Professional Documents
Culture Documents
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VOL. 5, NO. 3
EUROPE
CMC/REVIEW & GMP/INSPECTION
ICH Q8-11 Oriented Submission and GMP Expectations for Process Validation and Other
Quality Issues Taking Shape in Europe..........................................................................................................50
UPDATES IN BRIEF - p. 57
U.S.: Comments on NDA/ANDA Processes Global Ingredient Archival System BA/BE Draft Guidance Vial
Overfills Orphan MAb Sameness ISPE Metrics Pilot Geo-spatial Mapping
EUROPE: Drug Approval Fast Track Sterilization Processes Variation Stability Requirements UK Biologics
Research Center MHRA 2014-2015 Business Plan Advanced Therapies Regulation Post-authorization Q&A
EDQM CEP Policy EDQM Anti-Counterfeiting Database Applications/Advice Procedures Immungenicity
Concept Paper GDP Q&A Quality System GMPs
INTERNATIONAL: Brazil Withdrawal Notification EMA/TGA Orphan Drug Collaboration FDA/EMA QbD
Initiative WHO Hold Times
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2014 2014
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INTERNATIONAL
PHARMACEUTICAL
QUALITY
Editor-in-Chief
Bill Paulson
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MARCH/APRIL 2014
UNITED STATES
Warning Letters from 2012 Q1 2014 Show FDAs GMP Enforcement Focus
Shifting Overseas; Foreign Labs Draw Particular Attention
An analysis of FDA drug GMP warning letters issued since
the beginning of 2012 highlights the agencys increasing
focus on enforcement outside the US and on laboratory
practices at foreign facilities, in particular.
25
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Nearly half of the Indian firms receiving letters produce APIs.
Sharpening FDAs enforcement focus on India has been the
recurrent findings of data integrity issues at Indian facilities
(see story on p. 19). Of the 13 warning letters issued to
Indian plants since 2012, seven specifically address a lack of
integrity of their records, procedures, and/or interactions
with FDA investigators.
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Inspection Reports
Received
439
470
680
743
407
427
516
566
12
20
23
26
Import AlertsCGMP
Violations (66-40)
16
22
21
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--
Import AlertsHeparin
(55-03)
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Two 483 observations from the Marcy lEtoile, France plant
were also addressed related to the production of haemophilus
conjugated vaccine. Requested by Malarkey were progress
reports on finding root causes and implementing corrective
actions for lots that had extended filtration times and
displayed an adverse trend on bacterial content.
Sterility concerns were also cited by Australia's at
the Toronto facility a month after the 2012 FDA
inspection that prompted the warning letter. A
recall of four lots of the TB vaccine followed the
two inspections.
Sanofi shut down part of the Toronto plant for remediation,
which resulted in a shortage of the BCG vaccine that the
company does not anticipate being able to resolve until the
end of 2014.
In the wake of the compliance, recall and shortage
problems, the firm brought on board industry veteran and
former Genentech VP Anders Vinther as Chief Quality
Officer, a position that reports to the CEO. Vinther has
played an important role in advancing quality system
concepts and their application in the biotech industry, and
has served in various capacities at PDA, including as the
associations Chairman of the Board.
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section 201(G) defines drugs as articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of
diseaseintended to affect the structure or any function of the body. So the definition is not limited to drug products,
i.e. finished drug forms. This is important for our discussion of APIs.
The FDA definition of bulk drug components comes from the preamble to the 1978 revisions to the cGMP regulations.
Bulk drug components are defined as ingredients intended for use in the manufacture of a drug product. One more
definition from the FDA comes from our 21CFR part 210, which defines an active ingredient as any component intended
to furnish pharmacologic effect, and it includes components that may undergo chemical change in the manufacture of
a drug product.
One more definition of note then is the Q7A definition of an active pharmaceutical ingredient: Any substance or
mixture of substances intended to be used in manufacture of a drug product...intended to furnish pharmacological
activity or other direct effect.
Knowing this, knowing what FDA can inspect, and knowing what we define a drug to be not just a finished drug
product but also an active ingredient then we go into our actual regulation of the APIs.
They are subject primarily to the adulteration provisions of section 501(a)(2)(B) of the act, which requires all drugs
to be manufactured in conformance with good manufacturing practices. This is important because our regulations
for drugs, 21CFR 210 and 211, really dont apply to APIs, except in that small case of sterile APIs after the point of
sterilization.
Also, the cell culture fermentation uses language from related FDA regulations and that is discussed in section 18 of
Q7. So for us as regulators, it is a very nuanced use of 211 in terms of informing us as to what good manufacturing
practice is. In 2001, FDA adopted Q7 as a guidance document and continues to use Q7 as representative of FDA
thinking on the subject of APIs.
Another guidance document that is used internally and that is open to the public domain is our active pharmaceutical
ingredients process inspections guidance, which is 7356.002F. In that you find incorporate a systems-based inspection
approach. It was implemented in 2006, and there were some minor changes in 2013. One thing of note for that
particular guidance is that it doesnt cover biotechnology derived APIs for that you need to go to another document,
which is inspections of biologically licensed therapeutic drug products.
I think the take home message for this is that we really do not have much in the way of regulations a really small
amount of regulation but everything derives from the act itself.
API Inspections
When we do our onsite inspections of APIs, they tend to fall into several categories. One would be a surveillance
inspection, which is a routine GMP inspection and part of our work plan. Another would be a pre-approval inspection.
And the other could be a directed inspection. The types of directed inspections that we might have would be a followup to a regulatory action like a warning letter.
The other type of directed inspection that I have been more familiar with because, in addition to being an inspector,
I also run our field alert program we have actually seen recently a fair number of directed inspections related to
reports from finished drug manufacturers who have alerted us to the fact that APIs might have been the cause of
difficulties or problems or failures in their finished drug product. I would say in the last two or three years we have seen
a relatively large increase in the number of inspections that were generated in that way.
The other thing about onsite inspections of APIs is, because the primary areas where they are manufactured are out of the
U.S., 70-90% of our inspections are out of country for APIs. And pre-notification is required for the foreign inspections only.
Our onsite inspections are conducted as GMP qualifying inspections of APIs as they are assigned to us. They may
be product-specific. And really what we are trying to do is use a systems coverage to determine the ability of the
firm to produce any API using the same systems of controls and procedures, whether it be for chemical synthesis,
fermentation, biotech, etc.
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product quality and the firms choice not to escalate the
contamination event by notifying its customers. We are
concerned that your firm does not consider the entry of
pharmaceutical waste streams into your manufacturing
process a significant deviation with a potential quality
impact, the agency emphasized.
