Excipient sampling program
IPEA developed scientific data to demonstrate the quality of these excipients in the marketplace. The IPEA sampling protocol
for excipients from commercial packages was intended to obtain unbiased test results for these excipients in the USP-verified
laboratories for comparison against USP–NF requirements. Several excipients from the established manufacturers and the two Asian manufacturers were shipped to the sample
preparation site. The excipient packages provided were single samples; there were no excipients from multiple lots of the
IPEA supervised the preparation of test samples from the commercial packages. Before opening, each package was carefully examined
to confirm the tamper-evident seal was in-place and the appearance of each package was documented, both through written observation
and photography. Each package appeared to have been labeled and sealed by the manufacturer.
Table I: Copovidone NF from Asian manufacturer A.
Each package was opened in an environmentally controlled room (temperature ~70 °F, relative humidity ~35%) and the excipient
was scooped into plastic 1-L bottles. The excipient was surface sampled with a scoop and the first bottle from each package
was kept as retains. The sample bottles were labeled to indicate the excipient compendial name and coded so that their manufacturer
was not disclosed. They were then sealed and sent to the established manufacturers' USP-verified laboratories for compendial
Table II: Povidone USP K-17 from Asian manufacturer A.
On occasion, multiple samples of the same excipient from the same manufacturer were sent to the laboratories to reduce the
likelihood of the analyst identifying the manufacturer of the sample and thus potentially adding bias to the results. Assessment
of the reproducibility of laboratory test results was an added benefit arising from multiple samples. Matching excipient samples
were tested at both established manufacturers' laboratories assessed under the USP-verified program.
Table III: Povidone USP K-17 from Asian manufacturer B.
Results and discussion
The test results confirmed that all excipient produced at the established manufacturers met compendial requirements. Excipients
from the Asian-based manufacturers failed to meet monograph requirements. Specifically, Copovidone NF from Asian manufacturer
A failed to conform to the limit of monomers, content of polymerized vinyl acetate, and nitrogen. This is an indication that
the polymer is deficient in vinyl acetate (see Table I). Povidone USP K-17 from Asian manufacturer A exceeded the limit for
hydrazine and K-value (see Table II). Povidone USP K-17 from Asian manufacturer B exceeded the specified K-value and was high
in ash (residue on ignition) and aldehydes (see Table III). Povidone USP K-12 from Asian manufacturer B exceeded the allowable
limit for aldehydes (see Table IV). Povidone USP K-90 from Asian manufacturer B exceeded the allowable limit for vinyl pyrrolidinone
(see Table V).
Table IV: Povidone USP K-12 from Asian manufacturer B.
Several common excipients from the two Asian manufacturers, Nanhang Industrial and Tianjin Boai NKY International, and the
established producers were evaluated for conformance to the current USP–NF. For the Asian-based manufacturers, the data demonstrated that four of six Povidone lots sampled and one of two Copovidone
lots failed to conform to the monograph. It was noted that two of three lots of Crospovidone tested high for heavy metals
in one laboratory but was found to conform by the other.
Table V: Povidone USP K-90 from Asian manufacturer B.
The results of this study illustrate the importance of adequately qualifying the supplier of components. It is important to
confirm the quality of the excipient using a scientific sampling plan and to perform complete testing until there is adequate
assurance in the reliability of the manufacturers test data. In addition, it is essential to audit the site of manufacture
because no amount of laboratory testing can confirm that the quality system used to produce the excipient meets CGMPs. A site
audit also can provide confidence that the manufacturer has the technical ability to produce the excipient in the commercial
Irwin Silverstein is vice-president and chief operating officer of International Pharmaceutical Excipients Auditing, a subsidiary of the International
Pharmaceutical Excipients Council, tel. 732.463.8710, Irwin.S@verizon.net
1. S. Wolfgang, "Regulatory Perspective on Assuring Excipient Quality," presented at the USP International Excipient Workshop,
Washington, DC, July 2009.
2. A.R. Sibille, "Control of Components and Drug Product Containers and Closures, Subpart E" in Good Manufacturing Practices for Pharmaceuticals, J. Nally, Ed. (Informa Healthcare, 6th ed., 2007), pp. 76–77.