Cleaning+Procedures V5 Handouts

“‫طراحی و توسعه روشهای پاکسازی و شستشو با رویکرد "کیفیت منتج از طراحی‬
Quality by Design (QbD)

in Development of Cleaning Procedures
A. Shah Miri
App. Pharm.; M.Sc. Biopharmaceutics; DBA
QC/QA Consultant; Compliance Expert
shahmiri1999@yahoo.de
Nov 2023 QbD in Development of Cleaning Procedures 1
Presentation Outline
 Introduction
 Cleaning steps
 Cleaning approaches
 Water quality for cleaning
 Cleaning mechanisms
 Cleaning parameters
 Selection of cleaning agent
 Clean-ability testing
 Activities reducing bio-burden
 Holding times
A. Shah Miri
1
‫روشهای پاکسازی و شستشو )‪(Cleaning Procedures‬‬
‫محصوالت دارویی و مواد اولیه میتوانند با دیگر محصوالت دارویی یا مواد اولیه‪،‬‬
‫شوینده ها‪ ،‬میکروارگانیسمها و یا دیگر مواد (از قبیل ذرات معلق‪ ،‬گرد و غبار‪ ،‬چرب‬
‫کننده ها‪ ).... ،‬آلوده گردند‪.‬‬
‫در موارد زیادی ممکن است از یک دستگاه برای تولید محصوالت متفاوتی استفاده‬
‫گردد که بدین ترتیب امکان وقوع آلودگی متقابل دور از ذهن نیست‪.‬‬
‫بهمین دلیل به منظور جلوگیری از آلودگی متقابل اعمال روشهای پاکسازی و‬
‫شستشوی موثر‪ ،‬ضروری میباشند‪.‬‬
‫به منظور تصدیق اثربخشی روشهای پاکسازی و شستشو‪ ،‬میبایستی اعتبارسنجی این‬
‫روشها )‪ (Cleaning Validation‬به اجرا گذارده شود‪.‬‬
‫اثبات مستند صحت ادعا !!!‬

‫(شاهمیری)‬
‫‪Nov 2023‬‬ ‫‪QbD in Development of Cleaning Procedures‬‬ ‫‪3‬‬
‫مراحل پاکسازی و شستشوی )‪(Cleaning steps‬‬
‫‪ -1‬خشک شویی‪:‬‬
‫حتی االمکان بقایای پودر و گرد وغبار دارویی را از روی دستگاه به کمک جاروبرقی‬
‫جمع کنید‪.‬‬
‫در صورت لزوم از کاردک پالستیکی با احتیاط برای خراشیدن پودرهای خشک شده‬
‫استفاده کنید‪.‬‬
‫‪ -2‬شستشو‪:‬‬
‫مراحل شستشو طبق دستورالعمل دارای مراحل زیر میباشد‪:‬‬
‫‪ -2-1‬پیش شستشو با آب‬
‫‪ -2-2‬شستشو با آب و ماده شوینده مناسب‬
‫‪ -2-3‬آبکشی (حداقل دوبار شامل آبکشی اولیه و آبکشی نهایی)‬
‫‪ -2-4‬ضدعفونی‪/‬استریلیزاسیون ) در صورت لزوم(‬
‫‪ -3‬خشک کردن‬
‫‪Nov 2023‬‬ ‫‪QbD in Development of Cleaning Procedures‬‬ ‫‪4‬‬
‫‪2‬‬
Cleaning approaches
A. Shah Miri
Cleaning Approaches (1/4)
 There are different approaches to performing cleaning steps.

