide. Upcoming regulatory reforms to
lower R&D costs and provide incentives for new drug identification will create attractive opportunities for
pharmaceutical manufacturers.
New analysis from Frost & Sullivan, A Product and Pipeline Analysis of the Antibacterial Drugs Market,
finds that nearly 80 percent of drugs currently in the pipeline are from smaller pharmaceutical and
biotech companies, of which half do not have any commercialized products in the market.
GlaxoSmithKline (www.gsk.com), AstraZeneca (www.astrazeneca.com) and Merck & Co
(www.merck.com) are the only three established pharmaceutical organizations in the antibacterial drug
space.
"Thirty eight antibacterial drugs currently under development have the potential to address many, but
not all, resistant bacteria," said Frost & Sullivan Healthcare Senior Research Analyst Aiswariya

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Chidambaram. "Plazomicin and Eravacycline are two emerging compounds that have a broad-spectrum
activity against most MDR-GNBs."
Discovering new antibacterial drugs and identifying novel compounds that can successfully target
bacteria is scientifically challenging. Given the high probability of failure and steep research and
development (R&D) costs, big pharma companies that were once leaders are closing down their
antibacterial research facilities.
Agencies such as the Food and Drug Administration (FDA) and the Infectious Diseases Society of
America are deploying several initiatives to lure companies back into antibacterial R&D. The recently
implemented Generating Antibiotic Incentives Now (GAIN) Act is expected to facilitate more efficient
clinical studies and reduce barriers to market entry. In Europe, the Innovative Medicines Initiative (IMI)
has launched two projects – Combatting Bacterial Resistance in Europe (COMBACTE) and
TRANSLOCATION (molecular basis of the bacterial cell wall permeability) – that showcase an
unprecedented partnership between industry, biotech organizations, and academia to fight antibiotic
resistance.
"Further, collaborations in the form of public-private partnerships among industry, academia, investors
and key opinion leaders will effectively address the vast unmet clinical and commercial needs in the
antibacterial drugs market and quicken the journey towards commercialization," concluded
Chidambaram.
Pfizer to Cease Vaccine Commercial Operations in China
Pfizer Inc. is ceasing its vaccine commercial operations in China after the government failed to renew its
license for a key shot for children, the latest sign of the uncertainties facing international drugmakers in
the nation. The Chinese import license for the Prevenar-brand vaccine expired last year, the U.S.
pharmaceutical company said in a statement Thursday. It expects a shortage of the product in China
before the launch of a newer version, called Prevenar 13, that it already sells in other parts of the world.
Drugmakers in China have faced delays in approvals in recent years because of changing rules. At least
thirty-four applications from foreign multinationals have been or are set to be delayed after Chinese
regulators began requiring an added procedure, according to R&D-Based Pharmaceutical Association
Committee, an industry group. ―This won‘t have too big an effect on the children‘s immunization process‖
as the drug isn‘t included in China‘s vaccination program, said Shi Lichen, a manager at Beijing
Dingchen Medical Consultancy, a privately run company that gives advice on the industry. While
Prevenar is the only vaccine for pneumococcal disease approved in China for children under two, no
data proves infants have a high infection rate, Shi said. China has a much cheaper vaccine available for
older children, he said. The U.S. Centers for Disease Control and Prevention recommends the
vaccination for youngsters under 5 years old. Pneumococcal infection can lead to potentially fatal
sicknesses such as pneumonia, blood infections and meningitis.
An official at the China Food and Drug Administration‘s media office said it was looking into questions
from Bloomberg News and couldn‘t immediately comment.

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Only Vaccine
The effect of the lost license on Pfizer might be more pronounced as Prevenar is the only vaccine the
company sells in China. Most of the 200 employees at its China vaccine business will be ―impacted‖ and
it will work to help those affected to find new roles at its other business units, the statement said. The
company hires more than 9,000 people in China, according to its website. Pfizer is now in the process of
working with the Chinese government to get Prevenar 13 onto the market and the lost license won‘t
affect any of its other operations in China, spokeswoman Trupti Deepak Wagh said. ―The registration
application for Prevenar 13 is currently underway in China,‖ Pfizer‘s statement said. ―We can‘t speculate
on timelines but are working very closely with the relevant regulatory agencies to expedite the
availability of Prevenar 13 in China.‖ The relevant authorities are ―keen‖ to provide children with the new
vaccine, it said. Other foreign drugmakers have faced challenges in China. Johnson & Johnson‘s chief
scientific officer in January said that the Chinese market is becoming more challenging for drug
companies because of how long regulators there take to approve new medicines. GlaxoSmithKline Plc
was fined 3 billion yuan ($484 million) last year for bribery related to drug sales after a probe that lasted
for more than a year.
Aurobindo Pharma becomes fifth most valuable pharma firm
Aurobindo Pharma has surged 21% in the past one week, making it the fifth-most valuable Indian
pharma company behind Sun Pharmaceutical Industries, Lupin, Dr Reddy‘s Laboratories and Cipla.
The rally has seen Aurobindo surpass Ranbaxy Laboratories, Cadila Healthcare, Divi‘s Laboratories,
GlaxoSmithKline Pharmaceuticals, Glenmark Pharmaceuticals, Ipca Laboratories, Torrent Pharma,
Biocon and Sanofi India in market capitalisation (m-cap) ranking.
The stock, which has gained over five-fold in the past one year, has seen Aurobindo occupy the 65th
position in overall m-cap ranking, gaining 82 positions during the year. The company stood at 147
ranked with m-cap of Rs 5,882 crore as on September 30, 2013.
Strong show
Shares of pharmaceutical company have seen a sharp turnaround since it hit a multi-year low of Rs
82.35 on November 2011, after it reported a consolidated net loss of Rs 203 crore in first half of FY11-
12. However, the company has reported an impressive performance since the past few quarters due to
a strong growth in the US market.
In addition to being the market leader in Semi-Synthetic Penicillins, it has a presence in key therapeutic
segments such as neurosciences, cardiovascular, anti-retrovirals, anti-diabetics, gastroenterology and
cephalosporins, among others.
Foreign institutional investors (FIIs) holding in the company has also hit seven-year high. FIIs held
27.59% stake in June 2014 quarter, as against 12.45% at the end of September 2012 quarter. Their

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highest holding in the company was 31.29% in June 2006 quarter, data shows. The company yet to
announced September 2014 shareholding pattern.
The management indicated that the net debt was $537 million (Rs 3,220 crore) at the end of FY14 and
the majority was in foreign currency. The company has repaid $67 million (Rs 402 crore) in debt during
FY14 and has plans to repay $100-125 million (Rs 600-750 crore) during FY15, points out a Prabhudas
Lilladher report.
As on October 1, 2014 Returns in %
Company M-cap Rs cr Price in Rs 1 week 1 year
Sun Pharma 178,216 860.45 10.26 45.21
Lupin 62,282 1387.35 1.60 62.32
Dr Reddy's Labs 54,527 3200.60 -0.99 34.27
Cipla 50,041 623.25 3.81 44.27
Aurobindo 28,149 965.65 20.60 378.04
Ranbaxy Labs 27,065 638.30 10.06 93.01
Cadila Healthcare 26,782 1308.10 2.64 92.37
Divi's Lab. 23,736 1788.00 3.38 84.80
Glaxosmit Pharma 23,719 2800.35 5.04 14.92
Glenmark Pharma 19,076 703.20 0.47 32.44
Source: Capitalineplus
Data compiled by BS Research
Presence of impurities a serious threat to pharma manufacture & marketing: Dr AR
Ramesh
Presence of impurities is emerging as a serious threat to Indian pharmaceutical manufacturing and
marketing. Impurities are found to be generated during the development of active pharmaceutical
ingredients (APIs) and at times during the formulation development, said Dr AR Ramesh, vice president
technical, R L Fine Chem.
Therefore, impurity control at early stages is vital and critical in drug development. Moreover, with global
regulatory authorities being strict about formulation stability, and stern on data accuracy and reliability,
testing for impurities is now compulsory at every stage of research and manufacture, he added.
Prior to 2000, an API was judged on its purity but now global regulators mandate assessment of a drug‘s
impurity profile. This is because impurities could be toxic and life threatening. It does not offer any
therapeutic value instead blocks the curative value of the drug, stated Dr Ramesh.
Impurities could be any substance: organic or inorganic material. The presence of impurities is

