Validation of an Automated Glassware Washer

• Validation of an Automated Parts Washer: In the first blog post of this series, featured below, learn about the critical role parts washers play in maintaining the purity and performance of pharmaceutical processing equipment.
• Validation of an Automated Glassware Washer: Discover the procedures and technologies that ensure that the continuous washing process results in containers that are impeccably clean and ready for use.
• Validation of a Depyrogenation Tunnel: Explore how heat treatment is used to eliminate bacterial pyrogens, guaranteeing the quality and sterility of our products.
• Validation of an Autoclave Cycle: Uncover the science and precision behind autoclaving, a cornerstone process in achieving absolute sterilization.

The aim is to provide practical insights that will enhance your understanding of the topics covered.

The Sterile Products Processing CoP Steering Committee is a group of industry experts that are passionate about the field of sterile manufacturing of pharmaceuticals. We help the community reach better results and improved quality by sharing knowledge and encouraging others to do so as well.

Introduction

Due to their chemical resistance, cleanability, sterilizability, and ability to protect its contents, glass containers (vials, bottles, etc.) are often used as the primary packaging container for various pharmaceutical dosage forms. Although glass vials used for pharmaceutical purposes should be purchased from a reputable supplier meeting predetermined specifications for quality (USP <660> / EP 3.2.1)1^,2 and cleanliness, a typical first step during aseptic filling is washing of the internal and external surfaces of glass vials. The washing process is typically performed inline using an automated glassware washer that feeds cleaned containers to subsequent processing steps— depyrogenation followed by aseptic filling. Per Annex 1, Section 8.2, primary packaging containers and components should be cleaned using validated processes to ensure that particulate, pyrogen, and bioburden contamination is appropriately controlled.

The goal of this concept paper is to provide recommendations for a standardized and science-based approach for equipment qualification (IQ/OQ) of the automated glassware washer and process qualification (PQ) for the automatic cleaning process performed by the washer. For a successful and systematic qualification, a lifecycle approach to validation is recommended. The lifecycle approach reinforces a thorough understanding of the process through the design and qualification phases and encourages continued monitoring of the process to ensure it remains effective and consisten.t3^, 4^, 5

Lifecycle Approach to Validation for Automated Washers

For the qualification of equipment and processes, the lifecycle approach to validation is recommended as mentioned in the 2011 US Food and Drug Administration (US FDA) guidance document, “Process Validation: General Principles and Practices”, where it states that “the lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production.”4 Using the lifecycle approach, a typical validation for an automated washer follows the following three stages, as outlined in Table 1.

The lifecycle approach to validation promotes more focus on the process design stage (Stage 1) and ensures quality is built into the process – in contrast with traditional approaches that rely on testing to ensure the process is effective. Decisions for equipment selection and process design should be based on the principles of Quality by Design that require all decisions be made utilizing a risk-based approach.6 Risk analysis tools are deployed to understand how critical process parameters (CPP) affect the critical quality attributes (CQA) of the cleaning process. The goal of the lifecycle approach is to invest sufficient time in Stage 1 to develop a thorough understanding of the equipment design and the cleaning process. The time invested during Stage 1 provides confidence when going into the process qualification stage (Stage 2 of the lifecycle), ensuring a successful validation.

Stage 1 – Design

During Stage 1, the glassware washer equipment is specified (URS/FS/DS) and the cleaning cycle is developed in preparation for equipment qualification (IQ/OQ) and process qualification (PQ) phase (Stage 2). Typically, washer manufacturers offer pre-designed models that may or may not need to be modified to fit into an existing manufacturing facility. However, the responsibility relies on the end user to ensure that the washer is designed and constructed to meet the pre-determined critical quality attributes for their process.

The following are equipment attributes that should be evaluated when selecting a glassware washer. At minimum, the washer should be designed to comprise the following features:

• Clean glass containers to meet pre-determined specifications (visual, particulate, bioburden, etc.)
• Automatically clean and transfer glass containers without breaking them
• Depending on operation, be capable of handling and washing a range of vial/bottle/ampoule sizes
• Monitor critical process parameters: temperature, machine speed, pressure, time
• Automatically perform the washing cycle, in sequence, as designed
• Be constructed of compatible materials
  • Surfaces exposed to WFI are typically 316 stainless steel
  • Seal and gasket materials resistant to hot temperatures
• Connect directly to critical utilities (i.e., WFI, filtered compressed air)
• Self-cleaning or be designed to be easily cleaned and sanitized
• Fully drainable once operation and cleaning are complete

Although each user may have additional requirements, the above are some of the critical items that should be specified by the end user (URS) and agreed upon by the equipment manufacturer for designing the washer. The equipment manufacturer shall provide a specification (FS/DS) detailing how the washer being designed meets the user requirements. There are various designs for glassware washing machines, including in-line or rotary types; however, the concept remains the same—remove contaminants, such as particles and bioburden, from vial internal and external surfaces through spray wash (washing needles or nozzles) with pure water (typically WFI) prior to the next processing step (depyrogenation).

