CCK Discussion Forum on Impurity Emergence: A Wake Up Call for Drug Safety & Quality - 13 Oct 2019 at ICCBS, University of Karachi. Session largely participated by qualified and experienced pharmaceutical professionals having diversified educational background and experience.
New guidelines relating to elemental impurities from the International Conference on Harmonization (ICH), Q3D Guideline for Elemental Impurities have presented the pharmaceutical industry with new challenges. This new guidance has been developed to provide a global policy for limiting metal impurities qualitatively and quantitatively in drug products and ingredients.
To recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.
The guideline applies to all dosage forms and routes of administration.
This guidelines does not address all possible solvents, only those identified in drugs at that time, neither address solvents intentionally used as excipients nor solvates.
The maximum acceptable intake per day of residual solvent in pharmaceutical products is defined as “permitted daily exposure” (PDE)
Previously, another terms were used like “Tolerable daily intake” (TDI) & “Acceptable daily intake” (ADI) by different organization & authorities, but now usually this new term “PDE” is used
New guidelines relating to elemental impurities from the International Conference on Harmonization (ICH), Q3D Guideline for Elemental Impurities have presented the pharmaceutical industry with new challenges. This new guidance has been developed to provide a global policy for limiting metal impurities qualitatively and quantitatively in drug products and ingredients.
To recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.
The guideline applies to all dosage forms and routes of administration.
This guidelines does not address all possible solvents, only those identified in drugs at that time, neither address solvents intentionally used as excipients nor solvates.
The maximum acceptable intake per day of residual solvent in pharmaceutical products is defined as “permitted daily exposure” (PDE)
Previously, another terms were used like “Tolerable daily intake” (TDI) & “Acceptable daily intake” (ADI) by different organization & authorities, but now usually this new term “PDE” is used
ICH Q3D - Elemental impurities in pharmaceutical productspi
The ICH has developed the Q3D guideline on elemental impurities. Both the FDA and the EMA encourage the ICH Q3D guideline implementation. All companies will have to be compliant for already authorised and marketed products as of December 2017.
Setting Specification Limits for Impurities in Active Pharmaceutical Ingredient (API’s).
Setting Specification Limits for Impurities in Active Pharmaceutical Ingredient (API’s)
Setting Specification Limits for Impurities in Active Pharmaceutical Ingredient (API’s)
Risk-based Approach to evaluate Nitrosamines and Elemental Impurities from Si...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3usdjx7
Nitrosamines and elemental impurities are now a concern for regulatory agencies. A key issue related to plastic single-use systems (SUS) is potential leachables from contact materials. For SUS it’s essential to evaluate leachables as well as nitrosamines and elemental impurities risks.
Residual impurities can potentially be introduced into the biopharmaceutical manufacturing process at a variety of stages. Recently, nitrosamines and elemental impurities have been a concern for regulatory agencies. These impurities originate from various raw materials, process chemicals and manufacturing equipment. Single-use systems (SUS) incorporate a number of plastic components. A key concern related to plastic SUS is potential leachable compounds from contact materials. It’s essential to obtain information on leachables as well as nitrosamines and elemental impurities. This webinar looks into how to evaluate nitrosamine and elemental impurity risk related to SUS and filters.
In this webinar, you will:
• Understand of the potential of nitrosamine contamination
• Learn how to leverage industry, supplier, and scientific expertise to assess the risk of elemental impurities taking advantage of ICH Q3D guidance on biologic drug manufacturing
• See a case study using Emprove® Elemental Impurities to help you conduct an efficient elemental impurities safety evaluation D46
Presented by: Janmeet Anant
Senior Regulatory Consultant
This document is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state.
Nitrosamine impurities in drug substances and drug products-formatTabrez Shaikh
Nitrosamine impurities are known to be mutagenic and carcinogenic, very small exposure of these impurities can lead to cancer. These impurities may be formed and get incorporated into drug substance or drug product through reagent, catalyst, solvent or raw materials used in the process of manufacturing. The various regulatory authority has published the press release or notice regarding the control of these impurities with the interim limit. Nitrosamine impurities can be avoided by taking precaution in the manufacturing of drug substance and drug products. Validated analytical methods are to be used to identify and quantify these impurities hence it needs highly sensitive instrument which can detect these impurities to the trace level at given interim limit. Liquid chromatography or Gas chromatography, along with mass detector is majorly used for their determination.
ICH Q3D - Elemental impurities in pharmaceutical productspi
The ICH has developed the Q3D guideline on elemental impurities. Both the FDA and the EMA encourage the ICH Q3D guideline implementation. All companies will have to be compliant for already authorised and marketed products as of December 2017.
Setting Specification Limits for Impurities in Active Pharmaceutical Ingredient (API’s).
