Getting ahead of the regulatory curve for sterile compounded drugs

Kenneth Maxik, Director of Patient Safety and Compliance, CompleteRx, remarks on the sweeping changes to the USP in 2018 and the revisions likely to have the most significant consequences to clean environments

It is possible that the USP revision mandates a separate cleanroom dedicated solely to nonsterile compounding

Last spring, the United States Pharmacopeia (USP) announced plans to revise General Chapter (GC) <795> which sets standards for compounding nonsterile drugs, and <797>, which addresses pharmaceutical compounding for sterile preparations. The overarching goal was to better align these two chapters with USP GC <800> (“Hazardous Drugs – Handling in Healthcare Settings”), which was published in 2016 and is expected to become official 1 December 2019.

Facilities with cleanrooms are likely to be familiar with all three of these chapters already, as each addresses the rules for cleanroom design to varying degrees. But the proposed revisions to <795> and <797>, made this year, will warrant a second look for facility managers, as the new guidance could have a sizable impact on facility workflow and finances.

To give a sense of the timeframe: USP first unveiled its proposed revision to GC <795> 30 March 2018, at the same time beginning a period for public comment that ended 31 July 2018. We do not yet know the volume – or impact – of the comments the USP received on <795> and, while some clarity might be offered by late 2018, nothing truly official will be known until 1 June 2019, when the final version of GC <795> is due to be published.

As it stands now, the changes outlined in the proposed revision to GC <795> are substantive and affect a range of categories, from requirements for designated space, sanitation and dedicated staff, to the very definition of nonsterile compounding, itself. Even in advance of the final publication of <795> next year, healthcare facilities that perform any compounding in their pharmacies need to understand the scope of the proposed changes and determine how it could actually influence their practices if this chapter goes into effect as currently written. This article looks at some of the revisions likely to have the most significant consequences.

What defines compounding?

The proposed revision introduces a change to the definition of compounding. This could mean that facilities – which previously did not consider themselves to compound drugs – would now be subject to USP <795> standards. The USP definition states: “Reconstituting a conventionally manufactured nonsterile product in accordance with the directions contained in the approved labelling provided by the product’s manufacturer is not considered compounding as long as the product is prepared for an individual patient and not stored for future use.”

The “not stored for future use” clause is new and impactful, as it directly affects the very common practice – in both hospital and retail pharmacies – of reconstituting a powder by adding a diluent to make a suspension. So, if a pharmacist is making a simple amoxicillin suspension, to be immediately dispensed to a patient, USP <795> states that that process is not compounding.

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However, if the pharmacist chooses to make this suspension and place it on the shelf for future use, it now represents “nonsterile compounding” and could have numerous ramifications for pharmacists and facilities that subsequently have to operate by guidelines set for compounding pharmacies.

Requirements for dedicated persons

Section one states: “The compounding facility must designate one or more individuals (the designated person) to be responsible and accountable for the performance and operation of the site and staff in the preparation of compounded nonsterile preparations (CNSPs).”

This requirement is also new and represents a significant demand on facilities to provide a staffer who is uniquely responsible for training on nonsterile compounding, assuring competencies are done, record keeping and conducting observational studies.

For smaller facilities, such as a critical access hospital with a pharmacy staff of two people, this new requirement could necessitate hiring new personnel or bringing in a third party for training, both of which would weigh considerably on the facility’s budget.

Requirement for dedicated space

Section four of the Proposed Revision to GC <795>, which covers buildings and facilities, expands upon a requirement that “compounding facilities must have a space that is specifically designated for [nonsterile] compounding” and that “the surfaces of (...) a compounding area must be cleanable and must be kept clean.”

As written, this section is currently subject to interpretation, as the USP provides no clear definition of what constitutes a “designated space”, only that such an area must be “separated from areas not directly related to compounding.”

