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Whether it’s ibuprofen for a headache or statins for heart conditions, the public assumes the medicines they are taking are safe and effective. Consumers also expect that the research, development, and manufacturing of the drug meets or exceeds the highest standards. While patients are likely not aware of all the substances, both active and inactive, in their medicines, it is incumbent upon the pharmaceutical manufacturer to ensure all ingredients meet the highest standards and regulations.
Whether it’s ibuprofen for a headache or statins for heart conditions, the public assumes the medicines they are taking are safe and effective. Consumers also expect that the research, development, and manufacturing of the drug meets or exceeds the highest standards. While patients are likely not aware of all the substances, both active and inactive, in their medicines, it is incumbent upon the pharmaceutical manufacturer to ensure all ingredients meet the highest standards and regulations.
Most medicines contain both active and non-active substances. The active substances, or active pharmaceutical ingredient (API), are most often delivered with an excipient, a substance “formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred to as "bulking agents", "fillers", or "diluents"), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility.”
Inevitably, these excipients have an effect on the API and overall efficacy of the medicine. In many instances, the effect excipients have on the API are understood and accepted. For example, castor oil, glycols, and micro glycols used as binders have a secondary laxative effect and ethanol has secondary antibacterial effect. API exists under strict regulatory guidelines to ensure minimal impurities, stability control on the shelf, and minimal adverse effects. Excipients, however, are not as closely regulated.
As the demand for novel drugs continues to grow, so does the demand for excipients. Industry analysts forecast the global pharmaceutical excipients market to grow at a CAGR of 6.53% through 2021 to reach $7.7B by 2022. In the high stakes arena of drug manufacturing, pharmaceutical companies cannot risk excipient quality issues. The lack of regulatory controls around excipients, including defining any impurity thresholds, pose a significant risk. To ensure the purity, quality, and safety of any drug substance, it is essential to perform rigorous analytical tests and have a thorough quality assurance plan in place.
Under the US law, an excipient, unlike an active drug substance, has no regulatory status and may not be sold for use in approved drugs unless it can be qualified through one or more of the three U.S. Food and Drug Administration (FDA) approval mechanisms that are available for components used in medications. Reactive impurities in pharmaceutical excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants.
Excipients are an area of significant vulnerability and pharmaceutical manufacturers should be concerned as adverse reactions caused by excipients have been increasing. In fact, during a recent study, a team of investigators found that >90% of all oral medications contain at least one adverse reaction-associated inactive ingredient (ARAII) that can trigger an allergy or intolerance in sensitive patients.
Currently, the International Pharmaceutical Excipients Council (IPEC) has set out to provide guidance on excipient quality and use but it is left to the manufacturer to implement the proper tools and solutions to meet these guidelines. Without adequate regulatory control around excipients, pharmaceutical manufacturers need to have in place their own programs to guarantee excipient quality. While some strategies involve changes in drug product design and process, other approaches involve greater cooperation and collaboration between excipient manufacturers and end users of the excipients.
As there is no current silver bullet, pharmaceutical manufacturers need to determine which substances in the excipient need to be controlled as impurities. In the future, pharma can expect to see excipient regulations. Until then, ensuring the quality of excipients, and appropriate controls in their use, will be key.
Plan for the future
In addition to detailed information on assays, characterization tests, impurities, and equipment, USP-NF General Chapters include in-depth descriptions of good manufacturing practices (GMP) and good distribution practices (GDP) for bulk pharmaceutical excipients. Chapters cover such high level topics as Excipient Performance, Good Manufacturing Practices for Bulk Pharmaceutical Excipients, and Good Distribution Practices for Bulk Pharmaceutical Excipient.
Looking to the future, the The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has excipients on its radar but current guidelines still do not adequately address their efficacy and safety. For example, ICH Q3A applies to drug substances and ICH Q3B applies to drug products, but neither applies to excipients. Clearly, the current state of regulations leaves pharmaceutical companies to create their own testing modalities.
But how should they tackle testing? While under-testing can be disastrous, over-testing can stretch the ROI for the drug manufacturer. Ultimately, establishing practices and solutions that remove human intervention, incorporating comprehensive QA/QC programs focused on managing sophisticated instrumentation, and understanding current guidelines from organizations such as the USP and the ICH should be part of any excipient quality testing plan.
In addition, manufacturers need to look to the future by evaluating emergent technologies and planning for forthcoming regulations. In combination, these actions will help pharmaceutical manufacturers best understand and guarantee the safety of excipients.
The technology-dense environment of manufacturing is well-suited to support excipient quality testing. Specific instrumentation including atomic and molecular spectroscopy, which can scan at a near-infrared range, can assist in testing of excipient materials. Leveraging thermal analysis, chromatography, and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) for trace-elemental testing can help identify impurities in the excipients being used.
These technologies should be leveraged with future regulations in mind. Testing needs to rapidly evolve with the goal of supporting in-line and offline programs. Planning for technology may come at the price of meeting current regulatory guidelines, however. For example, in-line infrared does not currently comply with 21 CFR Part 11. However, keeping this technology at the forefront when planning for long-term excipient quality management should be part of any strategy.
Pharmaceutical manufacturers should also keep Process Analytical Technology (PAT) on their radar. PAT brings together the software, hardware, systems, people, and services that will support the objective of guaranteeing final product quality as it holds the promise to analyze raw and in-line materials. The Process Analytical Technology market is expected to exceed more than US$ 3.30 Billion by 2024 at a CAGR of 13.3%. Industry models that incorporate PAT exist and should be evaluated along with other systems and solutions.
In regards to excipients, QA/QC programs should model those of existing rigorous programs for API. In the QA/QC lab, pharmaceutical manufacturers can benefit from adopting sophisticated instrument-based methods that provide faster and more robust excipient characterization.
Properly resourced, QA/QC will allow for early and often excipient testing, starting when the product first comes through the door. A solid QA/QC program should target:
The QA/QC process needs to also adopt a risk-based approach rather than rely on tactical batch-based testing. Risk-based testing allows the pharmaceutical manufacturer to better identify impurities that will negatively impact a drug’s efficacy.
Pharmaceutical manufacturers have a significant role to play in ensuring excipient quality. Without the structure of regulations, the ultimate arbiter of safety is the pharmaceutical manufacturer. A crystal ball isn’t necessary to see the future. Regulations are coming. Pharmaceutical manufacturers can work with knowledgeable third-party experts to best integrate technologies and solutions that support ICH and USP guidelines and plan for future regulations and solutions such as PAT.
Pharmaceutical manufacturers must also understand the acceptable limits of impurities as outlined by USP 232 to ensure excipient quality. Most pharmaceutical companies aren’t identifying deviations themselves but are sending the process out for contract. Without regulations dictating QA/QC, is undertaking this activity in house really worth the risk?
Integrating equipment, technology, and solutions, and appropriately resourcing QA/QC can be done with the support of an expert partner. This will allow manufacturing functions and talent to remain focused on their end-goal of manufacturing therapies for the market.
An intersection of forthcoming regulations, available and emerging technologies, and a rapidly growing market demand for novel therapies create a perfect storm for critical missteps when working with excipients. While it may seem daunting, pharmaceutical manufacturing must implement and maintain the same rigorous QA/QC practices for excipients as they do for API and other parts of the manufacturing cycle.
Ensuring the identity, strength, and purity of excipients, along with implementing the best analytical methods to achieve this structure, can be accomplished with a strong technology and services partner.
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