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Supplementary Training Workshop on Good Manufacturing Practices GMP

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Supplementary Training Workshop on Good Manufacturing Practices (GMP) ... Thus contact of stavudine with the other two drugs was minimised.' 2005.06.28. ... – PowerPoint PPT presentation

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Title: Supplementary Training Workshop on Good Manufacturing Practices GMP


1
Supplementary Training Workshop on Good
Manufacturing Practices (GMP)
MANUFACTURING PROCESS VALIDATION Solid Dosage
Forms
János Pogány, pharmacist, PhD, consultant to
WHO Pretoria, South Africa, 28 June 2005 E-mail
pogany_at_t-online.hu
2
WHO GMP and related guides
  • WHO good manufacturing practices (GMP) main
    principles for pharmaceutical products
  • Section 4. Qualification and validation
  • Supplementary guidelines on good manufacturing
    practices (GMP) Validation (2003) Draft.

3
WHO GMP and related guides
  • WHO good manufacturing practices main principles
    for pharmaceutical products Validation of
    manufacturing processes
  • Good manufacturing practices for pharmaceutical
    products. In WHO Expert Committee on
    Specifications for Pharmaceutical Preparations.
    Thirty-second report. Geneva, World Health
    Organization, 19921479 (WHO Technical Report
    Series, No. 823).

4
ICH guidelines
  • PHARMACEUTICAL DEVELOPMENT, Q8, Draft ICH
    Consensus Guideline, Released for Consultation on
    18 November 2004, at Step 2 of the ICH Process
  • QUALITY RISK MANAGEMENT, Q9, Draft ICH Consensus
    Guideline, Released for Consultation on 22 March
    2005, at Step 2 of the ICH Process

5
PROSPECTIVE VALIDATION
  • Pharmaceutical Development
  • Laboratory scale R D

6
Physicochemical and physical properties of API
  • Physicochemical
  • hygroscopicity
  • solubility
  • water content
  • polymorphism
  • permeability
  • Physical
  • particle size
  • bulk density (g/100ml)
  • flowability
  • color, olor, taste
  • consistency

7
Equilibrium Moisture Content
  • At relative humidities (RHs) lt100, a solid API
    (that does not form crystalline compounds with
    water) will loose some bound and all its unbound
    water until it is in equilibrium with the
    surrounding atmosphere. The sum of both these
    moistures is the free moisture of the API
    (granules) at the specified RH.

8
Rate of Water Absorption at Different RHs
9
Solubility of Zidovudine at 25oC
10
Solubility of Artesunate
11
Decomposition of Artesunatein aqueous solution
12
Relationship between Permeability Coefficient and
Octanol-Water Partition
  • 1 Prednisolone
  • ...
  • 3 Dexamethazone
  • ...
  • 9 Dexamethazone-acetate
  • ...
  • 11 Progesterone

13
NORVIR (Ritonavir) EPAR/CPMP /527/96
  • No polymorphism observed at the time of first
    submission (only form I hard capsules and oral
    solution registered)
  • Failure in dissolution during stability studies
    for hard capsules
  • Emergence of form II (contamination of form I)
  • Production of hard capsules discontinued
  • Development and registration of soft capsules

14
Particle Size
  • When the solubility of an API is less than 0.1
    mg/ml, the optimization of the particle size
    during preformulation may be critical to efficacy
    or pharmaceutical equivalence. Other researchers
    believe that particle size may be critical at a
    solubility of 1 mg/ml or less.

15
Effect of Particle Size on Dissolution of
Nevirapine tablets
16
Screening of Compositions
  • Compatibility of an API with the excipients and
    the APIs with each other in FDCs is studied in
    open system stress stability experiments, e.g.,
    60-80 oC, 100 RH.
  • Regulatory stability studies of the final
    composition are frequently initiated in the
    pharmaceutical R D laboratory.

17
Compatibility of Acetylsalicylic Acid with
Excipients
18
Triomune - WHOPAR
  • Experimental studies showed chemical
    incompatibility for the lamivudine with stavudine
    and nevirapine with stavudine combination.
    Lamivudine with nevirapine showed no change
    indicating that they are compatible. Stavudine
    was found incompatible with both the drugs,
    indicated by the brown colouration and increase
    in the impurities.
  • Therefore it was decided to separate stavudine
    from the other two drugs. Hence the formulation
    was proposed to be bilayered tablet formulation,
    where stavudine is in one layer and lamivudine
    nevirapine in other layer. Thus contact of
    stavudine with the other two drugs was minimised.

