SUMMARY OF SERVICES
Wouldn’t it be nice to have the same people sent from the government to audit you,
build your Quality Assurance system, validate your cGxP, and draft your submissions?
As close as it gets. Hire Direct.
Keywords: Quality Management System (QMS) Implementation, GCP Gap Analysis, MDSAP, ISO 13485, ISO 14971, ISO 9001, cGxP, cGMP, cGCP, cGDP, cGLP, Regulatory Science, Regulatory Affairs, Remediation, Expert Witness, Clinical Trial, Design and Development, Biologics, Pharmaceuticals, CE Mark, Interacting with Regulatory Authorities (US FDA, Notified Bodies, Competent Authorities), FDA 483s, FDA Warning Letters, Product Recalls, Clinical Study Report (CSR) Audits, FDA style mock Inspection, FDA Submission, Pre-submissions, Market Approval Submissions, 510k, PMA, Trial Master File (TMF) Audits, Stress Test Audits, Internal Audits, CE Mark Requirements, Medical Device Regulations (MDR), Invitro Diagnostics Regulations (IVDR), Clinical Trial Regulations (CTR), Authorized Representative for CE and US FDA.
At the core of our services is experience. Tried and tested in the field as regulatory authorities, former US FDA inspectors and submission reviewers offer world-class, and globally recognized leadership for your manufacturing, design controls, and clinical trial needs. Whether it be US FDA, EU CE, or MDSAP and others, former US FDA regulators will develop, support, and stress-test your operation, so you can rest assured their former colleagues will be satisfied when they come to audit you or review your supporting documentation.
Although we cannot share all of our projects and clients as a testament to our abilities, we can share with you the operations we have investigated while serving the US FDA as this is public data. If you have not visited the “Whom have we Audited? page, please do so to get an idea of our foundational capabilities and experience.
Since then, we have expanded our services to include biologics, pharmaceuticals, and software.
FDA 483s
According to the US FDA:
An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant. Observations are made when in the investigator’s judgment, conditions or practices observed would indicate that any 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.
The FDA Form 483 notifies the company’s management of objectionable conditions. At the conclusion of an inspection, the FDA Form 483 is presented and discussed with the company’s senior management. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan expeditiously.
The FDA Form 483 does not constitute a final Agency determination of whether any condition is in violation of the FD&C Act or any of its relevant regulations. The FDA Form 483 is considered, along with a written report called an Establishment Inspection Report, all evidence or documentation collected on-site, and any responses made by the company. The Agency considers all of this information and then determines what further action, if any, is appropriate to protect public health.
How can we help?
As we have issued many 483s ourselves, we will first guide communications to give your organization time to remediate and respond correctly. Your initial response will be judged, and if a red flag is raised, the Agency will further scrutinize your organization and request more documentation from additional areas of your technical files. We will help you avoid this if possible. Once a proper response acquires the needed time, we will work with you to implement satisfactory corrective actions, and preventative actions (CAPAs) to meet regulatory requirements. The CAPAs in progress can buy your organization time once you demonstrate you are implementing them, but eventually, there will be a follow-up inspection wherein the inspectors will need to verify that the CAPAs are complete and have remediated the violations. We can support you throughout the whole process until your organization is up and running again. We will also equip and train your team, if desired, to ensure the violation or similar risks will never be repeated.
GCP Gap Analysis
A gap analysis is a technique used by a business or organization to determine if the current systems are compliant with the regulatory guidelines. With regards to GCP, a gap analysis reviews clinical research systems in a systematic way; identifying which areas are non-compliant and may lead to a compromise in data integrity, resulting in what can typically become disabling costs and delays. This method, known as a systems audit, is performed using ICH E6(R2) guidelines, US FDA 21 CFR 312 and 812 regulations, ensuring that the auditee's systems are GCP compliant for both the US, Europe, and other ICH observers. This approach can be applied to a variety of areas, from a set of departmental processes to an organization's entire quality management system.
How can we help?
At exFDA Consultants, we specialize in gap analyses for various types of clinical research quality systems, from sponsor systems to investigator sites, CROs, and laboratories. Our approach is systematic, utilizing at its core ICH E6(R2) guidelines, US FDA 21 CFR 312 and 812 regulations, in addition to their supporting regulations and guidelines, and focusing on people and their skills and training, processes and procedures, project management, and facilities, resources, and equipment in a logical and practical way.
