Right Team For The Right Job at The Right Time

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Here we are going to discuss about the manual for the Voluntary Use of HACCP Principles for Operators of Food Service and Retail Establishments

FDA endorses the voluntary implementation of food safety management systems in retail and food service establishments. Combined with good basic sanitation, a solid employee training program, and other prerequisite programs, HACCP can provide you and your employees a complete food safety management system.

The goal in applying HACCP principles in retail and food service is to have you, the operator, take purposeful actions to ensure safe food. You and your regulatory authority have a common objective in mind – providing safe, quality food to consumers. Your health inspector can help you achieve this common objective, but remember that the ultimate responsibility for food safety at the retail level lies with you and your ability to develop and maintain an effective food safety management system.

Managing food safety should be as fully integrated into your operation as those actions that you might take to open in the morning, ensure a profit, or manage cash flow. By putting in place an active, ongoing system, made up of actions intended to create the desired outcome, you can achieve your goal of improving food safety. The application of the HACCP principles provides one system that can help you accomplish that goal.

This Manual will provide details on how to organize your products so that you can voluntarily develop your own food safety management system using HACCP principles. The HACCP plans that you will develop using this Manual, in combination with prerequisite programs (discussed in Chapter 3), will constitute a complete food safety management system. Partnering with your regulatory authority or other food safety professional is recommended, but the design, implementation, and success of your system rests with you.

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Drug Study Design

Before a new drug or biologic can be marketed, its sponsor must show, through adequate and well-controlled clinical studies, that it is effective. A well-controlled study permits a comparison of subjects treated with the new agent with a suitable control population, so that the effect of the new agent can be determined and distinguished from other influences, such as spontaneous change, “placebo” effects, concomitant therapy, or observer expectations. FDA regulations [21 CFR 314.126] cite five different kinds of controls that can be useful in particular circumstances:
placebo concurrent control
dose-comparison concurrent control
no-treatment concurrent control
active-treatment concurrent control, and
historical control
No general preference is expressed for any one type, but the study design chosen must be adequate to the task. Thus, in discussing historical controls, the regulation notes that, because it is relatively difficult to be sure that historical control groups are comparable to the treated subjects with respect to variables that could effect outcome, use of historical control studies has been reserved for special circumstances, notably cases where the disease treated has high and predictable mortality (a large difference from this usual course would be easy to detect) and those in which the effect is self-evident (e.g., a general anesthetic).

Placebo control, no-treatment control (suitable where objective measurements are felt to make blinding unnecessary), and dose-comparison control studies are all study designs in which a difference is intended to be shown between the test article and some control. The alternative study design generally proposed to these kinds of studies is an active-treatment concurrent control in which a finding of no difference between the test article and the recognized effective agent (active-control) would be considered evidence of effectiveness of the new agent. There are circumstances in which this is a fully valid design. Active-controls are usually used in antibiotic trials, for example, because it is easy to tell the difference between antibiotics that have the expected effect on specific infections and those that do not. In many cases, however, the active-control design may be simply incapable of allowing any conclusion as to whether or not the test article is having an effect.

There are three principal difficulties in interpreting active-control trials. First, active-control trials are often too small to show that a clinically meaningful difference between the two treatments, if present, could have been detected with reasonable assurance; i.e., the trials have a high “beta-error.” In part, this can be overcome by increasing sample size, but two other problems remain even if studies are large. One problem is that there are numerous ways of conducting a study that can obscure differences between treatments, such as poor diagnostic criteria, poor methods of measurement, poor compliance, medication errors, or poor training of observers. As a general statement, carelessness of all kinds will tend to obscure differences between treatments. Where the objective of a study is to show a difference, investigators have powerful stimuli toward assuring study excellence. Active-control studies, however, which are intended to show no significant difference between treatments, do not provide the same incentives toward study excellence, and it is difficult to detect or assess the kinds of poor study quality that can arise. The other problem is that a finding of no difference between a test article and an effective treatment may not be meaningful. Even where all the incentives toward study excellence are present, i.e., in placebo-controlled trials, effective drugs are not necessarily demonstrably effective (i.e., superior to placebo) every time they are studied. In the absence of a placebo group, a finding of no difference in an active-control study therefore can mean that both agents are effective, that neither agent was effective in that study, or that the study was simply unable to tell effective from ineffective agents. In other words, to draw the conclusion that the test article was effective, one has to know with assurance that the active-control would have shown superior results to a placebo, had a placebo group been included in the study.

For certain drug classes, such as analgesics, antidepressants or antianxiety drugs, failure to show superiority to placebo in a given study is common. This is also often seen with antihypertensives, anti-angina drugs, anti-heart failure treatments, antihistamines, and drugs for asthma prophylaxis. In these situations, active-control trials showing no difference between the new drug and control are of little value as primary evidence of effectiveness and the active-control design (the study design most often proposed as an alternative to use of a placebo) is not credible.

In many situations, deciding whether an active-control design is likely to be a useful basis for providing data for marketing approval is a matter of judgment influenced by available evidence. If, for example, examination of prior studies of a proposed active-control reveals that the test article can very regularly (almost always) be distinguished from placebo in a particular setting (subject population, dose, and other defined parameters), an active-control design may be reasonable if it reproduces the setting in which the active-control has been regularly effective.

It is often possible to design a successful placebo-controlled trial that does not cause investigator discomfort nor raise ethical issues. Treatment periods can be kept short; early “escape” mechanisms can be built into the study so that subjects will not undergo prolonged placebo-treatment if they are not doing well. In some cases randomized placebo-controlled therapy withdrawal studies have been used to minimize exposure to placebo or unsuccessful therapy; in such studies apparent responders to a treatment in an open study are randomly assigned to continued treatment or to placebo. Subjects who fail (e.g., blood pressure rises, angina worsens) can be removed promptly, with such failure representing a study endpoint.

IRBs may face difficult issues in deciding on the acceptability of placebo-controlled and active-control trials. Placebo-controlled trials, regardless of any advantages in interpretation of results, are obviously not ethically acceptable where existing treatment is life-prolonging. A placebo-controlled study that exposes subjects to a documented serious risk is not acceptable, but it is critical to review the evidence that harm would result from denial of active treatment, because alternative study designs, especially active-control studies, may not be informative, exposing subjects to risk but without being able to collect useful information.

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FDA underscores that consumers should not use drugs, dietary supplements and devices recalled from Basic Reset and Biogenyx following consent decree for federal violations

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Here we are going to discuss about the recent drug alert

The U.S. Food and Drug Administration is alerting consumers of a recall of 25 drug, dietary supplement and medical device product lines distributed by Basic Reset and Biogenyx of Hendersonville, Tennessee. In September, a federal court entered a consent decree of permanent injunction between the United States and the two companies and their owner, Fred R. Kaufman III. Under the consent decree, Basic Reset and Biogenyx must recall and stop distributing products until the companies comply with the Federal Food, Drug, and Cosmetic Act and other requirements listed in the consent decree.

Basic Reset and Biogenyx products that have been recalled include drugs such as Earth Wash and Ionyte, as well as dietary supplements Mello-Tonin and Body Mass Reset and device Energy FX among others. Basic Reset and Biogenyx issued recall notices by email to their customers on Sept. 23 and Oct.18, requesting disposal or return to the place of purchase for products sold, purchased or distributed after Nov. 7, 2017. Given these products do not comply with appropriate FDA standards, they have the potential to be unsafe or ineffective for their particular uses, and could lead to adverse health impacts. The FDA is reminding consumers who may still have these products not to use them and distributors not to sell any of the recalled products as they do not meet FDA regulations.

“The FDA’s laws are designed to protect the public health by ensuring, among other things, that drugs and medical devices are safe and effective for their intended uses and that dietary supplements are manufactured and distributed appropriately,” said Melinda K. Plaisier, FDA Associate Commissioner for Regulatory Affairs. “All companies must follow the appropriate standards and are given the opportunity to ensure their actions are in accordance with these laws. We will continue to prevent the distribution of products that do not comply with applicable FDA requirements and ultimately place the public health at risk.”

Basic Reset and Biogenyx have not received the FDA’s approval for the sale of their drugs and one device, despite the companies’ claims that these products can be used to diagnose, cure, mitigate, treat or prevent conditions such as inflammation, chronic diarrhea, bacterial infections, head lice, allergies and pain. Consumer use of an unapproved product that claims to treat diseases may cause them to delay seeking appropriate medical care. Additionally, unapproved products have not been reviewed by the FDA for quality, safety or effectiveness. Basic Reset and Biogenyx also unlawfully distributed dietary supplements that are adulterated and misbranded.

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Final Rule to Collect Antimicrobial Sales and Distribution Information by Animal Species

December 10, 2019 Duraimurugan Anbalagan

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Here we are going to discuss about the final rule to collect Antimicrobial Sales and Distribution information by Animal Species

The FDA has issued a final rule to obtain more detailed information about antimicrobials sold or distributed for use in food-producing animals by including estimates of sales data by species. The additional data will improve understanding about the extent to which antimicrobials are sold or distributed for use in major food-producing species and help the FDA further target its efforts to ensure judicious use of medically important antimicrobials. It will also assist the agency in measuring the effectiveness of those efforts.

The final rule requires animal drug sponsors to submit species-specific estimates of antimicrobial sales for cattle, swine, chickens, and turkeys. The final rule also includes a provision to improve the timeliness of FDA’s annual summary report of these sales data by requiring the FDA to publish its annual summary report of antimicrobial sales and distribution information by December 31 of the following year.

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BIOSIMILAR DRUGS

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Today We are going to review the benefits and concerns on biosimilar drugs

Pathway for approvals was initiated in 2009.

Ten years later (or less than five years since the first FDA approval of a biosimilar), and just 42% (11 out of 26) of FDA-approved biosimilars have launched. But in the next three months , a clutch of new biosimilars will hit the market, including new ones in oncology, hinting at a wave of uptake.

For instance, Pfizer is expected to launch three biosimilars soon: one for Avastin (bevacizumab) later this month, one for Rituxan (rituximab) next month, and one in February for Herceptin (trastuzumab). Two other trastuzumab biosimilars may also launch soon, which would mean more than 60% of biosimilars approved in the US will have launched by early next year.

The rising number of launches, combined with an increasing amount of quick uptake, may put biosimilar foes on their heels.

For instance, Neulasta (pegfilgrastim) biosimilars have found recent success, with Coherus’ Udenyca (pegfilgrastim-cbqv) and Mylan and Biocon’s Fulphila (pegfilgrastim-jmdb) capturing 25% market share in just over a year, according to a report released last week from Bernstein.

Similarly, a sign of rapid uptake can be seen with Amgen’s Mvasi (bevacizumab-awwb), which has captured 10% of the Avastin market in just four months.

“Biosimilars are growing their market share and leading to meaningful price erosion over time; with the more recent biosimilar launches showing a lot of success – reflecting perhaps the growing market sophistication of the biosimilar companies,” former FDA Commissioner Scott Gottlieb, referring to the Bernstein report, noted recently.

