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
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)
Residual solvents
USP <467>
ICH Q3C
Classification of Residual Solvents by Risk Assessment
Options for Determining Levels of Class 2 Residual Solvents
Methods For Establishing Exposure Limits
Analytical Procedures
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
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)
Residual solvents
USP <467>
ICH Q3C
Classification of Residual Solvents by Risk Assessment
Options for Determining Levels of Class 2 Residual Solvents
Methods For Establishing Exposure Limits
Analytical Procedures
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.
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
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.
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.
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
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.
Residual Solvents, Their Limits and PDE A Reviewijtsrd
The objective of this Review Paper is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The Review Paper recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents. Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by practical manufacturing techniques. Nitin Thorat | Prof. Santosh Waghmare | Dr. Hemant Kamble "Residual Solvents, Their Limits and PDE: A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-5 , August 2022, URL: https://www.ijtsrd.com/papers/ijtsrd50465.pdf Paper URL: https://www.ijtsrd.com/pharmacy/other/50465/residual-solvents-their-limits-and-pde-a-review/nitin-thorat
Development and Validation of Analytical Methods for Simultaneous Spectrophot...ijtsrd
A simple, rapid UV Visible spectrophotometric method for the quantification of Pioglitazone hydrochloride and Glimepiride in bulk drug and tablet formulation was developed and validated. UV Visible spectrophotometric methods have been developed for the Derivative Spectrophotometric Method, of Pioglitazone and glimepiride in bulk and pharmaceutical dosage forms. the sampling wavelengths selected are 210 nm and 218 nm over the concentration ranges of 1.5 7.5 µg ml and 0.2 1.0 µg ml for pioglitazone and glimepiride respectively. Tejaswini Kande | Pallavi Dhekale | Supriya Khatal | Priyanka Borude "Development and Validation of Analytical Methods for Simultaneous Spectrophotometric Determination of Pioglitazone and Glimepiride by Derivative Method" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-4 | Issue-1 , December 2019, URL: https://www.ijtsrd.com/papers/ijtsrd29699.pdf Paper URL: https://www.ijtsrd.com/pharmacy/analytical-chemistry/29699/development-and-validation-of-analytical-methods-for-simultaneous-spectrophotometric-determination-of-pioglitazone-and-glimepiride-by-derivative-method/tejaswini-kande
A major part of Big Data collected in most industries is in the form of unstructured text. Some examples are log files in IT sector, analysts reports in the finance sector, patents, laboratory notes and papers, etc. Some of the challenges of gaining insights from unstructred text is converting it into structured information and generating training sets for machine learning. Typically training sets for supervised learning are generated through the process of human annotation. In case of text this involves reading several thousands to million lines of texts by subject matter experts. This is very expensive and may not always be available, hence it is important to solve the problem of generating training sets before attempting to build machine learning models. Our approach is to combine rule based techniques with small amounts of SME time to by pass time consuming manual creation of training data. Once we have a good set of rules mimicking the training data we will use them to create knowledgebases out of the structured data. This knowledgebase can be further queried to gain insight on the domain. I have applied this technique to several domains, such as data from drug labels and medical journals, log data generated through customer interaction, generation of market research reports, etc. I will talk about the results in some of these domains and the advantage of using this approach.
Part A: To developed analytical (UV) method for determination of TOPIRAMATE in bulk and in oral solid dosage form.
Part B: To validate developed method as per ICH guidelines for parameters:
COLORIMETRY
It is the science & technology used to quantify & describe physically the Human color perception.
selection of drug
1. Drugs which not have strong UV absorbance.
2. Drugs for which Colorimetric methods are not available.
3. Drugs for which methods are available but they are time consuming & complex.
Eg. Dicloxacillin, Topiramate etc.
conclusion
Colorimetric method was developed and validated as per ICH guidelines for estimation of Topiramate in tablets.
Development of color is by reaction of amino group of drug with Ninhydrin reagent in presence of pyridine.
The method was found to be simple, accurate, precise and specific.
So, the proposed method can be used for the routine quality control analysis of the bulk drug as well as oral dosage forms.
Dr. Roger Saltman - The NIAA Effort: Learning from the June RoundtableJohn Blue
The NIAA Effort: Learning from the June Roundtable - Dr. Roger Saltman, Group Director, Cattle and Equine Technical Services, Zoetis, from the 2016 NIAA Antibiotic Symposium - Working Together For Better Solutions, November 1 - 3, 2016, Herndon, Virginia, USA.
More presentations at http://www.swinecast.com/2016-niaa-symposium-antibiotic-use-working-together-for-better-solutions
This high performance liquid chromatograph (HPLC) is the first-ever instrument designed specifically for quantitative determination of cannabinoid content. Ready for use after one day of installation and testing, it provides a choice of three different HPLC methods and a dedicated user interface for a simplified workflow.
