1、 FDA Factory Review Overview

As an important branch of the US Department of Health and Human Services (DHHS), the FDA shoulders the responsibility of regulating drugs, food, biologics, cosmetics, veterinary drugs, medical devices, and diagnostic products nationwide. For medical device manufacturers, QSR820 (21 CFR 820) is a quality management system regulation that must be strictly followed. This regulation conducts spot checks on medical device manufacturing enterprises of different categories based on product risk levels to ensure compliance with relevant FDA regulations. Generally speaking, one type of product is inspected once every 4 years, while the second and third types of products are inspected once every 3 years. However, if a company's products encounter problems at customs or adverse events occur in the United States, the frequency of spot checks will increase accordingly.

On January 31, 2024, the FDA released the Final Rule of the Quality Management System Regulation (QMSR), which revised the current Good Manufacturing Practices (CGMP) requirements for medical devices in the Quality System Regulation (QSR) (21 CFR 820) and incorporated them into the international standard ISO 13485:2016 for medical device quality management systems developed by the International Organization for Standardization (ISO). This change marks a further alignment between FDA's requirements for medical device quality management systems and international standards.

In recent years, Chinese manufacturers have consistently ranked first in the world in terms of sample size in international markets outside the United States. At present, there are about 4500 manufacturers registered with the FDA in China, with an annual inspection probability ranging from 2% to 3%. Usually, FDA factory inspections are conducted by one inspector for a 4-day on-site inspection, and manufacturers do not need to bear any inspection costs.




2、 Purpose of FDA overseas supervision and inspection

The core purpose of FDA's overseas supervision and inspection is to identify potential medical device issues before products arrive in the United States; Determine the compliance status of enterprise facilities with FDA requirements and medical device standards, in order to assist FDA in deciding whether medical devices are allowed to enter the United States; At the same time, ensure that medical devices regulated by the FDA comply with various regulations in the United States. Although these routine checks are not part of a public health emergency, they are an important means for the FDA to ensure that facilities and products of companies exporting medical devices to the United States comply with US regulations. It is worth noting that these inspections aim to assess whether enterprise facilities comply with applicable US laws, rather than evaluating the medical device safety systems of relevant regulatory authorities, thus distinguishing them from system reviews. All reviews are conducted by staff from the US FDA, who represent the interests of the US government regardless of their ethnicity.




3、 FDA's criteria for selecting inspection objects

The regulatory basis for FDA inspection:

Pharmaceutical: 21 CFR 210&211 (GMP)

Equipment: 21 CFR 820 (QSR820), 21 CFR 803 (MDR Medical Device Adverse Reaction Report), 21 CFR 801 (Labeling), 21 CFR 806 (Medical Device Correction and Removal Report), 21 CFR 807 (510K Registration)

 

Medical Device QSIT Quality System Inspection Technology

Among the 7 major subsystems, 4 key subsystems are:

Management Control, Corrective and Preventive Action (CAPA) (with auxiliary medical device reporting system, corrective and removal system, medical device recording system), Design Control, Production and Process Control (P&PC) (with auxiliary sterilization process control system).

This manual is a reference material for investigators and other FDA personnel. The document does not bind the FDA and does not authorize, benefit, or exempt any individual.




4、 FDA factory review cycle

The duration of FDA inspections in various countries: FDA arranges multiple inspection trips to a country within a year, with each inspection trip typically lasting three to four weeks.

Number of medical facilities inspected during the four week inspection period: Within three to four weeks, a single inspection trip may include four or more medical facilities.

Duration of each medical facility inspection:

Pharmaceutical: 2 reviewers (1 with a background in biochemistry and pharmaceuticals, 1 quality system expert), 4-5 working days;

Equipment: Both Class I and Class II equipment require one examiner; Three types of devices require one or two reviewers, 4-5 working days




5、 Response measures after receiving FDA factory inspection notification

When Chinese manufacturers receive review notifications from the US FDA, they usually attach great importance to and actively respond, mobilizing internal and external forces and resources to ensure the smooth progress of the review. However, there are also some manufacturers who, due to a lack of understanding of the importance of review, fail to give sufficient attention, resulting in a passive situation.

