process validation conference 2006 san diego nk

PV Conference San Diego 2006 Katalin Nemák 1PV Conference San Diego 2006 Katalin Nemák 1

Minimizing / analyzing process validation risks

….think'st it much totread the ooze Of the salt deep,To run upon the sharp wind of the north, ...

(The Tempest)

PV Conference San Diego 2006 Katalin Nemák 2

Minimizing / analyzing risks Commonplace:„ If I had known I would fall, I would have set down before!”

We can minimize the risks by taking all necessary precautions:

- we have to get familiar with theproduct and

- we need to know all about theequipment to be used.

From risk management point of view the right phrase is PACA:ProActivity before process validation, andCorrective Actions according to the results.


Prospective, retrospective andconcurrent validations

Risk assessment RiskManagement

For each type of validations the risk management activities have to be performed in cycles to achievecontinuous product quality improvements


•1.Technology Transfers into a new facility (process validations as part in a big validation project)

•2. New product introduction to a controlled, monitored facility and working environment

Critical process parameters

Product quality attributes

1. Have to be defined for the new facility during validations

ICH Q8: „Design Space”

2. Have to be defined for the new product during validations


New product introduction to a controlled,monitored facility and working environment

(process development and scale-upor contract manufacturing)

Design Space: 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 postapprovalchange process.Design space is proposed by the applicant and is subject to regulatory assessment and approval.

Movement out of the design space is considered to be a changeand would normally initiate a regulatory postapproval changeprocess.


Technology: keeping the balance between technical parameters and „Design Space”

Solubility of the drugsubstance

Geometryof themixer

Visccosityof solutionSpeed

Time limits

Equipment and process related parameters

Material quality attributes in change withthe process

flow

Density


Process Validations regarding new facilities

In case of the most simple situation we have tocategorize the process parameters intotwo groups as “Acceptable" and „Unacceptable”

When starting work in a new facility we can get

the first information from the users instructions.

Nominal ranges of operation, capacity

parameters,time limitsfor permanent use are

usually given.

For the technical process parameters weneed to know the Proven Acceptable RangeProven Acceptable Rangess..

Stk # 7032: AREOMATIC S3 FLUID BED SPRAY GRANULATOR DRYERWith Blow Back System. Complete two stainless steel product bowls, Air Tank,Exhaust Air Filter, Steam Air Heater & Fan Peristaltic Pump.Fluid bed spray granulator: Transforms the fine granulate raw material into an even granulate. In the course of this process a suitable liquid is sprayed by means of injection device from top onto the fluidizing product, which causes the particles to agglomerate. The subsequent drying stabilizes the granulate.Pressure Shock Ressistance: 10 barHeating Capacity 175700kJ/h7.5Kw motor 415V 50Hz,Compressed Air Connection: 6 barEX proof: EX-BG3 Overhauled in 1994


GUIDANCE FOR INDUSTRY SUPAC-HUMR: IR / MR Solid Oral Dosage Forms

Manufacturing Equipment AddendumEquipment within the same class and subclass would be considered to have the same operating principle and design. - A change between diffusion mixers (same operating principle) (e.g, V-blender from manufacturer A to a similar from manufacturer B) would not represent a considerable change.

- A change from equipment in class „A” to another in class „B”: (e.g, change from a V-blender - diffusion blending -to a ribbon blender - convection blending) change in design and operating principle would represent a considerable change.


Special equipment requirements - manufacturing of topicals

GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS

IV. EQUIPMENT AND PRODUCTION CONTROLMixersOne important aspect of mixer design is how well the internal walls of the mixer are scraped during the mixing process. Generally, good design of a stainless steel mixer includes blades which are made of some hard plastic, such as teflon, which facilitates scrapping of the mixer walls without damaging the mixer.Filling and PackagingSuspension products often require constant mixing of the bulk suspensionduring filling to maintain uniformity.Process Temperature ControlTemperature uniformity within amixer should be controlled.http://www.fda.gov/ora/inspect_ref/igs/subst.html


Failure Mode and Effect Analysis

FMEA (see IEC 60812 or BS ISO 17359:2003)provides for an evaluation of potentialfailure modes for processes andthe likely effect on outcomesand/or product performance.

Based on results risk reductionand risk control can be initiated.

FMECA ( see IEC 60812)Incorporated an investigation of the degree of severity of the consequences, their respective probabilities of occurrence and their detectability it becomes a Failure Mode Effect and Criticality Analysis.