 Cleaning procedures may be completely manual to completely
automated.
• Manual cleaning
• Clean-In-Place (CIP)
• Clean Out-of-Place (COP)
• Sterile-In-Place (SIP)
3
 Manual Cleaning
Difficult to validate (Scrubbing/wiping, soaking, immersion, …)
• The risk involved in manual cleaning processes is taken care of
with following:
Detailed cleaning SOP!
Training/Qualification of
cleaning operators
 Manual Cleaning
• Proper washroom design with drying, protection and storage
requirement. ‫اتاق شستشو با طراحی مناسب‬
4
 Clean-Out-Of-Place (COP)
• Cleaning of disassembled equipment is performed in a central
washing machine / facility.
• The washing machine also requires validation such as:
‒ cleaning operation sequence
‒ the temperature
‒ ultrasonic activity
‒ detergent quantity
‒ cycle time
‒ etc.
 Clean-In-Place (CIP)
• Cleaning of the equipment is performed in place without
disassembling.
• Cleaning process may be controlled manually or by an automated
program.
Very consistent and reproducible cleaning method.

Can be validated easily.
Being a closed system visual inspection of all components is
difficult.
5
CIP Systems
 The principal objective is to achieve the desired cleanliness without

disassembling the process equipment.
Simplified scheme of a CIP skid Simplified scheme of a CIP system

connected to a manufacturing vessel embedded into the manufacturing vessel
A Typical CIP Program
 In the high flow, low pressure system, a cascading action serves to

clean the lower portions of the process vessels.
Pre-rinse:
with water at 40 °C – 60 °C to remove the bulk of the soil load
Alkali circulation:
A continuous wash of from 0.5 % to1.0 % alkaline detergent
at 65 °C – 80 °C to remove organics residues
Rinse with water to remove caustic residues
Acid circulation:
A continuous wash of from 0.5 % to 1.0 % nitric acid solution
at 65 °C – 80 °C to remove inorganic residues/salts
Rinse with water to remove acidic residues AND the final rinse
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A Typical CIP Program
 Conductivity can be used to monitor the various cleaning steps.

 Each cleaning solution’s flush is typically followed by a water
flush, so each step of the cleaning process will appear on a strip
chart as a series of conductivity increases.
 The progress of the final rinse can be followed as a decrease in
conductivity until the conductivity drops to the conductivity of the
rinse water, which indicates that rinsing is complete.
Water quality for cleaning ‫کیفیت آب برای تمیزکاری و پاکسازی‬
A. Shah Miri
7
Water Quality for Cleaning (1/4)
 The quality of the water used for aqueous cleaning is critical for
cleaning efficacy and performance.
 This includes the water quality for:

• any pre-wash
• the washing step
• any rinse (Initial rinse and final rinse)
 Water quality includes:

• pH, Conductivity
• Hardness
• TOC
• Biological properties
 Quality of water for pre-washing:

• The quality of water for pre-washing is the least critical of the
three cases.
• Pre-washing is solely used to flush residues from the previous
product prior to washing step itself.
• Water from previous final rinse could be recycled and used for
pre-washing.
(Not water from initial rinse because these will be highly

contaminated with residues and cleaning agents!)
8
 Quality of water for washing:

• Here the most critical element to control is the water hardness.
(Ca 2+, Mg2+ ions)
• If alkaline cleaning agents are used (e.g. NaOH or KOH),

hardness may precipitate as calcium carbonate at high pHs.
• This may be minimized by utilizing a cleaning agent with
chelants (e.g. EDTA) or by acidic post rinse.
 Quality of water for rinsing:

• Here the quality of the water for the final rinse should be at least
as good as the quality of water in the next manufacturing step.
The rationale for this is that any residues left behind from
the final rinse are residues that would be added in the next
manufacturing step anyway.
• Here some examples:
‒ For oral products formulated with PW  use PW
‒ For parentrals formulated with WFI  use WFI
‒ for API made by organic synthesis route  use PW
plus organic solvent rinse
(to remove any water from equipment)
9
Cleaning Mechanism ‫مکانیسم تمیزکاری‬
A. Shah Miri
Cleaning Mechanisms (1/2)
 Several basic mechanisms exist to remove residues from equipment,

