Pharmaceutical Development with Focus on Paediatric Formulations

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					Pharmaceutical Development with Focus on
        Paediatric Formulations


           WHO/FIP Training Workshop
                                  Hyatt Regency Hotel

                                   Sahar Airport Road

                               Andheri East, Mumbai, India

                               28 April 2008 – 2 May 2008



1|   Dr. Pogány | April 2008
Pharmaceutical Development with Focus on
        Paediatric Formulations

Presented by:

Name: Dr. János Pogány

Contact details:
pogany.janos@chello.hu




2|   Dr. Pogány | April 2008
                               Outline of presentation
Regulatory issues in development pharmaceutics
      Differences between the pharmaceutical development process
       of innovator and multisource (generic) FPPs

      WHO draft guideline on Pharmaceutical Development
           – Initial quality risk assessment
           – Multisource pharmaceutical product development
           – Pharmaceutical manufacturing process development

      Conclusions

3|   Dr. Pogány | April 2008
Pharmaceutical product target profile (PPTP)
 Innovator FPP                   Generic FPP

  Bioavailability and dosage     Bioavailability,
   regimen are established         pharmaceutical form and
   during Phase I-II clinical      strength are known. PPTF is
   trials                          the innovator FPP.

  PPTP will be achieved          PPTP is achieved through
   through clinical studies to     demonstration of
   ensure the required quality     pharmaceutical equivalence
   focused on safety and           and bioequivalence
   efficacy

 4|   Dr. Pogány | April 2008
Differences in pharmaceutical development
Innovator FPP                      Generic FPP
 Composition                       Qualitative composition of
                                     innovator FPP is known from
                                     regulatory websites (EMEA and
                                     US-FDA)
 Manufacturing method should be    Manufacturing method is
  selected                           determined by the composition and
                                     the dosage form of the innovator
                                     FPP
 Container closures system         Qualitative characteristics of
  (delivery device) of the FPP       primary packing materials are
  should be experimentally           known.
  developed

5|   Dr. Pogány | April 2008
Differences in pharmaceutical development
Innovator FPP                         Generic FPP
 API specifications are developed     API specifications are typically
  and contain the user requirements     available but user requirements
  for manufacturability                 should be established
                                        experimentally
 Shelf life and special storage
  conditions come from research        Target values are known




6|   Dr. Pogány | April 2008
            Generic pharmaceutical development
                                     Qualification Stage                  Validation Stage               C
                                                                                                         O
Key elements                D&C         Installation   Operation      Prospective   Concurrent
                                                                                                         N
                                                                                                         T
Facilities and              Engineering phase              Manufacturing Start-Up
                                                                                                         I
                                                                                                         N
Equipment                                                                                                U
                                                                                                         O
                                                                                                         U
                       (Validation Protocols)          (Batch Records and Validation documentation)      S

                                                                                                         I
                                                                                                         M
Target profile              Design (laboratory)            Scale-Up (pilot plant)   Production           P
(Bench marking              (Critical Q attributes,        (Critical process        (Final batch size,   R
                                                                                                         O
of innovator                formula screening,             parameters, primary      process              V
product)                    process design)                batches)                 controlled)          E
                                                                                                         M
                                                                                                         E
                                Generic product and process development                                  N
                                                                                                         T



   7|      Dr. Pogány | April 2008
                               Development strategy
INTERCHANGEABILITY (IC) OF GENERIC FPPs =
THERAPEUTICAL EQUIVALENCE WITH A
COMPARATOR (REFERENCE) FPP =
PHARMACEUTICAL EQUIVALENCE (PE) +
BIOEQUIVALENCE (BE) IC = PE + BE
The best strategy for generic product development is to
use the same qualitative and quantitative formula as that
of the comparator (reference/innovator) FPP

8|   Dr. Pogány | April 2008
WHO draft guidance on Pharmaceutical Development

       Section 3.2 (3.2.P.2 in CTD) in the „Guideline on
        Submission of Documentation for Prequalification of
        Multi-source (Generic) Finished Pharmaceutical Products
        (FPPs) Used in the Treatment of HIV/AIDS, Malaria and
        Tuberculosis” contains a section 3.2 Pharmaceutical
        Development but the contents do not provide sufficient
        details either for the Applicants or the Assessors.

       The ICH Q8 guideline describes a development process
        with new FPPs in mind and only partially applies to generic
        FPPs.



