What happens when an FDA Form 483 is issued?

An issued FDA Form 483 contains all of the inspector’s observations and judgments made during the inspection.

Advertisements

One of the chief aims of the FDA is to ensure the protection of public health and making sure that select types of organizations comply with the provisions of the Food, Drug and Cosmetic Act. It enforces these aims by conducting periodic inspections of the facilities and types of organizations that come under its purview. The FDA is empowered by the terms of the Federal Food, Drug, and Cosmetic Act, Sec. 704 to carry out these inspections to meet its stated intent. These organizations include:

  • Clinical trial sponsors
  • Clinical trial investigators
  • Institutional Review Boards (IRB)
  • Facilities that are involved in the business of manufacturing, processing or packing of FDA-regulated products

When the FDA finds that the organization is not meeting the set requirements; it issues either a Form 483 or a Warning Letter to the organization at the conclusion of the investigation. The first of these steps is the Form FDA 483. It is used to list the observations made from the inspection, in which it documents and communicates its concerns that it observes during its inspections. The FDA in its website says that the FDA Form 483 is issued to the management of the company “when an investigator(s) has observed any conditions that in their judgement may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts”.

SCMP

How does the FDA observe its findings?

The FDA ensures that there is no subjectivity in the matter of its observations, which is the prelude to issuing the company an FDA Form 483. There are no grey areas or any kind of arbitrariness on the part of the FDA investigators when they carry out their observations.

The FDA investigators are thoroughly trained to ensure that their observations are noted on the FDA Form 483 in a clear and specific format before it is issued. These are based on the thorough and demonstrable observations that the investigator makes. These observations should reflect that the “food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health.”

An issued FDA Form 483 contains all of the inspector’s observations and judgments made during the inspection. It will clearly specify the areas in which the organization fell short of regulatory requirements and expectations. When an FDA Form 483 is issued, it calls for a response within 15 working days of the issue. Although a written response is not a mandatory requirement; it constitutes good practice and is preferred. The response has to detail the reasons for the shortfalls and ways by which the organization will remedy them.

If the organization does not file a satisfactory response to the FDA Form 483 violations within the specified time period, it is issued a Warning Letter. The Warning Letter is the next action the FDA takes to elicit a response. The organization has to file a response to it within 15 working days. If it wants more time, it will have to ask for it in writing. If the FDA Form 483 and Warning Letter fail to evoke a proper and satisfactory response within this period, the FDA may proceed to take the appropriate legal action against the organization. Based on the nature and gravity of the deviations, these legal actions could include suspension or cancellation of the manufacturing license, withholding of the product approval, or even shutting down the business.

What is the purpose of lyophilization & Where it will be applied?

When an injectable drug is freeze-dried -this is the process of lyophilization -its compounds are stabilized.

Lyophilization is the clinical term for freeze-drying. In the simplest terms, it can be described as a technical process in which the moisture level of many materials is reduced, most times frozen, for the purpose of creating a new product or an ingredient.

When an injectable drug is freeze-dried -this is the process of lyophilization -its compounds are stabilized. This reconstitution process is helpful and necessary because substances in the drug get affected by outside or natural factors such as sunlight, oxygen, and pH values. These influences can bring down the effectiveness of these materials and molecules. It is to help them weather these countering factors that lyophilization is used. The aim of lyophilization is to make the best use of these compounds by preserving and protecting them in the form that can be used on patients.

pj_lifoAnim

Lyophilization not only shields the product from unwanted biological activity; it also extends shelf life, and can bring about greater precision in the dosage. This reconstitution is done just before administration.

Where is lyophilization technology applied?

Lyophilization technology is used in a number of applications. The most prominent ones that use lyophilization include biotech drugs, as well as a few complex or very sensitive molecules.

Many industries are in a state of flux, in that new technological keep coming up every now and then. Lyophilization should keep abreast of these technologies and help businesses in these industries to innovate their products to meet the market needs.