Our team of consultants at exFDA are highly qualified for such audits, as they consist of former FDA inspectors who specialize in GCP. They bring a wealth of experience and knowledge to the table, ensuring that the gap analysis is conducted to the highest standards and that any non-compliant areas are identified and addressed effectively.
During an on-site visit, our typical agenda includes an opening meeting, a review of people and their training and competencies, a review of current systems, processes and procedures, a review of facilities, resources and equipment, interviews with key personnel, a closing meeting and presentation of non-compliant areas identified, and follow-up. After completion, a gap analysis report is distributed which includes non-compliant areas identified and recommendations. Our clients can then prepare a corrective action preventative action (CAPA) plan for review by the exFDA Consultants panel of SMEs.
FDA Warning Letters
Warning letters are a subcategory of Advisory Action Letters.
According to the US FDA:
Warning Letters are issued to achieve voluntary compliance and to establish prior notice. Warning Letters are issued for violations of regulatory significance that may lead to enforcement action if not promptly and adequately corrected. A Warning Letter is the agency's principal means of achieving prompt voluntary compliance with the Federal Food, Drug, and Cosmetic Act (the Act). Warning Letters are posted on FDA’s website.
An Untitled Letter cites violations that do not meet the threshold of regulatory significance for a Warning Letter. However, Untitled Letters serve as an initial notification to firms that FDA is aware of their violations of federal law. It often serves to document formal notification by FDA to the person or firm, and allows the firm to come into compliance without further FDA action.
The US FDA website lists 3 types of warning letters. They are described as follows.
General FDA Warning Letters
When FDA finds that a manufacturer has significantly violated FDA regulations, FDA notifies the manufacturer. This notification is often in the form of a Warning Letter. The Warning Letter identifies the violation, such as poor manufacturing practices, problems with claims for what a product can do, or incorrect directions for use. The letter also makes clear that the company must correct the problem and provides directions and a timeframe for the company to inform FDA of its plans for correction. FDA then checks to ensure that the company’s corrections are adequate. Matters described in FDA warning letters may have been subject to subsequent interaction between FDA and the recipient of the letter that may have changed the regulatory status of the issues discussed in the letter.
Tobacco Retail Warning Letters
Compliance check inspections of tobacco retailers occur periodically, and are conducted to determine a retail establishment’s compliance with the Federal Food, Drug, and Cosmetic Act, as amended by the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) and its regulations in effect, such as the Regulations Restricting the Sale and Distribution of Cigarettes and Smokeless Tobacco to Protect Children and Adolescents, found at Title 21 of the Code of Federal Regulations, Part 1140 (21 C.F.R. Part 1140). Tobacco products covered in compliance check inspections of tobacco retailers include cigarettes and smokeless tobacco.
Drug Marketing and Advertising Warning Letters (and Untitled Letters to Pharmaceutical Companies)
These letters, sorted by month, only cover Division of Drug Marketing and Communications and Drug Warning Letters. Some of the letters have been redacted or edited to remove confidential information. "Cyber" letters are sent electronically via the Internet to web sites that offer to sell online prescription drugs that may be illegal. The letters warn these web site operators that they may be engaged in illegal activities and informs them of the laws that govern prescription drug sales.
How can we help?
As stated above, there are various categories and types of warning letters. Your initial communications with the Agency are important. Although it is less likely in the instance of an Advisory Action letter, raising a red flag in your formal response can trigger further scrutinization of your organization and in turn further requests for documentation. Fortunately, Advisory Action letters are typically remediated easily by demonstrating a simple correction or removal of false claims in way the FDA can verify. We will immediately assess the risk the warning letter brings to your operation and guide you to efficiently “close-out” the observed violation. We will work with you to produce the correct proof required, and if required assist during a follow-up inspection, to receive your close-out letter.
As described on the US FDA website,
FDA may issue a Warning Letter close-out letter ("close-out letter") once the Agency has completed an evaluation of corrective actions undertaken by a firm in response to a Warning Letter. A close-out letter may issue when, based on FDA’s evaluation, the firm has taken corrective action to address the violations contained in the Warning Letter. This procedure applies to Warning Letters issued on or after September 1, 2009.