And in the future, Humira (adalimumab) and Enbrel (etanercept) biosimilars (seven approved, zero launched int he US) may look more like outliers in a larger pool of approvals and subsequent launches. By contrast, in the EU, Humira biosimilars have already captured 35% of the multi-billion-dollar market in one year, and biosimilars have captured 50% of the Enbrel market in about three years, according to Bernstein.

The US Remicade (infliximab) biosimilar market is also an eyesore (Bernstein refers to it as “essentially a failed market”) as the two biosimilar entrants have only amassed 12% market share in more than two years. Amgen’s infliximab biosimilar was recently approved last week and may hit the market soon. And Johnson & Johnson said the Federal Trade Commission has launched an investigation into its contracting practices for Remicade, although similar investigations in Canada and the UK yielded little.

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FDA Provides Flexibility for Start of Routine Inspections on Small Farms

December 9, 2019 Duraimurugan Anbalagan

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Here we are going to discuss about flexibility for Start of Routine Inspection on small farms

The U.S. Food and Drug Administration is providing flexibility for when states may begin conducting routine inspections of small farms, other than sprouts operations, under the Food Safety Modernization Act (FSMA) Produce Safety Rule.

Routine inspections of small farms, other than sprouts operations, subject to the Produce Safety Rule, will generally begin in Spring 2020; however, the FDA is clarifying that states receiving competition A/B funding as part of the State Produce Implementation Cooperative Agreement Program (CAP) may begin routine inspections as early as January 1, 2020. This clarification is being made after several requests from states to have greater flexibility to align routine inspections with the winter growing season where applicable. Individual states will make final decisions on whether to initiate their first routine inspections of small farms at the earlier date in January 2020. States that want to begin routine inspections of small farms, other than sprouts operations, on January 1, 2020, should prioritize completing their planned inspections of large farms subject to the rule before conducting routine inspections of those small farms.

The major compliance date for small farms, other than sprouts operations, subject to the Produce Safety Rule arrived on January 28, 2019; however, FDA had previously announced that routine inspections would not begin until Spring 2020. The delayed start to routine inspection follows a similar delay for the start of routine inspections of large farms (other than sprout operations), both done to provide the FDA and its state partners additional time to conduct education and outreach.

On Farm Readiness Reviews (OFRR), offered in collaboration with the National Association of State Departments of Agriculture (NASDA), will continue to serve as a helpful tool to farmers as they determine how prepared they are to comply with the requirements of the Produce Safety Rule.

Additional information about inspections, the rule and any related resources can be found on the Produce Inspections webpage at FDA.gov.

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MUTUAL RECOGNITION AGREEMENT (MRA) FROM A GLOBAL PERSPECTIVE

December 8, 2019 Duraimurugan Anbalagan

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Here we are going to measuring the Impact of the Pharmaceutical Annex to the U.S./EU Mutual Recognition Agreement

When we first began discussing the prospects of a mutual recognition agreement with the European Union, in which EU member state (EUMS) regulators and the FDA would agree to rely on each other’s factual findings from their good manufacturing practice (GMP) inspections of drug facilities, the potential benefits seemed obvious.

European drug makers to benefits from MRA

By relying on each other’s expertise and ability to conduct GMP inspections under the Pharmaceutical Annex to the U.S./EU Mutual Recognition Agreement, we expected to avoid duplicate inspections of the same facilities, especially for facilities with a strong record of compliance. And these efficiencies would allow us to reallocate our inspectional resources to areas of higher risk. Of course, we knew we would have to wait until the agreement was implemented before we could confirm these assumptions.

Developing the MRA took time and resources. Beginning in 2014, FDA experts were sent to Europe to observe EU officials audit each of the 28 EUMS inspectorates to assure that they could conduct inspections at a standard similar to a U.S. inspection. In addition, we had to establish confidentiality commitments with each regulator to allow for the sharing of non-public information contained in inspection reports and be assured that each EUMS had a framework for preventing conflicts of interest that provided a similar level of protection as those in place at FDA. The FDA completed this work for the most common type of drug manufacturing inspections in July 2019.

The FDA and the EU have been collecting data on the operational impact of the MRA ever since the first countries were found capable on November 1, 2017, and the numbers are quite promising. So far the EU has conducted 29 inspections at FDA’s request and the FDA has conducted 14 inspections at the EU’s request. Moreover, FDA has deferred 157 inspections in the EU after review of the inspectional information provided by our trusted partners. We anticipate seeing an even greater impact now that the MRA has been implemented in all 28 EU countries for human drug products.
The need for such metrics was one of the recommendations from the National Academies of Sciences, Engineering, and Medicine (NASEM) in a recent report. FDA had asked an Ad Hoc NASEM committee to examine mutual recognition and mutual reliance agreements around the world (some dating back many years) and the committee found a surprising lack of data on the successes and challenges of these programs. To address that information gap, the committee called on regulatory authorities to create a results framework with clear indicators, metrics, and processes for monitoring and evaluating these programs. Such information would increase understanding of the program’s public health benefits and enable benefit-risk analyses over time, the report’s authors said.

We certainly agree that more data is needed on the U.S./EU MRA, beyond the operational data we’re collecting now. In fact, we’re working with our EU partners to explore what additional metrics might be informative. Having sufficient data will help the FDA decide not only how to allocate our inspectional resources, but also the scope and breadth of future mutual recognition and mutual reliance agreements that might include other categories of inspections and product types, such as veterinary medicines. Since these other categories often involve different inspectorates in Europe than those audited for human pharmaceuticals, implementation could take some time. Yet, eventually, with metrics in place, we could confirm their benefits as well, allowing manufacturers to avoid unneeded inspections while ensuring that medicines are safer for patients.

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FDA Issues Draft Guidance on Performance Criteria for Magnetic Resonance (MR) Coils

December 8, 2019 Duraimurugan Anbalagan

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Here we are going to discuss about the recent draft guidance on performance criteria for MR Coils

Facts about the draft guidance
This draft guidance is intended to provide performance criteria for magnetic resonance (MR) coils in support of the Safety and Performance Based Pathway.

Under the Safety and Performance Based Pathway, medical device manufacturers planning to submit a 510(k) will have the option to use the performance criteria as identified in a final guidance to support substantial equivalence, rather than direct comparison of the performance of the subject device to that of a predicate device.

What is MR Coils

Framework for the Safety and Performance Based Pathway
Overview
There are three types of Premarket Notification 510(k)s that may be submitted to FDA: Traditional; Special; and Abbreviated. The Special and Abbreviated 510(k) programs were developed in 1998 and described in the “New 510(k) Paradigm” to facilitate the 510(k) review process for certain types of submissions subject to 510(k) requirements. In 2019, the FDA split “The New 510(k) Paradigm” into separate guidance documents; The Special 510(k) Program and The Abbreviated 510(k) Program. The Safety and Performance Based Pathway is an expansion of the concept of the Abbreviated 510(k) pathway for certain, well understood device types.
The FDA expects to operationalize this pathway once the first device types and applicable performance criteria have been identified and final guidances have been published. Once the FDA begins to operationalize this pathway, a medical device manufacturer will have the option to meet FDA-identified performance criteria to demonstrate that its device is as safe and effective as a predicate device. The use of this pathway does not affect the FDA’s ability to request any information authorized by the statute or regulations.

What device types are appropriate for the Safety and Performance Pathway?

The Safety and Performance Based Pathway is appropriate when FDA has determined that:

The new device has the same indications for use as, and technological characteristics that do not raise different questions of safety and effectiveness than the identified predicate; and

The new device meets all the FDA-identified performance criteria.

If any of the above factors are not met, the submitter has the option to submit a Traditional, Special or Abbreviated 510(k).

The FDA will issue future final guidance(s) to apply this Safety and Performance Based Pathway to certain types of devices with corresponding FDA-identified performance criteria. Industry and other stakeholders may suggest device types for which the FDA should consider identifying performance criteria. For example, industry may suggest devices for which there are comprehensive FDA-recognized consensus standards. We encourage industry and other stakeholders to submit evidence-based suggestions on what the performance criteria should be for eligible device types. Input can be provided using the docket number FDA-2018-D-1387 at http://www.regulations.gov.

The FDA intends to maintain a list of device types appropriate for the Safety and Performance Based Pathway on this website, accompanied by the guidance documents that identify the performance criteria for each device type, as well as the testing methods recommended in the guidances where feasible, and any other relevant information.

Content of a Safety and Performance Based 510(k)

The amount and type of information necessary to support a finding of substantial equivalence under the Safety and Performance Based Pathway will depend on the underlying source for the performance criteria and testing methods. Table 1 and the Appendix within the Safety and Performance guidance summarize the types of information that should be included in a submission based on the submitter’s approach.

Importantly, 510(k) submitters still need to identify a predicate for certain aspects of substantial equivalence. However, instead of conducting direct comparison testing to demonstrate that a device is as safe and effective as a predicate device, manufacturers will have the option to use this pathway to demonstrate substantial equivalence, when appropriate.

More information on content that should be included within a Safety and Performance Based 510(k) will be available in the device-specific guidances that will be issued.

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Impurities found in diabetes drugs outside the U.S

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Here we are going to discuss about the Statement from Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research, on impurities found in diabetes drugs outside the U.S

The U.S. Food and Drug Administration has been investigating the presence of genotoxic impurities, called nitrosamines, in some types of drugs. Over the past year and a half, several drug products including angiotensin II receptor blockers (ARBs) and ranitidine, commonly known as Zantac, have been found to contain small amounts of nitrosamines such as N-Nitrosodimethylamine (NDMA). During this time, there has been an ongoing investigation into the presence of nitrosamines in other drug products. This effort is focused on ensuring the drugs used by Americans continue to meet strict quality standards.

The FDA is aware that some metformin diabetes medicines in other countries were reported to have low levels of NDMA. Based on the information we have available, the levels of NDMA seen outside the U.S. are within the range that is naturally occurring in some foods and in water. While we are aware that some regulatory agencies outside the U.S. may be recalling some metformin drugs, there are no metformin recalls affecting the U.S. market at this time. The FDA is investigating whether metformin in the U.S. market contains NDMA, and whether it is above the acceptable daily intake limit of 96 nanograms. The agency will also work with companies to test samples of metformin sold in the U.S. and will recommend recalls as appropriate if high levels of NDMA are found. If as part of our investigation, metformin drugs are recalled, the FDA will provide timely updates to patients and health care professionals.

Metformin is a prescription drug used to control high blood sugar in patients with type 2 diabetes. Patients should continue taking metformin to keep their diabetes under control. It could be dangerous for patients with this serious condition to stop taking their metformin without first talking to their health care professional. The FDA recommends prescribers continue to use metformin when clinically appropriate, as the FDA investigation is still ongoing, and there are no alternative medications that treat this condition in the same way.

NDMA is a common contaminant found in water and foods including cured and grilled meats, dairy products and vegetables. Everyone is exposed to some level of NDMA. The FDA and the international scientific community do not expect it to cause harm when ingested at low levels. The acceptable daily intake limit for NDMA in the U.S. is 96 nanograms. Genotoxic substances such as NDMA may increase the risk of cancer if people are exposed to them above acceptable levels and over long periods of time, but a person taking a drug that contains NDMA at-or-below the acceptable daily intake limit every day for 70 years is not expected to have an increased risk of cancer.

