FDA Inspections

Abstract

The regulation of the manufacturing of cellular therapy products and vectors is under the auspices of the Food and Drug Administration (FDA) in the United States. For cells that are more-than-minimally manipulated, the regulations require that manufacturing is performed according to current Good Manufacturing Practices (cGMPs) (1). To ensure compliance the FDA sends out inspectors to audit manufacturers of both cGMP products and producers of Human Cells, Tissues, and Cellular and Tissue-Based products (HCT/Ps) (2). The latter are inspected for current Good Tissue Practices (cGTPs). This chapter recommends procedures to be followed when an audit is performed by a regulatory authority.

1 FDA Inspection Program

1.1 Inspection of Type 361 Product Manufacturing Establishments (cGTP)

The inspection program for HCT/P is under the Center for Biologics Evaluation and Research (CBER) at the FDA. The recent history of the inspection program is shown in Fig. 1.

Fig. 1

Number of FDA HCT/P establishment inspections by year and actions taken

The average time taken per inspection was between 34 and 41 h. The agency generally identifies establishments to be inspected from its listing of registered establishments. This list is compiled from an annual registration procedure that is described in Title 21 of the Code of Federal Regulations Part 1271 Subpart B [1]. The registration form is completed online (FDA Form 3356), and full instruction for registration can be found at: https://www.fda.gov/media/109160/download

The HCT/P inspection program covers only products that are minimally manipulated, intended for homologous use, are not combined with another article and do not have a systemic effect or are dependent upon the metabolic activity of other cells for primary function and are for autologous use or allogenic use in a first- or second-degree relative, or are for reproductive use [2]. Cells not meeting these specifications may be regulated as biological drugs or medical devices and are inspected under different regulations described later. If the HCT/Ps were recovered before May 25, 2005, the inspections are performed according to the Inspection of Tissue Establishment regulations [2].

The frequency of HCT/P establishment inspection is not predetermined but is based upon potential risk, whether the establishment previously received an official action finding and whether the FDA has received information about potential violations. Inspections are usually unannounced with the exception of those relating to medical devices, inspections under the bioresearch monitoring program (unless being performed for cause), and pre-licensing biologics inspections.

At the start of the inspection, the inspector will issue the establishment with a Form FDA-482 “Notice of Inspection” and ask to see the most responsible person at the establishment. They will identify themselves and show their official credentials. The purpose of the inspection will be explained, and they will inform you as to which records they will want to see, whom they may want to interview, and which procedures they may wish to observe.

The inspection will be based on the elements of the current Good Tissue Practice regulations shown in Tables 1a, 1b and 1c.

Table 1a Donor eligibility inspection of HCT/P establishments shown by regulations and major inspection elements

Table 1b Labeling inspection of HCT/P establishments shown by regulations and major inspection elements

Table 1c Inspection of other components of HCT/P establishments shown by regulations and major inspection elements

There must be a quality program in place. Procedures must exist for receiving, investigating, evaluating, and documenting information related to core GTP requirements. Any corrective actions that are performed must be documented and their efficacy verified and, if appropriate, both short-term and long-term actions taken to prevent recurrence included. The program must include a system to ensure that all staff are properly trained and educated to perform their tasks. There must also be evidence of environmental control showing that systems are established and appropriately maintained. All deviations related to HCT/Ps must be investigated and documented. Investigations should include a review and evaluation of the deviation, efforts to determine the cause, and any corrective actions.

The inspector will check to ensure that reporting requirements have been met. These include reporting within 15 days adverse reactions to the FDA that are fatal, life-threatening, result in permanent damage or impairment of body functions, or which necessitate medical or surgical intervention, including hospitalization. Any HCT/P deviations which meets all of the following criteria must also be reported: deviations related to distribution and core cGTP and is related to the prevention of communicable disease transmission or HCT/P contamination. These reports can be made using Form 3486 or submitted electronically.

The inspection findings are documented by the inspectors using Form 483 “Inspectional Observation” at the conclusion of the inspection. There will be a formal report on the inspections (see Establishment Inspection Report) with a classification of the findings. Actions may be taken based on these findings as shown in Table 2

Table 2 Types of FDA HCT/P inspection findings

1.2 Inspection of Type 351 Product Manufacturing Establishments (GMPs)

Human cell and gene therapy product manufacturers are usually inspected under a Level 1 cGMP [2, 3]. This consists of an in-depth audit of three critical elements in at least four of the key systems (Table 3). In addition to the audit of the quality system, the Level 1 inspection should also include an audit of the production system [3].

Table 3 Key systems and critical elements of a cGMP inspection

cGMP inspections are normally conducted on a biennial schedule, or more often if warranted by circumstances.