NDSRIs - Nitrosamine Drug Substance-Related Impurities (NDSRIs)Chandra Prakash Singh
NDSRIs impurities share structural similarity to the API (having the API or API fragment in the chemical structure) and are therefore unique to each API.
NDSRIs generally form in the drug product through nitrosation of APIs (or API fragments) that have secondary or tertiary amines when exposed to nitrosating agents such as residual nitrites in excipients used to formulate the drug product.
Generally, the presence of high levels of NDSRIs has been associated with drug products rather than APIs because NDSRI formation usually results from a reaction between the API or API fragment and nitrosating agents in the drug formulation.
However, NDSRIs can potentially form in APIs when nitrosating agents are present in the API manufacturing process or when APIs undergo processing steps that can potentially induce their formation such as fluid bed drying at an elevated temperature and jet milling because these can create favorable conditions in which nitrogen oxides can react with at-risk APIs.
NDSRIs often lack carcinogenicity and mutagenicity study data (typically from animal studies) from which an AI limit can be determined.
This guidance provides a recommended methodology for AI limit determination that uses structural features of NDSRIs to generate a predicted carcinogenic potency categorization and corresponding recommended AI limit that manufacturers and applicants can apply, in the absence of other FDA recommended AI limits, in their evaluations of approved and marketed drug products as well as products in development or under review by FDA.
Currently Identified Risk Factors for Presence of Nitrosamines.pptxChandra Prakash Singh
N-Nitrosamines can be formed when an amine and nitrosating agent are combined under favourable conditions although other generation pathways are also possible, such as e.g. oxidation and reduction processes from hydrazine-type compounds and N-nitro derivatives.
Root causes for N-nitrosamines in medicinal products identified to date can be grouped as risk factors linked exclusively with the manufacturing process and storage of active substance and/or as risk factors associated with manufacture and storage of the finished product.
Moreover, there are risk factors specifically linked to GMP aspects.
Basic Understanding of LCMS
Ion Optics Path and Parameters.
Mass spectrometry measures the mass-to-charge ratio of ions to identify unknown compounds, to quantify known compounds, and to provide information about the structural and chemical properties of molecules.
The mass spectrometer has a series of quadrupole filters that transmit ions according to their mass-to-charge (m/z) ratio.
When the energy of the accelerated electrons is higher than a certain threshold value (which depends on the metal anode), a second type of spectrum is obtained superimposed on top of the white radiation. It is called the characteristic radiation and is composed of discrete peaks.
The energy (and wavelength) of the peaks depends solely on the metal used for the target and is due to the ejection of an electron from one of the inner electron shells of the metal atom.
This results in an electron from a higher atomic level dropping to the vacant level with the emission of an X-ray photon characterised by the difference in energy between the two levels.
CHARACTERIZATION OF CRYSTALLINE AND PARTIALLY CRYSTALLINE SOLIDS BY X-RAY POWDER DIFFRACTION (XRPD)
USP <941>
Every crystalline phase of a given substance produces a characteristic X-ray diffraction pattern.
Diffraction patterns can be obtained from a randomly oriented crystalline powder composed of crystallites (crystalline regions within a particle) or crystal fragments of finite size.
Essentially three types of information can be derived from a powder diffraction pattern:
The angular position of diffraction lines (depending on geometry and size of the unit cell).
The intensities of diffraction lines (depending mainly on atom type and arrangement and preferred orientation within the sample.
Diffraction line profiles (depending on instrumental resolution, crystallite size, strain, and specimen thickness).
LCMS - Ion Optics Path and Parameters
Source and gas parameters: These parameters can change depending on the ion source used.
Compound parameters: These parameters consist mostly of voltages in the ion path. Optimal values for compound-dependent parameters vary depending on the compound being analyzed.
Resolution parameters: These parameters affect the resolution and calibration.
Detector parameters: These parameters affect the detector.
A divert valve allows you to switch portions of the mobile phase to waste before the mass spectrometer.
This is particularly important for the portion containing all the un-retained components – many of which are likely to be involatile and contaminate the source. If you really want to keep things clean use a divert valve to divert everything to waste except the compounds of interest.
The integrated diverter valve, which is located next to the ion source, can be plumbed in injector mode or diverter mode.
LCMS Interface
API techniques (ESI, APCI and APPI)
In LCMS, ions can be generated through either the continuous or pulsed (discontinuous) modes.
The three API techniques (ESI, APCI and APPI) that were introduced operates in the continuous mode, giving a constant flow/supply of ions to the MS.
On the other hand, the pulsed mode generates a discontinuous source of ions such as the Matrix-Assisted Laser Desorption/Ionization (MALDI).
Analytical control strategy - Part -4 : How the ACS Applies to the Product Lifecycle and How the modern concept of a lifecycle model can be applied to analytical procedures.