FDA pointed out in the 2013 letter that its concerns regarding
investigations into sterility compromises in large volume
parenteral (LVP) bags that were the subject of customer
complaints and a product recall was a repeat citation
from a 2011 warning letter. Cited were numerous open
investigations regarding foreign material found in the bags
that purported to be sterile.
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But that alone is not enough. We must work to enhance safety and quality long before these products reach our
shores. We have enhanced overseas inspections and now haveFDA officesin many parts of the world. This is proving
very beneficial, but again, we must do more. We cannot inspect our way to safety with some 300,000 facilities in about
150 countries making products for export to the United States that we must oversee.
That is why the collaboration with both industry and our regulatory counterparts is increasingly vital. The rapid and
profound rise of global commerce and trade requires that we continue to evolve and meet new demands. We can take
comfort in the knowledge that we have significantly strengthened our ability to respond to these challenges and know
where and how we must do more.
Similarly, the rapid advances in science and technology offer great opportunity but place new and evolving demands
on us and the products we regulate.
Understanding the seriousness of these challenges structural, scientific, economic, and global is one reason why,
when I took over as Commissioner, I could not settle for incremental changes in how FDA intends to conduct business
for the 21st century. I am confident that the changes we are putting in place are sufficiently important and on track to
survive well into the future. I believe that they are, in fact, absolutely essential.
And so we will continue to implement changes that fundamentally transform how we address these challenges before
us, how our agency interacts with regulated industry and other stakeholders, and how the public understands and
supports the mission of this important and unique agency.
It will require the work not just of the FDA, but of partners such as FDLI, to ensure the continuing alignment of our
public health and medical care mission with the important regulatory and legal framework. I look forward to our
ongoing work together, with continuity of purpose, renewed commitment to key principles, and a sense of the dynamic
and changing world we live in that demands flexibility, resilience and an eye to the future.
12
Locaon
Boothwyn,
PA
Leer Date
03/07/14
Product Type
Compounded
Areas Cited
Sanitary condions Microbial control SOPs
CAPA
Village Ferlity
Pharmacy
Waltham,
MA
02/28/14
Compounded
Total Pharmacy
Services
Houma, LA
02/28/14
Compounded
Wedgewood
Village Pharmacy
Swedesboro,
NJ
02/21/14
Compounded
Pallimed
Soluons
Woburn, MA
02/19/14
Compounded
Olympia
Pharmacy
Orlando, FL
02/18/14
Compounded
Nora Apothecary
Pharmacy
Indianapolis,
ID
02/14/14
Compounded
Avella of Deer
Valley
Phoenix, AZ
01/17/14
Compounded
Recsei Labs
Triangle
Compounding
Goleta, CA
Cary, NC
1/15/14
01/14/14
Topical
Compounded
Internaonal (2014)
SmithKline
Beecham
Smruthi Organics
Canton Labs
Usv
CBSCHEM
Cork, Ireland
03/18/14
API
Solapur,
India
03/06/14
API
Vadodara,
India
02/27/14
API
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CBSCHEM
Tempe, AZ &
Hong Kong,
China
01/31/14
Ameriderm Labs
Paterson, NJ
12/02/13
Topical
Jubilant
HollisterSer
Allergy Labs
Spokane,
WA
Oklahoma
City, OK
11/27/13
Injectable
10/04/13
Injectable
Green Valley
Drugs
Henderson,
NV
08/30/13
Compounded
Stewart
Compounding
Pharmacy
Fenwal, a
Fresenius-Kaby
Company
Balanced
Soluons
Compounding
Fayeeville,
NC
08/21/13
Compounded
Maricao, PR
08/16/13
Injectable
Lake Mary,
FL
07/16/13
Compounded
Cispharma
Cranbury, NJ
07/02/13
Oral Solid
Baxter
Healthcare Corp.
Marion, NC
& Jayuya, PR
05/31/13
Injectable
Custom
Compounding
Centers
V-SAB Medical
Labs
Los Alamitos,
CA
05/15/13
Compounded
Cornelius,
NC
04/26/13
Topical
Alexion Pharma.
Smithfield,
RI
Memphis,
TN
03/22/13
API
03/18/13
Topical
Blacksburg,
SC
03/07/13
Compounded
Philadelphia,
PA
Rancho
02/19/13
API
Keystone Labs
Medi-Fare Drug
and
Home Health
Center
Abbey Color
Laclede
Repacking/
relabeling
IPQ
MARCH/APRIL 2014
14
02/14/13
Topical
01/29/13
Oral Solid
01/10/13
Packager/Labe
ler
Wockhardt
Aurangabad,
Maharashtra
, India
11/25/13
Injectable,
Oral Solid
Agila Specialies
Bangalore,
India
09/09/13
Injectable
Jabones Pardo
Madrid,
Spain
08/22/13
Topical
Promed Exports
Himachal
Pradesh,
India
Hyderabad,
India
08/09/13
Injectable
08/02/13
API
Aar Drugs
2 in Tarapur,
India
07/30/13
API
Wockhardt
Aurangabad,
India
07/18/13
Injectable,
Oral Solid
Fresenius Kabi
Oncology
West Bengal,
India
07/01/13
API
Ebewe Pharma
Ges MBH Nfg KG
Unterach am
Aersee,
Austria
05/28/13
Injectable
Hospira
Healthcare India
Irungaukot
tai,
Sriperumbur
dur (T.K.),
India
Gujarat,
India &
Maharashtra
, India
North Ryde,
Australia
05/28/13
Injectable
05/28/13
05/17/13
Oral Solid
Laclede
Sovereign
Pharma.
