Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallink City Hotel Tallinn, Estoni

1. Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallink City Hotel Tallinn, Estonia Date: 15 - 19 October 2007

2. Pharmaceutical Development Pre-Formulation Analytical Studies and Impact on API & Formulation Development Presenter: Simon Mills Email: Simon.n.mills@gsk.com

3. Outline and Objectives of Presentation • Stress Testing of API • Impact of Impurities on API Specifications • Pre-Formulation Investigations • Solid State Degradation & Stability Assessment • Role of Excipients in API Instability • Hydrolysis • Oxidation • Photolysis • API Solubility/Solution-state Stability Assessment • Selection of API & Drug Product Processing Methods • Degradation Issues for Combination Products • Role of API Processing in Product Instability

4. Stress Testing of API • Deliberate forced degradation of API - serves several purposes: • To facilitate development of a ‘stability indicating’ analytical method’, e.g. HPLC • To aid in development of the first API specification • To understand the degradation pathways of the API to facilitate rational product development • To screen for possible formation of potential genotoxins • Initially performed overa short period of time (28-days) using accelerated or stress conditions (so that reactions proceed more rapidly); target ~10% degradation. • Typical conditions for API in solid-state might be: • 80°/75%RH, 60°C/ambient RH, 40°/75%RH, • Light irradiation • Typical conditions for API in solution state might be: • pH 1-9 in buffered media • with peroxide (and/or free radical initiator) • Light irradiation

5. Impurities: Impact on API Specification • The allowable level of any given impurity or impurities that are permitted in API/drug product, without explicit non-clinical safety testing, are defined by ICH Q3A/B. • The amounts of impurities that are allowable are based on the total daily intake of the drug product. • There are separate limits (or thresholds) for reporting, identification and qualification of API impurities. • The reporting threshold is defined as the level that must be reported to regulatory agencies to alert them to the presence of a specified impurity. • Theidentification threshold is defined as the level that requires analytical identification of a specified impurity. • Finally, the qualification threshold is defined as the level where the specified impurity must be subjected to non-clinical toxicological testing to demonstrate safety. Threshold limits are defined as a percentage of the total daily intake (TDI) of the drug product, or in absolute terms as the total allowable amount, whichever is lower.

6. Impurities: Impact on API Specification

7. API solid-state stability study • An early indication of stability challenges for product development: • Accelerated stability challenge but not unrealistically severe and so allows confident extrapolation to provide an indication ofAPI shelf-life • Conditions less extreme than API stress testing: • 40ºC/75%RH open vial • 50ºC closed vial • At least l month storage data; typically 1w, 2w, 4w, 3m (potentially supporting 12m shelf-life at RT) • Light stability (ICH conditions); typically 1w • HPLC analysis • Monitor solid-state form (crystallinity) - DSC, TGA, pXRD • Allows comparison with other versions & forms of same API • Provides a control baseline for excipient compatibility studies • Important to bear in mind that API development is ongoing so API batch used in this early stability study may become unrepresentative of final selected API version & form.

8. API degradation pathways • Hydrolysis and Oxidation are the most common pathways for API degradation in the solid-state and in solution • Photolysis and trace metal catalysis are secondary processes of degradation • Temperature affects each of the above chemical degradation pathways; the rate of degradation increases with temperature. Extrapolation of accelerated temperature data to different temperatures, e.g. proposed storage conditions, is common practice (e.g. using Arrhenius plots) but we must be mindful of the pit-falls – the influence of the various degradation pathways and mechanisms can change with temperature. • It is well understood that pH, particularly extremes, can encourage hydrolysis of API when ionised in aqueous solution. This necessitates buffer control if such a dosage form is required. pH within the micro-environment of a solid oral dosage form can also impact on the stability of the formulation where the API degradation is pH sensitive; through understanding the aqueous pH imparted by typical excipients, a prudent choice can overcome this issue.

9. Excipients:API Interaction • Whereas excipients are usually biologically inactive, the same cannot be said from a chemical perspective. Excipients, and any impurities present, can stabilise and/or destabilise drug products. • Considerations for the formulation scientist: • the chemical structure of the API • the type of delivery system required • the proposed manufacturing process • Initial selection of excipients should be based on: • expert systems; predictive tools • desired delivery characteristics of dosage form • knowledge of potential mechanisms of degradation, e.g. Maillard reaction • There may be a preferred “A list” in your organisation • The objective of drug/excipient compatibility considerations and practical studies is to delineate, as quickly as possible, real and possible interactions between potential formulation excipients and the API. This is an important risk reduction exercise early in formulation development.

10. Excipient Compatibility Studies One option….Binary Mix Compatibility Testing: • In the typical drug/excipient compatibility testing program, binary (1:1 or customised) powder mixes are prepared by triturating API with the individual excipients. • These powder samples, usually with or without added water and occasionally compacted or prepared as slurries, are stored under accelerated conditions andanalysed by stability-indicating methodology, e.g. HPLC. • (The water slurry approach allows the pH of the drug-excipient blend and the role of moisture to be investigated.) • Alternatively, binary samples can be screened using thermal methods, such as DSC/ITC. No need for stability set-downs; hence cycle times and sample consumption are reduced. However, the data obtained are difficult to interpret and may be misleading; false positives and negatives are routinely encountered. Also sensitive to sample preparation.