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unavoidable during the manufacture of an API. The origin of impurities is attributed to what gets into the
drug during manufacture and the processes involved. Now these could depend on manpower monitoring
the manufacturing operation who could overlook the production process and equipment function besides
environmental factors like faulty temperature controls, pointed out Dr Ramesh in a presentation on the
criticality of impurities in APIs at the KAAPTICON-2015, the first annual convention of Association of
Pharmaceutical Teachers of India (APTI) Karnataka state branch held recently.
According to Dr Ramesh, pharma industry needs to comprehend and control all the three aspects of
people, production process and environment to ensure impurity control.
Impurities can be classified as organic when it covers the critical raw materials and intermediates. Even
if companies adhere to good manufacturing practices and implement the best monitoring systems, yet
there is the issue of degradation of impurities which occurs on account of oxidation, photo degradation,
thermal degradation and side reactions. Residual of solvents, inorganic salts from the process and
presence of heavy metals are also some of other causes of impurities. Besides impurities like
genotoxics, polymorphic, stereoisomer's and geometric, isomers and construction material are also
reasons for contamination, he pointed out.
The pharma industry now needs to increase stringent surveillance going by the increasing product
withdrawals in global and Indian markets. The industry needs to adopt new methodologies and invest in
advanced instruments to ensure that impurities are detected at an early stage. Keeping tabs on impurity
profiles of drugs is the need of the hour. It also opens up promising job opportunities in R&D and
manufacture where impurity identification has become indispensable, said Dr Ramesh.
CDSCO asks health ministry to release Rs. 1600 cr under 12th Plan for strengthening
regulatory apparatus
Keen to strengthen the regulatory mechanism of the Centre and state drug regulatory bodies as per the
current requirements, CDSCO has urged the health ministry to release funds allocated under the 12th
Five-Year Plan at the earliest. The planning commission, under the 12th Five-Year Plan had allocated
an amount of Rs. 1600 crore for upgradation of the regulatory agencies, which is yet to be released by
the government.
The proposed financial outlay is understood to be utilized for manpower augmentation, creation and
upgradation of labs, setting up of new offices of drugs regulatory control, strengthening
pharmacovigilance and creating awareness among people both care givers and receivers regarding safe
drugs both at the Centre and in the states. The funds will also be utilized for providing financial and
human resource support to the states, as under the Centrally sponsored scheme.
Industry insiders however pointed out that the funds are still stuck in bureaucratic logjam, which is
leading to lot of confusion and developmental delays in its wake. It is understood that to meet the
growing demands, there is an urgent need to focus on developing the inadequate or weak drug control
infrastructure, testing facilities, IT services and manpower at both the state and central level.
Dr G N Singh, drug controller general of India (DCGI) informed that considering the necessity of this

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funds, his office has been in touch with the health ministry on this issue. ―Keeping in view the
recommendations of various committees and reports and based on our current requirements, it is
important that the government takes requisite steps to release the funds for infrastructural development,
both physical and human resource, at the Centre as well as in the states. Going by our commitment to
ensure that no compromise is done with the health of the patients in the country, we have been pushing
for this case with the government, persistently. In fact, in a recent meeting with them we had impressed
upon the need to hasten the process as strengthening of drugs regulatory mechanisms is one of the
major public health interventions,‖ he stressed.
Dr Singh further added that taking cognizance of the issue, government has assured to hasten the
process and has given positive feelers that they may clear the funds in a span of six months.
Data manipulation: India contests EU charges against GVK Bio
India has challenged the allegations of data manipulation levelled by European and French drug
regulatory agencies against GVK Biosciences.
New Delhi is ready to take ―commercial and legal action‖ against the European Union (EU) if it does not
react positively to evidence, a senior official told BusinessLine. It has supplied evidence to establish that
the clinical trials were authentic.
―We have met the European Medicines Agency (EMA) and the French agency and given them evidence
to show the tests by GVK Biosciences were not manipulated,‖ Commerce Secretary Rajeev Kher said.
Moving WTO an option
If there is no response soon, India will be constrained to take commercial or legal action against the
countries, Kher said. ―Legal action could be in the form of action at the World Trade Organisation,‖ he
said. Late last year, French medicines agency (ANSM) alleged that its inspection of GVK Biosciences,
Hyderabad, an Indian contract research organisation, revealed data manipulation of electrocardiograms
(ECGs), over five years, during research on generic medicines.
In January, the EMA gave its harsh recommendation that a number of medicines for which authorisation
in the European Union (EU) were primarily based on clinical studies conducted at GVK Biosciences in
Hyderabad should be suspended. ―The European agencies have suspected the clinical trials on grounds
that are absolutely flimsy. Not just GVK, but the companies for which the clinical trials were done, which
include several multinationals, have given a plethora of evidence to show that there was no
manipulation,‖ Kher said.
The government has even got independent cardiologists to examine the ECGs, and they have given
GVK a clean chit. ―We have asked EMA and some other European agencies to cross check the ECGs
and get back to us,‖ Kher said.
The Secretary said that there were just a few big multinationals that were driving an agenda against the
generic (off-patent drug) industry, affecting India‘s annual drug exports of $15 billion. ―It is important for
us to take the matter to its logical conclusion,‖ Kher said.
India‘s strong retaliation against the EU action comes at a time when both the US and EU are taking an
unprecedented number of measures against Indian pharmaceutical companies over quality issues.
―The past few years have seen a lot of action where the fault was not seen in the substance of the
medicines but in the processes. We feel that this approach needs to be tempered,‖ Kher said.

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Australian eCTD submissions
TGA has finalised the specification for the Australian electronic Common Technical Document (eCTD)
format submissions.
In late 2014, the TGA commenced a pilot of electronic Common Technical Document (eCTD) format
submissions using Version 0.9 of the Australian eCTD Module 1 and Regional Specification. As a result
of experience gained during the pilot and feedback provided during the consultation, the TGA has
developed the final version of the Australian eCTD specification:
 Readiness assessmentAustralian eCTD specification: Module 1 and regional information, Version
3.0
 Australian eCTD regional specification and validation criteria 3.0 (Microsoft Excel,5.74Mb)*
The pilot phase has demonstrated the feasibility of the eCTD format in Australia and now the final
version of the specifications is available for incorporation of the Australian eCTD and Nees profiles into
your regulatory submission publishing software package. We are targeting 1 July 2015 as the date for
first receipt of Australian eCTD format submissions based on Version 3.0.
Business guidance material is being developed and will be linked to this web page when available.
We are continuing to work on refining TGA systems and processes to handle electronic submissions
and this includes an update to the eBS application form to match the Australian eCTD specification. If
you are considering an eCTD format submission and need the application form before eBS is updated,
please request a copy by emailing your request to esubmissions@tga.gov.au(link sends e-mail).
Timeline
Submissions in version 3.0 of the eCTD format will be valid from 1 June 2015 onwards.
Submissions in version 0.9 of the eCTD specification will be valid up until 31 December 2015. Applicants
submitting after this date must use version 3.0 of the specification as it will not validate.
Non-eCTD electronic Submissions (NeeS)
The TGA has included a revised NeeS format to match the new eCTD format in the validation criteria.
Additonal NeeS Guidance material is being updated and will be made available on this page.
TGA continues to accept submissions in NeeS format but we are currently considering the policy in
relation to this and further advice will be published when available. Any proposed change to our
approach will be implemented with an appropriate transition period.
eSubmission identifiers
eCTD submissions rely on the eSubmission Identifier to create the top level folder. This then forms the
anchor for subsequent sequences and relative file referencing so that hyperlinks can refer to previously
submitted documents. Applicants who have chosen the eCTD format must continue in the eCTD format
for all future regulatory activities.
We are developing functionality within eBS to allocate eSubmission Identifiers to replace the current
email process. We are also considering allocating an eSubmission Identifier to all unique sponsor/active
ingredient combinations within the Australian Register of Therapeutic Goods (ARTG) and storing them in
each registration on the ARTG. If we proceed with this, we will inform you and include instructions on
how to look up the allocated eSubmission Identifier.

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Prior to the development of the eSubmission Identifier functionality within eBS, if you do not have an
eSubmission Identifier, please email a request to esubmissions@tga.gov.au(link sends e-mail) with:
 your name as recorded in eBS
 the active ingredient, in the form of the Australian Approved Name (AAN)
 dosage information.
The format for eSubmission Identifiers is a letter (e or n) followed by six numerals, e.g. n123456. If a
sponsor switches from NeeS to eCTD format submissions, the same number can be used, e.g. e123456
but there are no linkages between documents in the two formats.
Validation
Submissions, in either NeeS or eCTD format, must have no validation errors and minimal warnings in
order to be accepted. The following vendors have provided links to their validation tools which may be
used to ensure submissions are acceptable:
 LORENZ eValidator(link is external)
If you think additional validation tools should be listed here, please send a request
toesubmissions@tga.gov.au(link sends e-mail) and include relevant information for assessment.
Australian eCTD file downloads
The eCTD XML schema and related files are available from http://apps.tga.gov.au/downloads/(link is
external) and allow the possibility of automated access by eCTD publishing tools.
 Australian regional backbone schema for module 1 (xsd,12kb)(link is external)
 Style sheet for Australian regional backbone (xsl,28kb)(link is external)
 W3C schema for XLink1.1 (xsd,10kb)(link is external)
 W3C schema for XML namespace (xsd,6kb)(link is external)
 Style sheet for the code files (xsl,3kb)(link is external)
 Codes and defined lists for Regulatory Activity Lead (xml,1kb)(link is external)
 Codes and defined lists for Sequence Description (xml,4kb)(link is external)
 Codes and defined lists for the Sequence Type (xml,6kb)
Govt to amend Sch Y of D&C Rules pertaining to authenticity of data submitted by
applicants
The Union Health Ministry will soon amend the Note under Schedule Y of the Drugs and Cosmetics
Rules, 1945 regarding the authenticity of the data or documents submitted by the applicant.
The Note under Schedule Y provides that only authentic data should be submitted for the application for
permission to import and/or manufacture of new drugs for sale or to undertake clinical trials. The data is
required to be self certified. It also provides the licensing authority reserves the right to reject any data or
any document(s) if such data or content of such document are found to be of doubtful integrity.

