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Supplementary T raining 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@t-online.hu. WHO GMP and related guides.

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supplementary t raining workshop on good manufacturing practices gmp
Supplementary TrainingWorkshop on GoodManufacturing Practices (GMP)

MANUFACTURING PROCESS VALIDATION

Solid Dosage Forms

János Pogány, pharmacist, PhD,

consultant to WHO

Pretoria, South Africa, 28 June 2005

E-mail: pogany@t-online.hu

Dr. Pogány - WHO, Pretoria

who gmp and related guides
WHO GMP and related guides
  • WHO good manufacturing practices (GMP): main principles for pharmaceutical products
    • Section 4.Qualificationand validation
  • Supplementary guidelines ongood manufacturing practices(GMP):Validation (2003) – Draft.

Dr. Pogány - WHO, Pretoria

who gmp and related guides3
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, 1992:14–79 (WHO Technical Report Series, No. 823).

Dr. Pogány - WHO, Pretoria

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

Dr. Pogány - WHO, Pretoria

prospective validation

PROSPECTIVE VALIDATION

Pharmaceutical Development

Laboratory scale R + D

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

Physicochemical and physical properties of API

Dr. Pogány - WHO, Pretoria

equilibrium moisture content
At relative humidities (RHs) <100%, 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.Equilibrium Moisture Content

Dr. Pogány - WHO, Pretoria

solubility of zidovudine at 25 o c
Solubility of Zidovudine at 25oC

Dr. Pogány - WHO, Pretoria

solubility of artesunate
Solubility of Artesunate

Dr. Pogány - WHO, Pretoria

relationship between permeability coefficient and octanol water partition
1 Prednisolone

...

3 Dexamethazone

...

9 Dexamethazone-acetate

...

11 Progesterone

Relationship between Permeability Coefficient and Octanol-Water Partition

Dr. Pogány - WHO, Pretoria

norvir ritonavir epar cpmp 527 96
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

Dr. Pogány - WHO, Pretoria

particle size
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.

Dr. Pogány - WHO, Pretoria

screening of compositions
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.

Dr. Pogány - WHO, Pretoria

triomune whopar
Triomune - WHOPAR

Experimental„studies showed chemical incompatibility for thelamivudine with stavudine and nevirapine with stavudine combination. Lamivudine withnevirapine showed no change indicating that they are compatible. Stavudine was foundincompatible with both the drugs, indicated by the brown colouration and increase in theimpurities.

Therefore it was decided to separate stavudine from the other two drugs. Hence theformulation was proposed to be bilayered tablet formulation, where stavudine is in one layerand lamivudine + nevirapine in other layer. Thus contact of stavudine with the other two drugswas minimised.”

Dr. Pogány - WHO, Pretoria

dissolution test and profile
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.

Dr. Pogány - WHO, Pretoria

dissolution profile of viramune and generic nevirapine tablets on the indian market

F2

20

73

Dissolution Profile of Viramune and Generic Nevirapine Tablets on the Indian Market

Dr. Pogány - WHO, Pretoria

pivotal batches
Pivotal Batches

A tabulated summary of the compositions of the clinical, bioequivalence, stability and validationFPP 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.

Dr. Pogány - WHO, Pretoria

excipients lactose l
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

Dr. Pogány - WHO, Pretoria

excipients lactose l24
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.

Dr. Pogány - WHO, Pretoria

surface of a film coated tablets containing a high level of a superdisintegrant
Surface of a film-coated tablets containing a high level of a superdisintegrant

Dr. Pogány - WHO, Pretoria

packaging materials
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.

Dr. Pogány - WHO, Pretoria

concurrent validation

CONCURRENT VALIDATION

Commitment Batches

technical pharmacy
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)

Dr. Pogány - WHO, Pretoria

causes of variation
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)

Dr. Pogány - WHO, Pretoria

4 10 scientific approach
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.

Dr. Pogány - WHO, Pretoria

process approach
Process approach

CONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT SYSTEM

CUSTOMER

SATISFACTION

CUSTOMER

Management

responsibility

REQUIREMENTS

Resource

management

Monitoring,

improvement

Manufacture

Product

Inputs

Dr. Pogány - WHO, Pretoria

measure of variation spread of data
Measure of variation (spread of data)

68.26%

95.46%

Dr. Pogány - WHO, Pretoria

mean average chart
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

Dr. Pogány - WHO, Pretoria

process capability index cp
Process capability index, Cp

acceptance limits UCL - LCL

Cp = =

process capability 6σ*

6σ*

Three sigma: Cp = = 1

6σ*

12σ*

Six sigma: Cp = = 2

6σ*

σ* ... is the measured standard deviation of the process

Dr. Pogány - WHO, Pretoria

process capability index cpk
Process capability index, Cpk

UCL - x

Cpk =

3σn

UCL ... upper control limit

x ... mean of the acceptance criteria, target value

σn ...is 50% of the measured standard deviation of the process

Cpk shows the closeness of the process mean to the target value.

Dr. Pogány - WHO, Pretoria

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

Objective and result of process control

UCL

N

LCL

UCL

N

LCL

UCL

N

LCL

Dr. Pogány - WHO, Pretoria

process under control
Process under control
  • Mostpoints 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)

Dr. Pogány - WHO, Pretoria

4 8 4 9 protocols and reports
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.

Dr. Pogány - WHO, Pretoria

process validation protocol report
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.

Dr. Pogány - WHO, Pretoria

indentation hardness profiles for tablets of different shape
Flat

Shallow convex

Standard convex

Deep convex

Ball-shaped

Indentation hardness profiles for tablets of different shape

Dr. Pogány - WHO, Pretoria

areas most prone to surface erosion for flat shallow convex caplet shaped and deep convex tablets
Areas most prone to surface erosion for flat, shallow convex, caplet-shaped and deep convex tablets

Dr. Pogány - WHO, Pretoria

twinning during the coating process for flat faced and caplet shaped tablets
Twinning during the coating process for flat-faced and caplet shaped tablets

Dr. Pogány - WHO, Pretoria

measurement points of film thickness across the tablet surfaces
Measurement points of film thickness across the tablet surfaces

FACE

EDGE

SIDE

Dr. Pogány - WHO, Pretoria

4 10 scientific approach50
4.10 Scientific approach
  • Processes and procedures should be established on the basis of the results of the validation performed.

Dr. Pogány - WHO, Pretoria

commitment validation batches
Commitment (validation) batches
  • Process validation reports should be submitted in the application forprequalification.
  • 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.

Dr. Pogány - WHO, Pretoria

retrospective validation

RETROSPECTIVE VALIDATION

Annual Product Review

annual fpp quality review 1
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.

Dr. Pogány - WHO, Pretoria

annual fpp quality review 2
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.

Dr. Pogány - WHO, Pretoria

case summary of 20 batches 1
Case summary of 20 batches (1)

Dr. Pogány - WHO, Pretoria

case summary of 20 batches 2
Case summaryof 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.

Dr. Pogány - WHO, Pretoria

best process
BEST PROCESS

MINIMUMREQUIRED INPUT

MAXIMUM OUTPUT

AT NO COST TO SOCIETY (industrial safety, labour safety, internal and external environment protection)

Dr. Pogány - WHO, Pretoria

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.

COSTS OF QUALITY

Dr. Pogány - WHO, Pretoria

main points again
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.

Dr. Pogány - WHO, Pretoria