Peficitinib hydrobromide, ペフィシチニブ臭化水素酸塩

New Drug Approvals

1353219-05-2.pngStructure of PEFICITINIB HYDROBROMIDEimgChemSpider 2D Image | PEFICITINIB HYDROBROMIDE | C18H23BrN4O2

Peficitinib hydrobromide

ペフィシチニブ臭化水素酸塩

ASP015K,

Rheumatoid Arthritis

1H-Pyrrolo(2,3-b)pyridine-5-carboxamide, 4-((5-hydroxytricyclo(3.3.1.13,7)dec-2-yl)amino)-, hydrobromide (1:1), stereoisomer

4-{[(1R,2s,3S,5r)-5-Hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrobromide (1:1)

1H-Pyrrolo[2,3-b]pyridine-5-carboxamide, 4-[[(1R,3S)-5-hydroxytricyclo[3.3.1.13,7]dec-2-yl]amino]-, hydrobromide (1:1)

U55XHZ5X6P

Formula
C18H22N4O2. HBr
CAS
1353219-05-2 HBR
944118-01-8 BASE
Mol weight
407.3048

PMDA, 2019/3/26 JAPAN APPROVED, Smyraf

Image result for Peficitinib hydrobromide

Peficitinib hydrobromide is used in the treatment of Psoriasis and Rheumatoid Arthritis

Peficitinib (formerly known as ASP015K) is a pyrrolo[2,3-b]pyridine derivative orally administered once-daily JAK inhibitor in development for the treatment of Rheumatoid Arthritis. In preclinical studied Peficitinib inhibited JAK1 and JAK3 with IC50 of 3.9 and 0.7 nM, respectively. Peficitinib also inhibited IL-2-dependent T cell proliferation in vitro and STAT5 phosphorylation in vitro and ex vivo. Furthermore, Peficitinib dose-dependently suppressed bone destruction and paw swelling in an adjuvant-induced arthritis model in rats via prophylactic or therapeutic oral dosing regimens.In clinical trials, Peficitinib treatment prescribed at 50, 100 and 150 mg amounts each showed statistically significantly higher ACR20 response rates compared to the placebo and response…

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VNRX-7145

New Drug Approvals

str1

str1

CAS 1842399-68-1

MF C19 H26 B N O7

MW 391.22

2H-1,2-Benzoxaborin-8-carboxylic acid, 3,4-dihydro-2-hydroxy-3-[(1-oxopropyl)amino]-, (2-ethyl-1-oxobutoxy)methyl ester, (3R)-

The VNRX-7145 combination is now in Phase I studies to treat resistant urinary tract infections.

str1

VNRX-7145

PATENT

WO 2015191907

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015191907

ntibiotics are the most effective drugs for curing bacteria-infectious diseases clinically. They have a wide market due to their advantages of good antibacterial effect with limited side effects. Among them, the beta-lactam class of antibiotics (for example, penicillins, cephalosporins, and carbapenems) is widely used because they have a strong bactericidal effect and low toxicity.

[0005] To counter the efficacy of the various beta-lactams, bacteria have evolved to produce variants of beta-lactam deactivating enzymes called beta-lactamases, and in the ability to share this tool inter- and intra-species. These beta-lactamases are categorized as“serine” or“metallo” based, respectively, on presence of a key serine or zinc in the enzyme active site. The rapid…

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Prabotulinumtoxin A, プラボツリナムトキシンA

New Drug Approvals

>Botulinum Toxin Type A Sequence
MPFVNKQFNYKDPVNGVDIAYIKIPNVGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN
PPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGG
STIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGY
GSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPN
RVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKA
KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV
LNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFT
GLFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEE
ITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNG
KKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEA
AMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSG
AVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAK
VNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKA
MININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDK
VNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINI
GSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNN
EYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTIT
NNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELN
EKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPR
GSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQA
GVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAK
LVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL

Prabotulinumtoxin A

プラボツリナムトキシンA;

