VOLUME 2 ISSUE MAY 2014
Have courage to say
“No” beyond the
capacity and should
always think about
the patient safety
says Quality head
Refer “Guest of the
Month” column for
PAGE 1PHARMA UPTODAY
About Pharma Uptoday :
The "Pharma Uptoday" Newsletter initiated on 18-Jul-2013 to refresh the subject,
update the guidelines, regulations & current happenings.
This website is restricted to people in Drugs & Pharmaceutical industry who are
enthusiastic to know about current happenings and learn and implement the
same. It doesn't include the topics related to Pre-clinical, Clinical, Biotech /
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avoid 483's, Warning letters, deviations etc as “Together we can make Global
Updates in this Newsletter include :
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Inside This Issue
1 Message from the Editor
2 News Uptoday
5 New Guidelines
11 Audit Findings
17 Guest of the Month
18 Regulations of the Month
Together we can make
Global Pharma excel.
VOLUME 2 ISSUE MAY 2014
PAGE 2 PHARMA UPTODAY
Canadian Generics Firm Apotex Put on Import Alert Over CGMP Failures at Indian Facility
Import Alert # 66-40; Published Date: 04/01/2014
Type: DWPE; Import Alert Name:
"Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs"
Reason for Alert:
*** Foreign inspections of pharmaceutical manufacturers are being performed. Detention without physical examination may
be appropriate when an FDA inspection has revealed that a firm is not operating in conformity with current good
manufacturing practices (GMP's).
Detention without physical examination may also be appropriate when FDA receives information concerning inspections
conducted by foreign or other government authorities under a Memorandum of Understanding or other agreement that
FDA concludes reveals conditions or practices warranting detention of either particular products or all products
manufactured by a firm.
DWPE of such firms remains in effect until such time as FDA is satisfied that the appearance of a violation has been
removed, either by reinspection or submission of appropriate documentation to the responsible FDA Center. ***
*** Districts may detain, without physical sampling and analysis, the indicated drug products from the foreign processors
noted in the Red List of this import alert.
Foreign processors listed on the Red List of this import alert who would like to request removal from that list should provide
information to FDA to adequately demonstrate that the manufacturer has resolved the conditions that gave rise to the
appearance of the violation, so that the agency will have confidence that future entries will be in compliance. This may
include a letter detailing its corrective actions, accompanied by documentation. For guidance on removal from detention
without physical examination, refer to FDAs Regulatory Procedures Manual, Chapter 9, "Detention Without Physical
Examination (DWPE)." Information supporting removal should be sent to CDER's Office of Compliance, (HFD-300). ***
Apotex Pharmachem India Pvt Ltd.; Plot No.: 1A, Bommasandra , Industrial Area, 4th Phase , Bangalore, INDIA
Vietnam bans drugs from 45 Indian pharma firms
Claiming that the drugs supplied by at least 45 Indian pharmaceutical companies are not of standard quality (NSQ), the
Drug Administration of Vietnam (DAV) has banned drugs by these firms on its land. Some major Indian drug makers like
Strides Arcolab, Medley Pharmaceuticals, Marck Biosciences, Marksans Pharma and UMedica Laboratories are also part
of the list of banned drug makers. News reports specified that all the companies in the banned list failed the DAV quality
tests between January 1, 2011 and October 25, 2013. Vietnam has also banned drugs from nine Korean companies, two
companies from Bangladesh, two from France, and one each from the US, Philippines, Pakistan, Russia, Indonesia,
Germany, Cyprus, and Canada.
As per Indian health ministry sources, India is one of the largest suppliers of medicines to South-East Asian countries like
Vietnam and African countries like Kenya, Nigeria and Ghana.
Mr Deepak Mittal, the Indian consul general in Vietnam is said to have written a strongly worded letter to the ministry of
health and family welfare. Copies of the letter have been sent to the external affairs ministry, the department of commerce,
the Indian embassy in Hanoi and to the office of the Drug Controller General of India (DCGI). Mr Mittal has said in his
letter, "In view of the fact that a large number of Indian companies have been listed defaulters by Vietnamese authorities, it
is requested that necessary background checks on these companies may kindly be undertaken in India to see if there are
complaints against them from other countries and steps be initiated to penalise them for bringing bad name to the Indian
pharma industries abroad."
