The US Food and Drug Administration (FDA) on Tuesday released a warning letter sent 10 April to Teva for deficiencies related to an active pharmaceutical ingredient (API) manufacturing site in Hangzhou, China.
Showing posts with label APR17. Show all posts
Showing posts with label APR17. Show all posts
Tuesday, April 25, 2017
Wednesday, April 12, 2017
FDA Warning letter @ Mylan Laboratories Limited, (Nashik FDF)
This warning letter summarizes
significant violations of current good manufacturing practice (cGMP)
regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
Because of methods, facilities, or
controls for manufacturing, processing, packing, or holding do not conform to
CGMP, your drug products are adulterated within the meaning of section
501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21
U.S.C. 351(a)(2)(B).
We reviewed your (Mylan) October 5,
2016, response in detail and acknowledge receipt of your subsequent
correspondence.
During our inspection, our investigator
observed specific violations including, but not limited to, the following.
1. Your
firm failed to thoroughly investigate any unexplained discrepancy or failure of
a batch or any of its components to meet any of its specifications, whether or
not the batch has already been distributed (21 CFR 211.192).
From January 1 to June 30, 2016, your
firm invalidated 101 out of 139 (about 72 percent) initial out-of-specification
(OOS) assay results without sufficient investigation to determine the root
cause of the initial failure.
For example, you opened laboratory
investigation report PR 908027 for an initial OOS six-month stability assay
result of (b)(4) percent (specification (b)(4)–(b)(4) percent)
for (b)(4) mg tablets, lot (b)(4). You invalidated
the initial failing result without adequate investigation, performed
re-testing, and then reported the (b)(4) results of these
replicate re-tests ((b)(4) percent). Your investigation did not
reach an assignable cause, nor did you take appropriate corrective actions and
preventive actions to ensure that the significant “analytical bias” to which
you ultimately attributed the initial failure would not affect other analytical
work in your laboratory.
In your response, you state that
laboratory decisions are to be made on the basis of scientific evaluation, and
that they are to determine whether OOS laboratory results are the result of the
laboratory process or the manufacturing process. However, in the example above,
your investigation assumed “analytical bias” in your laboratory process but
failed to determine how this apparently significant error in your analyses
could be eliminated or mitigated in the future.
Your response is inadequate because you
failed to implement a corrective action and preventive action (CAPA) plan to
mitigate errors that you attribute to laboratory process. Further, you did not
include these improperly invalidated OOS results in your analysis of laboratory
investigation trends. According to your Laboratory Investigation Report procedure
MLLNSK-SOP-QA-GMP-0138, version 6, only “confirmed” root causes are to be
identified and trended in laboratory investigation reports. Because your
laboratory investigations frequently invalidate initial failures without cause,
your laboratory trending excludes a large proportion of data that would
otherwise alert you to problems in your laboratory system. Failure to
identify trends in OOS investigations is a repeat observation from the previous
FDA inspection, March 19 to 26, 2015.
In response to this letter, conduct and
provide the results of a trend analysis of all your OOS results that includes
both “confirmed” root causes and the initial OOS results that you have
previously excluded as invalid without assignable root causes. For each
invalidated result, indicate the product tested, date of analysis, type of
analysis, purpose of the test, original result, retest results, and your
unconfirmed assignable root cause. Revise and provide your updated Laboratory
Investigation Report procedure. Specify how your revised procedure
ensures that all OOS investigations are included in your trending.
2. Your
firm failed to establish an adequate quality control unit with the authority to
review production records to assure that no errors have occurred or, if errors
have occurred, that they have been fully investigated (21 CFR 211.22(a)).
Your quality unit failed to monitor and
investigate error signals generated by the computerized systems that you use
for high performance liquid chromatography and gas chromatography. These
signals indicated the loss or deletion of original CGMP analytical data.
However, your quality unit did not comprehensively address the error signals or
determine the scope or impact of lost or deleted data until after these
problems were reviewed during our inspection.
For example, our investigator reviewed
audit trails from August 2016 assay testing on (b)(4) batch (b)(4) and
dissolution testing for (b)(4) tablets batch (b)(4).
