1. Understanding United States Pharmacopeia (USP) compounding standards and applying to daily clinical practice
Bridget Gegorski, PharmD, MS
Medication Safety Officer
University Hospitals
October 12th, 2018

2. Objectives Define USP <797> and <800> standards
Identify hospital practices and recognize necessary changes for USP compliance
Explain how USP <797> and <800> general chapter changes will affect practices in the pharmacy and on the practice units
Recognize applicability to your own area of practice

3. Why is this topic important to clinical pharmacists?
Sterile compounding regulations and enforcement have changed
Proposed changes to bedside compounding requirements and definitions have proposed changes
Changes to how hazardous drugs are defined
Definition of hazardous drug amended and handling requirements increased

4. Why all the fuss?
2012 New England Compounding Center (NECC) fungal meningitis outbreak due to contaminated steroid injections
753 patients in 20 states diagnosed with fungal meningitis
64 deaths
Cdc.gov. (2015). Multistate Outbreak of Fungal Meningitis and Other Infections – Case Count | HAI | CDC. [online] Available at: [Accessed 28 Aug. 2018].

5. Tragedy sparks reform
US Department of Justice named the NECC fungal meningitis outbreak largest US public health crisis caused by a pharmaceutical product in recent history
2013 Drug Quality and Security Act established 503(b) compounding pharmacies
Establishes FDA direct oversight of these pharmacy types
Increased oversight for all compounding practices from regulatory bodies
Not an isolated incident
Justice.gov. (2017). Owner of New England Compounding Center Sentenced for Racketeering Leading to Nationwide Fungal Meningitis Outbreak. [online] Available at: [Accessed 28 Aug. 2018].
Congress.gov. (2013). H.R th Congress ( ): Drug Quality and Security Act. [online] Available at: [Accessed 28 Aug. 2018].

6. United States Pharmacopeia (USP)
Not a government entity
Develops and publishes standards for drug substances, drug products, excipients, and dietary supplements in the United States Pharmacopeia–National Formulary (USP–NF)
USP general chapters are legally recognized in the Federal Food, Drug and Cosmetic (FD&C) Act since it was first enacted in 1938
No role in enforcement
Written by USP  recognized in FD&C  enforced by FDA  granted to the state boards of pharmacy to enforce
Usp.org. (2018). Legal Recognition of USP Standards | USP. [online] Available at: [Accessed 28 Aug. 2018].

7. USP <797> Pharmaceutical compounding sterile preparations

8. USP <797> Pharmaceutical compounding sterile preparations
Standard written with intent to prevent patient harm
Microbial contamination
Excessive bacterial endotoxins
Variability in intended strength that exceed monograph limits
Use of ingredients of inappropriate quality
Unintended physical or chemical contaminants
Establishes minimum practice and quality standards for compounded sterile preparations (CSPs)
Not going into any further detail because this standard has been around since 2004, and in its current state since 2008, will go into detail about the proposed revisions later in this presentation. Will specifically address those items that will affect practice on the floors.
<797> Pharmaceutical compounding sterile preparations. Found in: USP Compounding Compendium. The United States Pharmacopeial Convention. Rockville, MD. c2016:39-84.

9. USP <797> timeline 2nd revision intended official date 12/2019
2nd revision re-release 7/2018
USP received >10,000 public comments
2nd revision released 9/2015
Revision official 6/2008
Revision released 12/2007
Official 1/2004
Published 11/2003
Public comment period open until 11/30/2018
FIX BULLETS!!!!