PAGE 3PHARMA UPTODAY
A drug is declared NSQ if the active pharmaceutical ingredient (API) in it is lesser than the declared amount. In such a case,
the efficacy of the drug goes down. The other parameters that are checked are the quality of bonding agent, colouring agent,
and the time taken for dissolution. But this is not the first time Vietnam has banned Indian companies. About two years ago, it
had banned 19 pharma companies on the same ground, the health ministry source said. Mr T R Gopalakrishnan, advisor,
Indian Drug Manufacturers' Association (IDMA) told news media that, "Vietnam depends on India for procuring drugs. In
recent years, Chinese interference in the markets has been observed. But China is not yet at par with India in manufacturing
finished drugs. It should be noted that Vietnam hasn't banned any Chinese company." Mr DG Shah, the president of the
Indian Pharmaceutical Alliance (IPA), however said, "Vietnam sources drugs at the cheapest price. And quality is bound to
suffer. But if big pharma companies are figuring in the list then regulatory authorities should inspect the quality of their
injectables, tablets, capsules and syrups."
Sun Pharma to Acquire Ranbaxyin a US$ 4 Billion Landmark Transaction
Sun Pharma and Ranbaxy today announced entering into definitive agreements for Sun Pharma to acquire 100% of
Ranbaxy in an all-stock transaction. Under these agreements, Ranbaxy shareholders will receive 0.8 share of Sun
Pharma for each share of Ranbaxy. This exchange ratio represents an implied value of Rs 457 for each Ranbaxy
This combination creates the 5th largest specialty generics company in the world, and the largest pharma company in
India. The combined entity will have operations in 65 countries, 47 manufacturing facilities across 5 continents, and a
significant specialty + generic portfolio, including 629 ANDAs. On a pro forma basis, the combined entity’s revenues
are estimated at US$ 4.2 billion with EBITDA of US$ 1.2 billion for the twelve month period ended December 31, 2013.
The transaction value implies a revenue multiple of 2.2 based on 12 months ended December 31, 2013.
Aurobindo completes acquisition of select Actavis operations
Aurobindo Pharma has completed acquisition of certain commercial operations of Actavis Plc in Western Europe.
The agreement to acquire Dublin-based Actavis’ operations was announced in January 2014.
“Following receipt of clearances from competent authorities, Aurobindo intends to combine the strength of both
enterprises in these markets and to identify and maximise all opportunities to improve performance,” Aurobindo said in
Actavis and Aurobindo have also entered into a long term commercial and supply arrangement, it added.
Commenting on the development, Aurobindo SVP of European Operations V Muralidharan said: “The acquisition will
make Aurobindo one of the leading Indian pharmaceutical companies in Europe.”
The acquisition expands Aurobindo’s front-end operations into five segments (generics, prescription products, over-the-
counter products, hospital products and generics tenders) with approximately 1,200 products and an additional pipeline
of over 200 products.
Aurobindo has acquired personnel, commercial infrastructure, products, marketing authorisations and dossier licence
rights in seven European countries.
PAGE 4 PHARMA UPTODAY
Genpact to Acquire Leading Regulatory Affairs Company in Life Sciences
Genpact Ltd., a global leader in transforming and running business processes and operations, today announced it
has signed a definitive agreement to acquire Pharmalink Consulting, a leading global provider of regulatory services
to the life sciences industry for more than 15 years.
The acquisition will complement Genpact’s portfolio of services in the Life Sciences vertical and add significant
consulting, outsourcing and operations capabilities. With an ever-changing regulatory and commercial environment,
the life sciences industry continues to face new challenges that require them to rely increasingly on experienced
providers. It also significantly expands Genpact’s capabilities in supporting the life sciences research and
development functions, including regulatory strategy, filing submissions, complex compliance services and the
management of post-licensing activities.
Pharmalink’s specialised domain expertise, speed, responsiveness and ability to scalehave made it a leading
provider for sustainable outsourcing of regulatory affairs services. Their clients include nearly all of the twenty
largest global life sciences companies.Their specialized expertise includes the end-to-end range of regulatory
services including strategy, chemistry manufacturing & controls (CMC), regulatory operations and publishing
“This acquisition fits in exactly with our strategy to invest in solutions in specific growth areas in specific verticals
such as Life Sciences,” said NV ‘Tiger’ Tyagarajan, President and CEO, Genpact. “In an industry that’s undergoing
intense transformation, adding Pharmalink’s combination of talent, process expertise and domain knowledge to
Genpact’s portfolio will allow us to better serve our life sciences clients.”
