Fundamental of cleaning validation

www.julphar.net Gulf Pharmaceutical Industrieswww.julphar.net Gulf Pharmaceutical Industries

CLEANING VALIDATION Know – How of an Effective Cleaning Program

Cleaning

Visual Check

Validation

Quality Assurance

Presented By :Vishal Katiyar

www.julphar.net Gulf Pharmaceutical Industries

Cleaning Validation……………. At a glance

After completing this session we’ll come to know :

Definition Purpose Cleaning mechanisms Cleaning agents Cleaning Methods Cleaning parameters Cleaning continuum Grouping strategies Worst Case considerations

1Quality Assurance

Acceptance criteria Sampling Methods Analytical Methods Hold time studies


Cleaning Validation………… The definition

The process of removing contaminants from process equipment and monitoring the condition of equipment such that the equipment can be safely used for subsequent product manufacturing.

Dustin A. Leblanc.

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Cleaning Validation…………........... Purpose

Product integrity

Cross contaminationMicrobial integrityProduct impurityBatch integrity

Equipment reuse

Regulatory issues3

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Cleaning Validation……Cleaning Mechanisms

The chemistry of contaminant removal :

SolubilityWettingEmulsificationPhysical removal

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Solubility :Solubility involves the dissolution of one chemical (the contaminant) in a liquid solvent. For example, salts may be soluble in water, and certain organic actives may be soluble in acetone or methanol.

One of the primary cleaning mechanisms to be considered during design phase.

Rate of solubility, Insoluble form, Soluble – Insoluble species

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Wetting :Wetting involves the displacement of one fluid from a solid surface by another fluid. Wetting can be improved by the addition of surfactants.It improve penetration of the cleaning solution into cracks and crevices, which are usually difficult-to clean locations.

6Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc

Quality Assurance


Cleaning Validation……Cleaning MechanismsEmulsification :Breaking up an insoluble liquid residue into smaller droplets and then suspending those droplets throughout the water.

Emulsion = Mechanical energy + Surfactants / Polymers.

Emulsions are thermodynamically unstable (say, 5 to 10 mins.).

Redeposition of the cleaned residue back onto the equipment surfaces.

Agitation should be continued till the time to discharge the cleaning solution to the drain.

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Physical Removal:Cleaning by some mechanical force. the objective is to physically displace the residue.Pressurized water + Scrubbing

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In real life situation, more than one cleaning mechanisms are being used.

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Cleaning Validation………….Cleaning Agents

Cleaning Agents

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Aqueous Cleaning

Organic Solvents

Water Surfactants

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Detergents (citrus terpenes)


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Cleaning Validation……….Cleaning Agents

Organic Solvents

• Acetone• Methanol• Ethyl

Acetate

Surfactants

• SLS• Fatty acid

salts

Solvents (miscible)

• Glycol Ethers

Bases

• NaOH• KOH

Acids

• Glycolic Acid

• Citric Acid

Oxidants

• NaOCl• H2O2

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Cleaning Validation……….Cleaning Methods

Automated Cleaning:

o Fixed CIPo Portable CIP

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Manual Cleaning: Soak Brush Wipe Spray

Extent of automation……………..Extent of disassembly

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Fixed CIP :

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Cleaning Validation…….Cleaning Methods

Portable CIP :

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Parts Washer :

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Ultrasonic Washer :

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Cleaning Validation……Cleaning Parameters

Time Action Cleaning chemistry Concentration Temperature Mixing / flow /

turbulence Water quality Rinsing

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Parameter interactions :

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Cleaning Validation……Cleaning Parameters

Time vs Concentration :

Temp. vs Concentration :

Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc Quality Assurance


Parameter interactions :

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Cleaning Validation….……Cleaning Parameters

Time vs Temperature :

Time (min)

Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc

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Cleaning Validation.……Cleaning Continuum

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Continuum represent the extremes in the range of operating differences found within the industry. The continuum should be used during the initial phases of defining a cleaning validation program or during new product development.Manual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Automated CleaningCOP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..CIPDedicated Equipment . . . . . . . . . . . . . Non-Dedicated EquipmentProduct Contact Surfaces . . . . . . . Non-Product Contact SurfacesNon-Critical Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Critical SiteMinor Equipment . . . . . . . . . . . . . . . . . . . . . . . . Major Equipment

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Cleaning Validation……Cleaning Continuum

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Sterile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Sterile

Solid Formulations . . . . . . . . . . . . . . . . . . . . . Liquid Formulations

Soluble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insoluble

Single Product Facility . . . . . . . . . . . . . . . Multiple Product Facility

Campaigned Production . . . . . . . . . Non-Campaigned Production

Simple Equipment Train . . . . . . . . . . . Complex Equipment Train

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Cleaning Validation……Grouping Strategies

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"Grouping" is the concept of demonstrating that certain elements of cleaning are of a similar type, and selecting one (or more) representative object(s) on which to conduct the Cleaning Validation (Cleaning Process Qualification).