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However, the above provision does not explicitly provide for the administrative action which could be
taken in case any data on documents submitted is found to be of doubtful integrity.
It is therefore proposed that the note may be amended to read as: "Note.- The data requirements stated
in this Schedule are expected to provide adequate information to evaluate the efficacy, safety and
therapeutic Rational of new drugs (as defined under Rule 122-E) prior to the permission for sale.
Depending upon the nature of new drugs and disease(s), additional information may be required by the
Licensing Authority. The applicant shall certify the authenticity of the data and documents submitted in
support of an application for new drug. The Licensing Authority reserves the right to reject any data or
application or debar the applicant for a specific period to make any application to the office of Drugs
Controller General (I) as the case may be if such data or contents of such documents are found to be of
doubtful integrity."
The came up for discussion during the recently held Drugs Technical Advisory Board (DTAB) meeting.
The DTAB after deliberations agreed to the proposed amendment.
International convergence: Australia’s TGA proposes to adopt 10 EMA guidelines
In a sign that pharmaceutical regulators are merging their regulations further, Australia’s TGA
(Therapeutic Goods Administration) is seeking to adopt 10 EMA (European Medicines Agency)
guidelines on quality, biologics, clinical efficacy, safety, and more.
More specifically, the TGA is seeking public comment until May 22 on the adoption of ICH guidelines Q9
and Q10, which deal with quality risk management and pharma quality systems, as well as EMA
guidelines that will replace other, older guidelines first developed by the TGA.
For instance, the TGA is looking to replace parts of its guideline on the quality of modified release
products with the EMA‘s guideline on the quality of transdermal patches. Australia may also see the
EMA‘s guideline on Active Substance Master File Procedure come into effect soon.
If the guidelines are adopted, some of them, such as the EMA‘s most recent biosimilar guidelinefrom last
October, would be adopted by the end of the month to replace a guideline that had been in use since
2000. Others, though, like the EMA‘s guideline on biosimilars containing biotechnology-derived proteins
as active substance, might not make it into the TGA‘s regs until July.
This isn‘t the first time the TGA has sought to be more aligned with the EMA. Back in 2011, the TGA
adopted 15 other EMA guidelines on residual solvents, genotoxic impurities and other GMP topics.
The latest announcement seeking comment on the adoption of these EMA guidelines comes as the TGA
announced last October that it would conduct an independent review of its medicines and medical
device regulations in general as a way to streamline its efforts.
The review seeks to identify areas of unnecessary, duplicative, or ineffective regulation that could be
removed without undermining the safety or quality of medical products, as well as to find opportunities to
enhance the regulatory framework so that Australia can respond effectively to global trends in the
development, manufacture, marketing and regulation of therapeutic goods.

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Draft qualification opinion of qualification of exacerbations of chronic pulmonary
disease tool (EXACT), and EXACT-respiratory symptoms measure (E-RS) for evaluating
treatment outcomes in clinical trials in chronic pulmonary disease
The EXACT-PRO Initiative (EXAcerbations of Chronic Pulmonary Disease Tool – Patient-Reported
Outcome) brought together clinical, research, methodology, and regulatory experts to develop a new
patient-reported outcome (PRO) instrument to standardize the symptomatic assessment of
exacerbations of COPD for evaluating frequency, severity, and duration of exacerbations in clinical trials
of COPD (―EXACT‖, 14-items PRO).
Compilation of individual product-specific guidance on demonstration of bioequivalence
The general European Union requirements for bioequivalence demonstration are laid out in the
Guideline on Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1). In addition, the CHMP
started in 2009 to publish positions addressing specific questions in relation to the requirements and
assessment of bioequivalence studies (EMA/618604/2008). This document describes the regulatory
view on product specific aspects related to the demonstration of bioequivalence, based on previous
assessments of generic medicines. This should facilitate transparent, predictable and scientifically
robust evaluation of future generic marketing authorisation procedures.
FDA Issues Import Alert Agaisnt VUAB Pharma for CGMP Deficiencies
Import Alert # 66-40 Published Date: 04/10/2015
Type: DWPE Import Alert Name:
"Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs"
Reason for Alert:
*** Foreign inspections of pharmaceutical manufacturers are being performed. Detention without
physical examination may be appropriate when an FDA inspection has revealed that a firm is not
operating in conformity with current good manufacturing practices (GMP's).
Detention without physical examination may also be appropriate when FDA receives information
concerning inspections conducted by foreign or other government authorities under a Memorandum of
Understanding or other agreement that FDA concludes reveals conditions or practices warranting
detention of either particular products or all products manufactured by a firm.
DWPE of such firms remains in effect until such time as FDA is satisfied that the appearance of a
violation has been removed, either by reinspection or submission of appropriate documentation to the
responsible FDA Center. ***
Guidance:
*** Districts may detain, without physical sampling and analysis, the indicated drug products from the
foreign processors noted in the Red List of this import alert.

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Foreign processors listed on the Red List of this import alert who would like to request removal from that
list should provide information to FDA to adequately demonstrate that the manufacturer has resolved the
conditions that gave rise to the appearance of the violation, so that the agency will have confidence that
future entries will be in compliance. This may include a letter detailing its corrective actions,
accompanied by documentation. For guidance on removal from detention without physical examination,
refer to FDA-s Regulatory Procedures Manual, Chapter 9, "Detention Without Physical Examination
(DWPE)." Information supporting removal should be sent to CDER's Office of Compliance, (HFD-300).
***
Product Description: Various drugs
Charge:
"The article is subject to refusal of admission pursuant to Section 801(a)(3) in that the methods and
controls used in its manufacture and control of pharmaceutical products do not appear to conform to
current good manufacturing practices within the meaning of Section 501(a)(2)(B)."
OASIS Charge Code: DRUG GMPS
VUAB Pharma a.s.
Date Published : 04/10/2015
Vltavska 53 , Roztoky, CZECH REPUBLIC
55 - - - -- Pharm Necess & Ctnr For Drug/Bio Date Published: 04/10/2015
Notes:All drugs Problem(s): (GMP) Good Manufacturing Practices
56 - - - -- Antibiotics (Human/Animal) Date Published: 04/10/2015
Notes:All Antibiotics Problem(s): (GMP) Good Manufacturing Practices
60 - - - -- Human and Animal Drugs Date Published: 04/10/2015
Notes:All drugs Problem(s): (GMP) Good Manufacturing Practices ;

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Glaxo Plans Changes to Compensation Program for U.S. Sales Team
GlaxoSmithKline Plc, which replaced the head of its struggling U.S. operations in February, is
considering changes to its compensation model for sales staff, according to an internal memo obtained
by Bloomberg News.A task force is looking at ―more comprehensive options to simplify the Patient First
program‖ for incentive pay and will provide a report within a month, London-based Glaxo said in an April
1 statement to its U.S. sales employees. Sarah Alspach, a spokeswoman for the U.K.‘s largest
drugmaker, confirmed the contents of the memo.The review of the compensation model underscores the
pressure on Chief Executive Officer Andrew Witty to revive U.S. operations, which account for almost a
third of Glaxo‘s sales. The Patient First program was put in place in 2011 to end the focus on sales
targets following allegations that Glaxo had illegally promoted drugs and failed to report key safety
data.The company suspended some training programs for April and May while the review is underway in
response to ―feedback from the field,‖ according to the note, which was sent to sales employees
following a March 23 announcement by U.S. pharmaceuticals head Jack Bailey about the changes.
Bailey, who joined Glaxo in May 2009, replaced Deirdre Connelly on Feb. 16.―We remain resolutely
committed to our commercial model,‖ Glaxo said in an e-mailed statement today. ―Glaxo has led the
industry by changing the way we reward our sales representatives.‖
Bonus Targets
The Patient First program was rolled out in 150 countries earlier this year, according to the
company.U.S. sales staff will be paid their target bonus for a portion of the year while the compensation
system is under review, according to the memo earlier this month.―This pause allows us to concentrate
our attention on program improvements to be implemented in the second semester,‖ Glaxo told
employees. ―Until then, it is critical that our focus be on driving performance, and that we use the
removal of the simulations to increase business performance.‖Under the Patient First model, bonuses
are based on scientific knowledge, selling competency, customer evaluations and overall performance
of the representative‘s business unit, rather than linked to meeting sales targets. In November, Glaxo
amended the program to change the way sales professionals were tested on knowledge of products as
part of their evaluation, two people familiar with the matter said at that time.Glaxo‘s U.S. sales are
flagging amid increased competition for the company‘s best-selling Advair asthma medication. The
company is trying to establish new respiratory drugs in the U.S. to help replace the lost sales of Advair,

