1. The Effect of the Proposed Chapters & Revisions
USP<800>
The Effect of the Proposed Chapters & Revisions
Joe Cabaleiro R.Ph., BS Pharm, FACA

2. Joe Cabaleiro RPh, BS Pharm, FACA
Facilitator 2
Joe Cabaleiro RPh, BS Pharm, FACA
Consultant; MEDISCA Network Inc.
Consultant/Facilitator; LP3 Network Inc.
Senior Associate; Gates HealthCare Associates, Inc.

3. Disclosure 3
Joe Cabaleiro ‎is a consultant to both LP3 Network Inc. and MEDISCA Network Inc. and is a facilitator of LP3 Network Inc.’s copyright program materials.

4. Disclosure 4
Joe Cabaleiro declare(s) no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.
Material presented during this CPE Activity reflects current literature on the subject and is presented without commercial bias, prejudice or influence.
Additional material presented and any personal opinions on the part of the expert presenter will be notably specified.

5. Copyright and content disclaimer5
The material presented in this activity is Copyright © 2016, LP3 Network Inc.
Due to the very nature of compounding pharmacy practice, content may address aspects of facility design that may or may not be approved by Governmental regulatory bodies or medical associations.
Participants of this Activity should verify all information and data before advocating any information described in this educational activity.

6. Learning Objectives 6
Pharmacists will be able to describe the requirements for a USP<800> compliant compounding sterile/non-sterile compounding environment.
Pharmacists will recognize BUD requirements imposed by different sterile compounding facility designs as defined in the proposed USP<797> & <800> revisions.

7. So, What’s New? 7
USP<800> defines requirements for sterile and non-sterile HD drug storage and compounding.
Effective July 1, 2018
Proposed USP <797> revision changes/clarified some facility requirements.
Effective ?

8. Why should I worry about HD exposure?
Who cares? 8
Why should I worry about HD exposure?
Why should I spend money on this?

9. Males: Gynecomastia and loss of libido working with DES.
INDUSTRY EVIDENCE! 9
Males: Gynecomastia and loss of libido working with DES.
At very low exposure levels!
Females: Synthetic estrogens – breakthrough bleeding 4x more than control population.
Adrenal suppression in corticosteroid factories.
OC Packaging into blister packs:
Women: Elevated estrogens
Men: Decreased testosterone

10. 2010 - Healthcare workers HD study Chromosome 5 & 7 Abnormalities
PHARMACY EVIDENCE 10
Healthcare workers HD study
Chromosome 5 & 7 Abnormalities
Breast and prostate cancer both linked to C-5
1999 – Study: Pharmacists, technicians and nurses handling HDs
40% higher risk of still births and spontaneous abortions
2014: A pharmacy student dies of fentanyl exposure at a U.S. Compounding Pharmacy

11. 11
More information

12. PROTECTION FROM HDs IS NOTHING NEW12
Current USP<797> requires a negative pressure buffer room.
There is an undefined “low volume” exemption.
Current USP<795> addresses HDs.
The requirements are very general
WHMIS requirements
Existing requirements for HD handling and protection have not been strictly enforced.
USP<800> consolidates and clarifies many existing requirements.

13. USP<800> applies to an HD list generated by each pharmacy.
THE HD LIST 13
USP<800> applies to an HD list generated by each pharmacy.
The list must include any drugs used by the pharmacy which are:
Antineoplastic drugs requiring manipulation
Active Pharmaceutical Ingredients on the NIOSH list
New HDs not on the NIOSH list
Drugs for which there is no information
Exemptions:
Antineoplastics that only require counting
Provided manufacturer does not require containment
Finished dosage forms of other HDs on NIOSH list – based on organizational assessment of risk

14. Estradiol, progesterone, testosterone Reproductive only hazards
SOME EXAMPLES 14
Antineoplastics
Fluorouracil
Non-Antineoplastics
Estradiol, progesterone, testosterone
Reproductive only hazards
Misoprostol
Spironolactone
Fluconazole