A close-out letter will not be issued based on representations that some action will or has been taken. The corrective actions must actually have been made and verified by FDA. Usually, the standard for verifying that corrections have been implemented will be a follow-up inspection. If the Warning Letter contains violations that by their nature are not correctable, then no close-out letter will issue. Future FDA inspections and regulatory activities may further assess the adequacy and sustainability of these corrections. Should violations be observed during a subsequent inspection or through other means, enforcement action may be taken without further notice. The FDA office that issued the Warning Letter will issue the close-out letter, and that office may be contacted for information on a particular Warning Letter.
Product Recalls
According to the US FDA:
Recalls are actions taken by a firm to remove a product from the market. Recalls may be conducted on a firm's own initiative, by FDA request, or by FDA order under statutory authority.
Class I recall: a situation in which there is a reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death.
Class II recall: a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.
Class III recall: a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences.
Market withdrawal: occurs when a product has a minor violation that would not be subject to FDA legal action. The firm removes the product from the market or corrects the violation. For example, a product removed from the market due to tampering, without evidence of manufacturing or distribution problems, would be a market withdrawal.
Medical device safety alert: issued in situations where a medical device may present an unreasonable risk of substantial harm. In some case, these situations also are considered recalls.
How can we help?
If you have been requested by the FDA to recall your products, you must do so immediately. If you are unsure you require a recall, we can help assess the situation and provide guidance. In any case, you will want to do it fast and stay compliant. We can assess your situation and guide your next steps swiftly while keeping you compliant, which in this case may very well mean, keeping out of a courtroom.
Clinical Study Report (CSR) Audits
The Clinical Study Reports (CSR) are expected to be in a format harmonized by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Although the US FDA does not typically reference the ICH directly in audit observations, inspectors or report reviewers will use the ICH for guidance to which they will then link citations back to US legislation. The US FDA inspectors and submission reviewers are trained to assess Clinical Study Reports using the ICH E3 Guidance document, but again, will typically cite US federal legislation. The guidance further indicates that region-specific regulatory requirements will be added as appendices. As a result, the interpretation of the observations and citations from US federal law to ICH references, and discerning between harmonized and regional requirements make remediation all the more challenging.
According to the ICH E6 Guidance (Current Step 4 Version), the CSR shall be
the compilation of a single core clinical study report acceptable to all regulatory authorities of the ICH regions. The regulatory authority-specific additions will consist of modules to be considered as appendices, available upon request according to regional regulatory requirements. The clinical study report described in this guideline is an "integrated" full report of an individual study of any therapeutic, prophylactic or diagnostic agent (referred to herein as drug or treatment) conducted in patients, in which the clinical and statistical description, presentations, and analyses are integrated into a single report, incorporating tables and figures into the main text of the report, or at the end of the text, and with appendices containing the protocol, sample case report forms, investigator related information, information related to the test drugs/investigational products including active control/comparators, technical statistical documentation, related publications, patient data listings, and technical statistical details such as derivations, computations, analyses, and computer output etc. The integrated full report of a study should not be derived by simply joining a separate clinical and statistical report. Although this guideline is mainly aimed at efficacy and safety trials, the basic principles and structure described can be applied to other kinds of trials, such as clinical pharmacology studies.
How can we help?
As regulatory officials, members of exFDA Consultants directly assessed hundreds if not thousands of CSRs. As a result, we are familiar with what regulatory authorities critically examine and how to discern the differences between harmonized and regional requirements. In cases where you have been issued a warning letter or 483, we are versed in interpreting US federal law back into ICH requirements, which allows us to clearly describe the solutions for quick and efficient remediation. Post-FDA employment, our members have successfully drafted CSR submissions to regulatory authorities of the USA and across Europe. This means we can effectively assess and guide remediation prior to an audit, or efficiently remediate warnings, observations, or citations afterward. Managing a successful CSR starts with the design and implementation of your study. The exFDA Consultants team is experienced in the clinical trial process from start to finish and post-market surveillance of the final product. We can help you every step of the way.
Clinical Trial Master File (TMF) Audits
The Trial Master File (TMF) of a clinical study is a compilation of essential documents both trial specific and non-trial specific that allows for seamless reconstruction of clinical development activities. The TMF must be readily made available for audits and inspections, and demonstrate all legal and regulatory requirements are met. However, what is considered essential continues to take into account the ever-changing environment and factors that a clinical trial must navigate.
