Today, FDA published yet another draft guidance targeting drug compounders, entitled Insanitary Conditions at Compounding Facilities (the Draft Guidance). Notably, it makes clear to pharmacy compounders that although they may be exempt from FDA’s current Good Manufacturing Practice (cGMP) requirements, they are not exempt from FDA’s prohibition on insanitary conditions. And FDA, along with state governments, will be monitoring pharmacy compounders for such compliance. The Draft Guidance is available here. It applies to both pharmacies compounding under section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA) and outsourcing facilities compounding under section 503B of the FDCA—the Draft Guidance refers to these entities collectively as “compounding facilities.”

By way of background, pharmacies compounding under section 503A of the FDCA are exempt from FDA’s cGMP requirements. See 21 USC 353A(a); 21 USC 351(a)(2)(B). But they are not exempt from FDA’s prohibition on insanitary conditions—that is, any drug prepared, packed, or held under insanitary conditions is “deemed to be adulterated” within the meaning of the FDCA. 21 USC 351(a)(2)(A).

According to FDA, the Draft Guidance is intended to both “assist compounding facilities in identifying insanitary conditions so that they can implement appropriate corrective actions” and to “assist State regulatory agencies in understanding some examples of what FDA considers to be insanitary conditions that could cause a drug to become contaminated or rendered injurious to health.” Draft Guidance at 2. The goal of assisting State regulatory agencies appears to be the primary driving force behind the Draft Guidance, as in it FDA describes the Agency’s reliance on State regulatory agencies:

[C]ompounding facilities that are not registered with FDA as outsourcing facilities are primarily overseen by the States and, as explained above, generally are not routinely inspected by FDA. Therefore, FDA encourages State regulatory agencies to assess during inspections whether compounding facilities that they oversee engage in poor practices, including those described below, and if so, to take action, as appropriate, consistent with State laws and regulations, and to contact FDA.

Draft Guidance at 2 – 3.

The Draft Guidance also includes several examples of “conditions that would be considered insanitary conditions” under the FDCA, though the lists of examples are non-exhaustive. For sterile and non-sterile facilities, these conditions include:

  • Vermin (e.g., insects, rodents) observed in production areas or areas immediately adjacent to production;
  • Visible microbial contamination (e.g., bacteria, mold) in the production area;
  • Non-microbial contamination in the production area (e.g., rust, glass shavings, hairs);
  • Handling beta-lactam, hazardous, or highly potent drugs (e.g., hormones) without providing adequate containment, segregation, and cleaning of work surfaces, utensils, and personnel to prevent cross-contamination; and
  • Production of drugs while construction is underway in an adjacent area without adequate controls to prevent contamination of the production environment and product,

Draft Guidance at 3. The list of examples of conditions that would be considered insanitary conditions under the FDCA in a sterile facility is more extensive, and includes:

  • Putting on gowning apparel improperly, in a way that may cause the gowning apparel to become contaminated. This includes, for example, gowning in non-classified areas, gowning apparel touching the floor, or putting on sterile gloves improperly (e.g., touching the outside of a glove with bare hands);
  • Engaging in aseptic processing after leaving the cleanroom and re-entering from a non-classified area without first replacing gowning apparel (e.g., sterile gloves, gowns, mask, foot covers). Movement of personnel in and out of the cleanroom without regowning may bring contaminants from the non-classified areas into the cleanroom;
  • Failing to maintain unidirectional airflow in the ISO 5 area, either through the design of the ISO 5 area, the placement of equipment/supplies in that area, or the by personnel conducting aseptic manipulations;
  • Actionable microbial contamination of the ISO 5 area or in adjacent areas;
  • Cleanroom with unsealed, loose ceiling tiles;
  • ISO classified areas with difficult to clean (e.g., porous), particle-generating, or visibly dirty (e.g., rusty) equipment or surfaces such as shelving, floors, walls, doors, window sills, and ceilings. For example, wood is both difficult to clean and particle-generating; and
  • A facility designed and/or operated in a way that permits poor flow of personnel or materials, or allows the influx of poor quality air into a higher classified area.

Draft Guidance at 4 – 6.

The Draft Guidance also includes a non-exhaustive list of procedures that, in FDA’s view, will help compounding facilities “ensure that they can produce sterile products.” Draft Guidance at 6. These procedures include:

  • Conduct routine environmental monitoring, including a) nonviable airborne particulate sampling; b) viable airborne particulate sampling; c) personnel sampling (including glove fingertip sampling); and d) surface sampling, including but not limited to equipment, work surfaces, and room surfaces;
  • Certify the ISO 5 area every six months. Smoke studies should be conducted as part of the certification to assess the airflow patterns necessary to maintain unidirectional flow from areas of higher air quality (e.g., ISO 5) to areas of lower air quality (e.g., ISO 7) to prevent microbial contamination of the sterile drug products during processing. Conducting smoke studies under dynamic conditions helps to ensure that unidirectional airflow is maintained while personnel are working in the ISO 5 area;
  • Measure pressure differentials during operations to help ensure proper airflow (i.e., from areas of higher quality air to adjacent areas with lower quality air); and
  • Conduct media fill studies to closely simulate aseptic production operations incorporating, as appropriate, worst-case activities and conditions that provide a challenge to aseptic operations.

Draft Guidance at 6 – 7.

The Draft Guidance also includes examples of insanitary conditions that FDA considers to be “particularly serious, and if any one of these conditions exists, FDA strongly recommends that a compounding facility immediately initiate a recall” and “cease sterile operations . . . .” Draft Guidance at 7. When a compounding facility identifies one or more insanitary conditions, the facility should not, according to FDA, “rely on a passing sterility test as an indication of sterility assurance.” Draft Guidance at 8.