“Genpact will bring the global scale, process excellence, analytical insights and technology needed to further
enhance our outsourcing services offering demanded by the market,”said Peter Griffin, Chairman, Pharmalink
Consulting. “This combination will allow us todeliver more end-to-end regulatory affairs solutions based on
Genpact’s proprietary Smart Enterprise Processes SEPSM methodology.”
Gary Charbonneau, Vice President of Global Regulatory Affairs at Allergan adds, “The combination of Genpact and
Pharmalink is very exciting not just for me as a client, but for the industry at large. To have the deep experience and
reputation of Pharmalink within the Regulatory Affairs arena allied to the scale and process excellence of Genpact is
a compelling proposition.”
As part of the transaction, Pharmalink’s employees based in the US, the UK, India, Ireland and Puerto Rico will
become part of Genpact’s Life Sciences vertical.
PAGE 5PHARMA UPTODAY
Qualification and the new Annex 15 Draft
The comment period for the new Annex 15 draft "Qualification and Validation" started at the beginning of February.
Still, the coming into force of the new version is planned for October 2014. Yet, as the comment period should have
already begun from December 2013 on, the coming into force could also be postponed.
The consequent use of the risk management approach and lifecycle observation for validation and qualification is a
central and essential issue of the new document. Qualification should now start with the creation of the user
requirements URS; The Design Qualification (DQ) as verification will thus become the second step within
qualification. Until now, DQ had always been described as the first step.
The reference for the first time of FAT and SAT (Factory and Site Acceptance Test) is something new
whereas retrospective qualification has been completely removed. The FAT is even compulsory for more complex
equipment i.e. for their qualification.
An own new chapter entitled "Validation of utilities" is now dedicated to the qualification of media. Seasonal
variations should also be considered - where applicable - in the context of qualification. For risk assessment, a
difference is made between systems with direct (HVAC) and indirect (i.e. heat exchangers) contact with the product.
Also the chapter on re-qualification has now become a separate chapter and has thus become an explicit
requirement. Up to now, re-qualification had only been indirectly required via re-validation. As qualification is
regarded as part of validation, the requirement on regular re-validation has been transferred to re-qualification.
European Commission publishes Question & Answer Document on GDP
On 28 March 2014 the European Commission has published a new question and answers document which will
clarify some frequent asked questions about the interpretation of the new EU GDP Guideline. The document
contains 25 questions and answers. Some of the questions are simply for clarification and confirmation. However,
some other questions have become the basis for some discussion. The competent authorities of the different EU
Member States should use a harmonised approach when it comes to inspections.
Question 5 for example refers to the requirement 3.2 about the physical segregation of certain products. According
to the document, falsified, expired, recalled and rejected products need a physical segregation in any case. So a
validated computerized system would not be possible in these cases.
Question 7 refers to chapter 3.2.1. about the number of probes which are necessary to monitor the temperature. The
EU commission clarifies that "the number of probes and their placement depend on the risk analysis performed on
the site and the placement should be in agreement with the mapping results".
Also question 8 highlights the importance of a risk analysis. In this question the topic of initial temperature mapping
is covered. The document states that "initial temperature mapping is an exercise in which temperature sensors are
placed on the points identified as most critical through a risk analysis (e.g. at different heights, near a sunny window,
next to the doors, etc.). Once placed, a measurement is taken over a period of time and with the results obtained,
the temperature sensors will be places where greater fluctuation occurred. The mapping should be performed in
different seasons where highest and lowest temperatures are reached."
In question 22 reference was made to chapter 9 of the GDP Guide. Some stakeholders proposed to have a limited
time frame (e.g. of 6 hours) in which a deviation of a defined temperature range (e.g. 2-25 C) would be allowed. But
the EU Commission clearly states that this procedure would not be acceptable.
Source: EU Commission, Good Distribution Practice, Question and Answers, Version 1.0
PAGE 6 PHARMA UPTODAY
Q&A: New rules for clinical trials conducted in the EU
What are clinical trials?
Clinical trials are a vital step in the development of new and safe medicines and in improving medical treatment.
Volunteers are enrolled in a clinical trial for the following reasons: to test the safety and effectiveness of new
medicines, to test new indications for existing medicines or to compare two standard treatments.