How can we help?
The TMF is the showcase and index system of your clinical trial. As regulatory officials, members of exFDA Consultants directly assessed hundreds of TMFs and know what to prioritize. When foundational core documents such as the TMF are pulled, regulatory officials will first look for what we call in the industry, “low-lying fruit.” These are the most common errors found in the majority of trials and will create an opening for the regulators to dig deeper or expand the scope of their operations. Fortunately, we are familiar with what regulatory authorities prioritize and critically examine as we were once in their shoes. Post-FDA employment, our members have audited TMFs, reorganized TMFs, and guided gap remediation. Remediation prior to an audit not only prepares your team and stress-tests your system, but ensures your TMF will comply with the law allowing you to continue your study and support your intended claims.
Bioresearch Monitoring (BIMO) Audit
As stated on the FDA.gov website,
FDA's Bioresearch Monitoring (BIMO) program is a comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA-regulated research.
More specifically, the BIMO program objectives are to protect the rights, safety, and welfare of human research subjects; verify the accuracy, reliability, and integrity of clinical and non-clinical trial data submitted to the FDA; and assess compliance with FDA’s regulations governing the conduct of clinical and non-clinical trials, including regulations for informed consent and ethical review.
The BIMO program is housed in the ORA (Office of Regulatory Affairs) and is a shared inspection tool by all FDA centers. Notably, a large volume of BIMO inspections are initiated by FDA’s Center for Drug Evaluation and Research (CDER). Within CDER, the Office of Compliance works with ORA’s Office of Medical Products and Tobacco Operations (OMPTO), which is responsible for coordinating, interpreting, and evaluating the FDA’s field inspections for the research of medical products. Within the OMPTO sits the Office of Bioresearch Monitoring Operations (OBIMO), which is responsible for executing ORA’s BIMO program.
In this regard, it is important for Clinical investigators, Clinical research personnel (e.g., sub-investigators, study coordinators, regulatory specialists), Sponsors, Contract Research Organizations (CROs), Sponsor-Investigators, Institutional Review Board (IRBs) to understand how BIMO operates and what BIMO investigators look for. The foundation of the BIMO inspection will be Good Clinical Practice (GCP) and Good Laboratory Practice (GLP). In addition, BIMO will also target data integrity of Post-Market Adverse Event Reporting, Risk Evaluation and Mitigation Strategies Reporting, Nonclinical Lab operations, and Bioavailability/Bioequivalence Studies.
Since the foundation of a BIMO inspection is GCP, a prospective auditee should become familiar with the ICH E6. Although guidances such as the ICH E6R2 do not appear in the official citations to the auditee, they represent the current thinking on best practices of regulatory bodies.
The ICH E6R2 is a fundamental standard that provides recommendations on good clinical practice. Good Clinical Practice is the standard for the conduct of clinical trials that assures that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected. (1.24) Specifically, the ICH E6 lays the foundation for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of compliant clinical trials. Regulations relevant to GCP that a potential auditee should pay attention to are Electronic records and signature (21 CFR 11), Protection of human subjects (21 CFR 50), Financial disclosure (21 CFR 54), Institutional Review Boards (21 CFR 312), Applications for FDA approval to market a new drug (21 CFR 314), and Bioequivalence (21 CFR 320). Again, these regulations are not comprehensive, but adherence to these sections will ensure a strong foundation geared toward overall compliance and satisfying BIMO’s main objectives of human subject protection and data integrity.
Field guides referred to as Compliance Programs (CPs) describe how FDA BIMO investigators conduct these inspections and can be found in our Resources section. These field guides are meant to ensure uniformity across inspections to provide prospective, real-time and retrospective oversight of an operation.
Again, BIMO is an inspection tool all FDA departments utilize to oversee activity regarding human subjects and data collection. Therefore, multiple offices are involved and lend their expertise in analyzing areas respective of their departments. This includes the CDER Office of New Drugs, Office of Surveillance and Epidemiology, Office of Clinical Pharmacology, and Office of Biostatistics. At the conclusion of a BIMO inspection, an FDA investigator will often issue an FDA 483, inspectional observation form. This form will list all violative findings observed by the FDA investigator. It is imperative that any recipient of an FDA 483 responds in writing to the FDA as quickly as possible, noting all corrective and preventive actions.