How the modern concept of a lifecycle model, which is based on process validation and described in ICH guidelines Q8, Q9, and Q10, can be applied to analytical procedures.
3. Calculation of concentration limits in ppm for Residual Solvent
Concentration (ppm) = ----------------
1000 X PDE
Dose
PDE =Permitted Daily Exposure, given in terms of mg/day.
Dose is given in g/day.
The concentration were calculated using equation by assuming a
product mass of 10 g administered daily.
4. Calculation of concentration limits in ppm for Residual Solvent
PDE = 4.1 mg per day, Dose = 10 g
Acetonitrile Limit (ppm) = ---------------- = --------------- = 410 ppm
1000 X PDE
Dose
1000 X 4.1
10
Example - Acetonitrile Limit Calculation
PDE = 4.1 mg per day, Dose = 20 g
Acetonitrile Limit (ppm) = ---------------- = --------------- = 205 ppm
1000 X PDE
Dose
1000 X 4.1
20
PDE = 4.1 mg per day, Dose = 5 g
Acetonitrile Limit (ppm) = ---------------- = --------------- = 820 ppm
1000 X PDE
Dose
1000 X 4.1
5
6. Option 1
The concentration limits in ppm stated in ICH/USP/Guidelines can be used. These
limits are considered acceptable for all substances, excipients or products.
Example 1 - Acetonitrile Limit Calculation
Component
Amount in
formulation (g)
Acetonitrile
Content (ppm)
Daily exposure
(mg)
Acetonitrile Limit
(4.1 mg/day)
Drug Substance 0.6 200 0.12 Pass as per option 1
Excipient 1 1.0 400 0.40 Pass as per option 1
Excipient 2 5.0 100 0.50 Pass as per option 1
Drug Product 6.6 155 1.02 Pass as per option 1
7. Component
Amount in
formulation (g)
Acetonitrile
Content (ppm)
Daily exposure
(mg)
Acetonitrile Limit
(4.1 mg/day)
Drug Substance 0.3 200 0.06 Pass as per option 1
Excipient 1 0.9 400 0.36 Pass as per option 1
Excipient 2 3.8 100 0.38 Pass as per option 1
Drug Product 5.0 160 0.80 Pass as per option 1
Component
Amount in
formulation (g)
Acetonitrile
Content (ppm)
Daily exposure
(mg)
Acetonitrile Limit
(4.1 mg/day)
Drug Substance 0.6 200 0.12 Pass as per option 1
Excipient 1 1.8 400 0.72 Pass as per option 1
Excipient 2 7.6 100 0.76 Pass as per option 1
Drug Product 10.0 160 1.60 Pass as per option 1
Option 1Example 2 - Acetonitrile Limit Calculation
Example 3 - Acetonitrile Limit Calculation
8. If all excipients and drug substances in a formulation meet the limits given in
Option 1, then these components may be used in any proportion. No further
calculation is necessary provided the daily dose does not exceed 10 g.
Products that are administered in doses greater than 10 g per day should be
considered under Option 2.
Therefore this option may be applied if the daily dose is not known or fixed.
Option 1
9. Option 2
Option 2 may be applied by adding the amounts of a residual solvent present in
each of the components of the drug product. The sum of the amounts of solvent
per day should be less than that given by the PDE.
Example 4 - Acetonitrile Limit Calculation
Component
Amount in
formulation (g)
Acetonitrile
Content (ppm)
Daily exposure
(mg)
Acetonitrile Limit
(4.1 mg/day)
Drug Substance 0.3 800 0.24 As per option 1=?
Excipient 1 0.9 400 0.36 Pass as per option 1
Excipient 2 3.8 800 3.04 As per option 1=?
Drug Product 5.0 728 3.64 Pass as per option 2
10. Component
Amount in
formulation (g)
Acetonitrile
Content (ppm)
Daily exposure
(mg)
Acetonitrile Limit
(4.1 mg/day)
Drug Substance 0.3 800 0.24 As per option 1 or 2 =?
Excipient 1 0.9 2000 1.80 As per option 1 or 2 =?
Excipient 2 3.8 800 3.04 As per option 1 or 2 =?
Drug Product 5.0 1016 5.08 As per option 1 or 2 =?
Option 2
Example 5 - Acetonitrile Limit Calculation
11. Option 2
In this example, the product meets neither the Option 1 nor the Option 2
limit according to this summation. The manufacturer could test the drug
product to determine if the formulation process reduced the level of
Acetonitrile.
If all of these steps fail to reduce the level of
residual solvent, in exceptional cases the
manufacturer could provide a summary of efforts
made to reduce the solvent level to meet the
guideline value, and provide a risk benefit
analysis to support allowing the product to be
utilized with residual solvent at a higher level.
If the level of Acetonitrile was not reduced during formulation to the allowed
limit, then the manufacturer of the drug product should take other steps to reduce
the amount of Acetonitrile in the drug product.
12. Than
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