Is lyophilization a new process?

No. It may surprise many that its roots can be located to more than a millennium, to ninth-century Asia! However, it has regained some prominence of late, with the rise in the use of compounds, chemicals, molecules and other related substances in our daily lives. Today, nearly a third of products in the parenteral segment that come to the FDA for approvals are for lyophilized drugs. Market watchers speculate that in the very near future; this proportion to set to go up to 50 percent.

ics_flow

Characteristics of lyophilization

  • Products that are lyophilized can be expected to maintain their stability for 2 to 3 years in ideal conditions
  • Lyophilization calls for a high degree of expertise on the part of the manufacturer, since these drugs are derived out of formulations that are very complex
  • Labs form lyophilization cycles that help in optimizing its efficacy. They seek a reduction in the residual moisture, which is something that has to be done for every product. This process usually begins at a product’s clinical development stage and gets finessed at the time of commercial manufacture.

Biocompatibility testing and evaluations for medical devices

It is to prevent the occurrence of such events that biocompatibility testing and evaluations for medical devices has to be carried out.

Biocompatibility testing and evaluations for medical devices is a vital component of patient safety, for it is the only effective means to ensuring that a medical device or any related material, when it happens to come into contact with the patient’s body has to not only perform its intended purpose and function; it should also not result in adverse reactions for the patient.

When medical devices and/or materials come into contact with the patient’s body, they can cause problems or what may be termed adverse effects that can be either short-term or long-term adverse effects to the body. These effects, called acute to chronic, can result in mutagenic effects. It is to prevent the occurrence of such events that biocompatibility testing and evaluations for medical devices has to be carried out.

These evaluations for biocompatibility of medical devices are done to evaluate the interaction between a device and anything it comes into contact with within the patient’s body, such as cells, tissue or body fluids. Essentially, device biocompatibility is assessed to prevent biological risks from happening to the patient.

ISO standard for biocompatibility testing and evaluations for medical devices

The International Standards Organization (ISO) has a specific standard for carrying out and ensuring biocompatibility testing and evaluations for medical devices. It is called ISO 10993-1: 2009, and makes biological evaluation part of a structured biological evaluation program that comes under a risk management process. All these are carried out in accordance with ISO 14971.

ISO 10993-1, Biological Evaluation of Medical Devices – Part 1 The basis for biocompatibility testing and evaluations for medical devices is the Risk Management Process. This is the most prevalent standard for assessing biocompatibility testing and making evaluations for medical devices. In requiring biocompatibility testing and evaluations for medical devices to be conducted in compliance with Principles of Good Laboratory Practice (GLP) and/or ISO/IEC 17025 and requiring the consideration of evaluation of local and systemic risk factors; the ISO 10993-1 is considered the basis for determining the subsequent, necessary biocompatibility testing and evaluations for medical devices.

What factors are tested? In line with the principles set out in ISO 10993-1: 2009 on biocompatibility testing and evaluations for medical devices, specific testing is prescribed based on two factors: a) the type and the intended use of a medical device or related material, and b) the kind, tenure and extent of contact the medical device makes with the body.

ISO 10993-1: 2009 on biocompatibility testing and evaluations for medical devices requires assessment to be made for the following among others:

  • Cytotoxicity
  • Genotoxicity
  • Sub chronic toxicity
  • Sensitization
  • Irritation or intra-cutaneous reactivity
  • Implantation
  • Haemocompatibility
  • Systemic toxicity, etc.

Sources of contamination that exist in a clean room environment

Aseptic technique is suited for application in any clinical setting.

Aseptic technique is one of the methods used in eliminating or at least minimizing contamination in pathogens. It is also used to make compounding sterile products. Sterilized equipment, sterile apparel, high degree of processing, and cleaning on a continuous basis make up the important procedures used in aseptic technique.