How can we help?
Former FDA inspectors who have experience with the BIMO (Bioresearch Monitoring Program Information) program can help organizations prepare for and successfully navigate BIMO audits. They can provide guidance on what to expect during an audit and offer suggestions on how to effectively demonstrate compliance with BIMO regulations. This can include providing advice on how to effectively implement quality management systems and develop robust internal processes to ensure ongoing compliance with BIMO regulations. Additionally, former FDA inspectors may be able to provide insight on common areas of non-compliance and help organizations identify and address any potential issues before an audit occurs. This can help organizations avoid any potential penalties or fines associated with non-compliance and ensure that their research activities are carried out in compliance with BIMO regulations.
QMS Implementation
QMS stands for Quality Management System. It is a systematic approach to planning, implementing, and controlling the processes and activities that are necessary to ensure that a company's products and services meet the quality standards that are appropriate for their intended use. A QMS typically includes the policies, procedures, and processes that a company uses to manage and improve the quality of its products and services, as well as the resources, such as personnel and equipment, that are necessary to support these activities.
How can we help?
Former FDA investigators who have experience with QMS regulations can help with implementation by providing guidance and advice on how to develop and implement a QMS that is in compliance with relevant regulations and standards. This can include conducting inspections and investigations to assess a company's QMS and identify any potential areas for improvement, and providing recommendations for addressing any deficiencies or gaps in the system. Additionally, they can help a company develop and implement QMS-compliant policies, procedures, and processes, and provide guidance on how to continually monitor and improve the effectiveness of the system over time.
FDA Submissions / Applications
Q-Submissions (Q-Subs)
The FDA’s Q-Submission Program provides the industry an opportunity to collaborate with the FDA to discuss concerns in regard to a new device or intended submission of any kind in the form of a Pre-Submission (Pre-Sub). A potential submitter may have the FDA and the FDA’s subject matter experts address concerns directly in regard to a planned medical device or device-led combination product. The Q-Submittal Program is free and non-committal, which means the potential submitter, may choose to discontinue the submission process without record or consequence.
Premarket Notification (510k)
The 510k pathway is the most common premarket submission. The Traditional, Abbreviated, and Special application pathways for a 510k clearance can be discussed more during a consultation. The 510k is a premarket notification that refers to section 510(k) of the Federal FD&C Act. The information required in the application for premarket notification and market clearance is outlined in 21 CFR 807 Subpart E. The FDA will use the information to “clear” the subject product for market distribution within the USA by determining Substantial Equivalence. It is important to note that the 510(k) is not a form, establishment registration, device listing, or premarket approval. Once your device is cleared through the 510(k) program, it is only “cleared” and not to be promoted as “approved.” Only devices that pass the Premarket Approval (PMA) Process can be referred to as FDA Approved.
De Novo
The new Final Rule in regard to guidance and the RTA checklist changes, which was approved on October 5, 2021 , was implemented on January 3, 2022. The De Novo submission type is intended for devices that are automatically classified into class III by virtue of no known classification. In comparison to the 510k pathway, the De Novo is a pathway for devices or intended uses of combinations that have no clear substantial equivalence. As such, it requires a Premarket Approval (PMA) before it can be legally marketed. However, the device or intended use may be a class II or even only a class I after assessment. What the De Novo submission requests is for the FDA to determine reasonable assurance or safety and effectiveness of a new device. In this regard, the first goal of a De Novo is to determine whether the probable benefits of the device outweigh the probable risks to health — a standard benefit-risk analysis. Second, the FDA will determine what the risks are based on use to then decide on the appropriate regulatory controls. The De Novo submission is in essence, the request to create a new predicate device which would then be used as a substantial equivalent for further 510k pathway submission.
