Critical Process Parameters (CPP) in Pharmaceuticals

Imagine that a tablet compression machine is correctly functioning as highlighted in the process instruction document. The speed of compression is optimal, the machine is validated and the people running the process are competent. Still, the finished tablets fail the dissolution test. An inquiry reveals that the cause of the issue lay with unnoticed increase in the moisture of granules prior to compression. Only one variable in the process was inadequately controlled and that variable altered the properties of the final product significantly.

The described event leads to a better understanding of the reason why pharmaceutical companies concentrate on emphasizing Critical Process Parameters (CPPs). Each manufacturing technology involves a number of operating parameters, but only a few of them play the most important role in ensuring the quality of the final product. Defining these parameters and controlling them within scientifically founded limits is vital for achieving homogeneity of batches and retaining the state of their validation.

The regulatory authorities have intended for the manufacturers to understand not only how their process works but also why it operates successfully and produces quality products. The identification and control of CPPs is one of the most convincing proofs of this knowledge of the process.

Understanding Critical Process Parameters

A Critical Process Parameter (CPP) can be defined as a variable that influences Critical Quality Attributes (CQA). The quality, safety, effectiveness and performance of the product are subject to change if the variable deviates from its operating range.

The following are examples of various parameters of the process:

• Mixing speed
• Granulation time
• Drying temperature
• Compression force
• Coating spray rate
• Sterilization temperature
• Filling speed
• Filtration pressure

Not all the parameters mentioned above must be critical. A variable can be labeled a critical process parameter only when it is proved by science that its change in value can influence the quality of the product.

Why CPPs Matter

Contemporary drug manufacturing embraces the Quality by Design (QbD) approach, which involves incorporating quality during the manufacturing process rather than depending solely on testing the finished product.

Good management of CPPs provides the following advantages for producers:

• Regular production of consistent batches
• Elimination of variability in process
• Improvement of product quality
• Facilitation of successful validation of processes
• Reduction in the number of deviations and investigations
• Minimization of process waste
• Increase in capability of processes
• Compliance with regulations

Companies that know their CPPs are more capable of controlling and predicting process performance than those that only perform testing at the end of the process.

CPPs and Critical Quality Attributes

The Critical Process Parameters (CPPs) within the context of Critical Quality Attributes (CQAs) can be easily understood by looking at the connection between these two processes.

The CQAs are concerned with the properties making up the final product while the CPPs are associated with the manufacturing conditions that determine those properties.

For example:

• Compression force is linked to tablet hardness and dissolution.
• Granule moisture is linked to tablet friability and content uniformity.
• Coating spray rate is linked to coating uniformity and appearance.
• Sterilization temperature is linked to sterility assurance.
• Mixing time is linked to blend uniformity.

Each of the CPPs has a clear scientific correlation with one or several CQAs.

How Are CPPs Identified?

The identification of critical process parameters begins during the development phase of a drug and remains consistent till the end of its life cycle.

Advertisers have several different sources available for obtaining information. Some of them include:

• Research done on product development.
• Design of experiments (DoE).
• Laboratory process testing.
• Tests done on pilot batches.
• Studies conducted to define the process.
• Data gathered from the validation procedure.
• Information from leading production practices.
• Risk assessment evaluations made by manufacturing companies.

Instead of making assumptions while doing that, the companies are recommended to find experimental proof of the parameters impacting the quality of the product.

Risk Assessment Plays a Central Role

It is important to assess the risks before anything can be conclusively understood.

To begin assessing a process, one of the most effective methods is to conduct a Failure Mode and Effects Analysis (FMEA) where risks at each phase of the process are identified and assessed.

For example, during the drying process of a fluidized bed, some parameters such as inlet temperature of air, outlet temperature of air and time taken to dry the samples have been identified as factors that influence the moisture of granules. If a significant level of moisture leads to the sticking of the tablets later during the compression process, the original risk assessment shows why these factors have been referred to as Critical Process Parameters (CPPs) in this situation.

The involvement of people from Production, Quality Assurance, Engineering, Validation, Quality Control and Process Development departments is critical to ensure sufficient expertise is used to research the issue at hand.

Examples of Critical Process Parameters

CPPs differ from each other based on pharmaceutical dosage form and production technology.

1. Manufacturing of Oral Solid Dosage Form

Some examples of CPPs for this type of manufacturing include:

• Mixing time
• Speed of the mixer
• Rate of binder addition
• Granulation finish time
• Temperature for drying
• Humidity of the granules produced
• Screen size in milling machinery
• Force to compress tablets
• Speed of tablet press
• Speed of coating machinery
• Intermittent spray speed
• Pressure of air in the spray machinery

2. Sterile Manufacturing

Some of the common CPPs for this type of manufacturing are:

• Temperature at the time of sterilization
• Time for sterilization
• Pressure in the chamber
• Velocity of airflow
• Difference in pressures
• Velocity of filling the containers for product use
• Force to close the supplied containers
• Integrity of the filter

3. Water systems

Some of the typical CPPs include:

• Velocity of circulation through the loop
• Temperature used in sanitization
• Conductivity of the water
• Total amount of organic carbon present in water
• Amount of intermediate produced and flow rate
• Temperature for storage

4. Lyophilization

Some of the examples include:

• Shelf temperature
• Pressure in the chamber
• Temperature of the product
• Drying time
• Temperature of secondary drying

Different processes can have different critical process parameters that are defined by the understanding of the respective process.