Clinical trials are not only important for pharmaceutical companies or academic researchers. They are first and
foremost crucial for patients, in particular those affected by serious or rare diseases, as often they are the only way
for them to have access to the most advanced, life-saving treatments.
Who conducts clinical trials?
Clinical trials are mainly conducted by the pharmaceutical industry in order to generate data on the safety and
efficacy of medicinal products they are developing. In addition, approximately 40% of clinical trials in the EU are
conducted by non-industry actors, such as academics, foundations, hospitals, or research-networks (often referred
to as 'non-commercial sponsors'). Usually, these actors conduct clinical trials in order to improve and compare
treatments with existing (authorised) medicines.
What legislation is currently in place to regulate clinical trials?
The conduct of clinical trials in the EU is tightly regulated. This is to uphold the rights and ensure the safety of
clinical trial participants (referred to as 'subjects' in the proposed Regulation) and to ensure the reliability and
robustness of the data generated. These rules are set out in the 'Clinical Trials Directive' (2001/20/EC).
Why is the current legislation being replaced?
The 2001 Clinical Trials Directive has been criticised by patients, researchers and industry alike for its
disproportionate regulatory requirements. High costs and a lack of harmonisation of the applicable rules necessary
for multinational clinical trials are a few examples.
Taken together, these restrictions have contributed to a significant decline in the number of clinical trials in the EU –
a reduction of about 25 % in the last few years.
The new Regulation aims at restoring the EU’s competitiveness in clinical research and the development of new
and innovative treatments and medicines by cutting red-tape and bringing patient-oriented research back to
What are the main changes introduced by the Regulation?
The new Regulation will make it easier to conduct multinational clinical trials, i.e. conducted in more than one
Member State, in the EU. Measures that cut red tape and simplify the current rules are:
- A straightforward authorisation procedure allowing for a fast and thorough assessment of the application
by all Member States concerned and resulting in one single assessment outcome. The authorisation procedure
allows the individual EU countries to determine the roles of the bodies in charge of the assessment, on the
condition that the assessment is fully independent and based on the necessary expertise.
- Simplified reporting procedures so that researchers no longer have to submit largely identical information on
the clinical trial separately to various bodies and Member States.
- The possibility for the Commission to conduct controls in EU countries and third countries to make sure
the rules are being properly supervised and enforced.
PAGE 7PHARMA UPTODAY
Finally, the new legislation will take the legal form of a Regulation. This will ensure that the rules for conducting
clinical trials are identical throughout the EU. This is vital to ensure that Member States, in authorising and
supervising the conduct of a clinical trial, base themselves on identical rules.
What role will Ethics Committees have under the new rules?
Ethics committees will be involved in the assessment of clinical trials application. However, as with the current
situation, their responsibilities and detailed composition will be determined independently by each EU country. In
this way the different traditions in the various Member States are respected.
The Regulation introduces the concept of tacit agreement in the assessment phase of an application. Why
is this needed?
The concept of tacit agreement already exists in the current clinical trials Directive. The Regulation just extends its
application to all assessors, to avoid bottlenecks and delays in the procedure. This is to alleviate an unnecessary
and frustrating restriction that trial sponsors face under the current rules.
It is important, however, to emphasise that Member States will always have the possibility to stop any clinical trial
which they consider could endanger the heath of the participants.
How are risks to clinical trials subjects addressed in the new legislation?
The risk to subjects participating in clinical trials varies depending whether the trial is to test a new medicine or to
compare existing medicines. The regulatory framework needs to be sufficiently flexible to respond to this.
The Regulation, while continuing to uphold patient safety, takes better account of the actual risk to which subjects
will be exposed during the clinical trial and adapts the regulatory burden in relation to the risk posed. It introduces
the concept of a 'low-intervention clinical trial' – an example being clinical trials comparing already authorised
medicines. In such cases, the regulatory requirements will be lighter.
What about clinical trials conducted outside the EU?
There is a trend towards increased clinical trials in areas with emerging economies such as Asia, South America
The Regulation will ensure that, no matter where a clinical trial is being performed, the fundamental rules for the
protection of subjects are applied. It therefore includes rules for clinical trials which are conducted outside the EU
but referred to in a clinical trial application within the EU. For such trials, the rules call for compliance with
regulatory requirements at least equivalent to those in the EU, including rules on transparency.
Why is transparency important for clinical trials?