Physicians Total
Care
Internaonal (2013)
Posh Chemicals
Contract
Pharma. Services
of Australia
15
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Boehringer
Ingelheim
Pharma
CMI Cosmec
Manufacturers
Ingelheim
am Rhein,
Germany
Concord,
Ontario,
Canada
Kanagawa,
Japan
Catania, Italy
Hong Kong,
China
05/06/13
Asada Milling
Apotex
Kanebo
Cosmecs
Wyeth Lederle
Peking Medicine
Manufactory
Jubilant
HollisterSer
P.A. Benjamin
Manufacturing
04/25/13
API, Oral
Solid,
Inhalaon
Topical
04/01/13
Topical
03/27/13
03/25/13
Injectable
Topical
Gunma,
Japan
03/22/13
API
Toronto,
Ontario,
Canada
Quebec,
Canada
Kingston,
Jamaica
02/21/13
Injectable/Ora
l Solid
02/20/13
Injectable
01/29/13
Oral Liquid
Saint Louis,
MO
11/20/12
Veterinary
I Shay Cosmecs
Gardena, CA
10/22/12
Topical
Stat Rx USA
Jacksonville,
FL
Lakewood,
NJ
Hollywood,
FL
10/09/12
Oral Solid
08/27/12
Topical
07/30/12
Compounded
DPT Lakewood
Infupharma
Grato
Woodbine,
IA
07/30/12
Oral
Solid/Liquid
Franck's
Compounding
Lab
Oklahoma
Respiratory Care
Shamrock
Medical
Soluons Group
Ocala, FL
07/09/12
Compounded
Norman, OK
06/18/12
Inhalaon
Lewis
Center, OH
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Lewis
Center, OH
06/15/12
Repacking/
Relabeling
Bakerfield,
CA
Birmingham,
AL
Fajardo, PR
03/22/12
API
03/16/12
Compounded
03/08/12
Oral Solid
02/22/12
Injectable
02/17/12
Topical
02/03/12
Oral Solid
01/31/12
Injectable
Grand
Island, NYC
Lyndhurst,
NJ
West-Ward
Pharma.
Bracco
Diagnoscs
Eatontown,
NJ
Princeton, NJ
Beanne Chemical
Taipei,
Taiwan
12/19/12
Topical
Hameln Pharma.
Hameln,
Germany
Tainan City,
Taiwan
12/17/12
Injectable
12/17/13
Topical
Bagsvaerd,
Denmark
Shanghai,
China
12/12/12
Injectable
11/14/12
Topical
Calgary,
Alberta,
Canada
Zhejiang,
China
10/23/12
Topical
09/07/12
Topical
Jiangsu,
China
07/30/12
Topical
Marcy
l'Etoile,
France &
Toronto,
Ontario,
Canada
Vrsac, Serbia
07/12/12
Vaccine
06/20/12
Injectable
06/20/12
API
Taiwan Three
Mast Pharma.
Novo Nordisk
Shanghai Huhui
Daily Use
Chemical
Products
Internaonal
Labs
Personal Care
Products
Jianerkang
Medical Dressing
Sanofi Pasteur
Hemofarm
Ercros
Internaonal (2012)
Madrid,
Spain
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Ercros
Madrid,
Spain
06/20/12
API
Compania
Internacional de
Comercio
B.M.P. Pharma
Trading
Selder S.A. de
C.V.
Mexico City,
Mexico
06/13/12
Topical
Norderstedt,
Germany
Mexico City,
Mexico
05/04/12
API
04/27/12
Oral Solid
Tedec-Meiji
Farma
Alcala
DeHenares,
Spain
Cuautlan
Izcalli,
Mexico
Guadalajara,
Mexico
Missauga,
Ontario,
Canada
Cuautlan
Izcalli,
Mexico
Kutuno,
Poland
Bangalore,
India
Ras al
Khaimah,
UAE
4/24/12
Oral Solid
03/27/12
API
03/09/12
Topical
03/09/12
Topical
03/09/12
API
03/07/12
API
02/23/12
Injectable
02/23/12
Injectable
UNAM Facultad
De Estudios
Superiores
Laboratorios
Jaloma
Pax-All
Manufacturing
Farma Quimia
Nobilus Ent
Wintac
Gulf Pharma.
Industries
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MARCH/APRIL 2014
18
STRATEGY
FORUM
Best Practices
for Managing
Emerging Trends
and Challenges
of CMO Oversight
and Other Service
Providers
Forum Co-chairs:
Siddharth Advant, ImClone Systems Corporation
Julia Edwards, Genentech, a Member of the Roche Group
Jeffrey Staecker, Genzyme, A Sanofi Company
SCAN
to browse
CASSS
for program
updates at casss.org
ECA
ACADEMY
European GMPs
and the Role of the
Qualified Person (QP)
The Impact of EU Directives and Guidelines
on the Supply Chain
Jersey City, NJ (New York City Metro Area), USA July 8-9, 2014
A conference organised by the ECA Academy and the European QP Association
Speakers
Highlights:
Richard M. Bonner
FDA Speaker
Import/ Export
(invited)
Dr Rainer Gnibl
Tor Grberg
Medical Products Agency, Sweden
Dr Bernd Renger
Immediate Past Chair of the
European QP Association, Germany
Martine Tratsaert
Johnson & Johnson, Belgium
EU GMP Update
Plus:
Clinical Trial Supplies: IMP Handling in Europe and the Role of the QP
The Role of PIC/S in a globalising World
The View of the FDA
Delegates Voices:
The chemistry between speakers and delegates was great.
Very interactive conference, very informative with real life examples.
Great broad coverage on topics relating to the QP.
I really enjoyed a conference that also addresses IMPs ! Thank you!
Media Partners:
Smruthi Organics
India
API
3/2014
Canton Labs
India
API
2/2014
USV
India
Oral
2/2014
Wockhardt
India
Inj., oral
11/2013
Agila Specialies
India
Inj.
9/2013
Posh Chemicals
India
API
8/2013
Aar Drugs
India
API
7/2013
Wockhardt
India
Inj., oral
7/2013
Fresenius Kabi
India
API
7/2013
India
API, oral
5/2013
Infupharma
U.S.
Compound
7/2012
Mexico
Topical
6/2012
Biochem Labs
U.S.
Topical
2/2012
UAE
Inj.
2/2012
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record or a manufacturing form to document the results
contemporaneously.
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3,000 bottles of metformin hydrochloride extended release
tablets after a customer complained of the presence of some
gabapentin tablets, a drug used to treat seizures, in a bottle.
In late April, Ranbaxy announced a Class II recall that it
had begun in February of nearly 30,000 packs of an allergyrelief medicine containing loratadine and pseudoephedrine
sulphate extended release tablets for packaging defects. The
product was manufactured by the firms Ohm Labs plant in
New Jersey, which is the companys only facility currently
making generics for the U.S.
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22
I know for a fact, the FDA expert said, that some of the
[agency] people involved in the data integrity warning letters
are people who have a lot of experience, because they have
worked with these systems themselves. They know the lab
systems and how to work with them.
Rodriguez also pointed to the geographical location
of a firm as an important factor in being able to
attract and retain the expertise it needs to become
and remain compliant.
I have seen companies that have very knowledgeable
people, but their area of expertise is maybe for the same
processes, but for food establishments, not for drugs. I have
seen people who mean well. They were knowledgeable of
the processes, but they were not knowledgeable of the drug
regulations.
