Improving Microbiological Control Of Non-Sterile Pharmaceuticals: Unlocking The FDA Guidance

 

The document is the first time that the FDA has pieced together a compliance framework for non-sterile medicines, and, in some ways, the document stands as a companion piece to the Aseptic Processing Guidance (issued in 2004, although in clear need of an update). The trigger for the non-sterile document was based on the pattern of non-sterile product recalls involving microbial contamination, based on the period 2014 to 2017 when 197 bacterial and fungal contamination events, associated with either the manufacture, packaging, shipping, or storage of the drug, were recorded.

 

 

This paper critically assesses the regulatory text.

 

For details, see:

 

Sandle, T. (2021) Improving Microbiological Control Of Non-Sterile Pharmaceuticals: Unlocking The FDA Guidance, Journal of GxP Compliance, 25 (6). DOI: https://www.ivtnetwork.com/article/improving-microbiological-control-non-sterile-pharmaceuticals-unlocking-fda-guidance

 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

FDA updates its database about all licensed biological products

 

The FDA has recently updated the “Purple Book” — a database containing information about all licensed biological products — new additions include patent information relating to biologics as well as FDA regulatory exclusivity information.

 

According to Pharmaceutical Online, the directory provides the opportunity for:

(i) potential partnerships for licensing of existing intellectual property;

(ii) new strategies regarding intellectual property enforcement and protection; and, potentially,

(iii) opportunities for the development of new technology.


Here is the link: https://purplebooksearch.fda.gov/ 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Useful FDA links

The following links relating to the U.S. Food and Drug Administration (FDA) may be of interest to readers.

 

FDA Home Page: http://www.fda.gov/default.htm

 

FDA GMP Regulations (CFR21): http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfr211_ 01.html

 

FDA Inspections Operation Manual: http://www.fda.gov/ICECI/Inspections/IOM/default.htm  

 

FDA Inspection Guides: http://www.fda.gov/ora/inspect_ref/igs/iglist.html  

 

FDA CBER Guidance / Guidelines / Points to Consider: http://www.fda.gov/cber/guidelines.htm  

 

FDA Guidance on Drugs:  http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInfor mation/Guidances/default.htm

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

FDA ANDA Submissions

 

The U.S. FDA has issued a new guidance document ‘ANDA Submissions – Amendments and Requests for Final Approval to Tentatively Approved ANDAs Guidance for Industry’.

This refers to assist applicants in preparing and submitting amendments to tentatively approved abbreviated new drug applications (ANDAs), including requests for final approval. This guidance provides recommendations on the timing and content of amendments to tentatively approved ANDAs to facilitate submission in a timely fashion to enable final approval on the earliest date on which the ANDA may lawfully be approved based on patent and/or exclusivity protections ("earliest lawful ANDA approval date").

See: https://www.fda.gov/media/119718/download

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Geriatric information in human prescription

 

New FDA draft guidance has been issued, titled ‘Geriatric information in human prescription drug and biological product labeling’

The draft guidance is intended to assist applicants of human prescription drug and biological products in determining the appropriate placement and content of geriatric information in labelling as described in the regulations for the content and format of labelling for human prescription drug and biological products.

The goal of this guidance is to provide recommendations to help ensure that appropriate information on the use of prescription drugs in geriatric patients is consistently placed in the proper sections and subsections within labelling so that the information is clear and accessible to health care practitioners and includes content that guides the safe and effective use in geriatric patients.

See: https://www.fda.gov/media/142162/download 

 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Use of Liquids and/or Soft Foods as Vehicles for Drug Administration

FDA has issued new draft guidance: “Use of Liquids and/or Soft Foods as Vehicles for Drug

Administration: General Considerations for Selection and In Vitro Methods for Product Quality Assessments Guidance for Industry.”

