The interpretation of what constitutes a small scale batch for the purpose of
filing ANDAs is further elaborated below for various dosage forms and their
packaging recommendations. Unless specifically noted below, one primary
batch should be fully packaged.
Oral dosage forms
(a) Tablets/Capsules (e.g., immediate release, extended release, chewable,
orally disintegrating and delayed release tablets or capsules): Two of the
three batches should be of at least 10 percent of the proposed production batch
or 100,000 finished dosage units, whichever is greater (i.e., pilot scale
batches). The third batch can be smaller than the 10 percent of the proposed
production batch, but should not be less than 25 percent of the pilot scale
batch. We recommend stability data be generated for the three ANDA
submission batches in the proposed marketing container. A minimum of
100,000 units in all proposed presentations is recommended. Representative
samples from all three batches must be packaged in a sufficient number of
proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and
211.166(b) .
(b) Powders/Solutions/Suspensions: Two of the three batches should be at
least 10 percent of the proposed maximum size commercial batch. The third
batch can be smaller than 10 percent of the proposed commercial batch, but
should not be less than 25 percent of the pilot scale batch. To capture
variability introduced by packaging, the product from all the batches should
be used in the packaging process. We recommend packaging representative
samples from all three batches of a sufficient number of proposed marketing
presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b) .
Parenterals
Solutions/Powders for Solutions (lyophilized cakes)/Suspensions/Sterile
Topicals (Ophthalmic and Otic drug products): Two of the three batches
should be at least (a) 10 percent of the proposed maximum size commercial
batch (i.e., pilot scale size), (b) 50 L (per batch if the fill volume
configurations per vial is larger than 2.0 mL), or (c) 30 L (per batch if the fill
volume size is up to 2.0 mL) whichever is larger including packaging.12
When multiple fill volume sizes are proposed by the applicant (e.g., 1 mL, 2
mL, and 3 mL), then 50 L per batch size is recommended. The third batch can
be smaller than 10 percent of the proposed commercial batch, but should not
be less than 25 percent of the pilot scale batch (with packaging).
13 To capture
variability introduced by packaging, the product from each of multiple fill
volume batches should be used in the packaging process. We recommend
manufacturing all the batches to meet sterility requirements. Packaging
requirements are also discussed in 21 CFR 211.166(a) (1-5) and 211.166 (b).
Transdermal Patches
Two of the three batch sizes for each strength should be at least 10 percent of
the proposed commercial production batch (with packaging) or 25,000 units
(for each strength), whichever is greater. The third batch can be smaller than
10 percent of the proposed commercial batch (with packaging), but should not
be less than 60 percent of the pilot scale batch (with packaging). For
transdermal matrix products, where different strengths are identified by the
transdermal patch size (surface area), to comply with the three batch size
recommendation, we recommend providing data on patches manufactured
using three distinct matrix laminates at the time of submission (each laminate
can be cut to support multiple strengths in the application, where applicable).
We recommend you contact the appropriate OGD review division if you are
manufacturing transdermal patches using other technologies (e.g., reservoir).14
You should include a representative sample from all three batches using
different components of backing, adhesives, release liner, and other critical
excipients used in packaging a sufficient number of proposed marketing
presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b).
12 Amount packaged = 50 L or 30 L –(minus) filling/flushing loss. 13 Ibid. 14 See the guidance for industry on Residual Drug in Transdermal and Related Drug Delivery Systems.
Topicals
(a) Creams/Lotions/Gels: For nonsterile semi-solid dosage forms,
15 the two
pilot scale batches should be at least 100 Kg or 10 percent of the production
batch, whichever is larger, packaged.
16 The third batch can be smaller than 10
percent of the proposed commercial batch, but not less than 40 percent of the
pilot scale batch, packaged.
17 Packaging requirements are also discussed in
21 CFR 211.166(a) (1-5) and 211.166 (b).
(b) Inhalation Solutions/Nasal Sprays (nasal nonmetered dose atomizer):
Please refer to the following guidances for industry for information: Nasal
Spray and Inhalation Solution, Suspension, and Spray Drug Products –
Chemistry, Manufacturing, and Controls Documentation, and Bioavailability
and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local
Action.