It is not only the country, but even within a city, the expert
investigator commented. One company she is familiar with
face problems in getting people with the right expertise
due to its location outside of an area where people wanted
to live. They wanted to live near the nice city, not an hour
away. I have seen this with some companies that are having
trouble hiring the right expertise because their sites are not
located where people want to be.
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We are really not targeting any particular country. But the data integrity problems may reflect on several factors
regarding regulatory maturity of the companies and the country. There are a number of things that may be playing
into this recurrence of warning letters to particular countries.
Part of those warning letters were also related to the integrity of data that is coming from computer systems, which
is also part of data integrity. That was the point in showing warning letters relating computer systems to the integrity
issues. And there also was a failure to review and investigate production and QC laboratory deviations. Those are the
three things that stood out to me in those warning letters.
The data integrity issues were mostly related to HPLC processing methods for example, people runningmultiple
runs of the same samplesand changing integration parameters until they got the results they expected or wanted.
That is obviously not acceptable. That is basically testing into compliance. For whatever reason I am not saying it
was intentional, I am not going there it was happening.
Another issue that was found during these inspections was the documentation trail of the computer systems, of the
chromatographic systems, was disabled. Theaudit trailbasically tells you every time someone performs a critical
operation with a signature that the system documents that step, and that that action was taken. That trail was
disabled. They were changing data and changing parameters. Whatever the functions that the audit trail was supposed
to follow were not being documented. The absence of that audit trail was enabling people to delete data and change
operation parameters, integration parameters, and that kind of stuff. They used the same password and username.
That is a clear no-no. But we still find these things. I, myself, have found companies that are still doing this.
Another issue that the investigators found was that the system did not protect the data. It was possible to access the
system andmake changes or deletionsto the system. These are just similar iterations of the same issue the failure
to implement access controls to the system.
Excel spreadsheets were also mentioned. Calculations in the spreadsheets were not protected. People could make
changes to the formulas that were in the spreadsheets. This is pretty much the same stuff. These are just some of the
issues that were cited related to computer systems.
There were also less complex issues. Speaking of complexity or lack of complexity, in this particular case, people were
usingpost-it notesor small pieces of paper to write stuff, and then they were transferring that to worksheets or formal
documentation. That kind of practice lends itself to people documenting the data to meet whatever expectations they
have. So that is completely unacceptable.
And also, people were performing multiple runs of the same samples, and calling them different names such as trials
or demos, until they got the ones that were acceptable. Out-of-specification (OOS)results were ignoredand not
investigated they were accepting only the good results.
I thought this one was really interesting. In this case, the reason for the continuous testing and re-testing was that the
company was having API batches that failed. They wereblending the bad batcheswith the good batches and they
were running them again, so then they got a good result. The blending of a bad batch and a good batch is a GMP
violation in itself. Then they covered that up in the re-testing practice.
In this particular case, the managers of the company claimed in their response to the 483 that they didnt know why
operators were doing that. Personally, I have a hard time believing that. I dont have any stake in the company or
that batch. I am not getting the money for that batch. So I dont know how this practice was not being encouraged by
management. I just really wonder when I see stuff like this.
Other issues that they found were that people werepre-documentingoperations. If they were going to perform
a step, they would fill in the data before they performed a step. So that was a little bit of foreseeing an event or
something. This happened not only in lab operations, it was happening in manufacturing operations as well they
were not documenting operations as they were performed.
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24
inspected, he explained.
All in all, all of the good work that that company had
previously been doing building up share prices for investors
was just destroyed, Birse said.
Just imagine how much stock value was being lost during
that time. Imagine if a small slice of that had been taken off
and been spent on quality actually doing the right thing.
They would not be in this position now if they had really
thought about it.
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Cost of Non-Compliance to Wockhardt
The following charts depict the impact on Wockhardt share price in the wake of the adverse
inspection findings by FDA and MHRA, which included the lack of data integrity. The three
red circles in the second chart represent the MHRA and FDA inspections.
E U S N C S ite 1
E U S N C S ite 3
U S F D A W L S ite 1
1
E U S N C S ite 2
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PAREXEL International
www.PAREXEL.com
PAREXEL CONSULTING
Testing
Auditing
Consulting
Training
CM
MY
CY
CMY
HS@nsf.org
www.nsf.org
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Component Testing Gains Prominence in Drug Product GMP Warning Letters
as FDA Focus Intensifies on OTC Topicals and Upstream Supply Chain
Inadequate testing of incoming components is a leading
problem area being cited by FDA on finished drug product
GMP warning letters and is particularly prevalent in the
expanding number of those addressing compliance at
topical manufacturers worldwide.
FDA is expressing concern that each component is not being
tested by the dosage manufacturer for conformity with all
of its specifications and/or that specific identification tests
are not being conducted on components that have been
accepted based on the suppliers certificate of analysis
(CoA), as required by CFR 211.84.
IPQs analysis of drug product GMP warning letters issued
from 2012 through the first quarter of 2014 shows that
over one in three of those addressing finished product
manufacturing (20 of 56) have highlighted non-compliance
with 211.84. Among warning letters addressing topical
manufacturing, the percentage soars to three in four (16 of
21).
Topical manufacturing, meanwhile, emerges as the
leading target of drug GMP warning letters during
the past two years.
The 21 topical warning letters issued since the beginning
of 2012 represent 37% of those addressing dosage form
manufacturing exceeding the number issued to injectable
manufacturers (17) and oral dosage firms (13). Topical letters
also outpaced those addressing API manufacturing (15).
The finding is dramatic in that in the five years prior to 2012,
topical firms received only about one third as many letters
as oral manufacturers which led the warning letter totals
during that timeframe and significantly fewer than either
injectable or API operations.
It is clear that topical OTC manufacturing is getting more
attention as FDAs GMP enforcement efforts intensify in the
global arena. Also clear is the concern around how topical
firms are handling their component evaluation process and
that the agency will not be tolerant when the requirements
in this area are not being met.
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authenticity of a suppliers certificates of analysis.
I do not know how many times I go into firms and they are
not doing this, the ORA expert investigator said. They will
get a certificate of analysis in, they will do an identification
exam, but they do not validate the authenticity of that
suppliers CoA.
What is needed according to the GMPs, she explained, is
doing the full monograph testing at least annually. You
have to validate them for giving you a good CoA, not a
bogus one, she stressed, adding that the most difficult test
is the one suppliers are going to fudge on the most.
A reduced component testing approach can be
employed, Thoma said, if you have a solid scientific
basis for how you are doing that.
She would not want a firm that gets 10 or 20 raw materials
from the same supplier to test only one of them, even if the
supplier is a trusted one with reliable CoAs.