The audit trail for these tests included the message, “deleted result set,” but
neither of these two incidents were recorded in the analytical packages for
these batches of drug products, nor were they reviewed or investigated by the
quality unit.
In addition, during the inspection, our
investigator observed that your Empower 3 system audit trail displayed many
instances of a “Project Integrity Failed” message, which indicates that
injections were missing from the results of analytical testing. For example, in (b)(4) analysis
for (b)(4) tablets batch (b)(4) conducted on
June 20, 2016, no chromatogram was rendered for the initial run of testing. The
data package for this testing clearly shows that the initial run is missing,
but your quality unit did not investigate the incident.
Although you showed our investigator
isolated examples of interrupted, missing, deleted, and lost data for which you
had opened investigations, you reached similar conclusions in many of these
investigations regarding the root cause of your loss of data integrity but
failed to take appropriate corrective action and preventive action in response.
Our investigator observed that you attributed numerous incidents to power
interruptions, connectivity problems (disconnection of the Ethernet or power
cord), and instrument malfunctions. You could not explain why these events
occurred with frequency in your laboratory, nor had you undertaken a
comprehensive investigation into the problem or sought to correct it and
prevent its recurrence.
In your written response dated February
17, 2017, you identified seven samples from a single week of testing for which
original results were lost following data acquisition interruptions at the time
of initial analysis. Instead of uniformly initiating an investigation into the
root cause of each interruption when it occurred or even documenting it for
later review and investigation by the quality unit, you explained in your
response that you retested the samples immediately after the interruptions.
Your response is inadequate because you
have not identified and investigated each instance in which data acquisition
was interrupted. While you assessed a limited number of error codes from a
seven day period, you did not evaluate the effects of other error codes
identified in your simulation exercise report on the reliability, accuracy, or
completeness of the data you use to evaluate the quality of your drugs.
Although you have submitted multiple responses, you have not yet:
·
shown exactly how widespread these problems are;
·
evaluated their full effects on the quality of your drugs;
·
explained why these events occurred with frequency in your laboratory;
·
or demonstrated how you will ensure that your quality unit reviews,
investigates, and acts upon codes that affect the reliability of your CGMP
data.
In response to this letter, provide your
validation of laboratory instrument error codes. Identify the specific codes
that may impact product quality and the reliability of CGMP data, and provide
your procedures to demonstrate how your quality unit will review, investigate,
and respond to these specific codes.
Data Integrity Remediation
Your quality system does not adequately
ensure the accuracy and integrity of data to support the safety, effectiveness,
and quality of the drugs you manufacture. We acknowledge that you are using a
consultant to audit your operation and assist in meeting FDA requirements. In
response to this letter, provide the following.
A. A
comprehensive investigation into the extent of the inaccuracies in data records
and reporting. Your investigation should include:
·
A detailed investigation protocol and methodology; a summary of all
laboratories, manufacturing operations, and systems to be covered by the
assessment; and a justification for any part of your operation that you propose
to exclude.
·
An assessment of the extent of data integrity deficiencies at your
facility. Identify omissions, alterations, deletions, record destruction,
non-contemporaneous record completion, and other deficiencies. Describe all
parts of your facility’s operations in which you discovered data integrity
lapses.
·
A comprehensive retrospective evaluation of the nature of the testing
data integrity deficiencies.
B. A current risk
assessment of the potential effects of the observed failures on the quality of
your drugs. Your assessment should include analyses of the risks to
patients caused by the release of drugs affected by a lapse of data integrity,
and risks posed by ongoing operations.
C. A management
strategy for your firm that includes the details of your global corrective
action and preventive action plan. Your strategy should include:
·
A detailed corrective action plan that describes how you intend to
ensure the reliability and completeness of all of the data you generate,
including analytical data, manufacturing records, and all data submitted to
FDA.
·
A comprehensive description of the root causes of your data integrity
lapses, including evidence that the scope and depth of the current action plan
is commensurate with the findings of the investigation and risk assessment.
