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 /
Biosimilar, Medical device (with some exceptions).
This Group and the Website is initiated to share the knowledge, to minimise /
avoid 483's, Warning letters, deviations etc as “Together we can make Global
Updates in this Newsletter include:
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• Presentations, Webinars, Guidelines, Books, Articles etc.
Message from the Editor
Highlights of Pharma Uptoday :
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Inside This Issue
1 Message from the Editor
2 News Uptoday
3 News Uptoday
4 News Uptoday
5 New Guidelines
6 New Guidelines
7 New Guidelines
8 Audit Findings
9 Audit Findings
10 Audit Findings
11 Audit Findings
12 Regulations of the Month
Together we can make
Global Pharma excel.
VOLUME 1 ISSUE APR 2014
PAGE 2 PHARMA UPTODAY
Adjusted fees for applications to European Medicines Agency from 1 April 2014
The European Medicines Agency reminds applicants and marketing-authorisation holders that adjusted fees will be coming
into effect on Tuesday 1 April 2014.
Every year, the Agency adjusts its fees on 1 April, in line with the European Union (EU) inflation rate for the previous year. The
European Commission is currently in the process of adopting a regulation adjusting the fees payable to the Agency in line
with the 2013 inflation rate. Although the final adjustment is not yet known, the Agency expects its fees to increase by around
The Agency will publish full details of the revised fees at the end of March, once the European Commission has adopted the
regulation and published it in the Official Journal of the European Union and the Agency's Management Board has reached
a decision on its implementation.
All applications received by 31 March will be charged at the current fee and reduction rates. Applications received after
that date will be charged the adjusted fees and be subject to the revised reduction rates, where applicable. For scientific
advice and protocol assistance, the cut-off date will be the date of validation of the request for advice.
FDA-EMA extends pilot program of the QbD parallel-assessment
The FDA and the European Medicines Agency have agreed on a two-year extension of the joint pilot program for the parallel
evaluation of quality-by-design applications beginning April 1, 2014.
FDA and EMA began the joint venture in March, 2011, to share knowledge, ensure consistent adherence to international
guidelines related to QbD and promote the availability of pharmaceutical products of consistent quality throughout the
European Union and the U.S.
QbD is an approach to ensuring consistent drug quality through statistical, analytical and risk-management methodology in
drug design, development and manufacturing.
The three-year pilot program has created inter-agency agreement on a wide range of QbD topics, culminating in the
publication of two question-and-answer documents for the benefit of industry and agency regulators, while spurring joint
research efforts on QbD-related topics.
In spite of these successes, the agencies have agreed that there remain QbD areas that warrant additional inter-agency
harmonization, resulting in the decision to extend the pilot. The agencies expect to publish more documents in 2014.
TGA Upgraded over-the-counter medicines online application system
From 9th April 2014, over-the-counter medicines applications will be submitted through an upgrade to the OTC medicines
online application system.
Applications will be easier to submit and process and industry will benefit from this reduction in regulatory burden.
Access to the upgraded system will continue to be through the eBusiness Services website.
This upgrade is part of the staged implementation of the harmonisation of OTC medicines business processes in Australia and
PAGE 3PHARMA UPTODAY
FDA bans imports from Sun Pharma plant in India
The U.S. Food and Drug Administration (FDA) has banned imports from Indian generic drugmaker Sun Pharmaceutical Industries
Ltd's plant at Karkhadi in the western state of Gujarat, in the latest quality blow for India's drug sector.
The FDA has imposed a rash of regulatory sanctions on Indian generic makers in the last year, triggering concerns about the
quality of the medicines supplied by the $14 billion industry to countries including the United States, the biggest market.
Torn documents, partially destroyed raw data showing undesirable results and unclean toilets were among the reasons cited by
the US drug regulator for the ban it imposed last month on a Gujarat-based facility of Sun Pharma, the largest Indian drugmaker
by market capitalisation.
"Drug products failing to meet established specifications and quality control criteria are not rejected," said a form 483 issued to
the company, which spell out violations as observed by US investigators at the Karkhadi facility during their audit in November
Analysts had pointed out that the import alert by the US Food and Drug Administration (FDA) on the facility was unlikely to cause
any significant financial impact but said they awaited clarifications on the nature of violations.