Db00083

Formula
C6760H10447N1743O2010S32
CAS
93384-43-1
Mol weight
149320.8333

AGN 191622 / ANT-1207 / ANT-1401 / ANT-1403 / NT 201

        • APPROVED , FDA 2019, Jeuveau, 2019/2/1

Image result for Prabotulinumtoxina

  • Purified botulinum toxin from Clostridium botulinum, purified from culture via dialysis and acid precipitation.
  • Originator Daewoong Pharmaceutical
  • Developer Daewoong Pharmaceutical; Evolus
  • Class Analgesics; Antidepressants; Antimigraines; Antispasmodics; Bacterial proteins; Bacterial toxins; Botulinum toxins; Eye disorder therapies; Muscle relaxants; Skin disorder therapies; Urologics
  • Mechanism of Action Acetylcholine inhibitors; Glutamate antagonists; Membrane transport protein modulators; Neuromuscular blocking agents
  • Marketed Glabellar lines
  • Phase III Muscle spasticity
  • Phase II/III Blepharospasm; Facial wrinkles
  • 27 Feb 2019 Evolus plans to launch prabotulinumtoxin A for Glabellar lines in USA (IM)
  • 01 Feb 2019 Registered for Glabellar lines in USA (IM)
  • 26 Nov 2018 Daewoong Pharmaceutical expects…

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FDA permits marketing of two devices that detect parathyroid tissue in real-time during surgery

FDA permits marketing of two devices that detect parathyroid tissue in real-time during surgery
Today, the U.S. Food and Drug Administration permitted marketing of two devices that provide real-time location of parathyroid tissue during surgical procedures such as thyroidectomy (surgery to remove all or part of the thyroid) and parathyroidectomy (surgery to remove one or more parathyroid glands).
“For some patients with parathyroid disease, treatment may mean a surgical procedure,” said Binita Ashar, M.D., director of the Division of Surgical Devices in the FDA’s Center for Devices and Radiological Health.  “Real-time identification of parathyroid tissue during surgery can provide surgeons… Continue reading.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624982.htm?utm_campaign=11022018_PR_FDA%20authorizes%20devices%20to%20detect%20parathyroid%20tissue%20in%20during%20surgery&utm_medium=email&utm_source=Eloqua

November 2, 2018

Release

Today, the U.S. Food and Drug Administration permitted marketing of two devices that provide real-time location of parathyroid tissue during surgical procedures such as thyroidectomy (surgery to remove all or part of the thyroid) and parathyroidectomy (surgery to remove one or more parathyroid glands).

“For some patients with parathyroid disease, treatment may mean a surgical procedure,” said Binita Ashar, M.D., director of the Division of Surgical Devices in the FDA’s Center for Devices and Radiological Health. “Real-time identification of parathyroid tissue during surgery can provide surgeons with valuable information to help preserve healthy tissue or to remove diseased tissue.”

Disorders in the parathyroid tissue, which is tissue that borders the thyroid gland, are usually treated by surgeries to remove part of the thyroid gland or parathyroid tissue. Hyperparathyroidism, or the overproduction of parathyroid hormone, is the most common of parathyroid disorders and is diagnosed in approximately 100,000 Americans each year. For surgeons treating hyperparathyroidism or other disorders, parathyroid tissue can be visually difficult to locate and distinguish from nearby tissues during a surgery.

The Fluobeam 800 Clinic Imaging Device is used to assist in the imaging of parathyroid glands and can be used as a companion method to assist surgeons in locating parathyroid tissue visually during surgery. Parathyroid tissue emits a fluorescent glow when exposed to the device’s light source, avoiding the need for a contrast agent. The device was previously cleared as an imaging system used to capture and view fluorescent images for the visual assessment of blood flow as an adjunctive method for the evaluation of tissue perfusion.

The Parathyroid Detection PTeye System aids in detecting parathyroid tissue during surgery by using a probe that emits fluorescence light. Tissue detection is based on how the parathyroid tissue reacts to the fluorescent light. When parathyroid tissue is detected, the system provides an audio and visual display to indicate its presence.

Use of either device is intended to assist, not replace, experienced visual assessment in identifying the parathyroid tissue along with a biopsy to confirm thyroid tissue per standard of care. The systems are not intended to be used to confirm the absence of parathyroid tissue or glands and are only to be used to assist the surgeon in locating potential parathyroid tissue or glands.