Today, we have better testing methods than ever before, and we know what to look for in products’ chemical structure and manufacturing processes that may increase the risk of forming low levels of nitrosamines. Improved technology enables us to detect even trace amounts of impurities in drug products and may be the reason why more products have been found to have low levels of NDMA. The agency has strict standards for safety, effectiveness and quality, and our staff makes every effort to help keep the U.S. drug supply as safe as possible. We also work closely with international drug regulatory agencies so that we leverage resources and testing done outside the U.S. which can help inform testing of the U.S. drug supply. As our investigations and testing continues, along with the investigations done by other drug regulatory agencies, we may find low levels of nitrosamines in additional drugs.

1 Intestine: glucose absorption. 2 Muscle and adipose tissue: glucose uptake Metformin glucose utilization. Insulin resistance. Blood glucose. 4 Liver: hepatic. glucose output. Metformin HGO. Insulin resistance. 3 Pancreas: insulin secretion. ©1997 PPS. DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:

The FDA will continue to investigate the source of these impurities, but it is important to note that there are multiple reasons why NDMA can be present in drugs. Previously, we found the source of NDMA can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed. The FDA continues to test and research possible sources for the several drugs found to contain NDMA.

We are taking a systematic approach to identify medicines with nitrosamines above acceptable daily intake limits and remove them from the market. For example, yesterday we announced expanded testing requirements for ranitidine manufacturers to help give consumers confidence that the drugs on the market do not have NDMA above the acceptable daily intake limit.

Our investigations, including our current investigation of metformin, take into account the medical necessity of the drug, how many Americans may take it, and whether there may be alternative treatments available. The American public can expect that we will act quickly to address any issue as soon as we find out about it.

These investigations take time. We understand that these issues affect patients’ health and well-being in many ways, and the FDA’s goal is to provide patients and health care providers as much clarity and as many answers as possible to inform their health care decisions. The FDA will communicate any information we have scientifically confirmed to ensure the public knows as much as possible as soon as possible.

Protecting patients is the FDA’s highest priority, and Americans can be confident in the quality of the products the agency approves. We are patients too, and we’re committed to maintaining our high standards for quality, safety and efficacy for all drugs we, our families, friends, colleagues and millions of fellow Americans rely on for their health.

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FDA approves first generics of Gilenya

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Here we are going to discuss about the capsules for the treatment of relapsing forms of multiple sclerosis (MS) in adult patients

The U.S. Food and Drug Administration has approved three applications for first generics of Gilenya (fingolimod) capsules for the treatment of relapsing forms of multiple sclerosis (MS) in adult patients.

“Approving safe and effective generics so patients have more treatment options continues to be a priority for the FDA,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “Having access to affordable treatments is important for patients with conditions that require ongoing care. The FDA has a longstanding commitment to increasing patient access to lower-cost, high-quality generic medicines.”

MS is a chronic, inflammatory, autoimmune disease of the central nervous system that disrupts communication between the brain and other parts of the body. It is among the most common causes of neurological disability in young adults and occurs more frequently in women than men. For most people with MS, episodes of worsening function and appearance of new symptoms, called relapses or flare-ups, are initially followed by recovery periods (remissions). Over time, recovery may be incomplete, leading to progressive decline in function and increased disability. Gilenya is a widely used orally administered treatment option.

The most common side effects reported in the clinical trials for Gilenya include headache, elevation of liver enzymes, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain and pain in the extremities.

Fingolimod must be dispensed with a Medication Guide that contains important information about its uses and risks. Serious risks include slowing of the heart rate, especially after the first dose. Fingolimod may increase the risk of serious infections. Patients should be monitored for infection during treatment and for two months after discontinuation of treatment.

A rare brain infection that usually leads to death or severe disability, called progressive multifocal leukoencephalopathy (PML) has been reported in patients being treated with the drug. PML cases usually occur in patients with weakened immune systems. Fingolimod can cause vision problems. It may increase the risk for swelling and narrowing of the blood vessels in the brain (posterior reversible encephalopathy syndrome). Other serious risks include respiratory problems, liver injury, increased blood pressure and skin cancer. Fingolimod may cause harm to a developing fetus; health care professionals should advise women of child-bearing age of the potential risk to the fetus and to use effective contraception.

medical 3d illustration – female having backache

The FDA granted approvals of generic fingolimod applications to HEC Pharm Co. Limited, Biocon Limited and Sun Pharmaceutical Industries Limited.

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FDA authorizes marketing of diagnostic test that uses novel technology to detect MRSA bacteria

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The topic which we are going to discuss below is about MRSA (Methicillin-resistant Staphylococcus aureus)

On 5th Dec 2019, the U.S. Food and Drug Administration authorized marketing of a new diagnostic test based on bacterial viability and novel technology to detect Methicillin-resistant Staphylococcus aureus (MRSA) bacterial colonization, a widespread cause of hospital-acquired infections. The cobas vivoDx MRSA diagnostic test may allow health care professionals to evaluate patients for colonization with MRSA bacteria more quickly than traditional culture-based techniques when such testing is needed

“Diagnostics that are able to provide accurate results more quickly can offer health care providers an advantage when trying to prevent and contain the spread of resistant bacteria,” said Tim Stenzel, M.D., Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health. “Today’s authorization adds a new tool in the fight to prevent and control MRSA in high-risk settings. The FDA remains committed to supporting efforts to address antimicrobial resistance in order to better protect patients against this ongoing public health challenge.”

MRSA is a type of bacteria that can lead to serious illness, and even death, if a patient develops an infection. According to the Centers for Disease Control and Prevention (CDC), approximately 5% of U.S. hospital patients carry the MRSA bacteria, although many of those that carry the bacteria do not develop infections. MRSA has been defined as a serious antimicrobial resistant threat by the CDC. It is resistant to many common antibiotics, which means that if infections develop they can be very challenging to treat and control. The use of active screening to detect MRSA colonization and enable implementation of infection control measures has played an important role in reducing the rates of MRSA infection. The CDC estimates that there were more than 323,000 MRSA cases in hospitalized patients in the U.S. and more than 10,000 deaths in 2017.

The cobas vivoDx MRSA test uses a new bacteriophage technology based on bioluminescence to detect MRSA from nasal swab samples in as little as 5 hours compared to 24-48 hours for conventional culture. Diagnostic tests that can more quickly and easily detect MRSA could benefit patient care and may help healthcare providers prevent the spread of MRSA. The FDA reviewed data from performance studies in which the cobas vivoDx MRSA test correctly identified MRSA in approximately 90% of samples where MRSA was present and correctly identified no MRSA in 98.6% of samples that did not have MRSA present. The cobas vivoDx MRSA test authorized today is intended to aid in the prevention and control of MRSA infections in healthcare settings and can be used to identify patients needing enhanced precautions for infection control such as isolation and additional decolonization efforts.

The FDA reviewed the cobas vivoDx MRSA test through the de novo premarket review pathway, a regulatory pathway for low-to-moderate-risk devices of a new type. Along with this authorization, the FDA is establishing special controls for tests of this type, including requirements relating to labeling and design verification and validation to address certain risks, such as false positives. When met, the special controls, along with general controls, provide a reasonable assurance of safety and effectiveness for tests of this type. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) pathway, whereby devices can obtain clearance by demonstrating substantial equivalence to a predicate device.

The FDA granted marketing authorization of the cobas vivoDx MRSA test to Roche Molecular Systems Inc.

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FDA launches app for health care professionals to report novel uses of existing medicines for patients with difficult-to-treat infectious diseases

December 4, 2019 Duraimurugan Anbalagan

Welcome to Regulatory focus newsletter from FWQRC

Today’s review is about the recently launched application

The U.S. Food and Drug Administration today announced the global launch of CURE ID, an internet-based repository that will allow the clinical community to report their experiences treating difficult-to-treat infectious diseases with novel uses of existing FDA-approved drugs through a website, a smartphone or other mobile device. The platform enables the crowdsourcing of medical information from health care providers to guide potentially life-saving interventions and facilitate the development of new drugs for neglected diseases. The repository is a collaboration between the FDA and the National Center for Advancing Translational Sciences (NCATS), which is part of the National Institutes of Health (NIH).

“The CURE ID application focuses on drugs for infectious diseases lacking adequate treatments, including neglected tropical diseases, emerging infectious threats and infections caused by antimicrobial-resistant organisms. When health care professionals directly input their clinical cases into the app, CURE ID allows these real-world experiences to be organized and analyzed much faster, making it easier to spot promising new uses for existing drugs,” said Amy Abernethy, M.D., Ph.D., FDA Principal Deputy Commissioner. “Our hope is that this app will serve as a connector among major treatment centers, academics, private practitioners, government facilities and other health care professionals from around the world and ultimately get treatments to patients faster.”
The repository captures clinical outcomes when drugs are used for new indications, in new populations, in new doses or in new combinations. Health care professionals generally may choose to prescribe or use a legally marketed human drug or medical device for an unapproved or uncleared use when they judge that the unapproved use is medically appropriate for an individual patient. The systematic collection of real-world experience in the app will help identify drug candidates for additional study, encourage further drug development, and may serve as a resource for practitioners making individual patient treatment decisions in the absence of established safe and effective options. Repurposing approved drugs for new clinical indications can potentially offer an efficient drug-development pathway for treatments of diseases and conditions that have few or no therapeutic options.

“The potential importance of new therapeutic opportunities from repurposing drugs can’t be understated,” said NCATS Director Christopher P. Austin, M.D. “The CURE ID platform exemplifies how collaborative efforts can spark innovations that benefit patients. This new platform harnesses the power of crowdsourcing to help gather medical observations in the field and help identify potentially effective treatments for diseases.”

The app works by collecting a simple case report form from caregivers about their experience using an approved product for an unapproved use. Health care professionals can browse from a collection of cases that have already been documented, including successful and unsuccessful treatments, in addition to viewing relevant clinical trials and those open to enrollment at clinicaltrials.gov. App users can also participate in a treatment discussion forum where they can engage with fellow providers globally. The FDA plans to reach out to health care providers in various disciplines, including infectious and tropical diseases, to encourage them to use the app.
The full launch of the app follows the release of several pilot versions after an initial innovation award was received from the U.S. Department of Health & Human Services IDEA Lab in April 2015. During the pilots, extensive user-testing was conducted in India (2015 and 2017) and South Africa (2016). Additional feedback was also collected from users in the U.S., Europe and Peru. The updated app that launched today includes the addition of a newsfeed, an improved search feature with data from 325 different infectious diseases and syndromes to choose from, and the inclusion of nearly 1,500 initial cases from clinicians and the published literature and over 18,000 clinical trials.

To download and use the CURE ID application, visit https://cure.ncats.io or download “CURE ID” from the App or Play Store.

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Recent scientific and biomedical advances

Recent scientific and biomedical advances—from genomic sequencing to development of cell and gene therapies and nanotechnologies— have brought the promise of significant improvements to the health of many millions of Americans.

To date, however, we have seen little of this promise in our day-to-day lives because a large and persistent gap separates important scientific advances and the technologies needed to translate those advances into new therapies for patients and new ways to protect the public health.

