2005.06.28. Dr. Pogány - WHO, Pretoria 1/59 Supplementary Training Workshop on Good Manufacturing Practices (GMP) MANUFACTURING PROCESS VALIDATION Solid.

2005.06.28. Dr. Pogány - WHO, Pretoria 1/59

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 2005E-mail: [email protected]


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.


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).


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

PROSPECTIVE VALIDATION

Pharmaceutical DevelopmentLaboratory 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


Equilibrium Moisture ContentAt 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.


Rate of Water Absorption at Different RHs

0,20

0,25

0,30

0,35

0,40

0,451 4 7 10 13 16 19 22 25 28

Lg time, t (3 min. units)

Lg

RH

, %

35%

55%

75%

100%


Solubility of Zidovudine at 25oCpH Dissolved material (mg/ml)

3.0 21

4.0 20

5.3 20

6.0 21

7.0 22

Distilled water 20

8.0 21


Solubility of Artesunate

pH Dissolved API (mg/ml)

1 1,9

5 1,5

6 3,5

7 10,2

8 12,2


Decomposition of Artesunatein aqueous solution

Solvent Time (h) Decomposition (%)

Water 2 0

0.1N HCl 2 74

0.1N NaOH 2 100


Relationship between Permeability Coefficient and Octanol-Water Partition

1 Prednisolone

...

3 Dexamethazone

...

9 Dexamethazone-acetate

...

11 Progesterone


NORVIR (Ritonavir) EPAR/CPMP /527/96

1. No polymorphism observed at the time of first submission (only form I : hard capsules and oral solution registered)

2. Failure in dissolution during stability studies for hard capsules

3. Emergence of form II (contamination of form I)

4. Production of hard capsules discontinued

5. Development and registration of soft capsules


Particle SizeWhen 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.


Effect of Particle Size on Dissolution of Nevirapine tablets

USP Type II / 0.01N HCl 50 RPM / 900 ml

0

20

40

60

80

100

120

Time (Min)Nevipan MGS(1024)05 (90%LT81.12)Nevipan MGS(1024)60B (90%LT30.89)Viramune 992633B

0 10 20 300.00 50.80 73.80 83.980.00 80.00 92.00 96.000.00 83.30 96.60 97.70

% D

rug

Dis

solv

ed


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.


Compatibility of Acetylsalicylic Acid with Excipients

Time (week) Talc A Talc B

Salicylic acid, % Salicylic acid, %

0 0.10 0.10

4 0.32 5.85

8 0.41 13.00

12 0.80 28.50


Triomune - WHOPARExperimental „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.”


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.


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

USP Type II / 0.01N HCl 50 RPM / 900 ml

0

20

40

60

80

100

120

Time (Min)Viramune B.No.992633BBrand C B.No.C00139Ranbaxy B.No.(1024)17

0 10 20 30 450.0 83.3 96.6 97.7 99.70.0 34.3 51.3 61.2 70.80.0 88.9 97.6 99.2 99.7

% D

rug

Dis

so

lve

d

F2

20

73


Hypothetical Dissolution Profile of a 2-FDC FPP

020406080

100120

0 15 30 45 60

minutes

% d

isso

lved Series1

Series2

Series3

Series4


Pivotal BatchesA 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.


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


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.


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


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.

CONCURRENT VALIDATION

Commitment Batches


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)


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)


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.


Process approachCONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT SYSTEM

CUSTOMER

REQUIREMENTS

CUSTOMER

SATISFACTION

Management responsibility

Resourcemanagement

Monitoring,improvement

Manufacture ProductInputs


Measure of variation (spread of data)

95.46%68.26%


Mean (average) chart

Normal variation

due to common causes

UCL Upper control limit

LCL Lower control limit

Abnormal variation of process – special causes

Abnormal variation of process – special causes

average = mean


Process capability index, Cpacceptance 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


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.