Setting Specification Limits for Impurities in Active Pharmaceutical Ingredient (API’s)
Setting Specification Limits for Impurities in Active Pharmaceutical Ingredient (API’s)
Risk-based Approach to evaluate Nitrosamines and Elemental Impurities from Si...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3usdjx7
Nitrosamines and elemental impurities are now a concern for regulatory agencies. A key issue related to plastic single-use systems (SUS) is potential leachables from contact materials. For SUS it’s essential to evaluate leachables as well as nitrosamines and elemental impurities risks.
Residual impurities can potentially be introduced into the biopharmaceutical manufacturing process at a variety of stages. Recently, nitrosamines and elemental impurities have been a concern for regulatory agencies. These impurities originate from various raw materials, process chemicals and manufacturing equipment. Single-use systems (SUS) incorporate a number of plastic components. A key concern related to plastic SUS is potential leachable compounds from contact materials. It’s essential to obtain information on leachables as well as nitrosamines and elemental impurities. This webinar looks into how to evaluate nitrosamine and elemental impurity risk related to SUS and filters.
In this webinar, you will:
• Understand of the potential of nitrosamine contamination
• Learn how to leverage industry, supplier, and scientific expertise to assess the risk of elemental impurities taking advantage of ICH Q3D guidance on biologic drug manufacturing
• See a case study using Emprove® Elemental Impurities to help you conduct an efficient elemental impurities safety evaluation D46
Presented by: Janmeet Anant
Senior Regulatory Consultant
This document is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state.
Nitrosamine impurities in drug substances and drug products-formatTabrez Shaikh
Nitrosamine impurities are known to be mutagenic and carcinogenic, very small exposure of these impurities can lead to cancer. These impurities may be formed and get incorporated into drug substance or drug product through reagent, catalyst, solvent or raw materials used in the process of manufacturing. The various regulatory authority has published the press release or notice regarding the control of these impurities with the interim limit. Nitrosamine impurities can be avoided by taking precaution in the manufacturing of drug substance and drug products. Validated analytical methods are to be used to identify and quantify these impurities hence it needs highly sensitive instrument which can detect these impurities to the trace level at given interim limit. Liquid chromatography or Gas chromatography, along with mass detector is majorly used for their determination.
The importance of extractable/leachable testing in Pharmaceutical Dosage forms has grown considerably in the last few years.Recent USP general chapters <1663>, <1664> states the requirements for extractables and leachables in regulatory submissions. There were several criticalities associated in the container closure system assessment in identifying the probable leachables that could impact the
quality of the Drug product. Control extractions studies provide an insight based on the technical characteristics and logical conclusions made. Technology advancements and bundles of literature provided major insights in understanding the analytical evaluation limits,specifications and procedural things conducting extractable and leachable studies. This presentation provides a summary and overview of regulatory requirements for extractables and leachables with the current trend of FDA deficiencies for the drug products.
FDA Feedback Regarding Chemistry for Toxicological Risk Assessment – How to M...Greenlight Guru
One of the newest biocompatibility evaluation tools is extractable and leachable (E&L) testing. A correctly run E&L study, with an accompanying toxicological evaluation, can be used to replace traditional tests like systemic toxicity, genotoxicity, reproductive toxicity, and carcinogenicity. The data gained from these studies can help understand the total risk of your device to an intended population of users; but unlike the traditional animal tests, it comes with separate risks. These tests are not your typical “stamped” tests, where every lab gives a similar quality of results. Because of this, FDA has refined a strict, detailed, list of parameters that should be included in every test. This list is very dynamic and is changing rapidly; the best way to make sure you are performing the correct version of the test is to learn from the most recent FDA feedback on studies.
TAKEAWAY ITEMS:
• Understand recent FDA feedback and dissect what FDA is asking/looking for
• Learn how to address these concerns and develop a protocol to make sure you don’t receive similar questions
• Recognize how FDA is using the new ISO 10993-18 and where they deviate from that standard
This session took place live at the Greenlight Guru True Quality Virtual Summit, a three-day event for medical device professionals to learn to get their devices to market faster, stay ahead of regulatory changes, and use quality as their multiplier to grow their device business.
THE PRESENTATIONS DESCRIBES THE ICH GUIDELINE FOR RESIDUAL SOLVENTS i.e Q3C.
IT contains the basic of ICH and the complete description about the ICH guideline Q3C and its classification,limits,acceptance criteria in Pharma industries and the standards.
#Pharmaceuticalguideline
#medicine
#healthandmedicine
Pharmacopoeias,Sources of Impurities in Medicinal agents and Limit testssaimuniswetha1
Today's Topic Pharmacopoeias, Sources of Impurities in Medicinal agents and Limit tests for Chlorides, Sulphates, Heavy Metals, Lead, Iron in Pharmaceutical Analysis subject for B.pharmacy 1st year as per JNTUA Syllabus...
