NEW RESEARCH AND REQUIREMENT

The Food and Drug Administration (FDA) originally classified electronic cigarettes as drug delivery devices and subject to regulation under the Food, Drug, and Cosmetic Act (FDCA). This classification was challenged in court, and in January 2010 it was overruled by Federal District Court which stated that “the devices should be regulated as tobacco products rather than drug or medical products.” This ruling was upheld in December 2010 by the appeals court and confirmed that the FDA could only regulate electronic cigarettes as drug products if they were marketed for therapeutic use to quit smoking. Therefore, since e-cigarettes, do not make therapeutic claims, the FDAs Center for Tobacco Products (CTP) regulates them as tobacco products.

In April 2014, as part of its implementation of the Family Smoking Prevention and Tobacco Control Act signed by the President in 2009, the U.S. Food and Drug Administration proposed a new rule that would extend the agency’s tobacco authority to cover additional tobacco products. Products that would be “deemed” to be subject to FDA regulation are those that meet the statutory definition of a tobacco product, including currently unregulated marketed products, such as electronic cigarettes (e-cigarettes), cigars, pipe tobacco, nicotine gels, waterpipe (or hookah) tobacco, and dissolvables not already under the FDA’s authority. The FDA currently regulates cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco.

Consistent with currently regulated tobacco products, under the proposed rule, makers of newly deemed tobacco products would, among other requirements:

• Register with the FDA and report product and ingredient listings;
• Only market new tobacco products after FDA review;
• Only make direct and implied claims of reduced risk if the FDA confirms that scientific evidence supports the claim and marketing the product will benefit public health as a whole; and
• Not distribute free samples.

In addition, under the proposed rule, the following provisions would apply to newly “deemed” tobacco products: .

• Minimum age and identification restrictions to prevent sales to underage youth; Requirements to include health warnings; and
• Prohibition of vending machine sales, unless in a facility that never admits youth

The FDA proposes different compliance dates for various provisions so that all regulated entities, including small businesses, will have adequate time to comply with the requirements of the proposed rule. Products that are marketed for therapeutic purposes will continue to be regulated as medical products under the FDA’s existing drug and device authorities in the Food, Drug &Cosmetic Act. The FDA seeks answers to the many public health questions posed by products, such as e-cigarettes, that do not involve the burning of tobacco and inhalation of its smoke, as the agency develops an appropriate level of regulatory oversight for these products.

Since the CTP has not issued GMPs for any tobacco products, nor are there any CTP guidance documents for the manufacturing of tobacco products, they leave the assessment as to the proper design of a facility that manufactures eCigarettes or eLiquid up to the manufacturer to assess the requirement and determine how current requirements and specifications for aligned products, such as medical inhalers, or other similar device, may be applied to the manufacturing of e-cigarettes as inhaled tobacco products. Current manufacturing practices for products such as metered dose inhalers and Inhalation Solutions are the nearest aligned products

Based on the review of the available information, recommendations will be made regarding how one may apply the current FDA regulations and guidance to the design, manufacturing and testing of e-cigarettes facilities, so that the process would likely be compliant with the anticipated future proposed Tobacco GMPs by the CTP.

The FDA final rule on Current Good Manufacturing Practice Requirements for Combination Products basically states that the cGMP requirements applicable to a combination product can be satisfied by demonstrating compliance with Code of Federal Regulation Title 21: Food and Drugs Chapter 1: Food and Drug Administration, Subchapter C- Drugs: General, Part 210 Current Good Manufacturing Practice in Manufacturing, Processing, Packaging, or Holding of Drugs: General (21 CFR Part 210); and Code of Federal Regulation Title 21: Food and Drugs Chapter 1: Food and Drug Administration, Subchapter C- Drugs: General, Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals (21 CFR Part 211). Since the liquid product contains a diluent that is 85% Vegetable Glycerin and only 15% water, with a pH of 5.0 – 7.0, then we can assume this would not be considered an aqueous-based product and therefore sterile manufacturing requirements will not be applied to e-cigarettes. This assumes that the diluent is naturally effective in preventing microbial growth or the formulation contains preservatives. If sterility is not required, then the overall manufacturing process of the liquid would not need to meet aseptic processing requirements and may be manufactured under standard GMP clean room conditions, implementing conditions that are similar to ISO 7 or Class 10,000 conditions, as described in section IV pages 5-7 of the FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice This would include Floors, walls, and ceilings of smooth, non-porous, hard surfaces that are easily cleanable, air exchange systems that include filtered air and usually provide more than 50 air exchanges per hour, manufacturing areas that are positively pressured to the surrounding areas and an appropriate environmental monitoring program. This would also include implementing the recommendations as outlined in the USP 29 General Chapter Microbiological Evaluation of Clean Rooms and Other Controlled Environments, which describes how a clean room or controlled environment should be monitored and limits that should be applied. For example, microbial sampling and monitoring of the rooms may include quantification of the microbial content of the air, work surfaces, equipment, floors, and walls with limits similar to those included in Tables 3, 4 & 5 of Chapter .