Product grouping :

Same manufacturing equipments being used. Same cleaning SOPs being followed. Similar formulations. Similar risk / therapeutic group.

Equipment grouping, Cleaning method grouping, Cleaning agent grouping, …………….., etc.

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Cleaning Validation.……Grouping Strategies

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Sr. No.

Name of productFormulat

ionCleaning methods

Equipment train

Risk / Therap.

class

1 Product ATablet (FC)

Method 1 Train A General

2 Product B Tablet Method 1 Train B General

3 Product C Parenteral Method 2 Train C Cytotoxic

4 Product D Tablet Method 3 Train B General

5 Product ETablet (EC)


6 Product F Parenteral Method 2 Train C Cytotoxic

7 Product GTablet (FC)

Method 1 Train A Cytotoxic

8 Product H Tablet Method 3 Train B General

9 Product ITablet (EC)


10 Product J Parenteral Method 2 Train C Cytotoxic

All products in a facility (hypothetical):

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Cleaning Validation……Grouping Strategies

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Sr. No.


ionCleaning methods

Equipment train

Risk / Therap.

class















Before Grouping :

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Cleaning Validation…….Grouping Strategies

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Sr. No.


ionCleaning methods

Equipment train

Risk / Therap.

class















After Grouping :

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Cleaning Validation…..Worst Case considerations

Once the product groups have been established, the next step is to determine the so-called “worst case” representative of each group.

It is that member(s) who shows the highest challenge on cleaning program.

Worst case product : Toxicity / solubility / Single Therapeutic

Dosage.Worst case eq. train : Longest train.Worst case equipment : Larger size equipment

(identical design).Worst case acc. criteria: Stringent acceptance

criteria.Hold time studies : Longest possible

duration.Campaign Mfg. : Highest possible nos. of

batches.

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Cleaning Validation…..Worst Case considerations

There is no ‘hard & fast’ rule on worst case selection.

A good logic and science should always be used.

Grouping and worst case selection help to demonstrate cleaning method robustness.

It smartly reduces the load from cleaning validation program.

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Cleaning Validation……...Acceptance criteria

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How clean is clean ?What are the bases of defining

limits ?What are the impacts of after

cleaned residue ?Human Drug CGMP Notes, 9:2, 2Q 2001 :“Should equipment be as clean as the best possible method of residue detection or quantification?”

Answer: “No,……absolute cleanliness is neither valuable nor feasible…. It should be as clean as can be reasonably be achieved, to a residue limit that is medically safe and that causes no product quality concerns…………….”

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Three criteria :

It should be scientifically justifiable. Pacifically achievable. Methodically verifiable.

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Possible types of limits :

Visual Chemical Microbiological Endotoxin


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Visual clean criteria :

GMPs require inspection for visual cleanness before manufacture.

Key items to consider :o Angle of viewo Distance from equipment surfaceo Lighting conditionso Viewer’s knowledgeo Surface usually must be dry

Visual aids :Additional lighting / Magnifying glass / Mirror / Fiber-optic scope / UV light 3

0


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Application for visual limits :

A typical visual limit is NLT 4 μg / cm2.

“Visually clean” may not be enough by itself Potent drugs Microbial contamination Endotoxin

More suitable method for non-potent drug products and APIs.

PIC/S advocates spiked coupon study for determination of visual inspection limits (and for training of inspectors 3

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Chemical residue limits (Therapeutically or Toxicologically safe criteria) :

Therapeutic dose based criteriaMost suitable for drug product (finished product) manufacturing facility.

Toxicological criteria (Where Api STD Not Available)Most suitable for active drug (API) manufacturing facility.

Where cleaning agents are used (other than water).