Conclusion
·
Violations cited in this letter are not intended as an all-inclusive
list. You are responsible for investigating these violations, for determining
the causes, for preventing their recurrence, and for preventing other
violations. More details click here…
GMP News, GMP guidelines, GMP Violations, GMP warnings, GMP Trends. A Public Health Global News Portal. (This story has not been edited by GMP Violations staff and is auto-generated from a syndicated feed/ experts experiences sharing.) Disclaimer: The Logos/Images & content posted here are belongs to respective to Authority / owners of firm. The Article posted under public health importance news. Please ensure the guideline as per Regulatory agencies.
Sunday, April 9, 2017
GlaxoSmithKline Recalling Ventolin Inhalers for Possible Package Leakage
GlaxoSmithKline (GSK) issued a voluntary Class II recall on April 4,
2017 for three lots of Ventolin® HFA 200D Inhalers from U.S. hospitals,
pharmacies, retailers and wholesalers as a precautionary measure. It is not a
consumer recall.
The lot numbers are:
·
6ZP0003
·
6ZP9944
·
6ZP9848
A GSK spokesman spoke with AAFA and said the recall is due to some
complaints about the overwrap, or pouches containing the inhalers, becoming
inflated by leaking from the product. The leaking may cause the inhaler to
deliver fewer doses than shown on the dose counter.
Patients are not being told to return the inhalers. If you have a
question, call the company’s response center: 1-888-825-5249.
A Class II recall is one where "use of, or exposure to, a violative
product may cause temporary or medically reversible adverse health consequences
or where the probability of serious adverse health consequences is
remote," according to the U.S. Food and Drug Administration.
The company released a statement that said, “Though the overall benefit-risk
assessment for Ventolin® HFA 200D Inhaler when used at prescribed doses remains
favourable, in this situation, there is possible risk to patients of
experiencing diminished bronchodilation in the setting of acute bronchospasm if
reliant on a rescue inhaler that could potentially not deliver the stated
number of actuations. GSK is committed to supplying high quality product and
patient satisfaction, and we sincerely regret any inconvenience this recall may
cause."
If you need to fill a prescription for Ventolin HFA 200D, the voluntary
recall should not affect pharmacy supplies.
Source: AAFA
www.gmpviolations.com
GMP News, GMP guidelines, GMP Violations, GMP warnings, GMP Trends. A Public Health Global News Portal. (This story has not been edited by GMP Violations staff and is auto-generated from a syndicated feed/ experts experiences sharing.) Disclaimer: The Logos/Images & content posted here are belongs to respective to Authority / owners of firm. The Article posted under public health importance news. Please ensure the guideline as per Regulatory agencies.
EMA Issues Guidance on Periodic Safety Update Reports
The agency released guidance on single assessments of PSURs to improve safety and benefit-risk assessment of medicines
The European Medicines Agency (EMA) released two guidance documents to
help improve the process of assessing periodic safety update reports (PSURs).
Marketing authorization holders submit PSURs, which evaluate the benefits and
risks of a medication, to the agency after authorization. EMA uses the reports
to assess the benefit-to-risk balance of the medication to determine the
continued safety of the drug. Products that contain the same API or combination
of APIs are assessed jointly in a single assessment procedure.
The assessment process was streamlined to “ensure that all the evidence
generated about medicines containing the same active substance is
reviewed at the same time by one authority, resulting in consistent safety
information,” EMA stated in a press release. Explanatory Note to GVP Module VII addresses
concerns that companies have expressed during the two years since the PSUR
single assessment process started in 2015. The guidance discusses several
topics, such as the scope of information to be included in PSURs, changes to
therapeutic indications, information for generic drugs, reference product
information, safety actions taken by countries, patient exposure, and signal
evaluation.
Assessors' Questions and Answers (Q&A) Guidance on PSUR Single
Assessment (PSUSA) gives assessors guidance on the
evaluation process of PSURs. The agency is planning joint training in 2017 for
both industry and European Union authorities on the implementation of the
single assessment process.
Indian Pharmacopoeia Commission and U.S. Pharmacopeial Convention Partner to Strengthen the Quality of Medicines and Public Health
In an effort to promote the safety, quality, and effectiveness of
medicines, the Indian Pharmacopoeia Commission, an autonomous institution of
the Ministry of Health & Family Welfare, and the United States
Pharmacopeial Convention (USP), an independent, scientific nonprofit
organization, signed a Memorandum of Understanding (MOU) today to formally
recognize the organizations’ collaborations in the identification, development,
and dissemination of science-based standards at an international level.
