Sarah Riley is an associate with Life Sciences Technical Services, STERIS.

Sarah Riley

Intravenous therapy; drip chamber in focus against a colorful background | Image Credit: ©Anna Jurkovska -stock.adobe.com

Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use

, Annex 1 and Annex 15 provide guidance that must be followed in the design, qualification, and monitoring of cleaning processes to mitigate cross-contamination risks which includes cleaning direct, indirect, and non-direct product contact surfaces as detailed in the site’s contamination control strategy (CCS). Understanding the critical cleaning parameters (CCPs) for removal of silicone oil from direct and indirect product contact surfaces, qualifying an analytical test method, and setting practical, achievable, and justifiable limits are important to the CCS. This article explores the historical use of silicone oil in the performance of primary drug product packaging; design of experiment test results for selection of the cleaning agent and CCPs; assessment of visible residue limits and Fourier-transform infrared spectroscopy surface analysis; and setting health-based exposure limits for silicone oil using a non-uniform distribution model, and a previously published permitted daily exposure.

Siliconization of parenteral drug packaging has been in use as a lubricant for the past 50 years.

 The primary functions of the lubricant are to ensure machinability of the closure with metallic machinery, reduction of insertion force as the closure is fitted in the parenteral packaging, and integrity of the seal between the closure and primary packaging.

 Siliconization can refer to the use of silicone oil, silicone emulsion, and air-curable silicone. This article focuses on silicone oil that includes silicone fluid, siloxane, dimethicone, polydimethylsiloxane, and other terms which represent the base formula structure of the liquid silicone lubricant of (CH

There is a requirement to develop and maintain a contamination control strategy (CCS) to minimize risks of microbial, particulate, and endotoxin/pyrogen contamination of sterile drug product manufacturing.

 The CCS must include a rationale for the selection, application, and removal of any process aids, such as silicone oil, from direct, indirect, and non-direct product contact surfaces. Residual silicone oil on indirect product contact surfaces, such as the stopper bowl, transfer chutes, star wheels, and other equipment parts, can result in visual residue and sticky surfaces. This could reduce the efficacy of the cleaning and sterilizing process, which can impact the functionality of the siliconization process (machinability, insertion, and seal integrity) and increase particulate and microbial risk of the primary packaging system.

A validated sterilization process with steam or vaporized hydrogen peroxide (VHP) bio-decontamination process begins with a clean and dry surface. The use of laboratory testing and/or field trials are the preferred cleaning development tools. The effects of residual lubricant on the sterilization process have been investigated with healthcare no-rinse lubricants.

 The historical approach to cleaning silicone oil is to use a formulated alkaline detergent containing surfactants at elevated temperature in an automated parts washer or clean-in-place system; however, there are several manufactures utilizing a manual, water-only, sodium hydroxide (NaOH), or alcohol-only cleaning process at ambient to warm temperatures that can be a concern due to the low solubility of silicone oil.

This article explores the development of a cleaning process through laboratory testing, ease of surface detection of silicone oil and cleaning agent residue, and application of practical, achievable, and scientifically justified limits based on health-based exposure limits (HBEL).

Standard cleanability practices were used including a variety of cleaning methods such as agitated immersion (AI), spray wash (SW), cascading flow (CF), and manual cleaning (MC). In addition to this, visual residue limit (VRL) testing was used to determine an acceptable VRL for specified silicone oils. Lastly, bench top Fourier-transform infrared spectroscopy (FTIR) was used to determine the presence of silicone oil on stainless steel surfaces.

 Representative 304 stainless-steel coupons (3×6”) were used throughout the study.

The critical cleaning parameters have been well defined in literature; they include time, action, cleaning chemistry, concentration, temperature, water quality, surface, soil load and condition, and environmental factors.

 Laboratory testing was performed to investigate changes in the critical parameters listed in 

 using 3 different silicone oils widely used in the pharmaceutical industry. Environmental factors such as room temperature, humidity, and particulate levels, which primarily affect dirty and clean hold times, were not investigated in this study.

The following procedure was used throughout the study unless specifically noted:

Weighed dry, clean stainless-steel coupons on an analytical balance (±0.1 mg) to obtain the pre-coating weight.

Coated coupons with 1-3 ml of the sample.

Conditioned the sample on the coupon as indicated in each section.