10 PPM criteriaCGMP requirement widely applicable. 3

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Therapeutic dose based criteria :

Based on the assumption that 1/1000 part of therapeutic dose does not have any clinical impact on human (animal) body.

Determination of MACO (Maximum Allowable Carryover) of Product A (Previous) to Product B (Next)

STD (A) × BS (B) × SFMACO =

(unit of mass) LDD (B)

Where, STD = Single Therapeutic Daily Dose (Product A – ACTIVE CONTENT), BS = batch size (Product B), SF = safety factor and LDD and

LRDD = Largest Daily Dose (Product B – DRUG PRODUCT)

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Step 1

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Determination of Surface contamination (Shared Equipment)

MACOL1 = (mass / surface area)

TSA Where, TSA = Shared Equipment Total Surface Area (for both products)

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Step 2

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Step 3


Determination of Sampled residue (for swab sample)

L2 = L1 × Swab Area (mass / swab)

STD value represents the ACTIVE drug content only.

e.g. 10 mg, the dose strength.

LDD value represents the mass or volume of entire dose.

e.g. 250 mg three times a day.

BS = batch size (Product B). e.g. 150 kg.

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Safety Factors :

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Approach Approach Typically Applicable To

0.1 to 0.01 Topical products

0.01 to 0.001 Oral products

0.001 to 0.0001 Parenterals products

0.0001 to 0.00001

Research, investigational products

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Step 1

Therapeutic dose based criteria (an example) :

Determination of Maximum Allowable Carryover

10 mg × 150 kg × 0.001 × 1000000

(250 mg × 3)

= 2000 mg (MACO value)

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Step 2


Determination of Surface contamination level

2000 mg

3170 cm2

= 0.63 mg / cm2 (L1 value)

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Step 3


Determination of Swab residue

0.63 mg / cm2 × 100 cm2

= 63.00 mg / swab (L2 value)

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10 PPM criteria :

Based on the hypothesis that 10 parts of previous product is therapeutically ineffective if presents in million parts of next product.

Determination of MACO

10 × BSMACO =

(unit of mass) 1000000

Where, BS = batch size (smallest available batch size)

Then use and to derive final swab residue limit.

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Step 1

Step 3

Step 2 Quality Assurance


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Cleaning Validation…………...Acceptance criteria

Step 1

10 PPM criteria (an example) :

Determination of MAC

10 × 150 kg × 1000000MAC = = 1500 mg

1000000

The final Swab residue (L2) :

1500 mg × 25 cm2

3170 cm2= 11.83 mg/swab

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Toxicological criteria :

Based on the toxicological information available in Material Safety Data Sheets.

Determination of NOEL (No Observed Effect Level)

NOEL = LD50 × Emperical Factor

(unit of mass/kg of body weight)

Where, LD50 = lethal dose for 50% of animal population in study (mg/kg/day), Emperical Factor = derived from animal model developed by

Layton, et.al : 0.001*

* Used by expert panel of WHO (10-3).

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Step 1A

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Determination of ADI (Acceptable Daily Intake)

ADI = NOEL × AAW × SF

(unit of mass)Where, AAW = average adult weight : 70 kg,

SF = safety factor (0.01)

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Step 1B

Consider average body weight of child where there is any pediatric dose available.

Use LD50 value of mice.Quality Assurance



Determination of MAC (Maximum Allowable Carryover)

ADI × BSMAC =

LRDD (any next product)(unit of mass)

Then use and to derive final swab residue limit.

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Step 1C

Step 2

Step 3

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Step 1A

Toxicological criteria (an example) :

Determination of NOEL

(1750 mg /kg/day) × 0.001 = 1.75 mg/kg (NOEL

value)

Determination of ADI

(1.75 mg/kg) × 70 kg × 0.01 = 1.225 mg

(ADI value)

Step 1B

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Step 1C

Toxicological criteria (an example) :

Determination of MAC

1.225 mg × 150 kg × 1000000

(250 mg × 3)

= 245000 mg

The final Swab residue (L2) :

245000 mg × 25 cm2

3170 cm2= 1932 mg/swab

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The most stringent acceptance criteria shall be chosen for cleaning validation study (The worst case approach).

11.83

1932

63.00

mg / swab

In real life cases, therapeutic or 10 PPM criteria become final acceptance criterion for cleaning validation.