Transparency on the conduct and results of clinical trials has several benefits, and the Regulation strengthens the
rules accordingly. Transparency avoids redundancy and duplication. It ensures that even clinical trials with
unfavourable results are made public, thereby avoiding 'publication bias'. Finally, transparency gives patients the
possibility to find out about on-going clinical trials in which they may wish to participate.
Clinical trials authorised in the EU are published in an official EU-register since May 2011
Following the positive vote in Parliament, the Regulation now has to be formally adopted by Council and published
in the Official Journal. Its application is linked to the full functionality of the EU portal and database under
development by the European Medicines Agency. It is expected to come into effect in mid-2016 at the earliest.
For more information on clinical trials in the EU:
PAGE 8 PHARMA UPTODAY
EMA Releases Revised Pharmacovigilance Practice Guidelines
• Guideline on good pharmacovigilance practices (GVP) : Module XVI– Risk minimisation measures:
selection of tools and effectiveness indicators (Rev 1)
• Guideline on good pharmacovigilance practices (GVP) : Annex I - Definitions (Rev 3)
• Guideline on good pharmacovigilance practices (GVP) : Module V – Risk management systems (Rev 1)
Source : http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/02/WC500162051.pdf
WHO publishes revised draft on the Guideline on "Hold Time" studies
The key message of the Guideline has remained unchanged: manufacture in compliance with GMP requires the
definition of hold times for intermediates and bulk products. The scope stated is the manufacture of solid dosage
forms but it can also be applied to liquids and semi-solid dosage forms. Manufacturing of active pharmaceutical
ingredients is excluded explicitly, sterile dosage forms aren't mentioned. The paper's aim is to refer to aspects that
have to be taken into consideration when designing hold time studies. In most cases reference is made to
intermediates and bulk products for which it should be guaranteed that they remain of appropriate quality even with
hold times. But at one point reference is also made to raw materials and packaging materials.
Data to justify the hold times scientifically can be collected during development, on pilot scale or validation batches
but also from information gained from an investigation of a deviation. Typically, data of one batch are taken for this.
Otherwise, a risk-based approach is used to determine the appropriate number of batches to be tested. Hold times
should normally be determined prior to marketing of a product. However, for products already marketed there is
the possibility of retrospective risk-based, hold-time determination. For carrying out the study, the material to be
tested should be kept in either the original or simulated container used in production. If the headspace plays a role
the material to be tested should be stored with the maximum possible headspace. The data received should be
evaluated by statistical means in order to recognise trends and to be able to establish limits. It is not necessary to
carry on the study until the pre-defined acceptance criteria are exceeded. One paragraph in revision 2 that
proposes a "most probable" approach opposed to a "worst case approach" or a combination of both for the design
of the studies is a little nebulous.
The Guideline also contains a list of examples with the maximum hold times for the different stages of the tablet
production that do not necessitate hold times (such as 2 - 30 day for the granulate). But this is a slight
contradiction to the preceeding pages which require investigational studies for the determination of hold times. The
paragraph providing information on cumulative hold times also is new. Generally, a cumulative hold time of 90
days is acceptable without further data being required. In the case where cumulative hold times individually add to
>90 days, but there is an additional provision that time from dispensing of the ingredients to the final top coating
will not exceed 30 days, further justification of the cumulative hold time is considered unnecessary.
PAGE 9PHARMA UPTODAY
EMA Updates GMP Q&A Guidance
Further questions and answers are published as the need arises. Individual questions and answers may be
removed when the relevant GMP guidelines are updated.
Code H: applicable to human medicines; V: applicable to veterinary medicines
Table of contents
European Union (EU) GMP guide part I: Basic requirements for medicinal products: Chapter 5: Qualification of
EU GMP guide part II: Basic requirements for active substances used as starting materials: GMP compliance for
EU GMP guide part II: Basic requirements for active substances used as starting materials: GMP compliance for
active substances in investigational medicinal products (IMPs)
EU GMP guide annexes: Supplementary requirements: Annex 1: Manufacture of sterile medicinal products
EU GMP guide annexes: Supplementary requirements: Annex 6: Manufacture of medicinal gases
EU GMP guide annexes: Supplementary requirements: Annex 8: Sampling of starting and packaging materials:
EU GMP guide annexes: Supplementary requirements: Annex 8: Sampling of starting and packaging materials:
Use of near-infrared (NIR) technology for container-wise identity testing
EU GMP guide annexes: Supplementary requirements: Annex 11: Computerised systems
EU GMP guide annexes: Supplementary requirements: Annex 13
EU GMP guide annexes: Supplementary requirements: Annex 16
EU GMP guide annexes: Supplementary requirements: Annex 19: Reference and retention samples (Updated)
PAGE 10 PHARMA UPTODAY
USP–NF General Notices
Special Update related to 5.60.30 Elemental Impurities in USP Drug Products and Dietary Supplements
General Notices in USP 37–NF 32 (posted 08–Aug–2013; official 01–May–2014)
Monographs and General Chapters Affected by Revision to General Chapter <601>
AEROSOLS, NASAL SPRAYS, METERED-DOSE INHALERS, AND DRY POWDER
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 USP and its Expert Committees, as applicable, intend to revise multiple monographs and
General Chapters in response to the revision of General Chapter <601> Aerosols, Nasal Sprays, Metered-Dose
Inhalers, and Dry Powder Inhalers.
