Guidance 015 – Critical Process Parameters for Drug Product

Critical Quality Attributes and Critical Process Parameters

Critical quality attributes (CQA) are defined as physical, chemical or microbiological properties or characteristics of a material (drug product or API) that directly or indirectly impact the safety, identity, strength, purity or marketability of that material. These attributes are typically driven by characteristics of the API and excipients used in the drug product formulation that are affected by the parameters of the process. The raw materials used and the parameters under which they are processed may affect the CQA of the product. Critical quality attributes or characteristics are usually defined during development and are most often associated with in-process controls and final product release tests. These attributes are usually specified with allowable limits and filed for submission to the health authority. The critical quality attributes must be defined prior to assessing the manufacturing process for critical parameters.

Method of Defining Critical Process Parameters

Certain steps of the manufacturing process will affect the CQAs. Any manufacturing step that is responsible for generating, modifying or negatively impacting the attribute is a critical step. A critical step may have one or more critical process parameters (CPP).

Alternatively, a critical step may not have any critical process parameters if it can be established that the parameter(s) in question has a NOR that is strictly controlled well-within the PAR.

One way of determining what is a critical process parameter is to begin with the CQAs.

Technical experts and engineers from both development and production knowledgeable about the product and the production process should determine the CPP. Quality operations should be involved to verify that the CQA and CPP are properly documented and defendable. A flowchart of the manufacturing process should be made available to all participants. This flowchart should have sufficient detail to readily understand the primary function of each step. Then, each critical product attribute should be evaluated individually to determine what steps may or may not impact that attribute.

Any step or unit operation determined to be critical should be evaluated to determine if it contains one or more critical process parameters. The parameters must have some influence on a CQA to be considered for evaluation as critical. The degree of control over the parameter will determine if it is critical. It is possible to have a critical step that does not contain any critical parameters if control of process parameters is tight. This portion of the analysis requires both knowledge of the process and manufacturing equipment. An example might be a fully automated compression step. The step is critical but complete control over the parameters leads to defined noncritical process parameters. Critical parameters identified during the research and development phase are not necessarily reflective of production scale equipment. The analysis of the process at this level is analogous to a failure modes and effect analysis without estimating frequency of failure or severity of the effect.

Relevant information about any parameters suggested as potentially critical but determined to be non-critical should also be documented.

Example 1-Blending time and tablet lubrication evaluation during R&D

During R&D it is found that the lubricant blending time and the tablet press feed system are critical to tablet hardness. Over-blending of the lubricant leads to soft tablets. R&D conducts a study that defines the NOR limits of the blending step and tablet press feed conditions while still supporting adequate mixing of the lubricant. Blend time and press feed system are critical process parameters.

Defining Ranges for Critical Process Parameters

An understanding of each parameter is necessary before defining a parameter as critical.

Parameters may be defined as critical depending on their effect on critical quality attributes, ability to be controlled, and the process design and capability. Process design and process capability are related to the concepts of Edge of Failure (EOF), PAR and NOR.

NOR and PAR values are established during research and development, but may also be further characterized during the manufacturing phase. Some EOF and PAR values may only be determined using full-scale production equipment. Although it is desirable to have EOF values, they are often never obtained or determined due to time and resource constraints.

While knowledge of PAR values for a given parameter is important information for determining critical process parameters, it is the NOR that is used during process validation. Process validation requires equipment qualification and process data that supports the ability to control the process within the NOR, at a minimum.

Ideally, R&D and manufacturing development batches should focus on obtaining data that support the NOR and determine ways to control it. Manufacturing development batches are also referred to as technical transfer, demonstration, engineering, scale-up and ‘proof of concept’ batches.

The more data collected in the development phase, the more scientifically sound a risk assessment can be conducted. It is not scientifically necessary, or financially prudent, to evaluate every possible combination of manufacturing process parameters. Instead, it is of the most benefit to document a thorough understanding of the process and the process parameters.

The NOR of a parameter can then be individually considered for risk in terms of its relation to its corresponding PAR. The further the NOR limit is from the PAR limit, the less critical is the parameter. Conversely, the closer the NOR is to the PAR or EOF, the more critical the parameter becomes.

A proposed manufacturing batch record should be drafted with NOR and target (set point) for each parameter. The batch record ranges and targets should be based on the development data and knowledge of the equipment capability to control the parameter.

Example 2-Mixing speed NOR values based on equipment ranges

Mix speed typically has an upper and lower limit. The limits can be both mechanical and product-related. The lower limit has a mechanical limitation in that a certain minimum amount of speed is required to turn the mixing blades due to the viscosity of the given material. However, the lower limit also has product-related component since the intent of mixing is to ensure homogeneity. From a mechanical perspective, the upper limit is related to the capacity of the motor drive. In addition, there are typically product-related limitations to the upper mix speed such as air entrainment, shearing or inadvertent particle grinding.

When establishing the proposed batch record limitations, the equipment and product-related factors should be considered. Ideally, the NOR should be well within both the upper and lower PAR limits When establishing the proposed batch record limitations, the equipment and product-related factors should be considered. Ideally, the NOR should be well within both the upper and lower PAR limits.