19
Dissolution Test and Profile
  • A (discriminating) dissolution test method should
    be developed for the final composition of the
    FPP.
  • Limits should be set for each API in fixed-dose
    FPPs.
  • The dissolution method should be incorporated
    into the stability and quality control programs.
  • Multipoint dissolution profiles of both the test
    and the reference FPPs should be compared.

20
Dissolution Profile of Viramune and Generic
Nevirapine Tablets on the Indian Market
21
Hypothetical Dissolution Profile of a 2-FDC FPP
22
Pivotal Batches
  • A tabulated summary of the compositions of the
    clinical, bioequivalence, stability and
    validation FPP batches together with
    documentation (batch number, batch size,
    manufacturing date and certificate of analysis at
    batch release) and a presentation of dissolution
    profiles must be provided.
  • Results from comparative in vitro studies (e.g.,
    dissolution) or comparative in vivo studies
    (e.g., bioequivalence) should be discussed when
    appropriate.

23
Excipients Lactose (L)
  • Different grade, different physical properties
  • Angle of repose 32- 47o (Specs.)
  • Bulk density 0.34 0.80 g/cm3 (Specs.)
  • Bulk density (tapped) 0.41 0.95 g/cm3
  • Flowability (spray processed) 4.1 g/s (Specs.)
  • Hygroscopicity L monohydrate is stable in air at
    room temperature. Anhydrous L may absorb
    humidity.
  • Moisture content L monohydrate contains approx.
    5 w/w water of crystallization

24
Excipients Lactose (L)
  • Solubility in water
  • 1 in 4.63 at 25 oC
  • 1 in 3.14 at 40 oC
  • 1 in 2.04 at 50 oC
  • 1 in 1.68 at 60 oC
  • 1 in 1.07 at 80 oC
  • Particle size distribution depends on grade.
  • Stability may develop brown colouration ( 80
    RH)
  • Incompatibility APIs with a primary amine group
    (base catalysed), aminophylline and amphetamines.

25
Surface of a film-coated tablets containing a
high level of a superdisintegrant
26
Packaging Materials
  • Moisture-impermeable containers glass ampoules,
    vials closed with rubber stoppers and fixed with
    metal caps, aluminium/aluminium blisters, high
    density polyethylene (HDPE) or glass bottles
    fitted with metal metal or HDPE closures, etc.
  • Moisture-permeable containers polyvinyl chloride
    (PVC) blisters, low density polyethylene (LDPE)
    bottles, HDPE bottles fitted with polypropylene
    closures.
  • Specifications of packaging materials should
    include thickness and permeability coefficient.

27
CONCURRENT VALIDATION
  • Commitment Batches

28
Technical pharmacy
  • Pharmaceutical production system
  • (from purchasing API to packaging FP)
  • Utility support system (HVAC, water, HPLC, etc.
    equipment containing many items)
  • Process (tablet making)
  • (Unit) operation (granulation, compression)
  • Step (sifting, sizing)
  • Procedure, method, technique (SOP)

29
Causes of variation
  • Man (different operators - lack of proper
    training)
  • Machine / equipment (variation of tablet weight)
  • Measurement (lack of calibration)
  • Method (validated manufacturing methods)
  • Material (batch-to-batch variation of the same
    crystal form different crystal forms (ASA)
  • Environment (OoS T and RH in capsule filling)

30
4.10 Scientific approach
  • Processes and procedures should be established
    on the basis of the results of the validation
    performed.
  • Objectives
  • To prove that the tests, measurements, results
    and interpretation of formal studies on
    (manufacturing) processes and procedures/methods
    are appropriate and accurate.
  • To stabilize new processes (to reduce
    variability, to increase batch to batch
    consistency of quality attributes of products).
  • To reduce defect levels (standardize yields).
  • To reduce production costs.

31
Process approach
  • CONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT
    SYSTEM

CUSTOMER
CUSTOMER
SATISFACTION
Management responsibility
REQUIREMENTS
Resource management
Monitoring, improvement
Manufacture
Product
Inputs
32
Measure of variation (spread of data)
68.26
95.46
33
Mean (average) chart
Abnormal variation of process special causes
UCL Upper control limit
Normal variation due to common causes
average mean
LCL Lower control limit
Abnormal variation of process special causes
34
Process capability index, Cp
  • acceptance limits UCL - LCL
  • Cp
  • process capability 6s
  • 6s
  • Three sigma Cp 1
  • 6s
  • 12s
  • Six sigma Cp 2
  • 6s
  • s ... is the measured standard deviation of the
    process

35
Process capability index, Cpk
  • UCL - x
  • Cpk
  • 3sn
  • UCL ... upper control limit
  • x ... mean of the acceptance criteria, target
    value
  • sn ... is 50 of the measured standard deviation
    of the process
  • Cpk shows the closeness of the process mean to
    the target value.

