Formulation development of medicinal products - some considerations
Introduction
The information in this blog is a snapshot of some points and aspects to consider during the formulation development phase of medicinal products; the focus is on small molecules for generic applications, and the information contained here is not exhaustive.
Formulation development
When designing medicinal products, the priority should be to ensure that the drug product is of an appropriately defined quality; the drug product must be suitable for its intended use
The properties or characteristics of the drug substance that should be considered during formulation development are:
The solubility and permeability of the drug substance; this has direct bearing on bioavailability. Generic products are required to demonstrate bioequivalence through in vivo bioequivalence studies; this can be waived by scientific justification based on the Biopharmaceutics Classification System (BCS system) which categorises drug substances in one of the four BCS classes:
Class I: high solubility, high permeability
Class II: low solubility, high permeability
Class III: high solubility, low permeability
Class IV: low solubility, low permeability
The ICH guidelines on BCS system have been adopted by the EMA, the FDA, and a number of international markets. The BCS system can be used for justification of waivers for Class I and Class III drug substances.
The BCS system is applicable for medicinal product from clinical development through to commercialisation, is used to justify post-approval changes and generic applications. Regulatory submissions should include in vitro bioequivalence data (such as comparative dissolution profiles). Note that the BCS system is only applicable to solid oral dosage forms, immediate release formulation designed for systemic circulation, ideally the excipients should be identical to the reference medicinal product.
Crystalline and amorphous forms of the drug substance should be described; some drug substances have more than one crystalline form. Different crystalline forms have different solubility profiles because of the different stability of each crystal structure. Unspecified crystalline forms in batches of the final drug product, can result in unintended systemic exposure of the drug substance at the incorrect dose. This can potentially cause serious side effects or lack of efficacy. In Process Control (IPC) tests and confirmatory release tests to detect and monitor crystalline forms should be part of the control and testing strategy. A description of each crystalline form, including techniques for the detection and monitoring is required. Different crystalline forms could be generated during the manufacture of the drug substance, manufacture of the drug product (such as scale ups or minor changes in manufacturing processes) or on storage under certain conditions. Amorphous forms can also present problems if they convert to crystalline forms under certain conditions; amorphous to crystalline conversions can completely change the bioavailability profile of the drug product.
Bioavailability is affected by the particle size; bioavailability increases for smaller sized particles; formulation development studies to define the appropriate particle size range of micronised drug substance should be detailed in the dossier. The release criteria for the drug substance should include the particle size range since it is a critical quality attribute (CQA).
Manufacturing challenges include: the ability of the drug substance to form a homogenous granulate with the excipients, the flow properties of the drug substance, challenges encountered during scale up, temperature sensitivity, limitations of applicable solvent; also, the hygroscopicity, photosensitivity and compatibility of the drug substance with the manufacturing equipment; all of these criteria need to be considered during formulation development.
Organic molecules of the same molecular / structural formula can be manufactured using different synthetic routes. This can give rise to a variety of impurities for which the safety profiles are not always defined; the requirement for additional toxicology studies may need to be considered.
The residual solvent in the final formulation of drug substance should be within the accepted guidelines for the permitted daily exposure. These guidelines should be adhered to, or very strong justification provided when deviating from them.
Elemental impurities should be defined and controlled. Changes in synthetic organic routes used for the manufacture of the drug substance may involve the use of different catalysts with different metals. For all formulations elemental impurities must comply with the ICH guideline; strong justification must be provided when deviating from them.
Formulation considerations for the final drug products:
The proposed route of administration of the drug product may impose limitations on formulation excipients. For parenteral administered products the key formulation considerations and CQAs are sterility, stability, isotonicity, pH and viscosity. Parenteral administrations include intravenous, intramuscular and subcutaneous.
Shelf-life is important with regards to storage, use and distribution. Shelf-life impacts on the customer supply logistics. In addition, other global regions have different environments and require defined drug product (and sometimes drug substance) storage conditions justified by stability data applicable to those regions.