Investigation Device Exemption (IDE)
The IDE is a mechanism to request approval for a significant risk clinical study of an unapproved device or unapproved use of a device. Under section 520(g) of the FD&C Act, we are reminded that such programs exist with the main objective to protect the health and safety of the public with ethical standards while discovering and developing useful devices. This law is expressed through the regulations 21 CFR sections 812 (Investigational Device Exemptions), 50 (Protection for Human Subjects & Informed Consent, 54 (Financial Disclosure of Investigators, and 56 (Institutional Review Boards (IRBs)), and section 601 of the FDASIA (FDA Safety and Innovation Act). The common problems IDE applications encounter during submission to the FDA are inadequate report of prior investigations, inadequate investigational plan, and inadequate/incomplete design and manufacture. Applicants should invest early on in the development stage to ensure they maintain compliance throughout the study in regard to general responsibilities (§812.40), FDA and IRB approval (§812.42), selecting investigators (§812.43), selecting monitors (§812.43), device control (§812.43), investigator agreements (§812.43), informing investigators (§812.45), monitoring (§812.46), sponsor records (§812.140), sponsor reports (§812.43), labeling (§812.5), and promotion of investigational devices (§812.7).
Investigational New Drug (IND)
Once your preclinical studies are completed, you must compile animal study data, toxicity data, manufacturing information, data from any prior human research, information about the investigators, and the clinical protocols. Assuming all the pre-clinical and GxP evidence is sufficient, your application will be judged on its design. The IND is a mechanism to request a drug or biological drug be used in a clinical investigation. Clinical trials typically follow a 4 phase plan, but this is not required. As long as your pre-clinical studies demonstrate you have done your due diligence in determining the safety of the drug and that this has become the foundation of your clinical study design, you would then just focus on meeting the scientific requirements of conducting a study that prioritizes the protection of not only the participants but the integrity of the data. Everything must be planned. You must include selection criteria, number of required participants, the timeline of the study, whether there will be a control group or method of avoiding bias, the assessments including when and what, and how the data will be reviewed and analyzed. The FDA IND Review Team will consist of a project manager, a medical officer, a statistician, a pharmacologist, and pharmakineticist, a chemist, and a microbiologist. Provided your preclinical studies are complete and you have presented yourself as competent and capable, the FDA Team will work with you to develop your clinical trial in the areas it feels your study falls short. After the concerns of the FDA Team are addressed, your IND application will be approved and you will be clear to conduct your clinical trial in the US.
New Drug Application (NDA/ANDA)
The NDA is the final step in bringing your drug product to market. Much has been done to get to this point, which means preclinical studies, GxP documentation, and clinical trial design have all passed muster. Emphasis will be placed upon the reliability of clinical trial data and conclusions that can be scientifically drawn despite investigator and monitoring issues that arose during the study. Developers must include reports on all studies, data, and analyses in addition to proposed labeling, safety updates, drug abuse information, patient information, any data from studies that may have been conducted outside the United States, Institutional review board compliance information, and directions for use. During the review process, an appropriate SME will be assigned to each section of the application. Inspectors will also travel to the clinical study sites to conduct a routine inspection to find evidence of fabrication, manipulation, or withholding of data. The project manager will assemble all observations into an “action package” for the team to make recommendations, and a senior FDA official to make the final decision.
Biologics License Applications (BLA)
The BLA is a mechanism to request permission to manufacture and distribute a biological product across the USA. In addition to an approved IND, the manufacturer or agent responsible must demonstrate that the product is reliably “safe, pure, and potent” before manufacture and distribution. Surrounding this main objective, the applicant must guarantee that manufacturing facilities are readily available to inspect and provide supporting documentation upon request. To maintain the license, the sponsor must submit annual reports, reports on adverse events, and any changes in regard to design control and quality assurance. These requirements are defined in 21 CFR 600 to 680 and fall under the responsibility of the Center for Biologics Evaluation and Research (CBER).
Premarket Approval (PMA)
The PMA is a mechanism to request approval for a Class III device. A Class III device is the most regulated device; it is considered a private license granted to the applicant for marketing a particular device. The approval process is an in-depth scientific review to ensure the safety and effectiveness of the device. A Class III device is critically examined as it is defined as one that supports or sustains human life or is of substantial importance in preventing impairment of human health or presents a potential, unreasonable risk of illness or injury. The three categories of PMA devices are preamendment devices, post-amendment devices, and transitional Class III devices. If no final classification has been published, a preamendment device is not required to submit a PMA. However, all preamendment devices will eventually require a PMA. Post-amendment devices that are substantially equivalent to preamendment devices are subject to the same requirements as the preamendment devices and can be reviewed in accordance with section 510(k) as a Class III 510k. When deemed not substantially equivalent, these devices are designated as Class III transitional devices or “new” devices and require the submission of a PMA or Product Development Protocol (PDP). Clinical studies that arise from the submission process are subject to IDE regulations. The review of a PMA is a four-step process consisting of administrative and limited scientific review (21 CFR 814); in-depth scientific, regulatory, and Quality System review (21 CFR 814.44 & 820); review and recommendation by the appropriate advisory committee/panel review (21 CFR 814.44); and final deliberations, documentation, and notification of the FDA decision.
