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									              Pharmaceutical Development

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



    Training Workshop on Pharmaceutical Development
1 | with a Focus on Paediatric Medicines / 15-19 October 2007
              Pharmaceutical Development


           Pre-Formulation Analytical Studies and
       Impact on API & Formulation Development



Presenter:            Simon Mills

Email:                Simon.n.mills@gsk.com


    Training Workshop on Pharmaceutical Development
2 | with a Focus on Paediatric Medicines / 15-19 October 2007
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

    Training Workshop on Pharmaceutical Development
3 | with a Focus on Paediatric Medicines / 15-19 October 2007
                          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 over a 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




    Training Workshop on Pharmaceutical Development
4 | with a Focus on Paediatric Medicines / 15-19 October 2007
     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.
   The identification 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.



    Training Workshop on Pharmaceutical Development
5 | with a Focus on Paediatric Medicines / 15-19 October 2007
      Impurities: Impact on API Specification
              Threshold                Maximum Daily Dose of API   Threshold Limit Based on
                                            in Drug Product                  TDI

              Reporting                              ≤1g                    0.1%TDI

                                                     >1g                    0.05%TDI



             Identication                           <1mg                 1.0%TDI or 5µg
                                                  1mg-10mg              0.5%TDI or 20 µg
                                                   10mg-2g               0.2%TDI or 2mg

                                                     >2g                    0.1%TDI



             Qualification                          <10mg                1.0%TDI or 50µg

                                                 10mg-100mg             0.5%TDI or 200µg

                                                  100mg-2g               0.2%TDI or 3mg

                                                     >2g                    0.1%TDI


    Training Workshop on Pharmaceutical Development
6 | with a Focus on Paediatric Medicines / 15-19 October 2007
              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 of API 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.

    Training Workshop on Pharmaceutical Development
7 | with a Focus on Paediatric Medicines / 15-19 October 2007
                           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.

      Training Workshop on Pharmaceutical Development
  8 | with a Focus on Paediatric Medicines / 15-19 October 2007
                       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.

        Training Workshop on Pharmaceutical Development
    9 | with a Focus on Paediatric Medicines / 15-19 October 2007
                    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 and
      analysed 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.


     Training Workshop on Pharmaceutical Development
10 | with a Focus on Paediatric Medicines / 15-19 October 2007
               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



     Training Workshop on Pharmaceutical Development
11 | with a Focus on Paediatric Medicines / 15-19 October 2007
               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.


     Training Workshop on Pharmaceutical Development
12 | with a Focus on Paediatric Medicines / 15-19 October 2007
              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.




      Training Workshop on Pharmaceutical Development
 13 | with a Focus on Paediatric Medicines / 15-19 October 2007
            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.

     Training Workshop on Pharmaceutical Development
14 | with a Focus on Paediatric Medicines / 15-19 October 2007
 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


       Training Workshop on Pharmaceutical Development
  15 | with a Focus on Paediatric Medicines / 15-19 October 2007
Predicted Peff in Humans cm/sec x10-4          Dose/solubility ratio             250      500      1000             5000    10000               100000




                                        10           I                                                                     II
                                                     Good solubility                 (dissolution limited)
                                                                                                                           Good permeability,
                                                     and permeability                                                      poor solubility


                                                                                                          (solubility limited absorption)
                                         1



                                                  III                                                          IV
                                                  Good solubility, poor                                        Poor solubility and
                                                  permeability                                                 permeability
                                        0.1


                                 BCS plot with human jejunal permeability and aqueous dose solubility ratio as axes

                                              Training Workshop on Pharmaceutical Development
                                         16 | with a Focus on Paediatric Medicines / 15-19 October 2007
            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.




     Training Workshop on Pharmaceutical Development
17 | with a Focus on Paediatric Medicines / 15-19 October 2007
                  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)



     Training Workshop on Pharmaceutical Development
18 | with a Focus on Paediatric Medicines / 15-19 October 2007
  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.


     Training Workshop on Pharmaceutical Development
19 | with a Focus on Paediatric Medicines / 15-19 October 2007
                                     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?

     Training Workshop on Pharmaceutical Development
20 | with a Focus on Paediatric Medicines / 15-19 October 2007

								
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