I would want you to have some reasoning as to why you
do or do not test it, and then I would expect it to be on some
type of rotating basis where, overall, you are looking at all
of these. Thoma would not expect you to test every single
thing that comes in the door, but to have a procedure for
justifying why you are doing the testing you are doing.
She would want to see if a firm is either doing full
monograph testing, or ID testing and using the validation
of the authenticity of that suppliers CoA. She reminded
the conference attendees that for components that are
difficult to test, it may be in the firms best interest to do full
monograph testing, because if something goes wrong with
that API or that excipient, it is going to be your end product
that is majorly effected by that.
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and metal impurities limits without actually doing
the testing or having any supporting data.
Further, FDA had already found similar documentation
problems in its 2008 inspection of the firm, and stressed in
the warning letter its concern that proper actions had not
been taken to address the underlying issues.
Making the lack of integrity in the API firms CoAs even
more disturbing was FDAs findings of the lack of cleaning
validation in non-dedicated equipment, on which apparent
product residue was observed.
The warning letter goes on to cite a laundry list of other
GMP and documentation deviations that further undermine
the credibility of Cantons CoA reports that its APIs
conform to specs and that compromise the quality and
accountability of its API in the supply chain.
Following the warning letter, Canton was placed on FDAs
import alert list, banning all of the products made at the
Vadodara facility from entering the U.S.
The facility was also found not to have a quality unit that
would be responsible for reviewing and approving CGMP
documents and procedures and assuring product quality. In
the response to the letter, Lynn asked for written quality unit
procedures that would assure that the CGMP requirements
were met (see box below).
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35
U
nited States: Effectively Using FCC; Good Manufacturing Practices;
Analysis of Elemental Impurities; Dissolution: Theory and Best Practices
Webinars
Increase your knowledge of compendial activities!
The USP Global Education and Training Department has launched a series of
webinars to increase distance learning opportunities for the pharmaceutical
industry. These sessions are conducted by USP Scientific Liaisons or Expert
Committee Members who are directly involved in the standards-setting process.
GAMS292F _ 2014-1
www.usp.org
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Wave of FDA Warning Letters to Injectable Compounders in Q1 2014 Follows
2013 Inspection Blitz and Legislative Empowerment; Recipients Among Those
Applying for Outsourcing Status
A bolus of FDA warning letters to injectable compounding
operations in the first quarter of 2014 has followed in the
wake of the agencys 2013 inspection blitz of high-volume
sterile pharmacy compounding operations nationwide and
legislative empowerment through the Drug Quality and
Safety Act (DQSA), signed into law in November.
Nine of the 11 drug GMP warning letters issued in 2014
that were posted by FDA through March went to injectable
compounders.
The 2014 warning letters contain similar language
explaining the regulatory policy environment
that compounders are operating in, given the new
authorities granted to FDA in DQSA(see IPQ
Monthly Update Nov./Dec. 2013, pp. 28-30).
The agency explains in the letters that at the time the
recipients were inspected in 2013 prior to DQSAs passage,
there were conflicting judicial decisions regarding the
applicability of section 503A of the FDCA [21 U.S.C.
353a], which exempts compounded drugs from several key
statutory requirements if certain conditions are met. Title
I of DQSA referred to as the Compounding Quality Act
(CQA) the agency notes, amended that section of the Act
by eliminating the advertising restrictions that had been the
basis for the judicial conflicts.
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Firm
Date
EM
Contaminaon
Gowning
Stability
Infupharma
7/12
Medi-Fare
3/13
Custom Compound
5/13
Recall
Outsourcer
X
Balanced Soluons
7/13
Green Valley
8/13
Stewart Compound
8/13
Avella
1/14
Triangle
1/14
Olympia
2/14
Nora
2/14
Pallimed
2/14
Total Pharmacy
2/14
Village Ferlity
2/14
Wedgewood
2/14
Pentec
3/14
X
X
X
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2014 Warning Letters Show Commonalities
In addition to the common language in the majority of
the 2014 warning letters explaining FDAs new regulatory
authorities granted under the DQSA, six of the nine letters
cited the manufacturing and distributing of products without
valid prescriptions for individually-identified patients. The
agency explains that as these products are not the subject of
approved applications, they are rendered unapproved new
drugs and misbranded.
The majority of the letters contain a series of sections that
address: compounded drugs under the FDCA violations
of the FDCA unapproved new drug products misbranded
drug products adulteration charges the section in which
the main GMP concerns are explicated corrective actions,
and the agencys conclusions.
Each of the warning letters cited insanitary conditions or
serious deficiencies in aseptic practices in the compounding
of products that were intended or expected to be sterile,
which put patients at risk.
Along with Avella and Olympia, other recipients of the
warning letters were: Nora Apothecary and Alternative
Therapies (Indianapolis, IN) Pallimed Solutions (Woburn,
MA) Pentec Health (Boothwyn, PA) Total Pharmacy
Services (Houma, LA) Triangle Village Fertility Pharmacy
(Waltham, MA), and Wedgewood Village Pharmacy
(Swedesboro, NJ).
In the letters to Pallimed, Pentec, and Village Fertility
Pharmacy, the focus was primarily on unsanitary conditions
observed during the inspection, including aseptic breaches.
No reference was made to the agencys new authorities or
valid prescriptions. None of these three firms has applied
for outsourcer status.
In each of the nine letters, FDA strongly
recommended that the firms management
under-take a comprehensive assessment of
its manufacturing operations, including facility
design, procedures, personnel, processes, materials,
and systems.
In particular, the letters note, the review should assess
the acceptability of the aseptic processing operations. It is
advised that a third party consultant with relevant sterile
drug manufacturing expertise could be useful in conducting
this comprehensive evaluation.
As with most domestic GMP warning letters, this cohort
was signed by the director of the FDA district in which the
receiving facility is located.
At the University of Georgia/FDA International
GMP Conference in March, Atlanta District
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39
IPQ tracks the major industry/regulator conferences and forums to keep you informed on the
critical CMC/review and GMP/inspection developments in the US, Europe and internationally.
All the stories that appear in IPQs real-time In the News web coverage and in our
Weekly Alerts, Monthly Updates and Special Reports are text searchable on our website
with the relevant document links you need ready at hand.
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Comments on FDAs Draft Compounding Guidances Reflect Complex Factors
and Varied Stakeholders Involved
Draft guidances and Federal Register (FR) notices issued
by FDA in December to help implement the compounding
provisions in the Drug Quality and Safety Act (DQSA)
drew a wide array of comments that reflect the complexity
of the factors that need to be considered in advancing the
regulatory processes for compounding.