"We identified multiple torn/partially destroyed raw data cGMP (current good manufacturing practices) manufacturing and
quality records. Our review of these records identified the practice of maintaining duplicate versions of cGMP raw data records.
Undesirable data was found to be changed in the official versions in order to meet specifications," said the FDA inspection
"We have sent our response to the FDA and given that the facility now has an import alert, it's clear that the FDA does not
agree with our view. In this process, we have learnt and have resolved to work on further strengthening our systems and
controls," a spokesperson told.
With regard to the torn documents and partially destroyed data, the company said it has put remedial measures in place. "The
applicable SOP (standard operating procedure) in this case was not adhered to for which appropriate corrective action has
been taken," Sun said in an email.
"The reason this was not detected as part of our internal compliance checks is due to the equipment not being CFR (code of
federal regulation) compliant. We are now replacing this with CFR compliant equipment.
In addition, we are ensuring that equipment at all locations is CFR compliant. Also appropriate disciplinary action has been
taken." The report, which makes 11 observations on deviations from US prescribed quality standards, said the toilet for
manufacturing operators at the plant was in "total disrepair" and lists concerns about poor housekeeping.
"The two urinals present in the washing and toilet facility provided for quality control laboratory male employees were found to
drain directly onto the floor. Urine was found to be collected in and around an open drain. A strong smell of urine was observed
throughout your firm's quality control environment," said the report signed off by FDA investigators Peter Baker and Dipesh Shah.
The poor washing and toilet facilities have been fixed, Sun said. They also spotted a garbage dump in the perimeter of the
manufacturing area, apart from various forms of infestation. "Buildings used in the manufacture, processing, packing or holding
of drug products are not free of infestation by rodents, birds, insects and other vermin," the report said.
PAGE 4 PHARMA UPTODAY
Chinese API Manufacturers Zhejiang Jiuzhou Pharmaceutical, Zhejiang Zonebanne put on FDA Import Alert
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
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. ***
Source : http://www.accessdata.fda.gov/cms_ia/importalert_189.html
FDA Reduces GMP Inspections by 40 Percent, Focuses on Imports
The FDA is scaling back the number of routine quality inspections it plans to conduct in the U.S. each year by 40 percent in
favor of conducting more inspections overseas. The shift is part of a broader agency push to improve the quality of drugs
imported into the U.S. The change also brings the FDA closer to achieving its longtime goal of bringing parity to U.S. and foreign
inspections, so that foreign drug manufacturers would be as likely to be inspected as U.S.-based facilities.
The FDA plans to conduct 591 domestic good manufacturing practice (GMP) inspections in fiscal 2014 and 2015, down from
the 967 performed last year. The agency in turn hopes to perform 30 percent more foreign GMP inspections, conducting 843
inspections each year, up from last year’s 604. Companies will be chosen for inspection based on the agency’s risk-based
inspection model that grants leeway to high-quality companies. The FDA takes into account risk factors including Class I recalls
and adverse events, as well as compliance history, in applying the risk-based inspections model to its decision making.
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PAGE 5PHARMA UPTODAY
FDA Unveils New Guidance on Reporting Post-Approval Changes.
A new guidance finalized by the US Food and Drug Administration (FDA) is meant to clarify which events and changes
sponsors of new and generic drug products need to report in their annual reports to FDA.
Under FDA regulations, changes to an approved new drug application (NDA) or abbreviated new drug application
(ANDA) must be reported to regulators. Depending on the impact, reports of the change must either be approved in
advance (Prior Approval Supplement), reported at the time of the change (Changes Being Effected-0 Day) or right
before (CBE-30), or on an annual basis.
Those reported in an annual report are those that have the least potential to affect a product's safety, efficacy or quality.
As FDA explains in its new guidance, CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports,
many changes reported to FDA are of little risk to the product, and therefore would be better suited to annual reports—
As such, FDA has compiled a new list of changes (Appendix A and B in the guidance) that companies can reference to
see if their post-approval manufacturing changes would be appropriate to report in an annual report.