The FDA’s Technology Modernization Action Plan (TMAP), described in this document, is an important step FDA is taking to address and close this gap. It describes important near-term actions that FDA is taking to modernize use of technology—computer hardware, software, data, and analytics—to advance FDA’s public health mission.
TMAP has three elements:

modernization of FDA’s technical infrastructure;
enhancing FDA’s capabilities to develop technology products to support its regulatory mission; and
communication and collaboration with stakeholders to drive technological progress that is interoperable across the system and delivers value to consumers and patients.
The TMAP provides a sturdy technological foundation for development of FDA’s ongoing strategy around data itself—a strategy for the stewardship, security, quality control, analysis, and real-time use of data—that will accelerate the path to better therapeutic and diagnostic options for patients and clinical care providers, and better tools to enhance and promote public health.

COSMETIC REGULATORY COMPLIANCE

December 4, 2019 Duraimurugan Anbalagan

Voluntary Cosmetic Registration Program

FDA’s Voluntary Cosmetic Registration Program (VCRP) is a reporting system for use by manufacturers, packers, and distributors of cosmetic products that are in commercial distribution in the United States

About VRCP

There are two parts to the VCRP filing, described in detail in the sections below. You may participate in both parts of the program or only one part. The VCRP regulations can be found in 21 CFR, parts 710 and 720.

The VCRP applies only to cosmetic products being sold to consumers in the United States. It does not apply to cosmetic products for professional use only, such as products used in beauty salons, spas, or skin care clinics. It also does not apply to products that are not for sale, such as hotel samples, free gifts, or cosmetic products you make in your home to give to your friends.

Benefits of VCRP Participation

The VCRP assists FDA in carrying out its responsibility to regulate cosmetics marketed in the United States. Because product filings and establishment registrations are not mandatory, voluntary submissions provide FDA with the best estimate of information available about cosmetic products and ingredients, their frequency of use, and businesses engaged in their manufacture and distribution (Federal Register, vol. 73, p. 76360, and vol. 69, p. 9339).

Information from the VCRP database also has been used by the Cosmetic Ingredient Review (CIR), an independent, industry-funded panel of scientific experts, to assist the CIR Expert Panel in establishing their priorities for assessing ingredient safety as part of their ingredient safety review (Federal Register, vol. 73, p. 76360).

Some Important Things to Know

The VCRP is a voluntary registration system for cosmetic products as defined by the Federal Food, Drug, and Cosmetic Act (FD&C Act), section 201(i). Drugs are subject to different FDA registration and marketing requirements (FD&C Act, sec. 510; 21 CFR 207). Depending on the claims made, some cosmetic products may also be drugs. If a cosmetic product is also a drug, it must comply with the requirements for both cosmetics and drugs. Additional information on these types of products is available elsewhere on FDA’s website. For example, you may wish to refer to “Is It a Cosmetic, a Drug, or Both? (Or Is It Soap?).” If your products are drugs, or both cosmetics and drugs, see “Drug Registration and Listing System (DRLS & eDRLS)” and “Electronic Drug Registration and Listing Instructions.”

The VCRP is not a cosmetic approval program or a promotional tool. Cosmetics are not subject to FDA premarket approval. It is the firm’s responsibility to ensure that its cosmetic products and ingredients are safe and properly labeled, in full compliance with the law. Registration of a cosmetic establishment, assignment of an establishment registration number, filing a cosmetic product, or assignment of a CPIS number does not mean that FDA has approved the firm or its products (21 CFR 710.8 and 720.9) or that a product is a cosmetic as defined in the FD&C Act. Any representation in labeling or advertising that creates an impression of official approval because of registration or possession of a registration number is considered misleading (21 CFR 710.8 and 720.9). Misleading labeling makes a cosmetic misbranded (FD&C Act, 602(a)).

The VCRP is not part of a prior notice system for imported cosmetics. Firms importing products considered to be solely cosmetics in the United States are not required to register with FDA.

Certain information from the VCRP database is available through the Freedom of Information Act (FOIA). For example, FDA sometimes receives such requests from consumers or healthcare providers who wish to identify products that do or do not contain certain ingredients. Proprietary business information, however, is not releasable under FOIA. Please note, in late 2018, certain registration information from the VCRP, that is currently available to the public through FOIA, will be posted on the VCRP Registration Reports webpage.

The regulations authorizing this program are found in 21 CFR, parts 710 and 720.

How to Participate

1) Registering cosmetic manufacturing and/or packaging establishments. Cosmetic establishments are facilities where cosmetics are manufactured and/or packaged, not locations that house only business operations. Only owners or operators of cosmetic manufacturing or packing facilities can register their establishments, using a separate Form FDA 2511 for each facility location. Distributors cannot register an establishment (21 CFR 710.1). Domestic firms that have begun operations can register their establishments before or after their products are entered into commercial distribution and for sale to U.S. consumers. Foreign firms may voluntarily register their establishments after their products are exported for sale in the U.S. FDA assigns a registration number to each establishment location.

2) Filing Cosmetic Product Ingredient Statements (CPIS). A cosmetic manufacturer, packer, or distributor can file a statement for each product the firm has entered into commercial distribution in the United States. Use a separate Form FDA 2512 for each formulation. (If you are using printed forms, you will need both Form FDA 2512 and 2512a.) FDA assigns a CPIS number to each formulation filed in the VCRP.

3) Amending or Discontinuing a Product Formulation. A CPIS can be amended or discontinued by filing Form FDA 2512 and continuation Form FDA 2512a. Changes to a brand name or ingredients should be submitted within 60 days after the product enters commercial distribution. A CPIS should be discontinued within 180 days after discontinuance of commercial distribution becomes known to you.

FDA approves first treatment for inherited rare disease

December 2, 2019 Duraimurugan Anbalagan

U.S. Food and Drug Administration granted approval to Givlaari (givosiran) for the treatment of adult patients with acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules which are formed during the production of heme (which helps bind oxygen in the blood).

“This buildup can cause acute attacks, known as porphyria attacks, which can lead to severe pain and paralysis, respiratory failure, seizures and mental status changes. These attacks occur suddenly and can produce permanent neurological damage and death,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks. The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients.”

The approval of Givlaari was based on the results of a clinical trial of 94 patients with acute hepatic porphyria. Patients received a placebo or Givlaari. Givlaari’s performance was measured by the rate of porphyria attacks that required hospitalizations, urgent health care visits or intravenous infusion of hemin at home. Patients who received Givlaari experienced 70% fewer porphyria attacks compared to patients receiving a placebo.
Common side effects for patients taking Givlaari were nausea and injection site reactions. Health care professionals are advised to monitor patients for anaphylactic (allergic) reaction and renal (kidney) function. Patients should have their liver function tested before and periodically during treatment.

Outbreak Investigation of Hepatitis A Potentially Linked to Fresh Conventional Blackberries from Fresh Thyme Farmers Market, Fall 2019

December 2, 2019 Duraimurugan Anbalagan

The U.S. Food and Drug Administration (FDA), along with the Centers for Disease Control and Prevention (CDC), and state and local partners, are investigating a multistate outbreak of hepatitis A illnesses in Indiana, Nebraska, and Wisconsin potentially linked to fresh conventional (non-organic) blackberries from the grocery store, Fresh Thyme Farmers Market.

Based on the epidemiological information collected in the investigation thus far, ill patients reported consuming fresh conventional blackberries from Fresh Thyme Farmers Market stores in three states: Indiana, Nebraska, and Wisconsin.

However, traceback information to date shows that these berries came from a distribution center that ships fresh berries to Fresh Thyme Farmers Market stores in 11 states: IA, IL, IN, KY, MI, MO, MN, NE, OH, PA, and WI. As this investigation continues, the FDA will work with our federal and state partners to obtain additional information during the traceback investigation and will update this advisory as more information becomes available

Recommendation

The FDA is urging consumers to not eat any fresh conventional blackberries if purchased between September 9 and September 30, 2019, from Fresh Thyme Farmers Market stores in the 11 states mentioned above. People who purchased the fresh blackberries and then froze those berries for later consumption should not eat these berries. They should be thrown away.

If consumers purchased fresh conventional blackberries from Fresh Thyme Farmers Market stores in the 11 states listed above between September 9-30, ate those berries in the last two weeks, and have not been vaccinated for the hepatitis A virus (HAV), they should consult with their healthcare professional to determine whether post exposure prophylaxis (PEP) is indicated. PEP is recommended for unvaccinated people who have been exposed to HAV in the last two weeks. Those with evidence of previous hepatitis A vaccination or previous hepatitis A infection do not require PEP.

Contact your healthcare provider if you think you may have become ill from eating these blackberries, or if you believe that you have eaten these berries in the last two weeks

Health Canada Creates New Medical Devices Directorate

December 2, 2019 Duraimurugan Anbalagan

Welcome to our Asia Regulatory Roundup, our weekly overview of the top regulatory news in Asia.

Health Canada announced the creation of a new Medical Devices Directorate to better respond to the challenges and opportunities related to the growing medical device industry.

Similar to the US FDA’s push for a lifecycle approach to regulating devices, the new Canadian devices directorate will take a lifecycle approach by bringing together postmarket functions now led by the Marketed Health Products Directorate and the pre-market functions of the Therapeutic Products Directorate.

The directorate will include 165 positions and a budget of $15.85 million funded through resource transfers and reallocation within Canada’s Health Products and Food Branch. David Boudreau, executive director at Health Canada, was named the interim director general for the new device directorate.

Health Canada said the new organization will allow for additional capacity and focus on expanding Quality Management Systems to include both internal and external components, and the implementation of ISO 9001. It will also enable better postmarket surveillance capacity for devices.
A new policy group within the directorate will help to develop new guidance tailored to medical devices, including more meaningful and targeted interactions with stakeholders, in addition to building on the expertise and activities of the newly created Digital Health Unit.

“Large-scale initiatives are underway that are challenging us to: shift how we regulate investigational trials; re-examine risk-based approaches; find ways to regulate software that allow for rapid innovation cycles; and create new pathways for innovative technologies,” Health Canada said.

Last June, Health Canada began a consultation on a set of proposed regulations intended to provide the agency with better safety information for marketed Class II, III and IV medical devices. And last December, Health Canada created a medical device action plan to improve the safety, oversight and quality of devices.

China Opens Food and Drug Center of Excellence in Beijing

Welcome to our Asia Regulatory Roundup, our weekly overview of the top regulatory news in Asia

China has opened a food and drug center of excellence in Beijing. The United Nations Industrial Development Organization (UNIDO) is supporting the initiative to help China establish a harmonized, competency-based food and drug safety training system.

Representatives of UNIDO, the China International Center for Economic and Technical Exchanges and China Food and Drug Administration’s Institute of Executive Development (CFDAIED) signed off on the creation of the center of excellence earlier this year. The initiative has a total budget of $500,000, a little more than one-third of which is due to be spent this year. UNIDO reports $32,000 has been spent so far.

The investment is intended to equip China to create a country-wide food and drug safety training system that is in line with, and recognized by, international standards and organizations. Specific tasks include international training through profiling, benchmarking and capacity building.

