agileASO

CMC

Chemistry Manufacturing and Controls Strategy for Individualized ASOs

Individualized oligonucleotides are developed to treat severely debilitating or life-threatening diseases with well-identified single gene mutations, that affect very few individuals in the world (N-of-1).

The requirements for oligonucleotides intended to be used in clinical studies evolve depending on the stage of development, with increasing expectations going towards Phase 3. For early stages of development, which the N-of-1 trials is a special case, the main focus is on safety of the oligonucleotide.

To qualify for N-of-1 trials, the ASO should be:

  • from a well-characterized chemical class for which there is substantial clinical and nonclinical experience;
  • unconjugated, manufactured using conventional methods,
  • with formulations that are a simple aqueous or a lyophilized powder to be reconstituted before administration.

The sponsor should first submit a pre-IND meeting request to discuss the CMC plans with the FDA. FDA expects the CMC section of an initial IND to contain sufficient information to ensure the proper identifity, quality, purity, and strength of the investigational drug product, and to include:

  1. data and information regarding drug substance;
  2. data and information regarding drug product;
  3. the investigational drug immediate packaging and labelling.

The production of a single batch of an investigational drug product for use in an N-of-1 trial should follow the guidelines here.

FDA recommends the same batch of drug product used for nonclinical studies to be used in the N-of-1 treatment.

To support first-in-human exposure, the CMC section should include:

FOR DRUG SUBSTANCE

  1. A Description of the Drug Substance, Including Its Physical and Chemical Characteristics
  2. The Name and Address of the Drug Substance Manufacturer
  3. The General Method of Preparation of the Drug Substance
  4. Characterization
  5. Control of Drug Substance
  6. Stability

FOR DRUG PRODUCT

  1. Components
  2. Quantitative Composition of the Drug Product
  3. Name and Address of the Drug Product Manufacturer
  4. Brief General Description of the Manufacturing and Packaging Procedures for the Product
  5. Certificate of Analysis for the clinical lot
  6. Control of Drug Product
  7. Container Closure System
  8. Stability
  9. Investigational Labels

Manufacturing

The major challenges in CMC development of synthetic oligonucleotides are in controlling of the starting materials, synthesis of the drug substance, and manufacture of the drug product. At the IND stage, general method of preparation of the drug substance should be descried. However, detailed processing parameters such as those in lyophilization, are expected only in late clinical development.

Specifications for starting materials should be provided, however setting of limits for impurities based on criticality assessment is only expected for later development.

Changes introduced during manufacturing process development should be described in terms of potential impact on the quality of oligonucleotide; particular attention should be paid to differences in levels of critical impurities compared to pre-clinical batches.

Characterization

Testing of overall purity is mandatory in an IND submission for individualized ASOs. For both, active substance and finished drug product, suitable state-of-the-art analytical purity methods with stability indicating properties should be developed. However, characterization of product-related impurities may be limited compared to products which are not used for only one patient.

Risk assessments may be sufficient to omit testing of certain impurities as e.g. elemental impurities. However, at agileASO, we would perform full CoA for our clinical batches.

Stability

No full stability program is needed for clinical batches intended for individualized ASO treatments. However for each oligonucleotide intended to be used in a clinical trial some stability data will be required. At later timepoints when more comprehensive data are available alternative approaches based on prior knowledge may be feasible. The overall stability program should be justified sufficiently, citing comparable stability data from marketed ASO formulations.

In case stability data will be generated only for the active substance it needs to be justified that these data are also relevant for the drug product considering the intended storage conditions and the proposed shelf-life.

There are several options combining forced degradation / stress test studies with accelerated stability studies in a stability program for individualized ASOs. Omission of stability studies for active substance and drug product only based on public information available for approved medicinal products, without access to the actual data, is not acceptable to regulatory authorities.

Link to the orgininal FDA guidedance document.

agileASO works with highly experienced GMP-grade oligonucleotide manufacturers in China to provide high quality drug material for ASO human treatments.