The process of FDA notifying medical enterprises of facility inspections: Enterprises need to first reply to confirm receipt of FDA inspection notification. After confirming that the inspection intention is known, the FDA will contact the company again through a letter, detailing the proposed inspection date and logistical information, including whether translation, production, processing, packaging, or storage facilities have been arranged, the complete and actual addresses, and the contact information of relevant responsible persons. The supervisory department will receive a copy of this notice. After the inspection arrangement is confirmed, the FDA will share the final itinerary plan with the regulatory authorities. If the enterprise facility fails to respond to the FDA's inspection notification, its products may be refused entry into the United States.

Can FDA review notice be refused: If a medical enterprise (such as an overseas factory, warehouse, or other facility) refuses to undergo FDA inspection, the FDA may refuse the medical enterprise from entering the US market. When FDA is denied inspection, all regulatory options will be considered to determine whether the relevant product meets the conditions for being denied entry into the US trade market. The measures that the FDA can take include: adding the company to the import warning list; Increase sampling and/or detection; Refusal of entry; Or other regulatory, judicial, and administrative measures. If a company's facility fails to respond to the notification of FDA's planned inspection, FDA may consider it as having refused the inspection, resulting in the product being refused entry into the United States.




6、 Adequate preparation for FDA factory inspections

FDA factory inspections should become a short-term focus for businesses, and comprehensive preparation is crucial.

Determine the scope and purpose of the inspection: Clarify the reason for the FDA visit, whether it is a routine inspection, a follow-up after a warning letter, or a report from someone. At the same time, review the results of previous FDA inspections, including the conclusion on whether there is a 483/EIR report and whether the response is acceptable.

Background investigation of inspectors: Collect background information of inspectors through various channels, such as education, experience, personality, age, specialties, recent travel, etc., and review all 483 forms or warning letters they have opened to understand their inspection characteristics.

Personnel preparation:

Select a spokesperson who is fluent in English and familiar with the company's quality system and FDA regulations as the primary spokesperson for communication with FDA officials.

Establish a review preparation team; Responsible for promptly following up on the progress of the company's preparation work, organizing personnel from various departments to receive relevant training on FDA factory inspection preparation work.

Clear division of labor: Determine the list and division of labor of accompanying personnel and reception personnel during the review period.

Hardware preparation: including maintenance and updates of factory buildings, production equipment, production process equipment, instruments, laboratory equipment, warehouse facilities, as well as maintenance and review of the factory environment and hygiene. Preparation of activity venues (meeting rooms) and toilets.

Data preparation;

1. Factory Introduction (PPT);

2. List of export orders to the United States in the past three years;

3. Quality manual;

4. Program files;

5. Batch Records for the Past Three Years (DHR);

6. Main document DMR, design history document DHF;

7. Training records;

8. Supplier information;

9. Internal audit/management audit materials;

10. Process validation and equipment confirmation documents;

11. Data on production equipment and measuring equipment;

12. List of changes in the past three years;

13. CAPA checklist and records for the past three years;

14. List and records of non-conforming products in the past three years.

15. Feedback and complaint list and records for the past three years

Administrative affairs preparation:

Timely response: Upon receiving the FDA factory inspection notification, a written response should be provided within one week.

Assist in processing invitation letters and visas: provide necessary assistance to examiners.

Booking hotels and arranging transportation: Assist the inspector in booking hotels (small and medium-sized cities need to confirm in advance whether the hotel accepts foreign credit cards, etc.), and arrange transportation.

Time arrangement: Make a good schedule for the review period.

Environmental hygiene: Pay attention to the hygiene of the factory environment.

7、 FDA factory inspection and inspector's audit skills

The correct way to communicate with the examiner:

1) Quick response: After the review begins, the examiner's mood is generally good. At this time, it is important to listen carefully to the questions they raise. If you do not understand, do not pretend to understand. Be sure to understand before answering. The required materials should be delivered as soon as possible. If time is needed to search, record it in a notebook and arrange for the corresponding personnel to search for it. After finding the file, mark it on the notebook to demonstrate the basic skills of document control. At the same time, answer the examiner's questions and provide documents as quickly as possible, accompany the examiner around the clock, keep them moving within the designated location, and prepare a document list for them, providing multiple documents for their inspection at once as much as possible.

