Pharma Uptoday Monthly Magazine - Volume 10 issue Jan 2015

VOLUME: 10 - ISSUE: JAN 2015 |
PHARMA UPTODAY
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Inside this issue
3 News Uptoday
24 New Guidance
34 Audit Findings
483 Observations
- Teva Parenteral Medicines Inc (Jul-2009)
- Hovione API facility in Portugal
- Impax Hit With Another FDA 483
38 Warning Letters
- Novacyl Wuxi Pharmaceutical Co., Ltd.
40 EMA Non-Compliance Reports
- Medreich Limited – Unit V
- Sri Krishna Pharmaceuticals Ltd., Hyderabad, India
43 Regulations of the Month
§ 211.188 Batch production and control records

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News Uptoday
MHRA says it will review plans for new UK pharma plants free of charge
Expert advice was key to pursuading AstraZeneca to build a £120m ($188m)
manufacturing plant in the UK according to the MHRA, which says the same help is
available to all drugmakers free of charge.
When AstraZeneca choose a Macclesfield site for its Zoladex delivery device manufacturing
plant last November, the news was greeted as an indication the drugmaker intended to keep a
presence in the UK despite previous cutbacks at sites in Alderly Parkand Brixham.
UK chancellor George Osborne called the investment ―great news for the community‖
describing it as something he and Macclesfield MP David Rutley had ―fought really hard along
with the local council and local people to achieve.‖
Another factor that prompted AstraZeneca to build in the UK was advice provided by the MHRA
according to Gerald Heddell, director of inspection, enforcement and standards, who told in-
Pharmatechnologist.com the decision to seek regulatory help early, speeded up the planning
process.
―Both plants constructed with less MHRA collaboration and those with full involvement, must
ultimately meet the necessary standards but in the case of AstraZeneca the early intervention
allowed them to meet their targets more quickly.‖
Heddell explained that AstraZeneca approached the MHRA for a review of the construction plan
that involved site visits, manufacturing technology assessments and detailed analysis of its
validation strategy.
He also said that: ―The Government encourages us as a general rule to support innovation in
medicine. However AstraZeneca came to us independently of any government advice.‖
The approach differs from when fellow UK Big Pharma firm GSK decided to invest £370m in a
manufacturing plant in Ulverston, Cumbria. The UK firm only confirmed the investment after the
Government introduced tax cuts the firm had lobbied for for several years.
GSK's investment decision also followed CEO Andrew Witty‘s receipt of a Knighthood in the
2012 honours list.
MHRA says quality system deficiencies are most common issue from inspections
Deficiencies related to manufacturers’ quality systems are by far the most prevalent
issue cited from inspections by the UK’s MHRA (Medicines and Healthcare Products
Regulatory Agency), the agency said in a report on 2013 inspections

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The agency broke down its inspection work over the last five years and found that the ratio of
major deficiencies raised per inspection has remained relatively constant, and even decreased
since 2009. But the ratio of critical deficiencies remained constant until 2013, when the agency
reported ―a cluster of data integrity issues with potential impact to public health.‖
Data integrity issues -- both as a result of bad practice and to ―a significantly lesser extent
intentional fraud‖ -- have been observed by the agency across all locations and sectors of the
industry. ―There will therefore be a focus on this area during inspections in the near future,‖ the
agency says.
The MHRA also observed that the relative number of critical deficiencies raised per inspection
in a given continent is higher in Asia than the other continents.
In addition, the most frequently encountered defect categories raised over the previous five
years have remained relatively consistent, though there has been a significant increase in
physical or chemical contaminations.
―There has been a general trend towards higher potency active substances, therefore
increasing the potential for a contamination event to have a greater impact,‖ the MHRA says.
The analysis observed 630 GMP inspections in 2013, 216 of which resulted in major or critical
deficiencies and 174 of those were in the UK while 42 were overseas.
Quality Systems
In offering examples of quality system deficiencies, the MHRA cited the following:
 No self-inspections carried out in the previous year, nor was there a programme
established for the current year;
 Quality system was not being maintained in that Product Quality Reviews had not been
completed during the required period and a significant number of SOPs were past their
review date, among other things; and
 The laboratory pharmaceutical quality system was silent with respect to stability sample
management.
Dr Reddy's API plant receives USFDA 483 with nine observations
Dr Reddy’s says an API plant in India is unlikely to be subject to further regulatory
enforcement after receiving a US FDA 483 with nine observations.
The Srikakulam facility in the Andhra Pradesh region of India was inspected by the US Food
and Drug Administration (FDA) last week resulting in a Form 483 with nine observations, Shilpi
Lathia – a company spokesperson – told in-Pharmatechnologist.com
“The observations were largely related to procedural and other compliances of the plant
system,” she explained. As such “there is no implication on manufacturing and at this stage
production continues as normal,” she added.

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When asked what Dr Reddy‘s Laboratories is doing to fix the issues, Lathia told us it is currently
responding to the agency with its remediation plans and the firm is “confident it won’t lead to
any further enforcement” such as a Warning Letter or import alert.
The plant manufactures bulk active pharmaceutical ingredients (APIs) - including bromfenacna,
celecoxib, ibuprofen, ketorolac tromethamine, naproxen, naproxen sodium, glimepirid,
linagliptin, liraglutide, and nateglinide - used in Dr Reddy‘s finished formulated drugs for export
to the US and EU.
This is not the first time Dr Reddy‘s has fallen foul with the US. In August the US Government‘s
Consumer Product Safety Commission accused the firm of having violated childproof packaging
rules, while an inspection of an API plant in Mexico in 2010 was followed up with an FDA
warning letter banning imports from the site.
Source: http://www.in-pharmatechnologist.com/
MHRA - Department of Health triennial review of arm’s length bodies
The Department of Health (DH) reviews its arm‘s length bodies once every 3 years.
This review is looking at what MHRA, the British Pharmacopeia and the Commission on Human
Medicines do and how.
DH has sent out a public call for evidence to support the reviews.
British Pharmacopoeia Commission: triennial review (external link)
Commission on Human Medicines: triennial review (external link)
MHRA: triennial review (external link)
Source: http://www.mhra.gov.uk/NewsCentre/CON480101
Therapeutic Goods Administration (TGA) publishes business plan 2014-2015
The TGA Business Plan 2014-2015 provides an overview of the organisation's strategic
considerations including our:
 mission
 key roles and responsibilities
 priorities, and our approach to these
 areas of particular emphasis
 significant changes and challenges.
Mission

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As part of the Department of Health the TGA safeguards and enhances the health of the
Australian community through the effective and timely administration of the Therapeutic Goods
Act 1989.
Priorities for 2014-15
Our priorities for the next 12 months comprise:
Continuing to regulate therapeutic goods for safety, effectiveness/performance and
quality
International regulatory convergence and work sharing
Continuing a program of quality improvement in regulatory processes and reform in key
areas, according to government priorities.
For more details browse: https://www.tga.gov.au/book/export/html/283511
Government plans to make quality accreditation mandatory for new clinical trials
NEW DELHI: Starting early next year, the government is planning to make quality accreditation
mandatory for new clinical trials in the country.
"Pharma companies or sponsors keen to conduct new clinical trials in India would have to seek
accreditation from the Quality Council of India (QCI) for their sites, ethics committee and

