7.2 Compounding Supplies, Containers & Closures
Key Takeaways
USP <797> requires supplies that touch the CSP, such as needles, syringes, filters, tubing sets and containers, to be sterile and depyrogenated, and made of materials that do not react with or absorb the ingredients.
Each lot of commercially available sterile, depyrogenated containers and closures needs a certificate of analysis or equivalent documentation. In-house sterilization or depyrogenation must be shown effective (USP <1229>).
Sterilizing filters must be sterile, depyrogenated, 0.22 µm or smaller, and made for pharmaceutical use. A filter labeled 'for laboratory use only' must not be used.
An aqueous multiple-dose CSP must be Category 2 or 3, pass antimicrobial effectiveness testing (USP <51>), and use a container evaluated for closure integrity (USP <1207>).
Container choice affects the BUD (leachables, sorption, freezing, light), and connector design affects safety: ENFit is the enteral standard and NRFit the neuraxial one.
7.2 Compounding Supplies, Containers & Closures
A CSP is only as good as everything that touches it. Needles, syringes, filters, tubing, bags, vials, stoppers and cassettes can add microbes, endotoxin or particles, and they can react with the drug or absorb it. The BCSCP outline lists compounding supplies (1A3) and containers and closures (1A4) as separate tasks. This section covers both.
USP <797> requirements for supplies (Section 9.2)
- Supplies such as beakers, utensils, needles, syringes, filters and tubing sets should be of suitable composition. The surfaces that touch components must not be reactive or sorptive.
- Supplies in direct contact with the CSP must be sterile and depyrogenated.
- USP's FAQ adds that the chapter does not rule on specific disposable items such as dispensing pins. The facility decides whether a given item is appropriate.
USP <797> requirements for containers and closures
- Documentation: Each lot of commercially available sterile, depyrogenated containers and container-closure systems must come with a COA or other documentation showing it meets its sterility and depyrogenation specifications. USP's FAQ accepts supplier labeling that identifies sterile empty bags, with lot traceability.
- In-house processing: If the facility sterilizes or depyrogenates its own supplies or containers, it must establish and document that each process works (USP <1229>).
- Inspection: Sterile closures are visually reinspected before use for defects that could compromise sterility. Unacceptable lots are rejected, labeled and segregated, and other lots from the same vendor are checked.
How the container shapes the BUD
USP <797> Section 14.2 asks the compounder to consider the materials of composition of the container-closure system and its compatibility with the CSP. That covers leachables, interactions, adsorption and storage conditions.
| Container issue | Example | Consequence |
|---|---|---|
| Sorption into plastic | Nitroglycerin, amiodarone and tacrolimus in PVC | Loss of potency; use polyolefin, glass or non-PVC sets |
| Leaching of plasticizer | DEHP pulled out of PVC by lipids and surfactants (paclitaxel) | Patient exposure; use non-PVC containers |
| Freezing | Brittle containers crack when frozen | USP requires containers used for frozen CSPs to withstand freezing |
| Light | Photolabile drugs (nitroprusside, dacarbazine) | Light-resistant packaging or overwraps |
| Elastomer interaction | Syringe plunger and stopper extractables | A stability study must use the same container materials |
| Headspace and oxygen | Oxidation-prone drugs | Fill volume, headspace and closure all matter |
For Category 3, the stability study must use a container of the same materials of composition as the one the CSP is actually stored in (see 5.3).
Multiple-dose CSPs
A compounded multiple-dose CSP must be prepared as Category 2 or 3. If it is aqueous, it must pass antimicrobial effectiveness testing (USP <51>). Bracketing is allowed across strengths when every other ingredient stays the same. The container must be evaluated for, and meet, container closure integrity (USP <1207>). Once first entered, it may be used until its BUD or for 28 days, whichever is shorter, provided those limits are supported by the testing. One exception: a nonpreserved aqueous topical or topical ophthalmic multiple-dose CSP needs no USP <51> test if it is Category 2 or 3, for one patient, and labeled to be discarded 24 hours after opening at room temperature or 72 hours refrigerated.
Filters
| Filter | Specification | Use |
|---|---|---|
| Sterilizing filter | Sterile, depyrogenated, nominal pore 0.22 µm or smaller, made for pharmaceutical use, certified to retain at least Brevundimonas diminuta per cm² | Sterilizing filtration; must pass an integrity test after use |
| "For laboratory use only" filter | Not validated for patient use | Must not be used to compound CSPs |
| Prefilter (e.g., 1.2 µm) | Larger pore | Upstream of the sterilizing filter when the solution carries heavy particulate |
| Filter needle or straw (commonly 5 µm) | Particulate removal | Drawing up from glass ampules, one direction only |
| In-line administration filters | 0.2 µm for non-lipid PN and many drugs; 1.2 µm for lipid-containing PN | Set by the drug labeling and ASPEN guidance |
The designated person must confirm that the chosen sterilizing filter is chemically and physically compatible with the CSP (water-miscible alcohols, for example, can damage some membranes), stable at the pressure and temperature used, and big enough for the volume being filtered.
Syringes, bags, vials and devices
- Syringes: Use Luer-lock syringes for transport and caps that keep the tip sterile. Stability data for syringes must match the syringe brand and material when the BUD depends on it.
- Bags: Choose PVC, polyolefin or EVA based on drug compatibility. Non-PVC containers are used for drugs that sorb into or leach from PVC.
- Glass vials and stoppers: Type I glass. Stopper elastomer (chlorobutyl or bromobutyl) and crimp integrity matter for storage and for coring.
- Elastomeric and ambulatory pump reservoirs: BUDs need compatibility and stability data specific to the device.
Connectors that prevent wrong-route errors
Small-bore connectors that are not Luer-compatible make it physically hard to connect a device to the wrong route:
- ENFit (ISO 80369-3) for enteral devices, so oral or enteral syringes cannot connect to IV lines.
- NRFit (ISO 80369-6) for neuraxial devices (intrathecal and epidural), so IV syringes and lines cannot connect to spinal needles.
For intrathecal and epidural CSPs, NRFit syringes and needles add a physical barrier on top of labeling and independent checks.
A compounder has two 0.22 µm filters in stock. One is sterile, depyrogenated and certified to retain 10^7 Brevundimonas diminuta per cm². The other is a lower-cost filter labeled 'for laboratory use only.' Which may be used to sterilize a CSP made from nonsterile components?
Either, because both are 0.22 µm
Only the sterile, depyrogenated, pharmaceutical-grade filter certified for bacterial retention
Only the laboratory filter, if a 1.2 µm prefilter is added
Neither; USP <797> allows only terminal sterilization
A facility wants to make a preserved, aqueous, multiple-dose injectable CSP in vials. Which set of USP <797> requirements applies?
It may be Category 1 if a preservative is present
It must be Category 2 or 3, pass antimicrobial effectiveness testing (USP <51>), and use a container evaluated for closure integrity (USP <1207>); after first entry it is used until its BUD or for 28 days, whichever is shorter
It needs no testing, because preservatives make testing unnecessary
It may be entered for up to 90 days after first puncture regardless of its BUD
Which connector standard is designed to keep IV syringes and lines from being connected to intrathecal or epidural devices?
Standard Luer lock (ISO 80369-7)
ENFit (ISO 80369-3)
NRFit (ISO 80369-6)
A red syringe cap
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