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and pledged in October to cut costs by 1 billion pounds ($1.54 billion) over three years, with half the
savings coming in 2016.
In December, Glaxo said it would cut 900 jobs in North Carolina, in its commercial and research
operations. The drugmaker has about 98,000 employees in 115 countries. Most of its U.S. staff are at
North Carolina‘s Research Triangle Park and in Philadelphia.
Counterfeiting in Reimport of Viread in the legal Supply Chain
Counterfeit medicines in the legal supply chain are increasingly becoming a problem. Experts are sure
that counterfeiters will try more and more to sell fake medicines not only via the Internet, but through
"infiltrating" them into the legal supply chain - meaning pharmaceutical wholesalers and pharmacies.
Another case in a reimport became known now. The company of Gilead Sciences is the holder of the
marketing authorisation of the HIV drug Viread (Tenofovir) in Germany. The importers Medicopharm and
Axicorp (import to the German market) call back the batch 13VR029D because of obvious manipulations
of the packaging. According to issue 15 of the German Pharmacist Newspaper (Deutsche Apotheker
Zeitung) Axicorp reported that the film-coated tablets contained in the package have been identified as
counterfeits. As the (German) Portal adhoc online pharmacy informs the counterfeit tablets are included
in the original Gilead sealed packaging.
Just recently the Italian authority AIFA had published their research on illegal and stolen medicines in
parallel sales. Background is that end of March 2014 manipulated Herceptin from a theft in Italy was
noticed at a parallel distributor in Germany. Thus, it became apparent that the theft is not an isolated
case, but that medicines were repeatedly introduced illegally in the distribution chain in Italy. A press
release on the German website of the (German) Paul Ehrlich Institute states: "Based on calculations
more than 390 illegal transactions could be identified, partly again through multiple intermediaries. It is
possible that there will be further findings of illegal drug supplies in the still ongoing investigations in
Italy."
FDA to Extend Comment Period on Proposed Rule on Abbreviated New Drug
Applications and 505(b)(2) Applications
FDA has decided to extend the comment period by 30 days for the proposed rule on ―Abbreviated New
Drug Applications [ANDAs] and 505(b)(2) Applications.‖ The comment period on the proposed rule will
be extended to June 8, 2015. This extension is being provided in response to requests to provide
interested persons with additional time to submit comments. FDA is expediting publication of a notice in
the Federal Register to extend the comment period.
In the Federal Register of February 6, 2015, FDA published a proposed rule with a 90-day comment
period to request comments on its proposal to implement portions of Title XI of the Medicare
Prescription Drug, Improvement, and Modernization Act of 2003, which amended provisions of the
Federal Food, Drug, and Cosmetic Act (FD&C Act) that govern the approval of 505(b)(2) applications
and ANDAs. FDA also requested comment on its proposal to amend certain regulations regarding

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505(b)(2) applications and ANDAs to facilitate compliance with and efficient enforcement of the FD&C
Act. Comments on the proposed rule will inform FDA's rulemaking on ANDAs and 505(b)(2)
applications.
Submit comments electronically to the FDA docket on http://www.regulations.gov, use docket number
FDA-2011-N-0830.
To submit comments by mail, send to FDA at:
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852
Health Canada Launches New Drug and Product Inspections Database
Health Minister Rona Ambrose today launched the Drug and Health Product Inspections Database, a
new online resource designed to provide ready access to information on inspections of companies that
manufacture and sell drug products for the Canadian market. Canadians can search the site for
information on inspection findings, including which companies have a good history of meeting safety and
quality standards and which do not.
The tool provides centralized access to plain-language, timely information on inspections. Canadians
can use this information to have a better understanding of how Health Canada is enforcing -- and how
companies are meeting -- Canada‘s high standards for drug safety and quality.
Drugs made in Canada or abroad must meet standards known as Good Manufacturing Practices, which
are internationally accepted and enforced by health product regulators. Health Canada licenses and
regularly inspects companies that make, package/label, test, import, distribute and wholesale drugs. The
searchable Drug and Health Product Inspections Database brings together key data about drug
establishments and inspection results, including detailed report cards from inspections of drug
establishments in Canada and abroad.
The new tool is a milestone under the Regulatory Transparency and Openness Framework, Health
Canada‘s plan for improving access to timely, useful and relevant health and safety information for
Canadians.
Quick Facts
 The searchable web tool provides information on both foreign and domestic drug inspections
conducted by Health Canada and abroad since 2012.
 Onsite drug inspections are carried out on more than 400 drug companies every year in Canada.
 Health Canada also publishes the Inspection Tracker, which provides a snapshot of emerging
issues identified through the inspection program and the actions Health Canada is taking.
 This announcement builds on progress Health Canada has already made under the Regulatory
Transparency and Openness Framework, including the recent launch of the Drug and Health

PHARMA UPTODAY
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Product Register, a new tool designed to become the go-to resource for Canadians looking for
quick access to information on hundreds of prescription drugs.
Quotes
―Canadians deserve to know that they can trust the health products they use. While Health Canada has
always enforced internationally accepted manufacturing standards to help ensure the medicines we take
are safe and of high quality, Canadians can now have a better understanding of exactly how Health
Canada does this and how companies are measuring up.‖
Rona Ambrose – Minister of Health
EMA Introduces New Measures to Prevent Medication Errors in the EU
The good practice guide clarifies specific aspects related to recording, coding, reporting and the
assessment of medication errors in the context of EU pharmacovigilance activities with the objective of
improving reporting and learning from medication errors for the benefit of public health.
Reference number EMA/762563/2014
Status draft: consultation open
First published 14/04/2015
Last updated 14/04/2015
Consultation start date 14/04/2015
Consultation end date 14/06/2015
Email address for submissions medicationerrors2013@ema.europa.eu
Source: http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/document_detail.j
sp?webContentId=WC500185536&murl=menus/document_library/document_library.jsp&mid=0b01ac05
8009a3dc

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The good practice guide clarifies key principles of risk management planning in relation to medication
errors and describes the main sources and categories of medication errors and how the risk of such
errors can be minimised throughout the product life cycle.
Reference number EMA/606103/2014
Status draft: consultation open
First published 14/04/2015
Last updated 14/04/2015
Consultation start date 14/04/2015
Consultation end date 14/06/2015
Email address for submissions medicationerrors2013@ema.europa.eu
Source: http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/document_detail
.jsp?webContentId=WC500185538&murl=menus/document_library/document_library.jsp&mid=0b01ac0
58009a3dc
FDA Unveils $1 Million Postmarket Surveillance Grant
The FDA is offering a grant of up to $1 million to turn large amounts of electronic health record data into
usable figures highlighting postmarket risks of various drugs. The goal is for the agency to be able to
perform continuous risk/benefit assessments of drugs after they hit the market.
Eligibility for the grant is limited to the Reagan-Udall Foundation through its Innovations in Medical
Evidence Development and Surveillance-Methods program.
The FDA announced plans in January to build a database of electronic health records as part of the
Mini-Sentinel project. There are roughly 150 million patient records online, and the agency is hoping the
foundation will develop analytical processes that can turn that raw data into clear safety trends.
The endeavor should focus not only on the best uses of that data, while understanding its limitations, but
also account for biases in observational studies, the FDA says.

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EDQM seeks industry input on water for injection monograph revision
The EDQM is revising its water for injection (WFI) monograph to accomodate cheaper and
greener alternatives to distillation and has called on injectable drugmakers to contribute.
The in-progress revision is designed to allow for producers to use non-distillation technologies for the
production of water for injection (WFI ).
It will bring the European Pharmacopoeia more closely into line with monographs in the US and Japan.
The revision comes after decades of debate in Europe about which technologies are appropriate for
pharmaceutical water production.
Distillation has been the primary method for producing water used in injectable drugs for many years,
which contrasts with other industries where reverse osmosis (RO) and ultrafiltration (UF) have been
accepted methods for almost as long.
Revision
Initial calls for revision of the WFI monograph in the late 90s were rejected on the basis that there was a
lack of evidence to support the efficacy of RO, particularly in relation to its ability to prevent microbial
contamination.
In 2010 the European Directorate for the Quality of Medicines & HealthCare (EDQM) set out to see if
more supportive data was available and found that firms using such membrane-based technologies
were consistently able to meet specs detailed in the monograph
The finding did not prompt a revision because – as the EDQM noted at the time – most firms using RO
also used UF and ultraviolet or ozone treatments. In addition, most had access to high-quality feed
water.
Subsequent discussion of the findings by regulators and the drug industry acknowledged that
membrane-based tech manufacturers have advanced prompting the European Pharmacopoeia to
recommend revision of the monograph.
Webinar for industry
From a drug industry perspective other factors also came into play according to the EDQM, which told
us ―It seems that the advantage of using non-distillation technologies for the production of water for
pharmaceutical use is linked to cost savings and sustainability benefits.”
The Strasbourg-headquartered organisation added that ―use of such production systems is considered
to help build green economy.‖
The EDQM is holding a free online webinar for drugmakers and other industry stakeholders to learn
about the monograph revision and its implications for the production of injectable pharmaceuticals.
The organisation told us "we are organising this webinar to raise awareness about the revision process
and to ask stakeholder to contribute, the idea behind is to be sure at the end of the process to have
captured all issues."
Registration details are available here .

