Session 19: Mixing

Process Validation

6th Annual EU Validation Week

Amsterdam, Netherlands

March 17 – 19, 2015

PART 1

Copy Right - Property of Validation Technologies, Inc. (VTI)

Training Material cannot Sold, Copy and Distributed without Sole Permission of VTI.

2

CONTACT INFORMATION

for Course Leaders:

David Vincent, Process SME

Validation Technologies, Inc.

San Diego, CA

Toll Office: 800-930-9222

Phone: 858-673-3606

Email: davidv@validation.org

Website: www.validation.org

3

MIXING PROCESS

VALIDATION

OF SOLID ORAL

DOSAGE, BUFFER

SOLUTIONS,

OINTMENT,

CREAM AND

LIQUID ORALS

Where do we Begin?

Process Validation Objective

Objectives of assessment of quality part

To provide the highest assurance that all production

batches (unit doses) will be consistently efficacious

as the clinical batch(es)

To reduce risk to safety via the highest assurance of

acceptable and consistent quality of the product and

its components

Process

validation

Process validation

The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. (FDA)

Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets predetermined specifications and quality characteristics. (WHO)

The documented evidence that the process, operated

within established parameters, can perform effectively and

reproducibly to produce a medicinal product meeting its

predetermined specifications and quality attributes.(EMA)

Key Elements of Process Validation

1. Critical Quality

Attributes (CQAs)

2. Critical Process

Parameters (CPPs)

3. Process

Robustness

4. Reducing Process

Variability

Session 19: Mixing

Process Validation

API or Finished Oral Solid Dosage

PART 2

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Training Material cannot Sold, Copy and Distributed without Sole Permission of VTI.

When, Where and Why!!

Process validation

Traditional vs new paradigm

Post

approval

changes/ch

ange

controls/risk

analysis

Development-

Basic

Process

validation- 3

batches

Pilot batch

manufacturing

Enhanced-

Development and

process

qualification

Control

Strategy

Continuous and

extensive monitoring

of CQAs and CPPs

for each production

batch

ICH Q9

and Q10

ICH Q8,

QbD

Latest guidelines

FDA, January 2011 WHO, Revised Annex 7 of

WHO GMP guide (draft for

comment)

EMA, February 2014

Continuous process

verification (CPV)

Continuous process

verification (CPV)

Alternative approaches:

-Traditional approach

-Continuous process

verification

-Hybrid approach

Process design and Initial

validation (process

qualification- PPQ) are initial

phases of CPV

Process design and initial

validation (initial process

verification) are initial phases

of CPV

CPV protocol to be supported

by extensive development

information and lab or pilot

scale data. Executed on each

production batch

No mention of number of

batches for initial process

performance

qualification/validation (rather

must be justified based on

overall product and process

understanding)

Mentions data on at least

three pilot or production

batches collected as part of

process design

Number of batches specified

for traditional approach

- minimum of three production

batches unless other wise

justified

Process validation- Role of

assessment

Design

qualification

Operational

qualificationPerformance

qualification

Process

validation

GMP

Report

Process validation phases

Pre-validation

phase

Protocol

Preparation

Information from

product development

studies (identification

of critical attributes)

Information

from

primary/clinical

manufacturing

(scale up

information)

Process risk

assessment

information

(identification

of critical

steps)

Validation phase

Protocol execution

Post valdn phase:

Review of process,

deviations, failures,

need for

improvement, scale

up etc…

Includes

demonstration of

content uniformity of

the clinical batch

Risk assessment

Part of process development and protocol preparation

Risk matrix- usually as part of process development

Critical quality attributes (CQA) vs processing stages, e.g.

dissolution vs granulation

CQA vs critical process parameters, e.g., dissolution vs kneading

time

Failure mode analysis- usually as part of process validation

To identify critical attributes, processes and parameters

Informed validation

To establish control strategy

Example: risk matrix for low dose

capsule (CQA vs process stages)