General Chapter <601> was revised and published in Supplement 1 to USP 37–NF 32 with the new title “<601>
Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders—Performance Quality Tests,” and will
become official on August 1, 2014. This publication reflected several other revisions to the General Chapter to
address stakeholder comments and was accompanied by the publication of new General Chapters <602>
Propellants, <603> Topical Aerosols, and <604> Leak Rate, containing provisions previously addressed solely in
<601>. USP has identified the following monographs and general chapters that reference General Chapter <601>
and thus require some degree of revision to assure the appropriate General Chapter is referenced in USP-NF
webpage : http://www.usp.org/usp-nf/notices/revision-general-chapter-aerosols-nasal-sprays-metered-dose-
The process and timing for revisions to these monographs and general chapters will be determined following a
careful analysis of the effects of the revision to General Chapter <601> and implementation of General Chapters
<602>, <603>, and <604>. USP will post additional information as it becomes available. In the meantime,
interested parties are encouraged to alert USP staff to any other effects they may recognize related to the revision
of General Chapter <601>.
PAGE 11PHARMA UPTODAY
Anchen Pharmaceuticals, Inc.
• Changes to written procedures are not drafted, reviewed and approved by the appropriate organizational
unit and reviewed and approved by the quality control unit.
• Clothing of personnel engaged in the processing of drug products is not appropriate for the duties they
Wiley Chemists, Inc.
• Testing and release of drug product for distribution do not include appropriate laboratory determination of
satisfactory conformance to the final specifications and identity and strength of each active ingredient prior to
Xttrium Laboratories, Inc.
• The responsibilities and procedures applicable to the quality control unit are not fully followed.
Leiter's Cambrian Park Drugs, Inc., dba Leiter's Pharmacy
• Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do
not include adequate validation of the sterilization process.
Cantrell Drug Company
• Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are
Fougera Pharmaceuticals, Inc.
• Labeling and packaging materials not meeting the appropriate written specifications were approved and
released for use.
• Laboratory controls do not include the establishment of scientifically sound and appropriate specifications
designed to assure that components, in-process materials and drug products conform to appropriate standards of
identity, strength, quality and purity.
Akron Coating & Adhesives, Inc.
• Reports of analysis from component suppliers are accepted in lieu of testing each component for conformity
with all appropriate written specifications, without establishing the reliability of the supplier's analyses through
appropriate validation of the supplier's test results at appropriate intervals.
PAGE 12 PHARMA UPTODAY
PUNJAB CHEMICALS AND CROP CORPORATION LIMITED, Sas Nagar (Mohali), Lalru, Punjab, India:
Overall, 30 deficiencies were observed, including 8 major deficiencies:
• [Major 1] Despite its commitment following the last inspection (June 2010) to replace 4 pieces of
manufacturing equipment, the company has only decided to replace 2 of them and repair the 2 others,
without carrying any risk assessment or providing documented justification for this CAPA modification ;
• [Major 2] The tank used for the storage of crude Trimethoprim was found to be in an unacceptable
• [Major 3] One individual training file of an employee has been observed to be recently re-rewritten ;
• [Major 4] The Batch Manufacturing record was lacking details with regards to manufacturing steps and in-
process controls ;
• [Major 5] The sample retention log-book for Trimethoprim had falsified entries ;
• [Major 6] The storage of raw materials, intermediates and finished products was considered not to be
compliant with GMP requirements (e.g., materials segragation, housekeeping, etc.) ;
• [Major 7] The company did not establish different product codes for the different Trimethoprim processes ;
• [Major 8] The Validation Master Plan did not contain any clear description of the policy, intentions and
approach to validation.