Since standard GMP manufacturing requirements apply then the manufacturing of the liquid should potentially be manufactured according to GMPs similar to that of drugs/dietary supplements and should take into account some of the following general GMP requirements:

21 CFR 211.42(c) states, in part, that “Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mix-ups”

21 CFR 211.46(b) states that “Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product.”

21 CFR 211.46(c) states, in part, that “Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas …”

For products that utilize a traditional inhaler unitl, the parts of the delivery device are normally manufactured by an injection molding process that is performed in a non-sterile, dust free, Class 10,000 facility that is environmentally monitored. Therefore, If we apply a similar non-sterile approach to the manufacturing of the e-cigarette unit and the loading of the liquid into the cartridge, then the product should be manufactured under general conditions that meet GMPs; and, assuming e-cigarette liquid is self-preserving, then it would seem appropriate to manufacture the liquid under standard, non-sterile, drug/dietary supplement type GMP requirements utilizing facilities that are controlled and monitored similar to a Class 10,000 environment. Applying the same philosophy to the manufacturing of the parts of the e-cigarette, the filling of the cartridge or cartomizer and the assembly of the final unit, standard, non-sterile, device GMPs could be applied, including the implementation of Design Controls as described in Code of Federal Regulation Title 21: Food and Drugs Chapter 1: Food and Drug Administration, Subchapter H- Medical Devices: General, Part 820 Quality System Regulation (21 CFR Part 820)

Given the similarities of the proposed Tobacco GMPs to these current standards, if adopted by the FDA, the Tobacco GMPs, along with the added device requirements described above, could be appropriate for the manufacturing of e-cigarettes.

Analytical and Microbial Specifications Assessment

Based on a review of the available literature, there are a number of issues that must be considered when designing specifications for an e-cigarette product. They include:

• Particle size distribution – which may or may not be applicable to liquid.
• Moisture Content – which would be applicable to the liquid for microbial control
• Microbial Limits – Tests and specifications should be in place for total airborne count, total yeast and mold count and freedom from certain pathogens. The recommended limits for Inhalation drugs are:
  1. Total Aerobic Microbial Count: ≤ 10 cfu/g or mL
  2. Combined Yeast and Molds Count: ≤ 10 cfu/g or mL
  3. Absence of Objectionable Microorganisms: Escherichia coli, Pseudomonas aeruginosa and Salmonella species

Conclusion

Since e-cigarettes will be regulated as tobacco products, and no GMPs have been issued by the CTP, an assessment of the regulations and guidances in place for other FDA regulated products must be assessed in order to determine a preliminary approach to controlled and compliant manufacturing of e-cigarettes. Current FDA GMPs range from the least onerous Food GMPs (21 CFR Part 110), which are primarily sanitation based, to the manufacturing of sterile drug products under 21 CFR Part 211, which are the most complicated and challenging. Upon review of the purpose and use of an e-cigarette, neither of these ends of the GMP spectrum appear to be appropriate. The food GMPs under 21 CFR 110

are most likely inadequate since the liquid in the e-cigarette is inhaled, not ingested, and formulation consistency and microbial control will be imperative. It appears that manufacturing the e-cigarette under sterile conditions is also not warranted. Therefore, a more moderate, yet still controlled and monitored type of manufacturing process would seem to be appropriate. Manufacturing the liquid under a drug type GMP approach as a non-sterile solution to be inhaled seems to be most applicable. As discussed previously this would include utilizing the appropriate facilities, personnel, equipment and processes that are designed and controlled to prevent contamination of the product. Performing these operations in an area similar to a Class 10,000 facility, where the environment is controlled and monitored, would seem to provide the appropriate environment to prevent microbial contamination of the liquid, which has be identified as a critical parameter due to the inhalation of the product.

