Introduction
This Guidance provides a tabulation of potential critical process parameters and quality attributes of typical steps of primary solid drug product (i.e. dry products) packaging processes. It also includes packaging validation items such as evaluation of equipment, protocol and report contents, amount of data (e.g. number of runs) and if warranted, microbiological studies.
Some secondary packaging steps are also included which would also apply to sterile products. There are other guidances that contain general definitions, guidelines and general principles for selection of Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs). These documents describe how CPPs and CQAs can be used in subsequent packaging process validation or continuous verification studies and the criteria for assessing criticality.
Drug products come in a variety of packaged forms frequently packaged with common steps and equipment. The potential critical process parameters are often the same from process to process and this guidance captures these common CPPs and CQAs. The specific practices with respect to packaging process validation are described as well.
Packaged Process Parameters
Quality risk assessments are suggested to be used for determining the level of criticality of equipment and parameters. See guidance on Risk Assessment in Validation. Each packaging application should be evaluated on a case-by-case basis to determine impact assessments and which parameters are critical. Critical packaging process parameters and normal operating ranges, including justification or reference for these ranges, are to be determined before validation and included in the packaging validation protocol. Some examples of critical process parameters ranges to be determined in pre-studies, line trials or qualifications may include:
- Time
- Temperature
- Pressure
- Torque
- Speed
- Count quantity
- Fill Weight and Variation
- Inert atmosphere (liquid)
- Environmental Humidity
Steps using packaging equipment should be evaluated to determine which steps or pieces of equipment are considered critical. Examples of potential critical packaging steps/equipment systems may include:
- Reject systems (e.g. vision systems, weighing systems)
- Product and/or lot specific labeling systems
- Bottle and blister filling equipment
- Filling and capping equipment
- Induction seal units
- Tamper resistant packaging equipment
- Tablet and capsule feeding equipment
- Lot and bar coding equipment (both printing and reading of bar codes)
- Desiccant or other material feeders
- Bottle cleaning equipment (e.g. blowers and vacuums)
- Re-torque equipment
- Outserters and Inserters
- Other related to packaging (storage tanks prior to packaging, blow-fill-seal machines)
Equipment is subject to routine maintenance, calibration, challenges, etc. to ensure it is properly functioning. These practices should be taken into account when determining the criticality.
Potential CPPs and CQAs for these equipment and systems were addressed for some common packaging processes for solid dosage forms in Tables 1-3. Depending on the specific dosage form, product or packaging, some of the attributes listed below may not be applicable or additional attributes could be warranted. The following tables can be used as a starting point for the selection of CPPs and CQAs for an assessment of packaging validation requirements.
Packaging Validation Protocol and Report
The protocol should include or reference the following items at a minimum: Validation approach to be used (e.g. concurrent, bracketing and matrixing, continuous verification) and the related rationale for that approach Description of product, including product name, dosage form, strength where applicable, packaging instructions, bill of materials, and package configuration; Packaging process description with a list of major systems involved, process flow chart, and description of individual unit operations; Summary of the packaging process stages to be monitored or evaluated; Critical packaging process parameters and NOR (normal operating range) , including justification for these ranges or reference to other documents that include justification; Acceptance criteria; Sampling plan, including type, amount, and number of samples, together with any special sampling or handling requirements; Requirements for stability testing; if none is required, the protocol should include a statement to that effect together with justification for the decision; and Methods for recording and evaluating results (e.g.statistical analysis).
Validation reports should include or reference at least the following:
- Reference to validation protocol number and version; and any supplementary documentation describing changes to the protocol;
- Test results;
- Discussion of the data compared to their respective acceptance criteria;
- Review of critical process parameters from lot packaging records;
- Description of any deviations or failures, and their impact on the validation; and
- Conclusions.
Matrixing and Bracketing
Matrixing of the packaging processes can be performed when there are significant similarities between products. The rationale for matrixing must be included in the protocol.
Example:
A solid dosage form is compounded in various strengths affecting its overall shape and size. Solid dosage units are packaged with the same tools in the same type of container/closure. One validation run for each tablet strength should be included in the validation matrix.
Bracketing of the packaging processes can be performed when there is a range of process extremes of parameters. Different products may be bracketed due to similarities of package components, critical packaging process parameters, packaging lines, and product attributes.
The rationale for the bracketing approach should be included in the protocol.
Example:
In the case where bottle dimensions for different products are identical except for height and only a minor line adjustment is required.
Example:
Largest and smallest filling amounts, fastest and slowest operating speeds for the packaging process
Number of Validation Runs (or segments)
A packaging validation run should be representative of the typical packaging process and be of sufficient length such that the packaging validation run will exhibit normal packaging process variability such as equipment variability, operator and mechanic variability, material variability, start-ups, shut downs, shift changes, and environmental conditions. Some sites use a minimum run time such as 10 hours to capture any potential effects of a shift change.
However, within a continuous quality verification (CQV) approach, CQAs and/or CPPs may be continuously monitored, evaluated and adjusted (directly or indirectly via critical process parameters). In this approach, the number of packaging validation runs or segments is not applicable. Techniques such as control charting and trending may be performed in an at-line or on-line manner. This approach conforms to the Continued Process Verification (Stage 3) and controls, as described in the FDA’s new draft guidance on process validation.
Multiple packaging validation runs are required to demonstrate reproducibility of the packaging process. Due to the varying length and size of packaging lots, the packaging validation runs may be sub-sets (segments) of an entire packaging lot. Packaging runs for each formulation in each commercial package should be validated, unless justification exists to utilize a bracketing or matrixing approach.
For example, when three (3) runs are determined and agreed for validation, a full packaging lot may be based on three (3) filling shifts. Each shift or segment can be considered as a packaging validation run for validation purposes. The validation sampling plan should be based on the size of the validation run.
If required by the product market or a risk assessment, Microbiological Studieson the final packaged product should be included in packaging process validation studies to evaluate the effect of the packaging operation and packaging environment on product quality.
A documented microbiological risk assessment may be used to determine if there is a need to conduct microbiological testing during packaging validation of solid oral dosage forms.
A failure to meet the established defect limit criteria should be investigated to determine the impact on validation requirements, and the acceptability of the product.