including:
• Mechanical action ‫ مکانیکی‬/ ‫عملیات فیزیکی‬
refers to physical actions such as brushing or pressurized water
• Dissolution ‫انحالل‬
involves dissolving residues, considering solubility characteristics
of the materials (solute), with a suitable solvent such as:
:‫شامل حل کردن باقیمانده ها با در نظر گرفتن محلولیت مواد درحالل مناسب مانند‬
‒ water ‫آب‬
‒ non-aqueous solvent (environmental concerns!) ‫حاللهای آلی‬
‒ combination of aqueous and non-aqueous solvents. ‫ترکیب این دو‬
‒ alkaline or acidic solvents, enhancing dissolution of the materials
‫حاللهای اسیدی و قلیایی‬
10
Cleaning Mechanisms (2/2)
 Several basic mechanisms exist to remove residues from equipment,

including: (cont.)
• Detergency ‫شویندگی‬
requires the use of detergents / surfactants, usually in an aqueous
system, act in different ways:
‒ Wetting agents ‫خیس کننده‬
‒ Solubilizers ‫حل کننده‬
‒ Emulsifiers ‫امولسیفایر‬
‒ Dispersants ‫پخش کننده‬
• Chemical reactions ‫واکنشهای شیمیایی‬
in which the residues are chemically changed such as:
‒ Oxidation ‫اکسیداسیون‬
‒ Hydrolysis ‫هیدرولیز‬
Cleaning Parameters ‫پارامترهای تمیزکاری‬
A. Shah Miri
11
Cleaning Parameters (1/6)
 During developing of the cleaning procedure it should be noted that

the results of cleaning procedure are determined by four factors /
parameters (CTMT):
• Chemistry )‫شیمی (بقایا و شوینده‬

• Temperature ‫دما‬
• Mechanics ‫ مکانیکی‬/‫عملیات فیزیکی‬
• Time ‫مدت زمان‬
Forces acting on soil during cleaning
 The following checklist summarizes shortly all the aspects to be

taken into consideration during optimization of cleaning procedures:
(see next slides!)
 Chemistry ‫ بقایا (محصول ناخلف) و شوینده‬/ ‫شیمی مواد‬

• Identifying and characterizing the worst case product.
• Selecting the cleansing agent considering:
‒ Suitability for worst case product ‫مناسب زدودن محصول ناخلف‬
‒ Material compatibility ‫سازگاری با تجهیزات‬
‒ Environmental compatibility ‫سازگاری با محیط زیست‬
‒ Personnel safety at work ‫ایمنی پرسنل‬
‒ Knowledge of composition ‫ترکیب شوینده‬
• Establishing concentration of cleansing agent with regard to CTMT.
 Rule of thumb: as much as necessary, as little as possible.

‫ آنقدر که ضروری است و حتی االمکان کم‬
12
 Temperature ‫دما‬
• Consideration of manufacturers’ specification regarding the optimum
scope of action for the cleansing agent.
• Adapting to contamination.
• Adapting to working conditions (WIP, CIP / manual).
• Time-saving through external heating.
• Guaranteeing the temperature constancy.
• Guaranteeing the temperature control and checks.
 Rule of thumb: as high as possible.

. ‫ تا حد امکان باال‬:‫ قانون سرانگشتی‬
 Mechanics ‫ مکانیکی‬/ ‫عملیات فیزیکی‬

• Manual cleaning: (Mechanical / Physical action!)
‒ Selection of suitable tools (e.g. sponges, brushes, high-pressure
cleaners) whilst considering material and surface compatibility.
• WIP / CIP cleaning: (Pressurized water!)

‒ Selection of suitable spray nozzles.
‒ Sufficient number of spray nozzles.
‒ Correct positioning of spray nozzles. Checked through
‒ Prevention of dead spaces. “Riboflavin test”
‒ Ensuring sufficient spray pressure. during qualification!
‒ Ensuring sufficient flow rates.
 Rule of thumb: as efficient as possible.