Output of processes for differentCpk indices

nσn = 3σ UCL Cpk No. of products OoS (ppm)

1σ1 m + σ1-0.166 691 464

2σ2 m + 2σ20.166 308 536

3σ3 m + 3σ30.5 66 807

4σ4 m + 4σ40.833 6 210

5σ5 m + 5σ51.166 233

6σ6 m + 6σ61.5 3.4


Objective and result of process control

1.The process reveals serious risks and it is not controlled

2.The process is not yet controlled but acceptance criteria are met

3.The process is under control and the product has a consistently high quality

UCL

N

LCL

UCL

N

LCL

UCL

N

LCL


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)


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.


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.


Illustrative variables of wet granulationProcess step Control or manipulate

(independent) variablesMeasured responses or output (dependent) variables

CrystallizationMicronization

Particle sizeBulk density

Dissolution timeGranulation and granule variables

Pre-mixing Speed, time, order of addition

Blend uniformity

Wet kneading Batch (load) sizeSpeed Impeller Chopper Spraying rateVolume of binder solutionGranulation time

End-point amperage Impeller Chopper Additional solvent volume


Illustrative variables of wet granulationProcess step Control or manipulate


Drying Inlet air temperature (seasonal variation)Drying time (seasonal variation)Cooling time (if applicable)

Outlet air temperatureLODMoisture content

Sizing Screen type and size

Feed rate

Granule size distribution (variation of sub-batches)

Blending Batch size (sub-batches)SpeedBlending time

Blend uniformityBulk density untapped tappedFlowabilityYield


Indentation hardness profiles for tablets of different shape

Flat Shallow convex Standard convex Deep convex Ball-shaped


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

tablets


Erosion on the surface of the tablet with a logo


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


Measurement points of film thickness across the tablet surfaces

FACE EDGE

SIDE


Illustrative variables of compression and film-coating

Process step Control or manipulate (independent) variables

Measured responses or output (dependent) variables

Compression

Machine speedGranule feed ratePrecompression forceCompression forcePunches and dies

Weight variationContent uniformityFriabilityHardnessThicknessDisintegrationDissolution time and profileYield

Film-coating Inlet air temperature

Inlet air flow

Spray rate

Spray atomizing pressure

Outlet air temperature

Tablet-bed temperature

Coat quality

Yield


Illustrative variables of tablet packagingProcess step Control or manipulate


Blistering Machine speedMachinability of blister materialForming temperatureForming pressureSealing temperatureSealing pressure

Leak testingAppearanceMinimum information is legibleYield

Bulk packing

Tablet counter

Incomplete tablets

Machine speed

Number of tablets

Detection, counting

Pilfer-proof

Labeling

Yield


4.10 Scientific approach Processes and procedures should be established

on the basis of the results of the validation performed.


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.

RETROSPECTIVE VALIDATION

Annual Product Review


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.


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.


Case summary of 20 batches (1)Statistics Av. wt. mg Dissolution % Assay %

Mean 347,6 99,6 98,2

Median 346,9 100,0 97,5

SD 5,2 2.5 2.2

Range 22.3 10.0 8.8

Minimum 337.0 95.6 95.0

Maximum 359.3 105.6 103.8

Conf. level, 95% 2.4 1.3 1.0

Accept. Crit. 350±5% 75%, 40' 90-110


Case summary of 20 batches (2)

1. Acceptance criteria for assay and dissolution

rate are loose and should be tightened.

2. Potentially critical impurities are not tested.

3. IPC data are not included in the retrospective

analysis of batch records.


BEST PROCESS

MINIMUM REQUIRED INPUT

MAXIMUM OUTPUT

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


COSTS OF QUALITYVisible 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.


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.

2005.06.28. Dr. Pogány - WHO, Pretoria 1/59 Supplementary Training Workshop on Good Manufacturing Practices (GMP) MANUFACTURING PROCESS VALIDATION Solid.

Documents

ich process slide

d slide

pharmaceutical preparations

draft ich consensus

taste consistency slide

main principles

related guides

equilibrium moisture