The three draft guidances and three FR notices that
were issued in early December(see IPQ Monthly
Update Nov./Dec. 2013, pp. 28-30)received
significant numbers of comments from across the
broad spectrum of stakeholders impacted.
The draft guidances cover: overarching rules for what
constitutes pharmacy compounding and how enforcement
for violations may be applied a definition of a new category
of compounder created by the DQSA an outsourcing
facility and the registration requirements, and interim
requirements for ongoing reporting of information to FDA
by the outsourcers on their products and services.
One of the FR notices requests nominations for difficult-tocompound drugs. The other two provide instructions and
a template for completing the nominations. The comment
periods ended in early February for the draft guidances and
early March for the FR notices.
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sterile pharmacy compounding arena.)
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the difficulty in achieving reproducible bioavailability of the
compounded drug.
In recommending a TDS category, Public Citizen cited an
FDA concept paper from 2000 that recommended TDS
products be identified as presenting demonstrable
difficulties in compounding. Similarly to MDI products,
TDSs are complex products that require extensive
development to ensure dosing accuracy and reproducibility,
and precise formulation of the drug product is required to
achieving reproducible bioavailability.
An enteric-coated preparations category was recommended
because improperly formulated enteric-coated preparations
could impact bioavailability, potentially reducing the drugs
efficacy or increasing safety risks. Public Citizen stressed
that clinical testing is necessary to prevent these problems,
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Wes Schmidt
Ashley Readshaw
Richard Spoor
Allen Welsher
Matt Anderson
Thomas Paust
SVP Procurement
Bayer HealthCare
Global Head QA
Daiichi Sankyo Co., Ltd.
VP Quality
Merz North America, Inc.
William Reis
Peng Zhien
Debra Katter
Jennifer Finnegan
McCafferty
Patricia M. Latzo
President
Aurisco
VP External Quality
GlaxoSmithKline
Martin VanTrieste
Richard M Siberski
Luisa Paulo
SVP Quality
Amgen Inc.
Compliance Director
Hovione
Gary A. Baker
Jaspreet Gill
Robert Pantano
Michael Cohen
Managing Director
Myoderm
Tom Beil
Tom Tyner
VP Quality & Technical Service
Spectrum Chemicals and
Laboratory Products
Vincent Antle
VP, QARA
Ash Stevens, Inc.
John Nicols
President and CEO
Codexis, Inc.
Robert Nass
VP Quality and Regulatory
Management Merck Millipore
Merck KGaA
Michael Hoffman
Steve Feldman
VP Global Procurement
Pfizer Inc.
Heiko Hackel
VP Global Sourcing
Sartorius
Anglique Klootwijk
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45
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It is down around 0.1% or better, Madsen emphasized.
So we see orders of magnitude differences. And I relate
this to training and skill, and trying without the benefit
of scale-up, without the benefit of process development,
working with a very wide variety of materials and products
to produce sterile compounded products. It is very difficult
on its face.
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What makes this popular? What makes this demand for compounding pharmacies? Physicians do not want to inject a
preservative-containing product, intrathecal into the spinal canal. So what is our root cause?
Drug Shortages
These are recalls from us the pharmaceutical industry. [In December 2013] Baxter initiates a worldwide voluntary
recall of 5% dextrose injection and normal saline solution, 0.9% sodium chloride injection for IV solutions. Okay.
A doctor writes an order for a patient. What am I going to do? I am going to take 5% dextrose and I am going to
put enough sodium chloride in to get it up to 0.9%. I am going to start compounding, because the product is not
commercially available to me.
[Also in December 2013]Hospira issues a voluntary recall of one lot of Lidocaine injection of 2%, 5 ml in 5 ml vials
due to the presence of particulate matter. We receive an awful lot of particulate matter recalls. Recently there was
a recall where one company found a particle in a vial that was on stability, notified FDA, and wound up recalling the
whole lot.
That lot gets recalled. I need Lidocaine 2%. Now I probably have Lidocaine 50% on my shelf. So what am I going
to do? I am going to take Lidocaine 50% and dilute it and make up smaller vials. I am now compounding, because
commercially available products have been withdrawn from the market. These recalls creating drug shortages are
getting to be more and more of a problem.
Drug shortages are driving a lot of our compounding right now. Earlier I talked about how product simply wasnt
commercially available, and now I am talking about how the increasing amount of drug shortages is accelerating the
need and demand for compounding.
A Pfizer facility caused a drug shortage. [There] is an instruction to me as a pharmacist at a hospital from the director
of pharmacy to prepare these compounds because these compounds were no longer being made available. The one
I want to highlight for you is oxytocin, 10 units in a 500 ml normal saline solution bag. How many people know what
oxytocin is normally used for in a hospital? Wow. Didnt get a lot of hands raised.
It is crucial. If you have a doctor in the delivery room, if you have an OBGYN, and the delivery is scheduled, their hair
is going to be on fire if they dont have oxytocin available. That is the best way I can characterize it.
This is the instruction to the pharmacist: Currently, oxytocin 20 units of 100 and 1000 ml in normal saline solution must
still be made in the pharmacy and stocked in the Womens Care Unit. One of the reasons I point this out is because
earlier I said that prescriptions are made based upon the physicians order for a patient. This points out how we are
beginning to detach ourselves from that philosophy. Pharmacies in hospitals will compound these and stock them in
the nurses unit before the doctors order has been received, so that when the doctor wants the oxytocin it is there and
he can give it to the woman who is going to deliver.
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Cost Pressures
Cost remains a big concern. Everyone is on a tight budget. The Affordable Care Act (ACA) actually cuts reimbursements
further. For those of you who are not familiar with some of the things hospitals are struggling with in the ACA, if someone
is admitted to a hospital with one of three types of conditions, such as a heart attack, and they are discharged from
the hospital, if they need to be re-admitted to the hospital within a certain time-frame, the hospital will not be paid for
the re-admission. The hospital is being told that when it discharges that patient there have to be more effective aftercare activities that are taking place to ensure that the patient is not being re-admitted. And by the way, if you need to
re-admit the patient, you are not going to be reimbursed for your cost.
The cost demands are extreme on hospitals. I can tell you within the next three years you are probably going to 20%
of hospitals in the United States go out of business.
I want to talk more about this third factor. I actually have the article right here. US Medicine is a publication that
services healthcare providers in the military and also in the Veterans Administration. I continue to receive it, even
though I am now retired, as a courtesy.