Sifting/sizing blending lubrication Capsule filling

Assay Low Medium Medium Medium

Content

uniformity

High High High High

Dissolution Low Low High Low

Stability Low Low Low Low

Process steps to be validated

All steps that are generally considered critical (medium and high risk steps) should be monitored/scrutinized by summarizing actual process parameters applied and

observations recorded e.g. sifting stage, wet and dry granulation stages

observations serve as feedback for future refinement of process parameters

In addition, where feasible, sampling and testing should be performed

e.g. drying, mixing steps, compression, filling

results measure effectiveness and consistency of the immediate as well as preceding steps- e.g. final blend characteristics are mainly shaped by wet/dry granulation process

Validation scheme- example

Processing steps Critical parameters Validation scheme

Dispensing Weight checks Monitored

Sifting Mesh size Monitored

Wet Granulation and drying Amount and addition rate of

granulating agent, mixing speed,

time, as well as sequence of events

Monitored, Drying uniformity to be

tested

Dry Granulation Slugging /compaction parameters Monitored only or Monitored and

sampled?

Blending mixing speed, time Monitored; Blend uniformity to be

established

Lubrication mixing speed, time Monitored; Blend uniformity from

mixer and bulk container

Compression Initial set up parameters,

speed, applied pressure,

Monitored; Several samples to be

sampled and tested for IPQC

parameters

Fluidized bed coating Spray rate, inlet and product temp,

etc…

Monitored; appearance, weight gain

and full testing

Primary packaging, protocol

requested on case by case basis

Sealing temperature, speed Monitored; leak test

Blend uniformity

Early check for content uniformity of the

final dosage form

Uniform blend

with good flow

and

compressibility

characteristics

Compression with

optimum

conditions

Tablets meeting

criteria for

uniformity of

dosage units

Note: Blend uniformity is a routine test for low dose

products (i.e. active load <=5% or 5mg)

Blend uniformity- Sampling

location and method

Sampling location -usually predetermined as part of qualification of the mixer (i.e. mostly GMP issue) But, in the dossier, we at least check if periphery, center

positions and various other positions are considered

Samples from each location are usually taken in triplicate

Samples should also be taken from the blend container- to evaluate impact of transfer important for low dose products and particularly for DC

processed blend

Sampling should be done consistently and in away that does not disturb the bulk blend state – such aspects (e.g. type of sampling thief used) are better addressed at the time of inspection

Blend uniformity- Sample

size What is an acceptable amount for samples taken at each location?

Normally 1-3 time of the FPP unit dose weight

C. Morten, PIAT programme, University of Manchester

Blend uniformity- acceptance

criteria

Commonly used criteria Individual assays: 90.0-110.0% of label claim, RSD NMT 5.0%

Less common Individual assays:90.0-110.0% of the mean value, RSD NMT

5.0% In this case, setting mean = 95.0-105.0% of the label claim appears

reasonable

Rarely (in case of very low dose products) Individual assays: 85.0-105.0% of the label claim/mean value,

RSD: NMT 5.0%

May be acceptable provided that uniformity of dosage units is satisfactorily demonstrated on tablets/capsules manufactured from blend lot with close to limit blend uniformity results

Sampling and testing plan-

Lubrication- example

Sample

location

Sample size Sample

analysed

Tests Acceptance

limits

Lubrication 10 position

from

Octagonal

blender and

blend

container

850-2550mg

in triplicate

10 Individual

samples

Blend

uniformity

Mean: 95.0-

105.0%,

individual:

90-110%,

RSD: NMT

5%

Samples

from top,

middle and

bottom

50gm Composite

samples

Complete

analysis as

per routine

blend spec

As per blend

spec

Particle size

distribution,

bulk and

tapped

density

For

informationmissing

parameter?

Do you agree with

the acceptance

criteria?

What are the

minimum tests we

expect to see in

blend spec?

Acceptable?

How to demonstrate

consistency?

3 sigma

process

e.g. 4 sigma

process

Process validation-oral

solutions

Validation focuses on mixing time and conditions to clear solution, if

deemed relevant

bulk liquids: pH, specific gravity, clarity of

solutions; assay

filling process

filled units:- Volume/Wt variation and as per FPP

specs

Protocol with commitment is acceptable at

the time of review

Process Validation- Oral

suspensions

Focuses on API micronization processes (if applicable)

colloidal milling process (as applicable),

homogenization

filling

Viscosity, fill volume/weight variation,

Other critical attribute that may be affected by filling process?

