Routine, ongoing assessment of process performance and product quality is crucial to ensuring that high quality pharmaceuticals
reach the patient in a timely fashion. In traditional solid-dosage pharmaceutical manufacturing, process data are routinely
analyzed at two points in time to assess process stability and capability. During the production of each batch, process operators
and quality-control departments collect data to ensure stability and capability and take appropriate remedial actions when
needed. On a less frequent basis (i.e., monthly or quarterly), batch-to-batch variation is analyzed based on product parameters
to assess the long-term stability and capability of the process. The author discusses this system, including key challenges,
and describes a structured approach, including the role of quality by design (QbD), for operating the system effectively.
Process monitoring and control.
The industry and regulatory focus on QbD places an even greater emphasis on the quality of pharmaceutical products and the
performance of the pharmaceutical-manufacturing processes. Process and product control are major building blocks of QbD (1).
The strategic structure of the International Society for Pharmaceutical Engineering's (ISPE) Product Lifecycle Implementation
Plan (PQLI) lists the "process performance and product quality monitoring system" as one of its critical elements (2).
Process stability and capability.
Central to any system is the assessment of process stability and capability. Manufacturing processes that are stable and
capable over time can be expected to consistently produce product that is within specifications and thereby cause no harm
to patients due to nonconforming product. Stability and capability are described as follows (3, 4): A stable manufacturing
process is a process that is in a state of statistical control as each batch of tablets is being produced and as batches of
tablets are produced over time. A process in a state of statistical control consistently produces product that varies within
the process control limits; typically set at the process average (X-Bar) plus and minus three standard deviations (SD) of
the process variation for the parameter of interest. Separate control limits are set for each parameter (e.g., tablet thickness
and hardness). Any sample value that falls outside of these limits indicates that the process may not be in a state of statistical
A capable process is one that consistently produces tablets that are within specifications for all tablet parameters (3, 4).
A process-capability analysis compares the process variation to the lower and upper specification limits for the product.
A broadly used measure of process capability is the Ppk index, or process performance index, which is discussed in greater
detail later in this article.
A production process can include any one of the four combinations of stability and capability: stable and capable (desired
state), stable and incapable, unstable and capable, and unstable and incapable (worst possible situation).
Process stability and capability are typically evaluated twice:
1) During the production of each batch to ensure that the process is in control and to identify when process adjustments are
needed. Some key questions that need to be addressed during this analysis include:
- Is the batch production process stable during the production of the batch with no trends, shifts, or cycles present?
- Is the process capable of meeting specifications (i.e., are the process-capability indices acceptable)?
- Is the within-batch sampling variation small, indicating a stable batch production process?
2) Monthly or quarterly to ensure batch-to-batch control throughout a given year and between years. Some important questions
that should be addressed during this analysis include:
- Is the batch-to-batch variation stable from year to year and within years with no shifts, trends, or cycles present?
- Is the batch-to-batch variation small?
These two analyses also help to assess the robustness of the process.
Control limit versus specification limit.
Control limits are calculated from process data and applied to the process. Control limits are used to assess the stability
of the process and to determine the need for process adjustments when out of control samples are detected. On the other hand,
specification limits apply to the product. Specification limits are used to assess the capability of the process to produce
a product that has the desired properties and characteristics.