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 

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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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FDA adds four tropical diseases to priority review voucher program to encourage drug development in areas of unmet need

Today, the U.S. Food and Drug Administration announced the addition of Lassa fever, chikungunya virus disease, rabies and cryptococcal meningitis to the list of tropical diseases. Applicants who submit applications for drug or biological products to prevent or treat these diseases may qualify for a tropical disease priority review voucher (PRV). A tropical disease PRV can be used to obtain priority review of a subsequent drug application that does not itself qualify for priority review.

August 23, 2018

Media Inquiries

  Theresa Eisenman
  301-796-2969

“Part of our work to protect and promote public health of Americans includes monitoring global diseases and pathogens and ensuring we have a robust pipeline of drugs and biologics to treat or prevent the spread of these infectious diseases. Today we’ve added four diseases to a program designed to encourage development of new drug and biological products to prevent or treat certain tropical diseases affecting millions of people throughout the world, including Lassa fever, which impacted more than 400 people during an outbreak in Nigeria earlier this year, killing over 100 people. Tropical diseases cause a significant health burden globally. Yet, there has been remarkably little progress over the past 50 years in drug and biologic development to treat and prevent these diseases,” said FDA’s Chief Scientist RADM Denise Hinton. “Although tropical diseases generally are uncommon in the United States, tourism, immigration and military operations are increasing the direct effect these diseases can have on the health of Americans. But because these diseases are found primarily in low- and lower-middle income countries, existing incentives have been insufficient to encourage the development of new and innovative drug and biological products. With the tropical disease priority review voucher program, Congress intended to stimulate development of drugs and biologics to prevent and treat infectious diseases for which there are no significant markets in developed nations and that disproportionately affect poor and marginalized populations.”

Today, the U.S. Food and Drug Administration announced the addition of Lassa fever, chikungunya virus disease, rabies and cryptococcal meningitis to the list of tropical diseases. Applicants who submit applications for drug or biological products to prevent or treat these diseases may qualify for a tropical disease priority review voucher (PRV). A tropical disease PRV can be used to obtain priority review of a subsequent drug application that does not itself qualify for priority review.

To be eligible for a tropical disease PRV, a drug application must meet the criteria in section 524 of the Federal Food, Drug, and Cosmetic Act. The criteria include that the application must be for the prevention or treatment of a “tropical disease.” Beyond the list of “tropical diseases” in the statute, the FDA can issue an order to designate additional diseases as “tropical diseases” if the agency determines that a disease has no significant market in developed nations and disproportionately affects poor and marginalized populations. Interested parties can submit additional disease candidates for designation to a public docket (FDA-2008-N-0567-0011) for the FDA’s consideration.

Products developed to treat or prevent Lassa fever, chikungunya virus disease, rabies and cryptococcal meningitis that meet the other criteria for eligibility can now qualify for tropical disease PRVs, hopefully helping to encourage development of safe and effective products for these harmful diseases.

USFDA has released GUIDANCE for Quality Attributes of *CHEWABLE TABLETS

Image result for Quality Attributes of *CHEWABLE TABLETS

 

*CQAs of CHEWABLE TABLETS (CT)*
USFDA has released GUIDANCE for Quality Attributes of *CHEWABLE TABLETS*
According to this latest guideline, FDA has recommended sponsor/applicant should also incorporate following CQAs:
*1. PATIENT ACCEPTABILITY*
Acceptable Taste, Mouthfeel & Aftertaste With-
*2. HARDNESS / BREAKING FORCE / CRUSHING STRENGTH*
Hardness of CTshould be kept  low  (i.e.  <12 kp).
A higher hardness  value  (e.g.,  >12 kp)  may  be  considered if  justified.  An example  of  such justification could be  demonstrating  significant disintegration and/or  reduction in hardness  of  such  tablets  following  brief  i.e.  30 seconds  in-vitro exposure to simulated saliva (1 mL) before chewing to ensure patient compliance without  GI  obstruction (choking in throat / blocking bowel movement) in the case if patient swallow tablet without chewing due to high hardness
*3. CHEWING DIFFICULTY INDEX*
CDI is a value derived from the relationship between two methods used for measuring tablet strength: diametral compression (diametrical tensile strength) and flexural bending (flexure tensile strength test), to ensure patient compliance without damage to teeth or dentures
CDI should be also evaluated before & after in-vitro exposure to 1 mL of simulated saliva for 30 seconds
*4. DISINTEGRATION & DISSOLUTION*
CT should  typically  meet the  same  disintegration  and dissolution specifications  as _IR  tablets_. In vitro DT & Dissolution testing  should be  conducted on  _intact_ chewable  tablets since  _it is  possible  that some  patients  might swallow  the  tablets  without chewing_.
*5. Others*
If functional coated particles are present in chewable tablet then applicant has to ensure its functionality even after chewing tablets.
////////////USFDA, GUIDANCE, Quality Attributes, CHEWABLE TABLETS

FDA approves new treatment Galafold (migalastat) for a rare genetic disorder, Fabry disease

New Drug Approvals

FDA approves new treatment for a rare genetic disorder, Fabry disease

The U.S. Food and Drug Administration today approved Galafold (migalastat), the first oral medication for the treatment of adults with Fabry disease. The drug is indicated for adults with Fabry disease who have a genetic mutation determined to be responsive (“amenable”) to treatment with Galafold based on laboratory data. Fabry disease is a rare and serious genetic disease that results from buildup of a type of fat called globotriaosylceramide (GL-3) in blood vessels, the kidneys, the heart, the nerves and other organs.

August 10, 2018

Release

The U.S. Food and Drug Administration today approved Galafold (migalastat), the first oral medication for the treatment of adults with Fabry disease. The drug is indicated for adults with Fabry disease who have a genetic mutation determined to be responsive (“amenable”) to treatment with Galafold based on laboratory data. Fabry…

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FDA approves first-of-its kind targeted RNA-based therapy Onpattro (patisiran) to treat a rare disease

New Drug Approvals

Image result for patisiranFDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease

First treatment for the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adult patients

The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment

Continue reading…

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August 10, 2018

Release

The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment…

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FDA approves new vaginal ring for one year of birth control

New Drug Approvals

FDA approves new vaginal ring for one year of birth control

The U.S. Food and Drug Administration today approved Annovera (segesterone acetate and ethinyl estradiol vaginal system), which is a combined hormonal contraceptive for women of reproductive age used to prevent pregnancy and is the first vaginal ring contraceptive that can be used for an entire year. Annovera is a reusable donut-shaped (ring), non-biodegradable, flexible vaginal system that is placed in the vagina for three weeks followed by one week out of the vagina, at which time women may experience a period (a withdrawal bleed). This schedule is repeated every four weeks for one year (thirteen 28-day menstrual cycles).

August 10, 2018

Release

The U.S. Food and Drug Administration today approved Annovera (segesterone acetate and ethinyl estradiol vaginal system), which is a combined hormonal contraceptive for women of reproductive age used to prevent pregnancy and is the…

View original post 378 more words