. ‫ تا حد امکان کارآمد‬:‫ قانون سرانگشتی‬
13
 Time ‫مدت زمان‬

• Only the time the cleaning agent is left to work is of relevance here.
• Minimizing the time required to take effect using optimum
arrangement of chemical, temperature and mechanical factors.
• Critical inspection of working procedures within the total process
(pre-cleaning, assembly / disassembly, rinsing, drying).
• Guaranteeing the continuity/consistency of the total process.
 Rule of thumb: as short as possible.

‫ حتی االمکان کوتاه‬:‫ قانون سرانگشتی‬
 It is important to maintain consistency in the parameters and factors

that affect the cleaning process to obtain consistent cleaning.
(TACT/CTMT) ‫ حفظ ثبات در پارامترها و عوامل موثر بر فرآیند تمیزکاری و شستشو‬
. ‫ بسیار مهم است‬،‫برای به دستیابی مداوم به درجه تمیزی مشخص‬
Constraints imposed by the process on the various parameters:
14
Qualification and Validation *
:‫ ریبوفالوین تست‬
‫ مخلوط آالینده حاوی‬،‫• برای ارزیابی تمیزی سطوح‬
.‫ریبوفالوین روی سطوح مربوطه اعمال می شود‬
‫ به رنگ زرد فلورسنت است که‬UV‫• این آلودگی در نور‬
.‫به وضوح قابل مشاهده میباشد‬
‫• سطح آلوده متعاقبا با استفاده از یک فرآیند تمیزکاری‬
.‫ مورد بازرسی قرار میگیرد‬UV ‫شستشه و تحت نور‬
Riboflavin test /
Aim of the test: Criterion of quality after the test:
Fluorescence test:
Weak point test Localizing critical points; - Visible fluorescence at critical points;
provided as optional preliminary stage these are to be confirmed through a
to the cleanability test. cleanability test.
Cleanability test Verification of full cleanability. - No visible fluorescence
Optimization test Stepwise optimization and checking of - No visible fluorescence.
suitability of new parameter values - Improved parameter values
through separate, new cleanability tests. (e.g. reduced water consumption, shorter
cleaning time)
 Validation of these systems may be difficult because of the potential

incompatibilities in requirements for the design of CIP and SIP
facilities. ‫طراحی مناسب سیستمهای تمیزکاری و شستوی اتوماتیک‬
(PIC/S PI 007; Recommendations on validation of aseptic processes)
 All systems have dead legs* to a greater or lesser extent and the
required orientation of the dead legs differ for CIP and SIP.
The orientation for CIP dead legs is slightly sloping so that the
cleaning solution can enter and also drain away.
The orientation for SIP dead legs is vertically up so that steam
can downwardly displace the air.
.‫ مناطقی در سیستم لوله کشی که در آن مایع یا گاز راکد و در آن آب یا گاز در حین شستشو مبادله نمی شوند‬
15
.‫ مناطقی در سیستم لوله کشی که در آن مایع یا گاز راکد و در آن آب یا گاز در حین شستشو مبادله نمی شوند‬
 Potentially difficult to reach locations within the sterilizer load or

equipment train (for SIP applications) should be evaluated.
.SIP ‫ ارزیابی کیفی و کمی امکان دسترسی به مکان های بالقوه دشوار در سیستمهای‬
For example, filter installations in piping can cause a substantial
pressure differential across the filter, resulting in a significant
temperature drop on the downstream side.
‫بعنوان مثال افت ملموس فشار بعد از فیلترها که به افت معنی دار دما در پایین‬
.‫دست سیستم دامن میزند‬
FDA recommends placing biological indicators at appropriate
downstream locations of the filter.
‫ استفاده از بایواندیکاتورها در بخشهای پایین دستی فیلترها‬:FDA ‫توصیه‬
(GfI Sterile drug products produced by aseptic processing!)
16
Selection of cleaning agent ‫ شوینده‬/ ‫انتخاب پاک کننده‬
A. Shah Miri
Selection of Cleaning Agent (1/6)
 Cleaning agents / detergents (Secondary materials ‫ )مواد ثانویه‬should