The main aim of aseptic technique in cleanrooms is to ensure that the sterile product is sterile, safe and effective. Ensuring this is all the more important for injections that are administered to patients. Aseptic technique is suited for application in any clinical setting. Infections can be caused when pathogens come into contact with the patient through a number of sources such as equipment, the environment, or the personnel in the cleanroom.

bacteriology-laboratory-organization-36-728

The fact is that any patient is potentially vulnerable to infection. Further, certain conditions such as injuries caused by accident, immune disorders that upset the body’s natural defenses and extensive burns increase the susceptibility of the patient to greater levels of infection. Surgery, urinary catheters, drains and the insertion of intravenous lines are common situations that require the use of aseptic technique.

A learning session on all the areas of aseptic techniques

All the core aspects of aseptic techniques and the ways of applying them in a cleanroom environment will be the topic of a webinar that is being organized by Compliance4All, a leading provider of professional trainings for all the areas of regulatory compliance. The speaker at this webinar is Danielle DeLucy, who owns ASA Training and Consulting, LLC, which provides pharmaceutical and biologics-based companies with training and Quality Systems assistance that helps them meet regulatory compliance.

Please enroll for this webinar by visiting Aseptic Technique and Cleanroom Behavior

Why are cleanrooms built the way they are?

This course will review proper cleaning, gowning and ways to avoid the common sources of contamination that exist in a cleanroom environment. It serves as a good refresher for those personnel that are familiar with the way to properly work in the cleanroom. Danielle will explain the rationale behind designing cleanrooms the way they are and how this design helps in ensuring proper contamination control. She will review some of the proper methods of contamination control, such as cleaning and gowning.

gbhomeslider1

At this webinar, which is of high value to those involved in contamination control, such as aseptic operators, aseptic sample handlers, personnel who work in a Biological Safety Cabinet (BSC) and their management and Quality Assurance counterparts; Danielle will impart the following learning objectives:

  • Definition of Aseptic Processing (AP)
  • Terminal Sterilization vs. AP
  • Proper Personnel Behavior in a Cleanroom
  • Facility Design and how it impacts the product
  • A review of proper environmental monitoring practices and systems used
  • Aseptic Technique &clean room behavior.

FDA holds Cosmetic Manufacturers & distributors responsible for the safety and quality of their Cosmetics

In order to ensure compliance with its safety and quality standards; the FDA routinely carries out its own analysis of cosmetics.

Testing cosmetics before the FDA does it is a sound business strategy for cosmetic manufacturers. This is why: Cosmetic manufacturers and distributors are responsible for upholding the quality and safety standards set out by the FDA. This is a legal requirement on the part of players in the cosmetics industry. In order to ensure compliance with its safety and quality standards; the FDA routinely carries out its own analysis of cosmetics.

The regulatory agency is all the more proactive in carrying out its quality and safety checks on products that carry potential problems. It comes down heavily on such manufacturers by alerting consumers about the problem product. It also carries out regulatory and enforcement actions against such products and companies.

Another reason for which cosmetic products need to be tested thoroughly for their quality and safety is that although the FDA does not require cosmetic products and ingredients, except color additives, to get approved by the FDA before they enter the market; it has laws on how these cosmetic products need to be regulated in interstate commerce. This makes it necessary to comply with the FDA’s standards on cosmetic safety and quality.

One of the lines of defense for such companies is to carry out testing of their product themselves before they start selling it in the market. This is a sound practice that helps companies in the cosmetic industry avoid punitive actions from the FDA.

Getting the testing practice right

But then, this practice has to be inculcated in the right manner, or it serves little purpose. The ways of implementing the right methods for testing the quality and safety standards of cosmetics before they are distributed into the market will be taught at a webinar that is being organized by Compliance4All, a leading provider of professional trainings for all the areas of regulatory compliance.

At this webinar, the speaker is Rachelle D’Souza, who, as CEO of Regulatory Heights Inc., has successfully licensed various medical and consumer products and facilities with international regulatory authorities/agencies for multinational and start-up companies. The major learning Rachelle will offer at this webinar is the different ways by which to carry out practices that are prevalent in the cosmetic industry to help avoid enforcement actions from the FDA.

