Putting the Consumer First: Formulating with USP and GMP Standards for Cannabis Products

1. Putting the Consumer First: Formulating with USP and GMP Standards for Cannabis ProductsScott Karolchyk MS, RPh, FIACPMedPharm Holdings3855 Quentin StreetDenver, CO 80239scott@medpharmholdings.comwww.medpharmresearch.com

2. Objectives: • Understand formulation development, from pre-formulation, formulation development, analytical, process development, stability and packaging. • Understanding and applying USP and GMP standards to ensure a quality product as a product free of contamination and reproducibly delivering the therapeutic benefit promised on the label. • Understanding Quality by Design, which emphasizes product and process understanding and process control, based on sound science and quality risk management.

3. Formulation Development: * All products are formulated to specific dosage forms to be effectively delivered to consumers. A process to determine optimal dosage form, composition and manufacturing route. * A good formulation must be reproducible, deliver exact quantities of cannabis, be chemically and physically stable and bioavailable. * Products are researched for condition, dosages of cannabinoids and terpenes and final dosage form based on scientific research. * Quality standards of USP and GMP requirements must be met to ensure the efficacy and safety of the finished product.

4. Pre-Formulation: * Raw material sourcing * Solubility profile (in buffers and non-aqueous solvents) and partition coefficient of the active pharmaceutical ingredient (API) * API compatibility with excipients * Stability of API and factors affecting stability (including heat, light and pH) * Method development and method transfer for particle size of wet and dry particles by laser diffraction (for both API and the formulation) * API characterization by differential scanning calorimetry (DSC), powder x-ray diffraction, Fourier transform infrared (FTIR) spectroscopy and particle morphology by optical microscopy * Formulation and packaging compatibility * Surface tension of aqueous and non-aqueous liquids

5. Formulation: * Particle size (dry, wet and sprays) * Rheology/viscosity * pH * Specific gravity * Informal stability/formulation stress testing (both physical and chemical) * Antimicrobial effectiveness testing (AET) * Formulation container closure compatibility assessment

7. COMPONENT SELECTION * The manufacturer must first attempt to use USP–NF drug substances manufactured in an FDA-registered facility. * The manufacturer shall also first attempt to use inactive components manufactured in an FDA-registered facility. * If components are not obtainable from an FDA-registered facility or if the FDA and/or the providing company cannot document FDA registration, manufacturers shall use their professional judgment in first receiving, storing, or using the components that meet official compendial requirements or are provided by another high-quality source. * If components of compendial quality are not obtainable, components of high quality such as those that are chemically pure, analytical reagent grade, American Chemical Society-certified, or Food Chemicals Codex grade may be used.

8. * When a component is not obtained from an official compendial source or is not obtainable from the sources mentioned above, the component may be obtained from a source deemed acceptable and reliable in the professional judgment of the manufacturer. * When a component is derived from ruminant animals (e.g., bovine, caprine, ovine) the supplier shall provide written assurance that these animals were born, raised, and slaughtered in countries where bovine spongiform encephalopathy (BSE) and scrapie are known not to exist. * The manufacturer shall not use components that are listed by FDA to be withdrawn from the market for public health reasons. * Components shall be stored off the floor, handled and stored to prevent contamination, and rotated so that the oldest stock is used first.

9. USP: United States Pharmacopeia • GMP: Good Manufacturing Practice regulations, derived from USP. • Provide for a systems that assure proper design, monitoring and control of manufacturing processes and facilities. • Includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations and maintaining reliable testing laboratories. • GMP helps to prevent instances of contamination, mix-ups, deviations, failures and errors • Consumer quality = GMP + QbD

10. Master Formulation Record A Master Formulation Record must include at least the following information: Name, strength, and dosage form of the product Physical description of the final product Ingredient identities and amounts, and container–closure systems, including necessary characteristics of components (e.g., particle size, salt form, purity grade, solubility) Complete instructions for preparing the product, including equipment, supplies, and a description of the manufacturing steps Beyond-use date (BUD) assignment and storage requirements Reference source of the BUD assignment and storage requirements Quality control procedures (e.g., pH, visual inspection) Any other information needed to describe the operation and ensure its repeatability (e.g., adjusting pH, temperature)

11. Manufacturing Record Manufacturing Records must include at least the following information: Name, strength, and dosage form of the product Physical description of the final product Master Formulation Record reference for the product Date and time of preparation of the product Assigned internal identification number (e.g., prescription or lot number) Signature or initials of individuals involved in each step Name, vendor or manufacturer, lot number, and expiration date of each ingredient and container–closure system Weight or measurement of each ingredient Documentation of the calculations made to determine and verify quantities and/or concentrations of components, if appropriate Documentation of quality control procedures in accordance with the SOP (e.g., pH, visual inspection) Any deviations from the Master Formulation Record, and any problems or errors experienced during the manufacturing of the product Total quantity prepared BUD assignment and storage requirements Reference source of the BUD assignment and storage requirements

14. Quality by Design: A systemic approach to product and process design and development. Key elements: * Target the product profile: safety, efficacy, value, potency * Determine critical quality attributes (CQAs): controlled * Link raw material attributes and process parameters to CQAs and perform risk assessment: * Develop a design space: science based, process development * Design and implement a control strategy: control of process * Manage product life cycle including continual improvement

15. Systematic approach Predefined objectives * Define Quality Target Product Profile (QTPP) * Identify Critical Quality Attributes (CQA) Product and process understanding * Identify critical material attributes (CMA) and critical process parameters (CPP) * Understand the relationship between CMA/CPP and CQA Process control * Establish appropriate Control Strategy, including justifications Sound science * Science-driven development (scientific literature, prior knowledge, DOEs etc.) Quality risk management * Risk-based development (ICH Q9): Innovation and Continual Improvement

16. QbD Advantages: * Better process understanding * Less batch failure * GMP standards met * Greater active consistency for consumer * Improved yields, lower costs, reduced testing * Continuous improvement over the product life cycle * Process validation easier and consistent, real-time release possible * Consistent production of quality and safe products

17. Design and Development of Product * The physico-chemical and pharmacological properties of the active ingredients determine the critical attributes for product development. * A strong and thorough understanding of the product and its manufacturing process helps in identifying CQAs, which must be controlled. * Use of proper statistical methods such as DOE and proper RA will lead to successful and knowledge-based product development. * QbD is vital in developing science-based approaches in pharmaceutical product development

18. Conclusions: * Formulation development that includes QbD and GMP offers design and optimization of formulations based on research and science, including tablets, capsules, powders, solutions, tinctures, suspensions, other edibles, topical creams and ointments. Innovative formulations follow such as sterile injections, inhalations and nano-emulsified suspensions. * Pre-Formulation including excipient-API compatibility assessment and optimization is vital for product safety and bioavailability. * Proper formulation development leads to a wide range of formulations that are of the highest quality, safety and efficacy for consumer use and need.