The introduction reads: “This guidance applies to orally administered drug products and provides recommendations to sponsors who will use or recommend use of liquids3 18 and/or soft foods as vehicles for drug administration in investigational new drug applications (INDs), new drug applications (NDAs), Biologics License Applications (BLAs), as applicable, and in supplements to these applications. This guidance addresses the approaches recommended for suitability determination of vehicles intended for use with specific drug products by providing the following…Considerations for selection of liquids and/or soft foods as vehicles…Standardized in vitro methodology and data recommendations for drug product quality assessments to qualify vehicle(s) for drug product administration… Recommendations to communicate acceptable (qualified) vehicles in drug product labeling. If certain foods are found unacceptable, they should also be included in the labelling.

See: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM614401.pdf

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

FDA: Gluten and drug products

A new document from the U.S. Food and Drug Administration (FDA): This guidance is intended to convey to drug manufacturers FDA’s recommendations on how certain drug products should be labeled regarding gluten, a matter of interest to individuals with celiac disease. Some individuals with celiac disease have faced difficulty when trying to determine whether specific drug products contain gluten. Confronted by uncertainty, some patients may forego important medication rather than risk an adverse reaction to gluten. Thus, even if gluten is not present at levels that would harm a typical individual with celiac disease, that individual may be harmed through uncertainty and lack of information. 

Celiac disease (also known as celiac sprue) is an immune-based reaction to dietary gluten that

primarily affects the small intestine in susceptible individuals; unmanaged celiac disease can lead to serious health complications. Approximately 1 percent of the U.S. population has celiac disease. It is characterized by ongoing inflammation of part of the lining of the small intestine that generally heals if foods containing gluten are excluded from the diet and returns if they are reintroduced. At this time, the treatment for celiac disease is adherence to a gluten-free diet. 

FDA’s food labeling regulations define gluten as “proteins that naturally occur in [wheat, barley,and rye or their crossbred hybrids] and that may cause adverse health effects in persons with celiac disease (e.g., prolamins and glutelins)” (21 CFR 101.91(a)). Consistent with this definition, the term gluten in this document refers to certain proteins found in wheat, barley, and rye or their crossbred hybrids that lead to symptoms associated with celiac disease. This guidance pertains to human drug products that pass through the small intestine.

See FDA

Posted by Dr. Tim Sandle

50+ FDA acronyms that matter to your business

The Vaisala Measurement & Monitoring Program is offering a list of useful FDA acronyms. For further details see: Vaisala.

FDA unveils plan to eliminate orphan designation backlog

U.S. Food and Drug Administration unveiled a strategic plan to eliminate the agency’s existing orphan designation request backlog and ensure continued timely response to all new requests for designation with firm deadlines. The agency’s Orphan Drug Modernization Plan comes a week after FDA Commissioner Scott Gottlieb committed to eliminating the backlog within 90 days and responding to all new requests for designation within 90 days of receipt during his testimony before a Senate subcommittee.

As authorized under the Orphan Drug Act, the Orphan Drug Designation Programprovides orphan status to drugs and biologics that are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases, which are generally defined as diseases that affect fewer than 200,000 people in the United States. Orphan designation qualifies the sponsor of the drug for various development incentives, including tax credits for clinical trial costs, relief from prescription drug user fee if the indication is for a rare disease or condition, and eligibility for seven years of marketing exclusivity upon approval. A request for orphan designation is one step that can be taken in the drug development process and is different than the filing of a marketing application with the FDA.

Currently, the FDA has about 200 orphan drug designation requests that are pending review. The number of orphan drug designation requests has steadily increased over the past five years. In 2016, the FDA’s Office of Orphan Products Development received 568 new requests for designation – more than double the number of requests received in 2012. The increased interest in the program is a positive development for those with rare diseases and under this new plan, the agency remains committed to advancing the program to ensure it can efficiently and adequately review these requests.

