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By Trudy Yin
OVERVIEW OF BLENDING
ABSTRACT PROCESS AND EQUIPMENT
The powder blending process has been historically
identified as a challenging operation in Oral Solid The process of blending is commonly defined in the
Dosage (OSD) form manufacturing. Insufficient pharmaceutical industry as: the mixing of various bulk
blending results in poor active ingredient mixing with powder ingredients (e.g., drugs, excipients), targeted for
a homogeneity and uniform distribution of the mixture.
excipients. Excessive blending could adversely
Each pharmaceutical product has its unique blend of
impact the distribution of drug content (content
raw materials; therefore, a careful selection of manufac-
uniformity) in the final product. Companies suffer
turing process equipment and methods is inevitable.
financial setbacks due to rework of poor quality The quality of the resulting blend depends highly on the
product, and more severely, legal action being taken types of blenders or mixers used; the “flowability” (flow
because of non-compliance. With harmonizing behavior) of powder during the blend cycle is factored
efforts, government agencies, such as the U.S. Food into the finished product quality. The mechanics of
and Drug Administration (FDA), join with industry blending, which involves the principles of shear, convec-
experts and scientists to develop corresponding tion, and diffusion (or dispersion), is achieved by the
principles and guidelines in order to assist drug use of industrial blenders or mixers. The equipment
manufacturers. According to the FDA's current Good
employed to accomplish the process of blending can be
categorized as either rotating or fixed shell blenders.
Manufacturing Practice (cGMP) Code of Federal
Rotating shell blenders (i.e., drum, cross-flow, double
Regulations (CFR), Title 21, Part 211-Current Good
cone, and twin-shell) accomplish the mixing process by
Manufacturing Practice for Finished Pharmaceuticals rotating the blender shell around a fixed axis and by
standard; particularly section 211.110, Sampling and relying upon a sliding or rolling motion of the powder. To
testing of in-process materials and drug products aid in this mixing process, many systems will utilize
of Subpart F states, written procedures shall be internal baffles. Fixed shell blenders (i.e., ribbon, screw,
established and followed for “adequacy of mixing and impeller mixers), on the other hand, rotate internal
to assure uniformity and homogeneity…” In the blender parts, such as an impeller or paddle, and pro-
following blend uniformity discussion, we will duce a continuous cutting and shuffling motion. Shear-
examine this rule and demonstrate how guidelines ing force that breaks apart large conglomerates of pow-
emerge, how they are interpreted, and their practical
der is, therefore, developed by this kind of cutting and
shuffling motion. Pony, planetary, and high shear mixers
adoption to current industrial methodologies and/or
are commonly used in conjunction with blenders.
technologies.
There are a number of process and product vari-
ables and characteristics that influence the quality of
Figure 1
Blend Quality Factors
Category Sub-Category
Actives Excipients
• Particle Size • Particle Size
Physical
• Density • Density
Characteristics
• Morphology • Morphology
of the Ingredients
• Shape • Shape
• Amount • Amount
Actives Excipients
• Compatibility with excipients • Compatibility with actives
Chemical
• Adhesiveness • Adhesiveness
Compositions of
• Electrostatic charges • Electrostatic charges
the Ingredients
• Impurities
• Degradation profile
Factor
• Mixing Time
Process • Mixing Speed
Parameters • Flow Rate
• Volume
mixing and its final blend. Incorrect process parame- of the powder ingredients. Large coarse particles with
ters, for instance, when discharging the powder with higher molecular weight will, for example, settle to the
improper flow rate could create over-flooding or bottom of the blender vessel; whereas the smaller finer
unsteady flow issues, ultimately affecting the final particles will rise to the top. Particle density affects the
blend uniformity. Inadequate mixing time and speed sedimentation or floating ability, for which uniform dis-
could also result in poorly blended mixture, clump for- tribution of the powder mixture could be warranted.
mation, and segregation. Product characteristics Shape, stickiness, and electrostatic charge of the parti-
include particle size, density, morphology, shape, etc., cles may also resist or mark negative impact on the
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Trudy Yin
mixing process. Caution should be taken throughout monitor and validate the performance of processes
product and process development in order to eliminate that could be responsible for variability, including ade-
or minimize variability. Figure 1 summarizes some quacy of mixing to ensure uniformity and homogene-
major factors which contribute to the analysis and ity (21 CFR 211.110(a) (3)).1 An evaluation of unifor-
determination of the degree of confidence in these mity and/or equivalent testing may be necessary to
quality attributes, namely, the homogeneity and uni- fulfill cGMP requirements.
form distribution of the final blend mixture. Issued on October 2003, new draft guidance,
Scientifically valid procedures, appropriate test “Powder Blends and Finished Dosage Units- Strati-
methods, and in-process controls and limits should fied In-Process Dosage Unit Sampling and Assess-
be established in the developmental phase to evalu- ment,” was made available and distributed to solicit
ate the adequacy and effectiveness of such blending public comments and suggestions. “Stratified Sam-
process as well as to ensure uniformity and homo- pling” is defined in this new guidance and the sam-
geneity of the final blend product. The greatest chal- pling method, data evaluation, as well as analysis are
lenge confronting oral solid dosage form manufactur- further discussed in this guidance.2,3 However, the
ers today is the difficulty they encounter in applying guidance states that the methods described are not
sound methods and rationales to the blending opera- intended to be the only methods for meeting agency
tion and validation, respectively. requirements for the demonstration of the adequacy
of powder mix. Traditional powder blend
sampling/testing, finished product content uniformity
FDA GUIDANCE FOR INDUSTRY (CU) testing or alternate approaches may also be
used to satisfy cGMP requirements. The finalized
FDA announced the availability of a draft guidance for guidance represents the agency's current thinking on
industry entitled “ANDAs: Blend Uniformity Analysis,” “Powder Blends and Finished Dosage Units-Stratified
on August 27, 1999 (64 FR 46917) that was with- In-Process Dosage Unit Sampling and Assessment.”