 9|   Dr. Pogány | April 2008
Pharmaceutical Development with Focus on
        Paediatric formulations

                         WHO working document QAS/07….

         DRAFT PHARMACEUTICAL DEVELOPMENT
              FOR MULTISOURCE (GENERIC)
              PHARMACEUTICAL PRODUCTS


       INITIAL QUALITY-RISK ASSESSMENT


10 |   Dr. Pogány | April 2008
Initial quality risk assessment - Desk research
                                   Nevirapine is lipophilic (partition
                                    coefficient 83) and is essentially
                                    nonionized at physiologic pH.
                                   As a weak base (pKa 2.8), Nevirapine is
                                    showing increased solubility at acidic pH
                                    values.
                                  Source: Merck Index

                                   Aqueous solubility (anhydrate) (90μg/ml
                                     at 25°C).

                                   Nevirapine is highly stable

 11 |   Dr. Pogány | April 2008
       Viramune 50 mg/5 ml oral suspension
 Oral suspension containing 10 mg/ml of nevirapine as 10.35 mg/ml Nevirapine
  Hemihydrate as the API.
 Excipients: Carbomer, methyl parahydroxybenzoate, propyl parahydroxybenzoate,
  sorbitol, sucrose, polysorbate 80, sodium hydroxide and purified water. (FDA excipient
  list: Carbomer 934P).
 Shelf life: 3 years
  The product should be used within 2 months of opening.
 No special precautions for storage
 Nature and contents of container White HDPE bottle with two piece child-resistant
  closure (outer shell white HDPE, inner shell natural polypropylene) with LDPE foam
  liner. Each bottle contains 240 ml of oral suspension.
  Clear polypropylene 5-ml dispensing syringe (0.2 ml graduations) with silicone rubber
  piston seal.
  Clear low density polyethylene bottle-syringe adapter.
  http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf
  http://www.fda.gov/cder/ogd/rld/20933s3.PDF
 Nevirapine oral suspension monograph (PhInt) has reached a draft stage



12 |   Dr. Pogány | April 2008
       Viramune 50 mg/5 ml oral suspension
 The HDPE bottle material is inert and was shown to be compatible with
  the active substance and other ingredients of the formulation.
 The levels of preservatives have been correlated with antimicrobial
  effectiveness tested according to PhEur
 Acceptable data demonstrating the precision and accuracy of the dosing
  syringe were provided.
 Synthesis impurities are not degradants and not part of FPP specifications
 The method of preparation of the oral suspension is standard for this form
  and has been adequately described. Validation data presented on three
  production batches manufactured using three different lots of nevirapine
  anhydrous (?) were adequate to demonstrate that the process is under
  control and ensures both batch-to-batch reproducibility and compliance
  with standard specifications. Tests at release are standard and ensure
  reproducible clinical performance of the product.

13 |   Dr. Pogány | April 2008
       Viramune 50 mg/5 ml oral suspension
 Stability data up to 18 months for the newly recapped oral suspension and
  24 months with the old pulpboard liner confirmed the physical and
  chemical stability of the oral suspension and the antimicrobial efficacy of
  the preservative. These results support a shelf life of 24 months. Long-
  term stability data will be submitted on ongoing basis.

 An in-use stability study designed to mimic the delivery of 2 ml dose,
  which represents one of the lowest projected doses, twice a day, using the
  delivery device intended for marketing has been performed.

 An additional study is presented on the stability of the product exposed to
  freeze-thaw conditions. On the basis of results from both studies, the
  claimed in-use shelf life of 60 days with no special storage precautions is
  supported.


14 |   Dr. Pogány | April 2008
                Viramune - Clinical information
 Nevirapine was readily absorbed (> 90 %) after oral administration in healthy
  volunteers and in adults with HIV-1 infection.

 A 3-way crossover study compared the bioavailability from three
  production/commercial scale batches with varying dissolution profiles. All three
  batches were bioequivalent with respect to systemic exposure (AUC). The
  significantly different values for Cmax and tmax were considered not to be
  clinically relevant.

 In studies 1100.1231 and 1100.896 in which the suspension was administered
  directly using a syringe, it was demonstrated that the suspension and tablet
  formulations were comparably bioavailable with respect to extent of absorption.
  In study 1100.1213 the suspension was administered in a dosing cup without
  rinsing. The suspension intended for marketing was bioequivalent to the
  suspension used during clinical trials but was not bioequivalent to the marketed
  tablets. This could be attributed to incomplete dosing of the two suspensions
  since there was about 13 % of the dose remaining in the cup.