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investigators before they apply for the drug regulator's clearance," said a government official
aware of the proposal. For ongoing trials, it may not be made mandatory immediately but these
will also be brought under the accreditation fold eventually, he confirmed. This proposal,
initiated by the health ministry, is in the works and could be implemented as soon as next
month, the official added.
Currently, National Accreditation Board for Hospitals & Healthcare Providers (NABH), an arm
of QCI that offers quality certification to hospitals, clinics, blood banks, wellness centres, and
dental clinics, is firming up standards that trials sites, ethics committees and doctors conducting
such programmes need to maintain to get accreditation. However, the services of NABH have
remained voluntary in nature in the past.
Clinical research in India has been in the eye of a storm in the last three years with public
health activists accusing pharma companies and other stakeholders in the sector — contract
research organizations (CROs), doctors conducting trials, ethics panels— of not sticking to
global best practices and exploiting uninformed patients while testing experimental drugs.
They have accused pharma companies of skimping on compensation to trial victims in case of
death and injuries, doctors of not taking proper informed consent of trial volunteers and the
government of lax regulation in the space. The pharma companies argue that blaming the entire
industry for wrongs committed by a few is not only unfair but also counterproductive for new
drug research. The Supreme Court is currently hearing a public interest litigation on the matter.
"We wanted an independent third party to audit and certify the quality standards of trial sites,
ethics panels and of doctors undertaking trials if they qualify. That is the reason we approached
QCI to take up that responsibility," another government official said.
Of the 10 lakh trials conducted globally, India is home to only 15,000, estimates an expert panel
headed by Ranjit Roy Chaudhury. This panel had also recommended accreditation of sites,
investigators and ethics committees but by a central accreditation council, the constitution of
which it had proposed. Industry experts said this demand will be a tall order till such time NABH
is not staffed with specialised experts to carry out such technical audits.
"It is a well thought out plan but will be time consuming and demand substantial resource
investment. While thrashing out the modalities, all stakeholders should be consulted to make it
feasible," said Saurendra Das, executive director of Excel Life Sciences, a US-headquartered
clinical site management firm.
Another CRO said it will be particularly onerous for standalone clinics and small hospital set-
ups and new hospitals that are not already conducting trials.
" An audit can certify a trial site only if it has already conducted one or is conducting one but
what about those sites which want to start but have no past record?" he said.

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Health Canada publishes International Harmonized Requirements for Batch Certification
Content of the Fabricator's/Manufacturer's Batch Certificate for Drug/Medicinal Products
(Content of the Batch Certificate for Medicinal Products) Exported to Countries under the
Scope of a Mutual Recognition Agreement (MRA)
Explanatory Note
In the framework of Mutual Recognition Agreements (MRA), the Sectoral Annex on Good
Manufacturing Practices (GMP) requires a batch certification scheme for medicinal products
covered by the pharmaceutical Annex. The internationally harmonized requirements for the
content of the batch certificate of a medicinal product are provided in this document.
Each batch of medicinal product transferred between countries having appropriate
arrangements on GMP, must be accompanied by a batch certificate issued by the manufacturer
in the exporting country. In the framework of MRAs all manufacturing sites must be located in
the country issuing the certificate or in another MRA country, if reciprocal arrangements are in
force.
This certificate will be issued further to a full qualitative and quantitative analysis of all active
and other relevant constituents to ensure that the quality of the products complies with the
requirements of the marketing authorisation of the importing country. The batch certificate will
attest that the batch meets the specifications and has been manufactured in accordance with
the marketing authorisation of the importing country, detailing the specifications of the product,
the analytical methods referenced, the analytical results obtained, and containing a statement
that the batch processing, packaging and quality control records were reviewed and found in
conformity with GMP. The batch certificate will be signed by the person responsible for
certifying that the batch is suitable for release for sale or supply/export at the manufacturing
site.
The importer of the batch of medicinal product is to receive and maintain the batch certificate
issued by the manufacturer. It has to be available to regulatory authorities of the importing
country. This certification by the manufacturer on the conformity of each batch is essential to
exempt the importer from re-testing.
Where applicable this batch certificate shall also be used for non-finished medicinal products
such as intermediates, bulk or partially packed products.
This certificate may also be used for investigational medicinal products used in clinical trial
authorisations.
These harmonized requirements have been agreed bilaterally by Canada with the regulatory
authorities of the following countries: Australia, countries of the European Economic Area -
European Free Trade Association (EEA-EFTA), Member States of the European Union (EU)
and Switzerland.

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Content of the Batch Certificate for Medicinal Products
[ LETTER HEAD OF EXPORTING MANUFACTURER ]
1. Name of product
2. Importing country
3. Marketing authorisation number or Clinical Trial Authorisation Number
4. Strength/Potency
5. Dosage form
6. Package size and type
7. Batch number
8. Date of manufacture
9. Expiry date
10.Name, address and authorisation number of all manufacturing sites and quality control
sites
11.Certificates of GMP Compliance of all sites listed under 10 or, if available, EudraGMP
reference numbers
12.Results of analysis
13.Comments/remarks
14.Certification statement
15.Name and position/title of person authorising the batch release
16.Signature of person authorising the batch release
17.Date of signature
Explanatory Notes and Glossary
1. Name of product
Proprietary, brand, trade or proper name in the importing country, as applicable. For
Investigational Medicinal Products (IMPs) the code number as referred to in the clinical
trial application.
2. Importing Country
3. Marketing Authorisation Number or Clinical Trial Authorisation Number
The marketing authorisation number of the product in the importing country. For IMPs,
the Clinical Trial authorisation number or trial reference to be provided when available.
4. Strength/Potency
Identity (name) and amount per unit dose required for all active
ingredients/constituents.IMPs include placebos and the manner in which this information
is provided should not unblind the study.

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5. Dosage form or pharmaceutical form, e.g. tablets, capsules, ointments
6. Package size and type
This would be the contents of container and vials, bottles, blisters, etc.
7. Batch number
or Lot number related to the product. Unique combination of numbers, letters or symbols
that identifies a batch and from which the production and distribution history can be
determined.
8. Date of manufacture
In accordance with national (local) requirements of the importing country.
9. Expiry date
The date placed on the container/label of a product designating the time during which the
product is expected to remain within the authorised shelf life specifications authorised by
the importing country, if stored under defined conditions, and after which it should not be
used.
10. Name, address and authorisation number of all manufacturing and quality control
sites
All sites involved in the manufacture including packaging/labelling and quality control of
the batch should be listed with name, address and authorisation number. The name and
address must correspond to the information provided on the manufacturing authorisation.
11. Certificates of GMP Compliance of all sites listed under 10 or, if available, EudraGMP
reference numbers
Certificate numbers and/or EudraGMP reference numbers should be listed under this
item.
12. Results of analysis
Should include the authorised specifications, all results obtained and refer to the
methods used (may refer to a separate certificate of analysis which must be dated,
signed and attached).
13. Comments/remarks
Any additional information that can be of value to the importer and/or inspector verifying
the compliance of the batch certificate (e.g. specific storage or transportation conditions).
14. Certification statement

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This statement should cover the fabrication/manufacturing, including packaging/labelling
and quality control. The following text should be used: "I hereby certify that the above
information is authentic and accurate. This batch of product has been manufactured,
including packaging/labelling and quality control at the above mentioned site(s) in full
compliance with the GMP requirements of the local Regulatory Authority and with the
specifications in the Marketing Authorisation of the importing country or product
specification file for Investigational Medicinal Products. The batch processing, packaging
and analysis records were reviewed and found to be in compliance with GMP".
15. Name and position/title of person authorising the batch release
Including the name and address, if more than one site is mentioned under item 10.
16. Signature of person authorising the batch release
17. Date of signature
Glossary of equivalent terms used in the Certificate template (non-exhaustive)
 batch = lot
 dosage form = pharmaceutical form
 manufacturer = fabricator
 manufacturing/manufacture = fabrication
 manufacturing authorisation = establishment licence
 medicinal product = pharmaceutical product = drug product
 quality control = testing