How can we help?
Former FDA investigators can help with submissions by providing guidance and advice on how to prepare and submit regulatory documents and information to the Food and Drug Administration (FDA) in a way that is compliant with relevant regulations and standards. This can include reviewing submissions to ensure that they are complete and accurate, and providing recommendations for addressing any deficiencies or areas for improvement. Additionally, they can help a company understand the FDA's submission and review process, and provide guidance on how to effectively communicate with the FDA and respond to any questions or concerns that may arise during the review process. Overall, the expertise and knowledge of former FDA investigators can help a company successfully navigate the regulatory landscape and increase the likelihood of a successful outcome for their submission.
cGxP Implementation
Good Manufacturing Practice
cGMP stands for "current good manufacturing practice." It is a set of regulations established by the Food and Drug Administration (FDA) to ensure the quality of pharmaceutical products. These regulations cover all aspects of the manufacturing, processing, and packaging of pharmaceuticals, including facility design, equipment maintenance, and the purity and strength of the final product. Former FDA investigators are individuals who used to work for the FDA and have experience conducting investigations into pharmaceutical manufacturing facilities to ensure that they are in compliance with cGMP regulations. They can use their expertise and knowledge of cGMP regulations to help companies that manufacture pharmaceutical products to ensure that they are in compliance with these regulations and avoid potential FDA enforcement actions.
Good Clinical Practice
GCP stands for Good Clinical Practice. It is a set of internationally-recognized ethical and scientific quality standards for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials. These standards are intended to protect the rights, safety, and well-being of trial participants, and to ensure the integrity and accuracy of the clinical trial data. Former FDA investigators who have experience with GCP regulations can help with implementation by using their expertise and knowledge of the regulations to assist pharmaceutical companies in complying with GCP requirements. This can include conducting inspections and investigations to ensure that clinical trials are being conducted in accordance with GCP standards, and providing guidance and advice to companies on how to implement GCP-compliant processes and procedures. Additionally, they can help identify any potential gaps or areas for improvement in a company's GCP compliance program and provide recommendations for addressing these issues.
Good Laboratory Practice
GLP stands for Good Laboratory Practice. It is a set of regulations that apply to non-clinical laboratory studies that are conducted as part of the safety evaluation of chemicals and other products regulated by the Food and Drug Administration (FDA) in the United States. These regulations are intended to ensure the quality, integrity, and reliability of the data generated from these studies, and to protect the rights, safety, and well-being of animals used in the studies. Former FDA investigators who have experience with GLP regulations can help with implementation by using their expertise and knowledge of the regulations to assist companies in complying with GLP requirements. This can include conducting inspections and investigations to ensure that laboratory studies are being conducted in accordance with GLP standards, and providing guidance and advice to companies on how to implement GLP-compliant processes and procedures. Additionally, they can help identify any potential gaps or areas for improvement in a company's GLP compliance program and provide recommendations for addressing these issues.
Good Documentation Practice
Good Documentation Practices (GDP) are a set of guidelines that outline the requirements for creating, maintaining, and managing documentation in the pharmaceutical industry. These guidelines are intended to ensure that documentation is complete, accurate, and legible, and that it is created, handled, and stored in a way that maintains its integrity and facilitates easy retrieval. GDP guidelines are relevant to a wide range of documentation, including raw data, laboratory notebooks, study protocols and reports, manufacturing and control records, and other documents related to the development, manufacture, and control of pharmaceutical products. Former FDA investigators who have experience with GDP guidelines can help with implementation by providing guidance and advice on how to create, maintain, and manage documentation in compliance with GDP requirements. This can include conducting inspections and investigations to ensure that documentation practices are in compliance with GDP standards, and providing recommendations for improving documentation practices and procedures. Additionally, they can help identify any potential gaps or areas for improvement in a company's GDP compliance program and provide guidance on how to address these issues.
