Milasen and Its Successors Paving the Way for Accessible Patient-Customized Oligonucleotide Therapies.

Regulatory Insights from FDA Guidances on Patient-Customized Oligonucleotide Therapies for SDLT represent a significant effort to expedite the commencement of clinical trials for these innovative therapies. 

PART III. Investigational New Drug Application Submissions for Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases: Chemistry, Manufacturing, and Controls Recommendations

The purpose of this FDA guidance is to provide recommendations on the chemistry, manufacturing, and controls (CMC) information that should be included in an IND application submitted by a sponsor-investigator developing an individualized ASO drug for a SDLT disease caused by a unique genetic variant affecting only a small number of individuals (typically 1-2 patients).

The guidance covers individualized unconjugated ASO products manufactured using conventional methods with simple aqueous or lyophilized powder formulations to be reconstituted before administration. These individualized ASO drug should be from a well-characterized chemical class for which there is substantial clinical and nonclinical experience that is either publicly available or to which the sponsor has a right to reference ^[4].

The guidance provides recommendations on CMC information for the IND, including:

The CMC recommendations support FIH exposure but do not address long-term administration, non-SDLT diseases, broader patient populations beyond 1-2, or commercial development requirements.

A. Regulatory considerations

♦ This guidance provides recommendations on satisfying the general CMC requirements for an IND for individualized ASO products within its scope.

♦ For phase 1 clinical trials, investigational drug production is generally exempt from full compliance with 21 CFR 211 cGMP regulations, as described in the guidance "cGMP for Phase 1 Investigational Drugs."

♦ Individualized ASOs may not follow the traditional phase 1-3 clinical development. 

A. Description of the Drug Substance

B. Manufacturer Information

The sponsor must submit the full street address of the drug substance manufacturer, including any contract manufacturers or testing laboratories involved in producing the batches for clinical trials.

Submissions should provide a flow diagram and a comprehensive narrative describing the manufacturing process, including purification steps. The diagram must detail all representative coupling/chain elongation and deprotection steps, along with any purification or impurity reduction processes (e.g., chromatography, lyophilization, solvent removal, desalting). The narrative should outline the chemical structures and configurations, including stereochemical details for starting materials, intermediates, and significant side products. Unique or critical manufacturing steps must be described in detail. While the FDA does not require identification of specific column or equipment model numbers, the IND must include a clear description of process controls that ensure drug substance quality (e.g., impurity clearance). Lastly, a list of materials used in the manufacturing process (starting materials, reagents, solvents, auxiliary materials) should be provided. For sterile drug substances, a description of the sterilization process (e.g., moist or dry heat terminal sterilization, aseptic filtration) is necessary, but validation information is not required.

The sponsor must confirm the chemical structure of the drug substance using various physical and chemical techniques, including nucleotide sequencing, melting temperature (Tm) analysis, and mass spectral analysis. Sequence determination for the ASO drug substance is required; if not included in the initial IND, the sponsor must provide a justification and submit this information in an amendment as soon as possible. Additionally, the sponsor should detail impurities associated with the ASO drug substance, summarizing both actual and potential impurities that may arise during manufacturing, purification, and storage. The FDA recommends categorizing ASO-related impurities according to their structural class or retention times.

The sponsor is also responsible for discussing non-ASO related impurities (such as elemental impurities and residual solvents) and outlining measures for controlling these impurities. The submission must include specifications for these non-ASO impurities or a scientific rationale for why testing is not necessary, such as descriptions of manufacturing steps that remove specific non-ASO impurities. If the clinical batch differs from the nonclinical batch, comparative data (e.g., HPLC chromatograms) demonstrating the quality of both batches—such as homogeneity and purity—should be provided.

1. Specification

This section should present a comprehensive table of specifications for the drug substance batch, detailing tests, acceptance criteria, and references to the analytical procedures used. The sponsor should briefly describe the analytical methods employed. In addition to guidelines for IND submissions, the specifications should include:

♦ Identification of the ASO drug substance, using a combination of methods for verification (e.g., sequencing and molecular weight determination).

♦ Testing for the salt form (if applicable).

♦ A strength assay that reports the full-length drug product content, excluding any P=O impurities.

♦ Quantities of specified impurities and total impurities content.

♦ Residual solvents, moisture content, microbiological testing (e.g., microbial limits and sterility), and bacterial endotoxins.

♦ The certificate of analysis (CoA) for both the proposed clinical batch and any nonclinical batches must also be included.

The sponsor should provide stability information for the synthetic ASO drug substance, including available stability data and the monitoring protocol for ongoing stability. Preliminary data should be presented in a tabular format, along with a description of the container closure system used.

A. Components

The sponsor must provide a comprehensive list of all components utilized in the manufacture of the investigational drug product, including both those intended for the final product and those used in the manufacturing process. For inactive ingredients, quality should be referenced through a compendial monograph (e.g., USP or National Formulary) or include the supplier's Certificate of Analysis (CoA).

A brief summary, preferably in table format, of the individualized ASO drug product composition should be submitted. This summary must detail the amounts of any processing aids used and those removed during the manufacturing process (e.g., Water for Injection).

The full street address of the drug product manufacturer must be provided, including any contract manufacturers, packing facilities, or testing laboratories involved in producing the clinical trial batches.

A flow diagram and a concise written description outlining the manufacturing process should be submitted, detailing any bioburden reduction and sterilization steps (e.g., membrane filtration, terminal sterilization). The description must also specify the air classification of the manufacturing rooms (e.g., Class 100, Grade A, ISO 5).

The IND should include detailed specifications and corresponding test methods. The drug product must be tested for identity, strength, impurities, foreign and particulate matter, sterility, bacterial endotoxins, and any dosage form-specific tests. Acceptance criteria for bacterial endotoxins should be determined based on the proposed maximum dose and administration route, as specified in relevant guidelines.

A description of the container closure system for the individualized ASO drug product should be included, identifying the materials used for each primary packaging component (e.g., USP Type 1 glass vial, bromobutyl rubber stopper). Specifications for each component or the manufacturer's CoA should be provided, along with methods for depyrogenation and sterilization for non-sterile components.

The sponsor must monitor the stability of the individualized ASO drug product in its proposed container under specified storage conditions. A stability protocol for the clinical batch should be included, detailing the stability study, test methods, and any initial stability data in tabular format. If modifications to the drug product are made prior to use (e.g., reconstitution or dilution), guidelines for storage duration to minimize microbial contamination should be outlined, along with justifications for any extended storage conditions.

The sponsor is required to submit a copy of the proposed immediate packaging label as part of the IND submission. This label must prominently feature the statement: “Caution: New Drug — Limited by Federal (or United States) law to investigational use.”

IND sponsors must either claim a categorical exclusion from environmental analysis requirements under 21 CFR 25.30 or 25.31, or provide a comprehensive environmental assessment as outlined in 21 CFR 25.40. For an individualized ASO drug product under an IND, it is recommended that the sponsor include a claim for categorical exclusion under 21 CFR 25.31(e).

TriApex's commitment to advancing these cutting-edge treatments demonstrates our dedication to addressing urgent unmet medical needs. By leveraging our deep expertise in oligonucleotide drug development and aligning our research with regulatory guidelines, we aim to accelerate the translation of these promising therapies from bench to bedside.

We sincerely hope that these tailored oligonucleotide drugs will offer promising treatment options for patients with urgent needs, potentially transforming the landscape of care for those suffering from severe and life-threatening conditions. Our efforts underscore the potential of personalized medicine to provide hope and improved outcomes for individuals facing critical health challenges.