Use FMEA for investigationof equipment related problemsThe Delta filter-dryer had a relative big dead

volume as it has a lateral bottom valve. The supplier offerred to install a machine to turn

the equipment with an angle about 20 degrees.

On the liquid filling line a number of simulation tests has been performed (empty runs).- adjustments to centralize position of neddles,- test for probability of neddle break,- positioning of capping - probability of leakage, defects of crimping- probability of producing broken or defected

bottles

20°


Previous performance qualifications are needed!

100 min

20 min

For parenterals the CIP/SIP operations have to be qualified at first

Get to know equipment relatedprocess parameters

First test runs usually performedwith water or with placebo mixture.


Special challenge in aseptic processing:media fillA media fill program should incorporate the contamination risk factors that occur on a production line, worst-case activities and conditions that provide a challenge to aseptic operations. FDA recommends to address applicable issues : • Longest permitted runtime• Normal interventions and nonroutine interventions and events• Aseptic assembly of equipment• Connections /disconnections of equipment• Number of aseptic additions or transfers • Number of personnel and their activities • Shift changes, breaks, and gown changes • Aseptic sample collections, weight checks


“Worst Case” simulations for risky operations

Larry D. Taber E. Lilly TPO conference Earl Wood

Container – closure integrityMicrobiological test

– at the end of stability studies


Calculating the effect of scale-up: scale-up: V2 > V1,(similar geometry of equipment)

• Flow rate: time of addition can be the same: forliquids (linear speed v 1< v2) W1 ≈ W2gasses (linear speed v 1 ≈ v2) W1< W2

• Mixing: time of mixing can be the same

• Heat-exchange: time of heating increased(non-linear)

• Filtration: time of filtration increased(non-linear)

• Extraction: solvent volume increased (linear); mixing the phases

requires more time

Consistency lots and Demo batches (PAR vs “Design Space”)

d12 d2

2>

V1 V2

F1 F2>V1 V2

F1 F2>V1 V2

n1 d12 H1 n2 d2

2 H2≈V1 V2

VB1 VB2=VA1 VA2


I.9: Supporting statistical toolsProcess Capability Analysis• Estimate the potential percent of defective productCp value cp=0.5 cp=1 cp=3 graphical view of different cp values

UGW OGW

UGW OGW

UGW OGW

values statistically out of limit 13,58 % 0,27 % approx. 0

values in the limit 86,42 % 99,73 % > 99,999999 %

Result: process statistically out of control process statisticaly under control

ICH Q9 QUALITY RISK MANAGEMENTAnnex I: Methods & Tools


(trend analysis)

Validation

Production

A. Hussain, FDA, September 2004

Quality by design : “Special Cause” or “Common Cause”

• Reduce “Common Cause” Variability• Consequence: On the continuous improvement path

Result: Stable & Capable

ICH Q9 QUALITY RISK MANAGEMENT EXAMPLE

Potential Areas of Use(s)

•Monitor/measure process variability•Analyze data retrospectively

>Annual Product Review (PQR)•Determine the relationship betweenprocess variability and specification

•Requirement: Process specific data•Tool for both regulator and industry



Human factors – special roles in successfulprocess validations

Journal of Validation Technology May 2006 Volume 12, Number 3

What we wanted, they designed it, and finally we got this.

Figure 2 User Measurement Categories

overt = openly observable, not hidden or concealed;covert = we do mean hidden or concealed.

HUMAN FACTORS AND ERGONOMICSHF&E is fundamentally in designing, building,training, and maintaining for human use. HF&E considerations5 participate in the

- development of requirements,- in compliance with appropriate regulations and standards, - in the engineering of system reliability and- system integrity (e.g.: periodic re-validations). These are important at all stages of the system lifecycle (development, deployment, and disposal),since validations (and their pre-requisite requirements formulations) occur in each of these stages.

Aspects to the design of equipment and processes with better operability functions.

The operator must use only calibrated syringes for infusion of intravenous fluids and medications.