In the absence of any additional description, it is possible that a counter in the corner of the pharmacy could satisfy these criteria – but not necessarily. It is also possible that this revision mandates a separate room dedicated solely to nonsterile compounding. If facilities do not have such a room to spare, this could necessitate new, expensive construction.

Special application for cleanrooms

More specifically related to cleanrooms, section four states: “Areas related to nonsterile compounding must be separated from areas not directly related to compounding. Areas intended for nonsterile compounding must be separated and distinct from the areas intended for sterile compounding. Compounding areas used to compound hazardous compounded nonsterile preparations (CNSPs) must not be used for compounding nonhazardous CNSPs.”

As previously noted, while some other solution might be acceptable, it is possible that this revision mandates a separate cleanroom dedicated solely to nonsterile compounding. In fact, to maintain the required “separation”, the new language suggests that certain facilities could be compelled to have four separate cleanrooms:

  • Nonsterile compounding
  • Hazardous nonsterile compounding
  • Sterile compounding
  • Hazardous sterile compounding

If multiple cleanrooms are needed, potential construction costs – already significant in the case of just one cleanroom – could quickly become a major expenditure.

Complications related to alignment

As USP <795> must now align with USP <800>, facility managers must acknowledge the requirement from the latter chapter that designated areas must be available for receipt, unpacking and storage of hazardous drugs (HDs), while sterile HD compounding and nonsterile HD compounding must take place within a containment primary engineering control (C-PEC, a ventilation device that minimises worker and environmental exposure when handling HD), in turn located in a containment secondary engineering control (C-SEC).

Additional to being “physically separated” any C-SEC/cleanroom used for compounding of nonsterile HD must:

  • Be externally vented through high-efficiency particulate air (HEPA) filtration
  • Have an appropriate air exchange (eg ACPH) – for nonsterile HD this would be 12 ACPH
  • Have a negative pressure between 0.01 and 0.03 inches of water column relative to all adjacent areas

While, as noted above, one interpretation of the language in USP <795> could dictate the need for four separate cleanrooms, USP <800> allows a possible exception – for certain low- volume facilities – that would permit two C-PEC devices to be placed into the same room for sterile and nonsterile compounding. Sections four and five of USP <795> list out similar requirements for cleaning, temperature and humidity controls, as well as functionality of HVAC systems.

Keeping cleanrooms clean

Specific to cleaning, for example, there have been updates to the previous language in <795>, which stated that the “areas used for compounding shall be maintained in clean, orderly and sanitary conditions, and shall be maintained in a good state of repair.”

Corresponding language in the Proposed Revision to GC <795> now states: “The surfaces of ceilings, walls, floors, fixtures, shelving, counters, and cabinets in a compounding area must be cleanable and must be kept clean. Carpet is not allowed in the compounding area. Surfaces should be resistant to damage by cleaning and sanitizing agents.”

The specificity of this updated language could signal a requirement for at least some renovations to a cleanroom, as well as a potential need for different “cleaning and sanitizing agents” (or different surfaces) to ensure compatibility between the two. It also indicates a likely need for the addition of new procedural tasks, including training and staff time for the increased frequency of actual cleanings.

Next steps

Given the possible requirement for new staff, financial investment and procedural overhaul, healthcare executives and facility managers are faced with the responsibility of assessing operations to determine what compliance issues might arise if USP <795> is implemented as currently written. When this chapter is considered alongside USP <800>, it is clear that many organisations may well need new construction. If that is the case, waiting until 1 June 2019 for the final, official version of <795> would almost certainly not be sufficient, in light of the fact that the date all three chapters go into effect (1 December) is just six months later.

For facilities that require new cleanroom construction, the process to bring on an architect to draw up blueprints, complete all the requisite steps for approval and then complete the actual construction and subsequent inspections will be time- intensive. It is important, then, that this latest regulatory activity should be on the radar, now, of any facilities that compound medication for patients.

This article is featured in the October issue. The digital edition is available online.