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The Top 15 Pharmaceutical Deficiencies Cited by FDA in 2014
 The US Food and Drug Administration (FDA) has released data on the observations it
makes during inspections of pharmaceutical facilities, indicating the most common
issues faced by pharmaceutical companies.
 Total 483s Issued Declines for First Time in Six Years
 In its most recent report, FY 2014 Inspectional Observation Summaries, FDA said it
issued 645 Form 483s—forms indicating areas of noncompliance at a facility—to
pharmaceutical companies in fiscal year 2014.
 The number of 473s issued (645) marked the second consecutive year FDA has issued
fewer pharmaceutical 483s than the year prior, and the 2014 total (645) is 19% less than
its 2012 high water mark (787 inspections).
 FDA's inspections also noted common deficiencies by pharmaceutical manufacturers.
Regulatory
Citation
Short Description Long Description
Frequen
cy
21 CFR
211.22(d)
Procedures not in
writing, fully followed
The responsibilities and procedures
applicable to the quality control unit are not
[in writing] [fully followed].
145
21 CFR
211.160(b)
Scientifically sound
laboratory controls
Laboratory controls do not include the
establishment of scientifically sound and
appropriate [specifications] [standards]
[sampling plans] [test procedures] designed
to assure that [components] [drug product
containers] [closures] [in-process materials]
[labeling] [drug products] conform to
109

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appropriate standards of identity, strength,
quality and purity.
21 CFR
211.192
Investigations of
discrepancies, failures
There is a failure to thoroughly review [any
unexplained discrepancy] [the failure of a
batch or any of its components to meet any
of its specifications] whether or not the
batch has been already distributed.
94
21 CFR
211.100(a)
Absence of Written
Procedures
There are no written procedures for
production and process controls designed to
assure that the drug products have the
identity, strength, quality, and purity they
purport or are represented to possess.
87
21 CFR
211.67(b)
Written procedures not
established/followed
Written procedures are not [established]
[followed] for the cleaning and maintenance
of equipment, including utensils, used in the
manufacture, processing, packing or holding
of a drug product.
72
21 CFR
211.113(b)
Procedures for sterile
drug products
Procedures designed to prevent
microbiological contamination of drug
products purporting to be sterile are not
[established] [written] [followed].
72
21 CFR
211.165(a)
Testing and release for
distribution
Testing and release of drug product for
distribution do not include appropriate
laboratory determination of satisfactory
conformance to the [final specifications]
[identity and strength of each active
ingredient] prior to release.
64
21 CFR
211.67(a)
Cleaning / Sanitizing /
Maintenance
Equipment and utensils are not [cleaned]
[maintained] [sanitized] at appropriate
intervals to prevent [malfunctions]
[contamination] that would alter the safety,
identity, strength, quality or purity of the
drug product.
63
21 CFR
211.68(a)
Calibration/Inspection/C
hecking not done
Routine [calibration] [inspection] [checking]
of [automatic] [mechanical] [electronic]
equipment is not performed according to a
written program designed to assure proper
performance.
54
21 CFR
211.166(a)
Lack of written stability
program
There is no written testing program
designed to assess the stability
characteristics of drug products.
51
21 CFR
211.110(a)
Control procedures to
monitor and validate
performance
Control procedures are not established
which [monitor the output] [validate the
performance] of those manufacturing
processes that may be responsible for
51

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causing variability in the characteristics of
in-process material and the drug product. "
21 CFR
211.198(a)
Complaint Handling
Procedure
Procedures describing the handling of
written and oral complaints related to drug
products are [not written or followed]
[deficiently written or followed].
47
21 CFR
211.25(a)
Training--operations,
GMPs, written
procedures
Employees are not given training in [the
particular operations they perform as part of
their function] [current good manufacturing
practices] [written procedures required by
current good manufacturing practice
regulations].
46
21 CFR
211.100(b)
SOPs not followed /
documented
Written production and process control
procedures are not [followed in the
execution of production and process control
functions] [documented at the time of
performance].
43
21 CFR
211.188
Prepared for each batch,
include complete
information
Batch production and control records [are
not prepared for each batch of drug product
produced] [do not include complete
information relating to the production and
control of each batch].
43
Source: http://www.raps.org/

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The 11 biggest drug launches to watch in 2015
This past year was a milestone one in the United States for new drugs, with novel therapeutics
such as Gilead's pricey hep C cures Sovaldi and Harvoni coming to market (as well as a record
15 approvals for drugs to treat rare diseases), and huge sales of newer drugs like Roche's
breast cancer med Kadcyla and Biogen Idec's MS blockbuster Tecfidera.
But according to a new report by EvaluatePharma (gated), 2015 could be equally impressive in
terms of drug launches as innovative candidates in massive medical markets and exciting new
drug classes in cancer immuno-therapy work their way towards approval.
"The value of 2015 launches will be helped along by penetration into massive yet already well-
trodden sectors like cardiovascular and respiratory disease, along with diabetes and
schizophrenia," wrote the authors. "Drugs treating high cholesterol and heart failure are set to
dominate the year's new products, with combine 2020 sales forecast at $8bn."
"The most keenly awaited launches of the year should come from the competing cholesterol-
lowering drugs alirocumab from Sanofi and evolocumab from Amgen."
EvaluatePharma aggregated equity analysts' expectations for 2015's biggest potential drug
launches, including their predictions for 2015 and 2020 sales. Here are the 11 expected
launches that the industry should be watching next year:
1. Opdivo/nivolumab (Bristol-Myers Squibb)
Company: Bristol-Myers Squibb
Pharmaceutical class/therapeutic area: Cancer/anti-PD-1 monoclonal antibody
Current regulatory status: Filed for approval in U.S., EU
Anticipated 2015 sales: $658 million
Anticipated 2020 sales: $7.122 billion
What to watch: Opdivo is projected to be the biggest new drug launch in the U.S. and one of the
biggest launches worldwide this decade. It became the first approved anti-PD-1 medication
when it was cleared in Japan and has shown promise in treating Hodgkin's lymphoma on top of
multiple myeloma (and is being tested on many other cancers). But the really good news for
BMS is that Opdivo has produced a better response rate in trials than Merck's competing (and
historic) PD-1 inhibitor Keytruda (pembrolizumab). If that trend continues, then BMS could rule
this exciting new therapeutic class. The FDA is expected to decide on Opdivo approval by
March.

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2. Alirocumab (Sanofi/Regeneron)
Company: Sanofi/Regeneron
Pharmaceutical class/therapeutic area: LDL cholesterol reducer/anti-PCSK9 monoclonal
antibody
Current regulatory status: Phase III trials
What to watch: PCSK9 inhibitors, besides anti-PD-1 drugs, are the most exciting new
therapeutic class to come out of the woodwork in recent times. What makes these LDL-lowering
drugs particularly exciting is the timing of their filings, with doctors' groups in the U.S. and EU
having recently endorsed controversial new guidelines that significantly expand the use of
statins. If that course of action proves too risky, and PCSK9 drugs like alirocumab aren't
prohibitively pricey, these could become the go-to option in an absolutely critical field.
3. Evolocumab (Amgen/Astellas)
Company: Amgen/Astellas
Pharmaceutical class/therapeutic area: LDL cholesterol reducer/anti-PCSK9 monoclonal
antibody
Current regulatory status: Filed for approval
4. Toujeo (Sanofi)
Company: Sanofi
Pharmaceutical class/therapeutic area: Diabetes (long-acting insulin)
What to watch: You can bet that Sanofi execs will be looking closely at how well Toujeo, the
company's successor to the flagship (but now fading) long-acting insulin Lantus, performs in the
market as the company struggles with a flagging diabetes franchise. What's really giving Sanofi
heartburn is the prospect of competition from Eli Lilly's Lantus biosimilar, which is being
marketed as Abasria in the EU. The goal? $1.7 billion in sales in 2020.