The goal of the MOU is to enhance global public health by working
together to:
· Increase awareness of the importance of quality, safety and efficacy of
medicines, and
· Safeguard the integrity of the global supply chain by increasing the
availability of and access
to needed public standards for
medicines.
The MOU was signed by Dr. Gyanendra Nath Singh, IPC
Secretary-cum-Scientific Director, and Dr. Ronald T. Piervincenzi, USP Chief
Executive Officer, at IPC headquarters in Ghaziabad.
USP has an office near Hyderabad and has collaborated with IPC on a
number of projects for related to medication quality over the last several
years. “This MOU is a significant step forward in how two standard setting
bodies can work together to improve global health through quality standards,”
said Dr. Ronald T. Piervincenzi, USP Chief Executive Officer. “Our
collaboration will amplify the global public health impact of both
organizations by leveraging our mutual scientific resources to advance
international standards.”
About IPC
Indian
Pharmacopoeia Commission (IPC) is an Autonomous Institution of the Ministry of
Health and Family Welfare, Govt. of India. IPC is created to set standards of
drugs in India. Its basic function is to update regularly the standards of
drugs commonly required for treatment of diseases prevailing in this region. It
publishes official documents for improving Quality of Medicines by way of adding
new and updating existing monographs in the form of Indian Pharmacopoeia (IP).
It further promotes rational use of generic medicines by publishing National
Formulary of India.
Pharmacovigilance
Programme of India (PvPI) is another important mandate given to the IPC by the
Govt. of India which it is managing well. Further details about IPC visit www.ipc.nic.in.
About USP
The
U.S. Pharmacopeial Convention (USP) is a global health organization that
improves lives through public standards and related programs that help ensure
the quality, safety, and benefit of medicines and foods. USP’s standards are
used worldwide. For more information about USP visit http://www.usp.org.
For
media inquiries please email mediarelations@usp.org
Source: USP
Friday, April 7, 2017
EMA revises Guide on Pharmaceutical Water And open for Commnets
EMA revises Guide on Pharmaceutical Water
According to the European Pharmacopoeia, it will be allowed as of the 1st of April 2017 to produce water
for injection (WFI) using cold i.e. non-distillation methods (as already
reported under "WFI obtained by
non-distillation methods - What are the Next Steps?"). Now, the
European Medicines Agency (EMA) has published a concept paper on the revision
of the Note for (Click Here for Download) Guidance on Quality of water for pharmaceutical use
(CPMP/QWP/158/01 EMEA/CVMP/115/01). This Guideline
from 2002 describes the different qualities of water for pharmaceutical use and
their use in the production of medicinal products and/ or diverse dosage forms
(e.g. topical, oral or parenteral). The paper also mentions the production of
the different qualities and is in line with the present regulations of the
European Pharmacopoeia which only allowed distillation for the production of
WFI. The document also describes Highly Purified Water (HPW) and its use. HPW
meets WFI quality but can be produced by means of membrane processes. Here, an
essential aspect is the proposition of EMA's Quality Working Party to
remove in the future the monograph (1927) Highly Purified Water.
The (Click here) "Concept paper on the
need for revision of note for guidance on quality of water for pharmaceutical
use (H+V)". Comments to
this paper can be submitted until 6th June 2017.
www.gmpviolations.com
GMP News, GMP guidelines, GMP Violations, GMP warnings, GMP Trends. A Public Health Global News Portal. (This story has not been edited by GMP Violations staff and is auto-generated from a syndicated feed/ experts experiences sharing.) Disclaimer: The Logos/Images & content posted here are belongs to respective to Authority / owners of firm. The Article posted under public health importance news. Please ensure the guideline as per Regulatory agencies.
Tuesday, April 4, 2017
Warning Letter @ Singapore based company Opto-Pharm Pte Ltd
The US FDA
has issued the warning Letter to Singapore based
FDA investigators observed specific violations including, but not limited to, the following.
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)).
During aseptic manufacturing of your sterile ophthalmic products (b)(4) (lot (b)(4)) and (b)(4) (lot (b)(4)), you documented numerous leaking containers and other bottle formation defects. To address these defects, you routinely adjusted your (b)(4) ((b)(4)) equipment and resumed production. You subsequently released these lots. Following distribution, you received customer complaints of leaking containers.