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IPA urges DCGI to issue guidelines for specific storage temperature details on drug
labels
Concerned over non compliance in storage temperature instructions on medicine labels, the Indian
Pharmaceuticals Association (IPA) urged the Drug Controller General of India (DCGI) to immediately
take cognizance on the matter and take appropriate steps.
Considering the huge health risk associated with this negligence, IPA has suggested the Centre to
amend the drugs and cosmetics rules in lines with the DTABs recommendations and proposed good
distribution practices (GDP), while considering the suggestions of the association as well.
IPA made these observations based on an extensive study done on the labels of thousands of medical
products available across the Indian market. They found that there is complete non-uniformity in the
storage instructions of the labels of the pharma products. In fact, such is the situation that some of the
products do not even carry any storage temperature instruction on the label.
Experts cite that the only way to tackle this issue is by coming out with a clear-cut, unambiguous storage
temperature instruction guidelines, with mandatory requirements of mentioning proper storage
temperature on label. They strongly stressed that it should be made mandatory to mention minimum
specific storage temperature or else the product should be termed misbranded.
Another disturbing trend they noticed is that many of the products carry storage temperature instruction
like ‗store at room temperature‘, ‗store in a cool place‘, or ‗store between 2 degree C to 8‘, or ‗do not
store between 25 degree C‘ etc. which is confusing and very difficult to comprehend for a lay man. Most
importantly, IPA noted that having such ambiguous statements is highly risky as the room temperature
across the country varies widely, so does the temperature as per the changing climate.
IPA in its representation to the DCGI urged that using such confusing statements in the labels should be
completely stopped, instead replacing it with specific temperature requirements. Kaushik Desai, general
secretary of the IPA stressed that it is essential to mention precise room temperature on the label, which
includes upper as well as lower temperatures of storage range, while deleting all other unnecessary
wording that may confuse people.
He further pointed that there is an urgent need to bring about stringent, and uniform scientifically sound
guidelines for labeling of storage temperature requirements of drugs. ―Keeping in view with such serious
variation in the labeling, there is an urgent need to have very specific rules for mentioning the storage
temperature specifications on medicines' label. As this will go a long way in assisting and guiding the
stakeholders in the transport and storage chain as well as the public to properly decipher and
understand at what temperature the medicines needs to be kept. Also steps should be taken by the
CDSCO to immediately implement the proposed GDP,‖ he insisted.
The Central Drugs Standard Control Organization (CDSCO) in 2013 had published a draft GDP for
pharmaceutical products. The aim behind this was to ensure consistent quality of pharma products
throughout the distribution process where all parties in the supply chain contribute to maintaining the
quality of products until they reach the patient.

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EC Considering Amending Medicines Authorization Procedures
On the proposal for a regulation of the European Parliament and of the Council amending Regulation
(EC) No 726/2004 laying down Community procedures for the authorisation and supervision of
medicinal products for human and veterinary use and establishing a European Medicines Agency.
Source: http://www.europarl.europa.eu/sides/getDoc.do?type=COMPARL&reference=PE-
552.048&format=PDF&language=EN&secondRef=01
The "Industry Coalition" gives practical advice for the control of elemental impurities in
active substances and excipients
The requirements of the "Guideline for Elemental Impurities ICH Q3D" published in December of last
year mean a considerable expense for the affected pharmaceutical companies and drug manufacturers
in terms of laboratory and personnel upgrading (see also our news about "ICH Q3D - Elemental
Impurities" of 07 January 2015). In addition, the deadlines for the implementation of this guideline are
quite tight. (June 2016 for newly approved drugs and December 2017 for already approved drugs, see
our news "CHMP adopts ICH Q3D Guideline as "Scientific Guideline" of 21 January 2015).
In the March issue of "Pharmaceutical Technology Europe", an article of the "Industry Coalition" has
been published with the title "Implementation of ICH Q3D Elemental Impurities Guideline: Challenges
and Opportunities", which is intended to support the efffected companies with a number of pragmatic
pieces of advice in the implementation of these requirements.
The "Industry Coalition" (exact name: "Coalition for Rational Implementation of Elemental Impurities
Requirements") is a consortium of economic/industrial associations (members include IPEC Europe,
IPEC Americas, The Generic Pharmaceutical Association GPhA, etc.) and has been in existence since
2011. The aim of the coalition is to provide information regarding elemental impurities. To this end, the
Coalition has developed a standardised procedure (standardised information request) according to
which specific information can be requested through the use of a form. More information about the
"Industry Coalition", their goals and projects can be found in a Position Paper which appeared in
"Pharmaceutical Technology Europe" in November 2012.
The Guideline ICH Q3D calls upon drug manufacturer to conduct a risk assessment as part of a strategy
for the control of element impurities, but without specifying which aspects need to be considered in such
an assessment. Here, the article of the "Industry Coalition" provides helpful hints; it is described how, for
example, production equipment (various types of steel), processing aids (activated carbon, silica gel,
etc.), inorganic reagents, solvents, packaging materials and closure systems are to be included in the
risk assessment. A detailed section is dedicated to the subject of excipients, regarding which the
assessment of risks is often particularly difficult in terms of element impurities, due to the unclear origin
or the complex composition of the excipients.
The approaches described by the "Coalition" may be useful for many companies in their efforts to meet
the requirements of the Guideline ICH Q3D. In this context, the document which has recently been
published by the EMA entitled "Elemental impurities in marketed products. Recommendations for
implementation" should also be considered.

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GDP: Is Temperature Control required for each Transport?
The EU Good Distribution Practice (GDP) Guidelines (2013/C 343/01) revised in 2013 reflect the
requirements and expectations of the authorities during the transport and distribution of medicinal
products in a very detailed way. Nevertheless, there are still questions and insecurities.
Especially questions on temperature control during transport are recurring. This question is examined in
detail in a corresponding questions and answers paper of the German ZLG (Zentralstelle der Länder für
Gesundheitsschutz bei Arzneimitteln und Medizinprodukten/ Central Authority of the German Federal
Länder for Health Protection Regarding Medicinal Products and Medical Devices) (in German
language).
Here, it is stated that a temperature control is not required for each transport:
"If no constant monitoring of temperature is carried out during the transport of medicinal products a risk
assessment must be made of the transportation routes. This includes especially the travel duration
including special aspects of the route, the time of year and day, including the weather forecast, the
vehicles used and their equipment. The results of this risk assessment have to be part of the
transportation planning."
But at the same time this means that monitoring has to be done if no risk assessment was carried out or
if the risk assessment led to the result that a temperature control is necessary.
According to the ZLG document a lot of things have to be considered when carrying out the risk
assessment:
 The mean kinetic temperature (MKT) cannot be used. The reason is that it does not take into
consideration effects "that may lead to irreversible quality defects even when certain temperature
limits that are established during stability studies in connection with the marketing authorisation
are exceeded only for a short time. And it does not take into consideration the possible formation
of fissures in the glass of ampoules and injection bottles at temperatures around the freezing
point. Furthermore, calculation of the MKT requires that the temperature profiles of all transports
are known that have been carried out previously. But usually this data is not available ...."
 In order to assess deviations "appropriate procedures" must be established.
 Storage conditions must generally be respected also during transportation. "Only in cases
that according to the packaging or the confirmed written information given by the manufacturer,
the pharmaceutical entrepreneur or the marketing authorisation holder. a transport within the
aforementioned temperature range will not reduce the quality" this temperature range can be
handled more generously. It has been demonstrated for example "in connection with the
marketing authorisation of medicinal products on the labelling of which only storage between +2
and +8 °C is indicated that they remain sufficiently stable even if the temperature rises up to +25
°C for a short time."

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The new requirements of the "Guidelines on the formalised risk assessment for
excipients"
The most important document so far as concerns "GMP for excipients" was published in the Official
Journal of the European Union this year on 21 March. It has the somewhat ponderous title "Guidelines
of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good
manufacturing practice for excipients of medicinal products for human use" (document classification:
2015/C 95/02). We reported on this in our news "EU Commission issues two final Guidelines: GMP for
Excipients and GDP for APIs".
During the longer than two years period after the publication of the draft of these guidelines the
fundamental principles for ascertaining the appropriate good manufacturing practice formulated in the
draft were the main guides and the pharmaceutical industry had time to adapt to these requirements.
But the now valid final guidelines differ considerably from the draft document. This means the
companies concerned are now faced with additional requirements and they face the challenge to
implement these requirements for medicinal products being in the process of
development immediately and for medicinal products already authorised until 21 March 2016.
The following summary lists the newly formulated additional requirements from the final document that
were not already included in the guideline draft.
Determination of appropriate GMP based on type and use of excipient
The manufacturing authorisation holder should take into consideration the following:
 potential for any impurities carried over from other processes, in absence of dedicated
equipment and/or facilities;
 cold chain management, if appropriate;
 supply chain complexity;
 stability of excipient;
 packaging integrity evidence;
 known fraudulent adulterations related to the use and function of each single excipient;
 other factors identified or known to be relevant to assuring patient safety for each excipient;
 qualification program of suppliers;
 change management and deviation management system;
 environmental controls and storage conditions.
Confirmation of application of appropriate GMP
Once the appropriate GMP for the excipient and the risk profile of the excipient manufacturer have been
determined, ongoing risk review should be performed through mechanisms such as:
 monitoring and trend analysis of excipient quality;
 observed organisational, procedural or technical/process changes at the excipient manufacturer;
 questionnaires;