15 |   Dr. Pogány | April 2008
               Viramune - Clinical information
 It has been later determined in a single dose study in 9 patients aged between 9
  months and 14 years administered after an overnight fast (3 patients per dose
  level equivalent to 7.5 mg/m², 30.0 mg/m² and 120.0 mg/m²).

 Based on adult experience, a comparable lead-in period of two weeks was
  suggested for pediatric population. A 4 mg/kg dose is proposed for all children
  regardless the age. Although no particular study has been performed to find the
  optimal lead-in dose, this dose was considered acceptable considering the
  enzyme induction to achieve initial antiretroviral activity.

The final recommended doses for the different ages are therefore the following:

 Patients from 2 months to 8 years, 4 mg/kg once daily for 2 weeks followed by 7
  mg/kg bid

 Patients from 8 years to 16 years are 4 mg/kg once daily followed by 4-mg/kg
  bids.


16 |   Dr. Pogány | April 2008
Initial quality risk assessment - Experience
                                 Milling          Wetting              Wet
d              Dissolution
                                  API
                                         Weighing
                                                   API
                                                            Vehicle
                                                                      milling
                                                                                Filling   Packing


e              Assay
               Degradation

l              Content
               uniformity
               Stability
e               physical
                microbial
t              pH

e
        Not critical to Q                   Potentially                      Critical to Q
                                            critical to Q                   Control strategy
                                            Monitoring
                                              strategy

17 |   Dr. Pogány | April 2008
Pharmaceutical Development with Focus on
        Paediatric formulations

                         WHO working document QAS/07….

         DRAFT PHARMACEUTICAL DEVELOPMENT
              FOR MULTISOURCE (GENERIC)
              PHARMACEUTICAL PRODUCTS


       DEVELOPMENT and VERIFICATION of
           ANALYTICAL METHODS

18 |   Dr. Pogány | April 2008
          Product-specific analytical methods
 Analytical test methods help identify the acceptable ranges of
  critical quality attributes [CQA(s)] and critical process
  parameters [CPP(s)] of laboratory and pilot-scale product and
  process development experiments – ICH guidelines with non-
  compendial APIs and FPPs
 In-house reference standards should be established at the start
  of the development process and they should be qualified against
  compendial reference standards – Special issues with first-time
  generic FPPs
 A discriminatory dissolution method should be developed and
  validated at an early stage

19 |   Dr. Pogány | April 2008
       Dissolution (and bioequivalence) batch
                     Innovator FPP                 Generic FPP
                   Dissolution test            Production batch, or
                      3 batches                NLT 1/10 of final size
                     Select a batch showing
                    intermediate dissolution

                Reference product                  Test product


                                 Dissolution profile


20 |   Dr. Pogány | April 2008
                         Role of dissolution testing

 To determine if a dissolution method can discriminate product
  changes, the method must be challenged.
 Dissolution profile testing for solid oral dosage forms supports
  pharmaceutical development and regulatory decisions
       –    Formulation screening and dissolution equivalence
       –    In vitro bioequivalence test method
       –    Waiver for in vivo bioequivalence studies
       –    Stability studies
       –    Variations to the prequalified dossier
 It is primarily a QC tool to verify process and product
  consistency (if an in vitro-in vivo correlation (IVIVC) has not been
  established)

21 |   Dr. Pogány | April 2008
              Discriminatory power – 2FDC product

                                        Experiment A                                                        Experiment B

                                                                                                  120
                              120
       Dissolution (%)




                                                                                Dissolution (%)
                                                                                                  100
                              100

                                                                                                  80
                               80

                               60                                                                 60


                               40                                                                 40


                               20                                                                 20

                                0                                                                  0
                                    0    10   20    30   40      50   60   70                           0    10   20    30    40     50   60   70


                                    Withdrawal time in minutes                                          Withdrawal time in minutes




22 |                     Dr. Pogány | April 2008
                Discriminatory power– 2FDC product

                                    Experiment C                                                           Experiment D

                         120                                                                     120




                                                                               Dissolution (%)
       Dissolution (%)




                         100                                                                     100


                         80                                                                      80

                         60                                                                      60

                         40                                                                      40

                         20                                                                      20

                          0                                                                       0
                               0      10     20    30    40     50   60   70
                                                                                                       0      10    20   30    40       50   60   70

