FDA-regulated firms face an enormous challenge keeping up with agency priorities and expectations—especially companies that produce older products within an ever-changing regulatory landscape. While firms continue to manufacture these older products to serve their customers and protect their brand, there are many potential quality compliance issues that can arise.
The products in question are known as legacy products. Although the definition says, “typically developed 10 to 20 years ago,” there are legacy products that are much older than that.
A major change that took place in the early 2000s was the introduction of the pharmaceutical quality system (PQS).
ICH Q10 describes the model for an effective pharmaceutical quality system. It is based on the ISO quality concepts, references GMP, and complements ICH Q8 on Pharmaceutical Development and ICH Q9 on Quality Risk Management.
Within ICH Q10, the term continual improvement is used 25 times. This is important to note as continual improvement can be challenging in the context of legacy products.
The FDA, EMA and ICH have issued guidance stating that manufacturers are responsible for identifying sources of variation affecting process performance and product. Complying with this guidance from the FDA is commonly referred to as implementing Continued Process Verification (CPV). Europe’s Ongoing Process Verification is equivalent to the FDA’s CPV.
There are a number of reasons why implementing CPV for legacy programs may be complex:
- The process design for legacy products may be less rigorous than what would now be deemed acceptable for launching into a commercial phase.
- Older control strategies may be less rigorously developed and documented.
- Definitions of terms may not be aligned with the new.
- Process knowledge generated by the CPV program may be inconsistent with regulatory filings or commitments.
- Legacy data acquisition and IT infrastructure may not be capable of assembling the data required for a CPV program.
- Well-established legacy commercial products are likely to have multiple manufacturing sites, requiring multiple CPV implementation projects for one legacy product.
- A complex regulatory history for a legacy product licensed in multiple jurisdictions can make implementing CPV a challenge.
The potential benefits of implementing CPV for legacy products are numerous:
- Reduction of the number of unexpected process variations, emergency investigations, and product quality variability.
- More efficient identification, justification and implementation of process improvements.
- Ability to leverage data to potentially reduce regulatory approval requirements for process changes.
- More consistent methods for manufacturing monitoring and process control.
Risk management of legacy products may represent a challenge, since some documentation associated with development and technology transfer may not fully satisfy today’s expectations. For example, initial validation documents for legacy products may not provide details about criticality of process parameters, quality attributes or control strategy, or may not consider all potential risks that may affect product quality.
However, the experience developed during routine manufacturing throughout the years will provide the manufacturing facility with technical knowledge at full scale that is not feasible at laboratory- or pilot-scale levels. The CMO quality system and the sponsor granting the contract should be aligned on previously identified elements such as knowledge management, quality metrics, process performance, risk management and CPV.
Read also: The Challenge of Compliance for Lifesciences Companies
Resource Person: Barbara Pirola