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 based on the outcome of the risk review, the established control strategy should be reviewed and
revised if needed.
The requirements for ascertaining and ensuring the appropriate GMP laid down in the new guidelines
are rather challenging as a whole. The initial expense is enormous since the "GMP made-to-measure"
has to be defined not only for each single excipient but also for each pharmaceutical form (if the same
excipient is used in different pharmaceutical forms). The pharmaceutical companies concerned must
now extent their risk profiles for excipients already drawn up according to the new requirements.
Additionally, the appropriate GMP and the required two risk profiles (for the excipient and the
manufacturer of the excipient) must be drawn up for all authorised products in less than one year (!).
The new guidelines are also part of the EU GMP-Guideline Part III (Eudralex - Volume 4). They can be
found there in the respective national language of the EU member states.
New comprehensive GMP Inspection Database available
Just recently a so called "inspection tracker" was launched by Health Canada. Now, the agency offers
an additional database which contains 3,821 inspections (per March 2015) which have been performed
since 2012 - many of them outside Canada, e.g. in Europe or Asia. The information is available in an
online database. The use of the database is very easy and search results are excellent.
By using the database even inspections in progress can be displayed. This is a service no other agency
can provide. The database also offers further information about past inspections at the same production
site. No further search is necessary because the information about past inspections will be displayed in
the search result for a given production site. The rating of the inspection is also provided, and in case of
GMP non compliance a detailed and very structured information about the findings is provided. The
quality of information about the outcome of the inspection available from the database is outstanding.
Again, no other agency worldwide is able not only to list the observations but also link them to the
concrete GMP regulation paragraph in a structured and numbered table.
The database also provides information about past and present non-compliance situations. However, it
also shows when a company is currently licensed by Health Canada, as the company possibly improved
its GMP status and was licensed again.
The database allows three different options to search for information. The first option contains 1,301
Inspections (per March 2015) from the past three years performed in Canada. A second option allows to
access the non-compliance information. Currently 52 production sites with non compliance statements
are listed in the database (some of the sites received their license again after re-inspection). The third
option offers access to 2,520 inspections (per March 2015) performed outside of Canada.
To access the database please visit Health Canada Drug & Health product Inspections Webpage

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Evaluation of biosimilars - TGA guideline under review
Guideline under review
The understanding of biosimilar medicines is evolving and as a result the current guideline 'Evaluation of
Biosimilars' may need to be updated.
Therefore, in addition to TGA undertaking a review of the policy about the naming convention for
biosimilars (see below), the TGA is currently reviewing the rest of the TGA guideline on the Evaluation of
Biosimilars.
If you want further information or are intending to submit an application to register a biosimilar medicine,
you should seek advice early about the evaluation of biosimilars by emailing your query
tostreamlinedsubmission@tga.gov.au(link sends e-mail).
Naming conventions for biosimilars
21 January 2015
Following recent international developments in the area of biosimilar naming the TGA will not be
continuing with the previously proposed naming convention for biosimilars while a review of the policy is
undertaken.
In July 2013 the TGA published guidance on biosimilar naming based upon the combination of a
WHO Programme on International Nonproprietary Names (INN) issued biosimilar identifier with the
Australian biological name (ABN). In July 2014 the WHO - INN published a draft policy 'Biological
Qualifier - An INN Proposal'. This proposal has superseded the previous INN position on which the TGA
policy was based. This means the TGA biosimilar naming convention described below cannot be
implemented and the TGA is undertaking a review of the policy.
In the interim biosimilars will use the Australian biological name without a specific biosimilar identifier
suffix, for example a biosimilar to the reference product Neupogen filgrastim would be named
'TRADENAME' filgrastim.
30 July 2013
Introduction
'Evaluation of biosimilars' is an initial guideline on the regulation of biosimilar products. As the TGA's
understanding of these products is still evolving, this document will be updated from time to time. If
you would like to provide feedback to the TGA on this document please contact info@tga.gov.au(link
sends e-mail).

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The purpose of the guidance is to:
 Assist sponsors to identify the data necessary to support applications for the registration of
biosimilars
 Clarify the scientific and regulatory principles used by the TGA to evaluate those applications.
This guidance refers solely to the evaluation of biosimilars.
Most biosimilars are likely to contain biotechnology-derived proteins as the active substance(s), but this
guidance also applies to other biosimilars such as those consisting of:
 vaccines and monoclonal antibodies
 polysaccharides, such as low molecular weight heparins.
Contents
 What is a biosimilar?
 The legislative provisions for the evaluation of biosimilars
 The evaluation of biosimilars
 Reference products for biosimilars
 In-house primary reference standard for biosimilars
 Comparability studies for evaluating biosimilars
 Extrapolation of indications
 Post registration regulation of biosimilars
 Pharmacovigilance of biosimilars
 Naming conventions for biosimilars
 Labels, product information (PI) and consumer medicine information (CMI) for biosimilars
 Appendix 1 – Suggested techniques for inclusion in comparability studies.
Version history
Version Description of change Author Effective date
V1.0 Original publication Office of Medicines Authorisation 1/07/2013
Mylan introduces MyHep tablets in India to treat chronic hepatitis C
Mylan Pharmaceuticals has introduced generic version of Sofosbuvir 400mg tablets in India under the
brand name MyHep.
The tablets are indicated to treat chronic hepatitis C, a blood-borne infectious disease, as a component
of a combination antiviral treatment regimen.

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The virus affects over 100 million people in the developing world, including around 12 million people who
are chronically infected with hepatitis C in India.
Mylan has non-exclusive rights to manufacture and distribute generic Sofosbuvir in 91 developing
countries, including India.
The company secured product rights from Gilead under a licensing and technology transfer agreement
signed by the two firms in September 2014.
Mylan president Rajiv Malik said: "The launch of Mylan's MyHep offers hope to millions of hepatitis C
patients in India who are in need of a high quality, effective and affordable treatment option.
"We look forward to bringing that same hope to millions of more hepatitis C patients as we expand
access to MyHep in the developing world."
The company said that MyHep is an important addition to its growing commercial business in India and
is sold by its dedicated sales force as part of its Hepato Care segment
Mylan rejects Teva’s $40.1 billion cash and stock offer
Mylan has announced that its Board of Directors has unanimously rejected the unsolicited expression of
interest from Teva Pharmaceutical Industries to acquire the Company. Teva made a $40.1 billion cash
and stock offer for Mylan on 21 April 2015.
If Mylan had accepted the offer, the merger would have been the biggest in the pharmaceutical
industry this year.
After a comprehensive review conducted in consultation with its financial and legal advisors, the
Mylan Board concluded the approach did not meet any of the key criteria that would cause the
Mylan Board to consider engaging in discussions to sell the Company.
Mylan will not ―entertain offers that grossly undervalue the company‖
Robert J. Coury, Mylan Executive Chairman, commented, ―Our Board has a very important
fiduciary obligation to protect the best interests of the Company‘s shareholders and other
stakeholders, and has always been open to considering all paths forward in that regard, and this
situation is no different. However, that does not mean we will entertain offers that grossly
undervalue the company, and leave our shareholders and other stakeholders exposed to serious
risk.
―After thorough consideration, Mylan‘s Board unanimously determined that Teva‘s proposal
grossly undervalues Mylan, and would require Mylan‘s shareholders to accept what we believe
are low-quality Teva shares in exchange for their high-quality Mylan shares in a transaction that
lacks industrial logic and carries significant global antitrust risk. In addition, we also believe that
the proposal does not address the serious challenges of integrating two fundamentally different
and conflicting cultures under a Teva Board and leadership team with a poor record of delivering
sustainable shareholder value. We believe that these challenges would make it very difficult to
generate value from this combination for Mylan shareholders.

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29
―Furthermore, the proposal contains nothing meaningful indicating why a combination with Teva
would be in the best interest of Mylan‘s employees, patients, customers, communities and other
stakeholders. In summary, the Board determined that Teva‘s expression of interest is not in the
best interests of Mylan, its shareholders or other stakeholders, and we believe that this is only a
mere attempt by Teva to frustrate and distract Mylan from its business plan and strategy.‖
Meanwhile Mylan remains committed in its own pursuit of Perrigo in a separate $32 billion cash-and-
stock proposal. This equates to $60 per Perrigo share and an offering of 2.2 Mylan shares per Perrigo
share. Perrigo has issued a statement rejecting this offer and has advised shareholders to take no
action in relation to the offer.
Celgene to buy Quanticel Pharmaceuticals for $485m
Celgene has entered into a definitive share purchase agreement to acquire US-based cancer drug
discovery firm Quanticel Pharmaceuticals for about $485m. As part of the deal, Celgene will make an
upfront payment of $100m in cash and an additional $385m in contingent payments upon research,
development and regulatory advances.
The acquisition, which is subject to customary closing conditions, is expected to help advance Celgene's
pipeline of new cancer therapies.
Celgene Research and Early Development president Tom Daniel said: "This acquisition brings into
Celgene a highly productive, innovative organization deploying a unique platform of high strategic value.
"More than acquiring the great team, the novel technology, and the drug candidates, the deal validates
an innovative approach to building organizational capabilities."
The deal, which has its roots in a 2011 strategic alliance between the two firms, gives Celgene full
access to Quanticel's proprietary platform for single-cell genomic analysis of human cancer, as well as
its lead programs targeting specific epigenetic modifiers.
Celgene said in a statement that multiple drug candidates from Quanticel are expected to enter the clinic
in early 2016.
Quanticel chief executive officer Steve Kaldor said: "Celgene made clear from the start that they valued
both our technology and our team, and this resulted in an extremely collaborative and productive
partnership over the past three years.
"We look forward to supporting the continued maturation of our pipeline and platform as a part of the
Celgene organization."
First HIV home test goes on sale in the UK
The self-proclaimed most accurate HIV home-testing kit in the World has been launched across the UK,
in the hope of reducing the number of undiagnosed cases in circulation.