Other parameters as per FPP spec including, PSD, pH, dissolution,

Protocol with commitment is acceptable at the time of review

Matrixing/bracketing approach

Multiple strengths of same product

(common blend) until stages of final granules: 3 consecutive batches of

the common blend (instead of 3 separate blend

batches for each strength)

compression: 3 consecutive batches of each strength

Primary packaging of tablet/capsule

products

blistering of hygroscopic or moisture sensitive

products however should always be individually

validated

Review of protocol- main

aspects to check

Scope of the validation (type, batch size, reason)- do they reflect the planned validation? Highest batch size to be validated?

Major equipments identified (in line with BMR) and a provision for recording their Q status included?

Reference to current master production record included?

Summary of critical steps identified? is this convincing ?

Monitoring and sampling plan provided?- Do you agree with the steps monitored/sampled?

Sampling schedule, schematics, tests and acceptance criteria, as well as current specification codes included ? Are these acceptable?

Review of protocol- main

aspects to check-contd

For solid orals: final blending, compression/encapsulation, coating stages must be adequately sampled and tested. Are these being reflected? Blend uniformity: Sampling schemes and blend uniformity

acceptance criteria specified? Are these acceptable?

Compression/encapsulation at lower, target and upper speeds included?

Provision for performance of dissolution profile testing and comparison with the biobatch included?

Appropriate commitment (prospective validation on first three consecutive batches mentioned) provided?

Protocol reference and version number included in QIS?

Review of validation report

Is the reported data relevant for the proposed manufacturing process and scale equipment used, process parameters applied

All critical steps adequately monitored/sampled?

Level of sampling and size are acceptable?

All results within acceptable limits? Particular trend?

Deviations appropriately evaluated and discussed?

Is the overall process in sufficient control? Is there any thing that should be improved or refined for future production batches

Following protocol is suggested:

Purpose and prerequisites for validation

Presentation of whole process and sub processes

Validation protocol approval

Installation and operational qualifications

Qualification reports including methods, procedures, release criteria, etc.

Product qualification test data from prevalidation batches

29

PROCESS VALIDATION PROTOCOL

Continue….

Test data from formal validation batches

Evaluation of test data, conclusions, and

recommendations including the need for

requalification and revalidation

Certification and approval

Summary report of findings with conclusions30

Session 19: Mixing

Process Validation

Solution, Oral,

Injectable

PART 3

Copy Right - Property of Validation Technologies, Inc. (VTI)

Training Material cannot Sold, Copy and Distributed without Sole Permission of VTI.

32

ARE LIQUIDS EASIER TO MIX?

Oral Liquids are

homogeneous liquid

preparations, usually

consisting of a

solution, an

emulsion or a

suspension of one or

more medicaments

in a suitable vehicle.

33

WHAT ARE ORAL LIQUIDS?

Two main types:

1.Monophasic liquids: 2. Biphasic liquids:

Solutions Suspensions

Elixirs Emulsions

Syrup

Liquid drops …etc

34

CLASSIFICATION OF LIQUID ORALS

Test parameter Suspension Emulsion

Appearance yes

Specific gravity yes yes

Viscosity yes yes

PH yes yes

Content uniformity yes yes

Sedimentation yes No

Resuspendability yes No

Particle size yes yes

Release rate yes yes35

Test parameters for emulsion and suspension

CONTINUOUS

PHASE

WATER

SURFACTANTS

OTHER

HELPING

AGENTS

PRESERVATIVES

MIXING

AQUEOUS SOLUTION

DISPERSE PHASE

FOR SUSPENSION FOR EMULSION

DRUG SOLUTION

IN OILMILLED DRUG

GRINDING OF

DRUG &

OTHER SOLIDS

DISSOLVED

DRUG IN OIL

Manufacturing of Biphasic liquids:

36

PRE – MIX

OR

CRUDE DISPERSION

HOMOGENIZE

FINE DISPERSE DELIVERY SYSTEM

OTHER ADDITIVES

(FLAVOURS,

COLOURING AGENT)

VOLUME ADJUSTMENT

pH ADJUSTMENT

Disperse

phase

Continuous

phase

37

38

Manufacturing of Monophasic liquids:

Process Equipment Process variables Properties

affected by

variables

Monitoring

output

Mixing

of

liquid

Kettle &

Tank fitted

with agitator

Capacity of unit,

Shape & position

of agitation system,

Order of addition,

Rate of addition,

Fill volume,

Mixing speed of

agitator,

Temperature of

liquid,

Mixing time.

Appearance of

liquid,

Viscosity of

liquid.

Potency,

Appearance,

pH,

Viscosity,

Specific

gravity.

39

Process Variables

Process Equipment Process variables Properties

affected by

variables

Monitoring

Output

Mixing &

blending of

solids

Blade

mixers &

tumblers.

Capacity of unit,

Mixing speed of unit,

Shape of unit,

position of mixing

element within unit,

Product load.

Particle size

of solids,

Blending

uniformity.

Potency,

Particle size

analysis,

Content

uniformity of

active

component.

40

Process Variables

Process Equipment Process variables Properties

affected by

variables

Monitoring

output

Dispersing Homogenizer,

Colloid mill,

ultrasonic

device/

Bore opening/

clearance of rotor

& stator/power

setting,

Pressure/rotor

speed/power

consumption,

Feed rate,

Temperature,

Dispersion time,

Order of mixing.

Particle size

of solids,

Viscosity of

liquid.

Potency,

Particle size

Distribution,

Viscosity,

Specific

gravity.

41

Process Variables

Process validation concerns to following

operations:

Raw material validation

Monitoring outputs

Filling and packaging validation

42

Process Variables

Raw material validation:

It includes mainly following tests

Particle size and size distribution

Particle shape or morphology

Microbial count

Rheology of solvent or vehicle

PH of the solvent or vehicle

43

Process Variables

Continue…

Raw materials are checked and validated for,

Particle size and size distribution- Particle size

distribution range is 0.2-2microns for suspensions.

Particle shape(Morphology)-It is also important to

consider because it affects the product appearance,

solubility, settling rates and drug stability.

Microbial content-To prevent microbial growth on

the final product .

44

Continue….

Rheology of solvent- It will determine how well

liquid will suspend the insoluble particles. Viscosity of

the External phase is generated by one or more of

following components:

Suspended solids

Blend of oils and waxes

presence of polyols and polyoxyethylene derivatives

High concentration of dispersed solids in water

Dispersed clays, gums, cellulosic, and/or polymers45

Continue….

PH of the solvent-Solubility of the drug in the

solvent or vehicle can be markedly influenced by

the PH of the solvent. PH of the solvent is

important because large number of

chemotherapeutic agents are either weak acids or

weak bases so their solubility markedly affected

by the PH of the solvent.

46

Monitoring outputs

Some outputs to be monitored are as under,:

Appearance

pH

Osmolarity

Viscosity

Specific gravity

Microbial count

Content uniformity

Dissolution testing

47

Appearance:

Appearance of the final product is checked and

validated because it indicates the signs of instability

and degradation. For e.g. settling of solid particles

in case of suspension and turbidity in case of

emulsion.

Time for mixing or agitation and temperature of

process can effect the appearance greatly.

48

PH value

PH of aqueous oral formulations should be taken at a

given temperature and only after equilibrium has

been reached in order to minimize the PH drift.

Electrolytes , such as potassium chloride , may be

added to the aqueous external phase to stabilize their

PH drift.

49

Osmolarity Value

Its measure of the osmoles of solute per literof solution. Typically used for Buffer andReagents Homogeneity Profile

A relative standard deviation (RSD) percentage will be calculated from the test results and the equation is stated below. The SD is the standard deviation and xis the mean. The acceptance criteria of RSD % will be derived from the test results of the past lots. The test results from the previous lots will indicate the maximum variance allowed for the product.

