Susan J. Schniepp
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The United States Pharmacopeia (USP) adopted residual solvent requirements last month. The new standard requires companies
to retrospectively assess the level of solvents present in their active pharmaceutical ingredients (APIs), excipients, and
final dosage forms. USP General Chapter <467> Residual Solvents applies to all substances and products that are subject to relevant control of solvents
likely to be present in a substance or produt (1).
Several methods for determining residual solvents included in the chapter are, by USP's own admission, screening procedures
"...useful to identify and quantify residual solvents when information regarding which solvents are likely to be present in
the material is not available" (1). Even though these methods may be appropriate for some materials and products, they will
not be suitable for all monographed items. The need to attain compliance to this standard presents some companies with the
significant challenge of evaluating multiple products, excipients, and APIs while trying to maintain ongoing activities with
stagnant resources.
As a result, many companies have sought assistance from contract laboratories in developing and validating methodology to
evaluate their materials and achieve compliance under the new standard. In these situations (i.e., where every material and
dosage form needs to be evaluated for compliance in a short period of time), it is important for companies to understand what
information their contract laboratory requires so a satisfactory outcome for both parties can be realized.
"The best thing anyone can do in working with a contract lab [in these situations] is to have a general understanding of
what they want accomplished and when they want the work completed by," says John Daniels, vice-president and general manager
for Celsis Analytical Services, a contract laboratory based in Chicacgo. "They should review their process and understand
its impact to the work they are having us perform."
Similar thoughts are expressed by Assad Kazeminy, president and CEO of Irvine Analytical Laboratories (Irvine, CA), who says
he likes to see as much information as possible from the chemistry, manufacturing, and controls and the drug-master-file filings.
This data helps the laboratory "to fully understand the physical and chemical properties of the material we are researching,"
he says.
In a recent Pharmaceutical Technology web seminar on residual solvents, Harry Ingersol, director of chemical services for Celsis, elaborated on some key information
regarding what a contract laboratory needs to know to effectively and expeditiously evaluate material for residual-solvent
compliance.
Providing the best 411
As a general rule, says Ingersol, the information needed by a contract laboratory can be divided into two main categories:
sample information and method-verification information (2). At a minimum, sample information should include the material name,
chemical identity, and solubility profile. The requester also should indicate whether the material is an ingredient in the
final dosage form or is the final dosage form itself. The solubility profile should specify the diluent in which the material
is readily dissolved (e.g., water, dimethylformamide, dimethylsulfoxide).
According to Kazeminy, "Providing a material-safety data sheet along with the sample would greatly aid the contract laboratory.
It would inform us of any special handling requirements as well as indicate the proper storage for the material in question."
Information regarding test preparation (e.g., pulverize, sonicate) is helpful if the material is not completely soluble and
is not provided in a powder or granular form as noted in the text of Chapter <467>, which states, "...the substance under
test needs to be dissolved to release the residual solvent" and "...product may first need to be pulverized into a fine powder..."
(1).
In the case of residual solvents, the customer should also disclose what residual solvents and/or impurities they know to
be present based on their synthesis route, manufacturing process, and developmental work. By being aware of the impurity profile
of the material, the contract laboratory will be in a better position to determine potential interference with methodology.
Disclosing information regarding the sample is only part of the information needed by the contract laboratory for developing
and validating suitable methods. Information regarding current methods used to evaluate the identity, strength, quality, and
purity of the material or dosage form can assist the laboratory in developing appropriate methodology for detecting the presence
of residual solvents.
Customers should disclose global internal requirements associated with method development. Specific company validation parameters
help the contract laboratory develop methods that meet system suitability. At a minimum, information regarding the specificity,
resolution, sensitivity, signal-to-noise ratios, and whether multiple injections of spiked samples are desired for quantitative-test
development.
According to Ingersol, "Other requirements may be necessary for more complex situations such as when the sample is not completely
soluble or the solvent is not one of the Class 1, Class 2 Mix A, or Class 2 Mix B standards" (3). Specific equipment preferences
can also assist the laboratory in developing suitable methods if the customer intends to ultimately use the method as a routine
release procedure in their own quality-control laboratories.
The time required to purchase, install, and qualify new laboratory equipment needs to be addressed in the proposed work schedule
to help ensure that the contract laboratory develops and validates a method that is ultimately compatible with the customer's
equipment.