drawn on May17, 2002, after comments from the Manufacturers are not encouraged to blindly follow,
public raised scientific issues relating to the scope but evaluate the methods, criteria, and recommenda-
and methodology of the blend uniformity draft guide- tions, presented in this new guidance for appropriate-
line.1,8 This draft guidance was intended to provide ness before implementation.
recommendations to abbreviated new drug applica-
tion (ANDAs) filings based on 21 CFR 314, not on
cGMP regulations. In other words, it guided industry PDA TECHNICAL REPORT NO. 25
to what information should be provided in an ANDA
in order to demonstrate bioequivalence and to estab- In 1997, the International Association for Pharmaceu-
lish in-process acceptance criteria related to blend tical Science and Technology (PDA) issued Technical
uniformity analysis (BUA). After careful consideration Report No. 25, “Blend Uniformity Analysis: Validation
of the written comments submitted, FDA decided to and In-Process Testing,” to provide scientifically
withdraw the draft guidance due to (1) adequacy of sound methods for the appropriate evaluation of
current blend sampling techniques and (2) appropri- blending processes. The intent of this technical report
ateness of various test methods for assessing blend was to establish statistically derived methods (e.g.,
uniformity.1 Although this draft document has never Bergum's method) and criteria to overcome the
been implemented, and the 21 CFR 211.110 does impact of sampling errors. The report represented the
not require BUA, an applicant or manufacturer must views of authors, industry experts, and PDA's Solid
still comply with any predicate rules and applicable Dosage Process Validation Committee. The FDA's
regulations to ensure the identity, strength, quality, review of the draft of this report resulted in a letter
purity, and bioavailability of the drug product (21 CFR response from FDA's Center for Drug Evaluation and
314.50(d) (1) (ii) (a)).1 A manufacturer must also Research (CDER) office dated August 29, 1997, in
which FDA commented and questioned the rationale operations that have a higher risk of pro-
behind the statistical approach advocated in the ducing failing results in the finished prod-
report.4 PDA documented its response to FDA in a uct uniformity of content.” 3
letter dated October 9, 1997.3,4 Later, in regard to the A stratified sampling technique is used to collect in-
agency's Docket No. 99D-2635, “Draft Guidance for process dosage units throughout the compression/fill-
Industry, ANDA's Blend Uniformity Analysis” of 1999, ing process. It can be used, therefore, as an alterna-
PDA was given the opportunity to comment on the tive to routine blend sample analysis. Establishing a
proposed draft guidance, and suggestions were doc- sample size is important for the analysis of blend
umented in a letter dated October 26, 1999. A subse- samples. The FDA Draft Guidance document stated
quent workshop and meeting with the working group that the blend sample size should be 1 to 3 dosage
(BUWG) were also conducted in 2000 and a draft units. The Blend Uniformity Working Group (BUWG)
recommendation of the use of stratified sampling of from Product Quality Research Institute (PQRI) pro-
blend and dosage units to demonstrate adequacy of posed that sample quantities larger than 3X be
mix for powder blends was issued for peer review allowed if they could be scientifically justified. The
and then published in the PDA Journal of Pharma- demonstration of content uniformity of the final pow-
ceutical Science and Technology.3 This brief history der blends cannot be absolutely absent of sampling
of guideline development demonstrates how consen- bias and errors. Physical design of the thief, physical
sus is reached between FDA and the public. Informa- and chemical properties of the formulation, and
tion on Technical Report No. 25 has also been cross- sampling technique are major factors that can affect
referenced and incorporated into the FDA 2003 draft sampling errors.4 Since sampling errors make it a big
guidance: “Powder Blends and Finished Dosage challenge to validate the blending operation, blend
Units- Stratified In-Process Dosage Unit Sampling sample data should be used in conjunction with in-
and Assessment.” process dosage unit data.
Assessment and validation (i.e., exhibit and
process validation batches) should optimally be per-
SAMPLING AND ASSESSMENT formed separately on the uniformity of the powder
blend, the in-process dosage units, and on the fin-
In order to adequately measure between and within- ished product. The FDA has proposed the following
location variability, the most appropriate blend sam- acceptance criteria3:
pling techniques and procedures should be devel- 1. Assay one sample (n) per location, n≥10
oped and chosen. Blend sample analysis should be 2. RSD of all individual results ≤5.0%
conducted on both the blend and intermediate bulk 3. All individual results within 10.0% of the mean
containers (IBCs) to identify the range of blending
times, dead spots in blenders, segregation in IBCs, Only after an initial assessment/validation is com-
and the possibility of sampling errors, etc. Stratified pleted, routine manufacturing controls and criteria
sampling is defined in the FDA draft guidance, “Pow- shall follow. All these cGMP process controls and
der Blends and Finished Dosage Units- Stratified In- product testing are necessary to ensure batch homo-
Process Dosage Unit Sampling and Assessment” as: geneity and batch-to-batch reproducibility. Procedures
will be written for material handling, machine opera-
“the process of collecting a representative tions, cleaning, maintenance, as well as sample col-
sample by selecting units deliberately lection, and analysis as minimal. In analysis of batch
from various identified locations within a normality, the FDA has proposed results to be classi-
lot or batch, or from various phases or fied as readily or marginally pass. Readily pass
periods of a process to obtain a sample homogeneity shall meet the following criteria3:
dosage unit that specifically targets loca-
tions throughout the compression/filling
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Trudy Yin
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