11. Excipient Compatibility Studies • However, the binary mix approach takes time and resources and….it is well known that the chemical compatibility of an API in a binary mixture may differ completely from a multi-component prototype formulation. • An alternative is to test “prototype” formulations. The amount of API in the blend can be modified according to the anticipated drug-excipient ratio in the final compression blend. • Platform prototypes can be used for specific dosage forms, e.g. DC vs. wet gran tablets • There is better representation of likely formulation chemical and physical stability • However, this is a more complex system to interpret

12. Excipient Compatibility Studies • Drug-excipient interactions can be studied using both approaches in a complementary fashion. The first tier approach is to conduct short-term (1-3m) stability studies using generic prototype formulations under stressed conditions, with binary systems as diagnostic back-up: • Chemical stability measured by chromatographic methods • Physical stability measured by microscopic, particle analysis, in vitro dissolution methods, etc. • The idea is to diagnose any observed incompatibility from the prototype formulation work then hopefully identify the “culprit” excipients from the binary mix data. • Hopefully, a prototype formulation can then be taken forward as a foundation for product development. • Can apply statistical models (e.g. 2n factorial design) to determine the chemical interactions in more complex systems such as prototype formulations, with a view towards establishing which excipients cause incompatibility within a given mixture.

13. Oxidation and the Role of Excipients • Oxidation is broadly defined as a loss of electrons in a system, but it can be restated as an increase in oxygen or a decrease in hydrogen content. • Oxidation always occurs in tandem with reduction; the so-called REDOX reaction couple. • Oxidation reactions can be catalysed heavy metals, light, leading to free radical formation (initiation). Free radicals then react with oxygen to form peroxy radicals, which react with the oxidative substrate to yield further complex radicals (propagation), finally the reaction ceases (termination). • Excipients play a key role in oxidation; either as a primary source of oxidants, trace amounts of metals, or other contaminants. • E.g. Peroxides are a very common impurity in many excipients, particularly polymeric excipients. They are used as initiators in polymerisation reactions, but are difficult to remove.

14. Photolysis and the Role of Excipients • Sunlight (both in the UV and visible regions) may degrade drug products and excipients; and consequently photolabile APIs can raise many formulation (& phototoxicity) issues. • The addition of light absorbing agents is a well known approach to stabilising photolabile products. • Order of effectiveness: pigments > colorants > UV absorbers • However, beware variable performance between grades/sources. e.g. Surface-treated titanium dioxide is inferior to the untreated excipient as an opacifier.

15. Equilibrium Solubility/Solution State Stability Tests • Vital preformulation data to enable decision-making on choice of dosage form, excipients and processing possible and/or required. Typical studies: • pH Solubility profile at pHs 1-10 • Solubility in bio-relevant media (SGF, FeSSIF, FaSSIF) • Solubility in water, normal saline, IV buffers as needed • Poorly soluble drugs may present issues for IV formulation • Balance achieving solubility required vs. acceptable excipients for IV and their compatibility with drug • Solubility in co-solvents, surfactants, lipids as required • Solution Stability: • pH buffers at 25C and 50°C up to 7 days • in bio-relevant media at 37°C up to 24 hours • Light Stability (ICH) • HPLC analysis

16. Dose/solubility ratio 250 500 1000 5000 10000 100000 I Good solubility and permeability II Good permeability, poor solubility 10 (dissolution limited) Predicted Peff in Humans cm/sec x10-4 (solubility limited absorption) 1 III Good solubility, poor permeability IV Poor solubility and permeability 0.1 BCS plot with human jejunal permeability and aqueous dose solubility ratio as axes

17. Role of API Processing in Product Instability • High energy processes (milling, lyophilisation, granulating, roller-compaction, drying) can introduce a degree of amorphicity into otherwise highly crystalline material. This can lead to increased local levels of moisture and increased chemical reactivity in these areas. • With some materials, ball milling causes irregularity, surface faults and imperfections in crystals. The degree of crystal damage can be directly correlated with the energy of the milling process.

18. Selection of Product Processing • Understanding of degradation pathways of API will help to decide on most appropriate process: • For APIs showing severe moisture mediated degradation pathways, choose direct compression or dry granulation • Understanding of physical properties of API will help to decide on most appropriate process: • For APIs showing flow issues, choose a granulation approach (wet or dry granulation) • For APIs showing reduced crystallinity after processing e.g. milling, micronisation, etc., choose wet granulation (presence of water will anneal (crystallise) amorphous API) • For APIs with low melting point, choose an encapsulation approach (high speed rotary presses will generate significant frictional forces that could melt API)

19. Degradation Issues For Combination Products • Objective is to minimise incompatibilities. Degradation pathways of the two APIs could well be different, so a stabilisation strategy for API #1 could destabilise API #2. • In this situation, first intent strategy could be to prepare separate compression blends of each individual API and compress as a bi-layer tablet • Disadvantages: adds complexity and bi-layer rotary presses are expensive • Alternatively, could compress one of the APIs and over-encapsulate this into a capsule product, along with the powder blend from the second API • Disadvantage are that capsule size could be large, it requires specialised encapsulation equipment to fill tablets and blend… process is more complex and expensive • If however, simplicity and cost are significant issues, look to produce a common blend (particle size of APIs should be similar), and by understanding of degradation pathways stabilise the blend and compress or encapsulate.

20. Final thoughts Preformulation studies are an important foundation tool early in the development of both API and drug products. They influence…. • Selection of the drug candidate itself • Selection of formulation components • API & drug product manufacturing processes • Determination of the most appropriate container closure system • Development of analytical methods • Assignment of API retest periods • The synthetic route of the API • Toxicological strategy ANY QUESTIONS PLEASE?