Establishing Acceptable Operating Ranges

After the identification of CPPs, the next step for manufacturers is to set the acceptable operating ranges that help in ensuring product quality.

To arrive at these ranges, the following inputs are important:
- Process development studies.
- Experimental design implementation.
- Manufacturing runs.
- Process characterization.
- Trials for validation.
- Application of statistics.

For instance, such development studies may show that a tablet hardness will remain acceptable only if the pressure during compression is kept between 13 and 16 kN. Such a scientifically backed range shall become part of standard production controls.

It is critical for the establishment of the operating ranges to base them on data but not tradition only since it can be misleading.

Monitoring CPPs During Manufacturing

The monitoring and controlling of a CPP is essential to its effectiveness.

Depending on the process being used, monitoring may include:

• SCADA systems
• PLC-driven machinery
• Process Analytical Technology (PAT)
• Electronic Batch Documentation
• Testing during production
• Statistical Process Control (SPC)
• Automatic alarm systems
• Constant sensor tracking

Monitoring in real-time gives operators the chance to spot any process variations before any mistakes occur with the quality of the product.

CPPs During Process Validation

Process validation ascertains that specified CPPs are kept within tolerable limits and the process continually produces products that meet relevant specifications.

The validation study must show that:

• the chosen CPPs are suitable
• the set limits are scientifically substantiated
• the evaluation of extreme conditions has been conducted
• the variability of the process meets the requirements
• the product quality is stable during the entire series of the validation study

If unexpected variability occurs while conducting the validation, the process may need additional improvements and modifications before it can be used in regular mass production.

Continued Process Verification

The control of Commanded Process Parameters is just beginning with the completion of the validation of the process.

In the Continued Process Verification process, the producers check the details of the Commanded Process Parameters in order to be sure that the process keeps on being validated.

The tracked key points of the process may include:

• Performance of the process equipment.
• Variability in the temperature of the drying process.
• Uniformity of the mixer operation duration.
• Performance of sterilization process.
• Conductivity of water preparations.

Going through the statistics of the process ensures that it is detected long before it becomes a threat for the quality of the final product.

Common Challenges in Managing CPPs

Even established production facilities have problems in controlling CPPs.

Many of these problems include:

• The selection of too many parameters as critical ones.
• Inadequate scientific justification for selection of CPPs.
• Lack of re-evaluation of CPPs after changes in the operation.
• Neglecting the interaction of many parameters.
• Poor trend analysis of manufacturing statistics.
• Operating outside normal ranges without proper reasons.
• Weak connection between CPPs and CQAs.
• Little use of statistical methods in production process.

By overcoming these drawbacks, the processes can be stabilized and achieved regulatory compliance.

Best Practices for Effective CPP Management

• Implementing Best Practices when Managing Control of Critical Process Parameters
• Currently, there are several useful practices that can help agents improve the way they tolerate manufacturing processes.
• Identify control of critical process parameters based on development data and risk analyses.
• Record the connection of every CPP to its associated critical quality attribute.
• Define operating ranges based on scientific proofs.
• Monitor CPPs during manufacturing.
• Use trending of process data to identify issues earlier.
• Review CPPs periodically during Continued Process Verification.
• Re-evaluate CPPs in case of some changes in equipment, formulation, or technology.
• Make sure operators understand the reasons why each CPP is being managed, only knowing how to record it is not enough.

When the above-mentioned practices are used regularly, managing CPPs becomes not only a matter of compliance but also a valuable tool for the improvement of the process.

The Critical Process Parameters are an essential aspect of process control because they refer to conditions in a particular process that have a direct impact on the quality of the final product. When Critical Process Parameters are defined and managed correctly by the manufacturer, it helps decrease variability, increase the capability of the process and make products in compliance with both the requirements of the authorities and customers. While selecting Critical Process Parameters to manage it is important to base the choice on scientific knowledge, development studies and structured risk assessment and not just on knowledge gained through experience.

A common observation noted with high frequency in the course of process reviews is that the effective production process does not result from the control over all parameters but from understanding which factors in a particular process are important and how to keep them within specific limits. This focus on the most important parameters will lead to the successful validation of the process and will help to keep the process going beyond the validation phase and during the whole period of manufacturing the product.

Share

Tweet

Share

Pin it

Share