Endotoxins (pyrogens) are a significant concern for primary containers used for parenteral drug dosages. Per USP <1228>, bacterial endotoxins are components of the outer cell membrane of gram-negative bacteria and due to their structure, they tend to form bilayers, micelles, ribbons, and other conformations when in solution that may adsorb to surfaces making them difficult to extract and detect.7 Per the US FDA’s Inspection Technical Guide on “Bacterial Endotoxins/Pyrogens,” “it is difficult to remove endotoxins from products once present. It is far better to keep finished products and components relatively endotoxin-free rather than have to remove it once present.”8 Therefore, it is critical to develop controls in manufacturing to prevent and remove endotoxins/pyrogens from equipment and components that will contact drug product. The US FDA guide also states that “the most common depyrogenation procedures for physical components include incineration and removal by washing, also termed dilution.8 USP <1228.4> indicates that although depyrogenation may be best accomplished by dry heat, heat-labile components such as drug product containers can be depyrogenated through physical means, such as rinsing (also termed dilution) using high purity water (WFI), preferably above 60oC.9 Like sterilization process development, it is important to assess the endotoxin burden on glass containers prior to being subjected to the washing and depyrogenation process to demonstrate the removal or inactivation effectiveness of those processes. As part of the qualification, an endotoxin removal challenge should be incorporated utilizing inoculated glass containers that are subjected to the wash/depyrogenation process and analyzed for the recoverable level of limulus amebocyte lysate (LAL) activity (USP <161>10). The US FDA inspection guide explains that although there is no existing guideline for the endotoxin challenge, it is generally expected that there be a 3-log reduction when the dilution process is employed.8 Although it can be demonstrated that a glass washing process can remove endotoxins from surfaces, the main depyrogenation process is through a validated dry heat cycle demonstrating a 3-log reduction.

Once the washer has been constructed, under the guidance of the washer manufacturer and prior to delivery, the Factory Acceptance Test (FAT) allows end users to verify that the equipment was constructed as specified. The FAT provides an opportunity for any malfunctions or out-of-specifications (OOS) in equipment design to be detected at the manufacturer’s site, where quicker repairs or modifications can be performed. The FAT protocol should include a system check (physical, mechanical, electrical), verification of certificates of materials of construction, a functional verification, and safety and alarm checks. If agreed upon with the fabricator, the FAT can also include a test run that includes verification that all operation steps are performed sequentially, as per the user requirements, and glass containers are cleaned to pre-determined specifications (i.e., visual, particulate). An optimized FAT can reduce the amount of work required for equipment qualification once the washer is installed at the user’s site.

When developing the cleaning cycle, it is recommended to conduct multiple trials, varying process parameters (i.e., machine speed, pressure, temperature, vial sizes), to understand and optimize the process. If equipped, trials should be conducted for all sizes and configurations of glassware that are intended to be washed. These trials not only provide justification for the established process parameters for each vial configuration, but also justification for determining worst-case loading conditions to be employed when executing the PQ. During PQ, a bracketing approach can be employed, where a representative (worst-case) glassware loading configuration is selected for process performance runs.

Additionally, during process development, there are various tests that can be executed to test equipment functionality and make necessary adjustments, if needed. These tests may also be executed during the qualification phase to verify the designed equipment and process are functioning as intended. The purpose of these types of tests is to evaluate whether the washer design provides complete coverage of glass container surfaces, challenging the process by confirming effective removal of contaminants. The following are some industry-accepted tests that can be executed to confirm glassware washer functionality.

• Riboflavin coverage testing: prepare riboflavin solution and wet vials with solution, subject vials through water rinse cycle, and perform visual inspection using UV light to detect fluorescent riboflavin residuals
• Sodium chloride testing: spike vials with sodium chloride solution and allow to dry, subject soiled vials to washing cycle, and test for residual NaCl (per USP monograph)
• Charcoal slurry: prepare charcoal slurry and spike vials, subject to cleaning cycle and test per USP <788>11 for particulate matter

There may be other challenge tests that can be performed to verify process performance depending on the equipment selected and glassware characteristics. Nevertheless, the purpose of these equipment functionality tests and process trials is to increase process knowledge, reducing the risk of failure when transitioning to the qualification phase (Stage 2).

The main deliverable for Stage 1 is the development of the glassware washer cleaning SOP, which is the formal document listing all critical process parameters and procedures for the cleaning process. The SOP should include details for washer operation instructions, glassware loading instructions, washing cycle steps, critical process parameters to be monitored, troubleshooting procedures, and clean glassware inspection procedures. The SOP is the basis for the PQ study to be executed in Stage 2 of the validation lifecycle.