36
Output of processes for differentCpk indices
37
Objective and result of process control
  • The process reveals serious risks and it is not
    controlled
  • The process is not yet controlled but acceptance
    criteria are met
  • The process is under control and the product has
    a consistently high quality

UCL N LCL UCL N LCL UCL N LCL
38
Process under control
  • Most points fall near the central line (68
    within one s)
  • A few points fall near the control limits (5 in
    the third s)
  • 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)

39
4.8-4.9 Protocols and reports
  • Validation studies are an essential part of GMP
    and should be conducted in accordance with
    predefined and approved protocols.
  • A written report summarizing the results recorded
    and the conclusions reached should be prepared
    and stored.

40
Process validation protocol/report
  • Short description of the process with a summary
    of the critical processing steps or critical
    parameters to be monitored during validation.
  • Additional testing intended to be carried out
    (e.g. with proposed acceptance criteria and
    analytical validation as appropriate).
  • Sampling plan where, when, how and how many
    samples are taken.
  • Details of methods for recording and evaluation
    of results.

41
Illustrative variables of wet granulation
42
Illustrative variables of wet granulation
43
Indentation hardness profiles for tablets of
different shape
  • Flat
  • Shallow convex
  • Standard convex
  • Deep convex
  • Ball-shaped

44
Areas most prone to surface erosion for flat,
shallow convex, caplet-shaped and deep convex
tablets
45
Erosion on the surface of the tablet with a logo
46
Twinning during the coating process for
flat-faced and caplet shaped tablets
47
Measurement points of film thickness across the
tablet surfaces
FACE
EDGE
SIDE
48
Illustrative variables of compression and
film-coating
49
Illustrative variables of tablet packaging
50
4.10 Scientific approach
  • Processes and procedures should be established on
    the basis of the results of the validation
    performed.

51
Commitment (validation) batches
  • Process validation reports should be submitted in
    the application for prequalification.
  • Formal studies of production scale batches (not
    less than three) are required to identify the
    critical variables.
  • Provisional equipment control parameters and the
    corresponding in-process acceptance criteria must
    be deduced from the results of experiments with
    the validation batches.
  • Critical parameters are to be monitored,
    non-critical ones should be tested occasionally.

52
RETROSPECTIVE VALIDATION
  • Annual Product Review

53
Annual FPP quality review (1)
  • Starting materials used in the product,
    especially those from new sources.
  • Critical in-process controls and finished product
    results.
  • All batches that failed to meet established
    specification(s).
  • All critical deviations or non-conformances and
    related investigations.
  • All changes carried out to the processes or
    analytical methods.
  • Marketing Authorisation variations submitted, or
    granted, or refused, including those for third
    country dossiers.

54
Annual FPP quality review (2)
  • Results of the stability monitoring programme.
  • All quality-related returns, complaints and
    recalls, including export only medicinal
    products.
  • Adequacy of previous corrective actions.
  • For new marketing authorisations, a review of
    post-marketing commitments.
  • A list of validated procedures and their
    revalidation dates.
  • A list of qualified equipment, support utility
    systems and their requalification dates,
    including calibration programmes.

55
Case summary of 20 batches (1)
56
Case summary of 20 batches (2)
  • Acceptance criteria for assay and dissolution
    rate are loose and should be tightened.
  • Potentially critical impurities are not tested.
  • IPC data are not included in the retrospective
    analysis of batch records.

57
BEST PROCESS
  • MINIMUM REQUIRED INPUT
  • MAXIMUM OUTPUT
  • AT NO COST TO SOCIETY (industrial safety, labour
    safety, internal and external environment
    protection)

58
COSTS OF QUALITY
  • Visible costs, e.g., waste and returned goods
  • Hidden costs, e.g., wrong decisions,
    non-competitive manufacturing process,
  • low yield, maintenance, idle machine time,
    workers attitude, etc.

59
Main points again
  • Manufacturing methods are the same in the
    innovative and generic industries.
  • Pharmaceutical development is a major source of
    early identification of critical product and
    process parameters.
  • Validation batches should be tested extensively
    to establish preliminary/tentative IPC
    parameters.
  • Annual product review results in continuous
    improvement of products and processes.
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