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5. Mepolizumab (GlaxoSmithKline)
Company: GlaxoSmithKline
Pharmaceutical class/therapeutic area: Severe asthma/anti-IL-5 monoclonal antibody
6. Cosentyx (Novartis)
Company: Novartis
Pharmaceutical class/therapeutic area: Psoriasis/anti-IL-17A monoclonal antibody
7. VX-809 + Kalydeco/ivacaftor (Vertex Pharmaceuticals)
Company: Vertex Pharmaceuticals
Pharmaceutical class/therapeutic area: Cystic fibrosis/CFTR corrector
8. LCZ696 (Novartis)
Company: Novartis
Pharmaceutical class/therapeutic area: Heart failure/AT1 & ARNI
What to watch: This one will be huge. If approved (once Novartis moves ahead and files the
drug), LCZ696 will be the first new drug launch with a hospitalization/death prevention in heart
failure patients indication in years. It has been granted the EU's version of priority review status.
9. Palbociclib (Pfizer)
Company: Pfizer
Pharmaceutical class/therapeutic area: Breast cancer/CDK 4 & 6 inhibitor

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10. Selexipag (Actelion)
Company: Actelion
Pharmaceutical class/therapeutic area: Pulmonary arterial hypertension (PAH)/prostacyclin
agonist
What to watch: Selexipag has the advantage over Glaxo's mepolizumab in terms of respiratory
launches, according to the EvaluatePharma researchers. As the report authors note, payers will
likely be reticent to prescribe a lung biologic to a large host of patients.
11. Brexpiprazole (Otsuka Holdings)
Company: Otsuka Holdings
Pharmaceutical class/therapeutic area: Schizophrenia/5-HT1A & D2 & 5-HT2
What to watch: This could be a game-changer in a field that hasn't seen too many of them in
recent years. The FDA is currently reviewing an NDA for the drug as a first-line schizophrenia
treatment and a secondary therapy for major depression. It would also be a natural successor
to Otsuka's antipsychotic Abilify, whose sales slid to $1.03 million in Q1 2014.
IPC initiates work on Addendum 2016 & 53 monographs already identified by experts
After the launch of IP Addendum-2015 to IP-2014, the Indian Pharmacopoeia Commission
(IPC) has already started the work on Addendum 2016. For this, a list of 53 monographs has
already been identified by the experts for phase I drafting, which are approved by CDSCO
along with 13 monographs provided by the stakeholders.
Out of these, 17 monographs are already drafted awaiting comments from the stakeholders.
Sources inform that this Addendum will also have monographs that were not included in IP-
2014 and its Addendum-2015, but are in the compiled list of monographs that are CDSCO
approved, available in NLEM and accepted in market.
Interestingly, as a breather for many, formulations whose API monographs were not included in
IP-2014 and in it‘s Addendum-2015 may also be considered to be included in this. This is along
with the monographs proposed by the stakeholders as deemed fit by the IPC.

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It is understood that the experts will take important decision regarding the new addendum and
erratas, in a three-day working committee meeting, which started off in IPC Ghaziabad on
December 15. Erratas basically deals with monographs and appendices in IP 2014 and
addendum 2015 that needed corrections based on scientific in-puts.
Dr Raman Mohan Singh, principal scientific officer, quality manager and coordinator, Indian
Pharmacopoeia Laboratory, IPC informed that they have already issued erratas 001 and 002 to
IP 2014 in October itself by Dr G N Singh the secretary-cum-scientific director of IPC, for
immediate compliance of the stakeholders. He said that this meeting would further discuss
about details to be included in erratas 003.
―IPC is committed towards its aim to ensure availability of only the best and highest quality of
medicines in the country. It is in continuation with this, we have decided to not only keep on
upgrading the already existent monographs but also adding new to our list,‖ Dr Singh added.
IPC has already completed the preparation of list of new monographs and revised tests for the
new Addendum, while work is going on to acquire and verify new monographs, expected to be
completed by end of December 2014. Dr Raman Singh informs that, if things go as planned,
IPC plan to release the Addendum by September 2015 for its expected implementation in
January 2016.
Frequent GMP Question: How many Signatures are required for Validation Protocols/
Reports?
As part of the validation and qualification activities for the production of medicinal products, the
following question often arises: how many signatures have to be put under the respective
protocols and reports? What is the responsibility of the Head of Production and the QA
department in this matter?
Indications can be found in the chapters 1, 2 and 4 of the EU GMP Guide Part I. You can find in
Chapter 4 requirements on the topic "Documentation":
4.2. "Documents should be designed, prepared, reviewed, and distributed with care."
4.3. "Documents containing instructions should be approved, signed and dated by appropriate
and authorised persons."
This can be summarized as follows: each document should have one author, one reviewer and
one approver. The Head of Production is responsible for the qualification of his equipment and
the validation of his processes (Chapter 2.7 (4)); the same applies to the Head of QC in the lab
(2.8.).

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Since the introduction of the revised Chapter 2 in February this year, a new point has been
added. Moreover - depending on the size and the organisational structure of the company - an
independent Head of Quality Assurance or Quality Unit can be assigned. Where such a function
exists usually some of the responsibilities described in 2.6, 2.7 and 2.8 are shared with the
Head of Quality Control and Head of Production. Senior management should therefore take
care that roles, responsibilities, and authorities are defined. This means for example that the
QA can assume the tasks of the Head of Production. Basically, the QM system should ensure
that validation is performed (1.4 (10)).
Conclusion: Depending on your internal structure, you can specify the signature rules. You
should be aware of what "approved" and "released" mean as both can have various meanings.
"Approved" can be used for a document, for a technical review, for execution, or can even have
a completely different meaning in conjunction with other terms. Similarly, depending on the term
you use in combination with "released" its meaning is different, as, i.e., released formally or
textually. Some companies set such definitions in a SOP documentation.
Finally, the GMP Guide gives the freedom to do it otherwise; if you - at least - come to the same
conclusion and can prove it.
In the US, the procedure is slightly different. There, the personal responsibility of the Head of
Production / QC is not part of the GMP regulation. On the contrary, it is the QCU who has a
crucial role.
The American Society of Testing and Materials (ASTM) has a quite different
approach. The document ASTM E 2500 defines "Subject Matter Experts" for qualification.
According to this model, the QA department would only sign superordinate qualification
documents. This is an interesting and lean approach although not very common Europe yet.
Health products quarantined from two sites in India as Health Canada assesses data
integrity concerns
Starting date: December 23, 2014
Type of communication: Information Update
Subcategory: Drugs
Source of recall: Health Canada

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Issue: Improper Safety Mechanisms, Suspected quality concern, Product Safety, Quality
Audience: General Public
Identification number: RA-43061
Issue
At Health Canada's request, Canadian importers have agreed to quarantine health
products from the following two India-based sites due to data integrity concerns:
 Dr. Reddy's Laboratories in Srikakulam, India
 IPCA Laboratories in Pithampur, India
This action comes in light of recent information from a trusted regulatory partner that
raises concerns about the reliability of the laboratory data generated at these sites.
Health Canada is taking this action as an interim precautionary measure to help mitigate
any potential risk.
A quarantine means that the Canadian importers have agreed to stop the importation
and distribution of products from these two sites. At this time there is no identified risk to
health, and Health Canada is not requesting a recall of any of the products.
Health Canada's action applies to active pharmaceutical ingredients (APIs) from Dr.
Reddy's Laboratories as well as to finished drug products from a different IPCA
Laboratories facility than is currently subject to import restrictions by Health
Canada. Health Canada has compiled an initial list of products affected by the
quarantine. The list will be updated as new information becomes available. To date,
none of the affected products have been determined by Health Canada to be medically
necessary.
Health Canada will continue to work with international partners and Canadian importers
to gather and assess information regarding the situation and take action as necessary to
help protect Canadians.
Canadians should not make any changes to their medication without first consulting with
a healthcare professional.
Health Canada has also engaged provinces and territories to share information about the
situation and will continue to collaborate. The Department will continue to keep
Canadians informed as new information becomes available.