UNIDO will help out with the overall capacity development framework and provide support with the food safety side of the project. CFDAIED will leverage the food sector work to design drug-related content, possibly with the support of UNIDO. The project is due to run until October 2021

Malaysia’s MDA Seeks Feedback on Orphaned Medical Device Guidance

Welcome to our Asia Regulatory Roundup, our weekly overview of the top regulatory news in Asia

Malaysia’s Medical Device Authority (MDA) has published draft guidance on medical devices that are in use but no longer registered. Products can end up in this situation when their manufacturer or authorized representative stops operating.

Such products, which MDA calls “orphaned medical devices,” pose challenges as they are in use but no longer have a representative that is responsible for them. To ensure the ongoing safe use of these devices, MDA wants healthcare facilities that use orphaned medical devices to send it a notification covering details of the product.

The notification must identify a person who is responsible for the medical device. This person must live in Malaysia and hold a top managerial position at the organization that uses the device.

MDA’s focus on the seniority of the responsible person reflects the obligations the orphaned medical device status places on healthcare facilities. In the absence of a manufacturer or typical authorized representative, the healthcare facility is responsible for the risk of using the orphaned medical device and the monitoring of its safety and performance.

The draft guidance is open for feedback until 30 November

New Zealand’s Medsafe to Ban Sale of Migraine Drug Next Year

Welcome to our Asia Regulatory Roundup, our weekly overview of the top regulatory news in Asia

The New Zealand Medicines and Medical Devices Safety Authority (Medsafe) is set to ban the sale of the Cafergot migraine drug. Medsafe decided to stop the distribution of the AFT Pharmaceuticals’ product after concluding the benefits no longer outweigh the risks.

Cafergot, which contains ergotamine tartrate and caffeine, is used in the treatment of acute attacks of migraine with or without aura in adults. The drug was approved in New Zealand in the late 1960s. Other countries also used ergots such as ergotamine tartrate in the past but authorities including the United Kingdom’s National Institute for Health and Care Excellence and the German Society of Neurology now recommend against their use.

The recommendations against the use of ergots are underpinned by the lack of well-documented efficacy evidence from prospective studies and concerns that they have worse safety and tolerability profiles than other migraine drugs, such as triptans.

Adverse events linked to Cafergot in migraine are relatively rare, with the Centre for Adverse Reactions Monitoring (CARM) identifying five reports as of the end of June. One of the reports covered a case of potential pancreatitis that led the Medicines Adverse Reactions Committee (MARC) to look into the drug.

A report presented to MARC said there were “fewer reports than predicted,” although the authors think that may be because use is relatively low and, as an old drug, people may have stopped reporting side effects. The report identified close to 1,800 patients who used Cafergot in New Zealand last year.

Healthcare professionals who provided feedback for the report said Cafergot is rarely prescribed today, although one person noted they know of a “small handful” of patients who use it safely. Knowledge of those people led that healthcare professional to say, “It would be a shame to lose [Cafergot] altogether.” Some of the other healthcare professionals expressed similar sentiments.

Despite that, MARC recommended the withdrawal of Cafergot at a meeting earlier this year. That led to a Medsafe notice last week that set 1 May as the date of the withdrawal of Cafergot from the New Zealand market. The timeline reflects MARC’s recommendation of a six-month transition to enable patients to safely move to new medicines.

Asia Regulatory Roundup: China Opens Food and Drug Center of Excellence

Welcome to our Asia Regulatory Roundup, our weekly overview of the top regulatory news in Asia.

TGA Suspends Ranitidine Medicines Ahead of Possible License Cancellations

The Therapeutic Goods Administration (TGA) has suspended 23 ranitidine medicines from the Australian Register of Therapeutic Goods (ARTG). TGA suspended the products for six months but thinks there are grounds to ultimately cancel the medicines from the ARTG altogether.

Last month, TGA presented results from tests on 34 ranitidine medicines sold by 10 companies. The tests, which covered 135 batches, suggested most ranitidine medicines available in Australia contained more than 0.3 parts per million (PPM) of N-nitrosodimethylamine (NDMA), meaning they breached the internationally agreed limit for the carcinogen. Back then, TGA said it was considering “suspending the registration for products which cannot demonstrate adequate safety and quality.”

Now, TGA has revealed its response to the high levels of NDMA. The Australian regulator has put 23 ranitidine medicines on a six-month suspension that will run from 16 December to 16 June. Apotex, Arrow Pharma and Sandoz are among the companies with products affected by the suspension.

Ranitidine products absent from the list of suspended medicines include two ARTG entries sold by Arrow Pharma under the Chemists’ Own brand. The products were two of five ARTG entries with batches TGA found to contain levels of NDMA below 0.3ppm. Batches taken from two other Arrow Pharma ARTG entries and one Sandoz entry also passed the TGA test but were still suspended.

TGA uses suspensions to protect patients while giving manufacturers the chance to address issues with their products. In the case of the ranitidine medicines, if the affected companies fail to make changes to reassure TGA of the safety of their products, they face the prospect of losing their place on the ARTG permanently.

In the section on the grounds for suspension for each of the 23 products, TGA wrote that, “It is likely there are grounds for cancelling this medicine from the ARTG … on the basis that the quality of the goods is unacceptable.” The affected manufacturers now have a little more than six months to stop that happening, although in some cases TGA extends suspensions to give companies more time to fix problems with their products

Medical Devices: Current Good Manufacturing Practice Quality System Regulation—21 CFR Part 820

November 28, 2019 Duraimurugan Anbalagan

FDA has submitted the following proposed collection of information to OMB for review and clearance.
The CGMP quality system (QS) regulation implementing authority provided by this statutory provision is found under part 820 (21 CFR part 820) and sets forth basic CGMP requirements governing the design, manufacture, packing, labeling, storage, installation, and servicing of all finished medical devices intended for human use.
The authority for this regulation is covered under sections 501, 502, 510, 513, 514, 515, 518, 519, 520, 522, 701, 704, 801, and 803 of the FD&C Act (21 U.S.C. 351, 352, 360, 360c, 360d, 360e, 360h, 360i, 360j, 360l, 371, 374, 381, and 383).

The CGMP/QS regulation includes requirements for purchasing and service controls, clarifies recordkeeping requirements for device failure and complaint investigations, clarifies requirements for verifying/validating production processes and process or product changes, and clarifies requirements for product acceptance activities, quality data evaluations, and corrections of nonconforming product/quality problems.

Requirements are compatible with specifications in the international standards “ISO 9001: Quality Systems Model for Quality Assurance in Design/Development, Production, Installation, and Servicing.” The CGMP/QS information collections will assist FDA inspections of manufacturers for compliance with QS requirements encompassing design, production, installation, and servicing processes.

Regulatory focus news letter on USFDA Warning letters – Monthly Update (Nov 2019)

A summary of USFDA Warning letter is presented below for quick reference

In total 27 USFDA Warning letters were issued in the month of November 2019.
11 out of 27 related to various Pharmaceutical industries ( CGMP/Finished Pharmaceuticals/Adulterated )across the Globe
15 are related to Unapproved New Drugs/Misbranded/Cannabidiol (CBD) Products
01 is related to unapproved new drugs/misbranded

Find below some of the warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211

MARCS-CMS 581785 — SEPTEMBER 10, 2019

1. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

2. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

3. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

Hazard Analysis and Risk-Based Preventive Controls (21 CFR 117, Subpart C)

1. Your hazard analysis did not identify a known or reasonably foreseeable hazard for each type of food manufactured, processed, packed, or held at your facility to determine whether there are any hazards requiring a preventive control, as required by 21 CFR 117.130(a)(1). Specifically, your hazard analysis does not identify the hazard of recontamination with environmental pathogens at all steps where ready-to-eat (RTE) food is stored and processed while exposed to the environment in your facility after the (b)(4) step, such as at the “(b)(4),” “(b)(4),” and “(b)(4)” steps.

2. You did not identify and implement sanitation preventive controls to provide assurances that any hazards requiring a preventive control (i.e., recontamination with environmental pathogens) will be significantly minimized or prevented and the food manufactured, processed, packed, or held by your facility will not be adulterated under section 402 of the FD&C Act, as required by 21 CFR 117.135(a)(1) and (c)(3), as evidenced by the following:

a. From April 2019 to May 2019, you found five (5) environmental samples positive for L. monocytogenes in the environment in Zone 3, including areas within your RTE production area where RTE food is exposed to the environment. In addition, FDA laboratory analysis of environmental sample #1088400 collected at your facility on May 21, 2019, revealed that one (1) environmental swab in Zone 3 was positive for L. monocytogenes

b. Your written corrective action procedure for your “Environmental Microbial Sampling SOP,” issued 3/19/2019, states that “(b)(4).” However, between April 2019 and May 2019, you identified five positive environmental samples of L. monocytogenes, and you do not have records to show that you conducted an investigation of the potential source or cause of contamination.

Find below some of the warning letters related to Unapproved drugs / Misbranded products

Dietary Supplement Labeling

Information on your website at https://koicbd.com suggests that you intend to market your “KOI CBD Infused Shot” product as a dietary supplement that contains CBD because the “KOI CBD Infused Shot” is described as a “supplement.” However, your product cannot be a dietary supplement because it does not meet the definition of a dietary supplement under section 201(ff) of the FD&C Act, 21 U.S.C. 321(ff). FDA has concluded, based on available evidence, that CBD products are excluded from the dietary supplement definition under sections 201(ff)(3)(B)(i) and (ii) of the FD&C Act, 21 U.S.C. 321(ff)(3)(B)(i) and (ii). Under those provisions, if an article (such as CBD) is an active ingredient in a drug product that has been approved under section 505 of the FD&C Act, 21 U.S.C. 355, or has been authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, then products containing that substance are outside the definition of a dietary supplement.1 There is an exception if the substance was “marketed as” a dietary supplement or as a conventional food before the new drug investigations were authorized; however, based on available evidence, FDA has concluded that this is not the case for CBD. FDA is not aware of any evidence that would call into question its current conclusion that CBD products are excluded from the dietary substance definition under sections 201(ff)(3)(B)(i) and (ii) of the FD&C Act, but you may present FDA with any evidence bearing on this issue.

Unapproved New Drugs

Based on our review of your website, your “CBD HEALING BALM,” “CBD VAPE OIL,” “FULL SPECTRUM CBD TINCTURE,” “KOI LOTION,” “KOI CBD Gummies,” and “KOI CBD Infused Shot” products are drugs under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or intended to affect the structure or any function of the body.

Examples of claims observed on your website, https://koicbd.com, that establish the intended use of your products as drugs include, but may not be limited to, the following:

On your webpage titled “8 Proven Benefits of CBD”:

“CBD RELIEVES PAIN AND INFLAMMATION”
“studies show that CBD prevents human experimental psychosis and is effective in open case reports and clinical trials in patients with schizophrenia, with a remarkable safety profile.”
“Not only does the research show that CBD benefits including being effective in fighting breast cancer cells, data also suggest that it can be used to inhibit the invasion of lung and colon cancer, plus it possesses anti-tumor properties in gliomas and has been used to treat leukemia.”
“CBD LOWERS INCIDENCE OF DIABETES”

On your webpage titled “IS CBD RIGHT FOR YOU?”:

“several pre-clinical reports showing anti-tumor effects of CBD…have found reduced [cancer] [sic] cell viability, increased cancer cell death, decreased tumor growth, and inhibition of metastasis.”

