How Tobacco Manufacturers Can Prepare for an FDA Inspection

FDA takes tobacco manufacturer inspections as part of the PMTA approval process seriously. These inspections are rigorous, yet a necessary part of doing business in the US tobacco industry. If your tobacco and nicotine products weren’t already marketed prior to February 15, 2007, you must obtain an FDA premarket authorization.

Premarket Tobacco Applications (PMTA), Substantial Equivalence submissions (SE), or Exemption from Substantial Equivalence (EX REQ) are the only options to legally market tobacco products in the US. In fact, per sections 910 and 911 of the Food Drug and Cosmetic Act (FDCA), any tobacco products marketed in the US without a PMTA, SE, or Modified Risk Tobacco Product designation are misbranded, or in violation of FDA law.

FDA’s oversight of tobacco manufacturing establishments is serious business. Of the three FDA submissions allowing the sale of tobacco products in the US, the most common is a PMTA. An in-person FDA tobacco manufacturer inspection is required.

Manufacturing cigarettes in industrial plant — One thing the inspector will look for during an FDA inspection of a tobacco manufacturer is that the facility uses quality systems in line with FDA’s proposed Tobacco Product Manufacturing Practices (TPMPs).

What is a PMTA?

A rigorous application and review process, a PMTA is the principle pathway that new tobacco products must follow to be legally marketed in the US.

PMTA’s must include both tobacco and nicotine product laboratory testing data indicating the product protects consumer health as well as data that demonstrates the products were manufactured using acceptable quality principles such as those outlined in some of the FDA Good Manufacturing Practices (GMPs) which are the basis of FDA’s new Tobscco Product Manufacturing Practices (TPMPs). Additional requirements such as behavioral studies are required as well, so be sure to follow FDA’s PMTA submission instructions explicitly.

FDA aims to ensure marketed products will protect public health. Part of a PMTA evaluation includes FDA inspection of the tobacco manufacturer’s site, known as a “PMTA pre-approval inspection”. This inspection confirms whether current Good Manufacturing Practices (GMPs) are being used that support this initiative.

For more information on PMTAs, FDA prepared a Guidance for Industry in June 2019 called the Premarket Tobacco Product Applications for Electronic Delivery Systems (ENDS) and issued a final rule on Premarket Tobacco Product Applications and Record Keeping Requirements in October of 2021.

Tobacco leaves running down an assembly line in a tobacco manufacturing facility. — *An FDA inspection will cover both the facility in which your products are produced and the grounds around the facility.*

What are Tobacco TPMPs?

GMPs are systematic documented procedures and records covering the design, monitoring, and control of manufacturing practices and the facilities where products are produced. They can help ensure products being evaluated have the identity, strength, quality, and purity that they are represented to possess.

FDA recently published draft TPMPs for tobacco products, based on the Quality Management System (QMS) used by the tobacco industry as representative GMPs. The GMPs for dietary supplements found in the Code of Federal Regulations 21 CFR 111 have long been used as a base from which to build a tobacco QMS.

So, if TPMPs are not yet in final form, what types of QMS is FDA looking for during an inspection of a tobacco manufacturer as part of its PMTA evaluation?

The FDCA provides clues. For instance, section 907 references adulteration when products are manufactured in filthy, putrid, or insanitary conditions and those not conforming to tobacco standards established by FDA in FDCA section 907.

In section 906, use of GMPs during manufacturing, packaging, and storage are specifically mentioned, or an alternative in the form of a QMS. There are many other regulatory requirements for tobacco products, but sections 906 and 907 specifically reference use of GMP systems. Tobacco manufacturers should overlay the QMS currently in use with FDA’s draft TPMPs to gain and understanding of whether their current systems align with FDA recommendations.

Quality is Everyone’s Responsibility

While quality is everyone’s responsibility, a company’s Quality Unit (QU) has ultimate authority over the products produced and released. The QU has distinct oversight of manufacturing operations and creating, monitoring, and implementing the overarching quality system.

This includes assessing the suitability of incoming components to be used during manufacturing, ensuring in-process materials and finished products meet established specifications and that the packaging containers, closures, and labeling all meet clearly defined parameters.

The evaluation of incoming and in-process materials and finished goods is achieved largely through laboratory testing. The QU is also tasked with developing the processes and methods by which quality is evaluated to verify adherence to established controls, procedures, and specifications.

Finally, the QU has ultimate responsibility for approving each product batch for release based on their confirmation that all GMP-related activities have been performed accordingly through records that reflect use of Good Documentation Practices (GDPs).

FDA will ask to see confirmation of the QU’s execution of these responsibilities during an FDA inspection of a tobacco manufacturer’s site.