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FDA Making Changes to Drug and Manufacturing Oversight
FDA Commissioner Margaret Hamburg, MD, is seeking new ways for the agency to deal with its
complex regulatory roles, especially as it pertains to drugs.
In 2013, Hamburg came up with a new agency wide organization to make key
recommendations to improve how FDA centers deal with its audit employees. The result of that
effort is the new Program Alignment Group Plan that will integrate the centers and field
oversight operations.
CDER also is enacting a large reorganization that is made to improve old quality programs and
to better ensure drug quality. The director of CDER, Janet Woodcock, is setting up a new Office
of Pharmaceutical Quality or OPQ. The idea is to provide a single voice for drug quality that will
coordinate research, review and audit duties as they pertain to quality.
The inspection functions done by the Office of Regulatory Affairs are being revised. For drugs,
one of the big efforts will be to enact a pharmaceutical inspectorate with specialized expets that
will both inspect and evaluate manufacturing processes for drugs. CDER staff is going to work
in certain CGMP audits more and will give additional input into the scheduling of inspections, as
well as enforcement.
Also up for overhaul is the manufacture registration and inventory databases. This will
harmonize all center and data systems at ORA. This will use facility IDs that are most common,
codes for products and modern software platforms that allow everyone to access data of
facilities, AERs, risk info and field inventory.
The reorganization of CDER will go live in early 2016, and will shift most functions of the Office
of Pharmaceutical Science over to OPQ. OPQ is then going to evaluate CMC submissions for
pharmaceuticals, biotechnology and generic drugs.

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Calibration:
The set of operations that establish, under specified conditions, the relationship
between values indicated by an instrument or system for measuring (for
example, weight, temperature and pH), recording, and controlling, or the
values represented by a material measure, and the corresponding known
values of a reference standard. Limits for acceptance of the results of
measuring should be established. Always remember any reference standard is
always used in calibration.
Validation:
Action of proving and documenting that any process, procedure or method
actually and consistently leads to the expected results. It can better understand
that the validation is a documented evidence to and done to prove the
consistency of the expected results of any process, procedure or method.
Qualification:
Action of proving and documenting that any premises, systems and equipment
are properly installed, and/or work correctly and lead to the expected results.
Qualification is often a part (the initial stage) of validation, but the individual
qualification steps alone do not constitute process validation. Qualification is a
part of validation.

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New Guidance
FDA Draft Guidance for Industry: SUPAC: Manufacturing Equipment Addendum:
This guidance combines and supersedes the following scale-up and post-approval changes
(SUPAC) guidances for industry:
(1) SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms,
Manufacturing Equipment Addendum, and
(2) SUPAC-SS Nonsterile Semisolid Dosage Forms, Manufacturing Equipment Addendum.
It removes the lists of manufacturing equipment that were in both guidances and clarifies the
types of processes being referenced.
Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM346049.pdf
FDA Draft Guidance for Industry: DSCSA Standards for the Interoperable Exchange of
Information for Tracing of Certain Human, Finished, Prescription Drugs: How to
Exchange Product Tracing Information
This guidance addresses the pharmaceutical security provisions in section 582 of the Federal
Food, Drug, and Cosmetic Act (FD&C Act). Section 582 was added by the Drug Supply Chain
Security Act (DSCSA) (Title II of Public Law 113-54) and facilitates the tracing of products
through the pharmaceutical distribution supply chain by requiring certain trading partners
(manufacturers, repackagers, wholesale distributors, and dispensers) to exchange transaction
information, transaction history, and a transaction statement (product tracing information) when
engaging in transactions involving certain prescription drugs.3 25 This requirement goes into
effect on January 1, 2015, for manufacturers, repackagers, and wholesale distributors, and on
July 1, 2015, for dispensers. FDA, in consultation with other appropriate Federal officials and
pharmaceutical distribution supply chain stakeholders, is required, under section 582(a)(2)(A) of
the FD&C Act, to establish initial standards for the interoperable exchange of the product
tracing information related to each transaction of certain human, finished, prescription drugs
covered by the statute.
ances/UCM424895.pdf

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FDA Draft Guidance for Industry:Recommended Warning for Over-the-Counter
Acetaminophen-Containing Drug Products and Labeling Statements Regarding Serious
Skin Reactions
FDA is informing manufacturers, members of the medical and scientific community, and other
interested persons that at this time we do not intend to object to the marketing of single- and
combination-ingredient, acetaminophen-containing, nonprescription (commonly referred to as
over-the-counter (OTC)) drug products bearing a warning as described in this guidance (see
section III, Discussion and Policy) alerting consumers that the use of acetaminophen may
cause severe skin reactions. This guidance is intended to apply to single- and combination-
ingredient acetaminophen-containing products marketed under the Tentative Final Monograph
(TFM) for Internal Analgesic, Antipyretic, and Antirheumatic (IAAA) Drug Products for Over-the-
Counter Human Use, published in the Federal Register (53 FR 46204, November 16, 1988).
ances/UCM424898.pdf
FDA Draft Guidance for Industry: How to Obtain a Letter from FDA Stating that
Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable
REMS for RLD
This guidance describes how a prospective abbreviated new drug application (ANDA) applicant
may request a letter stating that FDA has determined: (1) that the prospective applicant‘s
bioequivalence (BE) study protocol contains safety protections comparable to those in the risk
evaluation and mitigation strategy (REMS) with elements to assure safe use (ETASU)
applicable to the reference listed drug (RLD), and (2) that FDA will not consider it a violation of
the REMS for the RLD sponsor to provide a sufficient quantity of the RLD to the interested
generic firm or its agent to allow the firm to perform the testing necessary to support its ANDA.
ances/UCM425662.pdf

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Guidance for Industry: Pregnancy, Lactation, and Reproductive Potential: Labeling for
Human Prescription Drug and Biological Products — Content and Format
This guidance is intended to assist applicants in complying with new content and format
requirements of the Pregnancy, Lactation, and Females and Males of Reproductive Potential
subsections of labeling for human prescription drug and biological products (as described in the
final rule published concurrently with this draft guidance). The guidance provides information for
preparing subsections 8.1 Pregnancy, 8.2 Lactation, and 8.3 Females and Males of
Reproductive Potential of the USE IN SPECIFIC POPULATIONS section of the full prescribing
information (FPI) described in 21 CFR 201.56(d)(1) and 201.57(c)(9)(i) through (iii).
ances/UCM425398.pdf
Pregnancy and Lactation Labeling Final Rule
The FDA published the Content and Format of Labeling for Human Prescription Drug and
Biological Products; Requirements for Pregnancy and Lactation Labeling, referred to as the
―Pregnancy and Lactation Labeling Rule‖ (PLLR or final rule).
The PLLR requires changes to the content and format for information presented in prescription
drug labeling in the Physician Labeling Rule (PLR) format to assist health care providers in
assessing benefit versus risk and in subsequent counseling of pregnant women and nursing
mothers who need to take medication, thus allowing them to make informed and educated
decisions for themselves and their children. The PLLR removes pregnancy letter categories –
A, B, C, D and X. The PLLR also requires the label to be updated when information becomes
outdated.
Below is a comparison of the current prescription drug labeling with the new PLLR labeling
requirements.