10. USP <797> standard enforcement
FDA and other government authorities
Federal Food, Drug, and Cosmetics Act
Insanitary conditions draft guidance (September 2018)
State Boards of Pharmacy
Ohio Administrative Code
Centers for Medicare and Medicaid (CMS)
Added as part of the Conditions of Participation in 2015
Insanitary Conditions at Compounding Facilities Guidance for Industry [internet]. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Compliance. [Revision Sept. 2018, cited 2018 Sept 27], Available from
Drugs compounded in a pharmacy. Ohio Laws and Rules. [Effective 2016 Feb 15; cited 2018 Jan 16], Available from
Explain other government authority

11. USP <797> standard enforcement
Joint Commission (JC)
Statement issued October 2017
“While activities associated with sterile compounding are currently assessed during JC surveys, accredited organizations performing sterile compounding should now expect increased attention on these processes.”
Assessments can occur during the
life safety code document review
medication management tracer
infection control tracer
competency assessment system tracers
Reducing Risk Associated with Sterile Medication Compounding. (2017). The Joint Commission Perspectives, 37(10), pp

12. JC FAQs USP <797> interpretations
Numerous FAQs that outline the JCs thought process on how they will enforce using standards that are already in existences. Cites LS, EC, IC, MM chapters
In 2018 JC Perspectives, a monthly publication from JC, has frequently written standards interpretation sections on USP compliance
Jointcommission.org. (2018). Standards Interpretation FAQs. [online] Available at: [Accessed 21 Aug. 2018].

13. Joint Commission survey experiences
IV hoods/rooms
Compounding level
low, medium, or high risk
Paperwork review
Equipment certifications
Environmental viable sampling (air and surface)
Competency documentations
Competencies must be current for any one compounding at anytime. (pharmacists and techs)

14. USP <800> Hazardous drugs – Handling in health care settings

15. USP <800> Hazardous drugs – Handling in health care settings
Standard written with intent to prevent unnecessary employee exposure to hazardous drugs (HDs)
Official December 1, 2019
Establishes practice and quality standards for the handling of HDs throughout the medication use life cycle
Receive
Transport
Store
Mix
Administer
Dispose
Delayed from original official date July 1, 2018 to coincide with intended official date for 2nd revision of USP <797>
<800> Hazardous drugs – Handling in health care settings. Found in: USP Compounding Compendium. The United States Pharmacopeial Convention. Rockville, MD. c2016:

16. Occupational HD exposure
Healthcare workers exposed to HDs by absorption through skin, mucous membranes, inadvertent ingestion, inhalation, or injection
Studies have detected levels of HDs in the urine of pharmacists and nurses
Oncology Nursing Society (ONS) cites extensive research on the subject
Polovich, M. and Olsen, M. Safe handling of hazardous drugs. 3rd ed. Pittsburgh: Oncology Nursing Society. 2018; pages 8-17.

17. NIOSH List of HDs
The National Institute for Occupational Safety and Health (NIOSH)
Table 1: Antineoplastics
Table 2: Non-antineoplastics
Table 3: Reproductive-only hazards
Cdc.gov. (2016). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, [online] Available at: [Accessed 28 Aug. 2018].

18. Personnel to consider Receiving Transport Pharmacy technicians
Pharmacists
Nursing
Procedural personnel
Surgical services
Emergency department
Obstetrics
Physicians
Medical office personnel
Kienle PC et al. Perform an assessment of risk to comply with USP <800>[Internet]. Pharmacy Purchasing & Products. 2017;14:34. [Cited 2017 May 8]. Available from:

19. CDC and NIOSH recommended controls
Cdc.gov. (2018). CDC - Hierarchy of Controls - NIOSH Workplace Safety and Health Topic. [online] Available at: [Accessed 28 Aug. 2018].

20. USP <800> HD list and HD handling
Entity specific HD list is required
Handling Option 1
Use the NIOSH list in its entirety and handle every drug in every dosage form with all the containment strategies and work practices listed in USP <800>
Not practical for workflow and not always possible with infrastructure
Handling Option 2
Perform an assessment of risk (AoR) on NIOSH listed drugs to determine alternative containment strategies for some drugs/dosage forms
Drugs that qualify include oral chemotherapy and NIOSH tables 2 and 3 drugs
Important to know how your site is approaching this. Option 1 would not allow for any NIOSH listed drugs to be stored in an ADC or prepped on the floor( essentially handling all these drugs as we currently handle chemo)
Kienle PC et al. Perform an assessment of risk to comply with USP <800>[Internet]. Pharmacy Purchasing & Products. 2017;14:34. [Cited 2017 May 8]. Available from:

21. USP <800> requirements
Creation of a HD list
JC requirement MM
Training, competency, and documentation needs for staff
HD handling, PPE use, and spill control
HD communication program
A signed employee statement acknowledging that they have been informed about hazardous drug exposure risks
<800> Hazardous drugs – Handling in health care settings. Found in: USP Compounding Compendium. The United States Pharmacopeial Convention. Rockville, MD. c2016:

22. USP <800> requirements
Describes acceptable facility designs and environmental controls
Necessitates designated areas for receipt, storage, and nonsterile and sterile compounding for HD use only
Defines decontamination/deactivation frequency and product requirements
Requires closed system transfer devices (CSTDs) for administration of HDs
CSTD is only Recommended for compounding (not required)
<800> Hazardous drugs – Handling in health care settings. Found in: USP Compounding Compendium. The United States Pharmacopeial Convention. Rockville, MD. c2016:

23. Components of an assessment of risk (AoR)
Type of HD
Specific dosage form
Risk of exposure
Packaging
Type of manipulation performed
Alternative containment strategy to reduce the risk of exposure
Emphasize: If you haven’t evaluated then it all needs stored in negative pressure space, externally ventilated and 12 ACPH
Allows for hospitals to continue to store qualified HDs in the general pharmacy areas and automatic dispensing cabinets (ADCs)
Kienle PC et al. Perform an assessment of risk to comply with USP <800>[Internet]. Pharmacy Purchasing & Products. 2017;14:34. [Cited 2017 May 8]. Available from:

24. USP <800> receipt and storage facility requirements
Handled under conditions that promote patient safety, worker safety, and environmental protection
Received in an area that is negative or neutral pressure to adjacent areas
HD storage:
Externally vented
Physically separate
Negative pressure
Minimum 12 air changes per hour (ACPH)
Negative pressure cleanroom will meet these storage requirements…
Reminder: if you have completed an AoR you can opt out of these storage requirements if your risk assessment determines that it is safe to do so.
Do not want to store non-sterile preps in the clean rooms.
<800> Hazardous drugs – Handling in health care settings. Found in: USP Compounding Compendium. The United States Pharmacopeial Convention. Rockville, MD. c2016:

25. USP <800> Engineering controls for sterile HD compounding and storage
Configuration
IV hood requirement
IV room requirements
Cleanroom suite:
ISO Class 7 buffer room with an ISO Class 7 ante-room
Externally vented
Example biological safety cabinet (BSC) or contained aseptic compounding isolator (CACI)
30 ACPH
Negative pressure inches or water column relative to adjacent areas
Unclassified:
Containment segregated compounding area (C-SCA)
Example BSC or CACI
12 ACPH
Define ISO- International Organization for Standardization- ISO 7 is an standard of cleanliness for air.
<800> Hazardous drugs – Handling in health care settings. Found in: USP Compounding Compendium. The United States Pharmacopeial Convention. Rockville, MD. c2016:

26. HD administration Closed system transfer device (CSTD)
CSTD - “when administration route allows”
<800> Hazardous drugs – Handling in health care settings. Found in: USP Compounding Compendium. The United States Pharmacopeial Convention. Rockville, MD. c2016:

27. HD administration Optional PPE based on dosage form: Impenetrable gown
Don PPE according to NIOSH Table 5 recommendations
Gloves must be worn for handling all HDs
American Society of Testing and Materials (ASTM) requirements
D6978 (or its successor)
“Chemotherapy gloves”
Optional PPE based on dosage form:
Impenetrable gown
Eye/face protection
Respiratory protection

28. HD administration All doses and storage areas labeled denoting HD
Clean area with a decontamination/deactivation agent
Spill kits and spill response planning
Labeling to alert end user of risk- end user should be educated as to what the label denotes
Decontamination/deactivation agent= Step 2, Peridox, HDClean (chemo Glo)
(EPA listed oxidizer)
Cleaning includes medication rooms and areas where chemotherapy administration has occurred