"We expect NDA and ANDA holders to evaluate the specific change that they are planning to make in the context of
their particular circumstances to determine whether the proposed change would present a minimal potential to have an
adverse effect on product quality," FDA writes. "When a risk-based evaluation shows that the proposed change would
have a minimal potential to have an adverse effect on product quality, the change can be documented in the next
The new guidance supersedes change reporting recommendations in all other guidance documents, FDA said.
The guidance also covers the basics of the changes that must be recorded in the annual report, including a list of the
changes, a summary of tests confirming the (non)impact of the changes, a description of the changes, and references
to products affected.
FDA Releases Guidance for Industry: Guidance on Antiviral Product Development — Conducting and Submitting
Virology Studies to the Agency: Guidance for Submitting HIV-1 Resistance Data: Attachment to the Guidance
PAGE 6 PHARMA UPTODAY
FDA Releases Guidance for Industry: Distributing Scientific and Medical Publications on Unapproved New Uses —
Recommended Practices (Revised Draft Guidance)
This guidance describes the Food and Drug Administration’s (FDA’s or Agency’s) current thinking on recommended
practices for drug and medical device manufacturers and their representatives to follow when distributing to health
care professionals or health care entities scientific or medical journal articles, scientific or medical reference texts, or
clinical practice guidelines (CPGs) that discuss unapproved new uses for approved drugs or approved or cleared
medical devices marketed in the United States. For the purposes of this guidance, these materials are generally referred
to as scientific and medical publications.
EMA publishes New Process Validation Guideline
Compared to the current Note for Guidance, the revision remains in its final version pretty difficult to read and rather
general. This is a marketing authorisation document, which is clearly addressed in the title and only applies to finished
dosage forms of chemical medicinal products for human and veterinary use but not for old ones, which are already
authorised and on the market. The introduction of a validation life cycle and the integration of continued process
verification (CPV) are completely new although this approach is already acquainted from ICH Q8. The "traditional
approach" remains accepted. Like in the Annex 15 draft the hybrid approach remains here in the final document
"nebulous". The idea to integrate modern elements from ICH Q8, Q10 (and Q11) into the document is clearly noticeable.
Yet, far less concrete references are made to ICH Q9.
A stronger overlap of the FDA Guidance would have been desirable. FDA's Guidance also deals with APIs and
biologicals, and the process validation life cycle runs like a thread through the whole FDA document. FDA's Guidance
also contains GMP aspects. The FDA Guidance explicitly addresses old products which should be integrated to stage 3
of the life cycle. Yet, there is another big difference. The revised document doesn't highlight statistical methods like the
Before the finalisation, a comparison with the Annex 15 has been made which is a nice thing. This explains the long
period between the publication of the draft (March 2012) and that of the finalisation (February 2014).
What is significant for the GMP world? On the one hand almost nothing, on the other hand quite a lot: one may wonder
why? Direct references to the Annex 15 can be found with regard to the "ongoing process verification" and "concurrent
validation", which is almost nothing looking at the whole document. Moreover, validation in general is required to be
executed according to the GMP regarding "continuous process verification" and "change control"; these are the
essential parts of the document, and (almost) the complete document should therefore be seen from a GMP
The new EMA guideline on process validation will apply by the end of August 2014.
PAGE 7PHARMA UPTODAY
FDA publishes Guidance for Industry: Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological
This draft guidance provides the pharmaceutical industry with the Center for Drug Evaluation and Research’s (CDER’s) and
the Center for Biologics Evaluation and Research’s (CBER’s) current thinking on allowable excess volume and labeled vial
fill size in injectable drug and biological products. Specifically, the draft guidance clarifies the FDA regulatory requirements
and recommendations pertaining to allowable excess volume in injectable vials and describes when justification is needed
for a proposed excess volume in these injectable drug products.
This guidance also discusses the importance of appropriate packaging sizes for injectable drug products and recommends
that labeled vial fill sizes be appropriate for the intended use and dosing of the drug product.
FDA published draft guidance, Bioavailability and Bioequivalence Studies Submitted in New Drug Applications or
Investigational New Drug Applications—also known as the NDA BA and BE Draft Guidance—is meant to clarify FDA's latest
views on complying with 21 CFR 320.