15. Ambient or Negative Pressure Wear PPE
RECEIVING HDs 15
Segregated area
Ambient or Negative Pressure
Wear PPE
Shipping containers cannot be unpacked in sterile buffer.
If a package is damaged – place in impervious container and contact supplier.
If the package must be opened – do it in a non-sterile HD PEC
This will control any leakage/spillage

16. HAZARDOUS DRUG STORAGE16
Storage – Antineoplastics and HD APIs
Externally vented (through HEPA filter) room
12 Air Changes per Hour
Negative pressure 0.01 to 0.03 inches of water column
Non-antineoplastic, reproductive risk only, and final dosage forms of antineoplastic HDs may be stored with other inventory.
***If a written risk assessment is performed***
Think about:
Uncoated tablets
Compounded HRT capsules with hormone residue on outside

17. HAZARDOUS DRUG STORAGE17
The storage area does not need to be a separate room:
The non-sterile HD compounding area can be used to store HDs for both non-sterile and sterile compounding.
The sterile HD compounding buffer room can be used to store HDs for sterile compounding.

18. HAZARDOUS DRUG STORAGE18
Refrigerated HDs
Antineoplastic HDs & APIs must be stored in a dedicated refrigerator in a negative pressure area.
The refrigerator can be in a negative buffer room.
Compressors should have air vented/captured
Other HDs – based on written organizational risk assessment?

19. FACILITY DESIGN – NON-STERILE HAZARDOUS RECEIVING WITHIN C-SCA19
HD Storage
Refrigerator
Sink
Non-Contaminated Side of Line of Demarcation
Negative Pressure
-0.01 to 0.03 inches water
12 ACPH
Contaminated Side of Line of Demarcation
Class I Biological Safety Cabinet (BSC) or Containment Ventilated Enclosure (CVE)
Designated doffing area
Containment Segregated Compounding Area (C-SCA)

20. NON-STERILE C-SEC REQUIREMENTS20
Smooth, seamless and impervious surfaces throughout.
Must be externally vented through HEPA filter.
12 ACPH
inches negative water column pressure.
HDs for both sterile and non-sterile compounding can be stored in this area.
A 10’ x 10’ room with 12 ACPH may have ~$5,000 annual electricity costs.

21. C-SEC MUST HAVE A PRIMARY ENGINEERING CONTROL (PEC)21
PEC may be either externally vented through a HEPA filter or redundant HEPA filters in series.
These devices can include:
Class I or II BSCs
Vented Balance Safety Enclosures
Compounding Aseptic Containment Isolators (CACIs)
The C-PEC must operate continuously if it supplies some or all of the negative pressure for the C-SEC.
SEC & PEC must be certified annually or per manufacturer.

22. EXTERNALLY VENTED ROOMS AND C-PECs EXHAUST A LOT OF HOT AIR (OR COLD AIR)!22
3m x 3m x 2.5m = 23 c3m(30 kg)
23 c3m=272 c3m ÷ 23 c3m=12 ACPH
About a 2 meter cube of air every minute
The exhaust will fill a typical hot
air balloon in 8 hours.
3 hours for a 30 ACPH room.
The air will weigh 2700 kg.

23. CONSEQUENCES OF MOVING ALL THAT AIR23
Significant impact on HVAC needs
Dedicated, commercial units capable of running 24/7.
~ A ton of AC Capacity per PEC
For sterile compounding: 20°C (68°F) or lower temperature
For sterile compounding: 30-60% Relative Humidity
Significant electrical cost
10’ x 10’ room with 12 ACPH ~ $5,000 per year
The C-PEC must operate continuously if it supplies some or all of the negative pressure for the C-SEC.
For non-sterile, can design to avoid this – save $
For sterile – CPECs must operate continuously