29. Examples of NIOSH listed drugs
Table 2 (non-antineoplastic HD):
Azathioprine
Chloramphenicol
Cidofovir
Conjugated Estrogens
Cyclosporine
Dexrazoxane
Fosphenytoin
Ganciclovir
Mycophenolate mofetil
Palifermin
Phenytoin
Progesterone
Tacrolimus
Zidovudine
Table 3 (reproductive risk only):
Cetrorelix
Choriogonadotropin
Fluconazole
Icatibant
Mentropins
Methylgonovine
Pamidronate
Plerixafor
Telavancin
Testosterone
Valproic Acid
Voriconazole
Ziprasidone
Zoledronic acid
Cdc.gov. (2016). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, [online] Available at: [Accessed 28 Aug. 2018].

30. Lexicomp® monograph warnings
For awareness- I’m sure we’ve all seen this in lexicomp. But we should know that lexicomp has copied NIOSH table 5 recommendations to the letter USP 800 assuming that an AoR has not been completed, and frontline practitioners will see this- may already be getting questions from nurses etc.
Phenytoin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, INC. Riverwoods, IL. Available at: Accessed 8/24/2018

31. USP <797> Revised

32. USP <797> revision Draft standard published
7/29/18
Draft standard published
11/30/19
Public comment period closes
6/1/19
Official publication
12/1/19
Standard will be enforceable
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from

33. Biggest changes Definition of compounding vs administration
Defined restrictions for immediate use compounding
Low, Medium, High Risk compounding categories are replaced with Category 1 and 2 compounds that are based on IV preparation location design
New competency requirements and frequencies
Increased frequency for environmental sampling required
Immediate use definition broadens its use
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from

34. CSPs in scope Injections, including infusions
Irrigations for internal body cavities
Mouth, rectal cavity, and sinus cavity are excluded
Ophthalmic dosage forms
Preparations for pulmonary inhalations
Baths and soaks for live organs and tissues
Implants
Internal body cavities = (any space that does not normally communicate with the outside environment)
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from

35. USP <797> revisions
Compounding definition:
“Combining, admixing, diluting, pooling, reconstituting, repackaging, or otherwise altering a drug or bulk drug substance to create a sterile medication”
Exclusions
“Preparing a conventionally manufactured sterile product in accordance with the directions contained in approved labeling provided by the product’s manufacturer is not compounding as long as the product is prepared for an individual patient”
Withdrawal of doses from a vial is considered part of administration
This is an important distinction because the JC and USP had previously conflicted on its definitions of compounding. This change moves USP’s definition to that of the JC, meaning withdrawing a medication from a vial for administration to a single patient (ie. Removing an IV push ondansetron from an ADC for preparation and administration in the ED is no longer considered compounding- instead USP refers to this process as administering.
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from

36. Proprietary bag and vial systems
If used in accordance with manufacturer’s instructions for immediate administration to a patient, it is not considered compounding
Must be attached using aseptic technique
Proprietary bags/vials systems do not follow the USP sterility guidance for risk level, instead they follow the manufacture recommended BUD because this is how it was approved for use by the FDA. Meaning the manufacturer proved as part of their FDA approval process that their product was sterile and stable using the bag and vial system for their defined period of time.
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from

37. Proprietary bag and vial systems
Docking of bag and vial for future activations must be performed in accordance to USP <797>
ISO 5 environment (IV hood)
Beyond use date (BUD) exception: BUD for proprietary bag and vials systems must not be longer than those specified in the manufacturer’s labeling

38. Immediate use CSP requirements
Single patient dose
Non-hazardous preparation
Use only sterile products
Administration must begin within 1 hour of the start of preparation
Single dose vials discarded after preparation complete
Aseptic technique
Follow evidenced based information for physical and chemical compatibilities
Procedures in place to prevent contact with nonsterile surface, particulate matter, biological fluids, and mix ups with other CSPs
Preparation of non-hazardous CSPs for a single patient using only sterile starting ingredients are not required to meet all the standards in USP <797>
USP <797> revision addresses the requirements in detail that are necessary to qualify for this exemption
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from