To gain knowledge of avoiding punitive actions from the FDA; please register for this webinar by visiting  Cosmetic Testing

Guidance on the FDA’s expectations

The important learning that this webinar will offer is that it will offer thorough guidance to cosmetic manufacturers and distributors, as also other entities such as color additive manufacturers and analytical and microbiological laboratories, on the recommendations and requirements that the FDA has with regard to the safety and quality testing of cosmetics.

In line with this topic, Rachelle will help participants explore important areas in this webinar, such as FDA considerations for microbiological testing, animal testing, potential contaminants, nanomaterials in cosmetics, cosmetic good manufacturing practices (GMP) compliance testing, shelf life/expiration dating, select cosmetic ingredients and color additive batch certification.

The content of this webinar is suited to act as a proper guidance to those involved in the various aspects of cosmetics, such as Cosmetic Manufacturers, Cosmetic Distributors, Cosmetic Ingredient Manufacturers, Color Additive Manufacturers, and Analytical and Microbiological Laboratories involved in Cosmetic/Cosmetic Ingredient Testing. They will benefit in a big way by learning about areas of FDA cosmetic regulations that Rachelle will explain at this session. She will cover the following areas at this webinar:

o  Microbiological Testing for cosmetics

o  Animal Testing & Cosmetics

o  Potential Contaminants

o  Color Additives & Batch Certification

o  Select Cosmetic Ingredients: Prohibited & Restricted Ingredients

o  Shelf Life/Expiration Dating

o  Nanomaterials in Cosmetics

o  Cosmetic Good Manufacturing Practices (GMP) Compliance Testing.

Understanding steam sterilization microbiology

The methods of steam sterilization microbiology need to be understood thoroughly, since they need to comply with regulatory requirements.

Steam sterilization is an important means of killing microorganisms in microbiology. Sterilization is the method of removing all viable organisms from a source in a defined environment. Microorganisms are said to be dead when they are rendered ineffective by a decrease in their population in an environment. When they are unable to grow within their environment; they are considered dead. They don’t usually die the moment they are exposed to an agent that kills them.

Autoclaving is an important device used in steam sterilization microbiology. In addition to being used for sterilizing many devices such as surgical instruments, laboratory items and many more; an autoclave is also used in microbiology to sterilize microorganisms that cannot be killed by normal methods such as boiling and the use of strong detergents.

Autoclave qualification

The methods of steam sterilization microbiology need to be understood thoroughly, since they need to comply with regulatory requirements. An autoclave needs to be qualified for its performance, the basis for which is a proper grasp of stream sterilization microbiology.

Sterilization process parameters need to be laid out as a basis for conducting autoclave performance qualification studies. Exact standards of steam sterilization need to be met, whether it is to qualify a new autoclave installation or to continue maintenance of existing equipment.

A learning session on these methods

The ways of doing this will be the learning a webinar from Compliance4All, a leading provider of professional trainings for all the areas of regulatory compliance, will be offering.

The speaker at this webinar is Danielle DeLucy, who owns ASA Training and Consulting, LLC, which provides pharmaceutical and biologics-based companies with training and quality systems assistance that helps them meet regulatory compliance. To understand the way by which your steam sterilization microbiology needs to meet regulatory compliance standards; please enroll for this webinar by visiting Steam Sterilization Microbiology

A full description of steam sterilization microbiology

Since successful autoclave Performance Qualification depends on a thorough grasp of steam sterilization microbiology; Danielle will describe the steam sterilization mechanism as it relates to bacterial cells and endospores. She will explain the process and key terminology, because understanding these fundamentals is critical to develop a successful autoclave sterilization process.

She will offer regulatory references requiring use of air removal verification tools, chemical indicators and biological indicators. She will also explain definitions for sterility assurance level, accumulated lethality, temperature mapping and biological verification.