Weighed the conditioned coupon on an analytical balance to obtain the pre-cleaning weight.

Cleaned each coupon by AI, SW, CF, or MC with a wipe as indicated in 

At specified time intervals, removed and visually observed each coupon for cleanliness.

Rinsed each side of coupon with tap water for 10 seconds at a flow rate of 0.5 gal/min.

Rinsed each side of coupon with deionized water and examined for a water break-free surface.

Dried, visually inspected, and then weighed coupons on an analytical balance to obtain the post-cleaning weight.

Table 2: Effect of Cleaning Agent, Dirty Hold Time (at ambient temperature), Concentration, and Temperature on Cleaning Time Required per Method

Table 3: Effect of Soil Load on Cleanability (Performed with AI at 80 °C)

Table 4: Effect of Cleaning Agent on Manual Cleaning Via Polyester Wipe

Table 5: Acceptance Criteria Used in Laboratory Testing

Two silicone oils (Ompi EZ Fill and 360 Dow Corning [DC] Medical Fluid) were evaluated in the laboratory tests. The following procedure was used throughout the study unless otherwise noted:

Diluted the silicone oils to 1, 2, 3, and 5 mg/mL using laboratory-grade, purified water ( Milli-Q, MilliporeSigma) water.

Applied 1 µL of the diluted detergent and 20 µl of purified water onto a stainless-steel coupon over a 1 cm

Air-dried the spiked coupons at ambient temperature for at least 16 hours; visually observed coupons as dry prior to testing.

Observed the coupons under a variety of conditions as described in 

Two analysts observed the visual residue on the coupons for each test.

The following measurement tools were used:

Lux meter (Cal-light 400, Cooke Corporation) to confirm light intensity.

Standard manual protractor to measure the viewing angle.

Recorded results as either visible (V) or not visible (NV) for each analyst.

Figure 1: Measured Angle of Coupon (Figure courtesy of the authors)

Table 6: VRL Testing Under Different Lighting, Angle, and Distance Conditions for Specified Silicone Oils on Stainless Steel

Test coupons were prepared and cleaned using a formulated alkaline detergent containing potassium hydroxide (KOH), NaOH, and deionized (DI) water. After cleaning, the coupon surfaces were dried and subsequently sampled by swabbing. The collected samples were analyzed by benchtop FTIR (Cary 660 FTIR spectrometer, Agilent) equipped with an attenuated total reflectance (ATR) crystal to evaluate the presence of silicone oil residues, allowing for direct analysis without additional sample preparation.

Effect of cleaning agent, concentration, time, and temperature in automated cleaning applications. 

To evaluate the effects on cleaning efficacy, the following cleaning agents were tested at different concentrations and temperatures:

1-5% v/v formulated alkaline detergent containing NaOH

1-5% v/v formulated alkaline detergent containing KOH

1-5% v/v formulated neutral detergent containing surfactants

Formulated 1:64 quaternary ammonium-based disinfectant

Formulated acidic detergents containing citric acid and oxalic acid were also tested but were not effective in initial cleanings and therefore not tested further. Lower temperatures, such as 25 ºC and 45 ºC, either did not clean the residue or did not clean in a sufficient time (less than 30 minutes).

When changing the critical parameters, the following general trends were seen to shorten cleaning time (see 

Increasing the cleaning solution concentration

Using SW rather than other methods due to impingement.

Increased dirty hold times did not affect the cleanability when using formulated alkaline detergents, while neutral detergents required increased concentration or temperature to achieve passing results.

Figure 2: Trace Residue on SW DI Water at 80°C. (Figure courtesy of the authors)

 Soil conditioning of the silicone oils onto the coupons was conducted in 2 different ways:

Air-drying at ambient temperature for a specified amount of time.

The baking at 121 °C significantly increased the conditions required to clean the surface.

Figure 3: Residue on AI 0.5M NaOH at 80°C. (Figure courtesy of the authors)

 The lab also investigated soil load, attempting to simulate campaigning in industry. Coupons were coated with either 1 or 10 layers of designated silicone oil and air dried for 120 hours. The 10-layers coupons required increased concentration, temperature, and cleaning time to achieve the same results as the 1-layer coupons (

Many applications in the industry include manual cleaning of silicone oil. A common example is the cleaning of silicone oil from stopper bowls.