The system shall calibrate the syringe output volume for a plunger step, prior to each infusion OR generic (un-calibrated) syringes will not fit the pump. √


Early considerations about the pharmaceutical behavior of the new Drugs Substances, materials

•„physico-chemical profiling”•„pharmaceutical profiling”

Development of drug-like attributes

Discoveryand optimisationof biological activity

Product development

Integrity(assay, purity)

Interactions(enzyme

inhibition)Stability

Metabo-lizam

solubility ionisation

lipofilicity perme-ability

„pharmaceutical profiling”

„physico-chemical profiling”

Dr. Révész Piroska CPH 2006


Classification of the products-based on physical properties

MATERIALS /CONTAINERS

Glass bottles/vials

Ampoules Syringes PE flacons PP bags

Water / diluted aq. solutions

1 a. 2 a. 3 a. 4 a. 5 a.

High density solutions

1 b. 2 b. 3 b. 4 b. 5 b.

Oilsand their solutions

1 c. 2 c. 3 c. 4 c. 5 c.

Suspensions 1 d. 2 d. 3 d. 4 d. 5 d.

Amorphoussolids

1 e. 2 e. N. A. 4 e. N. A.

Solids with nanoparticles

1 f. 2 f. 3 f. 4 f. 5 f.

Solids with small particles

1 g. 2 g. N. A. 4 g. N. A.

Solids with macro particles

1 h. 2 h. N. A. 4 h. N. A.


Biopharmaceutical Classification of substancesfor oral dosage forms

Class II. Class I.

Class IV. Class III.

formulation

solubility

perm

eabi

lity low solubility

high permeabilityhigh solubility

high permeability

pharmacon optim

isation

phar

mac

on o

ptim

isat

ion

high solubilitylow permeability

low solubilitylow permeability


Nowadays tendencies:

More problem with solubility-typical directions of discovery research:

anticancer drugs antibiotics

these drugs are usually sparingly soluble.

- special fields of medication need parenteraladministration - when rapid action needed:

major analgetics,anxiolytic,spasmolytic,anaesthetic drugs

in the formulation of parenterals the solubility is more critical.

Working with materialsshowing unusual behavior


Design of Experiments Investigation of multiparametric systems

Two approaches of reaction optimization

„Changing one separate factorat a time” (COST) method:

50

60

70

80

30 40 50 60 70

Yiel

d (%

)

Temperature (°C)

Interaction plot

pH (low)pH (high)

pH (low)

pH (low)

pH (high)

pH (high)

DoE gives the surface of reaction space:

DoE tools: Computer controlled multiple reactor systems

Monoacyl

90 80 70 60 56 58 60 62 64 66 68 70 72 74 76 78 80

Reaction temperature ( °C)

0.9

1.0

1.1

1.2

1.3

1.4

1.5

1.6

Am

ount

of a

cid

chlo

ride

(eq.

)

(COST method)


Amorphous phaseRap

id c

ryst

al fo

rmat

ion

nanocrystals

lipid forms (micelle, SEDDS)

solid amorphous dispersionsIncreasingaqueousSolubility

Prediction of crystalline, amorphous and lipid charactersbased on the function between the crystal lattice energy and

the lipophilicity of the pharmacon

Biopharmaceutical points in formulation relatingmainly to physical parameters

Dr. Révész Piroska CPH 2006


Optimization of biopharmaceuticalattributes:•Speed of dissolution•Solubility•Permeability

1. Selecting best native charactersof the compounds to achieve betterperformance during formulation:

• Salt selection• Polymorphia screening2. Modification of pharmaceutical

behavior• Stabilization of metastable

structure forms3. Chemical methodes for the

modification of interfacing surface elements

Strategies for the formulation of drug substances sparingly soluble in water


Salt selection

Polymorphia screening

1. Selecting the usefulforms


TOP Stories in Risk MinimizationTOP Stories in Risk Minimization

Controlled release of Nifedipin1 2

Journal of Controlled Release 82 (2002) 335– 343

unannealed

annealed (80°C)ethyl-cellulose polymer matrix

The Tale of the The Tale of the Punctured TabletsPunctured Tablets

ANNEALING:Phase transition temperaturereduction and glass formation

2. Physical modifications during formulation


Dissolution of60 mg Terfenadine

Different complex forms

Volum

e of water

excipients used in low amountsComplex formation with Cyclodextrins

Solubility increasingeffect of cyclodextrins

Gemfibrozil+compounds

conc.μg/mL

solubility increase

GEM 29,10 1,00GEM+α-CD 31,39 1,08GEM+β-CD 49,62 1,71GEM+γ-CD 253,44 8,71GEM+HP-β-CD 212,71 7,31GEM+HBU-β-CD 284,84 9,79

GEM+RAMEB 303,63 11,33GEM+DIMEB 655,44 22,53GEM+Captisol® 251,91 8,66

Modification of API characters 3.physico-chemical methods


Answers:Design of Experiment(DoE):More factors varying at a time to avoid the uncertainities!