This is the first element of several efforts the FDA will undertake under its new “Medical Innovation Development Plan,” which is aimed at ensuring that the FDA’s regulatory tools and policies are modern, risk based, and efficient. The goal of the plan is to seek ways the FDA can help facilitate the development of safe, effective and transformative medical innovations that have the potential to significantly impact disease and reduce overall health care costs.

This is an edited version of the FDA press release, full details can be found here.

Posted by Dr. Tim Sandle

Takeaways From The FDA's Revised Quality Metrics Guidance

On November 23, 2016, the Food and Drug Administration (FDA) published a revised draft guidance for Submission of Quality Metrics Data. The guidance includes significant changes to the earlier quality metrics draft guidance issued by the agency on July 28, 2015.

FDA's Quality Metrics Initiative, announced in April 2013, encourages pharmaceutical firms to embrace continuous improvement and foster a culture of quality by collecting and reporting manufacturing quality data. During the comment period for the 2015 draft guidance, manufacturers acknowledged that the initiative has the potential to transform the way the pharmaceutical industry approaches overall product quality and the reliability of the supply chain. However, manufacturers and participants in ISPE’s Wave 2 Quality Metrics Pilot Program, conducted across 28 companies (83 sites, 60 products), expressed concerns over lack of clarity regarding implementation, timelines, definitions, and evaluation guidelines.

The document has been reviewed by Aravindhan Ramakrishnan for Pharmaceutical Online. It makes for an interesting read, see PharmaOnline.

Purchase:



Posted by Dr. Tim Sandle

European and US regulators agree on mutual recognition of inspections

Important news for those who work in organizations that regularly receive both U.S. FDA and European medicines agency inspectors. This has been a long time coming...a new transatlantic agreement is now in place, designed to will help to make better use of inspection capacity and reduce duplication.

This means Regulators in the European Union (EU) and the United States (US) have agreed to recognize inspections of manufacturing sites for human medicines conducted in their respective territories on both sides of the Atlantic.

Here is a press release from the European Medicines Agency (dated March 2, 2017):

Each year, national competent authorities from the EU and the US Food and Drug Administration
(FDA) inspect many production sites of medicinal products in the EU, the US and elsewhere in the world, to ensure that these sites operate in compliance with good manufacturing practice (GMP). Under the new agreement, EU and US regulators will rely on each other’s inspections in their own territories. In future, the need for an EU authority to inspect a site located in the US, or vice versa, will be limited to exceptional circumstances.

The agreement will enable both the EU authorities and the FDA to make better use of their inspection resources to help them to focus on other parts of the world where active pharmaceutical ingredients (APIs) and medicines for the EU or US markets are manufactured. This will ensure that patients can rely on the quality, safety and efficacyof all medicines, no matter where they have been produced. Around 40% of finished medicines marketed in the EU come from overseas and 80% of the manufacturers of APIs for medicines available in the EU are located outside the Union.

In the EU, inspections of manufacturing sites are carried out by national competent authorities from EU Member States. The European Medicines Agency plays an important role in coordinating these activities in collaboration with Member States.

The agreement is underpinned by robust evidence on both sides of the Atlantic that the EU and the US have comparable regulatory and procedural frameworks for inspections of manufacturers of human medicines. Teams from the European Commission, EU national competent authorities, EMA and the US FDA have been auditing and assessing the respective supervisory systems since May 2014, and have worked closely together to reach this agreement.

The agreement is an annex to the EU-US MRA which was signed in 1998 but is not yet implemented. Many provisions of the agreement have already entered into force and others will enter into force on November 1, 2017. By that date, the EU will have completed its assessment of the FDA and the FDA is expected to have completed its assessment of at least eight EU Member States, and will be gradually expanded to all Member States. The text of this agreement is now published on the website of the European Commission’s Directorate General for Trade.