                                   Withdrawal time in minutes                                              Withdrawal time in minutes




23 |              Dr. Pogány | April 2008
       Discriminatory power – 2FDC product

                                       All 4 products
                                     All 4 experiments,                                                              All experiments,
                                                                                                                    All 4 4 products
                                       API: Isoniazid                                                               API: Ethambutol
                                                                                                                           API 2
                                           API 1
                           120                                                                            120



                           100                                                                            100
                                                                                    A




                                                                                        Dissolution (%)
                                                                                                          80
         Dissolution (%)




                           80

                                                                         B,C
                           60                                                                             60



                           40
                                                                                    D                     40



                           20                                                                             20



                            0                                                                              0
                                 0     10     20    30     40     50     60    70                               0    10    20     30     40     50     60   70

                                            Withdrawal time in minutes                                                    Withdrawal time in minutes




24 |   Dr. Pogány | April 2008
Establishment of dissolution specifications
 The in vitro specifications for generic products should be
  established based on a dissolution profile.
 Dissolution specifications should be based on acceptable
  clinical, bioavailability, and/or bioequivalence batches.
 In the case of a generic drug product, the dissolution
  specifications are generally the same as the reference listed
  drug.
 Once a dissolution specification is set, the drug product should
  comply with that specification throughout its shelf life.



25 |   Dr. Pogány | April 2008
                 WHO guidelines on dissolution
 Annex 7 - Multisource (generic) pharmaceutical products:
  guidelines on registration requirements to establish
  interchangeability, in WHO TRS, No. 937, 2006
 Annex 8 - Proposal to waive in vivo bioequivalence
  requirements for WHO Model List of Essential Medicines
  immediate-release, solid oral dosage forms (ibid)
 Annex 11 - Guidance on the selection of comparator
  pharmaceutical products for equivalence assessment of
  interchangeable multisource (generic) products, in WHO
  Technical Report Series, No. 902, 2002
 Annex 5 - Guidelines for registration of fixed-dose combination
  medicinal products, in WHO TRS, No. 929, 2005

26 |   Dr. Pogány | April 2008
Pharmaceutical Development with Focus on
        Paediatric formulations

                       WHO working document QAS/07….

       DRAFT PHARMACEUTICAL DEVELOPMENT
            FOR MULTISOURCE (GENERIC)
            PHARMACEUTICAL PRODUCTS


                        PRODUCT DEVELOPMENT

27 |   Dr. Pogány | April 2008
       Innovator suspension – target profile (1)
Each ml of oral suspension contains:
10 mg of nevirapine (as hemihydrate)
Carbomer 934P
Methyl parahydroxybenzoate (E218)
Propyl parahydroxybenzoate (E216)
Sorbitol
Sucrose
Polysorbate 80
Sodium hydroxide (for pH-adjustment)
Purified water

       http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/H-183-PI-en.pdf


28 |    Dr. Pogány | April 2008
 Light microscopic images of a suspension
                Stable suspension                           Aggregated suspension




 Moorthaemer and Sprakel: Improving the stability of a suspension, Pharm. Techn. Europe, Feb. 2006


29 |   Dr. Pogány | April 2008
           Adsorption isotherm of a surfactant




 Moorthaemer and Sprakel: Improving the stability of a suspension, Pharm. Techn. Europe, Feb. 2006


30 |   Dr. Pogány | April 2008
                             Surfactant concentration
                                                     Three formulations containing 50
                                                     mg, 25 mg of sodium laurylsulfate
                                                     (SLS) and no SLS, were evaluated
                                                     in the dissolution medium. The
                                                     dissolution profile of the
                                                     formulation containing no SLS
                                                     showed incomplete solubilization
                                                     of celecoxib (CEL), a poorly soluble
                                                     API. Addition of even 25 mg of
                                                     SLS into the formulation drastically
                                                     improved the dissolution of CEL.
Source: Bansal, A. K.: Criticality of functional excipients … Pharmaceutical Technology Europe, June 2006



 31 |   Dr. Pogány | April 2008
       Innovator suspension – target profile (2)
 Sample confirmation
        –    Batch numbers
        –    Shelf life: 3 years and within 2 months of opening.
        –    Storage instructions: No special precautions for storage
        –    Container and closure system: as per EPAR