In addition, you found numerous critical container-closure defects, including leaking products, during media fills studies. Container integrity is imperative to ensure sterility of ophthalmic drug products. The lack of assurance that your (b)(4) equipment consistently manufactures an integral container-closure system diminishes confidence in the sterility of your marketed products.
Additionally, our inspection found that your firm re-uses (b)(4) as many as (b)(4) times before discarding them. (b)(4) should normally be used once, then discarded after manufacturing a single product lot. Repeated use and re-sterilization can compromise (b)(4) efficacy and physical/chemical stability (e.g., particles, leachables, extractables).
During our inspection, you acknowledged your failure to validate your process prior to distributing drugs. In your response, you committed to develop and execute protocols for process performance qualification and equipment qualification.
In response to this letter, provide the validation protocols and studies that evaluate whether your (b)(4) equipment is reliable. This includes but is not limited to determining whether your process reproducibly yields an integral container-closure system, and whether other process parameters and quality attributes are consistently met.
Also, by definition, a validated process operates in an ongoing state of control. It is essential that your firm improves your process design and control to correct the root causes of your recurring container-closure integrity defects. Without such remediation, successful process performance qualification studies alone are insufficient to demonstrate that your process is truly capable of a continuing state of control. In your response, provide an analysis of the root causes of in-process integrity defects and container-closure defects affecting distributed products. Also provide an update on all CAPA activities that have been undertaken to improve your process.
2. Your firm failed to establish the reliability of the container-closure supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals (21 CFR 211.84(d)(3)).
Your firm uses (b)(4) supplied by (b)(4) in your (b)(4) equipment to manufacture the container-closures for your ophthalmic products. You accepted values reported on the supplier’s certificate of analysis for density and (b)(4) for each incoming lot but did not verify the reliability of the supplier’s results.
Using (b)(4) that does not meet its quality attributes, such as density and (b)(4), may result in container-closure integrity defects that could compromise the sterility of your ophthalmic drug products.
In your response, you committed to sending samples from (b)(4) batch of (b)(4) received to an external laboratory for density testing. You also committed to periodically evaluate your (b)(4) supplier. You did not provide justification for your acceptance criteria for the (b)(4). In addition, you did not provide external laboratory results for density and (b)(4) values, or any supplier evaluations.
In response to this letter, provide justification to demonstrate your (b)(4) specifications are appropriate for the drug products you manufacture. Provide your supplier evaluations and a summary of laboratory test results relating to all of the components, containers, and closures you use to manufacture your sterile drug products.
3. Your firm failed to ensure that your drug products bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).
Your firm failed to conduct stability studies for Buffered Saline and (b)(4) ophthalmic solutions produced in 2014 and 2015. Furthermore, at the time of the inspection, you could not provide raw data to support test results from stability studies you conducted for other products.
Your failure to conduct stability studies and lack of data supporting expiration dates compromises your ability to detect quality problems with marketed ophthalmic products. Without stability data, you cannot assure the quality of your products throughout their labeled shelf lives. In addition, you have received multiple customer complaints of leaking ophthalmic containers, which also calls into question your ability to maintain sterility of your ophthalmic products throughout their labeled expiration dates.
In your response, you commit to conducting stability studies on your Buffered Saline and (b)(4) products. However, you did not provide the raw stability data for other ophthalmic products.
In response to this letter, provide the following:
- raw stability data for all of your ophthalmic products manufactured for the U.S. market within expiry
- antimicrobial effectiveness testing that evaluates whether your products contain a suitable preservative system
- an evaluation of whether your products’ preservative systems remain effective at their expiration dates
Source: FDA
GMP News, GMP guidelines, GMP Violations, GMP warnings, GMP Trends. A Public Health Global News Portal. (This story has not been edited by GMP Violations staff and is auto-generated from a syndicated feed/ experts experiences sharing.) Disclaimer: The Logos/Images & content posted here are belongs to respective to Authority / owners of firm. The Article posted under public health importance news. Please ensure the guideline as per Regulatory agencies.
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