24. STERILE HD COMPOUNDING24
Negative Pressure inches water
30 ACPH
Positive Pressure >0.02 inches water
30 ACPH
Positive Pressure >0.02 inches water
30 ACPH
Externally vented through HEPA
To Roof Exhaust
ISO 7
ISO 7
ISO 7
To Roof Exhaust
Positive Pressure Non-HD Compounding
Shared Anteroom
Negative pressure HD
Compounding

25. STERILE HD COMPOUNDING - ANTEROOM25
Negative Pressure inches water
30 ACPH
Anteroom
ISO-7
30 ACPH
Positive Pressure >0.02 inches water
30 ACPH
Positive Pressure >0.02 inches water
30 ACPH
Externally vented through HEPA
Sink
At least 1 meter from negative buffer door
ISO 7
ISO 7
ISO 7
Sink
Positive Pressure Non-HD Compounding
Shared Anteroom

26. STERILE HD COMPOUNDING - BUFFER ROOM26
Room Requirements
ISO-7
Negative Pressure inches water
30 ACPH
Externally vented through HEPA
Refrigerator
Capture or vent compressor exhaust
Pass Throughs
Should be equipped with sealed doors
Non-sterile compounding
PEC may be used for occasional NS compounding
Decontaminated, cleaned, disinfected after use
No particle generating activities during sterile compounding
Eye Wash
Refrig
Positive Pressure >0.02 inches water
30 ACPH
Positive Pressure >0.02 inches water
30 ACPH
ISO 7
ISO 7
ISO 7
Pass
Through
PEC

27. Positive Pressure >0.02 inches water
ANTE WITH POSITIVE BUFFER AND NEGATIVE BUFFER OFF POSITIVE 27
Negative Pressure 0.01 to 0.03 inches water
Exhausted to exterior
Positive Pressure
>0.02 inches water
Positive Pressure >0.02 inches water
ISO 7
ISO 7
ISO 7
Exhaust to Exterior through HEPA
Exhaust to Exterior through HEPA
Doff
HD Buffer
Non HD Buffer
Anteroom

28. Permitted but not recommended: Garbing compromises Traffic compromises
ANTE WITH POSITIVE BUFFER AND NEGATIVE BUFFER OFF POSITIVE 28
Permitted but not recommended:
Garbing compromises
Traffic compromises
Moving HDs in and out compromises
Moving HDs in & out:
A pass through directly into the room or,
Sealed containers
No refrigerator pass throughs

29. PRIMARY ENGINEERING CONTROLS – CLASS I BSCs29
Internally vented dual HEPA device
HEPA Filter
Primary HEPA Filter
Lighting System
(Fluorescent)
Air Blower
Pre-Filter
Class I BSCs only protect the operator from exposure to the HD

30. PRIMARY ENGINEERING CONTROLS – CLASS II BSCs30
Externally vented device Type A
HEPA Filters
Air Blower
Class II BSCs protect the operator from exposure to the HD and the CSP from particulate contamination

31. 75 ft/min inflow velocity Exhaust into lab or through thimble
CLASS II PECS 31
Type A1
75 ft/min inflow velocity
Exhaust into lab or through thimble
Into lab would be non-compliant
70% of the air recirculated/30% exhausted
Suitable for minute quantities of volatile drugs
Type A2
100 ft/min inflow velocity
USP<800> says suitable for most known HDs

32. 100 ft/min inflow velocity
CLASS II PECS 32
Type B1
100 ft/min inflow velocity
Exhaust to outside via direct duct connection
70% of the air recirculated/30% exhausted
Suitable for minute quantities of volatile drugs
Type B2
100% of the air is exhausted
Suitable for volatile drugs

33. RESTRICTED ACCESS BARRIER DEVICES (“GLOVE BOXES”)33
Compounding Aseptic Containment Isolators:
Provides ISO-5 sterile compounding environment.
Protect the CSP and the compounder.
Externally vented.
May be used in a non-classified negative air pressure segregated compounding area for category 1 hazardous CSPs.
May be used in a negative pressure ISO-7 buffer room for hazardous Category 2 CSPs.

