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Researching excipient grades and sources, as well as screening suppliers and materials, form the basis of programs to mitigate risk.
Although not pharmacologically active, excipients have a direct impact on the performance of formulated drugs, and their quality and purity are equally important to assuring drug product safety. Because excipients are seldom pure compounds, consistent composition is of utmost importance, asserts Irwin Silverstein, president of IBS Consulting in Quality. Conformance to good manufacturing practices (GMP) is also important so that the customer can rely on the excipient manufacturer’s certificate of analysis (CoA). The wide variety of compounds approved for use as excipients in pharmaceutical formulations, however, creates challenges for sourcing.
Pharmaceutical excipients are typically multifunctional chemistries not exclusively designed and formulized for the pharmaceutical industry. As a result, these molecules often originate from other applications and industries and are later utilized within the pharmaceutical industry, according to Jessica Cansler, a senior quality management specialist with BASF. “The initial manufacturing and quality standards of these molecules were focused more to the requirements of the original application areas and industries, not to the manufacturing and quality requirements of the pharma industry,” she says.
It is incumbent upon pharmaceutical manufacturers to understand the full excipient supply chain and have in-depth knowledge about selected suppliers. Recognizing that risk cannot be avoided but must be mitigated is equally important.
The challenges to excipient sourcing vary according to the type of supplier from which the manufacturer is purchasing the material. “Lack of transparency about manufacturing locations and the entire excipient supply chain can provide challenges,” notes Fernanda Onofre, technical service manager for pharma solutions at DuPont Nutrition & Bioscience.
One of the biggest challenges, perhaps, is that many industrial-scale manufacturers make products in multi-application plants, and the volumes produced for the pharma industry are typically only a fraction of the total production, making it difficult to fulfill pharmaceutical industry expectations (GMP, quality, etc.), according to Cansler.
It can also be challenging to trace back the source of the original materials and understand the quality level of the ingredients, as many are ‘tested up’ to monograph standards rather than produced under the appropriate guidelines, she notes. In some cases, it can be difficult for drug manufacturers to find an appropriate excipient manufacturer fulfilling pharma quality expectations, particularly for legacy products; sometimes drug manufacturers must make compromises and accept what is available on the market.
When the excipient is shipped directly from the excipient manufacturer to the drug manufacturer, there should be no misunderstanding as to the source, according to Silverstein. “However,” he observes, “purchasing through a distributer, broker, or trader may raise a challenge, especially where the excipient has been packaged from bulk or repackaged from discrete packages. Tracing the excipient back to the source relies on having confidence in the packager or repackager and receiving the excipient manufacturer’s certificate of analysis.”
Issues in the past, according to Chris Moreton, principal with FinnBrit Consulting, have related to the sourcing by a distributor of excipients from multiple manufacturers without notifying the customer, which had only validated one source of supply, as well as the switching of plant species from which excipient starting materials have been derived, impacting excipient performance in the manufacture of the finished drug product. Distributors, Moreton says, must inform their customers of the manufacturing sites for every delivery of an excipient. The pharmaceutical customer must also confirm that the manufacturing site is on their approved list, adds Silverstein.
The excipient manufacturing process can also provide challenges. “This information is often proprietary, yet drug manufacturers need to understand the raw materials and processes that can impart variability in excipients,” Onofre notes. Regardless of the source, therefore, pharma manufacturers must be willing to invest the time and effort in establishing monitoring systems based on the use of advanced spectroscopic methods, notably for plant-derived excipients, in order to detect unexpected changes in impurity profiles from a single supplier or variations in profiles from different suppliers of the same excipient, according to Moreton. “The difference in levels of concomitant components may impact the performance (manufacture, in-use and/or stability) of the finished pharmaceutical product,” he explains.
Pharma companies should also be sure to conduct supplier qualifications to ascertain the necessary details about excipient suppliers, a process that can provide challenges as well, according to Onofre. “Thorough qualification requires an on-site audit of the excipient supplier, either by the pharma company themselves or by a trusted third party,” she says.
The first step, Onofre adds, is for pharma companies to fully engage with their excipient suppliers, asking for clarity on the excipient’s entire lifecycle. “Even in the instances where information may be proprietary, much can be clarified after a discussion with the supplier,” she comments. Detailed discussions under a confidential disclosure agreement (CDA) can also help in understanding excipient variability and how that can affect the formulation and process. “Such discussions aid in excipient risk management and the formulation of robust drug products,” Onofre states.