For the Fluobeam 800, the FDA reviewed data from five peer-reviewed published studies, including one study that compared the rate of postoperative hypocalcemia (PH), or a temporary reduction in calcium in the blood, that occurs when healthy parathyroid tissue is inadvertently removed. In 93 patients who had surgery using the device, 5 percent experienced fluctuating PH following surgery compared with 21 percent of the 153 patients who had surgery without the device.

For the PTeye System, the FDA reviewed data from a single-blinded study of 81 patients who had surgery using the device. Results demonstrated that the PTeye could correctly identify the presence of parathyroid tissue as compared to histology 93 percent of the time and correctly identify the absence of parathyroid tissue as compared to intraoperative visualization by an expert 97 percent of the time, with an overall accuracy of 96 percent.

The Fluobeam 800 and the PTeye were reviewed separately but concurrently under the FDA’s De Novo premarket review pathway, a regulatory pathway for some low- to moderate-risk devices that are novel and for which there is no prior legally marketed device.

The FDA granted marketing authorization of The Fluobeam 800 Clinic Imaging Device to Fluoptics.

The FDA granted marketing authorization of Parathyroid Detection PTeye System to AiBiomed.

///////////////FDA, marketing, devices, parathyroid tissue, surgery, marketing authorization, Parathyroid Detection PTeye System, AiBiomed.

Statement from FDA Commissioner Scott Gottlieb, M.D., on findings from the romaine lettuce E. coli O157:H7 outbreak investigation and FDA’s efforts to prevent future outbreaks

tatement from FDA Commissioner Scott Gottlieb, M.D., on findings from the romaine lettuce E. coli O157:H7 outbreak investigation and FDA’s efforts to prevent future outbreaks

Earlier this year, we experienced the largest E. coli O157:H7 outbreak the country has seen in the last decade, leaving hundreds sick and claiming the lives of five people who consumed contaminated romaine lettuce.
We’re committed to taking necessary actions to prevent future outbreaks like this and to improving the safety of leafy greens available in the marketplace. Since the next romaine growing season for the Yuma region is underway, it’s critical for all of us to understand what happened so we can identify the changes that can prevent future outbreaks and reduce the scope of any problems that could arise.
Since the first signs of the outbreak appeared…Continue reading

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624867.htm?utm_campaign=11012018_Statement_findings%20from%20the%20romaine%20lettuce%20E.%20coli%20O157%3AH7&utm_medium=email&utm_source=Eloqua

November 1, 2018

Statement

Earlier this year, we experienced the largest E. coli O157:H7 outbreak the country has seen in the last decade, leaving hundreds sick and claiming the lives of five people who consumed contaminated romaine lettuce.

We’re committed to taking necessary actions to prevent future outbreaks like this and to improving the safety of leafy greens available in the marketplace. Since the next romaine growing season for the Yuma region is underway, it’s critical for all of us to understand what happened so we can identify the changes that can prevent future outbreaks and reduce the scope of any problems that could arise.

Since the first signs of the outbreak appeared, our team has collaborated closely with our state, federal and local partners to determine the root cause of the outbreak. Today, the U.S. Food and Drug Administration is sharing an environmental assessment that details final findings from this investigation.

One of the investigation’s main objectives was to identify factors that potentially contributed to the introduction and spread of the strain of E. coli O157:H7 that contaminated the romaine lettuce associated with this outbreak. The FDA, the Centers for Disease Control and Prevention, and the Arizona Department of Agriculture launched an investigation of the outbreak, leading to the collection of samples in Yuma in order to help gather evidence needed to identify the source of the outbreak.

The environmental assessment issued today confirms the presence of E. coliO157:H7 in three samples of irrigation canal water collected as part of this investigation in the Yuma region. It considers that the most likely way the romaine lettuce became contaminated was from the use of water from the irrigation canal, since the outbreak strain was not found in any of the other samples collected in the region. How the water contaminated the lettuce is uncertain. But based on interviews with growers and pesticide applicators, possible explanations include direct application of irrigation canal water to the lettuce crop or the use of irrigation canal water to dilute crop-protection chemicals applied to the crops through both aerial and land-based spray applications. We cannot rule out other ways the lettuce became contaminated. It’s important to note that we have no evidence that any other product grown in Yuma was contaminated by this water.