It talks about how Walter Reed, one of the premier hospitals in the US military system, has saved $700,000. The gist
of the article is that by using a closed transfer device, they can now, on average, get ten doses out of nine single dose
vials. They know that there is over-filling in single dose vials. So by using a closed transfer system, they now know by
the time they open up nine vials, they have enough overfill to that they can get a tenth dose.
They are so proud of it that they published an article. [The pharmaceutical industry is] making single dose vials with
the intention that the single dose vial, obviously, will be used one time. Maybe you do it that way because you are able
to reduce or eliminate a preservative in that single dose vial. Remember earlier the demand for intrathecal use was
lets get the preservatives out. So now you want to use that single dose vial, and nine vials will be combined to give
ten doses, and they will save $700,000. It is that important to them. They do not realize the risk that they are putting
on the patients.
Between drug shortages, product not-available, plus savings, this is why as an industry we have to be interested in
compounding pharmacy.
For a pharmacist, I would tell you, whatever your role is, it is to ultimately meet the needs of the patient. You might
regard your customer as being the physician. You might regard your customer as being the healthcare system. But
ultimately the needs of the patient need to be met. All of these forces are impacting on what is causing more pharmacy
compounding skills, cost, and availability. But ultimately we have to ensure the patient is not being harmed.
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Parenteral
Manufacturing
24-25 June 2014
https://europe.pda.org/ParMan2014
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EUROPE
ICH Q8-11 Oriented Submission and GMP Expectations for Process
Validation and Other Quality Issues Taking Shape in Europe
The effort in Europe to update its expectations for process
validation (PV) to reflect the quality management principles
underpinning ICH Q8-11 moved closer to completion in
late February with the issuance of a final guideline on PV
submissions for medicinal products and a draft revision of
EU GMP Annex 15.
A draft of EMAs guideline on what should be submitted in
marketing dossiers regarding process validation for finished
products was put out for public comment in the spring of
2012(see IPQ Monthly Update May 2012, pp. 44-45). The
final guideline, modified to reflect the numerous comments
received on the draft, becomes effective in August.
Annex 15, which addresses the qualification and validation
of processes from a GMP vantage point, was last revised
in 2001. A concept paper explaining the motivations
for the revision was released by EMAs GMP/GDP
Inspectors Working Group (IWG) in late 2012(see IPQ
Monthly Update Jan./Feb 2013, pp. 24-30). Among them
are technology advances, changes to the EU GMPs, the
incorporation of ICH Q8-11 principles, and the rewrite of
the PV drug product submission guidance. Comments on
the Annex 15 revision are due by May 31.
A third EMA PV project is focused on biotech active
substances(ibid.). A concept paper on the need for a biotech
guideline was released for a three-month public consultation
in May 2011. Further industry input into the drafting
process was gathered at an agency/industry meeting at
EMA headquarters in London in mid-2013. Release of a
draft for comment is anticipated this year.
The biotech guide, being developed by EMAs Biologics
Working Party (BWP), will instruct assessors and industry
on submission expectations in key areas such as: clearance
of process and product-related impurities, such as host cell
proteins and DNA column and membrane sanitization
and life time hold times reprocessing pooling of
intermediates, and selection of batches to be included in
evaluation and validation batches.
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dossier, unless otherwise justified. A partial list of nonstandard processes was provided, and the onus was placed
on the company to make the determination regarding its
processes.
The European Federation of Pharmaceutical Industries and
Associations (EFPIA) maintained that the list in the draft
may have had merit years ago. However, many of the
cited examples are now common processes supported by a
history of successful manufacture. Some examples include
lyophilization, suspensions, modified release, and aseptic
processing.
EFPIA further commented that making a decision whether a
process is non-standard is subjective and could be open to
misinterpretation.
In the final guideline, EMA moved most of the
content of section eight into a new Annex II. In
the annex, it removed the list EFPIA referred to as
outdated, and provided some additional clarification
on non-standard process determination.
The annex states, for instance, that all biological products
are considered to be non-standard. While the examples of
specific manufacturing technologies were deleted, the current
draft maintains the same general categories of products
or processes which could be considered as nonstandard
as appeared in the draft. These are: the manufacture of
specialized pharmaceutical dose forms the incorporation
of some new technology into a conventional process
highly specialized processes involving new technologies
or an established process known, or likely, to be complex
and therefore to require particular care, and non-standard
methods of sterilization.
Regarding PV submission requirements for these categories,
the final version changed might need to be provided to the
more definitive should be provided.
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ISPE commented that the title of the document be adjusted
to more closely reflect its purpose. It suggested that the
Guideline on Process Validation be changed to Guideline
on Process Validation Information to be Included in
Regulatory Submissions, which EMA adopted.
of retrospective validation.
Also reflected in the Annex 15 revision are updates
made to Chapter 1 of the EU GMPs to align with ICH
Q10 change management expectations, expanding
the change control section from two paragraphs
to seven. The Chapter 1 revision became effective
in January 2013.
The Annex 15 draft now includes more detail regarding
change management systems and how they need to be
handled as part of the firms quality system. Incorporated
are the quality-by-design principles of risk management and
design space.
The draft notes that where design space is used, the impact
on changes to the design space should be considered
against the registered design space within the marketing
authorization and the need for any regulatory actions
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operations for which they are ultimately responsible the
introduction of new quality control strategies such as realtime release the implications of the FMD and the refining
of the GDPs in Europe the principles embedded in ICH
Q8-10 a new manufacturing and import authorization
(MIA) interpretation document, and differences between
member states in interpreting the existing Annex 16.
Among the significant changes EMA incorporated into the
2013 revision were a clearer distinction between the release
of a batch and its certification by the QP, directions for what
responsibilities the QP can share and how, and a template for
use by a QP to sign off on a subset of manufacturing steps.
The comments that came in on the revision have
been reviewed by the IWG and a revision is being
drafted, with a release anticipated in 2014.
In its 17-page comment letter, EFPIA expressed appreciation
for the efforts made in revising the annex to foster
harmonization of the requirements and their interpretations
throughout the EU. However, the association cautioned
that more attention would be needed to assure that those
objectives are achieved.
EFPIAs concern was specifically relevant to duties that have
to be performed by a QP and those that can be delegated.
The association stressed that allowing the QP to rely on the
company or site-based pharmaceutical quality systems as
given in ICH Q10 is a key aspect to ensure that requirements
laid down in this annex are being fulfilled.
Europes QP Association joined EFPIA in expressing concern
with the practical implementation of some of the provisions
and terminology in the revised draft.
wherever possible.