SCM PHARMA LIMITED, NORTHUMBERLAND, United Kingdom:
1. A critical deficiency was cited regarding potential product cross contamination, this deficiency was divided into
A. Potential chemical contamination, it was found that the company were manufacturing a potent cytotoxic
(Amsacrine) product in the non-potent suite. Processes intended to contain the product had failed and cleaning
process and verification were weak with contamination of general manufacturing areas seen.
B. Potential microbial contamination. There were contaminated process media simulations that were not
adequately investigated and root cause explained and mitigated. VHP sanitisation of the filling isolator
inadequately controlled and validated and weaknesses in the environmental monitoring program.
2. A major deficiency regarding the change control program (not all changes were controlled appropriately) and
investigations, which were poor in quality with regards to root cause analysis and corrective and preventative
actions and were not performed in a timely manner.
3. A second major deficiency regarding maintenance of equipment and facilities with poor controls witnessed.
PAGE 13PHARMA UPTODAY
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PAGE 14 PHARMA UPTODAY
Non-compliance Reports (Continued):
Seikagaku Corporation, Japan gets Non Compliance Report
During the inspection 1 critical, 1 major and 24 other deficiencies were found.
The critical deficiency concerns systematic rewriting/manipulation of documents, including QC raw data. The
company has not been able to provide acceptable investigations and explanations to the differences seen in official
and non-official versions of the same documents.
WOCKHARDT LIMITED, CHIKALTHANA, AURANGABAD, India:
1. A critical deficiency was cited with regards to data integrity of GMP records, entries were seen to be made when
personnel were not present on site, documentation was seen that was not completed contemporaneously despite
appearing to be completed in this manner.
2. A second critical deficiency was cited regarding potential product contamination, this included the use of
inappropriate materials close to product e.g. asbestos coated PTFE seals for centrifuge manways.
3. A major deficiency was cited with regards to equipment and facility, maintenance, design and qualification.
Examples included, inappropriate pressure differentials that were not in line with the original design but had not
been changed using change control, cleaning validation that was not sufficiently robust to confirm cleaning practices
and maintenance issues, such as the failure to spark test glass lined reactor vessels for integrity especially following
Additional comments :
There are no current GMP certificates in place for this API facility.
A restricted GMP certificate will be issued to permit continued testing of products considered to be medically critical,
as determined by the national competent authority National competent authorities should request marketing
authorisation holders conduct a risk assessment to evaluate the risk to product quality and patients from the issues
The risk assessments should contain sufficient information to inform decisions by competent authorities regarding
product recall or the acceptability of continued testing for critical products. Marketing authorisation holders are
requested to contact the relevant National Competent Authority to verify whether their products are considered
medically critical, and therefore outside the scope of this non-compliance statement.
TABUK PHARMACEUTICAL MANUFACTURING CO . - TABUK, SAUDI ARABIA:
One critical deficiency dealing with the documentation management system and the quality management system
has been raised during the inspection performed by ANSM, leading inspectorate and MPA, supporting inspectorate.
Indeed the documents provided by the site have been found by the inspectors unreliable and evidences of
manipulation of data have been found. As an illustration: - In an "In Process Control" room, located in plant A
(Cephalosporine products manufacturing) – non sterile manufacturing area, the following items have been found
PAGE 15PHARMA UPTODAY
• Parts of original batch record (from recent and non recent batches).
• Copies of batch records of products not manufactured on site such as Turbuhaler product (Budesonide).
• Blank batch records forms.
• Original analytical data (from recent and non recent batches).
• Reprocessing protocols. - Moreover, in another room which is an office located in plant A, the batch record of
Tabiclor MR 3BF168 has been found.
According to this batch record, the batch has been entirely packed (97330 tablets) on 26th September 2013 and
transferred in the Finished Goods Warehouse the same day. However, this batch has been found in the Work In
Progress area, as unpacked bulk tablets, in drums.
Warning letter for Americare Compounding, LLC.