When and how the irrigation canal became contaminated with the outbreak strain of E. coli O157:H7 is also uncertain. We know that a large concentrated animal feeding operation (CAFO) is located adjacent to this stretch of the irrigation canal where the samples were collected. This is one potential source. However, the investigation did not identify an obvious route for contamination of the irrigation canal from this facility. In addition, samples collected at the CAFO did not yield E. coli O157:H7. The investigation did not exclude other ways the irrigation canal could have become contaminated with this outbreak strain.

With the growing season underway in Yuma, we know just how important it is to continue collaborating closely with industry and our regulatory partners to ensure that leafy greens are safe. To assist with these efforts, our environmental assessment recommends a number of steps that can be taken to reduce the likelihood of another tragic outbreak from occurring in the future. Working with the produce industry to further reduce the risk of outbreaks is a key priority for the FDA.

Fully implementing the Food Safety Modernization Act (FSMA) is critical to these efforts. We must continue to advance FSMA’s Produce Safety Rule in collaboration with our state regulatory partners and ensure that we craft agricultural water standards that work across the incredible diversity of commodities and growing conditions. The FDA has resources available to help industry comply with FSMA requirements, including produce safety experts regionally located as part of the FDA’s Produce Safety Network and growers in the Yuma region can find the contact information for their area at this website.

Because leafy greens are a highly perishable commodity, the ability to traceback the route of a food product as it moves through the entire supply chain, or traceability, is critical to removing the product from commerce as quickly as possible, preventing additional consumer exposures, and properly focusing any recall actions. During the romaine investigation we found the typical traceback process to be particularly challenging because much of the finished lettuce product contained romaine that was sourced from multiple ranches As a result, our investigation involved collecting documentation from each point in the supply chain to verify the movement of product back to the Yuma area. Complicating this already large-scale investigation, the majority of the records collected in this investigation were either paper or handwritten.

Going forward, both FDA and industry need to explore better ways to standardize record keeping and determine whether the use of additional tools on product packaging could improve traceability.

We strongly encourage the leafy greens industry to adopt traceability best practices and state-of-the-art technologies to help assure quick and easy access to key data elements from farm to fork. We also strongly encourage the leafy greens industry to explore modern approaches to standardized record keeping and the use of additional tools or labels on product packaging that could improve traceability. We urge all segments of this industry and our government partners to review the findings of our environmental assessment and make necessary changes. For our part, the FDA is exploring ways to best tap into new technologies to significantly reduce the time needed for traceback investigations.

The agency is taking steps to improve our response times and provide actionable information to consumers as quickly as possible. We are also looking at our regulatory options and considering appropriate enforcement actions against companies and farms that grow, pack, or process fresh lettuce and leafy greens under insanitary conditions. We continue to explore additional ways to improve these processes and urge all segments of the leafy greens industry to review their operations in the same way.

As a next step, the FDA plans to collect and analyze romaine lettuce samples through a new special surveillance sampling assignment for contamination with human pathogens. This will help us determine whether products are safe to enter the U.S. marketplace. If samples are found to be contaminated, the FDA will follow-up with fresh-cut leafy greens processors and their growers or suppliers to determine if these foods were produced under insanitary conditions that render them harmful to consumers and take the appropriate action to remove them from the market.

We recognize and appreciate the efforts that the leafy greens industry has taken to date. But we know more must be done on all fronts to help prevent future foodborne illness outbreaks. I remain committed to investing in the FDA’s food program and applying our food safety expertise as we work to better safeguard the U.S. food supply. We want food to be safe because it promotes the American industries that grow and produce these products. That’s part of our dedication to these efforts. But first and foremost, we pursue food safety measures as key parts of our public health mandate to protect American consumers

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FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin

FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin

The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of the blood thinner, warfarin, that certain test strips used with the devices may provide inaccurate results and should not be relied upon to adjust the drug dosage. Roche Diagnostics issued a voluntary recall of certain test strip lots used with its CoaguChek test meter devices. The recall involves more than 1.1 million packages of CoaguChek XS PT Test Strips that were distributed nationwide from Jan. 12, 2018 to Oct. 29, 2018. Today, the FDA announced this action as…Continue reading 

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624904.htm?utm_campaign=11012018_PR_FDA%20warns%20of%20inaccurate%20test%20results%20for%20device%20to%20monitor%20warfarin&utm_medium=email&utm_source=Eloqua

 

November 1, 2018

Release

The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of the blood thinner, warfarin, that certain test strips used with the devices may provide inaccurate results and should not be relied upon to adjust the drug dosage. Roche Diagnostics issued a voluntary recall of certain test strip lots used with its CoaguChek test meter devices. The recall involves more than 1.1 million packages of CoaguChek XS PT Test Strips that were distributed nationwide from Jan. 12, 2018 to Oct. 29, 2018. Today, the FDA announced this action as a Class I recall, the most serious type of recall, which means use of these devices may cause serious injuries or death.

