Training Handbook… · Web viewThis exercise will look at the paracetamol tablet manufacturing...

Training HandbookDepartment

TRG [Department]Project No.

180102 Document No.

TRN_001 Doc Rev.

01

Process ValidationTraining Handbook

Presented ByAshley Isbel

© 2023 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. of 21 pages

TRG_TMP650_05_r03

Department TRG Project No. 180102 Document No. 001 Doc Rev.

01

How to use this handbookThe handbook is organized to focus on particular skills and revisions. These lessons allow you to learn and practice the skills used throughout the course.

The following icons are used in this handbook.

Activity Revision exercise or written task

Important Important points to remember for the assessment

Quick Link or Tip A shortcut, tip, or favourite link

Discussion Group discussion activity

This intellectual property remains the property of PharmOut Pty Ltd. It is intended for training purposes and its format and contents are copy written by ©PharmOut 2023. For further information go to www.pharmout.net


TRG_TMP650_05_r03


01

Table of Contents

How to use this handbook..............................................................2Table of Contents..........................................................................31. Introducing Your product.......................................................4

1.1. Process Flow Diagram............................................................................................51.2. QTPP...................................................................................................................... 61.3. Active Ingredient – Paracetamol............................................................................61.4. Content of Paracetamol Tablet..............................................................................7

2. Process Design......................................................................82.1. Activity 1a – Develop CQAs....................................................................................82.2. Activity 1b – Process Specific Risk Assessment - Blending.....................................92.3. Activity 1c – Develop CPPs...................................................................................102.4. Activity 1d – Control Strategy for the Blending Process.......................................12

3. Activity 2 – Qualification and Validation.................................134. Activity 3 – Continued Process Verification............................155. Activity 4 – Is your process in control?...................................17


TRG_TMP650_05_r03


01

Process Validation Training Activities1. Introducing Your product

This exercise will look at the paracetamol tablet manufacturing process through the three stages.Scenario for manufacture of paracetamol tablets:Reintroduction of an old product into a facility that has been making solid oral dose products for the past 20 years. New blender was to be used as the old one broke down and cannot be fixed. The intention is that it will be installed and validated in parallel with this product. As the facility is struggling, they have purchased a second hand blender made 20 years ago.Note: The information on the facility and the process does not represent a real facility, and has been put together for this workshop only.


TRG_TMP650_05_r03


01

1.1. Process Flow Diagram


TRG_TMP650_05_r03

purchase of materials

incoming receipt

sampling of SM

testing of SM

release of SM

dispensing

blending

granulation

drying

milling

lubrication

pressing

packaging

testing of FP

release of FP

distribution


01

1.2. QTPPProduct Attribute Target

Dose 500 mg tablet

Subjective propertiesAppearance, uniform, colour,No off taste or odour

Patient safety – chemical purity

Impurities and / or degradation products below ICH or to be qualified

Patient safety – biological purity

Acceptable level of non-pathogenic microorganismsFree from yeast or moulds or below the specified limit

Patient efficacy – particle size distribution (PSD)

PSD that does not impact bioperformance or pharmaceutical processing

Chemical and drug product stability: 2 year shelf life, below 30˚C

Degradation products below ICH or to be qualified and no changes in bioperformance over expiry period

1.3. Active Ingredient – ParacetamolTest Quality Attribute Specification / Acceptance

CriteriaGeneric name Paracetamol Tablet

Structural formula

Molecular formula C8H9NO2

Chemical Name N-(4-Hydroxyphenyl) acetamide

Molecular Weight 151.16

Macroscopic Appearance White, crystalline powder.


TRG_TMP650_05_r03


01

Test Quality Attribute Specification / Acceptance Criteria

Solubility water 1:70boiling water 1:20alcohol 1:10chloroform 1:50glycerin 1:40ether slightly soluble

pKa 9.51 at 25°C.

Stability of the drug to temperature, light, and moisture

Stable to temperature, light, and moisture.

pH range over which drug is stable in solution

Stable at a pH 4 to 7 at 25°C.

1.4. Content of Paracetamol TabletName Quantity Function

Active Substance

Paracetamol 500.00 mg Active ingredient

Excipient(s)

Lactose 23.00 mg Excipient

Microcrystalline cellulose 50.00 mg Disntegrant / binder

Starch 27.00 mg Binder

Magnesium stearate 5.00 mg Lubricant

Sodium starch glycolate 6.00 mg Disintegrant

Colloidal silicon dioxide 5.00 mg Lubricant

Purified talc 4.00 mg Lubricant

Total 620.00 mg


TRG_TMP650_05_r03


01

2. Process Design

2.1. Activity 1a – Develop CQAs

Paracetamol Tablet

Quality Target Profile (QTPP) Requirements

Translation into Critical Quality

Attributes (CQAs)

Dose 500 mg tablet

Subjective properties

Appearance, uniform, colour,

No off taste or odour

Patient safety – chemical purity

Impurities and / or degradation products

below ICH or to be qualified

Patient safety – biological purity

Acceptable level of non-pathogenic

microorganismsFree from yeast or moulds or below the specified limit

Patient efficacy – particle size distribution

(PSD)

PSD that does not impact bioperformance or

pharmaceutical processing

Chemical and drug product

stability: 2 year shelf life, below

30 ˚C

Degradation products below ICH or to be

qualified and no changes in bioperformance over

expiry period

Pharmacopoeial Compliance

Meets pharmacopoeial requirements for tablet

dosage formsMeets requirements of TGO

78 (Aust.)


TRG_TMP650_05_r03


01

Paracetamol Tablet

Quality Target Profile (QTPP) Requirements

Translation into Critical Quality

Attributes (CQAs)


TRG_TMP650_05_r03



180102 Document No.

TRN_001 Doc Rev.