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Microbiological criteria : Internal specifications Official specifications: e.g. USP <1111>, “Microbial Examination of nonsterile Products: Acceptance criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use”

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Adminstration route

TAMC Endotoxin

Oral 100 CFU/mL -

Liquid 20 CFU/mL -

Injectables 10 CFU/mL0.25

Unit/mLQuality Assurance


Determining acceptance criteria with more than one next products (The Matrix approach):


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Product NameActive

IngredientSTD[mg]

ToxicityLD50 in mg/kg

Solubility In Water

PRODUCTS IN AMPOULES

Scopinal 20mg/mL

Hyoscine-N-Butylbromide

20mg 18 mg/kg I.V. rat Freely Soluble

Premosan 10mg/2mL

Metoclopramide HCl

10mg 50 mg/kg I.V. rat Very Soluble

Cynovit Injection 1mg/mL

B12 – Cyanocobalami

n (Code #1013012)

1mg 2000 mg/kg I.V. mouseSparingly Soluble

Mikacin 100 mg/2 ml Injection

Amikacin Sulphate 1mg

(Code#0101057)

210mg 4000 mg/kg I.V. rat Freely Soluble

Salurin Injection 20mg/2mL

Furosamide(Code#

0106008)20mg 800 mg/kg I.V. rat Not soluble

Rantag 50 mg/2 ml Injection

Ranitidine HCL (Code#

0118014)25mg 85 mg/kg I.V. rat Very soluble


The sampling procedure refers to the method of collecting the residues from the surface so that they can be measured.

Cleaning Validation…......Sampling Methods

Types Advantages Limitations

Swabs & Wipes

Dissolves & physically removes sample, adaptable to wide variety of area

May introduce fibers, technique dependent, hard-to-reach areas

RinseEasy, quick, non-intrusive, large surface area

Limited information about actual surface cleanliness

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Swab sampling techniques:

(1)One of the most widely used technique for chemical and microbial sampling.

(2)Swabs are being wet with solvent aiding solubilization and physical removal of surface residues.

(3)Results are technique dependent.

Cleaning Validation…......Sampling Methods

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Microbial swab (sterile)

Chemical swabs (Texwipe)

Cotton wipes

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(5)Generally 1 swab sample per location is adequate.

(6)Multiple swabs can be taken to improve surface recovery.

(7)Typical swabbed per site varies from 25 cm2 to 100 cm2. There is no “magic” number.

(8)PTFE (chemically inert) templates may be used for accurate swabbing area. e.g. (Teflon)

(9)“Difficult to clean” equipment surfaces shall be identified and sampled.(10) Representative surfaces of different materials (MOCs) should be sampled.

Cleaning Validation……......Sampling Methods

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10 cm

10 cmSwab area templates

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(11)10 Nos. Wiping should be unidirectional at a time. Parallel strokes should be employed to cover entire swab area.


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Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc Quality Assurance



Example of “Difficult to clean” locations of an RMG:


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Courtesy: Rapid mixer granulator, Kevin.

The design aspect of the equipment should be considered to identify “difficult to clean” locations.Quality Assurance


Rinse sampling techniques:

Rinse sampling involves using a liquid to cover the surfaces to be sampled.(1)One of the easy and widely used sampling

method.(2)Most preferable liquid for rinsing is water.


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Specific vs non-specific methods:

(1)A non-specific assay may detect a variety of residues.

(2)A specific assay may quantify any anticipated residue.

(3)It is essential to correlate the results from a specific method to the results from other non-specific methods that might be used for routine monitoring of cleaning effectiveness.

Cleaning Validation……Analytical Methods

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HPLC

pH meter

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Specific Test Methods Non-Specific Test Methods

UV/Visible SpectrophotometryNear Infrared Spectrophotometry (NIR)High Performance Liquid Chromatography (HPLC)Mid Infrared Spectrophotometry (MIR)Atomic AbsorptionCapillary Zone ElectrophoresisEnzyme Linked Immunosorbant Assay (ELISA)

Total Organic Carbon (TOC)

pHTitration

ConductivityGravimetric

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The analytical methods used for testing cleaning samples must be validated for [ICH Q2 (R1)]:

Limit of Detection (LOD) Limit of Quantification (LOQ) Specificity Accuracy Repeatability Precision Range Linearity Recovery


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The analytical method used for evaluation of cleaning sample is different that used for product assay.

If the target limit in the analytical sample were 5.2 μg / mL, and a method was only able to detect down to 7.0 μg / mL, that method would not be useful for cleaning validation purposes.