 QC analysis (hypothetical figures)
        –    Assay: 99.9% of labelled amount (LA)
        –    Methylparaben (HPLC): 0.18% w/v
        –    Propylparaben (HPLC): 0.02% w/v
        –    Total related substances: 0.03%
        –    Specific gravity (at 25oC): 1.150
        –    Viscosity (at 25oC): 1,150 cPs
        –    pH: 5.80



32 |    Dr. Pogány | April 2008
   Innovator suspension – target profile (3)
                                 The composition suggests that:

                                  Sucrose and sorbitol are used to
                                   adjust the density of the medium

                                  Carbomer 934P is used to adjust
                                   viscosity

                                  Polysorbate 80 is a wetting agent

                                  Sodium hydroxide is used to adjust
                                   the pH to 5.8




33 |   Dr. Pogány | April 2008
         Innovator product – target profile (4)
       Time (minutes)             % API dissolved           Dissolution profile (% LA)
                                  (hypothetical figures)
               5                           27               Apparatus: USP II (paddle,
              10                           42                25rpm)
              15                           55               Medium: 0.1N HCl
              20                           65
                                                            Volume: 900ml
              30                           76
                                                            http://www.accessdata.fda.gov/scripts/cder/dis
                                                             solution/dsp_SearchResults_Dissolutions.cfm
              45                           88
              60                           92


34 |    Dr. Pogány | April 2008
         Innovator product – target profile (5)
                                  % API dissolved          % API dissolved            % API dissolved
       Time (minutes)             (hypothetical figures)   (hypothetical figures)     (hypothetical figures)

                                  pH 1.2 buffer               pH 4.5 buffer              pH 6.8 buffer
               5                         27                        15                         22
              10                             42                       25                         27
              15                             55                       36                         35
              20                             65                       42                         42
              30                             76                       48                         49
              45                             88                       49                         57
              60                             92                       49                         65
              90                            100                       50                         76
Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900ml – Different speeds to be investigated


35 |    Dr. Pogány | April 2008
       Pharmaceutical development protocol
 API experiments
        – Solubility at 37 oC
        – Particle size distribution
        – Density

 Formulation experiments
        – Screening laboratory batches with different proportions of excipients to match
          innovator dissolution
        – Stress testing of the selected composition
        – Compatibility with excipients
        – Antimicrobial effectiveness test according to PhEur

 Packing materials
        – Dimensions and tolerances of packing components
        – Precision and accuracy of the dosing syringe


36 |   Dr. Pogány | April 2008
   Product-specific physical API properties

       Introduction of
                                                                             Physical
       the API starting               Production        Isolation and     processing and
        materials into             of intermediate(s)    purification       packaging
           process

   PhInt specifications + residual solvents from APIMF.
   Product-specific physical properties depend on crystallization and subsequent
   physical processing. Density and particle size distribution of Nevirapine Hemihydrate
   are critical quality attributes of the API. Acceptance criteria are established by
   measurement of particle size of innovator’s API in suspension and through the
   similarity of dissolution profiles of innovator and generic products.



37 |     Dr. Pogány | April 2008
Solubility of nevirapine hemihydrate at 37oC
                         pH                       Dissolved material (mg/ml)
                                                             (hypothetical figures)

                         1.2                                         2.75
                         2.1                                         0.28
                         3.0                                         0.08
                         4.5                                         0.06
                         6.8                                         0.06
                         7.2                                         0.06
                         8.0                                         0.06
Nevirapine Hemihydrate belongs to BCS Class 2 (low solubility, high permeability).
Solubility data are also important for cleaning validation

38 |   Dr. Pogány | April 2008
Water sorption isotherm of Ethambutol•2H2O
                                  Water uptake in 24 hours at a
                                  temperature of 25oC ± 2oC

                                   45% RH: 0%

                                   60% RH: 0%

                                   80% RH: 3.31 to 5.18%




 39 |   Dr. Pogány | April 2008
  Dissolution profiles of innovator and generic FPPs
       M
       e         120
       a
       n
       %         100
                                                                                 ▀ innovator
        A          80                                                              ▀ generic
        P
        I          60
        d                                                                           Similarity
        i          40                                                            factor, f2=73
        s
        s          20
        o
        l           0
        v
        e               0        10   20   30    40     50   60   70   80   90
        d
                                           Time (minutes)



40 |   Dr. Pogány | April 2008
       Selected generic composition (hypothetical figures)
       Ingredients                                   mg/5ml
 Nevirapine hemihydrate                              51.7