Regulatory Aspects On Pharmaceutical Excipients By Mr. Pankaj DhapadePankaj Dhapade
This presentation covers latest understanding and regulatory scenario on pharmaceutical excipients.
1. What are Excipients?
2. Types of Excipients
3. Classification of Excipients
4. DP v/s Excipients
5. Composition profile of Excipients
6. Facts related to Excipients
7. Process Change
8. Information Disclosure
9. Difficulties and Challenges
10. Dossier Requirements
11. Development Pharmaceutics
12. Excipients Certification Scheme
Top 50 deficiencies in CTD Dossier - PharmaceuticalSumit Gupta
Article for Regulatory Affairs associates working in pharmaceutical company preparing Dossiers and Drug Master File for Marketing Authorization in various regulated and semi regulated market.
An article on contamination of Diethylene Glycol in Pharmaceuticals. Thanks to Dr. Ajaz S. Hussain for all teaching, sharing knowledge and supporting in professional development.
Modern Database Management 12th Global Edition by Hoffer solution manual.docxssuserf63bd7
https://qidiantiku.com/solution-manual-for-modern-database-management-12th-global-edition-by-hoffer.shtml
name:Solution manual for Modern Database Management 12th Global Edition by Hoffer
Edition:12th Global Edition
author:by Hoffer
ISBN:ISBN 10: 0133544613 / ISBN 13: 9780133544619
type:solution manual
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All chapter include
Focusing on what leading database practitioners say are the most important aspects to database development, Modern Database Management presents sound pedagogy, and topics that are critical for the practical success of database professionals. The 12th Edition further facilitates learning with illustrations that clarify important concepts and new media resources that make some of the more challenging material more engaging. Also included are general updates and expanded material in the areas undergoing rapid change due to improved managerial practices, database design tools and methodologies, and database technology.
Oprah Winfrey: A Leader in Media, Philanthropy, and Empowerment | CIO Women M...CIOWomenMagazine
This person is none other than Oprah Winfrey, a highly influential figure whose impact extends beyond television. This article will delve into the remarkable life and lasting legacy of Oprah. Her story serves as a reminder of the importance of perseverance, compassion, and firm determination.
The Team Member and Guest Experience - Lead and Take Care of your restaurant team. They are the people closest to and delivering Hospitality to your paying Guests!
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Artificial intelligence (AI) offers new opportunities to radically reinvent the way we do business. This study explores how CEOs and top decision makers around the world are responding to the transformative potential of AI.
3. Acknowledgment and thanks to
Anthony Fake, Theo Dekker, Rutendo Kawana & Lynda
Paleshnuik of World Health Organization
4. Most Common Abbreviations Used
• API – Active Pharmaceutical Ingredient
• FPP – Finished Pharmaceutical Product
• LOD – Loss on Drying
• PDE – Permitted daily exposure
• TDI – Total daily intake
• TTC – Threshold of Toxicological Concern
5. Focus
• Impurities and brief explanation – already given
• What are potential impurities
• What impurities actually occur
• When to specify impurities
• Setting Impurities limits
9. What potential impurities might be present,
based upon all available information.
This step is often poorly performed by
applicants.
There is a tendency to skip this step in
discussions and just adopt pharmacopoeial
specifications if a monograph exists.
What are the
potential impurities?
10. What potential impurities might be present,
based upon all available information.
This step is often poorly performed by
applicants.
There is a tendency to skip this step in
discussions and just adopt pharmacopoeial
specifications if a monograph exists.
What are the
potential impurities?
11. What potential impurities might be present,
based upon all available information.
This step is often poorly performed by
applicants.
There is a tendency to skip this step in
discussions and just adopt pharmacopoeial
specifications if a monograph exists.
What are the
potential impurities?
20. It is essential to have a detailed knowledge of the
Preparation of the API & the Controls placed upon the
API
Starting
Materials
Reaction
Inter-
mediates
Reagents Solvents
28. Impurities introduced
during manufacture
API degradation
products
API reaction by-
products
Determining most of the potential impurities does not require
a great deal of chemistry knowledge. Impurities can be
divided into:
29. These can be determined
from the detailed
manufacturing process
description
They are the solvents,
reagents, catalysts, residue
starting material, reaction
intermediates used in
manufacture
What impurities are introduced during manufacture?
30. These can be
determined from the
results of stress
studies.
Significant degradation
products should be
identified and treated
as potential impurities.
What are the possible degradation impurities?
36. API SM
Step 1
Step 3
Final API
Step 2
Chance
Chance of an impurity occurring
Step impurity is introduced
Enantiomers
37. Investigation of batch
analysis and long-
term stability data is
required.
Impurities present at
levels greater than the
ICH reporting
threshold should be
reported by the
manufacturer.
38. Potential impurities can be excluded
by either testing the final API or FPP,
or a relevant proceeding molecule.