34. Volatile HDs; examples: 5-FU Carmustine Nitrogen mustard
CONSIDER VOLATILE HDs 34
Volatile HDs; examples:
5-FU
Carmustine
Nitrogen mustard
Cyclophosphamide
Cisplatin
Ifosfamide
Class I BSCs:
Internally vented are not suitable
Class II BSCs:
Type A: Only minute quantities
Type B2 – (100% vented): Designed for volatile HDs

35. TRAINING REQUIREMENTS35
The list of HDs and their risks.
How to read HD labels and SDSs.

SOPs related to handling of HDs.

Proper use of personal protective equipment.
Proper use of equipment and devices (engineering controls).
Techniques for compounding with HDs.
Response to known or suspected HD exposure (including use of eyewashes).
Spill management
(including use of spill kits).
Proper disposal of HDs and trace-contaminated materials.
Personnel of reproductive capability must confirm in writing that they understand the risks of handling hazardous drugs.

36. Two pairs of chemo gloves
PPE REQUIREMENTS 36
Two pairs of chemo gloves
Outer pair is sterile (for sterile compounding)
Disposable chemo resistant gowns
Must close in back
Tight sealing cuffs (elastic or knit)
Eye protection
Hair covers
Shoe covers
Two pairs
Respiratory protection
Fit tested masks or respirator

37. Deactivation – render inert or inactive
CLEANING/DISINFECTION...AND DEACTIVATION/DECONTAMINATION 37
USP<800> Adds:
Deactivation – render inert or inactive
Decontamination – remove HD residue
Deactivation
Agent as specified by manufacturer
Commercial deactivating agent
Sodium hypochlorite (1 part bleach/2 parts water)
Must remove immediately or neutralize with sodium thiosulfate solution
Decontamination
Alcohol
Water
Peroxide
Sodium hypochlorite solution

38. Protecting yourself and staff is important38

39. PROPOSED USP<797> BUDs39
Eliminates Low, High, Medium Risk
BUDs are based on facility specs
Creates Category I & Category II CSPs
Category I CSPs
Prepared in an ISO-5 PEC unclassified air room
<=12 hours room temp, <=24 hours refrigerated
Category 2 CSPs
Prepared in ISO-5 PEC in ISO classified environment
BUD based on:
API vs Manufactured product
Preserved vs unpreserved
Sterility/endotoxin tested vs untested
Longest BUDs: 42 days room/temp or 45 days frozen

40. PROPOSED USP<797> REVISIONS:40
The devices we call “Isolators” today (CAI & CACIs):
“Demoted” to RAB (Restricted Access Barrier Devices)
Treated essentially the same same as LAFWs & Class II BSCs
New Category of device: Isolator
Receives some exemptions for buffer/ante requirements

41. PROPOSED USP<797> REVISIONS:41
Isolator specifications:
Equipped with high-integrity transfer ports to move supplies, ingredients, components, and devices into and out of the isolator.
It is decontaminated using a generator that distributes a sporicidal chemical agent throughout the isolator chamber.
The isolator maintains constant overpressure of at least 0.05-inch water column.
The manufacturer provides documentation that the isolator will continuously meet ISO Class 5 conditions, including during material transfer.

42. Personnel training and PPE requirements.
THE 30 SECOND REVIEW 42
USP<800>:
Imposes negative pressure storage and compounding environment requirements for HD CSPs.
Personnel training and PPE requirements.
Adds decontamination/deactivation
Proposed USP<797>:
CSP BUDs based on the environment they are prepared in.
Disqualifies some CAIs and CACIs from use in an ISO-8 to prepare CAT 2 CSPs.
Relevant if you currently use this setup for medium or high risk CSPs.

43. Questions? Joe Cabaleiro RPh, BS Pharm, FACA 43
Consultant; MEDISCA Network Inc.
Consultant/Facilitator; LP3 Network Inc.
Senior Associate; Gates HealthCare Associates

44. for your participation
Thank you
for your participation
in this activity.