- interactions- global maximum- effect estimation- yield estimation

(without further experiments!)

Questions:• Critical factor?• Optimal factor setting?

- maximum yield- productibility

• Robustness?- effect of factors on

the reaction around the optimum

• Hazard?

Built-in QualityOptimization of process steps

to developreliable and robust technology

for scale-up


Bisacyl

Monoacyl

The reaction is robust,10% parameter alteration

can be allowed

1 2

Yields Monoacyl Bisacyl Amine96.8 0.8

Optimum 2 97.6 1.8 0.62.4Optimum 1

amine acylation

2

Parameters temperature „acyl”agent addition timeOptimum 1(minimal Bisacyl yield): 74.5°C 1 eq. 41.3 minOptimum 2(maximal Monoacyl yield): 71.9°C 1.5 eq. 39.5 min

The Design Space can be definedusing DoE method


Control methods to detect correct operationHomogeneity of the bulk product have to be assured.This is espacially difficult in case of:-powder blends with low API concentration -concentrated viscosous solutions, gels-suspensions,-creams, ointments1. Efficiency of mixing have to bedemonstrated

-measuring mixing speed,-vibration,-power up-take2.Temperature uniformity within the mixer:heat distribution recommended to be controlled with temperature mapping - typically for themanufacturing of topicals


PAT – real time measurements for continous process monitoringControl methods to detect correct operation

One of the main targets of PAT application is the lyophilization process.As previously mentioned when assurance of the homogeneity of lots isin question we have to face difficulties. The 100% control of the vialscan be a good resolution of the problem butin the solid cakes the differences cannot beeasily observed during the visual control.• FT/NIR methods have beeninstalled in some of the facilitiesfor the measuring of residualwater content in each of the vials. • Nowdays new method has been developped for the monitoring of the ice crystal morphology during freeze-drying:photonic microscopywith episcopic coaxial lighting.


MM

MMLL

LL

LLLL

LL

LLLL

LL

SSMM

MM

LLMM

MM SSSSSS

MMMM

MM

LLMM

SS

MM

LL

SS

SS

MM

LL

SS

SS

SSSS

Sol React pH Extr Distil Cryst Filtr Wash Dry Mill Cleanreactant adjust

Prioritynumber

Appearance:(homogeneity) 8(particul. mat.) 9colour 11particle size d. 10crystallinity 7Solubility 6colour of sol. 12Identity 1Assay 2Purity:residual solv. 5related subst. 3unspec. imp. 4

SS

Effect of process steps on the quality:

S - SmallM - MediumL - Large

Where to measure which quality feature?Example for risk analysis


Preparing sampling plansstratified sampling,AQL tables

GUIDANCE FOR INDUSTRYPowder Blends and Finished Dosage Units – Stratified In-Process Dosage

Unit Sampling and Assessment

During the manufacture of process validation batches,assess the uniformity of the powder blend, the in-process dosage units, and the finished product independently.Test results are used to monitor the manufacturing process output that is most responsible for causing finished product variability to develop a single control procedure to ensure adequate powder mix and uniform content in finished product.

Powder-blend

In-process

Finished product


Preparing sampling plans – special concerns

IV. PROCESSINGIn the spray drying of sterile powders, there are some concerns.

These include the sterilization of the spray dryer, the source of air and its quality, the chamber temperatures and the particle residence or contact time. In some cases, charring and product degradation have been found for small portions of a batch.

With regard to bulk lyophilization, concerns include air classification and aseptic barriers for loading and unloading the unit, partial meltback, uneven freezing and heat transfer throughout the powder bed, and the additional aseptic manipulations required tobreak up the large cake. For bulk lyophilization, unlike other sterile bulk operations, media challenges can be performed. At this point in time, with today's level of technology, it would seem that itwould be difficult to justify the bulk lyophilization of sterilepowders (from a microbiological aspect). Refer to the Guide for the Inspection of a Lyophilization Process for additional direction regarding this process.http://www.fda.gov/ora/inspect_ref/igs/subst.html

GUIDE TO INSPECTIONS OF STERILEDRUG SUBSTANCE MANUFACTURERS



- processes having higher risks for scale-up:

GUIDE TO INSPECTIONS OF TOPICALDRUG PRODUCTS

VIII. TRANSDERMAL TOPICALBecause of the many quality parameters that must be considered in the manufacture and control of a transdermal dosage form, scale- up may be considerably more difficult than for many other dosage forms. Therefore, special attention should be given to evaluating the adequacy of the process validation efforts. (you may encounter tolerances and/or variances broader than for other dosage forms.)Uniformity and particle size are particularly significant where the drug substance is suspended or partially suspended in the vehicle. Viscosity also needs control because it can affect the absorption of the drug; the dissolution test is important in this regard.http://www.fda.gov/ora/inspect_ref/igs/topic.html


In the API manufacturing the scale-up of some processes are riskyas well:

- reactions with gassing always pose a high level of riskDuring scale-up the acceleration of the process can be more intensiveand the capacity of the scrubber can be a limitating parameter for thenormal process flow. The pressure can rise and the absorption in theliquid phase can be increased and as a consequence adduct productsand other by-products can be formed.

- the heating of viscosous fluids can also be riskyWhen the heat transfer capacity of the fluid is low the thermometerinside the material can show a relative low temperature even whenthe material at the surface of the jacketed wall got to be overheated,charing and degradation can be occured.

- transfer of the drying from the tray dryer into a fluid bed dryer

can cause significant changes in the solidcharacter of the product.


Katalin Nemák 37


System

Process

Equipment

Control methods

Training

Recording

Auditing

Logistics

SPECTRAL evaluationof observations

and datacoming from

production

– a useful tool forrisk communication

and risk review


System related aspects


Process related aspects

Direct observations during freez-drying procedures (see slide 31)prove that the

use of annealing techniqueresulted considerable advantages:•better shape+porosity of cake,•decreased primary drying time•decreased costs

Journal of Drying Technology Vol. 22. No 8p 2009-2021


mixing speed (50-200rpm) solubility (good) mixing time (1/2 – 1 h) viscosity of the fluid (?) geometry of the tankpore size (0,2 μm) (bioburden before andintegrity (FF≥24 ml/min) after filtration)time of filtration (1/2 – 1 h)line speed (50-60bottles/min) density of the fluid (≤ 1,070)position of needles (centered) viscosity bottles adjustment of filling volume stoppers positioning of the crimper capsheat distribution (even 120°C) heat sensitivity (?) pressure (2 bar) heat transfer capacity (?)penetration of steam (BD +)lighting (10.000 fcd) coloration of liquid (Y, GY1-7)line speed

4 out of 6 quality attributes labelswere not listed in monographs boxes

wrap foil

Conclusions: How we can preparefor Process Validations

Technical parameters Material quality attributes

Process flowTechnical parameters can be given

Labelling, packaging

Product

Solution making *

Filtration *

Filling *

Terminal sterilisation*

Visual control*


The technical parameters affecting the manufacturing procedure usually can be known but our knowledge is usually limited when speaking about the material quality attributes we have to achieveduring the production. A number of new directives came to light to give advice in the establishing of in-process sampling and acceptance criteria.

For the future our task is to discuss and to communicate the acceptable quality ranges we can work with in our daily routine. Both for the Industryand for the Agency it is worthwise to define what we should handle andvalidate as a similar procedure and when to perform special validation.

Future perspectives: characterisation of Future perspectives: characterisation of „„normalnormal””parameters, minimization of risks relating to extremsparameters, minimization of risks relating to extrems

Products/Technology

elements

Oral IM/RM dosage forms

Infusions Injec-tions

Freeze-dryed products

Aseptic-ally filled powders

Topicals Eye-drop

s

Bloodderivatives

Material quality attributes

BCS LFCS(biopharm)

classification

? ? ? ? ? ? ?

Technicalparameters

SUPAC –HUMR

equipment classification

Media fill -simulation, container closure integrity

? Guide to Inspection of sterile DS –attention to

homogeneity

? Guide to Inspection of topical DPs attention to

homogeneity

? ?


… promise you calm seas, auspicious gales And sail so expeditious that shall catch Your royal fleet far off...

(Prospero)

process validation conference 2006 san diego nk

Health & Medicine

change change

tempestpv conference

technical process parameters

katalin nemkkatalin

process validation risks

design spaceequipment

good design

considerable change