How can we help?
Claiming cGxP implementation is quite bold. However, we like to emphasize the core principles remain the same whether it is GMP, GCP, GLP, or even GDP. When FDA investigators examine a quality management system (QMS) during an audit, it is vital they recognize good practice across all spectrums of design & development, manufacturing, and quality assurance. These areas of good practice, however, will require a degree of knowledge or direct experience in a given field. Investigators acquire this knowledge over years of auditing similar classes of devices. At times when they must audit unfamiliar products or processes, they turn to internal subject matter experts (SMEs). Our team is a blend of subject matter experts with extensive education and experience across multiple fields suited for FDA-cleared or approved products with experienced former FDA investigators and submission reviewers from various departments. We will not only prioritize what is to be critically examined but ensure your system is in fact compliant from its foundation up.
MDSAP
MDSAP stands for Medical Device Single Audit Program. It is an audit program that allows medical device manufacturers to undergo a single audit that satisfies the requirements of multiple regulatory agencies, including the Food and Drug Administration (FDA) in the United States, as well as regulatory agencies in Australia, Brazil, Canada, and Japan. By participating in MDSAP, medical device manufacturers can demonstrate that their quality management systems are in compliance with the relevant regulations and standards, and can reduce the burden of undergoing multiple separate audits by different regulatory agencies.
MDSAP is important because it helps to ensure the safety and effectiveness of medical devices, and helps to facilitate international trade in medical devices by providing a streamlined, consistent approach to regulatory compliance. Additionally, MDSAP can help to improve the efficiency and effectiveness of the regulatory process, by reducing duplication and allowing manufacturers to focus on continuous improvement of their quality management systems.
MDSAP is desirable because it provides several benefits to medical device manufacturers. Some of the key advantages of MDSAP include:
MDSAP allows medical device manufacturers to undergo a single audit that satisfies the requirements of multiple regulatory agencies, including the Food and Drug Administration (FDA) in the United States, as well as regulatory agencies in Australia, Brazil, Canada, and Japan. This can reduce the burden of undergoing multiple separate audits by different regulatory agencies, and help to ensure that a company's quality management system is in compliance with the relevant regulations and standards.
MDSAP helps to ensure the safety and effectiveness of medical devices, by providing a consistent, internationally-recognized approach to evaluating the quality of these products. This helps to protect patients and healthcare providers, and to ensure that medical devices are reliable and effective.
MDSAP can facilitate international trade in medical devices by providing a streamlined, consistent approach to regulatory compliance. This can make it easier for medical device manufacturers to sell their products in multiple countries, and can help to support the global medical device industry.
MDSAP can improve the efficiency and effectiveness of the regulatory process, by reducing duplication and allowing manufacturers to focus on continuous improvement of their quality management systems. This can help to speed up the process of bringing new medical devices to market, and can help to ensure that manufacturers are able to respond quickly to changing regulations and market conditions.
To participate in the MDSAP, medical device manufacturers must undergo an audit by an MDSAP-recognized Auditing Organization (AO). The AO will conduct a thorough evaluation of the manufacturer's quality management system to assess its compliance with the relevant regulations and standards. If the manufacturer is found to be in compliance, the AO will issue a certificate of conformity, which will be recognized by all participating regulatory agencies. The manufacturer will then be subject to periodic surveillance audits to ensure that they continue to comply with the MDSAP requirements.
Overall, the MDSAP is implemented through a combination of collaboration among the participating regulatory agencies, thorough audits by MDSAP-recognized AOs, and ongoing surveillance to ensure continued compliance.
How can we help?
Former US FDA inspectors are able to help with acquiring MDSAP clearance and maintenance by providing guidance on the specific requirements and regulations that must be met in order to obtain MDSAP clearance. We offer advice on how to prepare for an MDSAP audit, including what information and documentation is required, and how to effectively demonstrate compliance with MDSAP standards. Additionally, our knowledge of the FDA's inspection processes and requirements can help manufacturers ensure that their facilities and processes are compliant and meet the standards necessary for MDSAP clearance.