2) Maintain a candid and open attitude: Once a problem with conclusive evidence is discovered, do not defend yourself, but avoid proactively disclosing the issue or displaying internal self inspection reports. On the premise of maintaining sincerity and politeness towards FDA inspectors, one should be able to speak as little as possible and know how to protect oneself.

Proactively guide and check the center of gravity:

1) Moderate guidance: Carefully observe the performance of the reviewer, identify their strengths and weaknesses, and provide moderate guidance and avoidance. For example, providing a painless internal self inspection report that leads to areas where the auditor is not proficient or where the company is doing very well, in order to avoid areas where the auditor is proficient or where the company has obvious deficiencies.

2) Consuming inspector time: FDA inspectors usually only have a few days in the factory, and may intentionally or unintentionally waste their time. For example, using PPT to provide a detailed introduction of the company, and then leading the auditor to visit the production process in detail. Due to the fact that the examiner is not very familiar with the specific production process of the equipment, a detailed introduction not only demonstrates professionalism, but also takes some time to visit the factory.

3) Prepare a case: Some reviewers may ask, 'Can you please show me a copy of the documents and cases related to xxx?' At this point, they will directly submit a pre selected perfect case.

Avoiding serious defects:

Not actively admitting intentional fraud: When preparing FDA factory review documents in advance, companies must carefully distinguish which documents may be suspected of intentional fraud and try to eliminate them as much as possible in advance.

Strive to reduce 483: When the inspector discovers a defect, try to communicate with them and provide sufficient evidence to persuade them to abandon listing it as an observation. At the final meeting, it is necessary to carefully read Form 483, and if there are different opinions, they should be firmly raised. Try to seize the opportunity to explain the defects before the reviewer leaves.




8、 Direct consequences of FDA factory review

There are three direct results of FDA factory audits, namely NAI, VAI, and OAI.

NAI (No Action Identified): Refers to the absence of any written form of non-compliance during FDA factory review, also known as "Zero 483".

VAI (Voluntary Action Identified): During the FDA factory inspection, the FDA inspector discovered that the factory's management system violated FDA quality system regulations, and subsequently issued a written form of non conformity, which can also be referred to as "483". The number of '483' may be 1, or it may be 20 or more. As long as the factory actively rectifies according to FDA requirements and provides sufficient evidence, it will not lead to further consequences.

OAI (Official Action Identified): A warning letter issued by FDA inspectors during a factory audit, indicating that the factory management system has serious violations of FDA quality system regulations or has not been able to promptly and adequately rectify VAI in accordance with FDA requirements. If only a warning letter is issued without an Import Alert, the manufacturer's products can still be exported, but the warning letter will be published on the FDA website, which will affect the confidence of American customers in the manufacturer. Measures must be taken to lift it as soon as possible.




9、 Professional assistance from Shenzhen Ruini Consulting Company

With 18 years of experience in FDA factory audit guidance, Shenzhen Ruienni Consulting Company has successfully helped more than 50 companies pass FDA factory audits (including several with zero defects). Our service advantages are significant:

Professional team: composed of experienced FDA regulatory experts familiar with the FDA factory inspection process and key points.

One stop service: providing full process companionship from early gap assessment to formulation, implementation, and follow-up of rectification plans.

Efficient communication: Provide professional translation and on-site support to ensure smooth communication with FDA reviewers.

Simulated inspection: By simulating FDA inspections, potential issues can be identified and resolved in advance.




10、 Experience sharing

Emphasize data integrity: strictly follow the principle of "traceability of data logic upstream and downstream chains" to ensure the authenticity and integrity of data.

Strengthen record management: Ensure that all records are clear, complete, and traceable, avoiding alterations or retroactive data.

Strengthen personnel training: Regularly conduct FDA regulations and data integrity training to enhance employees' compliance awareness.

Simulation inspection and self inspection: Conduct simulation inspection before FDA inspection to identify potential problems in advance and make corrections.

Efficient communication and quick response: During FDA inspections, actively communicate with reviewers to demonstrate determination and ability to make improvements.

Choose Shenzhen Ruienni Consulting to make FDA factory warning letter changes simple and efficient. We are committed to helping enterprises establish a sound quality management system, ensuring compliant operations, and assisting in their development.