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The Pregnancy subsection (8.1) includes information for a pregnancy exposure registry for the
drug when one is available. Pregnancy exposure registries collect and maintain data on the
effects of approved drugs that are prescribed to and used by pregnant women. Information
about the existence of any pregnancy registries in drug labeling has been recommended but
not required until now. Information in the Pregnancy sub-section includes a Risk Summary,
Clinical considerations, and Data. Information formerly found in the ―Labor and delivery‖
subsection is now included in the ―Pregnancy‖ subsection.
The Nursing mothers subsection was renamed, the Lactation subsection (8.2), and provides
information about using the drug while breastfeeding, such as the amount of drug in breast milk
and potential effects on the breastfed infant.
The Females and Males of Reproductive Potential subsection (8.3), new to the labeling,
includes information, when necessary, about the need for pregnancy testing, contraception
recommendations, and information about infertility as it relates to the drug.
The labeling changes go into effect on June 30, 2015. Prescription drugs and biologic
products submitted after June 30, 2015, will use the new format immediately, while labeling for
prescription drugs approved on or after June 30, 2001, will be phased in gradually.
Labeling for over-the-counter (OTC) medicines will not change; OTC drug products are not
affected by the final rule.
Concurrently with publishing the PLLR, FDA also issued draft guidance for industry to assist
drug manufacturers in complying with the new labeling content and format requirements.
Source: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Label
ing/ucm093307.ht

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Draft questions and answers on cyclodextrins in the context of the revision of the
guideline on ‘Excipients in the label and package leaflet of medicinal products for human
use'
Following the European Commission decision to revise the Annex of the guideline on
‗Excipients in the label and package leaflet of medicinal products for human use‘ (CPMP/463/00
Rev. 1), a multidisciplinary group of experts was created in 2011 to update the labelling of
selected excipients listed in the annex of the guideline and to add new excipients to the list,
based on a review of their safety. Draft Q&A documents on excipients are progressively
released for public consultation. They include proposals for new or updated information for the
labelling and package leaflet. A corresponding background report supporting the review is
published for information only.
Source: http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/docume
nt_detail.jsp?webContentId=WC500177944&murl=menus/document_library/document_library.j
sp&mid=0b01ac058009a3dc
Draft questions and answers on propylene glycol and esters in the context of the
revision of the guideline on ‘Excipients in the label and package leaflet of medicinal
products for human use’
Following the European Commission decision to revise the Annex of the guideline on
‗Excipients in the label and package leaflet of medicinal products for human use‘ (CPMP/463/00
Rev. 1), a multidisciplinary group of experts was created in 2011 to update the labelling of
selected excipients listed in the annex of the guideline and to add new excipients to the list,
based on a review of their safety. Draft Q&A documents on excipients are progressively
released for public consultation. They include proposals for new or updated information for the
labelling and package leaflet. A corresponding background report supporting the review is
published for information only.
Source: http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/docume
nt_detail.jsp?webContentId=WC500177945&murl=menus/document_library/document_library.j
sp&mid=0b01ac058009a3dc

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General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings
Type of Posting : Notice of Intent to Revise
Posting Date: 13–Oct–2014; updated 01–Dec–2014
Targeted Official Date: TBD
Expert Committee: Compounding
In accordance with section 7.05(c) of the 2010–2015 Rules and Procedures of the Council of
Experts, this is to provide notice that the Compounding Expert Committee intends to republish
General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings in the
Pharmacopeial Forum (PF). The General Chapter, which was originally published in PF 40(3)
[May–Jun. 2014], provides standards to protect personnel and the environment when handling
hazardous drugs.
The Compounding Expert Committee is republishing General Chapter <800> in PF 41(2) [Mar.–
Apr. 2015] due to the nature and significance of the comments received on the original PF
proposal. The revision clarifies wording and reflects new and revised guidance documents and
stakeholder input.
General Chapter <800> is being presented in advance of its publication in PF 41(2) to allow
additional time for public review and comment. To ensure that all comments are addressed,
please indicate the line number(s) corresponding to your comments and submit
toCompoundingSL@usp.org. The General Chapter is available with line numbers at the link
below. Comments will be accepted until May 31, 2015.
Proposed Revisions to the General Notices and Requirements to be Published for
Comment in Pharmacopeial Forum 41(1) [Jan.–Feb. 2015]
Type of Posting: General Announcement
Posting Date: 05–Dec–2014
Targeted Official Date: 01–May–2016
Expert Committee: Council of Experts Executive Committee
To provide additional time for review and input, USP is posting in advance the proposed
General Notices and Requirements (GN) section of the United States Pharmacopeia and the
National Formulary (USP–NF) that will be published for public notice and comment in

PHARMA UPTODAY
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Pharmacopeial Forum 41(1) [Jan.–Feb. 2015]. GN is regularly revised to refine and clarify its
content. GN was most recently revised in the Second Supplement to USP 37–NF 32 (published
June 1, 2014; official December 1, 2014). This current proposal has been informed by input
from stakeholders on the General Notices Project Team, representatives of the U.S. Food and
Drug Administration, and members of the Council of Experts Executive Committee, who
discussed these revisions in their September 16–17, 2014 meeting. The following links provide
access to both a summary of changes that are proposed for this round of GN revisions and to
the GN file itself.
ICH Releases Three New Guidance Documents
 Questions & Answers: Selection and Justification of Starting Materials for the
Manufacture of Drug Substances
This Implementation Working Group (IWG) was endorsed by the ICH Steering Committee
in November 2014.
Experience gained with the implementation of the ICH Q11 Guideline since its finalisation
in 2012 shows that some clarification is needed on what information about the selection
and justification of starting materials should be provided in marketing authorization
applications and/or Master Files.
The Q11 IWG is tasked to develop a Questions and Answers (Q&A) document which will
be focusing on chemical entity drug substances as that is where most of the differences of
opinion have been experienced.
 Implementation of Guideline for Elemental Impurities
This Implementation Working Group (IWG) was endorsed by the ICH Steering Committee
in October 2014. Throughout the development of the Q3D Guideline, external audiences,
constituents and interested parties have clearly communicated the complexity of the
implementation approaches for this guideline. While the Q11 Guideline provides the
framework, it cannot provide the detailed examples covering the breadth of potential case
studies for products within scope of the guideline. Consequently, the ICH SC considered
that the development of a comprehensive training programme and supporting
documentation sponsored by ICH was necessary to ensure the proper interpretation and

PHARMA UPTODAY
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effective utilisation by industry and regulators alike to enable a harmonised and smooth
implementation of Q3D on a global basis.
 Safety single
This topic was endorsed by the ICH Steering Committee in November 2014.
The S11 Guideline is proposed to provide direction on the nonclinical safety studies
important to support a pediatric development program. It will recommend standards for the
conditions under which nonclinical juvenile animal testing is considered informative and
necessary to support paediatric clinical trials, and also provide guidance on the design of
the studies. A streamlined drug development and higher scientific rigor while minimizing
the unnecessary use of animals will be achieved with the implementation of this new
harmonised ICH Guideline.
EMA releases Guideline on quality of transdermal patches
This guideline addresses new marketing authorisation applications (including generic or
abridged applications) and subsequent variation submissions for transdermal patches for
systemic delivery.
Guidance is provided on the quality requirements for the description, development,
manufacture, characterisation of excipients, control of drug product, packaging and stability of
transdermal patches. In particular, in vitro performance testing with respect to drug release,
adhesion and skin permeation is discussed, together with its relation to clinical and in vivo
performance.
It should be read in conjunction with the Guideline on the Pharmacokinetic and clinical
evaluation of modified-release dosage forms.
Transdermal patches are designed to provide a controlled delivery of the active substance(s)
through the skin, principally by diffusion, resulting in a defined rate and extent of systemic
delivery of active substance

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FDA issues Guidance for a clear Identification of pharmaceutical Companies
In our GMP News from September 2013 you learned about a draft of a FDA Guidance for
Industry entitled "Specification of the Unique Facility Identifier (UFI) System for Drug
Establishment Registration". This document's goal was to clearly identify pharmaceutical sites.
The draft comprised (manageable) five pages - including the cover page. And in terms of
volume this didn't change. However, some of the alternatives still mentioned in the draft, are not
stated any longer - as one can find out when contacting the authority in these cases. The
method now wanted is a registration by a D-U-N-S- (Data Universal Numbering System)
number. This number - which is a 9-digit code - is supplied by the company Dun & Bradstreet.
Providing Regulatory Submissions In Electronic Format — Standardized Study Data
Under section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), at least 24
months after the issuance of a final guidance document in which the Food and Drug
Administration (FDA) has specified the electronic format for submitting certain submission types
to the Agency, such content must be submitted electronically and in the format specified by
FDA. This guidance and the technical specifications documents it incorporates by reference
describe the requirements for an electronic submission of standardized clinical and nonclinical
study data under section 745A(a) of the FD&C Act. In accordance with section 745A(a),
following the issuance of a final guidance on this topic, study data contained in the submission
types identified in this guidance must be submitted electronically in a format that FDA can
process, review, and archive.
Providing Regulatory Submissions in Electronic Format — Submissions Under Section
745A(a) of the Federal Food, Drug, and Cosmetic Act
Section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), added by section
1136 of the Food and Drug Administration Safety and Innovation Act (FDASIA) (Public Law
112-144), requires that submissions under section 505(b), (i), or (j) of the FD&C Act and
submissions under section 351(a) or (k) of the Public Health Service Act (PHS Act) be
submitted in electronic format specified by the Food and Drug Administration (FDA or the
Agency) beginning no earlier than 24 months after FDA issues a final guidance specifying an
electronic submission format.