Drug makers should also insist that the manufacturing site of the excipient be identified on each lot of the excipient received at the product manufacturing site, Moreton asserts. The International Pharmaceutical Excipients Council (IPEC) CoA guide (1) establishes that the site of manufacture should be disclosed on this document, according to Silverstein. “Ideally, the batch numbering system of the excipient should be site specific, such that a change in the format of the batch number would act as a check for the site of origin,” Moreton adds. Any change in sourcing of the excipient starting material sourcing should also be included as part of the change notification requirements in the quality agreement or in a commercial agreement, with change notification completed per the IPEC significant change guide (2).
On-site audits conducted by the pharma company itself or via a third party, such as EXCiPACT- an international consortium of excipient, chemical, and quality organizations-should be conducted to gather as much information as possible about the supplier and the excipient, Onofre says. If a third-party has been used for the audit, Silverstein adds that it is important to obtain a copy of the audit report to help assure the validity of the audit conclusions concerning production of an excipient in conformance to GMP.
To verify the source of the delivered excipient, whether in the original manufacturer’s container, packaged from bulk, or repackaged, Silverstein comments that the user should verify the authenticity of the excipient label, package, and tamper-evident seal.
Overall, the best approach is to source excipients from excipient manufacturers that clearly commit themselves to the pharmaceutical market and the expectations of the pharmaceutical industry, Cansler asserts. “Usually these excipient manufacturers are appropriately certified to pharmaceutical industry quality standards (e.g., NSF/IPEC/ANSI 363 and/or EXCiPACT),” she says.
When considering different excipient suppliers, there are some warning signs that could indicate potential issues for pharmaceutical manufacturers. For Moreton, a top red flag is not naming the site of manufacture because that precludes physical audits. “Reliance on the distributer’s paper audits or third-party audits for and on behalf of the distributer-and in which the excipient user has no control and is not consulted ahead of time-should not be acceptable,” he says.
The claim that an excipient will meet the United States Pharmacopeia (USP) monograph when tested is a key warning sign for Silverstein. “This language may indicate that the excipient was not produced under ‘appropriate’ GMP as required by USP. Refusal to share non-compendial test methods is another red flag; a good supplier wants to facilitate the proper testing of their excipient, he says.
Pharma manufacturers should also be wary of excipient suppliers that are not aware of current issues, concerns, and trends in the industry they serve, or have to custom-make standard documents, according to Cansler.
Suppliers that are not known in the pharma industry or only have a small presence, as well as those that are unable to provide the required qualification documentation, historical manufacturing trend data under CDA, and support manufacturing location audits raise concerns as well, adds Onofre. Finally, Moreton points to suppliers that are unwilling to enter into quality/change notification agreements as raising red flags.
On the flip side, reliable excipient suppliers exhibit a number of recognizable attributes that should be sought. Most importantly, reliable excipient suppliers are open, albeit under confidential disclosure agreements, according to Moreton. They will allow either customer audits or certification to excipient GMP by a recognized accreditation body or certification scheme, adds Silverstein.
These excipient suppliers recognize the importance of the pharma market to their business profitability and participate in appropriate trade associations and meetings. They also have deep knowledge of their products and can provide technical support for their use in drug formulations and provide products with reliable excipient quality, consistent composition, documentation in order, and an established quality management system at the excipient manufacturing site that complies with pharma excipient GMP requirements and expectations, according to Cansler.
“Highly reputable companies in the pharma market, with consistently good performance and proven experience over the years tend to strive for customer satisfaction and fulfillment through the reliability of their own services and products provided,” Onofre concludes.
In addition to an initial onsite audit, pharma manufacturers should closely evaluate several aspects of excipient supplier performance during the selection process. Identification of the GMPs to which the supplier intends to conform is paramount, according to Silverstein. Standard quality, regulatory, and technical documentation for the excipient should be readily available and complete, coupled with a point of contact to ask questions, Cansler observes. Evidence of the supply chain, quality, and services being offered by the supplier should also be provided, along with in-depth information on the manufacturing locations, notes Onofre.
Access to multiple excipient samples from different campaigns and different raw material lots for qualification is also important, adds Cansler. Excipient suppliers should also sign quality/change notification agreements as part of the overall supply or quality agreement, says Moreton.
