In the human health field, injectable medications, ophthalmic preparations, irrigation fluids, dialysis solutions, sutures and ligatures, implants, and certain surgical dressings, as well as the instruments necessary for their use or administration, must be presented in a sterile condition. USP <797> states: “Medications that are required to be sterile include those administered through injection, intravenous infusion (IV), intraocular (injection in the eye) or intrathecal (injection in the spine).”

There is a growing demand for sterilization of small-molecule parenteral products, including heart medications, eye drops, analgesics, and antibiotics, as well as common intravenous solutions such as glucose, potassium, and saline. Many such products are used by medical professionals in hospitals, and to ensure patient safety, the drug products and related instruments and materials are sterilized at manufacture. This ensures there are no microbial contaminants like fungi or bacteria present when the product is used.

In Issue 21 of The Altascientist, we review:

• the benefits of terminal sterilization over aseptic sterilization
• selecting the best terminal sterilization method for your pharmaceutical product
  process validation

Terminal Versus Aseptic Sterilization for Pharmaceutical Products

Generally, regulatory agencies such as the FDA, EMA, among others, prefer terminal sterilization over aseptic, as it provides a high level of sterility assurance.

With terminal sterilization, most drug products are produced by mixing the ingredients to form the bulk drug product solution. The bulk product is filled into a tightly sealed container and the entire container is sterilized.

Terminal sterilization also offers time savings and cost advantages to pharmaceutical companies. Since terminal sterilization takes place after the formulation and filling steps, these initial manufacturing processes can occur in a less rigidly structured environment, which lowers the complexity, increases the speed, and therefore positively impacts the cost of manufacturing.

When terminal sterilization is not an option, aseptic processing is used. Each component (drug, container, closure, etc.) is individually sterilized first, then carefully assembled in a dedicated clean room with a highly controlled environment to make the finished drug product in a manner that prevents contamination. Containers, closures, and filling materials go through their own validated sterilization cycles.

Aseptic processing cannot provide the same quantitative level of sterility assurance as terminal sterilization, but it features several layers of control to minimize the risk of contamination.

Why Terminal Sterilization is the Ideal Choice for Pharmaceutical Products

Terminal sterilization is the preferred method for drug products because sterilization takes place after the product has been filled into the primary packaging, thus severely limiting further opportunities for contamination due to human intervention. The process is reliable, repeatable, and delivers an excellent quality product.

Terminal sterilization is also less complex, less costly, and more easily reproducible than aseptic processing. When conducted by well-trained, knowledgeable experts, sterilization conditions can be adapted to ensure they are appropriate to the drug product in question, and deliver the robust, thorough sterility results expected from this type of process.

In Altasciences’ Grade C suites, we develop injectable drug products and topical ophthalmic preparations that can be terminally sterilized after manufacture. All such drug processing is conducted in our Grade C, cGMP facility, which has been inspected by both the FDA and the European Union Quality Personnel.

Our team will guide you in the selection, method development and validation, and final delivery of fully sterilized product. We have decades of experience as a CDMO, and will ensure the efficient, effective implementation of the most appropriate sterilization method for your drug products.

Explore all issues of The Altascientist in our Resource Center. And don’t forget to subscribe to “The Altascientist: Audiobooks” on Spotify, Apple Podcasts, or wherever you get your audio content. 
 

Under the Controlled Substances Act (CSA) in the United States, drugs that have the potential to be abused are scheduled into one of five Classes or Schedules (CI-V) as controlled substances. The scheduling method makes a distinction between drugs that have abuse potential and are not approved for medical use (i.e., Schedule I) and drugs that are approved for medical use and have abuse potential (Schedules II-V). In the classification, the higher the number of the Schedule, the lower the abuse potential of the drug and the less restrictive the conditions regarding its distribution, storage, and prescribing.

Schedule I, or Class I (CI), drugs are currently restricted to research in the U.S., meaning that they are not approved for medical use, and are deemed at highest risk for abuse.

Recent research on psychedelics and entactogens, both of which are Schedule I, is beginning to demonstrate the potential therapeutic effects of these drugs for various medical indications. Approvals of such drugs for medical or therapeutic use will inevitably result in the rescheduling of these drugs from their current CI status.

In Issue 19 of The Altascientist, we review:

• the regulatory environment and challenges (Drug Enforcement Administration
• the research site requirements associated with the development of Schedule I drugs for therapeutic 
• required preclinical studies of Schedule I drugs
• required clinical studies of Schedule I drugs
• specialized clinical assessments of Schedule I controlled substances
• formulation, manufacturing, and analytical considerations for Schedule I drugs

Preclinical Assessment of Abuse and Dependency Risks of Schedule I Therapeutics

In addition to safety pharmacology and toxicity studies for psychedelic compounds, abuse potential and dependence evaluation is necessary as part of the final proof of concept for preclinical research. Novel psychedelic drugs for medical use will have to undergo rigorous preclinical assessments to determine the abuse and/or dependence risks that they carry. Based on current evidence, the abuse risks posed by psychedelics are no greater or more onerous than those associated with CII opiates or stimulants. The potential therapeutic benefit and the capacity to properly assess and develop mitigation strategies add to the argument in support of further research on such compounds.

Formulation, Manufacturing and Analytical Considerations for Schedule I Therapeutics

Before any research can be conducted, the active pharmaceutical ingredient (API) has to be formulated and produced in an appropriate dosage form. Choosing a manufacturing partner that already has a CI license will reduce timelines, and ensure that the site has the expertise and experience to work with controlled substances. Once a license is in place for a particular substance, it remains in place as long as the site is in good standing with the Drug Enforcement Administration (DEA). Future projects will therefore be able to start quickly, with less logistical challenge.

The storage and handling requirements maintained by a Schedule I-licensed CDMO are rigorous, with CI material stored in a locked vault dedicated for this purpose, with secure, controlled, and limited access. Detailed records for vault access must be maintained and be available for audit.

Safety Considerations and Guidelines for Schedule I Clinical Studies

As with other new chemical entities (NCEs) entering clinical development, novel psychedelics need to be assessed for safety, pharmacokinetics, and efficacy. Given the drug class and associated risks, abuse/dependence evaluation is a central part of any drug development program. Because of the known serious safety concerns around psychedelic substances, extremely thorough, robust, and precise safety monitoring must be an integral part of the protocol, and the recruitment needs to carefully screen subjects for clinical research eligibility.

How Altasciences Can Help With Schedule I Therapeutic Development

For novel CNS-active Schedule I drugs, tremendous benefit can be achieved by engaging with a drug development partner that has Schedule I licenses across every stage of early-phase development. Integration across preclinical, clinical, bioanalytical, and formulation/manufacturing phases ensures complete continuity, data transfer, information sharing, and efficient, active timeline management. At Altasciences’ CNS Center of Excellence, you have a team of well-recognized experts to ensure that your psychedelic research and studies are conducted with the rigor and efficiency needed to meet regulatory requirements, and fulfill your drug development goals.

Explore all issues of The Altascientist in our Resource Center. And don’t forget to subscribe to “The Altascientist: Audiobooks” on Spotify, Apple Podcasts, or wherever you get your audio content.