The Food and Drug Administration (FDA) primary responsibility is the enforcement of the Federal Food, Drug and Cosmetic (FD&C) Act that tasked the agency with protecting and promoting public health and authorized the “legality of an FDA inspection, conducted at a reasonable time, within reasonable limits, and in a reasonable manner, depends not on consent but on the validity of statutory authority.” (Compliance Policy Guide Sec 130.100) This means that FDA does not require consent to conduct an inspection and that any firm that registers with the FDA for the manufacture of either Drug, Biologics or Medical Devices will likely be subject to an inspection at some point. The U.S. Food and Drug Administration’s Office of Regulatory Affairs (ORA) is the lead office for all agency field activities. ORA inspects regulated products and manufacturers, conducts sample analyses of regulated products and reviews imported products offered for entry into the United States. ORA operates on a risk-based approach, meaning they will prioritize their inspection schedules on those higher risk regulated products that may adversely affect public health, such as Pre-Market and Pre-Clearance inspections for Class III medical devices and Pre-Approval Inspections for sterile pharmaceuticals & biologics. Lower risk products are most likely not inspected in a biannual frequency- due to the lack of resources: See – https://www.fda.gov/about-fda/fda-organization/office-regulatory-affairs.
On January 31, 2020, Health and Human Services (HHS) issued a declaration of a public health emergency related to COVID-19 and mobilized the Operating Divisions of HHS. In addition, on March 13, 2020, the President declared a national emergency in response to the COVID-19 pandemic.
As a result, FDA prioritized their focus on regulated products that will help address the COVID-19 crisis through the Emergency Use Authorization or EUA process (See EUA blog post) as well as other regulatory approvals and pathways that fast track effective COVID-19 solutions to the market. Because of this, as well as the fact that physical inspections are currently out of the question due to COVID transmissibility, as of March 18, 2020 FDA inspectors have postponed most foreign facility inspections and all domestic routine surveillance facility inspections. However, this does not mean that they will not resume and that any firm should loosen or forgo good manufacturing practices, FDA can and is still issuing warning letters and other enforcement actions such as disbarment, seizure or a recall and the outcomes can be severe and crippling to a business that receives them.
It is critical to understand that the types and methods of inspection differ whether a firm manufactures, imports or distributes pharmaceuticals, biologics or medical devices, in the next section will go into the unique differences of each.
There are 4 types of Drug Manufacturing Inspections:
The first type of pharmaceutical inspections is “Surveillance” which are initial or routine biennial (every two years) inspections once a facility is up and running that cover actual conditions and practices, these can either be a full inspection which entails a verification of the four of the CGMP (Current Good Manufacturing Practices) systems (with Quality being mandatory) which are: Quality, Facilities & Equipment, Materials, Production, Packaging and Labeling and Laboratory Control Systems. The other Surveillance Inspection is an Abbreviated option which is only when a firm has a record of CGMP compliance and will cover usually two systems, one of which must be the Quality System.
Second is “Compliance” or “State of Control” which occur following a regulatory action taken and is usually a re-inspection to ensure compliance when significant changes in a firm’s personnel or operations have occurred, or if there is doubt about a firm’s GMP compliance. A firm is considered out of control if any one system is out of control. A system is out of control if the quality, identity, strength and purity of the products resulting from one or more system(s) cannot be adequately assured, this is indicated by documented CGMP deficiencies.
Third is “For Cause” which is a subset of compliance inspection which includes: follow-up compliance inspections to verify corrective actions after a regulatory action has been taken, or is regarding specific events or information such as field alert reports, industry complaints or a recall that bring into question the compliance of a facility or practice.
Last is the “Pre-approval” inspection which is required before any NDA is granted for a new drug. These inspections focus on Product development documentation, biologic/clinical batch manufacturing, the proposed manufacturing process, operational procedures, and batch records and the analytical method development.
