Disclaimer: This article is merely an incomplete overview of a particular section/definition in each of the standards/guidelines addressed below. It is not meant to exempt you from accessing each of these publications, read, understand, and verify their requirements as it applies to your entity. You must download the latest update of each (if freely available online) or purchase a copy from the corresponding organization.
This brief article aims to compare the required facilities and handling conditions as required by the United States Pharmacopeia (USP) and National Association of Pharmacy Regulatory Authorities (NAPRA) in regards to compounding of Hazardous Non-Sterile drugs.
Prior to going into details, we need to establish a reference to the definition of Hazardous Drugs (HD). Both USP and NAPRA refer to a public domain list by National Institute for Occupational Safety and Health (NIOSH). The Following excerpt is from 2016 revision. Currently a 2018 update to the list is being peer reviewed for public release. This publication is freely available online and you are strongly advised to have the most current list downloaded/printed from https://www.cdc.gov/niosh.
The current NIOSH approach involves three groups of drugs:
Group 1: Antineoplastic drugs (AHFS Classification 10:00) [ASHP/AHFS DI 2016]. Note that many of these drugs may also pose a reproductive risk for susceptible populations (Table 1).
Group 2: Non-antineoplastic drugs that meet one or more of the NIOSH criteria for a hazardous drug. Note that some of these drugs may also pose a reproductive risk for susceptible populations (Table 2).
Group 3: Drugs that primarily pose a reproductive risk to men and women who are actively trying to conceive and women who are pregnant or breast feeding, because some of these drugs may be present in breast milk (Table 3).
NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016
While the requirements of both USP and NAPRA are very similar, the approach and classification of Standards are slightly different.
The required space and conditions in which the preparations and compounding take place, is mainly addressed in three chapters of US Pharmacopeia:
- USP <795> Pharmaceutical Compounding – Nonsterile Preparations
- USP <797> Pharmaceutical Compounding – Sterile Preparations
- USP <800> Hazardous Drugs – Handling in Healthcare Settings
In order to comply with the required facility conditions and controls for hazardous nonsterile compounding as outlined by USP we require to fully understand the content of chapters 800, and 795. These two chapters along with other chapters containing mandatory guidelines for compounding facilities are available in a compendium package available for purchase through www.usp.org.
USP 795 defines three categories of simple, moderate, and complex for compounding. If the USP has a compounding monograph for a particular preparation or such preparation has appeared on peer-reviewed journal with specific quantities, procedures, and equipments, it is categorized as “simple“. If special calculations or procedures are required to determine the quantities of components, or if the stability data for a specific formulation is not available, such preparations fall within “moderate” category. Finally “complex” category refers to a preparation that requires special training, facilities, procedures and equipments in order to target the specific therapeutic outcome.
As for the required compounding facilities, <795> briefly mentions “…an adequate space that is specifically designated for compounding of prescription“, and that it “shall provide an orderly placement of equipments and materials…” also it mentions that such space has to be well lighted and heat, ventilation, and air conditioning has to be controlled to prevent the decomposition and contamination of chemicals. Further, the appropriate temperature and humidity monitoring should be maintained.
In case any of the preparations involve HD ingredient or manipulation, chapter <800> outlines the required facilities and controls. USP <800> calls for containment requirements for
- Any HD API (Active Pharmaceutical Ingredient)
- Any antineoplastic requiring HD manipulation
This vaguely articulated classification arises two questions:
– What list does “any HD API” refer to?
– Does “any antineoplastic requiring HD manipulation” mean groups 2 and 3 do not need the containment requirement of chapter <800>?
Despite such questions, the common recommendation of the industry is to consider the “containment requirement” for any HD compounding on the NIOSH list.
USP <800> requires the following conditions for the HD Nonsterile Compounding.
CVE: Containment Ventilated Enclosure
BSC: Biological Safety Cabinet
CACI: Compounding Aseptic Containment Isolator
C-PEC: Containment Primary Engineering Control
C-SEC: Containment Secondary Engineering Control
NAPRA offers three model standards as guidlines for the pharmaceutical compounding.
- Model Standards for Pharmacy Compounding of Non-Sterile Preparation (Draft 5b/Not final as of the date of this article)
- Model Standards for Pharmacy Compounding of Non-Hazardous Sterile Preparations
- Model Standards for Pharmacy Compounding of Hazardous Sterile Preparations
The subject matter of this article wholly addressed in the first model (which is still in draft).
NAPRA model standards for non-sterile preparation outlines the required facilities and control in case of hazardous (non-sterile) preparations as well. The approach NAPRA is taking seems to be better structured and less vague, however as mentioned in the beginning, the bottom line requirements are quite in sync with USP <800>.
It shall be also mentioned that NAPRA, in addition to NIOSH, follows the guidelines of Workplace Hazardous Materials Information System (WHMIS), Canada’s national hazard communication standard, as well. The WHMIS portal can be accessed through www.whmis.org.
NAPRA defines three levels of requirements when it comes to non-sterile preparations.
Level A refers to requirements which need to be met when making “simple” and “moderate” compounds as defined in USP <795>. The compound can include items of Group 2, and 3 of NIOSH HD list or materials designated as hazardous by WHMIS which pose little or no risk for compounding personnel when compounded in small quantities.
Level B refers to requirements which must be met when making complex compounds as defined in USP <795>. The compound can include the items of Group 2, and 3 of NIOSH HD list or some hazardous materials categorized by WHMIS.
Level C refers to requirements which must be met when compounding any amount and all dosage forms of hazardous drugs which are classified by NIOSH as Group 1 or hazardous materials classified by WHMIS as very irritating to the respiratory tract, the skin and the mucous membrane. It may also apply to NIOSH Group 2, and 3 depending on risk assessment.
While NAPRA states certain requirement for Level A, and B compounding, such as a “well ventilated entirely closed off room or room with a ventilated containment device…“, it is the level C compounding that requires the same conditions as <800> required in the table above.
– C-SEC must be externally vented though HEPA filter,
– Be Physically separated from other preparation rooms, and
– Have a minimum of 12 ACPH, and a negative pressure of -2.5 Pa relative to the surrounding areas.
– Presence of a C-PEC is required as well.
Although NAPRA requires the HEPA filtration before exhaust to the outside of the building, it is speculated to be removed from the final draft. This requirement (HEPA filtered before exhaust) was also required before final draft of <800>. Further NAPRA does not elaborate on the C-PEC conditions. However it is expected to be in line with <800>.
There are other requirements mentioned in NAPRA model standard which are not required by <800> as far as non-sterile HDs are compounded. For example NAPRA requires maintaining temperature of 20C or less while <800> requires such condition only for sterile preparation (HD or Non-HD).