Source: EMA

Posted by Dr. Tim Sandle

Compounded Drug Products That Are Essentially Copies

U. S. FDA has produced a draft guidance document titled “Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act.”

Section 503A, added to the FD&C Act by the Food and Drug Administration Modernization Act in 1997 and amended by the Drug Quality and Security Act in 2013, describes the conditions that must be satisfied for human drug products compounded by a licensed pharmacist in a State-licensed pharmacy or Federal facility, or by a licensed physician, to qualify for exemptions from the FD&C Act.

To qualify for exemptions under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act or the Act), a drug product must be compounded by a licensed pharmacist or physician who does not compound regularly or in inordinate amounts any drug products that are essentially copies of a commercially available drug product, among other conditions. This guidance sets forth the FDA’s policies regarding this provision of section 503A, including the terms commercially available, essentially a copy of a commercially available drug product, and regularly or in inordinate amounts.

The document can be found here: FDA



Posted by Dr. Tim Sandle

FDA - Product Design to Minimize Medication Errors

The U.S. Food and Drug Administration has produced a new guidance for industry of interest. It is titled “Safety Considerations for Product Design to Minimize Medication Errors.”

The introduction reads:

The recommendations in this guidance apply broadly to the development of drug and biologic products. Accordingly, this guidance is intended for sponsors of investigational new drug applications (INDs); applicants of new drug applications (NDAs), biologics licensing applications (BLAs), abbreviated new drug applications (ANDAs); and manufacturers of prescription drugs marketed without an approved application or over-the-counter (OTC) monograph drugs. This guidance provides a set of principles for using a systems approach to minimize medication errors relating to product design and container closure design and thus enhance patient safety.

The recommendations in this guidance document are intended to provide best practices on how to improve the drug product and container closure design for all prescription and non-prescription drugs and biologic products regulated by the Center for Drug Evaluation and Research (CDER), which are referred to collectively in this guidance as products. The guidance also provides examples of product designs that have resulted in postmarketing medication errors…”

The document can be accessed here: FDA

Posted by Dr. Tim Sandle

FDA Drug Regulation Procedure

The Food and Drug Administration (FDA) has the highest responsibility of regulating the safety of drugs and other medicines sold in the U.S. The approval process is divided into a pre and post phase and drugs cannot be sold on the market without FDA approval.

By Michael Monheit

How Information About Drugs Is Collected By The FDA

The FDA collects facts regarding new drugs entering the U.S. market by following these basic guidelines:

Perform Tests

When a company seeks approval for selling a drug on the U.S. market, it must first perform a drug test on animals in a laboratory to establish how the drug works in humans. Once these tests are complete, the company must present an Investigational New Drug Application (IND) and must get FDA approval before it can test the drug on humans.

Clinical Trials

The company will then undertake a three-phased human clinical trial process, which is monitored closely by the FDA. This is undertaken to ensure that the drug is safe and effective for the general public.

Data Sent To FDA Regulatory Body For Review

Once the data has been collected from the clinical trials, the company sends this information from all the tests as a New Drug Application (NDA) to the Center for Drug Evaluation and Research (CDER) of the FDA. The CDER statisticians, pharmacologists, toxicologists and physicians study and review the information given by the company. If this review determines that the benefits are more valuable than the potential risks during use, the FDA approves the drug for selling on the market.

After-Market Performance And FDA Monitoring

After the drug hits the market, the FDA monitors its performance in a myriad of ways. Medwatch, the safety information, and reporting program generally receives reports about any side effects or adverse reactions to any drugs from health care practitioners, pharma companies, and consumers. Medwatch also accesses databases that gather information about health results and use of prescription drugs. This data enables FDA staff to understand and identify medicinal side effects.

If the drug presents unexpected risks, then consumers and healthcare practitioners are issued with Drug Safety Communication from the FDA. A new drug label is introduced with a safety concern statement to ensure that the drug is used in a safe and effective manner. For instance, Xarelto, a blood thinning medication was prescribed to millions of patients across the country to prevent stroke-causing blood clots. While there hasn't been a recall of the drug, the FDA has issued a series of safety communications about the drug, along with two black box warnings. BloodThinnerHelp.com has stated that this black box type of warning is the strictest form of warning that the FDA can issue for any drug. This warning comes because there is reasonable evidence of major side effects associated with Xarelto.