The role and focus of these inspections are to examine system-wide controls that ensure manufacturing processes produce quality drugs and abide by CGMPs as per 501(a)(2)(B) of the FD&C Act, and if not, to provide input to firms to improve their compliance with regulations. If guidance is not followed then the agencies responsibility is to prevent adulterated products from entering the market and to act to protect public safety through legal or regulatory actions.
Biologics Manufacturers have a different set of inspections that include:
The compliance program of the Center for Biologics Evaluation and Research (CBER) provides two options for Biologics Manufacturers: Level I or Level II inspections, both of which fulfill the biennial inspection requirement. Note that CBER-regulated biological drug products include fractionated blood and their recombinant analogues; antitoxins; allergenic products; vaccines; products of manipulated, cultured or expanded human cells, and gene therapy products that introduce genetic material into the body to replace faulty or missing genetic material.
The Level I or Full inspection is meant to be a full evaluation of an establishment’s compliance with applicable CGMP requirements. They can apply in all of the following situations: Initial GMP inspection, firms that have a history of compliance problems, compliance follow-up inspections, for firms that are under a consent decree, permanent injunction, notice of intent to revoke, or after two previous inspections under the Level II option. The Level I option includes an in-depth audit of the three critical elements (procedures, training/personnel and records) in at least four of the systems, one of which must be the Quality System. Note that the Systems are similar to the systems inspected in the Drug inspection process, with the addition of the Donor Eligibility System, which includes the measures and controls that are related to determining the eligibility of a donor of allogeneic and family-related allogeneic HCT/P (Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P’s) products, including donor screening and testing.
A Level II or Abbreviated Inspection is focused on surveillance CGMP inspection that covers two of the key systems and can include reviewing and substantial to the facilities, manufacturing process, equipment, or other license supplements since the last inspection. The Level II inspection includes an in-depth audit of the three critical elements (procedures, training/personnel and records) of the Quality System and one additional system, which is determined during work planning. In successive inspections coverage of additional systems will be rotated in, unless there are issues identified during the current or previous inspection.
CBER’s responsibility and role in these inspections is to ensure biological products are safe and effective, and follow FDA guidelines and other applicable laws and regulations including CGMPS. Biological drug products are subject to both the drug CGMPS (21 CFR Part 210 and 211) and the Biologics regulations (21 CFR Parts 600-680) and are held to any commitments of their FDA-approved biologics license application (BLA). In total these inspections are necessary to reduce the potential risk of adulterated or misbranded biological drug products reaching the marketplace.
Types and Priorities of Medical Device Quality System Inspections
Medical devices inspections target manufacturers of Class II and Class III devices utilizing a risk-based methodology. The agency uses the risk-based model below to determine which firms to inspect and in what order to ensure they meet their internal FDA performance goals and allocate resources accordingly to ensure the highest level of safety across the industry.
- Pre-Market and Pre-Clearance inspections under MDUFMA (Inspections of manufacturers of devices with a pending PMA approval will be assigned under the PMA Compliance Program 7383.001)
- Manufacturers of Class III devices that have never been inspected
- Compliance Follow Up/For Cause Inspections
- Manufacturers of high-risk devices which can be identified by:
- Special Assignment from CDRH;
- Devices with a higher frequency of recalls and MDRs;
- Devices that are driven by software and those with rapidly evolving technological changes. Both of these types of devices are subject to rapid and potentially poorly controlled modifications that could affect their continued safety and efficacy; or,
- New devices that have not been manufactured and distributed for very long.
- Single Use Device Re-processors: Hospital re-processors and third-party re-processors.
Highest priority should be given to MDUFMA assignments and those Class III device manufacturers that have not been previously inspected. The high-risk device category noted in 4) above, lists suggestions to inspectors on how to identify firms for surveillance inspections based on a risk model. The Quality Systems regulation can be grouped into seven subsystems, with four being foundational to a firm’s quality system: Management Controls, Design Controls, Corrective and Preventative Actions (CAPA), and Production and Process Controls (P&PC). Medical Device Reporting (MDR), Corrections and Removals, and tracking requirements (where applicable) should be covered when covering the CAPA system. The three remaining subsystems are included across the quality management system and cover Facilities and Equipment Controls, Materials Controls and Document/Change Controls.
