ISPE Talks Process Validation: Managing CMOs, Figuring PPQ Batches
This article was originally published in The Gold Sheet
Executive Summary
The pharmaceutical industry is proposing new approaches for managing validation activities of contract manufacturing organizations and for estimating the number of batches to run during process validation.
A pharmaceutical industry group is recommending some new ideas for overseeing the process validation activities of contract manufacturers and for calculating the number of batches to run to ensure that a process is in a state of control.
These were the topics of two recent discussion papers issued by the International Society for Pharmaceutical Engineering.
ISPE has issued a multitude of discussion papers is recent years to help manufacturers comply with FDA’s regulatory guidance on process validation. Many areas have been left up to industry to figure out as FDA’s 2011 process validation guidance did not get into many specifics.
Delicate Balancing Act
The complexities of managing the validation activities of CMOs were addressed in the first discussion paper. The paper is called “Implementing Lifecycle Validation Practices at Contract Manufacturing Organization” and was released in November 2015.
The paper spells out who is responsible for what during each stage of the validation lifecycle.
“Typically, the MAH [marketing authorization holder] is responsible for the quality target product profile (QTPP) and CQA [Critical Quality Attribute] identification; these should be identified before the technology transfer to the CMO.”
The paper notes that while scientific knowledge about the product and the process is “owned” by the MAH, such areas as equipment capability, level of automation, alarming and batch record writing are primarily “owned” by the CMO.
The paper also specifies that a key part in managing these relationships is having confidentiality agreements in place at the start of the outsourcing arrangement. This agreement should be in place prior to starting any project.
If manufacturers want to have an onsite presence at the plant at all times, known as having a “man in the plant”, this should also be spelled out in the commercial contract.
Members of ISPE announced at a recent process validation conference in Silver Spring, Md., that a paper would soon be forthcoming on this topic (Also see "Discussion Paper to Explore Managing Validation Activities of CMOs" - Pink Sheet, 20 Nov, 2015.).
Determining Statistical Methods
The second paper, “Determining the Number of Process Performance Qualification Batches Using Statistical Tools”, presents four statistical methods that can be applied to determine the number of batches to run to ensure that a process is in a state of control.
The paper, which was released in January 2016, is a supplement to a previous version issued in August 2012. The 2012 paper proposed a three-step approach in determining the number of PPQ batches to run. Two of these approaches are statistically based and one is experience based (Also see "Pharmaceutical lndustry Proposes Ideas for Number of Batches, Monitoring Production" - Pink Sheet, 28 Feb, 2013.).
The discussion paper proposes ideas for answering the question “how many process performance qualification batches are needed to demonstrate a high degree of assurance in the manufacturing process and that the control strategy is sufficiently robust to support commercial release of the product?”
The paper proposes four additional approaches in determining the number of PPQ batches to run:
- The “Tolerance Interval” approach uses intervals that cover a fixed proportion of the population with a stated confidence. “For example a 95%/99% Tolerance Interval of 98.5 to 101.7 means that there is at least 95% confidence that at least 99% of future results will be between 98.5 and 101.7.
- The second statistical approach is the “Probability of Batch Success Approach.” This method is “particularly useful for a high-volume process with a large number of critical quality attributes.”
- The third approach is the “Combinational Approach of Analysis of Variance with Risk Assessments.” Under this approach the number of batches required is estimated by determining the between-batch variation using an Analysis of Variance (ANOVA) technique.
- The fourth approach, the “Variability Approach,” works best for processes that undergo a significant change or for processes that have been transferred from one site to another.
According to Dilip Ayyala Somayajula, validation manager at Grand River Aseptic Manufacturing, the paper was “conceptualized” soon after the ISPE‘s Statistician Forum held in 2014. Somayajula was a member of the team working on the guideline.
He said that “the intention of the team is to present more ways and approaches in determining the number of process validation batches. If you look closely each approach is unique and has specific applications and limitations.”