Quality Controls & Calibrators: Achieving Lot-to-Lot Consistency in IVD Manufacturing

Understanding the Challenges of Quality Control Manufacturers

IVD manufacturers face a range of challenges when sourcing biological raw materials. Each manufacturer has unique requirements based on the specific assays and controls they produce, making the selection process highly nuanced. The need for consistent, scalable, and high-quality raw materials is critical, yet these attributes can be difficult to guarantee due to the inherent variability of biological sources.

Lot-to-lot consistency ensures that Quality Control (QC) manufacturers can maintain consistent analyte target concentrations in their products, facilitating smooth validation processes and ensuring regulatory compliance. This article explores the key considerations for QC manufacturers in achieving lot-to-lot consistency when utilising bulk biological raw materials.

The Importance of Lot-to-Lot Consistency

For a QC manufacturer, obtaining multiple samples across multiple lots of raw material is critical for qualification and validation purposes. The primary concerns include:

• Consistent Analyte Values: QC manufacturers must ensure that each lot of material maintains expected analyte concentrations, enabling laboratory personnel to perform accurate patient testing. Variability in analyte values can result in regulatory challenges and usability issues.
• Reliable Availability: Uninterrupted supply of biological raw materials ensures that QC manufacturers can meet demand and avoid backorders due to material rejection.
• Scalability: As QC manufacturers expand their market share, the ability to scale raw material supply without compromising quality is crucial.

Requirements for Raw Materials

Lot-to-Lot Consistency

Ensuring lot-to-lot consistency is essential to maintaining QC product performance. Variability in raw material specifications such as titre, analyte concentration, and pH can lead to significant manufacturing disruptions. If a batch of raw material falls outside of predefined specifications, it can result in product rejection, requiring costly deviations and re-validations.

Raw material suppliers must implement validated manufacturing processes to guarantee uniformity. By maintaining strict quality controls, suppliers help QC manufacturers achieve seamless transitions when onboarding new lots of control materials.

Reliable Supply Chain

A dependable supply chain is vital for ensuring that QC manufacturers receive raw materials in a timely and stable manner. Delays in raw material shipments can cause backorders, disrupting production and impacting end users. Global shortages of certain biological materials have, in the past, forced manufacturers to implement deviations or retrospective validations—costly challenges that highlight the importance of a supplier with robust inventory management and production planning.

Scalability and Growth

As QC manufacturers expand their market share, their need for increased raw material volumes grows. A supplier’s ability to scale production in tandem with demand is an important factor. Without the capacity to meet growing requirements, manufacturers may face interruptions or be forced to qualify alternative materials mid-production—an expensive and time-consuming process. Scalability ensures manufacturers can confidently plan for future needs without compromising product integrity.

Certificate of Analysis and Stability Testing

A comprehensive Certificate of Analysis (CoA) that includes testing of critical parameters is an essential requirement for QC manufacturers. This ensures that each lot meets established specifications and reduces the risk of unexpected performance issues.

Biological raw materials must maintain stability over time to ensure consistent performance. Real-time stability testing assesses parameters such as titre, activity, concentration, and microbial contamination over a defined shelf-life. If materials degrade over time or accumulate contaminants, they may no longer be suitable for QC applications, leading to batch rejections, customer complaints, backorders, patient safety issues, and increased costs.

Sampling and Retain Program

QC manufacturers benefit from suppliers who implement robust sampling and retain programs. These programs serve multiple purposes:

• Design and development validation: While raw materials are not typically subject to the same stringent design controls as medical devices, they must undergo validation to support product claims.

• Validation Processes: At least three lots of raw materials are typically required for design and process validation, making access to multiple retained lots a significant advantage.

• Troubleshooting: Retained samples enable QC manufacturers to investigate and resolve potential issues efficiently.

Technical Considerations for Quality Control Manufacturers

Certain technical challenges can complicate the use of biological raw materials in QC applications. Understanding these issues helps manufacturers make informed decisions.

Protease Activity and Analyte Stability

Protease activity can degrade sensitive analytes in many QC materials. It may originate from microbial contamination and may persist despite efforts to eradicate, neutralize or filter out the microbes. Proteases may also arise from endogenous sources from delayed or improper processing leading to lysis of cells prior to the separation of the plasma/serum component.  Once active, these enzymes can reduce analyte stability and compromise test accuracy.

Albumin Conformation and Stability

Denatured or partially denatured albumin is a lesser-known but significant problem in serum-based products. The three-dimensional structure of albumin plays a crucial role in maintaining analyte stability. Exposure to heat, pH shifts, or denaturing compounds like urea, guanidine or organic solvents, can alter this structure, causing analytes to bind unpredictably. Partially denatured albumin may bind analytes such as hormones, peptides, and enzymes, causing analyte loss and inconsistencies in QC products. Even slight misfolding can lead to assay discrepancies across different instrument platforms, making consistent albumin conformation a critical consideration.

Co-Morbidities in Disease State Materials

Disease state materials often contain a complex mix of cross-reactive antibodies, which can lead to unexpected interferences in QC manufacturing. Ensuring that disease state specimens meet specific inclusion criteria is essential to maintaining product reliability.

Inactivation Processes and Their Trade-Offs

Some inactivation processes, such as heat treatments used to eliminate proteases, can have unintended consequences. While effective at reducing protease activity, these treatments may also denature critical proteins, reducing marker titres and affecting overall performance. Understanding the impact of inactivation techniques on raw material integrity is key to selecting suitable specimens.

The Value of Validated Processes

Robust processes that preserve biological raw material integrity are essential for ensuring consistent, reliable performance of QC manufacturers controls and ensuring commutability across different instrument platforms. Selecting the right raw material from the outset minimises the need for costly reformulations and process deviations.

At Logical Biological, we are committed to working closely with our customers to define customised specifications that deliver the performance and consistency their applications demand. Our vision is to provide Insightful Solutions that Make a Difference—ultimately contributing to Improved Health Outcomes.

To turn this vision into reality, we have made significant investments over the past year, in new, expanded state-of-the-art laboratory space, broadening our R&D capabilities, and scaling up our processes and operations. These advancements strengthen our ability to support Quality Control and IVD Assay manufacturers with a sustainable, high-quality supply of critical biological raw materials—ensuring they can meet both operational and regulatory requirements with confidence.