Medical Device Inspections have three levels of Inspections as well as two Special Inspections, however unlike the Biologics Levels of inspection, a level I medical device inspection is the abbreviated version, focusing on CAPA, Production and Process Controls or Design Controls. These Level I inspections may be used for routine surveillance and initial inspection of Class II medical devices manufacturers. Level II inspections are comprehensive inspections which cover all four major quality subsystems and are performed for all initial inspection of Class III device manufacturers and where possible higher risk Class II device manufacturers. Additionally, these Level II inspections are done for foreign inspections, or when an inspection, which started as Level I, reveal conditions or information that warrant a deeper inspection that Level I could not properly investigate.
Level III inspections are compliance follow-up to a Level I or Level II inspection and are to ensure that major deficiencies identified in prior inspections which are marked as Official Action Indicated (OAI) are resolved and addressed. The focus of the inspection is to ensure that adequate corrective actions to the problems identified in a prior inspection are addressed, if not then legal actions will be pursued for non-compliance. The first of the Special Inspection types is For Cause Inspections which are initiated from; results of a sample analysis, observations made during prior inspections, a recall or market withdrawal, a customer or employee complaint, adverse reaction report or suspicion of fraud. The second type is Risk Based Work Plan Inspections is a program developed by the agency to utilize science-based risk management to select and prioritize the facilities and medical devices to provide the most health promotion and protection to the public at the least cost. These work plan inspections are initiated at the request of CDRH based on their data analysis to make informed risk management decisions.
There are multiple objectives of these Medical Device inspections, first is to ensure compliance and proper implementation of Quality systems and to identify domestic or foreign manufacturers who are not in compliance with the Quality System Regulation. The second and third objectives are to identify manufacturers who are not reporting information to FDA in compliance with the Medical Device Reporting (MDR) and the Medical Device Tracking regulation. Fourth is to identify manufacturers and distributors who are not in compliance with the Corrections and Removals (CAR) regulation and bring them into compliance. The final objective of CDRH with these inspections is to identify and correct firms that are not in compliance with the Registration and Listing regulation and requirements.
Due to the nature and the complexity of managing and handling these site audits, as well as ensuring processes and procedures are adequate and running properly and covering all the systems based on the product, it is highly recommended to hire a third-party experienced auditor to conduct internal audits or gap analysis to provide critical feedback and recommendations before any FDA representatives arrive for inspection.
Here are the essentials for a successful FDA Inspection:
-Be Proactive in preparation and providing information and communication to FDA – Mitigate any FDA Issues immediately
-Facilities/Equipment/Systems need to be In Order
-Documents (SOP) and Records that are Compliant & Retrievable
-Demonstrate Firm is Operating in Control – produces finished drug products for which there is an adequate level of assurance of quality, strength, identity, and purity.
-SOP-Policy and Management of FDA Inspection
-Designate Right People for Handling Inspections
-Designated Inspection Work Space/Flow
If you or your firm has any regulatory needs or questions regarding a regulatory submission, mock inspections/audits or other issues please send us an email at email@example.com for a rapid response and quote for the required services.
- Compliance Program Guidance Manual Chapter 56: Drug Quality Assurance – Drug Manufacturing Inspections Program 7356.002. Food and Drug Administration. Published October 31, 2017.
- Compliance Program Guidance Manual Chapter 45:Biological Drug Products Program 7345.848. Food and Drug Administration. Implemented October 1, 2010.
- Compliance Program Guidance Manual Inspection of Medical Device Manufacturers Program 7382.845. Food and Drug Administration. Implemented February 2, 2011.
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