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There are health and safety implications involved with reusing manufacturing lines for biopharmaceutical products. Meet regulatory requirements while simultaneously refining manufacturing processes to keep costs low with Element’s comprehensive cleaning validation and verification service offerings.

Satisfactory cleaning procedures are an important component in the prevention of contamination and cross-contamination in drug products. Regulations, including the US Food and Drug Administration’s (FDA’s) Guide to Inspection of Bulk Pharmaceutical Chemicals and , as well as the , require the cleaning of product lines to strict standards prior to manufacturing drugs from different pharmaceutical formulations. Furthermore, the processes used to clean the lines must be validated in advance of releasing pharmaceuticals to the market.

Cleaning validation studies are conducted in order to demonstrate cleaning processes, as well as the frequency of cleaning, sufficiently remove harmful residues to predetermined safety levels. Element’s teams of consultative scientists work with large and small molecule drug manufacturers to develop cleaning validation test methods, as well as carry out cleaning method validation, to verify cleaning processes.

Cleaning validation and verification process

In order validate cleaning methods and processes used to clean manufacturing lines, our teams of expert scientists and chemists must first understand the pharmaceutical manufacturing environment and cleaning procedure by identifying chemical components of cleaning agents used, as well as the excipients, active pharmaceutical ingredients (APIs), decomposition products, and preservatives present in drug product formulations. Cleaning verification, which typically includes measures of total organic carbon (TOC) and pH conductivity, ensures the validated cleaning process has been executed effectively. Samples can be procured using three distinct methods:

Rinse method: The rinse water sampling method allows analysts to characterize all the chemical substances present in a water sample of an equilibrated post-final rinse recirculated over all surfaces in the environment.

Swab method: The swab method uses a wipe or swab moistened with highly purified water to pick up chemical substances from a defined area systematically.

Coupon method: The coupon method dips sample coupons into high purity water that extracts residues.

Biopharmaceutical manufacturers and compounding pharmacies can create medicines that consistently avoid contamination by providing documented evidence that the cleaning methods at their manufacturing facilities can reliably control the carryover of APIs, extraneous materials, and cleaning agents into subsequent product.

Comprehensive cleaning validation services

• Sampling plan development (technique, determination of acceptable residue limit (ARL), method of detection, analytes of interest)
• Cleaning detection method development
• Cleaner residue detection method development
• Cleaning validation protocol writing
• Method validation and recovery studies
• Cleaning process verification
• Routine cleaning monitoring sample analysis

Determining acceptable residue limits (ARLs) in cleaning validation

As part of the standards of cleaning validation undertaken in the pharmaceutical and biopharmaceutical industries, an acceptable residue limit (ARL) is the upper level of residues allowed to remain on a product while controlling subsequent product contamination. Acceptable residue limits must be set to ensure consumers remain unaffected by residues and the efficacy and accuracy of all products manufactured on a single manufacturing line are unaffected by residual materials and chemicals. To construct a complete ARL for a pharmaceutical or biopharmaceutical product, it is necessary that a measurement of each product contact surface on manufacturing equipment is obtained. Once measurements are completed, they need only be measured again in the event of a fully documented change to manufacturing equipment or practices. To define the level at which residues will not affect a product and subsequent products, Element’s experienced scientists consider several factors, including:

Dosage levels: Dosage levels are typically pre-determined during the research and development phase. Knowing the standard dosage helps develop a safe and accurate ratio of active pharmaceutical ingredients (APIs), excipients, and residues.

Batch sizes: Batch sizes are also usually pre-determined during the research and development phase. An understanding of the batch size helps fine-tune the ratio of ingredients to residues to scale.

Equipment product contact surface areas: Vendors typically do not offer information on product contact surface areas or dimensions of surface areas. Knowledge of these surface areas helps make clear what exposure products will have to surfaces during the manufacturing process.

The importance of ARLs in biopharmaceutical cleaning validation

Cleaning validation studies that incorporate each level of cleaning validation help to build a more complete picture of the cleaning process and eliminate the need to reconcile separate points of data. An established acceptable residue limit forms the foundation of a complete and uncompromising cleaning validation that meets the regulations set forth in FDA and ICH guidelines. This helps establish baselines for cleanliness and works in tandem with:

Visible residue limits (VRLs): VRLs determine at what level a residue is no longer visible after cleaning. Viewing conditions are defined as well, which allow VRLs to be used to perform routine checks on cleaning validation procedures.

Worst-case residues: Through the creation of a worst-case matrix, it is possible to determine which residues will be the most difficult to clean and cause the greatest problems if not properly cleaned.

Recovery factors: It is still imperative that manufacturers can prove that the equipment that has been cleaned underwent tests with swabs and rinses that accurately represent the cleanliness of equipment.

The Element advantage

Accuracy is largely determined by the combination of data and careful analysis. By prioritizing the determination of acceptable residue limits within cleaning validation programs, Element helps increase the efficacy and longevity of cleaning validation for leading biopharmaceutical manufacturing facilities, compounding pharmacies, and more.

To learn about our customized approach to controlling contaminants and monitoring cleanliness in your facility, or to speak with one of our experts, contact us today.