Components of an FDA Pre-approval Inspection

Once you get to the pre-approval inspection phase of a PMTA, it is reasonable to assume that FDA has some confidence that your product, including its manufacturing, may meet the Agency’s requirements for the protection of public health. Even so, the future of your product is at stake, so preparing for an FDA inspection of a tobacco manufacturer should be given the attention it deserves.

FDA’s PMTA pre-approval inspection is meant to confirm that appropriate GMP principles and QMS have been developed and are being used in the manufacturing, packaging, and distribution of products. As the facility under review, it is your job to convey as completely as possible that robust GMP principles are in place for all systems.

FDA will inspect your Standard Operating Procedures (SOPs) for hiring qualified personnel, ensuring adequate and regular training for those personnel and that all who work in GMP areas are wearing appropriate garments to prevent product contamination.

They’ll inspect both the physical plant where products are produced and the grounds around the facility to ensure they are well maintained and adequate to manufacture products in a GMP compliant manner.
FDA will want to see a thorough and organized system of identifying and maintaining materials at all stages of manufacturing. This includes receiving, holding, and returned materials.
They will evaluate equipment and utensils used in manufacturing to verify they are in good order and are easy to clean and maintain.
The instruments and controls must be calibrated both before the first use and at routine intervals or as necessary to ensure their accuracy and precision. FDA will ask to see the calibration methods and logs during their tobacco manufacturer inspection.
A major part of FDA’s pre-approval inspection is a review of Master Manufacturing Records (MMR) and Product Record.

Container of tobacco snus — *An FDA inspection will include review of your Master Manufacturing Records and Production Records, which help ensure your tobacco products are made to high standards.*

MMR and BPR – Getting it Right

Master Manufacturing Records (MMR)s provide detailed instructions for each point, step, or stage of the manufacturing and packaging process so that the product is consistently made to quality standards.

Production Records are prepared for each product lot, documented at the time of performance, and should accurately follow the corresponding MMR. This includes the measure of each component and a statement of the actual yield and theoretical yield percentage at all appropriate phases of processing.

Component specifications covering the identity, microbiological purity, strength, composition, and a qualitative and quantitative confirmation of any contaminants must be established for every stage in the manufacturing process from raw materials through finished goods.

These controls are necessary to ensure each components’ quality. Production trends must be audited and analyzed, and FDA will not only want to see these calculations and their results but also the performance and verification steps of doing so. The QU must review and approve of all completed BPRs. This is an essential aspect of GMP principles.

Even with the best controls, sometimes batches will be rejected for non-conformance, meaning the component is out of specification (OOS) or there is a deviation. Each instance of non-conformance and OOS must be investigated and managed with established Corrective and Preventive Actions (CAPAs).

During an FDA inspection of a tobacco manufacturer, the inspector will review your manufacturing operations, including the MMR, Production Records, non-conformances, and CAPAs to verify adequate controls are in place.

Managing an FDA Inspection of a Tobacco Manufacturer

Now that you have the documentation prepared for FDA’s arrival, it is time to prepare for the main event.

Though FDA inspections are serious, they should not be adversarial. You can help ensure your PMTA pre-approval inspection goes well by having an Inspection Plan in place. Usually this is accomplished with a SOP for handling an FDA inspection.

Since the QU is in charge of product quality, a member of the QU team should be assigned the role of managing the FDA inspection. After all, the purpose of the pre-approval inspection is to verify quality.

During the inspection, FDA will walk around the facility and interact with personnel in all areas of the facility and at all levels of the organization, including Human Resources, Shipping and Receiving, Facilities, Material Management, Engineering, Production, Laboratories, and Quality. Ensure all employees in these departments are aware of when the inspection will occur.

Be prepared for FDA’s arrival. Ensure the designated quality representative from your organization is immediately available to greet the investigators upon their arrival. Reserve a conference room so that documents can be reviewed and discussions can take place without disruptions. Have documents ready for FDA’s review. Some common documents that are initially requested include the following:

Organization charts indicating key personnel
Facility floor plan
Product list
Manufacturing process diagram and flowchart
Equipment list (Production and Laboratory)
SOP index

Document control and retrieval is one of the most critical aspects of managing an FDA inspection, so it is a good idea to assign an additional employee to the FDA inspection team as the “runner” who will retrieve additional requested documentation, make photocopies as needed, and log which documents were requested and any FDA comments.

Practice is the key to being prepared. Your FDA Inspection SOP is a living document. Practice mock FDA inspections to ensure everyone at your company is prepared. Make sure important documents are easily retrievable, accurate, complete, and maintained with GDPs.

Good luck with your PMTA Pre-Approval FDA Inspection. If you’ve made it this far, with preparation and diligent attention to GMP principles, your marketing authorization may be just around the corner.

We created this handy FDA Inspection for Tobacco Manufacturers checklist so you will be ready when the inspector arrives.