 Excipients
        –    Carbomer 934P                             8.0
        –    Methyl parahydroxybenzoate               10.0
        –    Propyl parahydroxybenzoate                1.0
        –    Sorbitol                                800.0
        –    Sucrose                                 700.0
        –    Polysorbate 80                            3.0
        –    Sodium hydroxide                          q.s.
        –    Purified water          to make   5.0 ml


41 |    Dr. Pogány | April 2008
                     Compatibility with excipients
                    Nevirapine Hemihydrate in solid state – illustrative example: heat

         Stress                                Treatment                        Observations
         Condition                                                        Assay:
                                                                          SI1:
         None                     Initial values API                      D1:
                                                                          Total unspecified:
                                                                          Total impurities:
                                  API is mixed with excipient, the        Assay:
                                  mixture is wetted and a thin layer of   SI1:
         Heat                     the powder blend is kept at 60°C for    D2:
                                  4 weeks in a Petri dish (open           Total unspecified:
                                  system)                                 Total impurities:


       To do: stress testing the dose-proportional mixture of the APIs in aqueous medium.

42 |    Dr. Pogány | April 2008
                     Container and closure system
 Primary packing materials for the comparator FPP are
  recommended. Plastic materials should comply with relevant
  pharmacopoeial and food contact regulations.
 Market specific needs (e.g., Climatic Zone IVb) and patient
  handling needs (hygienic and pilfer-proof blister cards) should be
  taken into account.
 Stability testing of primary batches should be conducted in the
  selected markets packs.
 When the container and closure system is a critical factor of FPP
  stability, batch or supplier variations should be minimized through
  tight specifications and extended sampling plans for QC testing.

 43 |   Dr. Pogány | April 2008
                       Proposed FPP specifications
      Description
      Identification (HPLC)
      Dissolution (UV): Q = 70% in 45 minutes
      pH = 4.8 – 6.2
      Deliverable volume
        – Average fill volume: NLT 240 ml
        – Fill volume variation: should meet Ph. Int. requirements
 Related substances: not tested
 Preservative content (HPLC)
        – Methylparaben: 98 to 102% of LA           [End of shelf life: 80 to 102% of LA]
        – Propylparaben: 98 to 102% of LA           [End of shelf life: 80 to 102% of LA]
 Assay: 95.0 to 105.0% of LA
End-of shelf-life acceptance limits for assay should not be proposed at this stage.


44 |    Dr. Pogány | April 2008
Pharmaceutical Development with Focus on
        Paediatric formulations

                         WHO working document QAS/07….

         DRAFT PHARMACEUTICAL DEVELOPMENT
              FOR MULTISOURCE (GENERIC)
              PHARMACEUTICAL PRODUCTS

                       PROCESS DEVELOPMENT

45 |   Dr. Pogány | April 2008
                                 Key terms
Critical Quality Attribute (CQA):
 A physical, chemical, biological or microbiological property or
  characteristic (of starting materials and intermediates) that
  should be within an appropriate limit, range, or distribution to
  ensure the desired product quality.

Critical Process Parameter (CPP):
 A process parameter whose variability has an impact on a (or
  more) critical quality attribute(s) and therefore should be
  monitored or controlled to ensure that the process produces the
  desired quality.


46 |   Dr. Pogány | April 2008
                                 Key terms
Proven Acceptable Range (PAR):
 „A characterised range of a process parameter for which operation within
  this range, while keeping other parameters constant, will result in
  producing a material meeting relevant quality criteria.”

Design Space (DS):
 „The multidimensional combination and interaction of input variables
  (e.g., material attributes) and process parameters that have been
  demonstrated to provide assurance of quality. Working within the design
  space is not considered as a change. Movement out of the design space is
  considered to be a change and would normally initiate a regulatory post
  approval change process. Design space is proposed by the applicant and is
  subject to regulatory assessment and approval.”


47 |   Dr. Pogány | April 2008
                  Design range and design space




Design space determined from the common region of successful operating
ranges for multiple CQAs. The relations of two CQAs, i.e., friability and
dissolution, to two interacting process parameters (e.g., impeller speed and spray
rate) of a granulation operation are shown in Figures 1 and 2 (from left to
right).Figure 3 shows the overlap of these regions and the maximum ranges of
the potential design space.

