Blend Uniformity Analysis (BUA) involves quantitative determination of individual components of a blend in order to ascertain the mixture ratio. BUA is recommended for those drug products for which USP requires content uniformity analysis.
USP requires this test when the drug product contain less than 50 mg API or when API amount is less than 50% w/w of drug product.
But recently FDA stated that the USP <905> Uniformity of Dosage Unit should not be applied for product release testing due to concerns that the results of the test did not provide sufficient assurance that future sample taken from the batch would also comply with the same acceptance criteria.
CGMP (21 CFR.211.110) requires an in-process testing of powder blends to demonstrate adequacy of mixing, but it does not state that the blend has to be directly assessed for uniformity. It was on this premise that the original draft stratified sampling guidance document allowed the use of in-process dosage unit data as a surrogate to demonstrate dosage unit uniformity during routine manufacture. Blend uniformity should be assessed during process design (Stage 1 Validation) and process qualification (Stage 2 Validation). Defaulting directly to the testing of in-process dosage units is discouraged, the exception being when blend sampling presents severe risks to the operators taking the samples (which should be discussed and accepted by regulators).
For complex dosage form (MR tablet and capsule), complex process (multi step granulation) applicant advised to consult with appropriate chemistry reviewing division to determine if required or not.
BUA is recommended for bioequivalence, test and commercial production batch of drug product.
As per ISPE
During the manufacture of development, clinical and stability batches, scientists should seize the opportunity to generate data regarding the process’s ability to produce acceptable blend and dosage unit uniformity. The number of batches manufactured during process development will likely vary from product to product. Factors such as the availability of drug substance, number of batches required for development, clinical supplies and registration stability studies will impact the number of batches manufactured during Stage 1 Process Design.
The number of locations sampled in the blend should be sufficient to adequately “map” it, and target problematic areas such as above discharge valves and along the center axis of rotation. Triplicate samples should be taken and assayed for each location to allow VCA to be performed on the data, which can then be used to improve formulation and/or process performance. The number of dosage unit samples to be tested should ensure comprehensive coverage of the batch. Batches made with bench-top or pilot scale equipment will likely require fewer sampling locations. Note that acceptance criteria depend on the sampling plan. Therefore, if data obtained from the sampling plan are evaluated using acceptance criteria, the criteria for blend and content uniformity should be appropriate for the Phase of development. For example, looser criteria may be acceptable during the manufacture of Phase 2 clinical supplies (e.g., tested against USP <905>). At Stage 2, the sampling plan should be chosen so that acceptable batches will meet the associated acceptance criteria. As the process is further developed and additional knowledge/experience gained, the acceptance criteria should approach that to be used for the commercial product.
Stage 3 Continued Process Verification applies to the lifecycle of the product. A risk based approach should be used to define the level of testing used during Stage 3A. Products that have higher SDs for blend and dosage unit uniformity may require larger sample sizes. Other considerations that can impact Stage 3A sampling plans include the overall control strategy, use of SPC charts, the amount of confidence in the predictive powers of model(s) used to predict content uniformity.
When the acceptance criteria are easily met during Stage 2 Process Qualification or Stage 3A (if reduced testing is required based on Stage 2 results), the team’s framework for CU (and inferred BU) sampling and testing is to progress to Stage 3B process verification. For each production batch, one acceptable sampling plan is to take a sample of 30 dosage units across the batch. 10 of these dosage units, selected across the batch, should be tested and if needed, the additional 20 dosage units tested using Sampling Plan 1 or the company’s chosen acceptance criteria/methodology.
As per FDA Draft Guidance for Industry (Which is withdrawn by FDA)
Sample size is to be 1-10X of dosage unit range while developing a technique capable of measuring the true uniformity of the blend. Sample quantities larger than 3X can be used with adequate scientific justification.
Identify at least 10 sampling locations in the blender to represent potential areas of poor blending.
Collect at least 3 replicate samples from each location. Samples should meet the following criteria:
- Assay one sample per location (number of samples (n) ≥ 10) (n = 20 for ribbon blender).
- RSD (relative standard deviation) of all individual results ≤ 5.0 percent.
- All individual results are within 10.0 percent (absolute) of the mean of the results.
If samples do not meet these criteria, we recommend that you investigate the failure according to the flow chart in Attachment 1.
A Typical BU Sampling Point
Reference:
- ISPE
- USFDA
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