Proposed DP specifications
Quality attributes that affect DP performance are typically not known during the early stages of drug development. Regulatory
specifications should focus on ensuring that accurate and reproducible dosing can be achieved in the clinic and that patient
safety is not compromised. For many tests, it is important that characterization data be acquired, reported, and monitored
to gain an understanding of the DP in the context of characterizing chemical, processing, and packaging sensitivities. As
product development continues, the DP formulation and process, along with the corresponding analytical methods usually undergo
significant changes. The specifications evolve as additional knowledge is gained (e.g., tightening or widening acceptance
criteria, adding tests).
As mentioned in the introduction to this paper, the authors have purposely limited the scope to oral dosage forms with an
emphasis on US filings. The following sections outline proposed specifications for powder-in-bottle (PIB), powder-in-capsule
(PIC), and tablets and capsules used in early development.
Powder-in-bottle and powder-in-capsule specifications.
The PIB formulation is the simplest presentation of a DP for early clinical trials. It involves extemporaneous compounding
of the DS into a solution or suspension for oral administration. The development of PIB requires a solubility assessment of
the DS and selection of a pharmaceutically acceptable vehicle based on the expected clinical dose range. The DP is then manufactured
by weighing the DS into appropriately sized bottles for reconstitution with the chosen vehicle at the clinical site. With
the selection of PIB for clinical trials, the product development resources and timelines can be reduced significantly as
there is no formal formulation development and thus additional analytical testing for stability, content uniformity, and dissolution
are not necessary.
Because only neat DS is weighed into the bottles, the specifications for the release of the DS can be readily used to release
the DP. Thus, the results of the appearance and identification tests used initially for releasing the DS can be used for the
DP as well. Similarly, the initial impurity results for the DP are normally taken from the DS release data and the degradation
products are monitored as part of the recommended DP stability assessment. For PIB assay, the 90.0–110.0% range covers the
typical variability observed in fill weights for this formulation. A stability study of the reconstituted PIB is normally
conducted to support its use at the clinical site within the recommended storage conditions, as well as holding and dosing
Verifying the uniformity of the dosage units is recommended as an internal specification test only. In PIB cases where it
is intended to be weighed at the clinical site, a simple weight check during release testing assures that sufficient DS is
contained in the bottle. This weight check may be omitted from the DP specifications if it is conducted as part of an in-process
control. In cases where the entire contents of the PIB are to be used to make the clinical dosing solution and only a small
amount of material (e.g., 1–2 mg) is provided in the bottle, then a more suitable quantitative analytical technique (e.g.,
a chromatographic method) may be required to verify the accuracy of the dosing concentration.
Similar to PIB, the PIC formulation is another simple presentation of neat DS in a capsule. PIC also provides dosing flexibility
but has the added advantage of allowing easy manufacture of matching placebos. The only major difference in its development
process compared with PIB is that a compatibility study of the DS with the capsule shell should be done to select a suitable
The typical PIC specification tests used in early development are comparable to those used for PIB formulations (see Table III). Specifically, appearance, identification, and assay all rely on the DS release results. Uniformity of PIC dosage units
is performed according to USP General Chapter <905> but it can be omitted as a regulatory specification if it is part of an in-process control. In addition,
disintegration test per USP General Chapter <701> is recommended to ensure that the capsules rupture to allow the release of the drug for absorption.
Table III: Proposed specifications for powder-in-bottle (PIB) and powder-in-capsule (PIC).
Tablet and capsule specifications.
In early development, tablet and capsules for oral administration often employ "fit-for-purpose" formulation approaches designed
to be suitable for wide classes of compounds, with the ultimate goal of facilitating rapid entry into FIH clinical trials.
In the case of tablets and dry fill capsules (DFC), these formulations often employ a dry blend or granulations of a nonreactive
diluent, a disintegrant, and a glidant to aid in processing. As shown in Table IV, standardized specifications are frequently established for capsules and tablets that are used in early development that
can be segregated into the following attributes:
Table IV: Proposed specifications for tablets and capsules.
Description and identification: Visual description of the dosage form and correct identification of the active dose are critical
to the integrity of the clinical study and thus are important attributes to be included in the DP specifications. The appearance
specification should note the external color and shape of the dosage form. A single discerning identification test is normally
sufficient and may be derived from the HPLC test used for assay or impurities based on the comparison of the sample retention
time or photodiode array spectrum to that of a comparator DS batch.