The following is a typical wash cycle for glass containers in a rotary washing machine:

1. Glass containers are loaded onto infeed rotating table.
2. Grippers pick up glass containers and rotate containers upside down.
3. Upside-down containers are rotated through the different washing stations following a specific sequence for washing and drying internal and external surfaces. 
   Note: For the initial washing steps, recycled water may be used; however, fresh water is used in the last washing station.
   1. Rinse with recycled WFI (internal and external surfaces)
   2. Transport containers to next station
   3. Blow dry internal surfaces using filtered air 
      * a repeat recycle WFI wash may be performed depending on the washer
   4. Transport containers to next station
   5. Rinse with fresh WFI (internal and external surfaces)
   6. Transport containers to next station
   7. Blow dry internal surfaces using filtered air
   8. Rotate containers back up and feed into discharge station

Stage 2 - Qualification

Stage 2, or the qualification stage, principally confirms that the equipment and cleaning SOP developed is effective, robust, and reproducible for cleaning glassware using the automated washer. Table 2 lists some of the critical aspects for equipment and performance qualification (IQ/OQ/PQ) that need to be evaluated during Stage 2.

* As mentioned above, typically, the glass vial washing process is followed by a validated depyrogenation process using dry heat; however, it is advisable that the bioburden and/or endotoxin removal capacity of the washer equipment be challenged during qualification.

Providing additional background on the qualification approach, the International Society for Pharmaceutical Engineering (ISPE) Baseline Guide for Sterile Product Manufacturing Facilities (Third Edition) “Chapter 3.3 Equipment Integration,”12 lists the following factors to be considered for the design and qualification of an automated glassware washer:

• Capacity:
  • Containers/hour
• Utilities:
  • Air and water pressure and flow
• Cleaning performance:
  • Efficiency of removal of particulates
  • Efficiency of bioburden control achieved
• Functionality:
  • WFI quality water for final rinse
  • Particle-filtered, oil-free air for drying
  • Protect washed and dried vial to minimize endotoxin and particle (re-)contamination
  • Utility lines drained when not in use
• Instrumentation:
  • WFI temperature and pressure
  • Clean air pressure

Once the PQ has been executed, a final report is written, which summarizes the results of all testing performed and clearly indicates that the equipment and cleaning process are qualified. The protocol may also include critical attributes of the process that may require continued monitoring during routine operation that would give assurance of the validated state of the process.

Table 3 lists topics to consider for qualification of an automated parts washer and provides troubleshooting considerations for some common failures that may occur during qualification.

Stage 3 – Continued Process Verification

Stage 3, or the continued process verification stage, consists of preventive maintenance activities, periodic reviews of generated data, and continued monitoring of the process that helps maintain a state of control when running washing cycles at the commercial scale. Proper maintenance of the equipment is fundamental to the consistent performance of the system. Preventative maintenance procedures, based on the washer manufacturer’s recommendation and the user’s experience with the equipment, should include periodic inspections of critical equipment components to facilitate immediate repairs or replacement. A periodic review of cleaning process-related documentation should be included in Stage 3 activities. The review should include analysis of process parameter data as well as analysis of any quality test results (i.e., bioburden) produced throughout the review period. Additionally, a review of any change controls, investigations, corrective and preventive actions (CAPAs), or other quality system activities13 should be performed to confirm whether any changes to the system have been made to the process that warrant revalidation. Using risk analysis tools, the continued process verification stage should indicate opportunities for cleaning cycle optimization, process improvement, and/or revalidation requirements.

Conclusion

As stated above, it is recommended to invest time during the equipment and process design phase (Stage 1) to really understand how the equipment functions as well as the limits of the developed wash cycle. In addition to ensuring success during equipment and process qualification, the obtained knowledge is particularly valuable when conducting root cause analysis in cases when either the equipment or the cleaning process fails. A well-executed and documented development phase will provide the information necessary to deal with unanticipated failure modes. Root cause analysis should prompt a review of prior risk assessments performed to indicate whether new process controls are needed and to identify opportunities for process optimization and improvement. The lifecycle approach promotes continuous data collection and analysis, which prompts continuous process improvement. This methodical approach to cleaning process development and qualification harmonizes well with manufacturing, quality control, and operational excellence initiatives in a manufacturing facility.

Acronyms

• CPP – Critical Process Parameter
• CQA – Critical Quality Attribute
• DS – Design Specification
• EP – European Pharmacopoeia
• FAT – Factory Acceptance Test
• FS – Functional Specification
• IQ – Installation Qualification
• OQ – Operational Qualification
• PQ – Performance Qualification
• SOP – Standard Operating Procedure
• URS – User Requirement Specification
• USP – United States Pharmacopoeia
• WFI – Water for Injection

Acknowledgements

The author(s) would like to thank members of the ISPE Sterile Product Processing Committee for the opportunity to post this blog and Christian Mrotzek, Klaus Ullherr, and Michael Meyer for the original concept of the blog series covering Critical Quality Attributes essential in aseptic manufacturing of parenteral drug products. Additional thanks to Klaus Ullherr, Michael Meyer, Jeff Pettet, and Ryan Waldhart for technical review, comments, and input on the blog.