In some instances, drugs with major adverse effects will be withdrawn from being sold on the market because of the safety hazards they pose. This is because the FDA determines that the risks of that particular drug outweigh the benefits it provides. In December 2014, the FDA delivered an Adverse Reaction report about Xarelto resulting in low blood platelet counts or thrombocytopenia. Before this, the FDA issued several warnings about Xarelto to the public. The FDA cautions patients taking certain medications to discontinue the use of Xarelto, as a way to responsibly communicate with them.

Limitations Associated With Garnering Safety Data

While the FDA makes a strong effort to properly regulate drugs, some limitations are associated with safety data:

The FDA offers guidance during clinical trials, but the number of people is small in comparison to when the drug reaches the market. This makes it hard to determine side effects initially.
Even though experts review clinical trial data, it is hard to detect all possible side effects from the drug.
When people on other drugs take a certain drug, it is practically impossible to ascertain the kind of reactions the combination creates.

At the end, the FDA faces several challenges when evaluating new drugs. A particular drug will be effective for some people while it may produce side effects in others. Once a drug is on the market, the FDA must continuously review it during its lifecycle to ensure safety for patients.

Bio:

Michael Monheit, the managing attorney at Monheit Law, has been working to assist individuals and families who have been harmed by defective drugs and products. In fact, Mr. Monheit served on the Plaintiff’s Steering and Executive Committee for MDL 1148. He understands how stressful it can be to stand up to a major corporation and is committed to making sure that plaintiffs know they have someone on their side.

FDA issues recommendations to reduce the risk of Zika virus transmission

The U.S. Food and Drug Administration  (FDA) has issued recommendations to reduce the risk of Zika virus transmission by human cell and tissue products. There is a potential risk that the Zika virus can be transmitted by HCT/Ps used as part of a medical, surgical, or reproductive procedure.

The guidance addresses donation of HCT/Ps from both living and deceased donors, including donors of umbilical cord blood, placenta, or other gestational tissues. The new guidance is a part of the FDA’s on-going efforts to protect HCT/Ps and blood products from Zika virus transmission.

Commenting further, Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research, stated: “Though there is more to be learned about the transmission of Zika virus, given what we know about the virus at this point, which also is informed by our understanding of similar viruses, we must address the potential risk of Zika virus transmission by human cells and tissues. Providing HCT/P establishments with donor eligibility recommendations will help reduce that potential risk.”

The report can be accessed here.



Posted by Dr. Tim Sandle

FDA - Data Integrity and Compliance With CGMP

The U.S. Food and Drug Administration (FDA) has released an important draft guidance for industry. the title is: "Data Integrity and Compliance With CGMP Guidance for Industry."

Data integrity refers to maintaining and assuring the accuracy and consistency of data over its entire life-cycle, and is a critical aspect to the design, implementation and usage of any system which stores, processes, or retrieves information. Data integrity is fundamental in a pharmaceutical quality system which ensures that medicines are of the required quality.

The introduction to the FDA guidance reads:

"The purpose of this guidance is to clarify the role of data integrity in current good manufacturing practice (CGMP) for drugs, as required in 21 CFR parts 210, 211, and 212. Part 210 covers Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General; part 211 covers Current Good Manufacturing Practice for Finished Pharmaceuticals; and part 212 covers Current Good Manufacturing Practice for Positron Emission Tomography Drugs. This guidance provides the Agency’s current thinking on the creation and handling of data in accordance with CGMP requirements.

FDA expects that data be reliable and accurate (see the “Background” section). CGMP regulations and guidance allow for flexible and risk-based strategies to prevent and detect data integrity issues. Firms should implement meaningful and effective strategies to manage their data integrity risks based upon their process understanding and knowledge management of technologies and business models."