A variety of cleaning agents were used for manual cleaning, with a focus on operator safety when using specified cleaning agents. Formulated alkaline detergents outperformed formulated neutral detergents, as well as formulated quaternary ammonium disinfectant, IPA, NaOH, and DI water. All tests were performed with a polyester wipe rather than a nylon brush as the brush would smear the residue. Prepared residue had a 24-hour dirty hold time with 1 layer application.

The VRL is determined by the point in which 2 analysts can no longer see the residue at any given condition with the unaided eye. Silicone oil was visible by 2 separate analysts under all conditions when applied at 1 µg/cm

). No further concentrations were tested as this was the lowest concentration.

Coated coupon: Absorbance bands characteristic of silicone oil residue, most notably in the ~1000–1100 cm⁻¹ region, which are absent in the control coupon.

Coupon cleaned with hot water (80 °C, SW): Though less intensity than the coated coupon, distinct silicone‑related peaks remained.

Coupon cleaned with 0.5 M NaOH (80 °C, AI): A pronounced absorbance band persisted in the ~1000–1100 cm⁻¹ region.

Coupon cleaned with 1% formulated alkaline detergent (80°C, AI): A profile comparable to that of the control coupon, with no distinct residual silicone oil signatures.

These results demonstrate that water alone and 0.5 M NaOH were insufficient to remove the coating residue, whereas the formulated alkaline detergent achieved effective cleaning under the conditions evaluated.

Figure 4: FTIR-ATR Spectra of a Non-Coated and Coated Sample Compared to Coupons Cleaned with NaOH or a Formulated Alkaline Detergent (Figure courtesy of the authors)

Figure 5: FTIR-ATR Spectra of a Non-Coated and Coated Sample Compared to Coupons Cleaned with 80°C Water or a Formulated Alkaline Detergent (Figure courtesy of the authors)

Case Study: Identifying Practical Cleaning Conditions for DC360 Residue

A pharmaceutical manufacturer was interested in determining the cleaning parameters needed to remove silicone/dimethicone (DC360) residue from stainless steel surfaces. Controlled coupon testing was used to identify these parameters using AI, SW, and CF. Representative stainless-steel coupons were soiled with 1–2 g of sample, air‑dried at ambient temperature for 120 hours (

), and then cleaned by AI, SW, or CF. Performance was judged using defined acceptance criteria as per 

Figure 6: Stainless-Steel Coupon Coated with Silicone Oil and Stoppers (Figure courtesy of the authors)

Across all 3 cleaning methods, a consistent set of conditions achieved removal on stainless steel:

Baseline condition: CIP 100 detergent at 4% v/v, 75 °C, for 15 minutes.

Addendum testing with high-pressure spray at 44 psi (3.0 bar), CIP 100 detergent at 3% v/v, 75 °C, for 5 minutes.

Addendum testing with hot water pre-rinse at 75 °C for 1 minute, followed by CIP 100 detergent at 3% v/v, 75 °C, for 3 minutes with SW and CF.

The pharmaceutical manufacturer successfully reproduced and validated the recommended cleaning approach as in the addendum testing with hot-water pre-rinse.

Establishing residue limits for silicone oil residues

In this example, a residue limit for silicone oil on stopper bowls was established using the VRL and permitted daily exposure (PDE) value, to determine the potential silicon remaining on stainless-steel surface after visual inspection. When establishing residue limits, the risk of leaving those residues on the surfaces should be assessed and understood. For direct product contact surfaces, the risk is associated with cross-contamination of product A to a subsequently produced product B. In the case of silicone oil on indirect surfaces within a filling line, those risks are mostly related to:

An increase in the risk of particle contamination due to sticky surfaces, which may increase the risk of microbial contamination.

For direct product contact surfaces, residue limit calculation includes a PDE value, which is an exposure or dose that is unlikely to cause an adverse health effect if an individual were to be exposed by any route at or below this amount daily for a lifetime.

 For indirect surfaces, the residue limits may include a calculation with a PDE value and confirmation via:

Articles

This article explores the historical use of silicone oil in the performance of primary drug product packaging; design of experiment test results for selection of the cleaning agent and CCPs; assessment of visible residue limits and Fourier-transform infrared spectroscopy surface analysis; and setting health-based exposure limits for silicone oil using a non-uniform distribution model, and a previously published permitted daily exposure.