39. CSP category IV hood location requirements used to determine category
UH has LAFS and RABS, none of our PECs will qualify as an isolator. Most “gloveboxes” as you know them have been downgraded to a RABS because they do not have a decontamination process where the device disperses a sporicidal agent before and after opening the chambers.
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from

40. IV hood and room acronyms
ISO- international organization for standardization
LAFS- Laminar airflow system
LAFW- Laminar airflow workbench
IVLFZ- Integrated vertical laminar flow zone
BSC- Biological Safety Cabinet
RABS- Restricted access barrier system
CAI- Compounding aseptic isolator
CACI- Containment aseptic compounding isolator
RABS= “glove boxes”
True Isolators have a
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from

41. Category 1 and 2 CSPs maximum allowable BUD
Controlled room temperature
(20 to 25 °C)
Refrigerated
(2 to 8 °C)
Frozen
(-25 to -10 °C)
Category 1
12 hours
24 hours
Category 2
4 days
9 days
45 days
Category 2 with passing sterility testing
30 days
60 days
Longer BUDs available for products sent to the pt drawers on the floor
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from

42. BUD vs expiration date Term Definition Applicability BUD
Either the date, or hour and date after which a CSP must not be used or administration must not begin
The BUD is determined from the date/time that preparation of the CSP is initiated
Applies to all CSPs
Expiration Date
Time during which a product can be expected to meet the requirements of the compendial monograph, if one exists, provided it is kept under the prescribed conditions
Applies to all conventionally manufactured products, APIs, and excipients
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from

43. Summary
USP <800> will require increased precautions for medication storage, preparation, administration, and disposal on the floors
AoRs must be completed to avoid requiring all NIOSH listed drugs to be treated the same as a chemotherapy product
USP <797> revision will expand the availability of the immediate use exemption for compounding on the floor
BUDs of medications at your facility may change based on pharmacy IV room design

44. Questions?

45. References
Cdc.gov. (2015). Multistate Outbreak of Fungal Meningitis and Other Infections – Case Count | HAI | CDC. [online] Available at: [Accessed 28 Aug. 2018].
Justice.gov. (2017). Owner of New England Compounding Center Sentenced for Racketeering Leading to Nationwide Fungal Meningitis Outbreak. [online] Available at: [Accessed 28 Aug. 2018].
Congress.gov. (2013). H.R th Congress ( ): Drug Quality and Security Act. [online] Available at: [Accessed 28 Aug. 2018].
Usp.org. (2018). Legal Recognition of USP Standards | USP. [online] Available at: [Accessed 28 Aug. 2018].
<797> Pharmaceutical compounding sterile preparations. Found in: USP Compounding Compendium. The United States Pharmacopeial Convention. Rockville, MD. c2016:39-84.
Insanitary Conditions at Compounding Facilities Guidance for Industry [internet]. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Compliance. [Revision Sept. 2018, cited 2018 Sept 27], Available from
Drugs compounded in a pharmacy. Ohio Laws and Rules. [Effective 2016 Feb 15; cited 2018 Jan 16], Available from
Reducing Risk Associated with Sterile Medication Compounding. (2017). The Joint Commission Perspectives, 37(10), pp
Jointcommission.org. (2018). Standards Interpretation FAQs. [online] Available at: [Accessed 21 Aug. 2018].
<800> Hazardous drugs – Handling in health care settings. Found in: USP Compounding Compendium. The United States Pharmacopeial Convention. Rockville, MD. c2016:
Polovich, M. and Olsen, M. Safe handling of hazardous drugs. 3rd ed. Pittsburgh: Oncology Nursing Society. 2018; pages 8-17.
Cdc.gov. (2016). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, [online] Available at: [Accessed 28 Aug. 2018].
Kienle PC et al. Perform an assessment of risk to comply with USP <800>[Internet]. Pharmacy Purchasing & Products. 2017;14:34. [Cited 2017 May 8]. Available from:
Cdc.gov. (2018). CDC - Hierarchy of Controls - NIOSH Workplace Safety and Health Topic. [online] Available at: [Accessed 28 Aug. 2018].
Proposed revision to GC <797> Pharmaceutical compounding sterile preparations. USP-NF. Published 2018 July 29. Available from