The rigorous cleaning of manufacturing equipment via well-defined standard operating procedures (SOPs) is one of the pharmaceutical industry’s primary defenses against contamination and adulteration. Cleaning validation confirms the efficacy of such procedures but can present challenges, generating large numbers of samples for analysis and potentially keeping equipment offline for too long, compromising productivity.
This article examines high-performance ion mobility spectrometry (HPIMS) as a technique for cleaning validation, comparing it with conventional alternatives. Experimental data illustrate the linearity, reproducibility, and detection limits of HPIMS for relevant compounds, which offers rapid, inexpensive, high sensitivity, at-line measurement for cleaning validation.
Meeting regulatory requirements for cleaning validation
FDA regulations provide a clear and concise explanation of cleaning requirements for pharmaceutical manufacturing, stating that:
“Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements”1
EMA guidance similarly emphasizes the need to maintain product safety by ensuring that exposure to contaminants and medicinal products lies within health-based limits2. Meeting such requirements relies on the regular validation of cleaning procedures to confirm that contaminant levels are reliably reduced to an acceptable level. Cleaning validation calls for written protocols, clearly justified acceptance criteria, robust documentation and critically, appropriate analytical technology.
The limitations of conventional analyses
A closer examination of the practicalities of cleaning validation helps differentiate analytical techniques regarding their utility.
Contaminant levels are checked post-cleaning by analyzing either swab or rinse solution samples with swabbing, offering the advantage of direct sampling for hard-to-clean areas3. The dissolution of captured contaminants from the used swab using a suitable solvent produces a sample for analysis. With either strategy, the sensitivity and specificity of the analytical technique determines its value. A primary requirement for a suitable technique is that it must unambiguously detect the analyte of interest at a sufficiently low concentration, the acceptance limit associated with the test.
Beyond this core requirement lie a range of practical considerations that impact day-to-day operation. These range from the speed of measurement to cost, solvent consumption (and disposal) and ease-of-use factors such as the extent of automation. Table 1 summarizes the strengths and limitations of some of the techniques most commonly used for cleaning validation, including high-performance liquid chromatography (HPLC), ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) and total organic carbon (TOC) analysis.
This table highlights certain limitations associated with established techniques, which include:
- Lengthy analysis times: keeping equipment offline for longer than necessary
- Lab-based measurement: an additional source of delay which can also result in excessive pressure on QC labs.
- Complexity: detrimentally affects ease-of-use, increases the risk of error and is often associated with more demanding method development.
The characteristics of HPIMS are also included for comparative purposes. Though IMS is a well-established technique, its refinement to HPIMS over recent years has created a technique particularly well-suited to cleaning validation.
In HPIMS, solvent-free ions are pulsed into a drift tube and then separated under the guidance of a constant electric field in a drift gas (air) flowing in the opposite direction (see Figure 1). Ions with a compact cross-section encounter less resistance than those that are bulkier, making drift time a function of molecular size and shape. Detection with a Faraday plate detector or mass spectrometer generates an ion mobility spectrum that, notably, can differentiate isomers or detect conformational change.
Conventional IMS is a well-established technique used routinely in the security industry and in combination with MS. HPIMS builds on its inherent attractions, which include simplicity and speed of measurement, but offers breakthrough performance for independent application including substantially higher (between 2 and 10 times) resolution and compact technology for at-line implementation, in the field. Crucially the costs associated with standalone HPIMS are relatively modest, particularly compared to access via an add-on to an MS.
Furthermore, commercial systems pair HPIMS with electrospray ionization (ESI), a ‘soft ionization technique that aerosolizes the sample while avoiding molecular fragmentation, thereby extending the range of molecules that can be successfully analyzed with simple spectra. Using HPIMS paired with ESI, it is possible to analyze an almost limitless range of chemicals and biologics with high specificity and resolution.
Applying HPIMS in cleaning validation
Figure 2 shows HPIMS data relevant to cleaning validation applications; Dasatinib is a cancer drug. The results show the sensitivity of the technique, which securely detects a drug at a concentration of 1 ppm, and its ability to identically detect the active, a potential contaminant, in the presence of detergent.
Figure 3 and Table 2 demonstrate the application of HPIMS to detect Acetaminophen during swab cleaning. The calibration curve was generated by measuring a dilution series of samples created from a spiked swab, with each sample measured five times. These results demonstrate good reproducibility – <5% for all calibration points – and excellent linearity over the range of 1–100 ppm. With the calibration curve in place, measurements were made of different swabs to assess method performance (see table). These results show that at both 5 ppm and 50 ppm, the level of Acetaminophen on the swab is reliably determined, with good recovery observed for all samples.
Figure 3 and Table 2: HPIMS exhibits good reproducibility and linearity for Acetaminophen and can be reliably used to determine the level of drug on spiked swabs.
The characteristics of HPIMS make it a valuable technique for cleaning validation. Offering specificity and sensitivity for a wide range of relevant components, HPIMS allows rapid analysis at-line using small-footprint technology designed for the industrial environment. While instrument costs are comparable to those associated with other techniques, operating costs are lower and return on investment can be extremely attractive, less than three months. With high-performance, regulatory compliant HPIMS systems commercially available, this technology is recommended for cleaning validation applications.
- Code of Federal Regulations Title 21, Part 211 Good Manufacturing Practice for Finished Pharmaceuticals. Subpart D – Equipment. Sec 211.67
- EMA ‘Guideline for setting health-based exposure limits for use in risk-identification in the manufacture of different medicinal products in shared facilities’ 20th November 2014
- FDA ‘Validation of Cleaning Processes (7/93)’ Content current as of 08/26/2014
Ching Wu, Ph.D., is the founder and chief executive officer at Excellims. Ching has more than 25 years of experience been working on ion mobility spectrometry and mass spectrometry technology. Before founding Excellims, he worked as the research leader for GE Security’s chem/bio and explosives detection business and as the mass spectrometry software manager at Bruker Daltonics.
He holds multiple advanced degrees, including Ph.D. and MS degrees in chemistry and computer science from Washington State University. In addition, Ching has an MS in chemical engineering from Yokohama National University.
Ching has authored more than 90 peer reviewed papers and patents/patent applications in ion mobility spectrometry and mass spectrometry field.