PHARMA UPTODAY
30
The BioSURE HIV Self Test requires just a tiny drop of blood for a simple-to-read result in 15 minutes,
with 99.7% accuracy from three months after infection, and is the only such product approved for sale in
the UK.
It is thought that around 26,000 people in the UK are unaware that they are carrying HIV, and thus risk
unknowingly infecting thousands more with the disease.
Also, as early diagnosis is key to attaining the best outcomes, patients would massively benefit from
receiving treatment as soon as possible.
―We know that if people are diagnosed with HIV and start treatment early then they can avoid serious
complications and lead long and healthy lives. Unfortunately 24% of people living with HIV in the UK
remain undiagnosed so we have to do much more to encourage people to test,‖ said Rosemary
Gillespie, Chief Executive at Terrence Higgins Trust, which has long campaigned for the availability of
home tests.
―The main difference between this and other testing options is that it gives the convenience of doing an
HIV test at home, with the result delivered outside a clinical setting, which we know some people prefer,‖
she added, but also stressed the importance of ensuring patient can get ―quick access‖ to support
should on getting their result.
The single-use home test costs £29.95; HIV testing on the National Health Service is free.
Commerce ministry to talk to industry bodies to take a call on joining pharma regulator
PICS
Small and medium-sizedpharmaceutical companies are wary ahead of a meeting called by the
government to decide whether India should become part of a multinational regulatory regime.
Stricter standards, many fear, could drive up costs and make them uncompetitive, but being a part of the
new system could make it smoother for Indian firms to access lucrative export markets. The commerce
ministry will talk to industry bodies on Monday about whether there is value in joining the Pharmaceutical
Inspection Convention andPharmaceutical Inspection Cooperation Scheme, known as PICS.
The agency , now consisting of 45 drug importing countries, wants exporters such as India to comply
with strict regulations to gain access to their markets.
The government had asked the Pharmaceuticals Export Promotion Council (Pharmexcil) to study the
impact on the drug and a global agency appointed by the Pharmexcil for the study has recently
submitted its draft report to the government.
Officials from the department of pharmaceuticals, the drug regulator, and executives representing Indian
medicine manufacturers have been invited to attend the meeting on Monday , said PV Appaji, director
general of Pharmexcil.

PHARMA UPTODAY
31
PICS, headquartered in Geneva, Switzerland, prescribes two international instruments for member
countries and their pharmaceutical authorities for "active and constructive cooperation" in the field of
good manufacturing practices.
A PICS committee has also resolved to expand its mandate from the existing manufacturing standards
to new fields such as good clinical practices and good pharmacovigilance practices. Adhering to the new
rules mean that Indian companies that export their drugs will be having one single regulatory body -
PICS - for the procurement of drugs from any exporting country . However, small and medium size drug
companies, especially those that only cater to the domestic market, would not support the idea of joining
the global league as their units should be upgraded to global standards, which may result in expenditure
of Rs 5 crore to Rs 20 crore per unit, according to a senior official of a mid-sized Hyderabadbased
pharma company .
"Some of the member countries are asking us whether India is PICS compliant for procuring medicines
for their government orders. Small countries which do not have regulatory expertise are insisting on it,"
Appaji said.
Health Canada Posting information in the Drug Product Database Online
Health Canada is planning to include all approved but not marketed products in the Drug product
Database (DPD) online. Human, veterinary, disinfectants and Schedule C drugs (for example,
radiopharmaceutical products) approved products will be available to the general public at the time of
authorisation.
The inclusion of these products in the DPD online at the time of approval supports two important
government initiatives:
 the Department's commitment to enhance transparency and openness in the drug approval
process; and
 the implementation of the brand name assessment required in the new regulations amending
the Food and Drug Regulations as part of the Plain Language Labelling Initiative (Plain
Language Labelling Regulations).
Health Canada is committed to:
 making relevant, timely and useful information available to the public in easy to access formats;
and
 sharing information with the public, once regulatory decisions are made.
The Plain Language Labelling Regulations will require sponsors to conduct a brand name assessment
to be done against all products in respect of which a Drug Identification Number (DIN) has been
assigned and all Schedule C drugs authorized for sale in Canada. As a result, Health Canada is
planning to make all brand names of approved drug products searchable in the DPD Online.

PHARMA UPTODAY
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In order to implement this change, the DPD online will undergo alterations in the way it displays
information. In its current configuration, the DPD online displays marketed products as "active" and
discontinued products as "discontinued" or "discontinued (by company post-market)". Approved but not
marketed products do not appear online.
In the new version of the DPD online, products will appear as follows:
 Approved but not marketed products will show as "Approved";
 Marketed products will show as "Marketed";
 Cancelled products will show as:
o "Cancelled Pre-Market" if the DIN is cancelled before the market notification.
o "Cancelled Post-Market" if the DIN is cancelled after the market notification.
 Approved products that are in the process of changing the brand name and/or company name
(administrative change to an approved product) will appear as "Pending change in brand
name/manufacturer".
The implementation of these changes to the DPD online has been delayed due to technical issues. The
changes are now scheduled to be implemented in June 2015.
In the interim, a product information extract file of the DPD online will be available upon request to
sponsors who have to perform a brand name assessment. The extract will be available as of April 24,
2015 and will contain the following information:
 DIN (if applicable)
 Brand name
 Schedule
 Active ingredient
 Strength
 Dosage form
 Route of administration
 Anatomical Therapeutic Chemical (ATC) classification
 American Hospital Formulary Service (AHFS) classification
 Class
 Status
 Date
If you have any further questions regarding this new process, please do not hesitate to contact the
Office of Submissions and Intellectual Property (OSIP) by phone at 613-941-0832 or by email at: SIPD-
DINREQUEST@hc-sc.gc.ca.

PHARMA UPTODAY
33
Terminology
Risk – The combination of the probability of occurrence of harm and the severity of that
harm
Risk Assessment – A systematic process for organizing information to support a risk
decision that is made within a risk management process. The process consists of the
identification of hazards and the analysis and evaluation of risks associated with exposure to
those hazards.
Risk analysis is the estimation of the risk associated with the identified hazards. It is the
qualitative or quantitative process of linking the likelihood of occurrence and severity of
harms. In some risk management tools, the ability to detect the harm (detectability) also
factors in the estimation of risk.
Risk evaluation compares the identified and analyzed risk against given risk criteria. Risk
evaluations consider the strength of evidence for all three of the fundamental questions.
Risk control includes decision making to reduce and/or accept risks. The purpose of risk
control is to reduce the risk to an acceptable level. The amount of effort used for risk control
should be proportional to the significance of the risk.
Risk reduction focuses on processes for mitigation or avoidance of quality risk when it
exceeds a specified (acceptable) level. Risk reduction might include actions taken to mitigate
the severity and probability of harm.
Risk acceptance is a decision to accept risk. Risk acceptance can be a formal decision to
accept the residual risk or it can be a passive decision in which residual risks are not
specified.
Risk communication is the sharing of information about risk and risk management
between the decision makers and others.
Risk review: Review or monitoring of output/results of the risk management process
considering (if appropriate) new knowledge and experience about the risk.
Risk Management: The systematic application of quality management policies,
procedures, and practices to the tasks of assessing, controlling, communicating, and
reviewing risk

PHARMA UPTODAY
34
New Guidance
FDA issues final guidance on the evaluation and labeling of abuse-deterrent opioids
The U.S. Food and Drug Administration today issued a final guidance to assist industry in developing
opioid drug products with potentially abuse-deterrent properties.
Opioid drugs provide significant benefit for patients when used properly; however opioids also carry a
risk of misuse, abuse and death. To combat opioid misuse and abuse, the FDA is encouraging
manufacturers to develop abuse-deterrent drugs that work correctly when taken as prescribed, but, for
example, may be formulated in such a way that deters misuse and abuse, including making it difficult to
snort or inject the drug for a more intense high. While drugs with abuse-deterrent properties are not
―abuse-proof,‖ the FDA sees this guidance as an important step toward balancing appropriate access to
opioids for patients with pain with the importance of reducing opioid misuse and abuse.
The document ―Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling‖ explains the
FDA‘s current thinking about the studies that should be conducted to demonstrate that a given
formulation has abuse-deterrent properties. It also makes recommendations about how those studies
should be performed and evaluated, and discusses what labeling claims may be approved based on the
results of those studies.
―The science of abuse-deterrent medication is rapidly evolving, and the FDA is eager to engage with
manufacturers to help make these medications available to patients who need them,‖ said FDA
Commissioner Margaret A. Hamburg, M.D. ―We feel this is a key part of combating opioid abuse. We
have to work hard with industry to support the development of new formulations that are difficult to
abuse but are effective and available when needed.‖
The science of abuse-deterrent technology is still relatively new and evolving. The final guidance is
intended to assist drug makers who wish to develop opioid drug products with potentially abuse-
deterrent properties. The FDA is working with many drug makers to support advancements in this area
and help drug makers navigate the regulatory path to market as quickly as possible. In working with
industry, the FDA will take a flexible, adaptive approach to the evaluation and labeling of potentially
abuse-deterrent products.
―Development of abuse-deterrent products is a priority for the FDA, and we hope this guidance will lead
to more approved drugs with meaningful abuse-deterrent properties,‖ said Janet Woodcock, M.D.,
director of the FDA‘s Center for Drug Evaluation and Research. ―While abuse-deterrent formulations do
not make an opioid impossible to abuse and cannot wholly prevent overdose and death, they are an
important part of the effort to reduce opioid misuse and abuse.‖
While this final guidance does not address generic opioid products, the agency understands the
importance of available generic options to ensure appropriate access to effective opioid drugs for
patients who need them. The FDA is committed to supporting the development and use of generic drugs
that have abuse-deterrent properties and is working on draft guidance in this area.