01

2.2. Activity 1b – Process Specific Risk Assessment - BlendingWhat is the impact that an operation will have on an attribute? Low - minimal medium highWhat is the probability that variations in the attribute will occur? Low - unlikely medium - moderately likely high – highly likelyWhat is our ability to detect a meaningful variation in the attribute at a control point? certain medium high - unlikely

Unit operatio

nAttribute Impact Probability Detectability Risk Level Comment

Blending


TRG_TMP650_05_r03


01


TRG_TMP650_05_r03



180102 Document No.

TRN_001 Doc Rev.

01

2.3. Activity 1c – Develop CPPs

Process Step Description of operational / QC tests CPP

Dispensing Check: the weight of all (active/inactive) raw

materials and their name and material codes

batch numbers Manufacturing dates Expiry dates Status labels 1.Pass Paracetamol through 20# sieve.2.Pass MCCP, Lactose Starch through 30# sieve.

Blending Transfer above sifted material (Step-2) to planetary mixer bowl and mix for 10 minutes at slow speed.

Preparation of granulating paste

1. Add 8 litres of purified water to s.s. vessel.

2. Boil it.3. Take starch, add purified water and make

slurry with stirring.4. Add this starch slurry & boil5. Mix well for homogeneous mixture.

Granulation 1. Slowly add granulating paste to the dry mixed powder in Planetary Mixer.

2. Granulate for 10 minutes at slow speed. 3. Check the mass for binding. 4. Add purified water if required. 5. Note down quantity of purified water

added.(Added quantity of purified water: 12.0 litres)


TRG_TMP650_05_r03


01

Process Step Description of operational / QC tests CPP

Drying 1. Transfer above mass to FBD 30KG trolley 1 & 2.

2. Trolley 1: Dry using hot air 40°C (without starting Heater) for about 30 minutes until mass is dry.

3. Trolley 2:Dry using hot air 40°C for about 30

minutes until mass is dry.Sift the dried granules through 20# sieve in sifter and collect sifted granules in a poly bag kept in a plastic drum.%L.O.D : NMT 3%

Milling 1. Collect the oversize granules and mill using 2 mm sieve, and at slowest speed through Multi Mill.

2. Collect the milled granules and add to the sifted granule (drying step).

3. Weigh the total granules obtained.

Final mixing / Lubrication

1. Sift the following material through 40 # after mixing magnesium stearate, talc, sodium starch glycolate on sifter and collect in a poly bag.

2. Transfer dry granules (drying step), lubricant in PLM and lubricate for 10 minutes at slow speed.

Compression

QC checks:1. Weight of 20 tablets: GM. ± 3 %2. Individual weight of tablet ; MG. ± 5 %3. Disintegration time (NMT 15 minutes)4. Thickness ± 0.2 mm5. Hardness 2-5 kg/cm²6. Friability NMT 1 %

Packing QC checks: visual appearance of strips:

Aesthetically good, legible coding, no smudging of strips.

Sealing and cutting: proper sealing and uniform cutting

Cut pocket: Free from damaged pocket


TRG_TMP650_05_r03

Department TRG [Department]Project No.

180102 Document No. 001 Doc Rev. 01

2.4. Activity 1d – Control Strategy for the Blending ProcessCQA Process Step Parameter Specification Control


TRG_TMP650_05_r03



3. Activity 2 – Qualification and Validation

List some key process variables that will cause your process outcome to vary?

Are these variables understood and adequately controlled?

How does your validation prove that the process is under control?


TRG_TMP650_05_r03



Assuming you are validating a new process, when do you have the confidence to go into commercial manufacture?

Do you use PAT, if so where in the process, and where else might PAT be introduced?

What are some of the prerequisites that need to be in place before starting Process Validation?


TRG_TMP650_05_r03




TRG_TMP650_05_r03



4. Activity 3 – Continued Process Verification

What quality system tools do you have, or think you need, for acquiring and evaluating post commercial manufacturing information?

What information would you look for?

How much data, what type of data, and how would you interpret that data?


TRG_TMP650_05_r03



How will OOS, deviations, and process ‘improvements’ be assessed?

How much sampling & for how long?


TRG_TMP650_05_r03


180102 Document No. 001 Doc Rev.

01

5. Activity 4 – Is your process in control?So, your product has been running for some time now. Here is a statistical analysis of the batches since the conclusion of stage 2. Is the process in control? Can you safely move to stage 3b? What are your next steps?

33129826523219916613310067341

56.0

55.2

54.4

Indi

vidua

l Valu

e

_X=55.166

UCL=55.738

LCL=54.595

33129826523219916613310067341

1.0

0.5

0.0

Mov

ing

Rang

e

__MR=0.215

UCL=0.702

LCL=0

335330325320315

55.4

55.2

55.0

Observation

Valu

es

58.558.057.557.056.556.055.555.0

LSL 54.59USL 58.45

Specifications

LSL USLOverallWithin

56.055.555.054.5

StDev 0.1904Cp 3.38Cpk 1.01PPM 1237.43

WithinStDev 0.2220Pp 2.90Ppk 0.87Cpm *PPM 4711.54

OverallOverall

Within

Specs

111111

1

111

11

111

1

1

111

1

1

1111

Process Capability Sixpack Report for Head3I Chart

Moving Range Chart

Last 25 Observations

Capability Histogram

Normal Prob PlotAD: 5.110, P: < 0.005

Capability Plot

Thoughts on Statistical analysis above


TRG_TMP650_05_r03


180102 Document No. 001 Doc Rev.

01

DOCUMENT END


TRG_TMP650_05_r03

Training Handbook… · Web viewThis exercise will look at the paracetamol tablet manufacturing...

Documents

Transcript of Training Handbook… · Web viewThis exercise will look at the paracetamol tablet manufacturing...