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Health Canada Draft Guidance - Tamper-Resistant Formulations of Opioid Drug Product
Submissions
This document is intended to provide guidance to sponsors seeking a Notice of Compliance for
their tamper-resistant controlled-release opioid products. It provides information on what
evidence is required to demonstrate tamper-resistance of the product to support a drug
submission under the Food and Drug Regulations.
Opioids are also controlled substances and are, therefore, also subject to the Controlled Drugs
and Substances Act (CDSA) and its regulations. The CDSA and its regulations provide
oversight for the control of substances that can alter mental processes or may cause harm to
individuals and to society when diverted or misused, with the aim of supporting their legitimate
use.
In recent years, the Therapeutic Products Directorate (TPD) has seen a steady increase in the
number of drug submissions received for opioid drugs with tamper-resistant formulations.
These formulations are designed to resist a number of common tampering methods and
potentially provide barriers to certain methods of drug abuse. The abuse of opioids is an
important public health and safety issue. Health Canada, as the federal regulator of
pharmaceuticals, is committed to decreasing the risk of abuse associated with opioid drugs
while ensuring these products remain available to patients. Other controls aimed at reducing
opioid abuse may be imposed by provinces or professional provincial licensing bodies.
This document is intended to provide guidance to sponsors seeking a Notice of Compliance for
their tamper-resistant controlled-release opioid products. It provides information on what
evidence is required to demonstrate tamper-resistance of the product to support a drug
submission under the Food and Drug Regulations.

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AUDIT FINDINGS - 483 Observations
Firm Name 483 Observation
L. Perrigo Co. The reproducibility of test methods have not been established and
documented.
Pfizer Ireland
Pharmaceuticals, Inc.
All records related to the manufacture of intermediates or API were
not adequately reviewed.
Mayo Clinic PET
Radiochemistry
Facility
Periodic reports of non-alert adverse drug experiences have not
been submitted quarterly for an application which was approved less
than three years ago.
3M Drug Delivery
Systems
Appropriate controls are not exercised over computers or related
systems to assure that changes in master production and control
records or other records are instituted only by authorized personnel.
Ishihara Sangyo
Kaisha, Ltd.
Validation of the production process and testing methods used in the
manufacture of ** and ** intended for use as active pharmaceutical
ingredients in ** products have not been demonstrated.
Abraxis Bioscience,
LLC
Laboratory controls do not include a determination of conformance to
written descriptions of sampling procedures for drug products.
Hieber's Pharmacy Procedures designed to prevent microbiological contamination of
drug products purporting to be sterile do not include validation of the
sterilization process.
Brenntag Great
Lakes, LLC
The cleaning procedures for bulk blending tanks ** used to
manufacture OTC drug blends, are not validated.
Abbvie Ltd. Procedures describing the handling of written and oral complaints
related to drug products are not written or followed.
High Chemical
Company
There is a failure to thoroughly review any unexplained discrepancy
and the failure of a batch or any of its components to meet any of its
specifications whether or not the batch has been already distributed.
Lifetech Resources,
LLC
Written procedures are not established and followed for the cleaning
and maintenance of equipment, including utensils, used in the
manufacture, processing, packing or holding of a drug product.
DNA Pharmacy
Services, Inc. dba
Palm Beach
Compounding
There is no written testing program designed to assess the stability
characteristics of drug products.

PHARMA UPTODAY
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483 of Teva Parenteral Medicines Inc (Jul-2009)
QUALITY SYSTEM:
 The quality control unit lacks responsibility to approve and reject all procedures or
specifications impacting on the identity, strength, quality, and purity of drug products.
 Testing and release of drug product for distribution do not include appropriate laboratory
determination of satisfactory conformance to the final specifications prior to release.
 In-process materials are not tested for quality and purity and approved or rejected by the
quality control unit during the production process.
 Acceptance criteria for the sampling and testing conducted by the quality control unit is
not adequate to assure that batches of drug products meet appropriate statistical quality
control criteria as a condition for their approval and release.
 There is a failure to thoroughly review any unexplained discrepancy whether or not the
batch has been already distributed.
 Investigations of an unexplained discrepancy did not extend to other batches of the
same drug product and other drug products that may have been associated with the
specific failure or discrepancy.
 The responsibilities and procedures applicable to the quality control unit are not in
writing.
 Drug product production and control records, are not reviewed by the quality control unit
to determine compliance with all established, approved written procedures before a
batch is released or distributed.
FACILITIES AND EQUIPMENT SYSTEM:
 Equipment used in the manufacture, processing, packing or holding of drug products is
not of appropriate design to facilitate operations for its intended use.
 Aseptic processing areas are deficient regarding systems for maintaining any equipment
used to control the aseptic conditions.
 Equipment and utensils are not cleaned and sanitized at appropriate intervals to prevent
contamination that would alter the safety, identity, strength, quality or purity of the drug
product.
 Records are not kept for the cleaning and sanitizing of equipment.
 Aseptic processing areas are deficient regarding the system for monitoring
environmental conditions.
LABORATORY SYSTEM:
 Each batch of drug product required to be free of objectionable microorganisms is not
tested through appropriate laboratory testing.

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PRODUCTION SYSTEM:
 Procedures designed to prevent microbiological contamination of drug products
purporting to be sterile are not established and written.
RAW MATERIALS SYSTEM:
 Each lot of a component liable to objectionable microbiological contamination is
deficiently subjected to microbiological tests before use.
US FDA issues Form 483 to Hovione API facility in Portugal
The US FDA’s pre-approval inspection at Hovione’s API plant in Loures, Portugal,
covering two NDA filings, resulted in a Form 483 with three inspectional observations.
The five day inspection carried out by investigators Ramon Hernandez and Jose Lopez Rubet
still confirmed the site to be compliant with the principles and guidelines of Good Manufacturing
Practices (GMP), but the company did not disclose what the inspectional observations were.
"Addressing these observations is the top priority of the site management and the points raised
will be replied to within 15 working days from the receipt of the Form 483,‖ Luisa Paulo,
Hovione's Compliance Director, said. ―We are taking this result to improve our quality system
both here and at our other sites. The investigators spoke positively of many of our initiatives.‖
Back in 2009, the same site was approved by the FDA without any deviations or Form 483s.
Earlier this year, Guy Villax, CEO of Hovione, also questioned the quality of products coming
out of China and India , noting that audit reports need to be shared more widely.
―We have a culture of quality that puts patient safety first. This shapes our behaviors and
motivates us to improve. This is a team effort, and I am very encouraged to see everyone so
committed,‖ said Villax.