The target value should be within the linearity range

of the specific method.What if the calculated acceptance value is less than the detectable level of an analytical method?There may be two options available……….


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Choose more efficient analytical method !

Example: Derived acceptance limit = NMT 4.0 μg / mLAnalytical LOQ = 5.5 μg / mLAnalytical Method = UV/Visible Spectrophotometry

New method adopted = Ion mobility spectrometry

New LOQ = 2.0 μg / mL


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Increase the sampling area to achieve at least LOQ value!

Example: Derived acceptance limit = NMT 4.0 μg / mLAnalytical LOQ = 5.5 μg / mLSwab area = 25 cm2


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Revised swab area =

25 cm2

4.0 μg / mL

× 5.5 μg / mL

= 35 cm2 (7 cm × 5 cm)

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Recovery studies :Procedure :o Spike coupon with known amounto Allow to dryo Remove in swab or simulated rinse procedureo For swab, desorbo Analyze sampleo Compare to expected 100% value

This is done at surface acceptance (or below) limit.

Cleaning Validation………Analytical Methods

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Swab recovery schematic :

Cleaning Validation…………Analytical Methods

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1. Spike control diluent directly

ControlB

μg/mL

ControlC

μg/mL

Standard

solutionA

μg/mL

2a. Spike

coupon

2b. Swab

coupon

2c. Extract swab Quality Assurance


Recovery calculation 1 (Spiked against Standard):

(C μg/mL) × (Conc. of standard mL)

% Recovery = × 100

(A μg/mL) × (Conc. of Sample mL)


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Recovery depends on spiked standard of known concentration.Recovery depends on material surface, sampling method and some what on analytical method.

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Recovery calculation 2 (Spiked against Positive control) :

(C μg/mL) × (mL)% Recovery = × 100

(B μg/mL) × (mL)


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More useful if defined standard is not readily available.

Swab recover study with multiple analysts : Usually 3 replicates by one sampler. Use lowest value of any one run. Quality Assurance


Rinse recovery schematic :


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Pipette with rinse

solution (known volume)

Spiked coupon

Collection beaker

Spike bottom of SS beaker

Lab shaker

Case 1 Case 2

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Minimum acceptable recovery:

Specify in cleaning validation master plan or master protocol.

Minimum swab recovery of 70 % - 80 %. Carry out recovery study for different material

surfaces (Material Of Constructions). Chose right wetting solvent (soluble) and

absorbent swab material to improve recovery. May allow <50 % recovery with written

justification.


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o DEHT = Max. allowed time, between end of usage and employing cleaning

o CEHT = Max. allowed time, between end of cleaning and further usage

Cleaning Validation………………Hold Times

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Hold Time studies

Cleaned Equipment Hold Time

(CEHT)

Dirty Equipment Hold Time

(DEHT)

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Dirty equipment hold time study (DEHT) :

Soils may become more difficult to clean over time.

Maximum DEHT should be in SOPs. Maximum time shall be set in conjunction with

production. Representative / worst case product can be

selected for study. Equipments support wet processing can be

selected. If extra cleaning is desirable, then it should be

in SOP. May be expressed in days but preferably by

hours.

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Cleaning Validation……………Hold Times

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Dirty equipment hold time study (DEHT) :

Method

Carry out microbiological sampling at 24 hr., 48 hr., 36 hr., …... from the dirty equipments.

Clean the equipments as per SOPs. Carry out chemical sampling after cleaning. Compile all results (chemical and microbial). Successful results shall standardize the

maximum DEHT. Failure of any results shall reduce the max.

DEHT followed by another 3 verification runs. 75


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Cleaned equipment hold time study (CEHT) :

Microbiological evaluation is the key focus area. Maximum CEHT should be in SOPs. Representative / worst case product can be

selected for study. Vitamins, nutritional supplements, product

containing Starch or Gelatin may represent worst cases.

Protection during storage of cleaned equipments should be as per SOPs.

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Cleaned equipment hold time study (CEHT) :

Method

Clean the equipments as per SOPs. Store under protection (as per routine

procedure). Carry out microbiological sampling at 24 hr., 48

hr., 36 hr., …... Verify the results against limit (less than

validation limit). Successful results shall standardize the

maximum CEHT. Failure of any results shall reduce the max.