Some pharmacopoeial impurities
may not be present if a different
manner of preparation,
(reagents, synthesis) is used.
39. For degradants, look to long-term
stability data.
The presence of an impurity under
accelerated conditions does not mean it
will appear under long-term conditions
40. If you are looking for an impurity using
a test method that can not detect the
impurity then you are wasting your
time.
Demonstrated specificity and
appropriate LOD/LOQs are important,
especially for genotoxins.
Analytical
methods
41. It is important for the manufacturer to
detail the methods used.
This is often not clear in submitted
dossiers if different test methods have
been used at different times.
Analytical
methods
44. Any impurity routinely observed in
batch data or long-term stability
trials should be controlled by the
impurity specifications
Organic
Impurities
45. Impurities observed below the ICH
identification threshold need not be
individually specified in the
specifications. They can be
controlled under the limit for any
unspecified impurity
Organic
Impurities
46. Impurities above the ICH
identification threshold need to be
identified and individually specified
in the specifications
Organic
Impurities
47. If a genotoxin is formed or is likely to be
formed during manufacture or storage then a
limit for this impurity should be included in
specifications
GENOTOXINS
48. If batch data (6 pilot or 3
production) demonstrate that levels
of the impurity are at or below 30%
of the allowable limit then non-
routine testing may be adopted. It
should still be specified
49.
50. For instance, if
methylsulphonic acid
and methanol were used
in the last step, but
methane
methylsulphonate was
not detected then it may
be appropriate to test
once annually.
51. For instance, if
methylsulphonic acid
and methanol were used
in the last step, but
methane
methylsulphonate was
not detected then it may
be appropriate to test
once annually.
If methylsulphonic acid
and methanol were used
in the first of three steps,
but methane
methylsulphonate was
not detected then it may
be appropriate to specify
the test is to be applied
when there is a change
in manufacture.
53. The limits must be qualified as
safe.
The limits should realistically
reflect batch and stability data.
54. Through toxicological trials.
By comparison to levels found in an innovator or prequalified FPP.
By comparison to a limit previously approved in a prequalified FPP. This
is a last resort.
If the impurity is greater than the ICH qualification
threshold then it should be qualified:
55. If the impurity is greater than the ICH
qualification threshold then it should be
qualified:
56. By comparison to a limit specified in the Ph.Int., Ph.Eur.,
or USP for a specific impurity. It could even be in a
monograph for another substance. A statement in a
monograph of "any other impurity NMT 0.5%" can not be
used as justification for an impurity limit, as it is not
specific
If the impurity is greater than the ICH
qualification threshold then it should be
qualified:
57. The limit for any
unspecified impurity
should be at the ICH
identification threshold.
The limit for total
impurity content should
reflect batch data.
61. Any component of the
medicinal product which
is not the chemical entity
defined as the active
substance or an excipient
of the product
Impurity
62. Any component of the
medicinal product which
is not the chemical entity
defined as the active
substance or an excipient
of the product
Impurity
An impurity for which
structural
characterisation has been
achieved
Identified Impurity
63. Any component of the
medicinal product which
is not the chemical entity
defined as the active
substance or an excipient
of the product
Impurity
An impurity defined
only by qualitative
properties e.g. Rt
Unidentified
Degradation Product
An impurity for which
structural
characterisation has been
achieved
Identified Impurity
66. If a manufacturer controls impurity
content in accordance with a pharmacopoeial monograph,
Can we accept the specifications?
Yes/No
67. Unfortunately NO
Monographs are developed based upon how the API was prepared
historically.
If a manufacturer controls impurity
content in accordance with a pharmacopoeial monograph,
Can we accept the specifications?
68. Remember
A particular manufacturing method may lead to unexpected
impurities, due to a different route of synthesis, different reagents,
etc.
If a manufacturer controls impurity
content in accordance with a pharmacopoeial monograph,
Can we accept the specifications?
71. Preparation and potency determination/specification of primary and
secondary (working) standards, with CoAs
Analytical methods with validation
Impurities to be characterised and limits set
Synthesis/ degradation according to Q3A(R) Residual solvents according to Q3C
Requires justification for proposed specifications
72. Impurities
Moisture content (or LOD: moisture + residual solvents)
Identification (at least one specific, e.g. IR spectrum)
Appearance/description
Typical set of specifications
73. Residual solvent(s)
Inorganic impurities, including
catalysts
Related organic substances (synthesis
degradation)
specified unspecified
total organic
impurities
Impurities
Additional parameters
important for specific API
such as particle size,
polymorphic form,
microbial limits
Assay
74. • The current monograph always applicable
• Additional critical specifications that are not included in
monograph e.g.
– Particle size & polymorphic form
– Synthesis related impurities resulting from specific
process which may be additional to monograph
– Residual solvents (specific to process)
CEP normally states tests additional to the monograph
– e.g. residual solvents & impurities