That section, "Bioavailability and Bioequivalence Requirements," calls for all applicants of full new drug applications (NDAs)
to either submit data measuring the in vivo bioavailability of a drug or data showing why BA data is unnecessary. It also
calls for any sponsor of an ANDA to submit data establishing bioequivalence between the generic drug and the drug it
references, known to FDA as the reference listed drug (RLD).
These data are crucial during various stages of FDA's regulatory approval process. For example, FDA will require any drug
seeking approval to submit BA and BE data. Similarly, once a drug is approved by FDA, the agency will require BE testing
after any major changes (such as to the manufacturing process) to ensure that the test drug product has not changed
relative to the approved reference drug product.
Another example is when a company is advancing a drug through investigational testing. Companies often make changes
to a drug product's manufacturing process during this time (known as scale-up changes), and testing is necessary to ensure
that a product hasn't changed.
FDA publishes Draft Guidance for Industry: Labeling for Human Prescription Drug and Biological Products Approved Under
the Accelerated Approval Regulatory Pathway
This guidance is intended to assist applicants in developing the INDICATIONS AND USAGE section of labeling for human
prescription drug and biological products for indications that are approved under the accelerated approval regulatory
pathway (hereafter accelerated approval) as defined in section 506(c) of the Federal Food, Drug, and Cosmetic Act
(FD&C Act) and 21 CFR part 314, subpart H, or 21 CFR part 601, subpart E. More specifically, this guidance focuses on
indications and usage statements for drugs approved on the basis of a surrogate endpoint or an effect on a clinical
endpoint other than survival or irreversible morbidity. This guidance also addresses labeling considerations for indications
that were approved under accelerated approval and for which clinical benefit subsequently has been verified and the
FDA terminates the conditions of accelerated approval under 21 CFR 314.560 or 21 CFR 601.46, or when the FDA withdraws
accelerated approval of an indication while other indications for the drug remain approved.
PAGE 8 PHARMA UPTODAY
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.
There was a failure to handle and store components at all times in a manner to prevent contamination.
Written procedures are not established for the cleaning and maintenance of equipment, including utensils, used in the
manufacture, processing, packing or holding of a drug product.
University of Iowa Pharmaceuticals
Investigations of an unexplained discrepancy and a failure of a batch or any of its components to meet any of its
specifications 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.
Brookfield Prescription Center, Inc., dba MD Custom Rx
Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not
established, written and followed.
Millipore UK Ltd.
Effective contamination control has not been demonstrated.
Everglo Natural Veterinary Services, Inc.
Batch production and control records are not prepared for each batch of drug product produced and do not include
complete information relating to the production and control of each batch.
Specialty Medicine Compounding Pharmacy
Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not
established, written and followed.
Aurolife Pharma, LLC
There is a failure to thoroughly review the failure of a batch or any of its components to meet any of its specifications
whether or not the batch has been already distributed.
Pharma Pac, LLC
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.
Baxter Manufacturing S.p.A.
Manufacturing equipment are not adequately maintained to prevent contamination of manufactured products and
manufacturing personnel are not adequately trained in the use and assembling of manufacturing equipment.
Process validation activities and results have not been documented.
PAGE 9PHARMA UPTODAY
VAKOS XT a.s., Czech Republic:
VAKOS XT, a.s. produced and exported to Slovak Republic sterile medicinal product MULTIPEN HD. VAKOS XT, a.s. is not
autorised to manufacture and release sterile medicinal products. The pharmaceutical quality system in the company is
dysfunctional and VAKOS XT, a.s. does not meet GMP requirements.
Smruthi Organics Limited, Solapur, Maharashtra, India:
[Critical 1] Manipulation and falsification of documents and data were observed in different departments ;
[Critical 2] Some Corrective and Preventive Actions, related to deficiencies raised during the previous inspection were
not satisfactorily addressed ;
[Major 1] An out-of-specification result obtained for an In-Process Control, performed by TLC, was considered as
compliant by the analyst ;
[Major 2] The documentation practices for process validation were found unacceptable ;
[Major 3] The company's approach and understanding of the GMP requirements for the re-qualification of the
equipment was found to be unsufficient ;
[Major 4] There was no raw data available in the Quality Control laboratory for the verification of compendial analytical
IND-SWIFT LIMITED, Punjab:
It was not possible to confirm the validity of stability testing data. Several falsified and inaccurate results had been
reported in long term stability and batch testing.