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Impax Hit With Another FDA 483
Impax Laboratories was hit with its second FDA 483 recently on its plant in Hayward CA. This
follows an inspection and 483 for its plant in Taiwan earlier this year.
This latest 483 came just a few months after Impax stated that it was confident that its
manufacturing processes were good enough to resubmit an NDA for a drug for Parkinson‘s
disease. The approval for that drug had been delayed due to concerns from FDA about the
firm‘s cGMP controls.
In the most recent 483, two of the observations were repeats from the first inspection, which is
something FDA particularly frowns upon.
In 2013, the company had to let go over 100 employees at the plant in CA because GMP
problems there led GSK to abandon a $180 million partnership with Impax.
The Hayward CA 483 stated that the firm had many pyridostigmine tablets that were not in
spec. After they ruled out lab errors, the plant failed to determine if there was a problem in the
manufacturing of the pills, and released the product.
Also criticized in the FDA report was plant maintenance, which noted that ceiling tiles were
sagging, there was a rusty drain and several problems with a walk in chamber that is used for
stability studies and storing product.
Repeat 483 violations concerned not having sufficient protections in place to be sure analysts
cannot rewrite and/or delete data during an analysis.
This plant in Hayward has been a major problem for Impax in the last few years. cGMP
violations led to a warning letter being issued in 2011.
At the Taiwan plant, observations included validation related problems and also problems with
testing during the production of Rytary.

PHARMA UPTODAY
38
FDA Warning letters
Novacyl Wuxi Pharmaceutical Co., Ltd. 12/19/14 (WL: 320-15-04):
API: CGMP DEVIATION
1. Failure to manage laboratory systems with sufficient controls to ensure
conformance to established specifications and prevent omission of data.
Serious deficiencies related to your documentation practices, including missing raw data.
the analyst discarded the chromatogram because it was present in the blank
injection. However, the analyst was unable to retrieve the blank chromatogram from the system
because it was overwritten by a subsequent injection.
changes to integration parameters for the impurities test without appropriate documentation or
justification.
Your firm relied upon hand written notes on a chromatogram discovered in a drawer at the
laboratory as the documentation for this change. Furthermore, your firm implemented this
change without an audit trail that would have captured the date of the change and who made
the change.
Other significant deficiencies noted in your laboratory system include:
a) Failure to have a written procedure for manual integration despite its prevalence.
b) Failure to use separate passwords for each analyst‘s access to the laboratory systems.
c) Use of uncontrolled worksheets for raw analytical data in your laboratory.
d) Presence of many uncontrolled chromatograms, spreadsheets and notes of unknown origin
found in a drawer.
FINISHED PRODUCT: CGMP VIOLATIONS
2. Your firm did not properly document or investigate out-of-specifications (OOS) and
other discrepancies(21 CFR 211.192).
For example, the inspection documented that OOS Investigation #1203, related to the presence
of metal particles in (b)(4), failed to determine the root cause of the contamination or explain
why the (b)(4) step was unable to prevent the contamination.

PHARMA UPTODAY
39
3. Your firm failed to establish laboratory controls that include scientifically sound and
appropriate specifications, standards, sampling plans, and test procedures designed to
assure that components, drug product containers, closures, in-process materials,
labeling, and drug products conform to appropriate standards of identity, strength,
quality, and purity (21 CFR 211.160(b)); and,
4. Your firm did not record all CGMP activities at the time these were performed. The
lack of contemporaneous documentation of CGMP activities increases the likelihood of
recording erroneous data(21 CFR 211.188).
your firm failed to ensure testing documentation was complete and accurate.

PHARMA UPTODAY
40
AUDIT FINDINGS - EMA Non Compliance Reports
Non Compliance Report: Medreich Limited – Unit V:
Site address : Plot n°45 A & B, Anrich Industriel Estate, Bollaram, Medak District, Andra
Pradesh, 502325, India
From the knowledge gained during inspection of this manufacturer, the latest of which was
conducted on 2014-05-16 , it is considered that it does not comply with the Good Manufacturing
Practice requirements referred to in "The principles and guidelines of Good Manufacturing
Practice laid down in Directive 2003/94/EC".
Nature of non-compliance :
58 deficiencies have been raised during the inspection which was a follow-up of the inspection
conducted from 28 January 2013 to 1 February 2013 (see NCR/HPF/FR/1/2013).
1 deficiency related to data falsification has been classified as "critical" .
29 deficiencies have been classified as "major". Among them,
- 5 were related to poor level of quality management (inadequate deviations management
system with no exhaustive record, no classification and no thorough investigation),
- 3 were related to personnel (no formal policy on temporary workers specially for quality critical
activities such as visual inspection),
- 5 were related to the maintenance of equipment (depyrogenisation tunnel and RABS used for
the filling operation, LAF used for the sampling of sterile starting materials ...),
- 4 were related to documentation (documentation management and data integrity with difficulty
to demonstrate that the actions recorded were genuine),
- 9 were related to production (sterile and non-sterile products) including risk of cross
contamination, poor visual inspection process handling, poor in-process control handling
(weight of vials, weight of tablets and hard capsules), poor handling of broken vials issues.
Non-Compliance Report: Sri Krishna Pharmaceuticals Ltd., Hyderabad, India
Nature of non-compliance :
During the inspection 10 Major deviations from EU GMP have been found. In particular, main
concerns were:
1. Drug products failing to meet established quality control criteria are not rejected. In particular:

PHARMA UPTODAY
41
a) analysts routinely use the PC administrator privileges to set the controlling time and date
settings back to over-write previously collected failing and/or undesirable sample results. This
practice is performed until passing and/or desirable results are achieved;
b) Analysts routinely perform ―trial‖ injections of sample aliquots prior to performing the
official/reported analysis. There are no documented sample preparation details for these trial
analyses. The results of these trial injections are not reported, and were found to differ
significantly from the subsequent reported results;
c) Analysts routinely perform ―trial‖ injections of sample aliquots prior to performing the
official/reported analysis. The resulting raw data chromatogram files were often found to have
been deleted and unavailable for review;
d) Analysts delete undesirable and/or failing results (entire sample sequences) and retest
samples until desirable results are achieved.
2. Established laboratory control mechanisms are not followed. Electronic records are used, but
they do not meet systems validation requirements to ensure that they are trustworthy, reliable
and generally equivalent to paper records;
3. Missing or poor quality agreement;
4. Written production and process control procedures are not documented at the time of
performance. Specifically, Too Numerous to Count (TNTC) torn and discarded controlled
manufacturing batch records for a variety of different products issued by the Quality Unit were
found during a walk-through inspection of the facility. Five batch records were compared with
the archived manufacturing one and it was ascertained that no records had been made for
duplicate issuance of these five batches chosen for review, as required per SOP
QA/SOP/DOC/001. Notably, after subsequent investigation it was found that the Master Batch
Record (version 0) had been back-dated by the most responsible persons within your firm‘s
Quality and Manufacturing departments, which was confirmed by these persons during our
inspection.

PHARMA UPTODAY
42
Check your area for ….
Are all protocols, methods, reports, etc. are
 written,
 reviewed
 approved and
 filed where
 they are secure,
 but easily retrieved?

PHARMA UPTODAY
43
Regulations of the Month
Subpart J--Records and Reports
§ 211.188 Batch production and control records.
Batch production and control records shall be prepared for each batch of drug product
produced and shall include complete information relating to the production and control of
each batch. These records shall include:
(b) Documentation that each significant step in the manufacture, processing, packing, or
holding of the batch was accomplished, including:
(4) Weights and measures of components used in the course of processing;
(5) In-process and laboratory control results;
(6) Inspection of the packaging and labeling area before and after use.
(7) A statement of the actual yield and a statement of the percentage of
theoretical yield at appropriate phases of processing.
(8) Complete labeling control records, including specimens or copies of all
labeling used.
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Pharma Uptoday Monthly Magazine - Volume 10 issue Jan 2015

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Pharma Uptoday Monthly Magazine - Volume 10 issue Jan 2015