On your webpage titled “CBD AND OPIOID ADDICTION”:

“CBD FOR OPIOID ADDICTION”
“A potential new treatment for opioid addiction has been found in a new review of previous research of cannabidiol (CBD).”

On your webpage titled “10 LITTLE KNOWN USES FOR CBD”:

“PTSD”
“Fibromyalgia”
“Schizophrenia”
“Diabetes”
“MS”
“Crohn’s Disease”
“Opioid Addiction”
“The advantage of cannabidiol as a potential treatment for opioid addiction is that it doesn’t give users a high and thus doesn’t involve a risk of misuse.”

Your “CBD HEALING BALM,” “CBD VAPE OIL,” “FULL SPECTRUM CBD TINCTURE,” “KOI LOTION,” “KOI CBD Gummies,” and “KOI CBD Infused Shot” products are not generally recognized as safe and effective for the above referenced uses and, therefore, the products are “new drugs” under section 201(p) of the FD&C Act, 21 U.S.C. 321(p). New drugs may not be legally introduced or delivered for introduction into interstate commerce without prior approval from the FDA, as described in sections 301(d) and 505(a) of the FD&C Act, 21 U.S.C. 331(d) and 355(a). FDA approves a new drug on the basis of scientific data and information demonstrating that the drug is safe and effective. There are no FDA-approved applications in effect for any of the above mentioned products.

Misbranded Drugs

Your “CBD HEALING BALM,” “CBD VAPE OIL,” “FULL SPECTRUM CBD TINCTURE,” “KOI LOTION,” “KOI CBD Gummies,” and “KOI CBD Infused Shot” products are also misbranded within the meaning of section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1), in that their labeling fails to bear adequate directions for use. “Adequate directions for use” means directions under which a layperson can use a drug safely and for the purposes for which it is intended. (See 21 CFR 201.5.) The aforementioned products are offered for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, adequate directions for use cannot be written so that a layperson can use these drugs safely for their intended purposes. FDA-approved prescription drugs that bear their FDA-approved labeling are exempt from the requirements that they bear adequate directions for use by a layperson. However, your products are not exempt from the requirement that their labeling bear adequate directions for use, 21 CFR 201.100(c)(2) and 201.115, because no FDA-approved applications are in effect for them. The introduction or delivery for introduction into interstate commerce of these misbranded drugs violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

Prohibited Act under 301(ll) and Adulterated Human Foods

We note that your “KOI CBD Gummies” product appears to be promoted as a conventional human food. Specifically, your website refers to the gummies as “delicious, edible CBD snacks.” However, you should be aware that it is a prohibited act under section 301(ll) of the FD&C Act, 21 U.S.C. 331(ll), to introduce or deliver for introduction into interstate commerce any food to which has been added a drug approved under section 505 of the FD&C Act or for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public. Based on available evidence, FDA has concluded that the prohibition in section 301(ll) applies to CBD. There is an exception if the substance was marketed in food before the drug was approved or before the substantial clinical investigations involving the drug had been instituted. However, based on the available evidence discussed above, FDA has concluded that this is not the case for CBD. FDA is not aware of any evidence that would call into question its current conclusion that section 301(ll) of the FD&C Act prohibits the introduction into interstate commerce of any food to which CBD has been added, but you may present FDA with any evidence bearing on this issue.

You should also be aware that, as defined in section 201(s) of the FD&C Act (21 U.S.C. 321(s)), the term “food additive” refers to any substance the intended use of which results in its becoming a component of any food, unless the substance is generally recognized as safe (GRAS) among qualified experts under the conditions of its intended use, or unless the substance meets a listed exception.2

Food additives require premarket approval based on data demonstrating safety. Any food additive that has not been approved for its intended use in food is deemed to be unsafe under section 409(a) of the FD&C Act (21 U.S.C. 348(a)), and causes the food to be adulterated under section 402(a)(2)(C)(i) of the FD&C Act, 21 U.S.C. 342(a)(2)(C)(i). Introduction of an adulterated food into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

There is no food additive regulation which authorizes the use of CBD. We are not aware of any information to indicate that CBD is the subject of a prior sanction (see 21 CFR Part 181). Furthermore, we are not aware of any basis to conclude that CBD is GRAS for use in conventional foods. FDA’s regulations in 21 CFR 170.30(a)-(c) describe the criteria for eligibility for classification of a food ingredient as GRAS. The use of a food substance may be GRAS based on either scientific procedures or, for a substance used in food before 1958, through experience based on common use in food (see 21 CFR 170.30).

We know of no basis for general recognition of safety for CBD based either on scientific procedures or common use in food prior to January 1, 1958. Based on our review of published, scientific literature, existing data and information do not provide an adequate basis to conclude that the use of CBD in food meets the criteria for GRAS status. Many unanswered questions and data gaps about CBD toxicity exist, and some of the available data raise serious concerns about potential harm from CBD. Our review of publicly available data associated with the one FDA-approved CBD drug, as well as our review of published scientific literature, identified potential for liver injury from CBD and potentially harmful interactions with certain drugs. In addition, studies in animals have shown that CBD can interfere with the development and function of testes and sperm, decrease testosterone levels, and impair sexual behavior in males. Therefore, based on our review, the use of CBD in conventional food products does not satisfy the criteria for GRAS status under 21 CFR 170.30.

FDA is not aware of any other exception to the food additive definition that would apply to CBD for use as an ingredient in a conventional food. Therefore, CBD added to a conventional food is a food additive under section 201(s) of the FD&C Act and is subject to the provisions of section 409 of the FD&C Act. Under section 409, a food additive is deemed unsafe unless it is approved by FDA for its intended use prior to marketing. CBD is not approved for use in any conventional food. Food containing an unsafe food additive within the meaning of section 409 is adulterated within the meaning of section 402(a)(2)(C)(i). Therefore, to the extent that you intend to market this products as a food, your “KOI CBD Gummies” product is also adulterated within the meaning of section 402(a)(2)(C)(i) of the FD&C Act. Introduction of an adulterated food into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

Unapproved New Animal Drugs

During our review of your website, https://koicbd.com, FDA determined that your firm is marketing the unapproved new animal drugs “KOI Naturals CBD Spray for Pets” and “KOI CBD Soft Chews.” Based on our review of your website, your “KOI Naturals CBD Spray for Pets” and “KOI CBD Soft Chews” products are drugs under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in animals and/or intended to affect the structure or any function of the body of an animal. Further, as discussed below, these products are unapproved new animal drugs and marketing them violates the FD&C Act.

Examples of claims observed on your firm’s website https://koicbd.com that show the intended uses of these products include, but are not limited to, the following:

On your webpage titled “Is CBD Oil Good for Pets”:

“Do you have a pet who is exhibiting notable discomfort? Consider giving them CBD oil to alleviate their symptoms.”
“So although it helps to alleviate pain, there is no risk of addiction or psychoactive side effects.”

These products are “new animal drugs” under section 201(v) of the FD&C Act, 21 U.S.C. 321(v), because they are not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of animal drugs, as safe
and effective for use under the conditions prescribed, recommended, or suggested in the labeling.

To be legally marketed, a new animal drug must have an approved new animal drug application, conditionally approved new animal drug application, or index listing under sections 512, 571, and 572 of the FD&C Act, 21 U.S.C. 360b, 360ccc, and 360ccc-l. These products are not approved or index listed by the FDA, and therefore these products are considered unsafe under section 512(a) of the FD&C Act, 21 U.S.C. 360b(a), and adulterated under section 501(a)(5) of the FD&C Act, 21 U.S.C. 351(a)(5). Introduction of these adulterated drugs into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

301(ll) and Adulterated Animal Foods

Moreover, to the extent that you market any of your products containing CBD as animal food, you should be aware that it is a prohibited act under section 301(ll) of the FD&C Act, 21 U.S.C. 331(ll), to introduce or deliver for introduction into interstate commerce any animal food to which has been added a drug approved under section 505 of the FD&C Act or for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public. Based on available evidence, FDA has concluded that the prohibition in section 301(ll) applies to CBD, as described above.

You should also be aware that, as defined in section 201(s) of the FD&C Act (21 U.S.C. 321(s)), the term “food additive” refers to any substance the intended use of which results in its becoming a component of any animal food, unless the substance is generally recognized as safe (GRAS) among qualified experts under the conditions of its intended use, or unless the substance meets a listed exception.3

There is no animal food additive regulation that authorizes the use of CBD. We are not aware of any information to indicate that CBD is the subject of a prior sanction (i.e., a sanction or approval granted prior to the enactment of the Food Additives Amendment of 1958 under the FD&C Act, the Poultry Products Inspection Act, or the Meat Inspection Act). Furthermore, we are not aware of any basis to conclude that CBD is GRAS for use in animal foods. FDA’s regulations in 21 CFR 570.30(a)-(c) describe the criteria for eligibility for classification of an animal food ingredient as GRAS. The use of an animal food substance may be GRAS based on either scientific procedures or, for a substance used in animal food before 1958, through experience based on common use in animal food (see 21 CFR 570.30). We know of no basis for general recognition of safety for CBD based either on scientific procedures or common use in animal food prior to January 1, 1958. Based on our review of the publicly available literature, the data and information necessary to support the safe use of CBD in animal foods are lacking. In fact, literature reports have raised safety concerns for animals consuming CBD, including, but not limited to, male reproductive toxicity and liver toxicity. Therefore, based on our review, the use of CBD in animal products does not satisfy the criteria for GRAS status under 21 CFR 570.30.

Under section 409 of the FD&C Act, 21 U.S.C. 348, an animal food additive is deemed unsafe unless it is approved by FDA for its intended use prior to marketing. CBD is not approved for use in any animal food. Animal food containing an unsafe food additive within the meaning of section 409 is adulterated within the meaning of section 402(a)(2)(C)(i) of the FD&C Act. Introduction of an adulterated animal food into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

CVM GFI #256 – Compounding Animal Drugs from Bulk Drug Substances

November 27, 2019 Duraimurugan Anbalagan

On 19^th Nov 2019 FDA circulated draft guideline for compounding animal drugs from Bulk drug Substances for public review comments. The comments shall be submitted to FDA through online by 18^th Feb 2020

This draft guidance is intended for veterinarians, State-licensed pharmacies, and Federal facilities interested in compounding animal drugs from bulk drug substances for use in nonfood-producing animals or for use as antidotes in food-producing animals under limited circumstances when no other medically appropriate treatment options exist.

Under the Federal Food, Drug, and Cosmetic Act (FD&C Act), the compounding of an animal drug from bulk drug substances results in a “new animal drug” that must comply with the FD&C Act’s animal drug approval, conditional approval, or indexing requirements (sections 512, 517, and 572 of the FD&C Act). In addition, all animal drugs are require to, among other things, be made in accordance with current good manufacturing practice (cGMP) requirements (section 501(a)(2)(B) of the FD&C Act) and have adequate directions for use (section 502(f)(1) of the FD&C Act).