Utilizing the same philosophy, the manufacturing of the parts of the e-cigarette, the filling of the cartridge/cartomizer with the liquid and the final assembly of the product should be permitted to be performed under standard drug/device type GMPs in a facility, and with equipment and processes, that will not have an adverse effect on the product, and will be operated using procedures that adequately control the environmental conditions. This should be attainable without having to implement sterile manufacturing requirements.

Though this assessment bases its recommendations on current FDA supported practices and guidance, it is not possible to accurately predict how the CTP will eventually regulate and control the manufacturing of nicotine based e-cigarettes. This assessment is only meant to provide guidance on how to approach the manufacturing of these products in the absence of formal FDA direction.

A cleanroom is an environment, typically used in manufacturing or scientific research, that has a low level of dust, airborne microbes, aerosol particles, and chemical vapors. More accurately, a cleanroom has a controlled level of contamination that is specified by the number of particles per cubic meter at a specified particle size. Cleanrooms are classified according to the number and size of particles permitted per volume of air. Numbers like “class 1000” or “class 10,000” refer to FED-STD-209E and denotes the number of particles of size 0.5 µm or larger permitted per cubic foot of air. The International Standards Organization (ISO) has developed a standard section related to cleanrooms (Section 14644) and denotes the number of particles of size 0.5 µm or larger permitted per meter of air. ISO classification are numbered from 1 to 9 (1 being the cleanest classification). Although not identically translated there is a reasonable correlation between rooms classified by FED-STD-209E and ISO 14644-1. As an example a “class 10,000” cleanroom is similar to an “ISO 7” cleanroom. To give perspective, the ambient air in a typical office environment contains 1,000,000 particles per cubic meter in the size range 0.5 μm and larger in diameter, while a class 10,000 cleanroom allows only 10,000 particles per cubic foot of 0.5 μm and smaller. Cleanrooms maintain particulate-free air through the use of HEPA filters employing laminar or turbulent air flow principles. Laminar, or unidirectional, air flow systems direct filtered air downward in a constant stream towards returns located on walls near the cleanroom floor or through raised perforated floor panels to be recirculated. Turbulent, or non-unidirectional, air flow keeps air in a cleanroom in constant motion, although not all in the same direction. The rough air seeks to trap particles that may be in the air and drive them towards the floor, where they enter grills and leave the cleanroom environment. Non-shedding materials are used to construct cleanrooms to prevent excess particles entering the air. The air entering a cleanroom from outside is filtered to exclude dust, and the air inside is constantly recirculated through high-efficiency particulate air (HEPA) filters to remove internally generated contaminants. Staff enter and leave through airlocks, and wear protective clothing such as hoods, face masks, gloves, boots and coveralls. Equipment inside the cleanroom is designed to generate minimal air contamination. Only special mops and buckets are used. Cleanroom furniture is designed to produce a minimum of particles and to be easily cleaned. Common materials such as paper, pencils, and fabrics made from natural fibers are often excluded, and alternatives used. Cleanrooms are not sterile (i.e., free of uncontrolled microbes); only airborne particles are controlled. Particle levels are usually tested using a particle counter and microorganisms detected and counted through environmental monitoring methods. Cleanrooms are kept at a positive pressure so that if there are any leaks, air leaks out of the chamber instead of unfiltered air coming in.

For the purposes of creating a Basis of Design (BOD) for eCig facilities, the facility should meet the following parameters:

• Cleanroom spaces should be controlled to ISO 7 (Class 10,000) standards for all classified spaces.
• Temperature should be maintained at 68 degrees F.
• Relative Humidity should be maintained to 45% RH, at 68 degrees F.
• There should be recirculating air in accordance with the ISO guidelines for an ISO 7 cleanroom.
• Noise Level should be less than NC65 “As Built” (as defined by ISO 14644)
• Positive room pressurization with a hierarchy to keep dust from entering the room, the gowning area, and the supply air plenum. All designated clean areas should be positive to ambient building pressure by a minimum of .03 wg., with conjugate areas positive to gowning by .03 wg. The supply air plenum should be positive to ambient by a minimum of .01 wg.
• The design should incorporate low wall returns with return air grills incorporating opposed blade dampers to allow for pressure adjustment from room to room. Flow across grill face should not exceed 500 fpm.
• The finishes should meet the requirements of 21 CFR Part 211 including the utilization of surfaces and finishes consistent with cleanroom requirements including the minimization of horizontal surfaces that can collect dust and incorporation of rounded edges and corners for ease of cleaning.

ISO 14644-1 cleanroom standards