Example 3-Mixing speed PAR values

Returning to the mixing speed example, it is determined during a full-scale development batch that adequate homogeneity is achieved using a minimum mixing speed of 50 rpm and air-entrainment (foaming) begins at 100 rpm. These are the PAR values (minimum 50 rpm/maximum 100 rpm).

The NOR should not be estimated. It should be supported with data as outlined below.

Consideration should first be given to the equipment qualification and the accuracy and precision of the instrument reporting the monitored parameter.

Example 4-Mixing speed NOR, considering calibration

Continuing with the mixing speed example (minimum 50 rpm/maximum 100 rpm), we will assume the calibrated certainty of the measurement of the mix speed is +/-5 rpm. Therefore, the NOR for mixing speed can be no greater than 55 to 95 rpm to allow for the uncertainty of the measurement (i.e. a set point of 55 rpm may provide an actual mix speed of 50 rpm).

The NOR should be centered, where possible, between the PAR limits, but equipment capability and other operating considerations may not permit this ideal to be realized.

Example 5 – Mixing speed; selecting NOR based on PAR

In the mix speed example, we will assume that 100 rpm is the maximum capacity of the mixer. We do not want to run the mixer near capacity so we prefer to select a NOR closer to the lower limit. However, we would also like to establish a buffer or safety factor between the lower PAR and the lower NOR since homogeneity is the most important factor in this step. We will select a NOR of 70-80 rpm with a target of 75 rpm. This provides us the assurance that we are at least 15 rpm (70 rpm – 50 rpm lower limit – 5 rpm uncertainty = 15 rpm) above the lower PAR value and 15 rpm below (100 rpm upper limit – 80 rpm – 5 rpm = 15 rpm) the upper PAR value. In this example, the criticality of the parameter has been reduced since the PAR is large, NOR is small and the parameter is reliably controlled. The NOR for mix speed can be expected to be a robust process parameter.

In practice, it is not always possible to center the NOR due to equipment and/or product-related limitations. However, the concept demonstrated through the examples above remains applicable to all variable parameters.

For legacy processes, variable critical parameters may not have an established NOR. Instead, only a target or set point value is specified. Establishing the NOR in this situation is possible in a number of ways. The first approach is to determine if control of the parameter is easily and robustly maintained. In this case, the NOR becomes the tolerance of the equipment measurement and control capability. An actual NOR is not established, instead this parameter is treated as a fixed value or set point.

An alternative approach for legacy processes is to review the historical process data and determine if a variety of ranges or set points have been used. All set points used that resulted in acceptable batches within specifications are suitable for inclusion in the NOR.

If these data are not available, additional development work may be required. However, before such work is performed, it is useful to review the process and conduct a risk assessment to determine which parameters are likely to be most critical. The analysis ensures that the development work is focused correctly. With an adequate understanding of the product and process, the development may be performed on a reduced scale or through sub-lotting of the batch.

Definitions of Fixed, Variable and Dependent Parameters

A variable parameter is one that can be directly adjusted during processing. A fixed parameter is one that cannot be adjusted during processing, instead it is set prior to processing (e.g. mixing blade design, rotator/stator combinations, milling screen size, on/off motor speeds, etc.).

A dependent parameter is one that is the result from the effects of one or more variable and fixed parameters. A dependent parameter cannot be adjusted directly, but it can be changed through changes to other parameters or by making equipment changes. It is helpful during the review of the process to identify parameters that are fixed, variable and dependent.

Example 6-Output or dependent parameter

The pH of a solution is a dependent parameter. The pH itself cannot be adjusted directly like changing the speed of a motor. Instead an amount of acid or base must be added and often the rate of the addition must be controlled. The pH is an output or dependent parameter of the amount and rate of the addition.

Non-Critical Parameters

Those parameters that will have no effect on critical quality attributes are classified as non-critical. These would include parameters that if taken to an extreme might have an effect, but is highly unlikely the extreme would ever be reached. It may be useful to identify those non-critical parameters that, unless otherwise controlled, have the potential to impact the quality of The product. For example, these may be parameters that have a NOR well within the PAR owing to highly sophisticated automated controls. However, if this process were transferred to a facility which lacked this level of control, the parameter may then become critical. These parameters should be monitored and/or verified during validation and routine production, but are not required to be challenged during qualification and validation.

Example 7: Non-critical parameter

Protein will typically denature at temperatures exceeding 70°C. Some protein products will denature or degrade at a lower temperature such as 50°C. The routine processing condition for a protein product is often room temperature or 20-25°C. In the manufacturing environment even without special control it is highly unlikely that the ambient temperature could potentially reach the denaturation point. Therefore, temperature would not be a critical parameter for the routine process even though the effect of high temperature on protein is real and non-reversible.

It is also important to distinguish between parameters that affect CQAs and parameters that affect efficiency, yield or safety. Parameters influencing efficiency, yield and safety are not typically considered critical parameters unless they also impact product quality.

However, the practitioner is cautioned that yield is a GMP concern. Most processes are required to report an overall yield from bulk to semi-finished or finished product. A deviation from an acceptable yield range would typically receive additional scrutiny since the reason for the yield deviation may be due to a lack of process control. In the event a process produces a yield deviation it becomes important to be able to demonstrate thorough process understanding and control.