48 |   Dr. Pogány | April 2008
Regulatory expectations on process development
 Selection of process: standard for oral aqueous suspensions
 The progress from pre-formulation (size:1x) → formulation (10x) → pilot
  manufacture (100x but not less than 1/10th of production batch) →
  production scale (approved batch size) manufacture should be shown in the
  dossier submitted for prequalification to be logical, reasoned and
  continuous.
 A pilot batch is manufactured by a procedure fully representative of and
  simulating that to be applied to a full production scale batch.
 Manufacture of primary batches in the proposed container and closure
  systems for:
       – Bioequivalence and dissolution studies from the same batch
       – Regulatory stability studies ( including in-use stability study and an additional study
         under freeze-thaw conditions.)
       – Prospective validation of bioequivalence, dissolution and stability batches


49 |   Dr. Pogány | April 2008
                                 Scale up activities
 Stability protocol is prepared
 A large number of samples is tested from pilot scale batches to
  establish provisional acceptance limits for the control of critical
  process parameters (prospective validation, IPC limits) in order
  to define design space (process knowledge) and control strategy
  (risk mitigation) that encompasses aspects of scale,
  environmental aspects of site, packaging, as well as final
  product stability.
 Validation protocol is written
 Dossier is submitted for prequalification


50 |   Dr. Pogány | April 2008
                                 Prospective validation
 The manufacturing process used for primary batches should simulate
  that to be applied to production batches and should provide product of
  the same quality and meeting the same specification as that intended
  for marketing.
 Based on monitoring closely the manufacturing process of primary
  batches, provisional acceptance ranges should be proposed for the
  CQAs of intermediates and CPPs that impact on downstream
  processing. Interim acceptance criteria may be approved until enough
  knowledge is available to finalize CQAs of intermediates and CPPs.
 Manufacturing control strategy is proposed for the mitigation of
  quality risks

51 |   Dr. Pogány | April 2008
  High-shear batch mixer and in-line mixer




52 |   Dr. Pogány | April 2008
                                 General principles
 A process is well understood when:
       – all critical sources of variability have been identified and explained
       – variability is managed by the process
       – product quality attributes can be accurately and reliably predicted

 All critical process parameters should be identified, monitored
  or controlled to ensure that the product is of the desired quality

 The manufacturing process of the generic FPP should be the
  same as that of the reference FPP



53 |   Dr. Pogány | April 2008
       Objective and result of process control

                                 UCL 1.The process reveals serious
                                   N   risks and it is not controlled
                                 LCL
                                 UCL 2.The process is not yet
                                       controlled but acceptance
                                   N
                                       criteria are met
                                 LCL
                                 UCL 3.The process is under control

                                   N   and the product has a
                                 LCL   consistently high quality



54 |   Dr. Pogány | April 2008
                                 Process under control
 Most points fall near the central line (68% within one σ)

 A few points fall near the control limits (5% in the third σ)

 Points shold balance on both sides of the mean

 Points should cross the mean line often

 Points should show a random pattern (no trends, cycles,
  clustering)



55 |   Dr. Pogány | April 2008
ICH Q9 - Annex I.9: Supporting statistical tools
  Process Capability Analysis
  Estimate the potential percent of defective product
   Cp value                              cp=0.5                   cp=1                   cp=3
   graphical view of               UGW             OGW     UGW             OGW   UGW            OGW

   different cp values




   values statistically
                                         13,58 %                 0,27 %                approx. 0
   out of limit
   values in the limit
                                         86,42 %                 99,73 %         > 99,999999 %

                                 process statistically
   Result:                                               process statisticaly under control
                                    out of control



56 |   Dr. Pogány | April 2008
                                 Main points again
 Pharmaceutical development is an essential part of applications for
  prequalification. Guidance is needed also for those Applicants and DRAs
  that do not use the ICH Q8 guideline.
 Desk research gives valuable information for generic pharmaceutical
  product and process development
 FPP-specific quality and processability requirements are integrated into the
  API specifications during pharmaceutical development studies.
 Dissolution profile testing plays a key role in establishing pharmaceutical
  equivalence
 A science- and risk-based pharmaceutical development of generic FPPs
  provides a high level of assurance for interchangeability with the innovator
  product.
 Manufacturing process design and optimization identifies the critical
  attributes whose control leads to the batch-to-batch consistency of quality


57 |   Dr. Pogány | April 2008
                                 THANK YOU!




58 |   Dr. Pogány | April 2008

				
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