The FDA is warning patients and health care professionals that they should not rely on these test meter devices to monitor warfarin levels if they’re using test strips affected by the recall. Instead, they should have blood drawn from a vein and have their levels measured by a laboratory test or use an alternative meter device.

“These strips are widely used and we are working diligently to warn health care providers and the public about the dangers associated with this recall. Using faulty strips can lead to serious errors in medication dosage that could cause serious harm or death in some patients,” said Jeffrey Shuren, M.D., director of the FDA’s Center for Devices and Radiological Health. “We are also working with the company on the swift removal of the recalled strips and to ensure the new corrected strips are distributed to patients and health care providers as quickly as possible.”

Millions of Americans take the blood thinner warfarin (also known by the brand names Coumadin and Jantoven) to prevent and treat blood clots. The drug may be prescribed for patients with certain types of irregular heartbeats, blood clots in the legs or lungs, or certain medical device implants such as artificial heart valves. Achieving the correct warfarin dosage is crucial, and patients need regular monitoring to test how long it takes their blood to clot. The response is measured by a blood test to check the International Normalized Ratio, or INR. This test can be performed by an accredited laboratory on blood drawn from a vein or with a fingerstick blood draw using an INR test meter at home or in a doctor’s office.

The FDA’s warning concerning the CoaguChek XS PT Test Strips is based on medical device reports submitted by Roche Diagnostics to the agency indicating that the test strips may provide results that are higher than the actual INR. As a result of incorrect INR results, some patients may be prescribed an insufficient warfarin dose or instructed to interrupt warfarin use, which may increase the risk for dangerous blood clots. Approximately 90 medical device reports and two serious patient injuries involving strokes were reported to the FDA.

Incorrect INR results are of particular concern for individuals at an increased risk of blood clots including those with mechanical heart valves, atrial fibrillation (irregular heartbeat) who are at a high risk of stroke, or those who had a recent blood clot. It is important to note that problems with the CoaguChek XS PT test strips are not likely to be evident to the patient.

Roche Diagnostics attributes the cause of the problem to a recent re-calibration of the test strips to a different international standard that occurred earlier this year. They plan to provide new batches of re-calibrated test strips, based on the previous international standard, to their customers by the end of November; the FDA reviewed validation data submitted by the company for these recalibrated strips. The test strips are used with the CoaguChek XS plus, CoaguChek XS Pro, CoaguChek XS professional, CoaguChek XS PST and CoaguChek Vantus test meter devices.

Patients who are using CoaguChek meters should contact their health care provider to get information about alternative test methods and to address questions regarding their individual testing schedule. Patients should also contact their patient self-testing service providers to find out when they will be getting their corrected test strips. Health care providers and patients may contact Roche Diagnostics to learn more details about the recall.

All health care providers, patients and caregivers, are strongly encouraged to voluntarily report INR test meter problems directly to the FDA through MedWatch, the FDA’s voluntary reporting program. Problems should be reported whenever one suspects that there may be an issue with an INR test meter such as a malfunction or incorrect result, or that the meter caused or contributed to a serious injury or death.

The FDA is committed to continuing to communicate publicly on this issue and will provide updates related to this recall when available.

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API, Impurities and Regulatory aspects

Image result for impurities
The impurities in pharmaceuticals are unwanted chemicals that remain with the active pharmaceutical ingredients (APIs) or develop during formulation or upon aging of both API and formulation. The presence of these unwanted chemicals even in trace amount may influence the efficacy and safety of pharmaceutical product
Impurities is defined as an entity of drug substances or drug product that is not chemical entity defined as drug substances an excipients or other additives to drugproduct.