Animal drugs that are compounded from bulk drug substances do not meet the FD&C Act’s new animal drug approval, cGMP, or adequate directions for use requirements. However, FDA has generally exercised enforcement discretion with regard to animal drug compounding from bulk drug substances under certain circumstances. This draft guidance is a continuation of this practice and is intended to provide additional information and clarity to veterinarians and pharmacists about FDA’s current thinking on this matter. The guidance describes the circumstances under which FDA, at this time and based on our current understanding of the risks of animal drugs compounded from bulk drug substances, does not intend to take enforcement action for violations of the FD&C Act with respect to the compounding of animal drugs from bulk drug substances.

Contact FWQRC™ for GMP Training, Auditing by QP, eCTD, GAP Analysis, Risk Assessment, CAPA, CSV, Method development/Validation, ADE/PDE Values, Facility & Product Registrations

FDA Releases 105 Product-Specific Guidances

The US Food and Drug Administration (FDA) on Thursday released 105 product-specific guidance documents to aid generic drug development, including 27 new draft guidances and 78 revised draft guidances.

The guidances, when finalized, are intended to promote generic competition by clarifying FDA’s expectations for the studies required to demonstrate that a generic drug is equivalent to a reference listed drug. So far, FDA has issued nearly 1,800 product-specific guidances.

As part of its commitments under the Generic Drug User Fee Amendments (GDUFA II) reauthorization, FDA committed to issuing product-specific guidances for 90% of non-complex new chemical entity new drug applications (NDAs) approved after 1 October 2017 at least two years ahead of the earliest abbreviated new drug application (ANDA) filing date. The agency also committed to issuing product-specific guidances for complex products “as soon as scientific recommendations are available.”

Among the new guidances are recommendations for the studies necessary to support ANDA approvals for Viiv Healthcare’s two-drug once-daily HIV drug Juluca (dolutegravir/rilpivirine), Amicus Therapeutics’ Fabry disease drug Galafold (migalastat) and Advanced Accelerator Applications’ cancer drug Lutathera (lutetium dotatate Lu-177).

Most of the new draft guidances are for oral formulations, though a few are for ophthalmic, intravenous and subcutaneous formulations.

Most of the revised draft guidances are for topical and transdermal formulations, including extended release film formulations of estradiol, fentanyl and nicotine. In an email to Focus, FDA spokesperson Charles Kohler said that most of the revisions “are minor or editorial in nature, meant to ensure the PSGs are consistent, clear, up-to-date, and include links to the most current related guidances.”

New catalyst efficiently produces hydrogen from seawater

Seawater is one of the most abundant resources on earth, offering promise both as a source of hydrogen – desirable as a source of clean energy – and of drinking water in arid climates. But even as water-splitting technologies capable of producing hydrogen from freshwater have become more effective, seawater has remained a challenge.

Researchers from the University of Houston have reported a significant breakthrough with a new oxygen evolution reaction catalyst that, combined with a hydrogen evolution reaction catalyst, achieved current densities capable of supporting industrial demands while requiring relatively low voltage to start seawater electrolysis.

Researchers say the device, composed of inexpensive non-noble metal nitrides, manages to avoid many of the obstacles that have limited earlier attempts to inexpensively produce hydrogen or safe drinking water from seawater. The work is described in Nature Communications.

Zhifeng Ren, director of the Texas Center for Superconductivity at UH and a corresponding author for the paper, said a major obstacle has been the lack of a catalyst that can effectively split seawater to produce hydrogen without also setting free ions of sodium, chlorine, calcium and other components of seawater, which once freed can settle on the catalyst and render it inactive. Chlorine ions are especially problematic, in part because chlorine requires just slightly higher voltage to free than is needed to free hydrogen.

The researchers tested the catalysts with seawater drawn from Galveston Bay off the Texas coast. Ren, M.D. Anderson Chair Professor of physics at UH, said it also would work with wastewater, providing another source of hydrogen from water that is otherwise unusable without costly treatment.

“Most people use clean freshwater to produce hydrogen by water splitting,” he said. “But the availability of clean freshwater is limited.”

To address the challenges, the researchers designed and synthesized a three-dimensional core-shell oxygen evolution reaction catalyst using transition metal-nitride, with nanoparticles made of a nickle-iron-nitride compound and nickle-molybdenum-nitride nanorods on porous nickle foam.

First author Luo Yu, a postdoctoral researcher at UH who is also affiliated with Central China Normal University, said the new oxygen evolution reaction catalyst was paired with a previously reported hydrogen evolution reaction catalyst of nickle-molybdenum-nitride nanorods.

The catalysts were integrated into a two-electrode alkaline electrolyzer, which can be powered by waste heat via a thermoelectric device or by an AA battery.

Cell voltages required to produce a current density of 100 milliamperes per square centimeter (a measure of current density, or mA cm-2) ranged from 1.564 V to 1.581 V.

The voltage is significant, Yu said, because while a voltage of at least 1.23 V is required to produce hydrogen, chlorine is produced at a voltage of 1.73 V, meaning the device had to be able to produce meaningful levels of current density with a voltage between the two levels.

Announcement to all CEP holders for synthesised APIs regarding presence of nitrosamines

Since July 2018, EDQM has been actively involved in activities related to the detection and control of nitrosamine impurities in sartan active substances (APIs) with a tetrazole ring for which there are CEPs. These activities have included contacting CEP holders to request data and corrective actions, assessing responses to such requests, GMP inspections of manufacturing sites, suspension of CEPs, where appropriate, and their restoration after appropriate corrective actions had been implemented. Additionally, for any APIs, for new applications for a CEP, during the renewal of a CEP or during any revisions where the synthetic route or sourcing is modified, the potential for presence of such nitrosamine impurities is systematically assessed. EDQM has also been involved in the activities of the OMCL network including coordination of sampling and testing. The Ph. Eur. monographs for the sartan APIs with a tetrazole ring have been revised as a consequence of the presence of nitrosamines in these substances.

As has been announced on the EMA and EDQM website recently, the presence of a nitrosamine impurity has recently been identified in ranitidine-containing medicinal products. As a result of this, action has been taken to suspend the relevant CEPs and more information is awaited to better understand the root cause of the presence of this nitrosamine impurity.

EMA and CMDh have published documents on their websites, (EMA/189634/2019 and CMDh/404/2019), “Information on nitrosamines for marketing authorisation holders” which request marketing authorisation holders (MAH) to follow an investigation process described for synthesised APIs (other than sartans with a tetrazole ring). Although EDQM does not expect that this issue impacts many substances, it is now appropriate to expand the review to all other APIs manufactured from chemical synthesis for which CEPs have been granted. EDQM therefore requests that the holders of such CEPs follow the process described here (which is a similar stepwise approach to that for MAH):

Step 1 – Risk evaluation: Companies holding CEPs should perform a risk evaluation of their chemically synthesised APIs with regards nitrosamine formation, using quality risk management principles, as outlined in the ICH Q9 guideline. The principles described in the ICH M7 guideline in relation to toxicology assessment, control strategy and changes to the manufacturing process for active substances should be applied.

The CEP holders should prioritise substances in order to establish the sequence in which they are to be evaluated. The factors that can be taken into account are outlined in the dedicated Questions and Answers documents EMA/CHMP/428592/2019 Rev. 1 and CMDh/405/2019, Rev.1 which are available on the EMA and CMDh websites and if any substances are identified as high priority, the risk evaluation should be done immediately. The risk evaluation should address not only risks from the manufacturing process but also those from the introduction of materials used in the manufacturing process (e.g. starting materials, reagents, solvents – fresh and recovered etc.).

The risk evaluation for all CEPs should be concluded at the latest by 26^th March 2020.

CEP holders are not required to confirm to EDQM that step 1 has been completed where no risk is identified. However where a risk is identified, EDQM should be immediately informed and the company should progress to step 2, confirmatory testing, and the timescales for when the confirmatory testing results will be provided to EDQM should be indicated to EDQM.

The outcome of step 1 relating to the risk evaluation performed for a CEP should be communicated to the customers in all cases (even if no risk is identified) such that the MAHs can use this information to fulfil their responsibilities as described in the documents, EMA/189634/2019 and CMDh/404/2019 mentioned earlier.

Step 2 – Confirmatory testing: in the event that a risk of presence of nitrosamines is identified as a result of the risk evaluation, confirmatory testing should be carried out using appropriately validated and sensitive methods in accordance with the prioritisation deriving from the risk evaluation conducted in step 1. Substances identified as high priority should be tested as soon as possible.

All APIs identified to be at risk of presence of nitrosamines should be tested and the results provided to EDQM with, if needed, a proposal for subsequent actions (such as revision of the CEP).

CEP holders should inform the EDQM immediately if the tests confirm the presence of a nitrosamine impurity, irrespective of the amount detected, and provide the results. The companies should then progress to step 3 after informing EDQM of the plan and timescales to complete step 3.

Step 3 – Revision to the CEP: Where nitrosamine impurities have been detected, CEP holders should apply for a revision to their application(s) in a timely manner to introduce any required changes, such as amendment of the manufacturing process or changes to specifications and introduction of controls.

The required revisions to the CEP applications should be concluded at the latest by 26^th September 2022 or at an earlier time if otherwise justified.

CEP holders are reminded that it is their responsibility to complete the procedure described in this announcement for all their impacted CEPs.

EDQM may contact CEP holders for information on the risk of nitrosamines at any step of this review and any such requests should be responded to fully and in a timely manner. EDQM will take action on any CEP (e.g. suspension) where information becomes available regarding an unacceptable level of nitrosamine impurities in the active substance which is the subject of a CEP.

EDQM reminds CEP holders that they should provide the appropriate information relating to the risk evaluation they have performed for their CEP to their customers in all cases (for steps 1 to 3, and for step 1 even if no risk has been identified) such that the MAHs can use this information to fulfil their responsibilities in a timely manner as described in the documents, EMA/189634/2019 and CMDh/404/2019 mentioned earlier.

Fall Regulatory Agenda: FDA Delays Release of Several Proposed Rulemakings

The latest regulatory agenda for the US Food and Drug Administration (FDA) was released on Wednesday, announcing the delays of several proposed rulemakings, and one new but expected addition on the importation of prescription drugs.

On importation, the proposed rule, which has been under review at the Office of Management and Budget since the beginning of November and is expected to be released by January, would allow pharmacists and wholesalers to import prescription drugs from Canada if the imports pose no additional risks and will save money.

The proposed rule is expected to have several key limitations (i.e. only facilities that also manufacture API for the FDA-approved version would be allowed) and exclusions (no costly biologics, drugs with a REMS or infused or injected drugs) that may raise questions about what drugs could be imported and how much could be saved.

And as the latest agenda says, this regulatory action “will be likely to have international trade and investment effects,” and Canadian pharmacists and Health Canada officials have pushed back against the proposal. FDA is also expected to release draft guidance to allow manufacturers to voluntarily import US versions of drugs sold in foreign countries.

Some Proposed Rulemakings Delayed

All of the other proposed and final rulemakings in the fall regulatory agenda were previously published in prior agendas, including the agenda from last May. But this latest agenda shows how a few of the proposed rulemakings are being held up.