Quality Assurance Managers, Supervisors, Validation personnel and Sterility Assurance personnel will find this course useful. It is to meet the following objectives that this webinar is being organized:

o  Steam sterilization on a microbial level

o  Autoclave Performance Qualification expectations

o  Regulatory and GMP requirements for steam sterilization

o  Process verification tools for use in an autoclave Common questions, problems and cGMPs.

Danielle will cover the following areas at this webinar:

o  Autoclave Performance Qualification expectations

o  Regulatory and GMP requirements for steam sterilization

o  Validation tools for use in an autoclave

o  Common questions, problems and cGMPs.

Regulations governing how combination products are regulated

Charles will explain all the facets of combination products, beginning with their definition.

The knowledge of combination products and their regulations is essential for regulatory professionals. This is because of the high proportion of combination products in the market, as well as the array of regulations that govern them.

21 CFR 3.2 (e) has a complete definition of a combination product. A combination product is one that is made by combining:

o  A drug and a biological product

o  A drug and a device

o  A biological product and a device

o  A drug, a biological product and a device

A combination drug is one that becomes a single product and is obtained by combining any of the above.

The FDA has a number of regulations on combination products that drug, medical device and biological companies need to show compliance with. 21 CFR Part 3 has regulations that relate to how companies need to assign their combination products to the FDA for review, and Part 3.4 explains how the FDA goes about in its work of designating the review of these products.

Recent regulation from the FDA

The FDA passed a recent regulation: the Final rule on postmarketing safety requirements for combination products, on December 20, 2016. This Rule, which came into effect from January 19, 2017, sets out the postmarketing safety reporting requirements for products

o  That are termed as constituent products, meaning the parts of the drug or devices or biological product that go into a combination product

o  Which are deemed as combination products since two or more different types of regulated products have gone into it, and whose constituent parts have received an FDA marketing authorization.

The FDA’s regulations for devices, drugs and biological products have many similarities. Yet, there are unique and different standards, reporting requirements and timeframes for each of these regulations. It is to harmonize the variations in these standards, which the FDA believes result in inconsistent and/or incomplete reporting relating to post-marketing safety, that the Final Rule came into effect. It seeks to bring about consistency and completeness in the safety reporting requirements of post-marketing activity of these products and avoid repetitive reporting for combination products that have received FDA marketing authorization.

ucm522943

An understanding of the complexities and intricacies of combination product regulation

A webinar that is being organized by Compliance4All, a leading provider of professional trainings for all the areas of regulatory compliance, will give a thorough understanding of combination products and their regulations. The speaker at this webinar, Charles H. Paul, who is the President of C. H. Paul Consulting, Inc., a regulatory, manufacturing, training, and technical documentation consulting firm which is in its twentieth year of business, will be the speaker.

To gain clarity on the regulations that govern combination products, please register for this webinar by visiting How combination products are regulated

Learning session with value add-ons

Charles will offer valuable learning during this session for professionals who are currently involved in the manufacture of combination products or are about to submit products in the near future for approval. Charles will explain all the facets of combination products, beginning with their definition. He will explain the complexities associated with these kinds of products to an organization from the perspective of the constituents of the combination product and give an understanding of how to overcome them.

Charles will also present scenarios that will discuss how and which regulations apply based on the device and the kind of facility manufacturing it. He will facilitate easier understanding of the complex process of regulation application by providing a job aid that will be a value addition to this webinar.

Different regulations for different combination products

In explaining the various regulations that govern combination products; Charles will explain how the regulatory process applies to them, since the approval process for a purely medical product varies from that of a purely biological or a purely pharmaceutical product. He will also review the kind of actions that attract 483’s from the FDA to give a clearer understanding of the approaches for GMP and regulatory applications.

Charles will cover the following areas at this session:

o  Definition of Combination Products

o  Combination Products and US Regulations

o  Combination Product Approval Process

o  GMPs for Combination Products

Warning Letter Case Study Review.