ORAL ADMINISTERED DRUGS
RESOURCE CENTER

WHAT ARE ORAL ADMINISTERED DRUGS?

Oral administered drugs are drugs that are taken by a patient through the mouth. Commonly, this is referred to as oral drugs. This form of delivery is the most common, convenient, and typically the safest for patients. During the production of orally administered drugs, there are nearly endless production options to help preserve the formulation, produce the intended effect at the precise time, and improve patients' experience. Some common oral administered drugs include: tablets, soft gel capsules, coated tablets, tablets, and powders.

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Oral Drug Formulation:
Solubility, Bioavailability & Lipophilicity

As with every drug, there are many considerations. During the formulation process it is important to look at the substances involved, how and when to distribute the substances to the patient, 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 terms are applied throughout the formulation and commercialization of an orally administered drug.

Solubility

The substance's ability to be dissolved, typically this is looked at in terms of water and certain gelatins. 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 when the intended effect begins.

Lipophilicity

The substance’s ability to be dissolved in fats, oils, & 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 (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

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Complex Drug Formulation: High Potent APIs, DEA Controlled Substances, & Hormones

For complex drug manufacturing, one of the main concerns are the challenges related to bioavailability. Poor solubility of 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, leading to added costs.

 

Improving the bioavailability of a compound requires extensive knowledge and experience in oral solid dose development. If a company does not have the capabilities in-house to do this successfully, they will need to find a competent partner with the appropriate resources to help bring their drug to market.

Highly Potent Compounds (HPAPI)

A high potency active pharmaceutical ingredient (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/Non-Potent Compounds

Excipients play a central role in the drug development process, in the formulation of stable dosage forms and in their administration. An excipient is an inactive substance formulated alongside the active ingredient (API) of a medication, for the purpose of bulking-up formulations that contain potent active ingredients.

DEA-Controlled Substances (Schedule I-V, L1)

The Controlled Substances Act (CSA) places all substances which 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 solid dosage drugs and to prepare inhaled therapies.

Active Pharmaceutical Ingredient (API)

The API is the biologically active ingredient(s) that produce intended effects to a patient. The API affects the regulation & manufacturing of an oral drug in many ways including: stability, storage, shipping, purification, 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

Soft Gel Capsules

Soft Gel Capsules are a growing production field in the pharmaceutical industry. The main difference is that capsules tend to act faster due to them being more easily digestible. Both products tend to use gelatin as the source of distribution

Creating a Soft Gel Capsule that performs as intended is extremely complicated and difficult. However, due to the flexibility of the substance, Soft Gel 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

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 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

Soft Gel Manufacturing

 

 

Tablets & Coated Tablets, Orally Disentagrating

Tablets come in many shapes and sizes. They include one or more active ingredient, combined with excipients (carrier substances that help hold the tablet together), and pressed into tablet form.

Coated tablets (sugar or film coated) are designed to control the release profile of the drug, masking odor and taste. The coating layer protects the tablet from external influences, such as dampness or bacteria.

Orally disintegrating tablets (ODTs) provide an alternative 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.

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 drug and excipients. The powder is contained inside a folded and sealed piece of special paper.

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.

Small Batch Formulations 3

Oral Administered Drugs Tech Transfer

What is a 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 small and medium size pharmaceutical companies, it is common to partner with a 3rd Party CDMO to assist in the manufacturing process. This typically happens to offset the complicated process of hiring consultants, purchasing expensive equipment, and attempting the FDA Regulatory Process.

The Tech Transfer will include teams such as:

 

Working with a trustworthy team throughout the development, tech transfer, and/or commercialization of Oral Drug Manufacturing is crucial for the product's approval, commercial success, and most importantly the impact on patient's life.

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 has predictive outcomes —determining how the formulation will behave when produced in larger quantities, but it 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 failure and success.

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 with 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 $35 billion market value by 2027.

multiple oral drugs

PROJECT MANAGEMENT

Project management should be formally educated and certified. They often receive ongoing professional development that immerses them in the latest best practices that will be applied to client projects.

Project manager's are formally educated and certified and they receive on-going professional development immersing them in the latest best practices that will be applied to client projects.

Project managers are assigned for the lifecycle of the project and serve as agents for the client with full transparency. It is important for the project manager to fully understand the client's programs and their desired outcomes.

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Project Manager Responsibilities

Project Managers are responsible for:

  • Project Continuity
  • Serves as the Client’s Agent
  • Facilitates Collaboration Across Functional Areas
  • Maintains a Strategic View while Working to Help Advance Daily Outcomes
  • Adapts the CDMO’s Communications for the Client’s Needs
  • Has the Trust of the CDMO’s Senior Leadership to Work for the Client

A great project manager will have the visibility of a senior decision-maker; anticipate FDA needs, supply chain, technology challenges, and plan accordingly for success.

cGMP & FDA Regulations for Oral Administered Drugs

pills glove

cGMP stands for the Current Good Manufacturing Process. The United States FDA sets the cGMP standards and enforces the regulations. cGMP also provides guidelines for a variety of systems to assure proper design, monitoring, and control of pharmaceutical manufacturing processes and facilities. By following the cGMP 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 cGMP guidelines provided by the FDA. Whether you are producing the drug yourself, or more likely, partnering with a cGMP Certified CDMO - it is important to be aware of the guidelines.

When looking at the cGMP Requirements for your drug development, the best resource is the entity reviewing cGMP 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 the Oral Dose Experts

Dr Sundeep Sethia

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 generic 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

Irina 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 clients 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.

Irina earned a Master of Science in Chemistry with a focus in Analytical Chemistry from Lomonosov Moscow State University.