For instance, in April 2020, FDA expects to publish a proposed rule on the modernization of the quality system regulation for medical devices. FDA previously said it would publish the proposed rule last September.

FDA also delayed its proposed rulemaking on excluding certain medical software functions from the definition of a device until next May. The agency previously said the proposed rule was coming in December.

The proposed rulemaking on the annual summary reporting requirements under the Right to Try Act were also delayed from last September to sometime this month.

The agency further held the release of its rulemaking on post approval changes to approved drug and biologic applications from next March to next September.

The fall agenda also includes a proposed rulemaking on pediatric study plan requirements for new drug and biologic applications, which is due for release in September 2020, but which had a legal deadline of July 2013.

And another proposed rulemaking to better define and clarify the roles and responsibilities of those engaged in the initiation, conduct and oversight of clinical investigations subject to IND requirements was also pushed back from April 2020 to September 2020.

Other proposed rulemakings have stayed the course since last May, including one on clinical holds in medical device investigations, which is due in February 2020, one on biologics regulation modernization, which is still slated for December and one on patent term restoration due in February 2020.

Final Rules

Some of the final rules expected to be released later this year or in 2020 also reveal how long or how quickly it can take a rulemaking to go from proposal to finalization.

For instance, a proposed rulemaking on changes to the way risks are presented in direct-to-consumer drug advertising may end up taking more than a decade to go from proposal through three comment periods to finalization next June.

A proposed rulemaking on postmarket safety reporting requirements for drugs and biologics has been lingering since 2003, but is expected to be re-proposed next June.

In contrast, the so-called “deemed to be a license” rule transitioning some new drug applications to biologic license applications is expected to go from proposal to finalization in less than a year. Similarly, a proposed rule on the de novo classification process for medical devices is expected to be finalized in June after being first proposed last December.

Fall 2019 Unified Agenda of Regulatory and Deregulatory Actions

FDA Raises Concerns With API Manufacturers

As quality issues have led to drug shortages, Donald Ashley, director of FDA’s Office of Compliance, raised several major concerns on Tuesday with the active pharmaceutical ingredient (API) industry, noting three trends related to the obfuscation of supply chain information, an increasing number of data integrity question marks and impurity concerns that have led to recalls.

On the obfuscation front, Ashley, speaking at the Association for Accessible Medicines’ conference in Bethesda, MD, noted that API companies sometimes fail to obtain and retain documents with the identity of the original manufacturer and certificate of analysis.

In addition, APIs, including opioids, are often distributed with inadequate certificates of analysis, which he said, “compromises supply chain accountability and traceability and may put consumers at risk.”

On data integrity, which often includes incomplete, inconsistent or inaccurate data, Ashley noted that of the warning letters issued to API manufacturers over the past four years, 73% have included including data integrity charges.

He also quoted from a warning letter sent to API manufacturer Lantech Pharmaceuticals in August, in which the firm admitted to “routinely deleting recovered solvents gas chromatography data older than three months permanently, without any backup.”

Ashley added: “Data integrity problems you can see are the tip of the iceberg,” noting that lapses often obscure other problems.

He also highlighted ICH’s Q7 guideline, which deals with the cGMPs for APIs, and which explains: “Agents, brokers, distributors, repackers, or relabelers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.”

On the impurities front, he also advised companies to consult ICH guidelines Q3A, Q3B(R2), Q3C, Q3D and M7(R1), as N-Nitrosodimethylamine (NDMA) and N-Nitrosodimethylamine (NDEA) have been found in a few different medicines. Recalls of the heartburn medicine ranitidine and the blood pressure medicine valsartan have occurred because of such impurities. However, FDA recently downplayed the levels of impurities in some ranitidine medicines, noting they “are similar to the levels you would expect to be exposed to if you ate common foods like grilled or smoked meats.”

Outside the API concerns, Ashley noted that overall, the number of warning letters issued by FDA has increased between FY 2015 and 2019, although the agency has seen improvements in reducing the time between when an inspection ends and when a warning letter is issued, from a median of 11.6 months in 2015 to 6.5 months in 2019. He noted FDA is hoping to bring the time between inspection and issuance of the warning letter to six months by FY 2020.

FDA issues final guidance for development of smallpox treatments as part of preparedness efforts

November 24, 2019 FWQRC

“While the World Health Organization declared smallpox eradicated in 1980, concerns have persisted that smallpox could be used as a biological weapon. The FDA plays a pivotal role preparing our nation to be able to protect the American people from biological threats, including by providing guidance and support for the development of medical countermeasures that can be used safely, effectively and reliably during public health emergencies,” said Anna Abram, FDA Deputy Commissioner for Policy, Legislation, and International Affairs.

“We work with government partners as well as non-government organizations, universities and research centers, and industry to further the development of medical countermeasures as part of our vital public health mission. Despite recent advances in developing an effective treatment for smallpox, drug developers still face challenges in bringing forward these medical countermeasures, which are critical should smallpox ever be used as a biological weapon. The agency’s work to advance safe and effective medical countermeasures is a high priority, and today’s final guidance on the development of drugs to treat or prevent smallpox builds upon currently available guidance, further advancing the agency’s long-standing commitment to the development of robust medical countermeasure preparedness efforts.”

On November 15, 2019, FDA issued final guidance, Smallpox (Variola Virus) Infection: Developing Drugs for Treatment or Prevention, which is designed to assist drug manufacturers designing studies to appropriately establish the safety and efficacy of drugs to treat or prevent smallpox infection.

Ebola survivor study expanded to include new technologies

November 24, 2019 FWQRC

In addition to supporting ongoing response to Ebola outbreaks in the Democratic Republic of the Congo (DRC), FDA and government partners are conducting studies in West Africa to better understand how Ebola affects patients who have survived, and to learn how to more effectively treat these patients’ chronic health problems

In 2016, FDA awarded a contract to Stanford University to help the global scientific community better understand the course of Ebola virus infection—an important factor in finding new treatments. In 2017, research was expanded to include Zika virus infection.
In September 2019, the project was again expanded, to apply a new method to the study of Ebola and Zika tissue samples. The Stanford laboratory will use multiplexed ion beam imaging (MIBI) to identify viral reservoirs—cells or anatomical sites where viruses accumulate and persist—for both Ebola and Zika infection, ultimately facilitating the deployment of novel, effective analytical technologies into federal laboratory space.

What is E. coli?

E. coli are mostly harmless bacteria that live in the intestines of people and animals and contribute to intestinal health. However, eating or drinking food or water contaminated with certain types of E. coli can cause mild to severe gastrointestinal illness. Some types of pathogenic (illness-causing) E. coli, such as Shiga toxin-producing E. coli (STEC), can be life-threatening.

People infected with pathogenic E. coli can start to notice symptoms anywhere from a few days after consuming contaminated food or as much as nine days later. Generally, the symptoms include severe stomach cramps, diarrhea, fever, nausea, and/or vomiting.

The severity or presence of certain symptoms may depend on the type of pathogenic E. coli causing the infection. Some infections can cause severe bloody diarrhea and lead to life-threatening conditions, such as a type of kidney failure called hemolytic uremic syndrome (HUS), or the development of high blood pressure, chronic kidney disease, and neurologic problems. Other infections may have no symptoms or may resolve without medical treatment within five to seven days.

Due to the range in severity of illness, people should consult their health care provider if they suspect that they have developed symptoms that resemble an E. coli infection, including HUS, but even healthy older children and young adults can become seriously ill.

People of any age can become infected with pathogenic E. coli. Children under the age of 5 years, adults older than 65, and people with weakened immune systems are more likely to develop severe illness as a result of an E. coliinfection. However, even healthy older children and young adults can become seriously

Outbreak Investigation of lllnesses caused by E. coli O157:H7 November 2019

FDA working to determine the source of contamination found in Ready Pac Bistro Chicken Caesar Salad, FSIS Announces Recall

On Nov. 21, 2019, the U.S. Department of Agriculture’s Food Safety and Inspection Service (FSIS) announced a recall by Missa Bay, LLC, a Swedesboro, N.J. establishment. The salad products subject to the recall can be found in a spreadsheeton the FSIS website and bear the USDA mark of inspection.

Do not eat the recalled products.

The salad product items were produced from Oct. 14, 2019 through Oct. 16, 2019, and the recommended “use by” date for all of the product was Nov. 1, 2019, or earlier. There is concern that some products may be in consumers’ refrigerators, or that portions may have been frozen, even though they are past their use by dates. These products should be thrown away or returned to the place of purchase.

Background

FDA, CDC, FSIS and state health authorities are investigating an outbreak of illnesses caused by E. coli O157:H7 in the U.S.

Products in the recall noted above were produced with the same lot of lettuce that was used to produce the packaged salad that the Maryland Department of Health found to contain E. coli 0157:H7.

That product was Ready Pac Bistro® Chicken Caesar Salad, lot #255406963, UPC 0 77745 27249 8, “Best By” date Oct. 31, 2019, and it is included in this recall.

FDA is tracing back the supply of the romaine lettuce in the Caesar salad. FDA has identified possible farms in Salinas, California. FDA is deploying investigators to determine the source and extent of the contamination. More information will be forthcoming as the investigation proceeds.

Although the ill people interviewed in Maryland reported eating Ready Pac Bistro® Chicken Caesar Salad, at this time, ill people in other states have not reported eating this particular salad. Therefore, exposure to this product alone does not fully explain other cases in the outbreak.

Case Counts

Total Illnesses: 17
Hospitalizations: 7
Deaths: 0
Last illness onset: November 8, 2019
States with Cases: AZ (1), CA (2), CO (1), ID (3), MD (2), MT (1), WA

FDA APPROVES NEW TREATMENT FOR ADULTS WITH PARTIAL ONSET-SEIZURES

The U.S. Food and Drug Administration today approved XCOPRI (cenobamate tablets) to treat partial-onset seizures in adults“XCOPRI is a new option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Patients can have different responses to the various seizure medicines that are available. This approval provides an additional needed treatment option for people with this condition.”

A seizure is a usually short episode of abnormal electrical activity in the brain. Seizures can cause uncontrolled movements, abnormal thinking or behavior, and abnormal sensations. Movements can be violent, and changes in consciousness can occur. Seizures occur when clusters of nerve cells (neurons) in the brain undergo uncontrolled activation. A partial-onset seizure begins in a limited area of the brain

The safety and efficacy of XCOPRI to treat partial-onset seizures was established in two randomized, double-blind, placebo-controlled studies that enrolled 655 adults. In these studies, patients had partial-onset seizures with or without secondary generalization for an average of approximately 24 years and median seizure frequency of 8.5 seizures per 28 days during an 8-week baseline period.

During the trials, doses of 100, 200, and 400 milligrams (mg) daily of XCOPRI reduced the percent of seizures per 28 days compared with the placebo group. The recommended maintenance dose of XCOPRI, following a titration (medication adjustment) period, is 200 mg daily; however, some patients may need an additional titration to 400 mg daily, the maximum recommended dose, based on their clinical response and tolerability

FDA, CDC, and state health authorities are investigating an outbreak of illnesses caused by E. coli O157: H7 in the U.S.