The FDA has indicated that manufacturing for Phase 1 clinical trials does not have to fully conform to cGMP regulations [4]. In a guidance document, they recommend a comprehensive and systematic evaluation of the manufacturing setting to identify potential hazards and appropriate actions to eliminate or mitigate them. These can include the use of disposable equipment and process aids; use of commercial and prepackaged materials, e.g., water for injection; and use of closed systems for manufacturing. The basic requirements, however, are similar in terms of adequate facilities, trained personnel, quality program, maintenance of records, etc. It is advisable to review this guidance [4] before an inspection takes place.

In a GMP inspection, a major element will be the use of written approved standard operating procedures (SOPs) and associated records. This may include observation that these are being followed. Training records will be reviewed to ensure that staff have the appropriate educational background, training, and experience and that they are adequate in number.

The inspector will also verify through observation whether the establishment is adhering to applicable regulations. One way to help determine this is to look at documented deficiencies as an indicator of the state of control. Other elements of the inspection are shown in Tables 4a, 4b, 4c, 4d, 4e and 4f, together with examples of the types of deficiencies that may be reported. There are additional elements for specific types of products, for example, vaccines and allergens. The most relevant regulations for the cellular therapy community pertain to master and working viral seed banks. There should be a complete history, including passaging and testing profiles. The storage must be secure, and it should be at multiple locations with adequate control to prevent unauthorized access and materials loss due to equipment failure. There must be a complete inventory which correlates with the amount of material on hand, and the storage locations should be fitted with an alarm system. Similar regulations apply to master and working cell banks, with additional attention to the passage numbers at which the cells are used. Establishment of new working cell banks from the master bank should be documented in the annual report to the FDA.

Table 4a GMP inspection: Elements of quality system and deficiencies

Table 4b GMP inspection: Elements of facilities and equipment system and deficiencies

Table 4c GMP inspection: Elements of materials system and deficiencies

Table 4d GMP inspection: Elements of production system and deficiencies

Table 4e GMP inspection: Elements of packaging and labeling system and deficiencies

Table 4f GMP inspection: Elements of laboratory control system and deficiencies

For aseptic processing emphasis is put on ensuring that all transfers, transports, and storage stages are carefully controlled to maintain sterility. Wherever possible closed systems should be used. If this is not possible, the product must be handled in a unidirectional Class 100 (ISO 5) environment located in a Class 10,000 (ISO 7), or better, surrounding room. Monitoring activities should include obtaining the identity of detected microorganisms. There must be microbial surface monitoring at the end of production before cleaning and also personnel monitoring. There should be a process simulation performed to demonstrate that process controls are adequate to protect the product [5]. These should model the worst case scenario, e.g., maximum number of open operations. The inspector may ask to observe aseptic technique.

At the conclusion of the inspection, a Form 483 will be issued that lists significant findings that relate to observed or potential problems detected at the establishment. The most critical observations are listed first. It may include deficiencies from prior inspections that have not been corrected.

1.3 Establishment Inspection Reports (EIR)

The establishment will receive an EIR after the inspection. This provides documentation of what the inspector(s) did from the time at the establishment until the issuance of the Form 483. It includes a summary of the findings, a history of the establishment, a listing of individual’s responsibilities and persons interviewed, a discussion of the quality operation and training program, manufacturing design and operations, product testing, recall procedures, objectionable conditions and responses, and a description of general discussion with the management.

It will state whether the facility is found to be acceptable and provide classification of the findings. These are official action indicated (OAI), voluntary action indicated (VAI), or no action indicated (NAI). A VAI indicates that re-inspection is required within 12–24 months. An OAI indicates that a warning letter will be issued until the observations have been addresses and have been verified by the FDA through an inspection.

A warning letter may be issued subsequently that lists violations of regulatory significance that cause one or more systems not to be a state of control. For licensed product manufacturing other actions may include license revocation or suspension, seizure of products, injunctions in the case of the existence of a current health hazard, and finally prosecution. Deficiencies are listed by the systems shown in Tables 4a, 4b, 4c, 4d, 4e and 4f.

2 EU Inspections

cGMP in Europe is regulated by the European Medicines Agency [6, 7], and inspections are performed by the appropriate national competent authority (NCA). Manufacturing sites outside the EU are inspected by the NCA of the Member State where the EU importer is located, unless a mutual recognition agreement is in place between the EU and the country concerned. If an MRA applies, the authorities mutually rely on each other’s inspections. The results of national cGMP inspections and details of nonconformances are reported on the EudraGMDP website [8].

3 Behavior During a Regulatory Inspection

Establishments should pre-designate one or more people to facilitate inspections. It is also a good idea to have a written SOP for regulatory inspections. This will contain the procedure to be followed, the people to be notified, the names of additional contact people, where the meeting will be held, how requests for documents will be handled, and behavior to follow during the inspection. All staff and relevant ancillary people must be trained on this SOP. It is critical that the staff are already familiar with the relevant regulations upon which the inspection will be based and have ready the appropriate guidance documents.