PHARMA UPTODAY
35
In addition to the numerous comments on the draft guidance submitted to the public docket, the FDA
convened a public meeting in Oct. 30-31, 2014, to discuss the development, assessment and regulation
of abuse-deterrent formulations of opioid medications.
To help support the safe use of all opioid products, the FDA is working in many other ways to help
prescribers and patients make the best possible choices about how to use these powerful drugs. The
agency‘s goal is to find the balance between appropriate access to opioids for patients with pain and the
need to reduce opioid misuse and abuse.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public
health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and
other biological products for human use, and medical devices. The agency also is responsible for the
safety and security of our nation‘s food supply, cosmetics, dietary supplements, products that give off
electronic radiation, and for regulating tobacco products.
TGA updates Guidance 15: Biopharmaceutic studies
This guidance is to assist sponsors of prescription medicines to prepare applications to:
 register new prescription medicines on the ARTG
 vary the registration of a prescription medicine on the ARTG.
This guidance covers:
 all matters relating to bioavailability and/or bioequivalence aspects of prescription medicines
containing active substances that are synthetic chemical entities
 active substances that are:
o antibiotics
o short-chain synthetic polypeptides
 some hormones (steroid hormones and synthetic peptides of usually less than 32 amino acids-
some exceptions may apply).
This guidance does not cover:
 Matters relating to other pharmacokinetic studies.
Contents
 15.1 Adopted European guidelines for biopharmaceutic studies
 15.2 Comparative dissolution profiles for biopharmaceutic studies
 15.3 Medicines that do not require biopharmaceutic data
 15.4 Medicines that require biopharmaceutic data
 15.5 Validation and quality control of assay procedures used in biopharmaceutic studies
 15.6 Choice of the reference product for bioequivalence of generic medicines

PHARMA UPTODAY
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 15.7 Managing dropouts in bioequivalence studies
 15.8 Where to include biopharmaceutic data
 15.9 Justification for not submitting biopharmaceutic data
Version history
Version Description of change Author Effective date
V1.0 Original Publication Office of Medicines Authorisation 1 July 2014
V1.1 Minor text update Scientific Evaluation and Special
Product Access Branch
1 April 2015
New EU GMP Annex 15 Revision published - Valid as of 1 October 2015
In February 2014 the draft for the revision of EU GMP Annex 15 was published (see the GMP-News
from 11 February 2014 "Revision of the EU GMP Annex 15 for Qualification and Validation
published"). Compared with the currently valid version the changes were significant in some parts (see
also the GMP-News from 21 March 2014 "Detailed Analysis of Annex 15 Draft". Now the draft was
published as final document and will be valid as of 1 October 2015.
What will change? Following you will find an overview about the changes.
With 16 pages the document is much more comprehensive than the current version (11 pages). In the
section "principles" it is stated that the new EU GMP Annex 15 may also be used as supplementary
optional guidance for active substances without introduction of additional requirements to EudraLex,
Volume 4, Part II"
Life cycles build the centre of the new Annex 15, whether with regard to the product or to the process,
whether with regard to equipment and the process validation itself. A special emphasis is on risk
management which is mentioned in several sections in the guideline instead of being mentioned in one
section only on risk assessment.
The new Annex 15 now specifically excludes a retrospective validation.
Validation Master Plan
The content of the validation master plan (VMP) has been extended. Deviation management is also
supposed to be described in the VMP in the future, just as well as the standards for the development of
acceptance criteria and the organisational structure. Compared to the draft version the mention of an
"ongoing validation strategy" has been deleted. The request for naming the resources has also been
omitted compared to the draft.

PHARMA UPTODAY
37
Qualification
The possibility to combine qualification documents (e.g. IQ and OQ as IOQ) is explicitly mentioned. It is
also foreseen to include manufacturer documents. Fortunately there is the possibility of conditional
releases in the area of qualification. The final document contains a requirement to establish user
requirements and/or functional specifications as a starting point of a qualification. The DQ is now the
second step in a qualification. Additional new requirements are the Factory Acceptance Test (FAT) and
the Site Acceptance Test (SAT). Especially for equipment with new or complex technology a FAT "may"
be conducted. Compared to the draft this is a less strict requirement. In the draft document it was stated
that a FAT "should" be conducted. If appropriate and assessed, tests and documentation reviews as
part of the FAT can be taken over in other steps without repeating them in the IQ/OQ. This is a very
helpful definition.
With regard to the PQ it is now also explicitly mentioned that (in certain cases) it can be combined with
the OQ or the process validation. In difference to the draft it is stated that IQ, OQ and PQ "should" be
conducted.
The chapter "Requalification" is new. Unfortunately the sub-chapter on established (in-use) equipment
qualification has been completely omitted.
Process Validation
The options with regard to process validation have been extended. The previous "traditional" approach
is still mentioned as a possibility, though - also with the determination of 3 validation batches. For a 3
batch validation further data from following batches may be necessary according to an "ongoing process
verification". The possibility of a "continuous process verification" as described in ICH Q8, and a hybrid
approach as a mix of the before mentioned two approaches is new. This is a clear difference to the US
FDA Process Validation Guidance where only one approach is mentioned. According to the final EU
GMP Annex 15 a "bracketing" approach can be used with respect to the number of runs, strength, batch
size, packaging sizes and types. This is already known from the US.
As part of the "ongoing process verification" the product quality should be monitored during the product
life cycle to show that the "state of control" is fulfilled and that trends are assessed. This is also known
as "Continued Process Verification" from the US. The "ongoing process verification" should be based
and reported according to a protocol or equivalent documents, latter is new compared to the draft.
Completely omitted has been the subject of a (regular) revalidation.
The chapters "Transport Verification", "Packaging Validation" and "Qualification of Utilities" as well as a
separate chapter on "Validation of Analytical Methods" are new. Compared to the draft the new final
document now addresses also the qualification of equipment for secondary packaging.
Cleaning Validation
The chapter Cleaning Validation comprises clear changes. The number of subitems is more than double

PHARMA UPTODAY
38
now. Fortunately it is possible now to group equipment if this grouping is justified accordingly. The
acceptance criterion "visibly clean" as single acceptance criterion is designated as not acceptable.
Limits for the carryover of contaminations are supposed to be based on a toxicological evaluation. There
is a reference to the EMA Guideline on Shared Facilities (see GMP News from 21 November 2014
"Shared and Dedicated Facilities: EMA publishes final Guideline on Setting health based exposure limits
(PDEs)". The so far common acceptance criteria 1/1000-Dose or 10 ppm are not mentioned. As part of
the cleaning validation "dirty und clean-hold times" should be defined. The request from the draft to use
the last rinse water as a sample in the application of rinsing methods has been omitted. Recovery rates
should be determined. Interestingly the number of validation runs is supposed to be determined risk
based. When producing clinical trial samples a cleaning verification could replace a cleaning validation.
In the chapter Change Control it is defined that an efficiency control is supposed to follow a change. This
is an adaption to chapter 1, part I of the EU GMP Guide.
The glossary contains new terms.
Conclusion
The revision is quite comprehensive. Influences from the ICH Guides ICH Q8, Q9 and Q10 can be
clearly noticed. This makes the document more modern, and it is more adapted to the current state of
science and technology. The addressing of API manufacturer is somewhat irritating. Although the new
Annex 15 comprises clear changes it is not supposed to cause new requirements in the area of APIs.
But how is that supposed to work?
The statement that Process Validation is a life cycle is comparable to the FDA view.
The clear focus on user requirements in the area of qualification will also have an impact on equipment
suppliers. Process validation will become a difficult task in the future. With 3 different approaches there
are clear differences to the US. However, the ongoing process verification means additional effort and is
now comparable to the US requirements.
Transport verification, the qualification of utilities as well as the validation of analytical methods are not
new in the GMP enviroment. However, the topic packaging validation was not the main focus so far.
This probably means additional effort for some companies.
The new Annex will result in considerable changes in the area of cleaning validation. A lot has
fortunately been adapted to the current state of technology. However, the strong focus on toxicological
evaluations as acceptance criteria with regard to existing products will certainly cause uncertainties.
Altogether there are plenty of new requirements which, however, partly only show the state of
technology. Due to the (necessary) integration of ICH Q8-Q11 and the life cycle approach the new
Annex 15 is now more comprehensive, but unfortunately also more vague. A close coordination with the
FDA Guideline on process validation would have been desirable.
Please find the new EU GMP Annex 15 on the EU Commission Webpage
The new EU GMP Annex 15 will be covered at two ECA events. On 22/23 April the ECA offers the
seminar "The new FDA/EU Approach to Process Validation" in Hamburg. And, at the 6th European
GMP Conference on 9/10 June in Heidelberg the EU GMP Annex and the consequences will be
discussed in a dedicated session.

Pharma Uptoday Monthly Magazine Volume 14 Issue May 2015

Pharma Uptoday Monthly Magazine Volume 14 Issue May 2015

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Pharma Uptoday Monthly Magazine Volume 14 Issue May 2015