The draft guidance can be accessed here.




Posted by Dr. Tim Sandle

Why it is Imperative that the FDA Oversee Lab Developed Tests

What are Laboratory Developed Tests (LDTs)? These are artificial diagnostic tests that are constructed and used in laboratories to detect diseases and infections. Edward Simpson looks at the matter further...

FDA laboratory developed tests are different from the standard diagnostic tools that medical practitioners are used to. Even though these tests have been there for years now, they have been subject to serious qualms. At present, The Food and Drug administration (FDA) is focused on regulating laboratory tests and coming up with FDA approved lab tests. The reason behind this is that the FDA claims that LDTs may have caused harm to patients as a direct result of misdiagnosis.

The move to regulate the diagnostic tests that have been developed in over a hundred laboratories is picking up quite a debate. The FDA seems to overlook the fact that doctors use diagnostic laboratory developed tests to determine if their patients are at risk for developing serious illnesses. It is for this reason that hospitals strictly use FDA approved kits. However, the a thousand plus single laboratories in the USA are overly motivated and dedicated to designing and using their own tests.

When it all Began

Since 1976, the USFood and Drug Administration have the mandate of regulating LabDeveloped Tests. In the past, the FDA chose not to enforce applicable regulatory requirements because LDTs were just basic lab tests that were used on restricted cases and only for rare conditions.

For over 4 decades now, the FDA has been keeping tabs on several LDTs which are said to pose high risks. The main concern being that people might get carried away and begin to administer treatment that might lead to over and/or under treatment.

The fact that we quickly become accustomed to advancement in technology also means that LDTs are ever evolving. Laboratory developed tests are becoming more complex and since they are widely used across the country, these tests may present higher risks to patients especially those diagnosed with cancer and Alzheimer’s disease.

The FDA made it publicly known that it intended to issue a draft stipulating its oversight framework over LDTs. This was on 31^st July 2014.  Since then, The Food and Drug Administration decided to focus on what LDTs can do for patients rather than shunning them just because they are manufactured and designed in a lab. An excerpt of this draft reads, “The FDA will continue to exercise enforcement discretion for LDTs that are used for rare diseases…”

Should the FDA oversee all Lab Developed Tests?

In its quest to start a premarket view for LabDeveloped Tests, the FDA pays attention to the use of LDTs by observing the following information

• Whether FDA approved diagnostic tests will give patients an effective diagnosis and treatment option.
• Whether these LDTs are used for diagnosis or screening.
• Whether medical practitioners will go beyond LDT results and find more means for diagnosis and treatment.
• Whether the laboratory developed tests used are intended for high risk diseases or not.
•  Whether where LDTs fail, there will be other alternative testing and treatment options used to save lives.
• Whether the adverse effects associated with LDTs is a risk worth taking.

After a recent agency meeting, the FDA informed Congress that is intends to exercise authority over LDTs. The agency went ahead to introduce a proposed regulatory framework and their suggestion to oversee all LDTs elicited a strong response for and against.

The truth of the matter is, times have changed and so have LDTs. Compared to some years back, LDTs have now increased not only in complexity but also in availability hence the urgent need for a FDA test. Having in mind that LDTs are now used to diagnoseboth common and serious medical conditions like heart disease, cancer and Alzheimer’s disease, it is only proper that the FDA oversee these tests to ensure that patients are safe.

With all that said, the answer to the question whether the FDA’s involvement in regulating all LDTs is good or not, the answer is a big Yes!

Fortunately, the FDA is now stepping up efforts to completea proposal for the premarket review of FDA laboratory developed tests. This means that the agency is willing to intensify its oversight role over high risk and low risk Laboratory Developed Tests. As the watch dog agency, the FDA will ensure that LDT tests are supported by evidence in addition to promoting patient confidence in the test results. Plus, it is the responsibility of the FDA to ensure that all LDTs have more accurate product labeling.



 Posted by Edward Simpson