A sign-in sheet should be used for all those attending the inspection meeting, and the inspectors should complete the visitor log when entering the facility. The meeting should take place in a room with adequate space and sufficient chairs for the inspection team and establishment staff. The locations of toilets and water fountains and beverages should be provided. An offer should be made to bring in lunch for the team (which will be paid for by them) or to provide the location of nearby eating facilities. Normally, after initial introductions and an explanation of the purpose of the visit, the team will indicate when they want to meet with establishment staff and when they wish to be alone. They should be provided with contact information for the establishment representative.

They should be accompanied at all times (except when they ask to meet alone) by a facility representative(s) who takes meeting notes and designates who should meet with the team when information is requested. It is a good idea to have a current table of contents available to enable the establishment staff to rapidly find and provide copies of requested procedures. A list should be maintained of all documents provided to the inspection team, and there should be a designated person available to make copies. Ideally there should be a person available to retrieve requested documentation from the files or to locate it electronically. Only documents specifically requested by the team should be provided. The speed with which documents are provided indicates familiarity with the quality system and facility operations. Requests for information should be answered directly and specifically without offering supplementary details.

Staff should be familiar with how to interact with inspectors. During observation of procedures, it is acceptable to tell an inspector to wait until questions can be asked or answered. If the staff member does not know the answer, they should indicate this and tell the inspector that they will find out the answer or refer him/her to another staff member. They should not be evasive. Again, the staff member should not volunteer supplementary information, but should directly answer the question posed.

Toward the end of the day, the team will usually indicate how they wish to close out the day’s activities. This may include meeting with certain establishment staff and requests for additional information to be provided on the following day and/or the agenda for the next day. If deficiencies have been detected during the day, it is usually acceptable for the establishment to try to correct these and to provide the team with evidence of their correction on the following day.

On the final day of the inspection, an exit interview will normally be held, after the team has met together to plan their findings. Usually the establishment representative can decide who will attend this meeting. The team will normally thank the establishment for facilitating the inspection, and FDA inspectors will then present their findings and the Form 483. There may be an opportunity for the establishment to seek clarification of the findings and ask to supplementary questions. The team should be thanked for performing the inspection. In the United States responses to deficiencies may be made at the meeting or should be submitted to the District Office within 15 days of the inspection. A formal EIR will be provided by CBER after the inspection (see Establishment Inspection Report). Actions to be taken will be documented.

4 Complaints About FDA Inspections

If you have complaints about the inspectors or the conduct of the inspection, these should not be raised during the inspections itself. The District Office should be contacted in writing after the inspection.

5 FDA Pre-inspection Opportunities

In the United States, the FDA offers a number of opportunities for pre-operational inspection of the manufacturing facility [9]. These are of four types:

5.1 Design Review

A design review usually involves a review of conceptual drawings, proposed plant layouts, and flow diagrams for the entire facility including critical systems and areas. Such reviews provide an opportunity to emphasize the importance of the fundamental principles of good design as outlined in the cGMPs. As a result, extensive changes in design can be made with little cost and very minor delay to the design and construction cycle. The FDA expects the facility to prepare complete final plans and to identify, if possible, specific questions regarding how the facility will meet cGMPs or areas where the FDA’s comments are specifically desired. When the review includes a meeting with the facility, advance delivery of the package of documents to the District Office is recommended. This type of review is particularly valuable for academic cGMP facilities.

5.2 Pre-construction Review

A pre-construction review involves a study of the plan, elevation, and isometric drawings for all manufacturing areas and utility and process systems for the plant; i.e., drainage and water systems; product systems; compressed air systems; heating ventilation and air-conditioning (HVAC) systems; and all equipment, layouts, and piping in the manufacturing and laboratory areas. Further examples, where applicable, include zones of positive air pressure; HEPA filtration and laminar flow; air locks; protective clothing; change rooms; toilet and washup facilities; pedestrian traffic patterns; raw materials and components, and similar considerations.

The various packages of prints, specifications, design standards, and vendors’ descriptions should be supplied in advance to permit meaningful review and comment prior to any meeting.

5.3 Construction/Equipment Installation and Qualification Review

Facilities may request an FDA on-site review of specific portions of the plant, while construction is in progress. This is an excellent opportunity to review piping systems and methods of construction before they are concealed by walls, floors, and ceilings. These reviews or site visits may be done in phases. The final inspectional review of validation and control data from production runs can then be accomplished quickly and more efficiently.

5.4 Pre-production Review

At the pre-production stage, the review will normally be an inspection. Additionally, facilities may request investigators to visit new buildings or production areas during inspections on the same campus. Investigators conducting the review should provide the facility with general feedback and can provide examples of what they have seen at similar facilities.

6 Conclusions

Regulatory inspections are a component of GMP/GTP compliance. They may be random or based upon specific issues. In either case it is important to have (i) an understanding of the regulations against which compliance is being evaluated and (ii) procedures in place on how your facility will deal with the inspection. These include keeping good documentation of what happens, knowing how to deal with requests for information, behavior of staff, and ensuring effective and timely follow-up. Attention to such details will ultimately result in a smooth and effective inspection.