Discrepancies between electronic data and those results formally reported were identified.
Established processes to verify data accuracy and integrity had failed and there had been no formal investigation
raised by the company.
The company provided commitments to address the data integrity concerns and initiated a wider review of quality
critical data. Additional discrepancies were identified in process validation and release data.
During on-going communications with the licensing authority regarding the data review, the company failed to disclose
data integrity issues for all products. No satisfactory explanation was given for this discrepancy.
PAGE 10 PHARMA UPTODAY
Non-compliance Reports: (Continued)
• [Critical] The manufacturing and cleaning operations during and between the campaigns of 15 APIs, whose 2 are used in
injectable dosage forms and one is an ectoparasiticide (Fipronil), are not traceable. Many records are missing.
• [Critical] Cleaning procedures are not detailed to enable operators to clean each piece of equipment in a reproductible
and effective manner.
• Cleaning procedures of the critical pieces of equipment used after final isolation of pure APIs are not validated.
• Analytical methods by TLC used for cleanliness verification are not validated. Complete records of raw data generated
during cleanliness tests by thin layer chromatography are missing. Moreover, cleanliness tests are not conducted for
plates of dryers used for APIs.
• The other major findings were mainly related to the manufacturing of an ectoparasiticide for veterinary use (Fipronil) in
multi-products manufacturing area and equipment without any study based on QRM principles regarding cross-
contamination and containment, highlighting the non compliance status to the GMPs.
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PAGE 11PHARMA UPTODAY
Failure to maintain complete and accurate laboratory test data generated in the course of establishing compliance of
your APIs to established specifications and standards.
Failure to maintain and make available for inspectional review production and control records for currently marketed
Inadequate investigations of critical deviations or a failure of a batch to meet its specifications or quality standards.
There was no record made describing the reason for the replacement of the original logbook.
you are unable to recover the integration parameters used for API assay and impurity tests.
Reassess your analytical test method validation and verification activities and identify those methods which do not have
complete supporting data
Canton Laboratories, Vadodara:
• Failure to perform laboratory testing of APIs to ensure conformance to specifications and to accurately report results
on Certificates of Analysis (CoA)
• Failure to maintain complete data derived from all laboratory tests conducted to ensure compliance with established
specifications and standards.
• Failure to ensure equipment is cleaned in a reproducible and effective manner to prevent contamination of a
material that would alter the quality of the APIs.
• Failure to ensure that APIs are produced according to pre-approved instructions and that batch production records
include complete information pertaining to the production of each batch.
• Failure to properly investigate customer complaints.
• Failure to properly investigate out-of-specification results.
• Failure to follow your Master Validation Plan for process validations or equipment calibrations.
• Failure to provide adequate resources to the quality unit.
• Failure of your quality unit to properly review production records and detect instances where testing was not
performed to support your company’s certifications on your COAs.
• Failure to perform appropriate stability studies for product currently in the market.
• Failure to establish an impurity profile for product currently in the market.
Source : http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm387960.htm
PAGE 12 PHARMA UPTODAY
§ 211.142 Warehousing procedures.
Written procedures describing the warehousing of drug products shall be established and followed. They shall include:
(a) Quarantine of drug products before release by the quality control unit.
(b) Storage of drug products under appropriate conditions of temperature, humidity and light so that the identity,
strength, quality, and purity of the drug products are not affected.
§ 211.150 Distribution procedures.
Written procedures shall be established, and followed, describing the distribution of drug products. They shall include:
(a) A procedure whereby the oldest approved stock of a drug product is distributed first. Deviation from this requirement
is permitted if such deviation is temporary and appropriate.
(b) A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if
Subpart I--Laboratory Controls
§ 211.160 General requirements.
(a) The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control
mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test
procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and
reviewed and approved by the quality control unit. The requirements in this subpart shall be followed and shall be
documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test
procedures, or other laboratory control mechanisms shall be recorded and justified.
(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.
Regulations of the Month
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