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Susan J. Schniepp is a fellow at Regulatory Compliance Associates, Inc. and a member of Pharmaceutical Technology's Editorial Advisory Board.
Providing the right information upfront may ease new requirements to assess solvent levels.
The United States Pharmacopeia (USP) is scheduled to adopt residual solvent requirements this month. This 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).
Susan J. Schniepp
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."
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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.
Getting to know the regs
Understanding the regulations and their impact on company-specific products, policies, and procedures is another necessary requirement to ensure a smooth and productive relationship between the contract laboratory and the potential customer. Many companies have product commitments to regulatory authorities. Communicating these obligations upfront via a confidentiality agreement will help alleviate misunderstanding and frustration as the project moves forward.
The material details and scope of work should be documented in a project initiation form. Many contract laboratories have a standardized form for potential customers to complete before they start work. In some cases, the forms can be downloaded directly from the laboratory's website and can help expedite turnaround time.
Using the standardized forms provided by the contract laboratory will help increase efficiency as well. The laboratory is familiar with these forms and can readily locate and interpret the work that is being contracted. There are also employees available at these laboratories to assist clients in completing these forms to ensure completeness and accuracy. This helps open up the communication lines early in the process and establishes a solid foundation for the successful completion of the project.
Preparing for more
As regulations continue to evolve, companies are more likely going to be required to retrospectively review their product portfolio. For example, the European Medicines Agency guideline on specification limits for residues of metal catalysts or metal reagents scheduled to come into effect this September aims to "recommend maximum acceptable concentration limits for the residues of metal catalysts or metal reagents that may be present in pharmaceutical substances or in drug products" (3). Achieving compliance to this standard may require companies to seek assistance from contract laboratories because, as with residual solvents, the assessment requires an evaluation of excipients, APIs, and final product.
Being prepared to provide complete documentation regarding a project and understanding the regulatory impact of compliance requirements is critical for establishing and maintaining a productive relationship with a contract laboratory. This groundwork is especially important as industry faces more of these new and comprehensive regulations.
Susan J. Schniepp is a guest writer this month while columnist Jim Miller is on vacation. A member of Pharmaceutical Technology's Editorial Advisory Board, Schniepp is a pharmaceutical consulstant at Schniepp & Associates in Boxborough, MA, firstname.lastname@example.org
1. USP, General Chapter <467> Residual Solvents (Rockville, MD, 2008).
2. H. Ingersol, "Beyond Theory: How to Implement Changes to USP Chapter <467> Residual Solvents," web seminar presentation hosted by Pharmaceutical Technology and sponsored by Celsis, Apr. 22, 2008, available at pharmtech.com.
3. EMEA, Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents (London, Feb. 2008).