ORAL ADMINISTERED DRUGS
RESOURCE CENTER
WHAT ARE ORAL ADMINISTERED DRUGS?
Oral administered drugs continue to be the most preferred drug administration route due to convenience, ease of administration, cost-effectiveness, and high patient compliance. But formulating oral drugs is plagued by specific challenges, such as solubility, bioavailability, membrane permeability, and chemical and enzymatic stability. Some common oral administered drugs include tablets, soft gel capsules, chewables, orally disintegrating tablets, sublingual tablets, capsules, liquids and powders.
Oral Drug Formulation: Three Factors Affect Drug Formulation
As with every drug in development, there are many considerations. During the formulation process, it is important to look at the substances involved, how and when to distribute the drug to the patient, the total dose required, and how the patient will take the drug.
For orally administered drugs, three of the key considerations are solubility, bioavailability, and lipophilicity. These three factors affect the drug formulation, manufacturing, and the intended effect on various levels. It is important to understand how these factors are applied throughout the formulation development and clinical evaluation of an orally administered drug.
Solubility
The substance's ability to be dissolved; typically this is looked at in terms of aqueous solubility. Drugs that are poorly soluble tend to require higher dosage amounts. Typically, solubility issues are the most common hurdles in achieving ideal bioavailability.
Bioavailability
The amount of a substance that enters circulation, when the substance is introduced to the body, and thus is able to have an active effect.
Lipophilicity
The substance’s ability to be dissolved in fats, oils, and lipids. Typically, higher lipophilicity of a drug means greater distribution and binding to targets. Lipophilicity affects the solubility of a drug.
Biopharmaceutics Classification System (BCS)
The Biopharmaceutics Classification System differentiates drugs on the basis of their solubility and permeability. Understanding the classification of the drug substance provides a tool for assessing the potential effects of formulation on the drug’s oral bioavailability.
BCS is defined as:
Class I - high permeability, high solubility
Class II - high permeability, low solubility
Class III - low permeability, high solubility
Class IV - low permeability, low solubility
COMPLEX DRUG FORMULATION AND MANUFACTURING: HIGH POTENT APIs, HORMONES & DEA-CONTROLLED SUBSTANCES
For complex drug formulation and manufacturing, one of the main concerns is the challenge related to bioavailability. Poor solubility of the drug substance is a major challenge in early oral formulation development. When a drug candidate has poor or low solubility, this can have a major impact on the ability of a drug to be absorbed into a patient’s gastrointestinal tract. The development process needs to be focused on improving the rate of dissolution and maintaining the supersaturated solubility state at the site of absorption. If it is not, it can lead to delays in development or even clinical trial failures, adding costs and time to your program.
Improving the bioavailability of a compound requires extensive knowledge and experience in oral solid dose development. Often, pharmaceutical companies may not have the necessary capabilities in-house to address this challenge. They will need to find a competent CDMO partner, like Pii, with the appropriate resources and expertise to tackle this issue and to help bring their drug to market quickly and efficiently.
Highly Potent Compounds (HPAPI)
Highly Potent Active Pharmaceutical Ingredients (HPAPI) can be:
- a novel compound of unknown potency and toxicity, but generally is a pharmacologically active ingredient or intermediate with biological activity at approximately 150μg/kg of body weight or below in humans (therapeutic daily dose at or below 10mg);
- an API or intermediate with an occupational exposure limit (OEL) at or below 10μg/m3 of air as an 8-hour, time-weighted average; sex hormones and certain other steroids; or
- a pharmacologically active ingredient or intermediate with high selectivity with the potential to cause cancer, mutations, developmental defects or reproductive toxicity at low doses.
About 25% of drugs globally are based on highly potent active pharmaceutical ingredients.
Excipients for Formulating Potent Compounds
Excipients play a central role in the drug development process, in the formulation of stable dosage forms, and their administration. An excipient is an inactive substance formulated with the active ingredient (API) of a medication and can be used, for example, to bulk-up formulations that contain small amounts of potent active drug.
DEA-Controlled Substances (Schedule I-V, L1)
The Controlled Substances Act (CSA) places all substances that were in some manner regulated under existing federal law into one of five schedules. This placement is based upon the substance's medical use, potential for abuse, and safety or dependence liability.
Hormones
Hormones are chemical messengers that are secreted directly into the blood, which carries them to organs and tissues of the body to exert their functions. Many hormones act on different aspects of bodily functions and processes, such as development and growth, metabolism, sexual function and reproductive growth and health, cognitive function and mood, and maintenance of body temperature and thirst.
Particle Engineering
Particle engineering involves obtaining the optimal particle size and size distribution, as well as other aspects of the particle's morphology and surface characteristics, used to improve bioavailability and homogeneity for oral dosage drugs and to prepare inhaled therapies.
