Excipients are used in most drug products, and their quality, manufacturing processes and test methods are vital to the production of safe, effective therapies
Although industry guidelines, excipient monographs and compendial test methods provide some direction, the sourcing and testing of excipients is an ongoing challenge for drug manufacturers. In pharmaceutical manufacturing, the active pharmaceutical ingredient (API) needs to be formulated into a final dosage form that must fulfil a number of objectives and goals. The dose form must be a convenient method for administration while also ensuring accurate and consistent dosing; it must improve bioavailability and palatability through taste masking, provide a controlled and predictable method of drug dissolution and release, and reduce any side-effects of the medication.
The objective of a successful formulation project is to develop robust formulations that meet the appropriate performance requirements for drug bioequivalence and stability, and that are suitable for validated production at commercial scale. However, such formulations need to be developed in time to meet production and commercialisation deadlines.
A robust formulation is one that is able to accommodate the typical variability seen in API and excipient properties, such as chemical purity and physical characteristics — including particle size and particle shape — and to accommodate any variability in production processes without compromising the manufacture, stability, performance or any other attribute of the product. Any deviations from the parameters set in formulation development can have significant consequences to the patients’ care or well-being.
In the United States, excipients fall under the authority of the FDA, their manufacture and use being governed by the Federal Food, Drug and Cosmetic Act, Subchapter II — Definitions; 21 CFR Chapter 9 §321 (g)(1) and by the United States Pharmacopeia-National Formulary. In Europe, excipient manufacture and use fall under the authority of the EMA, and are governed by the Falsified Medicines Directive (8 June 2011) amended Directive 2001/83/EC Relating to Medicinal Products for Human Use and by the European Pharmacopoeia (EP).
The relevant regulations of these regulatory bodies are designed to ensure that excipient manufacture and use complies with the overall drug specification according to the appropriate pharmacopoeial monograph — if one is available — or the manufacturer’s specification if no monograph is available. Excipients must be manufactured to the appropriate standards of Good Manufacturing Practice (GMP), as well as being fit for purpose in the application, while the manufacturing process itself needs to meet the drug company’s Quality by Design (QbD), Quality Target Product Profile (QTPP), Design of Experiments (DoE) and Design Space and Control Strategy requirements.
Put simply, excipients add properties to the formulation that allow the API to be made into a drug product, and the performance of these excipients may be related to the manufacturability, stability and performance of the drug product during and after its administration. The minimum standard/set of tests required is given in the excipient monograph specification, but there may be other non-monograph characteristics that can affect product performance: such characteristics come under the heading of critical quality attributes (CQAs). In addition, excipient variability can also contribute to product variability.
Quality by Design requires enhanced understanding of the Critical Material Attributes (CMAs) and process parameters that can affect the CQAs of the product; therefore, the effects of excipient variability on CQAs need to be assessed. Such assessments should include a documented risk assessment, the use of prior knowledge and any relevant literature, and the assessment of the potential of these material properties to be CMAs. The effect of excipient variability itself can be assessed by a laboratory services provider by including excipient variability in the DoE using samples provided by the pharmaceutical company. However, it is important to note that the supplier may not be able to provide all the samples the contract laboratory may think it will need. Non-GMP grades of excipient are acceptable for test purposes... but definitely not for clinical use.
Other considerations that need to be taken into account include the use of engineered samples — including sieve fractions — and experimental conditions such as the laboratory humidity, the presence of organic solvents in the samples, the testing of spiked samples to assess the effects of concomitant and/or undesirable components, and the effects of under- and/or over-addition of the excipient to the formulation. In addition, the use of “adjacent” grades of excipient can provide useful information, and this procedure is referred to as “bracketing.” The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) Quality by Design Sampling Guide 2016 provides invaluable information relevant to this area. Ultimately, the purpose of QbD is to ensure that the potential for excipients to affect drug product CQAs are understood and that steps are taken to mitigate that risk.
When running an excipient testing programme, it is essential for a laboratory services provider to verify the material Certificate of Analysis (COA) supplied by the manufacturer. Testing must be done in accordance with the recommendations of relevant compendia (method verification of compendial tests may be required) and, in addition, non-compendial testing may be performed as needed. Important material properties that should be tested include particle size distribution and bulk density following methods validated by the supplier.
According to FDA mandate 21 CFR Part 211 Section 194 (a)(2), “The suitability of all testing methods used shall be verified under actual conditions of use,” whereas USP <1226> Verification of Compendial Procedures provides excellent guidance on how to ensure that test methods comply with FDA regulations. There are, however, exclusions from having to go through compendial method verification procedures, including when a sample is being used to assess a test method for the first time — in this instance, the sample tests the method, rather than the method testing the sample! Method verification need not be done for methods that are already successfully established, as well as basic general procedures such as loss on drying, residue on ignition and pH measurement. Thus, it is important to establish a procedure to evaluate which methods will require verification and those that can be waived, thereby saving time, resources and expense.
The verification requirements themselves will be based on the complexity of the procedure and the test article. Important method parameters are listed in USP <1225> Validation of Compendial Procedures, and include the specificity, accuracy, precision, linearity and range, and the limit of detection (LOD) and limit of quantification (LOQ) of test methods. It is also important to evaluate which parameters are needed to verify the suitability of the method under actual conditions of use.
Case study 1: testing for lead and mercury
In evaluating an inductively coupled plasma mass spectrometry (ICP-MS) procedure to assess lead and mercury content, a sample digestion procedure similar to the current USP <231> Heavy Metals Method III was employed … but resulted in poor recovery of these metals in a spiked sample. The sample preparation method was therefore changed to a closed-vessel microwave digestion procedure with gold added to act as a stabiliser for mercury.
Case study 2: HPLC assay
In a typical HPLC assay, sample preparation involved digestion at 105 °C for 6 hours, the solution to be used “as is” without reconstitution or dilution to an accurate volume. However, the solution evaporated, causing an error in the sample concentration determined for assay calculation. To overcome this, quantitative transfer and dilution to a known volume was performed to ensure an accurate solution concentration was prepared for assay calculation.
Case study 3: quantitative limit test by HPLC
In an established test procedure, a standard sample concentration did not support the product specification, it being 2.5 times higher than required. The laboratory undertaking the analysis therefore chose to evaluate LOQ, linearity and range, and accuracy at both LOQ and the specification as additional parameters.
Case study 4: testing for heavy metals
Microwave digestion of the sample with visual colour determination of a filter is the test procedure for heavy metal content described in the European Pharmacopoeia (EP) 2.4.8 Method G. However, when performing a test, the laboratory was unable to determine microwave parameters that would provide an acceptable test solution and spiked sample solution. The EP heavy metals general chapter does not provide specific parameters because of the variability of microwaves available for testing. In addition, colorimetric determination for a heavy metal limit test is problematic: the spiked sample (the monitor) must be equal to or greater in colour than the standard or reference sample. The sample may also be inhibitory for the detection of lead.
These case studies demonstrate the importance of contract laboratories planning and preparing for excipient testing and evaluating whether test methods will or will not require verification. Laboratory staff must not assume that methods will work as written … and they must be prepared to adapt accordingly.