The generic medicinal product formulation should be equivalent in terms of its pharmacokinetic profile to the reference drug product (e.g. area under the concentration time curve (AUC), maximum concentration (cmax)). The justification for the choice of excipients used to prepare a formulation must be demonstrated through comparative dissolutions profiles and excipient compatibility studies during the formulation development. This information must be included in the Pharmaceutical Development section of the dossier.
Excipients are in principle, generally regarded as safe; they are supposed to be inert and inactive; they are in the formulation because they have a specific function, such as, stabilisers, bulking agents, glidants, coating agents and colouring. However, in practice, excipients are not always necessarily safe for all patients. Some excipients are irritants when used in certain pharmaceutical dosage forms; other excipients, such as sugars are unsuitable for diabetics; lactose is unsuitable for those with lactose intolerance. The same is true for gluten intolerance. The EMA have provided a list of the excipients with known action or effect; these excipients must be stated in the Summary of Product Characteristics (SmPC) and the labels and leaflets in the EU and the UK.
Some excipients impart properties that control, modify or delay the release of the drug substance from the drug product; these are modified release formulations.
Colouring agents are included in the formulation to distinguish between different strengths, medicinal products, or branded products or to disguise the colour of the drug product for patient compliance.
Formulation development should include strategies and therefore excipients designed to aid with patient compliance. Flavourings are added to the formulation for palatability; it should be noted that no two suppliers produces the same formulation for a specific flavouring (such as strawberry flavour); the components of flavouring can interact with the active substance or other excipients. Stability studies should be conducted on the final drug product if information on flavourings used in the reference product is not available to the manufacturer. Stability studies should also be conducted when changing suppliers of flavourings. When I was last working with these kinds of marketed products, I noted that it was not really acceptable to change the formulation (particularly flavourings) on certain branded products unless there was a strong justification (at least in the UK).
Excipient can function as preservatives maintaining a bacteriostatic antiseptic environment (such as sodium benzoates); formulation development should consider the use of the sodium salt of benzoates in patients on a low sodium diet; information on sodium benzoate is documented in the EMA guidelines; this should be complied with.
During formulation development, consideration should be given to the onset time of the therapy since this determines the route of administration. For example, intravenous injections have a short onset time (e.g. adrenaline); some tablets and capsules are designed to release over a duration of time (modified release formulations); the onset time of implants can be weeks and months.
The total amount of impurities delivered to the patient over the course of the treatment also requires consideration during the formulation development stage; some medications for long term chronic conditions need to be safe and fit for purpose in terms of the potential long term exposure and accumulation of toxic impurities.
Manufacturers are required to continuously optimise their product and process as they gain more experience. This should lead to manufacturing process improvements and efficiencies, improvements in the stability of the drug product and the reduction of the cost of goods. The cost of goods may affect the availability of or access to medicines for certain socio-economic groups in developed countries or other countries in the developing world.
From a business perspective the final drug product should be designed in a way that maximises the patient populations that can benefit from it for the duration of the treatment.
Patient compliance and other matters
At the end of the day, no matter how well designed the formulated drug product is, patient compliance is ultimately what we want to achieve. Therefore the drug product has to be designed with the patient in mind. The elderly may have difficulty gripping small tablets, large tablets may be challenging for those who have difficulty swallowing since most tablets should not be broken or crushed. Challenges relating to taste and smell for elderly and paediatric populations must be considered during formulation development as opposed to after the product has been marketed.
The appearance of the final drug products is also important from the perspective of carers or health care professionals; oral pharmaceutical dosage forms (tablets and capsules) of different strengths should be distinguishable from one another. They should also be distinguishable from the reference medicinal drug product or a competitor’s medicinal drug products, in terms of the strength of each dosage form; this to avoid mistakes leading to inadvertently administering the incorrect dose due to the similarities in appearances.
There are many other factors to consider during the formulation development of medicinal products. This blog just represents a snapshot. Other examples that I haven’t discussed are, formulations developed to mitigate the abuse of medication, formulations that mitigate non-acceptance of medication (e.g. in psychiatric institutions) and many more. Hope this blog has given you a flavour, I have certainly enjoyed reminding myself of this area since my stint in cell and gene therapy.
Best wishes!!