Active Pharmaceutical Ingredient (API)
The API is the biologically active ingredient(s) that produces intended effects to a patient. The API affects the development, regulation and manufacturing of an oral drug in many ways including: absorption, bioavailability, pharmacologic effect, stability, storage, shipping, and overall handling.
Multiple APIs
A drug that has multiple Active Pharmaceutical Ingredients (APIs) that all participate in producing the intended effects to a patient.
Oral Administered Drug Forms
Liquids
Soft Gel Capsules
Soft Gel Capsules are a growing production field in the pharmaceutical industry. The main difference is that these gelatin capsules are more easily digested and tend to provide faster absorption.
Creating a Soft Gel Capsule that performs as intended is extremely complicated and difficult. However, due to the flexibility of the fill material, Soft Gels can perform well for complex formulations, including DEA-Controlled Substances, Hormones, and Products with Multiple APIs.
Some of the benefits of Soft Gel Capsules include:
- Suspension -- effective distribution of substances that do not dissolve in water
- A higher concentration of drugs can be incorporated
- Ability to avoid cosolvent products (two or more separate substances)
- Improved resistance to drug degradation
- Easy-to-swallow for patients
- Masking of unpleasant taste
- Variety of dosage sizes, shapes, and colors
Liquid Filled Hard Shells (LFHS)
Some of the benefits of Liquid Filled Hard Shells (LFHS) includes:
- Suspension - Effective distribution of substances that do not dissolve in water
- Higher concentrations of drugs can be incorporated
- Improved absorption of drugs
- Ability to avoid cosolvent products (two or more separate substances)
- Improved resistance to drug degradation
- Easy to swallow for patients
- Masking of unpleasant taste
Soft Gel Manufacturing is an Art Form
Tablets & Coated Tablets, Orally Disintegrating and Sublingual Tablets
Tablets come in many shapes and sizes. They include one or more active ingredients combined with excipients (carrier substances that help hold the tablet together) and compressed into tablet form.
Coated tablets (functional and non-functional, solvent and aqueous coated) are often designed to control the release profile of the drug, mask odor and taste, or provide ease of swallowing. The coating layer may also protect the tablet from external influences, such as moisture, brittleness, or bacteria.
Orally Disintegrating Tablets (ODTs) provide an alternative to tablets and capsules, particularly for pediatric patients. ODTs resemble a traditional tablet but have one important difference: they disintegrate rapidly in the mouth and therefore do not need to be swallowed. Taste-masking is often a challenge when designing an ODT.
Capsules
Capsules include medication enclosed in an outer shell. This outer shell is broken down in the digestive tract and the medication is absorbed into the bloodstream and distributed and metabolized in much the same way as medication from a tablet.
Powders
Powders are mixtures of active drugs and excipients. The powder can be packaged into specialized papers or stick-packs.
Chewables
Chewable tablets are an oral dosage form intended to be chewed and then swallowed by the patient rather than swallowed whole. They should be designed to be palatable and be easily chewed and swallowed.
ORAL ADMINISTERED DRUGS TECH TRANSFER
Technology transfer is the transfer of drug product and process knowledge between development and manufacturing or between two manufacturing sites or organizations.
Tech Transfer Process for Oral Drugs
Whether you are producing an oral drug for the first time, increasing production, or performing a full tech transfer, the key to successful manufacturing is a trusted project manager.
For virtual, small- and medium-sized pharmaceutical companies, it is common to partner with an experienced third-party CDMO, such as Pii, to assist in the manufacturing process. This typically happens to offset the complicated process of hiring consultants, purchasing expensive equipment, maintaining a facility, and navigating the FDA Regulatory Process.
The Tech Transfer will include the following functional teams:
- R&D Formulation/Process Development
- Quality Assurance
- Commercial Manufacturing
- Clinical Trial Manufacturing
- Packaging
- Regulatory Affairs
- Analytical R&D
- Analytical QC
- Project Management
- Materials Management and Warehousing
Working with a trustworthy and experienced CDMO like Pii throughout the development, tech transfer, and/or commercialization of Oral Drug Manufacturing is crucial for the product's quick approval, commercial launch success, and, most importantly, the impact on patients' lives.
Commercial Production of Oral Drugs
Sometimes we tend to delink drug development from production, but the purpose for development is commercial production that delivers therapies to patients. Most testing and development have predictive outcomes —determining how the formulation will behave when produced in larger quantities – but this is not perfect. Agility can help sustain the momentum of the drug development process when unexpected challenges arise.
The outcomes desired by pharmaceutical development require stability and reliability. Any disruption to the process is costly and can place the drug product and patients at risk. Add in the complexity and inherent risks associated with aseptic processes, operational practices that deliver agility, stability, and reliability can be the difference between success and failure.