From June 3, 2013, to June 19, 2013, U.S. Food and Drug Administration (FDA) investigators conducted an
inspection of your facility, Americare Compounding, LLC, located at 319 Nassau Blvd, Garden City South, NY
11530. During the inspection, the investigators noted that you were not receiving valid prescriptions for individually-
identified patients for a portion of the drug products you were producing. In addition, the investigators
observedserious deficiencies in your practices for producing sterile drug products, which put patients at
risk. For example, our investigators noted that your operators performed aseptic operations wearing gowns that can
be reused for a week and your firm did not use a disinfectant with sporicidal properties in the cleanroom. FDA
investigators also found that the firm failed to demonstrate through appropriate studies that hoods are able to
provide adequate protection of the ISO 5 area in which sterile products are processed. Therefore, the products are
produced in an environment that poses a significant contamination risk. These observations were noted on Form
FDA-483, issued on June 19, 2013.
FDA investigators noted that your sterile drug products were prepared, packed, or held under insanitary conditions,
whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products
to be adulterated under section 501(a)(2)(A) of the FDCA [21 U.S.C. § 351(a)(2)(A)]. The conditions include
operators performing aseptic operations with gowns that could be reused for a week.
PAGE 16 PHARMA UPTODAY
The cGMP violations include, for example:
1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent
microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and
sterilization processes (21 CFR 211.113(b)).
2. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from
contamination (21 CFR 211.28(a)).
3. Your firm failed to adequately design the facility with adequate separation or defined areas or such other control
systems necessary to prevent contamination or mix-ups (21 CFR 211.42 (b)).
4. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing
areas (21 CFR 211.42(c)(10)(iv)).
5. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to
produce aseptic conditions (21 CFR 211.42(c)(10)(v)).
6. Your firm does not have, for each batch of drug product purporting to be sterile and/or pyrogen-free, appropriate
laboratory determination of satisfactory conformance to final specifications for the drug product (21 CFR
7. Your firm failed to establish and follow an adequate written testing program designed to assess the stability
characteristics of drug products and to use results of such stability testing to determine appropriate storage
conditions and expiration dates (21 CFR 211.166(a)).
8. Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory
conformance to final specifications for the drug product, including the identity and strength of each active ingredient,
prior to release (21 CFR 211.165(a)).
Source : http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm394485.htm
To Advertise in Monthly magazine contact “email@example.com”
PAGE 17PHARMA UPTODAY
Pharma Uptoday: What are the major challenges in pharmaceutical industry?
How to overcome these challenges?
Mahesh Shinde: Quality compliance & Availability of the drug to
the patient with affordable price.
Cost to the company shall be maintained effectively to
keep the systems compliant. To keep the effective quality
compliance first in right to establish strong systems at place and to
maintain consistent quality product supply in the market. Another
challenge in the market is to supply the medicinal products within
the timelines to avoid penalty.
Capacity, Capability, Quality & in-time in market should be
renewed to avoid rejection from the market.
Pharma Uptoday: What are the current expectations of US FDA from Indian
Mahesh Shinde: US FDA expects GMP and GLP to be followed
across the world. Due to the incidences / very reactive
observations FDA has shifted its paradigm to overall GMP and
Quality compliance. They want to challenge all pharma industries
across the country.
Pharma Uptoday: Suggestion to the Pharma Uptoday group members?
Mahesh Shinde: Members should have good compliance &
governance system, should have courage to say “No” beyond the
capacity and should always think about the patient safety and risk
rather than market / organization risk.
Quality Risk Management should focus on the patient safety and it
should be the top most priority to any pharma industry.
Mahesh B. Shinde
Currently Site Quality
Head – Aurobindo
Pharma Limited, Unit –
Formerly Worked in
Alembic pharma &
Ranbaxy Labs Limited.
PAGE 18 PHARMA UPTODAY
Subpart I--Laboratory Controls
§ 211.160 General requirements.
(b) Laboratory controls shall include the establishment of 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
(1) Determination of conformity to applicable written specifications for the acceptance
of each lot within each shipment of components, drug product containers, closures,
and labeling used in the manufacture, processing, packing, or holding of drug products.
The specifications shall include a description of the sampling and testing procedures
used. Samples shall be representative and adequately identified. Such procedures
shall also require appropriate retesting of any component, drug product container, or
closure that is subject to deterioration.
(2) Determination of conformance to written specifications and a description of
sampling and testing procedures for in-process materials. Such samples shall be
representative and properly identified.
(3) Determination of conformance to written descriptions of sampling procedures
and appropriate specifications for drug products. Such samples shall be
representative and properly identified.
Regulations of the Month
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