The control of pharmaceutical impurities is currently a critical issue to the pharmaceutical industry. Structure elucidation of pharmaceutical impurities is an important part of the drug product development process. Impurities can have unwanted pharmacological or toxicological effects that seriously impact product quality and patient safety. Potential sources and mechanisms of impurity formation are discussed for both drugs. The International Conference on Harmonization (ICH) has formulated a workable guideline regarding the control of impurities. In this review, a description of different types and origins of impurities in relation to ICH guidelines and, degradation routes, including specific examples, are presented. The article further discusses measures regarding the control of impurities in pharmaceuticals substance and drug product applications.

Impurities in pharmaceuticals are the unwanted chemicals that remain with the active pharmaceutical ingredients (APIs), or develop during formulation, or upon aging of both API and formulated APIs to medicines. The presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the pharmaceutical products.

According to ICH, an impurity in a drug substance is defined as-“any component of the new drug substance that is not the chemical entity defined as the new drug substance”. There is an ever increasing interest in impurities present in APIs recently, not only purity profile but also impurity profile has become essential as per various regulatory requirements. The presence of the unwanted chemicals, even in small amount, may influence the efficacy and safety of the pharmaceutical products.

“In the pharmaceutical world, an impurity is considered as any other organic material, besides the drug substance, or ingredients, arise out of synthesis or unwanted chemicals that remains with API’s”

The control of pharmaceutical impurities is currently a critical issue to the pharmaceutical industry. The International Conference on Harmonization (ICH) has formulated a workable guideline regarding the control of impurities.

CLASSIFICATIONS OF IMPURITIES:
Impurities have been named differently or classified as per the ICH guidelines as follows:

A] Common names
1. By-products
2. Degradation products
3. Interaction products
4. Intermediates
5. Penultimate intermediates
6. Related products
7. Transformation products

B] United State Pharmacopeia
The United States Pharmacopoeia (USP) classifies impurities in various sections:
1. Impurities in Official Articles
2. Ordinary Impurities
3. Organic Volatile Impurities

C] ICH Terminology
According to ICH guidelines, impurities in the drug substance produced by chemical synthesis can broadly be classified into following three categories –
1. Organic Impurities (Process and Drug related)
2. Inorganic Impurities
3. Residual Solvents

Organic impurities may arise during the manufacturing process and or storage of the drug substance may be identified or unidentified, volatile or non-volatile, and may include
1. Starting materials or intermediates
2. By-products
3. Degradation products

Impurities are found in API’s unless, a proper care is taken in every step involved throughout the multi-step synthesis for example; in paracetamol bulk, there is a limit test for p-aminophenol, which could be a starting material for one manufacturer or be an intermediate for the others. Impurities can also be formed by degradation of the end product during manufacturing of the bulk drugs.

The degradation of penicillin and cephalosporin are well-known examples of degradation products. The presence of a β-lactam ring as well as that of an a-amino in the C6 or C7 side chain plays a critical role in their degradation.