Relative standard déviation % = (SD / x) *10050

Viscosity:

Viscosity is defined as the study of fluid flow. or

It is a measurement of the applied stress per unit area

to maintain a certain flow rate.

The viscometer used for the measurement of

viscosity should be properly calibrated at

equilibrium at a given temperature to establish

system reproducibility.

51

Continue….

Viscosity of the liquid oral dosage form is

important because it affects the settling rate of

suspended particles in suspension and of

globules of internal phase in emulsions and

also in case of oral solutions it affects the

overall appearance of the final product so it

must be measured and validated properly.

52

Specific gravity:

Specific gravity is the weight of the product per unit

volume.

For most of the liquid oral products it is 1gm/cube

centimeter.

A decrease in specific gravity of the product like

suspensions indicates the presence of air within the

structure of the formulation.

Hydrometer is used to measure the specific gravity

of liquid orals at a given temperature using well

mixed uniform solution.53

Microbial count

Microbial count for the final product is essential to

validate because by performing microbial count we

can select the preservative for the final product

storage.

There are specifications for each liquid oral product

for the bioburden content.

54

Continue….

Preservative system used in the formulation-

The use of small amounts of propylene glycol(5-

15%) or disodium edetate(about 0.1%) or

decrease in the PH of the disperse system have

often been use to increase the efficiency of the

preservative system.

55

Continue….

Criteria for selection of preservatives:

Must be effective against a broad spectrumof microorganisms.

Must be chemically, physically, andmicrobiologically stable.

It must be nontoxic, nonsensitizing, solubleand compatible with other formulationcomponents.

56

Content uniformity:

In solution, suspensions and emulsions determination

of content uniformity affects the dose uniformity

in case of multidose formulations and also affects

the homogeneity of the drug within solvent system.

57

Continue…

Content uniformity of suspension is affected

by settling rate which is governed by

following factors,

Particle size of the internal phase

Particle density of the internal phase

Density of the external phase

Viscosity and structure of the external phase

58

Dissolution testing:

There is not any official method for dissolution

testing of dispersed system , but the best way to

perform dissolution of suspension like system is to

place a small amount of formulation inside a secure

Durapore (polyvinylidene fluoride) membrane pouch

of suitable viscosity and suspend it in a suitable

dissolution medium using a USP method 1 paddle

apparatus.

59

60

Test parameters specific for suspension

Sedimentation rateResuspendibilityParticle size & particle size distributionZeta potential measurement ( is a scientific term

for electrokinetic potential in colloidal dispersions.

Test parameters specific for solution

Clarity of solutionColor of solution

Type of emulsion determination by

Dilution test

Conductivity test

Dye solubility test

COCl2 filter paper

Fluorescence test

61

Continue….

Some precautions to be taken while filling

and packaging

Proper control of product temperature

Proper agitation in holding tanks and filling heads

Uniformity and homogeneity of active ingredient

Maintain stability in the primary container closure

system

62

The validation of suspension and emulsion can behandled in the same way, because their similaritiesrather than their differences are subjected tovalidation

Common similarities are

Particle size distribution of the drug itself

Homogeneity of the drug throughout theexternal phase

Reproducibility and stability of the viscosityand/or density in the final product 63

Practical approach for managing

validation of emulsion and suspension

Processing variables Lower control limit(LCL) Upper control limit(UCL)

Moisture content 5% 15%

Processing temperature 50 degree Celsius 70degree Celsius

PH value 5.0 7.0

Processing time 2 hr 6 hr

Apparent viscosity 20,000cps 200,000cps

Blender speed 4,000rpm 20,000rpm

Avg. particle size 20 micron 40 micron64

Limits of Process variables for factorial analysis

Mixing Validation Workshop

Group Session

You are given a tablet

manufacturing flow chart

to study

Identify mixing and/or blending steps

List the critical mixing steps that are

required to be validated

List the critical equipment required to

be qualified mixing process

Identify the input variables (CPP) and

CQAs construct a table as listing

mixing process steps, equipment

including CPPs and CQAs

Thank you

End of Mixing