CEHT followed by another 3 verification runs. Do not set max. CEHT on “until failure” basis.


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Campaign hold study (CHS) :

Cleaning after production of definite number consecutive batches.

Negotiate with production related to number of batches.

Simulate max. anticipated hours of campaign production.

Cumulative deposition of residues may accelerate product degredation.

Perform cleaning and sampling at the end of campaign.

Max. CHS (no. of batches + time) should be in SOPs.

Batch to batch or lot to lot cleaning is advisable. More suitable for dedicated product

equipments.


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Cleaning Validation……....All aspects of CV

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Courtesy: Biopharm internationalQuality Assurance


Swab Recovery

Study

Rinse Recovery

StudyDeciding Sampling

Points

Cleaning Limit(Swab/Rinse)

Method Validation

Swab Sample

Sampling

Rinse Sample

Hold Time Study

Clean Hold Time

Dirty Hold Time

MACO Calculation

Dose Base Criteria

10 ppm Criteria

Testing

API Testing Microbial Testing

Non-SpecificTesting

Single Therapeutic Dose

Toxicity

Solubility

Calculation Surface Area of product contact equipment

Requirements

Conclusion

CLEANING VALIDATION MASTER PLAN + SOP

Worst Case Product Matrix approach

+Equipment Train

Cleaning Validation Protocol

Product Identified

Cleaning Validation

Report

Cleaning Validation....Julphar aspects of CV

Quality Assurance


Cleaning Validation……USFDA 483 Citations

Cleaning Parameters

“….. cleaning of ….. has not been validated, nor is the spray temperature, volume or time defined.”

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Time of Cleaning

“Equipment cleaning is performed on a “clean until clean” basis. There has been no determination of the number of cleanings required to ensure the cleanliness of the equipment.”

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Manual Cleaning

“Hands on training for equipment cleaning operations is not provided and there is no program in place to assure cleaning consistency between operators.”

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Cleaning Log

“There is no assurance that cleaning is conducted as stated in their SOPs…… There are no cleaning logs to indicate that this has been done.”

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Poor Cleaning

“….. we observed foreign material on the filter grates….. Daily cleaning as per SOP…..failed to remove the material. End of process cleaning as per SOP…..failed to remove the material. Weekly cleaning as per SOP……failed to remove the material.”

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Detergent Concentration

“Detergent is dispensed into the ……Stopper Washer reservoir every third cycle. No data has been collected to determine the detergent concentration each cycle…..”

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Cleaning Agent Labeling

“The firm’s control over IPA 100% used to clean equipment in production is inadequate. …..bottles are not labeled…..with date, expiration or who dispensed, ….no scientific information….which would establish an expiration date…..”

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Acceptance Limit

“….. acceptance criteria….shall not exceed…..μg/cm2. There is no data to justify this limit.”

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Sampling Locations

“Swabbing was performed on general contact areas without taking into consideration area such as edges and crevices.”

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Sampling Locations

“Exact / precise swab locations are not identified.”

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Swab Sampling

“Swab samples collected…..from different locations from each piece of equipment are combined into one sample and tested such.”

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Rinse Sampling

“….firm’s validation…..is inadequate in that the rinse solutions were not analyzed for the presence of the active ingredient residues that might be present.”

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Rinse Sampling

“There is not an exact sampling procedure for the collection of rinse water samples which takes into account the surface area involved, time of contact….., volume of rinse, and temperature of rinse, along with a formula to calculate the amount of possible contamination based on analysis.”

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Dirty Equipment Hold Time

“No time frames / limitations have been established for production equipment from end of use to start cleaning.”

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Cleaned Equipment Hold Time

“A time limit for the length of time allowed between cleaning and the use of the manufacturing equipment…..has not been established.”

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Recovery Studies

“Equipment cleaning validation studies for…..did not include…..present recovery studies on rinse samples.”

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Recovery Studies

“…..each drug’s recovery test was performed only once, therefore there is no data to show reproducibility.”

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Recovery Studies

“Your firm is using the average of recovery results (from different amounts of spiked solution) instead of the worst case result. Using a value that represents the average does not ensure that contamination is not higher than calculated.”

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Change Control

“The SOP has been revised twice. No review was performed to determine if a re-validation was necessary for the changes……”

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Cleaning Validation……….......................???

Are we missing anything

Quality Assurance


Cleaning Validation

Health & Medicine

Fundamental of cleaning validation