The primary objectives of process chemical research are the development of efficient, scalable, and safe reproducible synthetic routes to drug candidates within the developmental space and acting as a framework for commercial production in order to meet the requirement of various regulatory agencies. Therefore, assessment and control of the impurities in a drug substance and drug product are important aspects of drug development for the development team to obtain various marketing approvals. It is extremely challenging for an organic chemist to identify the impurities which are formed in very small quantities in a drug substance and wearisome if the product is nonpharmacopeial. A study describes the formation, identification, synthesis, and characterization of impurities found in the preparation of API. A study will help a synthetic organic chemist to understand the potential impurities in API synthesis and thereby obtain the pure compound.
Care to taken ensure that desired drug metabolism, safety and clinical studies are not jeopardized by inconsistent purity or impurities having potential harmful toxicological properties,
As regulatory guidelines promulgated by the International Conference on Harmonization (ICH)(1) dictate rigorous identification of impurities at levels of 0.1%,
It is important to develop commercially viable processes for drug substance manufacture to allow greater and more affordable access in the health care sector. In regard to the process development of drug substances, it is essential to know the origin and method of control of any unwanted substances present in it. The limit should be controlled under the threshold of toxicological concern (TTC) for the purpose of ensuring safety and efficacy of the drug and to meet the requirements of various drug regulatory agencies.(2,3)
The impurities in drug substances mostly come from starting substrates, reagents, solvents, and side reactions of the synthetic route employed. Therefore, assessment and control of the undesired substances is an essential aspect of the drug development journey, with special consideration of patient health risk.(4,5)
The isolation/synthesis and characterization of process-related critical impurities (more difficult to control under the desired regulatory limits) of any drug substance in order to evaluate their origin/fate and thereafter their control strategies in the developed process as per International Council for Harmonisation (ICH) guidelines.(4)
The goal of pharmaceutical development is to develop process understanding and control which will yield procedures that consistently deliver products possessing the desired key quality attributes. To achieve this, the quality by design (QbD) paradigm has been employed in combination with process-risk assessment strategies to systematically gather knowledge through the application of sound scientific approaches.(6)
Ganzer et al. recently published an article about critical process parameters and API synthesis.(7) The article presented an in-depth discussion of a stepwise, process risk assessment approach to facilitate the identification and understanding of critical quality attributes, process parameters, and in-process controls. The primary benefit of working within the QbD conceptual framework and employing process risk assessment strategies is the reproducible delivery of high-quality active pharmaceutical ingredient (API). However, a secondary benefit is the ability to obtain regulatory flexibility with respect to filing requirements.(8)
The control of impurities observed in an API is critical in delivering an API of high quality. Identification and understanding of the mechanism of formation of process-related impurities are critical pieces of information required for the development of control strategies. In addition, to ensure a continuing supply of API for drug product clinical manufacture, timely identification of key impurities is essential. These synthesis-related impurities and their precursors are considered as critical impurities because they directly affect the quality and impurity profile of the API. It is our practice that critical impurities be identified if practicable. Therefore, the timely identification of critical impurities becomes an integral part of process development.
There are different approaches to the identification of impurities. Described, herein, a general strategy that we have used in our laboratory, which leads to the rapid identification of impurities. To identify the structure of a low-level unknown impurity, we usually use liquid chromatography/mass spectrometry (LC/MS)/high-resolution MS (HRMS) and tandem MS (MS/MS) for molecular weight (MW) determination, elemental composition, and fragmentation patterns. On the basis of the mass spectrometric data and knowledge of the process chemistry, one or more possible structure(s) may be assigned for the impurity, with definitive structure information obtained by inspection of the HPLC retention time, UV spectrum, and MS profile of an authentic compound.
If an authentic sample is not available, the isolation of a pure sample of the impurity is undertaken for structure elucidation using NMR spectroscopy. The isolation of low-level impurities is usually conducted using preparative HPLC chromatography
REFERENCES
 1 ICH Q3A Impurities in New Drug Substances, R2International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)Geneva, Switzerland, October 2006http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q3A_R2__Guideline.pdf.
  • 2. Patil, G. D.; Kshirsagar, S. W.Shinde, S. B.Patil, P. S.Deshpande, M. S.Chaudhari, A. T.Sonawane, S. P.Maikap, G. C.Gurjar, M. K.Identification, Synthesis, and Strategy For Minimization of Potential Impurities Observed In Raltegravir Potassium Drug SubstanceOrg. Process Res. Dev. 2012161422– 1429DOI: 10.1021/op300077m
  • 3. Huang, Y.; Ye, Q.Guo, Z.Palaniswamy, V. A.Grosso, J. A. Identification of Critical Process Impurities and Their Impact on Process Research and DevelopmentOrg. Process Res. Dev.200812632– 636DOI: 10.1021/op800067v

4. ICH Harmonised Tripartite Guideline Q3A(R): Impurities in New Drug SubstancesInternational Conference on HarmonizationGeneva2002.

5. Mishra, B.Thakur, A.Mahata, P. P. Pharmaceutical Impurities: A ReviewInt. J. Pharm. Chem.20155 (7), 232– 239

6 International Conference on Harmonisation (ICH) Guidelines; Q8, Pharmaceutical Development, 2005; Q9, Quality Risk Management, 2006.

GanzerW. R.MaternaJ. A.MitchellM. B.WallL. K. Pharm. Technol. 2005July 21–12.

NasrM. Drug Information Association Annual Meeting, Philadelphia, PA, June 19, 2006; Pharmaceutical Quality Assessment System (PQAS) in the 21st Century, 2006.

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