Other aspects of the international component of the IWG
responsibilities are also targeted for attention, including
simplifying all operational aspects of the EU mutual
recognition agreements and encouraging the use by MRA
partners of the EudraGMDP database to replace the paper
exchange of GMP certificates. Specifically targeted are
managing the Health Canada audits of new EU member
states, and extending the scope of the MRA with Japan.
The IWG will continue its dialogue with EDQM, WHO,
PIC/S, and other international regulators paying particular
attention to supporting collaborative activities aimed at
optimizing the use of inspection resources and capacity
buildingthrough existing international platforms.
Similarly to the workload facing FDAs drug
compliance office in implementing the FDA Safety
and Innovation Act (FDASIA) and the Drug Quality
and Security Act (DQSA)(see IPQ Monthly
Update January 2014, pp. 13-20), the EMA IWG will
have its plate full in implementing the EU Falsified
Medicines Directive (FMD)(see IPQ Monthly
Update July/August 2013, pp. 16-21).
Included under the FMD umbrella are refining the procedures
for coordinating third country inspections and dealing with
serious GDP non-compliance. Other FMD topics that will
be receiving attention are the GMP and GDP principles
and guidelines for active substances, and finalizing the risk
assessment guideline regarding excipient GMPs.
The IWG will continue its focus on the implementation of the
rules for API importation under the directive and the effort
to avoid product shortages when written confirmations are
not available from exporting third country authorities(ibid.).
The plan also calls for IWG involvement in implementing an
improved procedure for managing GMP non-compliance
linking to processes under development to manage
shortages.
EMAs recent description of the IWG explains that
there is increasing awareness of the importance
of interactions between GMP inspectors and
assessors.
IWG meets with the Quality Working Party at least once
a year, and contributes along with the QWP and Biologics
Working Party (BWP) to EMAs PAT team. Among the joint
projects with the QWP was a workshop on QbD held at the
end of January in London, which was coordinated by PDA
Europe.
The IWG and QWP will be working with EDQM on issues
related to reverse osmosis for production of water for
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Finalize the guideline on GDP principles for active substances
Finalize the risk assessment guideline to establish appropriate GMPs for excipients
Revise the procedure for coordination of third country inspections
Finalize the procedure for dealing with serious GDP non-compliance
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West NovaPure
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Copyright 2012 West Pharmaceutical Services, Inc.
3/29/2012 8:46:01 AM
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EMA to Launch Drug Approval Fast-track
EMA announced in mid-March that it will launch a fast-track for drug approval termed the adaptive licensing pilot project.
Like FDAs breakthrough therapy pathway (see IPQ Monthly Update September 2013, pp. 2-23), the program is intended to
grant early access for medicines meant to treat unmet needs. Companies who are interested in participating in the pilot are requested to submit ongoing drug development programs for consideration.
EMA Concept Paper Proposes a Guideline for the Selection of Sterilization Processes
In early April, EMA released a concept paper on developing a guideline for the selection of sterilization procedures that would
align EMAs advice with ICH Q8. The period for public consultation lasts until July 9, 2014.
EMA Finalizes Guideline on Stability Requirements for Variations
In mid-March, EMA published a revision to its 2005 guideline on stability testing for changes made to a marketing authorization.
The revision provides specific indications for a variety of Type II variations previously unaddressed. It clarifies that three months
of stability data is required for products known to be stable. For products known to be unstable or if there are changes to the quality characteristics of the active substance, the requirements increase to six months of data. The guideline also requires six months
of stability data following changes made to: excipients that may impact quality dosage forms batch size, or fill volume.
UK Begins Construction on Biologics Research Center
The groundbreaking of the National Biologics Manufacturing Centre in the UK took place in mid-April with completion estimated for 2015. The UK government is putting 38 mill. pounds into the NBMC to facilitate innovation in the field of biologics and
to help strengthen the UKs bio-pharma sector by reducing risks for companies involved in developing new biologic products.
MHRA Releases 2014-2015 Business Plan
The MHRA has released their business plan for 2014-2015 as of mid-April. The key strategic activities section of the plan shows
an emphasis on surveillance as well as on increasing collaboration with other regulators to better ensure the quality of medicinal
products.
EC Reports on Advanced Therapy Regulatory Uncertainties
In late March, the EC published a report about currently unaddressed issues for advanced therapy medicinal products(ATMP),
such as gene therapy or tissue engineering. Of concern in the report is that only four ATMPs have been approved in Europe, despite numerous applications, and that different member states have come to different conclusions regarding the same ATMPs.
EMA Q&A Addresses Post-Authorization
In early April, EMA released the first installment of a Q&A intended to provide an overview of EMAs position on issues typically
discussed with marketing authorisation holders regarding post-authorization procedures. The Q&A is a running list and will be
updated as new questions and answers emerge.
EDQM Clarifies CEP Evaluation Policy
In late March, EDQM clarified its approach to assessing new applications for CEPs. The policy document explains that the process
is handled in two rounds: the evaluation of the original application, and if necessary, the evaluation of additional information upon request from EDQM. Following these two rounds, an application lacking the necessary data or response will be closed,
though the application may be resubmitted.updated as new questions and answers emerge.
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INTERNATIONAL
CMC/REVIEW
Brazil to Require Notice One Year Prior to Drug Withdrawal
A new mandate, approved by Brazils Anvisa in late March, requires drug manufacturers to provide a years notice prior to
removing a drug from the market if that withdrawal could lead to a shortage. If the withdrawal would not pose a risk of a
shortage, the notice can be given six months ahead rather than twelve. Additionally, there is a 72-hour requirement of notice if
sudden, previously unforeseen circumstances could lead to a drug shortage.
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EMA and TGA to Collaborate on Orphan Drugs
In a statement published in early April, EMA announced its collaboration with TGA on creating better access to orphan drugs.
In the statement, EMA noted that the two regulators have agreed to share the full assessment reports related to marketing
authorisations of orphan medicines. The statement goes on to note that this strengthens pre-exisiting collaborations, such as
those involved in GMPs.
GMP/INSPECTION
FDA and EMA Extend QbD Pilot, Plan More QbD Guidance
In early March, FDA and EMA announced a two year extension of their pilot program for collaborative review of QbD applications
launched in 2011. FDA and EMA also indicated that additional QbD guidances are expected to be published in 2014. [See story
on p. 50 for more on EMAs 2014 quality initiatives.]
WHO Revising its Guideline on Hold Time
In late February, WHO published a revised draft of its guideline on best practices to follow when designing hold time studies. The
new draft adds the recommendation that manufacturers consider using a most probable rather than a worst case approach
to hold times.
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