Risk Assessments for Quality by Design

[#1]

For a new manufacturing process for a pharmaceutical product, risk assessments are expected to be performed during the development of the process.  The purpose of the risk assessment is to:

• Identify potential risks to product quality that may arise during the manufacturing process
• Identify the potential material and process factors that may impact those risks
• Determine where knowledge is lacking regarding those risks and where new knowledge should be generated so that the risks can be more fully understood and characterized
• Guide the design of risk-based experimental study plans
• Communicate the risks to key-stakeholders
• Aid in the development of process control strategies that reduce or eliminate manufacturing process risk

Using a risk-based process development strategy is at the heart of what is known as Quality by Design. The ICH Q8, Q9, Q10, Q12 guidelines outline this approach (available at https://ich.org/page/quality-guidelines). Risk assessments are part of the overall risk management approach described in the International Council on Harmonization (ICH) guideline ICH Q9 (Quality Risk Management). This guideline defines the overall approach pharmaceutical manufacturers should use for managing risks associated with the product. Elements of risk management include risk assessment, risk reduction, quality monitoring, and risk review.  

The starting point for pharmaceutical product development  risk assessment is the Quality Target Product Profile (QTPP). The QTPP is a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.  A simple example QTPP for a solid oral dosage (tablet) drug product is shown in the table below.

QTPP Element	Description and Summary
Dosage	Tablet dosage forms with active ingredient dosages of 5 mg, 10mg, and 20 mg.  An accurate dose is delivered to the patient.
Pharmacokinetics	Active ingredient is readily absorbed after ingestion within 30 minutes, with sufficient blood plasma concentration to provide target efficacy
Safety	Drug causes no serious adverse events or side effects due to toxicity, drug delivery, or impurities
Stability	Drug product is stable with an intended shelf-life of at least 24 months.

With a QTPP defined, the list of important attributes of the drug product that are measurable and that are believed to be indicative of product quality is determined, and each of these quality attributes is mapped to each of the QTPP elements. Note that a quality attribute may be related to more than one QTPP element.  Each QTPP element can be ranked (e.g., low, medium, high), which is useful if other goals such as product cost or ease of manufacturing is included in the QTPP, but in general all QTPP elements related to the safety and efficacy of the drug product should be ranked high.   

QTPP Element	Rank	Quality Attributes
Dosage	High	Identification Tablet weight, friability Assay Content Uniformity
Pharmacokinetics	High	Dissolution Tablet hardness and thickness
Safety	High	Impurities Assay Degradation Products Assay Microbial Purity Residual Solvents
Stability	High	Water Content Degradation Products Dissolution

In many cases, these attributes are labeled as Critical Quality Attributes (CQAs). CQAs are attributes that are known to direct measure product quality as it relates to product safety or efficacy.  Initially, most attributes are considered critical until further study demonstrates that they can be considered not critical.

The depth of the impact of each of the critical quality attributes can be rated on a risk scale (as shown below using a {1,3,9} rating scale) with a higher number indicating higher impact. This allows for a better determination of whether the proposed quality attribute is truly critical, as well as what quality attribute most directly relates to the QTPP elements. 

Once the quality targets and attributes have been defined, the next step in the risk assessment is to look at the design of the manufacturing process. A process map is typically used, and the process factors for each step in the process are listed. 

Those process factors are then ranked for their potential impact (Severity) on each quality attribute. This ranking is based on several factors, including previous research, experience with similar products and processes, and industry expectations. Also, a lack of knowledge about the impact that the process parameter has on quality should link to a higher risk ranking. Initially, each process parameter could be considered to be Critical Process Parameters (i.e., process parameters that directly impact one of more CQAs). 

As a final step, an assessment of the operational risk associated with each parameter is performed. Each parameter is ranked according to the likelihood that there would be a problem with controlling the parameter (the probability of Occurrence) as well as the likelihood that if the parameter could not be controlled it would be detected (Detection Uncertainty).

With all these risk rankings determined, an overall risk score for each process parameter can be developed by multiplying Severity, Occurrence, and Detection scores to get a risk priority number (RPN) score.  In the example above, the RPN for the coating step process parameter Spray Rate on Dissolution is:

(Spray Rate Dissolution Severity) x (Spray Rate Occurrence) x (Spray Rate Detection Uncertainty) = 9 x 3 x 9 = 243

while the RPN for the granulation step process parameter Impeller Speed on Dissolution is

(Impeller Speed Dissolution Severity) x (Impeller Speed Occurrence) x (Impeller Detection Uncertainty) = 9 x 1 x 1 = 9

Calculating the RPNs for all process parameters and all quality attributes allows you to determine RPNs for each process parameter.

The sum of the RPNs (across all CQAs) is tabulated or graphed to show which parameters may have the highest risk to product quality.

This process parameter risk ranking can then be used as a guide for what parts of the process and what process parameters need closer attention during the development cycle. In the example above, the Coating step in the process has the most factors with a high RPN, so that step would definitely require further study and characterization. 

Ultimately, the goal is to be able to reduce the risk associated with the process by:

• Gaining further knowledge about the actual impact of the process parameter on the quality attributes. Design of Experiments is one of the most commonly used methods to aid in performing the process characterization and developing process knowledge. The risk ranking also helps identify which factors should be included in your experimental design.  
• Developing a process control strategy:
  • Determining appropriate target operating conditions for each process factor.
  • Determining the range within which each process parameter should be controlled to ensure product quality. This is often denoted as the Proven Acceptable Range (PAR). 
  • Determining the process factors that should be considered truly Critical (low ranking parameters may be able to be considered not critical).
  • JMP's Profilers are incredibly useful for interpreting the results of an experimental design and helping you to determine a control strategy.
• The Risk Assessment is updated after all of the process knowledge has been summarized and evaluated. The list of CPPs, targets operating conditions, and PARs form the core of the risk reduction and process control strategy. The knowledge gained during process characterization should lead to an overall reduction in the risks associated with the process.

We have developed a Quality by Design Risk Assessment Add-in as a tool to aid our customers who are doing this type of work. With the add-in, you can define the QTPP elements, quality attributes, process steps, and associated process parameters. These defined processes can be saved and re-used, and you can switch between saved processes. You can then use the risk-ranking method to automatically create RPN score reports. We hope that this new tool will make it easier for you to do this important Risk Assessment work, and we encourage you to download and try the new add-in.