Benefits of Oral Drug Repurposing
Drug repurposing is the process of identifying new therapeutic use(s) for old/existing/available drugs. It is an effective strategy in discovering or developing drug molecules that may have new pharmacological/therapeutic indications.
Thanks to a decreased time during the formulation and regulatory processes, drug repurposing is a growing market and is expected to reach $46 billion market value by 2028.1
PROJECT MANAGEMENT
Project management should be formally educated and certified. At Pii, our project managers receive ongoing professional development that immerses them in the latest best practices that will be applied to customer projects. Working with a Pii project manager who has extensive knowledge of the drug development process, will help expedite your development process, eliminating costly delays in timelines.
Pii project managers are assigned for the lifecycle of the project and serve as agents for the customer with full transparency. Our project managers take the time to fully understand our customers’ programs and their desired outcomes. Communication is key to a successful project, and choosing a CDMO with skilled project managers, is critical.
Pii Project Managers are responsible for:
- Project continuity
- Serving as the customer’s agent
- Facilitating collaboration across functional areas
- Maintaining a strategic view while working to help advance daily outcomes
- Adapting communications and processes to match our customer’s needs
- Updating senior leadership to help drive the project and minimize delays
A great project manager will have the visibility of a senior decision-maker; understand and anticipate FDA requirements, supply chain needs, technology challenges, and plan accordingly for success.
GMP & FDA Regulations for Oral Administered Drugs
The United States FDA sets the Good Manufacturing Process (GMP) standards and enforces the regulations. GMP also provides guidelines for a variety of systems to assure proper design, monitoring, and control of pharmaceutical manufacturing processes and facilities. By following GMP regulations, patients can be assured that the identity, strength, quality, and purity of drug products have been properly produced by a CDMO or manufacturer.
When looking to produce an Orally Administered Drug, it is crucial to follow the GMP guidelines provided by the FDA. Whether you are producing the drug yourself, or more likely, partnering with a GMP-certified CDMO like Pii, it is important to be aware of the guidelines.
When looking at the GMP requirements for your drug development, the best resource is the entity reviewing GMP practices. The FDA keeps its current regulations and practices updated on its website.
Orally Administered Drug Resources
There are many questions and concerns when developing orally administered drugs. Some items can be addressed by looking at your respective governing bodies' drug approval process.
Following, or exceeding, the most up-to-date standards for Orally Administered Drugs is crucial for product approval. Some of the most useful resources include:
MEET Pii’s ORAL DOSE EXPERTS
Dr. Sundeep Sethia, Head of R&D
Sundeep Sethia joined Pii in September 2018 as Senior Director of Pharmaceutical R&D. He has over 15 years of experience in the pharmaceutical industry. Dr. Sethia formerly served as the Director of Pharmaceutical R&D at Amneal Pharmaceuticals. Prior to Amneal, he held positions of increasing responsibility at both Teva and Barr Laboratories in R&D. His expertise is in drug development across a broad range of therapeutic areas and dosage forms. He has a proven track record in drug development and approvals. Dr. Sethia received his Ph.D. in Pharmaceutical Sciences from St. John’s University, NY. He earned a Master’s and a Bachelor’s degree in Biotechnology and Pharmacy, respectively, from Jadavpur University in India. He has co-authored various peer-reviewed scientific publications and patents/patent applications.
Irina Prudnikova, Associate Director, R&D
Irina Prudnikova leads the Analytical R&D team at Pii, responsible for developing chemical test methods, providing support for formulation development, and validating all methods before transferring them to Quality Control. The work of the Analytical R&D team is critical to enabling technology transfer for drug developer customers and streamlining the scaling of drug production. She has experience in supporting the development of a variety of medicines for orphan diseases, oncology, and nervous system disorders. Irina is often the catalyst that helps to transform a development candidate, be it a small or large molecule, into a viable drug formulation that improves, and even saves, the lives of patients. Ms. Prudnikova earned a Master of Science in Chemistry with a focus in Analytical Chemistry from Lomonosov Moscow State University.
Dylan Amig, Head of Manufacturing and Packaging
Dylan Amig is the Head of Manufacturing and Packaging for orals, solids, and non-sterile liquids. Dylan’s leadership has grown in increasing responsibility where he leads and supports strong Manufacturing Science & Technology (MS&T), Manufacturing, and Primary/Secondary Packaging teams. Mr. Amig practically grew up at Pii, starting as a Manufacturing Technician for solid dose production in 1999 while still in high school. Mentored by Pii’s founder and former CEO, Dr. Syed Abidi, Mr. Amig went on to hold a variety of positions at Pii, including Production Supervisor; Senior Supervisor, Manufacturing; and Senior Manager, Manufacturing. Throughout those years, he cemented himself as an integral part of Pii’s growth, successfully working on programs from early stages of development and seeing them through to commercialization – having been an integral part of commercializing over 30 programs.