Finally, once a supply agreement is in place, Moreton and Silverstein both note that an effective monitoring program at the excipient user site should be implemented to assess the quality and technical characteristics of the excipient.
Excipient grades are typically differentiated based on a certain physical characteristic (e.g., particle size, molecular weight, degree of substitution, or viscosity). A change in grade means a change in that physical characteristic. For some formulations, a change in grade may not impact product performance, but for others it could be detrimental to the finished product, according to Moreton.
“Different grades allow for flexibility in formulation and process design to address various technical challenges in other raw materials or processes used to manufacture the final dosage form,” Onofre explains. She adds that different grades are also critical for optimizing the right process, which can help in cost-saving efforts in areas from wet granulation to direct compression.
If a specified excipient grade is important to the quality attributes of the drug product, then the formulator should demonstrate in what manner the grade is important, adds Silverstein. “In this case, the homogeneity of the excipient lot for that attribute becomes critical to drug product quality, and the excipient manufacturer should be asked about homogeneity within each lot,” he says. In addition, a change in grade most likely would necessitate a revalidation and a notification under the scale-up and post-approval change (SUPAC) rules, Moreton comments.
Choosing the right excipient grade used to be at the personal preference of the formulator, but with quality by design widely implemented today, properly designed and executed design of experiments studies give support to the choice of excipient grade, according to Moreton.
In addition to information provided by excipient suppliers, pharma companies may also conduct grade-differentiating testing when establishing excipient specifications. Talking to the excipient technical experts and sharing the intended use for the excipient and the issues to be addressed in the designed formulation can also help in grade selection, according to Onofre. “Based on the API, the formulation, and the intended process, the excipient supplier can recommend the right excipient and the right grades,” she says.
Assuring receipt of the right excipient grade starts at a minimum with identification testing and testing against the CoA/monograph listed tests and parameters, according to Cansler. Services such as infrared scanning flaps/windows in packages, whenever possible, can help reassure the customer about the accuracy of the product and reliability of the supply, adds Onofre.
It is also important to confirm product labeling and product documentation and compare them with the purchase request, Cansler observes. “The excipient specification at the drug maker should clearly link to the excipient supplier’s specification for the grade, and the purchase order should also clearly delineate the grade as it will appear on the excipient package label and CoA,” Silverstein explains. In some cases, he notes that it may also be necessary to discuss with the excipient manufacturer the recommended test method for the parameter that designates the grade and that the accuracy and precision are sufficient to confirm the grade.
As with all excipients, conducting due diligence when approving an excipient supplier and ensuring quality and supply agreements are in place should result in the right product being sent, according to Onofre. Auditing the site of manufacture and the supply chain are important, agrees Moreton. “Testing of the excipient upon receipt at the customer site is often necessary as well because the grade is critical for the particular application, and formulators would be well-advised to test each lot,” he states. Having a sampling plan based on lot homogeneity is also recommended by Silverstein.
The most important concept to grasp when dealing with the excipient supply is “Caveat emptor: let the buyer beware!” asserts Moreton. “There are no certainties, and there is always a risk that something may go wrong. However, the risk can be reduced to an acceptable level, but only by acquiring as much knowledge as possible about the excipient and using a combination of site and supply chain auditing, quality/change notification agreements, and an effective monitoring program for all excipient deliveries to the site of use,” he states.
In addition to risks associated with manufacturing processes for excipients, there is risk associated with the distribution and supply chain of excipients globally, notes Cansler. She points to risks associated with the intermediate storage and transportation of excipients. “Trending topics including fraud and adulteration within the supply chain are of serious concern. In addition to raw material qualification, appropriately established supply-chain traceability and supply-chain security processes should be in place,” she observes.
The IPEC excipient qualification guide (3), according to Onofre, provides details on recommendations for building a robust supplier qualification process. “Building customer-supplier relationships that are transparent and provide robust information-sharing opportunities is the foundation for success,” she concludes.
1. IPEC, Certificate of Analysis Guide for Pharmaceutical Excipients (2012).
2. IPEC, Significant Change Guide for Pharmaceutical Excipients (3rd revision, 2014).
3. IPEC, Qualification of Excipients for Use in Pharmaceuticals (2008).
Vol. 44, No. 2â¨
When referring to this article, please cite it as C. Challener, “The Search for Transparency in Excipient Sourcing," Pharmaceutical Technology 44 (2) 2020.