 facilitate the cleaning process and ‫تسهیل فرآیند تمیزکاری‬
 be easily removable. ‫قابلیت حذف‬
 Broadly, three categories of cleaning agents are used:
• Organic solvents (Alcohols, Acetone, Chloroform), ‫حاللهای آلی‬
• Commodity acids and alkalis, ‫حاللهای اسیدی و بازی‬
• Formulated detergents (multi-components). ‫شوینده های فرموله شده‬
 The composition of the detergent should be known and its removal
during rinsing, demonstrated.
. ‫ ترکیب ماده شوینده باید مشخص و حذف آن در حین شستشو نشان داده شود‬
17
 Cleaning agents: ‫پاک کننده‬

are substances that are used to remove dirt or contaminants.
(acidic, alkaline, neutral cleaning agents)
 Detergents: ‫شوینده‬
are compounds with lipophilic - hydrophilic parts (HLB system)
and hence a “dual nature” that lower the surface tension between
two immiscible phases. (ionic, non-ionic surfactants)
 Process cleaners may contain: ‫ترکیبات پاک کننده های صنعتی‬
• single component, such as an organic solvent,
• multicomponent formulations that use multiple cleaning mechanisms such as:
‒ Dissolution ‫انحالل‬
‒ Detergency ‫شویندگی‬
‒ Chemical reactions ‫واکنشهای شیمیایی‬
 Alkaline cleaning agents: ‫پاک کننده های قلیایی‬

such as NaOH or KOH are used to remove organic soils using
alkaline hydrolysis.
 Acidic cleaning agents: ‫پاک کننده های اسیدی‬
such as HCl or HNO3 are used to remove inorganics and salts.
 Neutral cleaning agents: ‫پاک کنده های خنثی‬
are used in manual cleaning applications or with sensitive substrates
due to their mild pH and enhanced compatibility.
 Specialty Chemistries: ‫ترکیبات خاص‬
for applications responding to other cleaning mechanisms such as:
• oxidation by NaOCl which produces smaller and more water
soluble residues or
• other unique characteristics (like heavy foam).
18
 Hydrophilic - Lipophilic Balance, HLB: ‫تراز آب دوستی – چربی دوستی‬

• HLB system classifies the surfactants based on their size and strength
of water-loving and oil-loving groups of the emulsifier.
‫ سورفکتانت ها را بر اساس اندازه و قدرت گروه های آب دوست و چربی‬HLB ‫• سیستم‬
.‫دوست امولسیفایر طبقه بندی می کند‬
The HLB of an emulsifier is an excellent indication of:
“what the emulsifier system will do?”
HLB Range Usage
1.5 - 3 Anti-foaming agents
4–6 W/O emulsifiers
7–9 Wetting agents
8 – 18 O/W emulsifiers
13 – 15 Detergents
10 - 18 Solubilizers
 Points to consider regarding foaming detergents:

• A moderate-to-high foaming detergent is not desirable when used in a
CIP application, as it creates high-shear and thus is prone to foam
formation which provides inefficient surface coverage when sprayed
on the inside of a vessel through a spray ball.
،‫ مطلوب نیست‬CIP ‫• یک شوینده با کف متوسط تا زیاد هنگام استفاده در یک برنامه‬
‫زیرا تحت تاثیر برش باالی ایجاد شده مستعد تشکیل کف بوده که هنگام پاشش از طریق‬
.‫نازلها پوشش سطحی ناکارآمدی را در داخل ظرف فراهم می کند‬
• Conversely, it is desirable in a manual application, as this gives the

operator a visual indication of where the detergent solution has been
applied to the surface.
‫ زیرا برای اپراتور یک نشانه بصری از‬،‫• برعکس در تمیزکاریهای دستی کف زایی مطلوب است‬
. ‫محل استفاده از محلول شوینده روی سطح می باشد‬
19
 Further criteria are:

• Personnel safety at work ‫ایمنی پرسنل‬
(in manual applications, a neutral or mildly alkaline detergent,
pH 7.0 – 10.0 is desirable)
• Material compatibility ‫سازگاری با تجهیزات‬
(glass is not compatible with high pH-values while it is ideal in
CIP applications)
• Environmental compatibility ‫سازگاری با محیط زیست‬
(Effluent restrictions such as extreme pH-values, Phosphate,
BOD, COD, TOC …)
• No color or fragrances! ‫فاقد افزودنی های رنگی یا رایحه دار‬
‫آزمون قابلیت پاک شوندگی‬

Clean-ability Testing
(Cleaning Process Development)
A. Shah Miri
20
What is Clean-ability?
 Clean-ability is clearly an important parameter for determining the

“hardest-to-clean” product for use in cleaning validation studies.
 Cleaning processes that have been optimized through the selection
of the most appropriate cleaning agents/parameters (CTMT/TACT)
can reduce residues to the lowest risk level and provide a high
assurance of safety to patients. (Margin of safety!)
 Cleaning process development should begin in the laboratory with
bench-scale testing to develop the initial cleaning process
knowledge and understanding.
 As described in the American Society for Testing and Materials
(ASTM) E3106-18 “Standard Guide for Science- and Risk-Based
Cleaning Process Development and Validation,” cleaning process
development is now expected in the validation process.
What is Clean-ability?
 ASTM E3106 defines clean-ability as “the relative difficulty for

cleaning a piece of equipment or product.”
 Laboratory-scale studies are quick, economical and can answer
typical cleaning validation questions such as:
1. Which product is the hardest to clean?
2. Which cleaning agent provides the best cleaning?
3. Can we demonstrate that two cleaning agents are equivalent?
4. Which cleaning input parameters are critical?
5. What are the optimal cleaning parameter settings?
6. How long does it take to clean the equipment?
7. Are dirty-hold-time studies necessary at commercial scale?
21
 Clean-ability testing consists of applying products or compounds

onto the surfaces of coupons, recording the weight of the product or
compound applied, and then exposing the coupons to a simulated
cleaning process.
 The coupons may be tested with products applied “as is,” or the
products may be “dried onto the coupons” before testing to simulate
equipment surface conditions prior to cleaning.
 Replicate coupons for each product are necessary if a statistical
analysis is desired.
 The coupons are then removed and examined to determine how
much product was removed or remains on the surface and the
significance of the result.
 The coupon is SS-316L with a #4 finish and engraved with:
• (A) the MOC,
• (B) the date of manufacture,
• (C) the coupon number,
• (D) the manufacturer ID
• (E) the test area (55 cm)

Example Coupon Used For Cleanability Studies;
Compliant with ASTM standard G121
22
 Once the coupons have been exposed to the cleaning process, the
overall effectiveness of the cleaning of the product or compound
needs to be measured in some way.
 A few qualitative or quantitative methods are used:
• Visually clean (qualitative, debated sensitivity!)
• Analytical methods (quantitative)
• Gravimetric method (quantitative)
Gravimetric Method
 This quantitative method measures the amount of residue removed

from or remaining on the test coupons after the cleaning test.
 Two or more coupons made of the MOC of the equipment are
weighed and then coated with the products being tested and weighed
again.
 These coupons are then subjected to the test conditions & reweighed
after the test.
 The difference in weight may define either how much product was
removed or how much remains.
 The gravimetric method can detect residues on coupon surfaces
down to the mg to μg/cm level.
23
Gravimetric Method
 Approximately 1 gram of product is

applied (spiked) onto the previously
weighed test coupons and the spiked
weight recorded.
 The spiked coupons are cleaned using
the same specified cleaning conditions.
(controlled agitated immersion or under
simulated flow conditions)
 The cleaned coupons are dried in the
oven (40 ºC/12Hrs)
 The dried coupons are re-weighed and Simple Manual Beaker Test Technique.
dry weight recorded.
Cleaning Effectiveness Factor (CEF)

Gravimetric Method
 In the ASTM method G122 “Standard Test Method for Evaluating the
Effectiveness of Cleaning Agents,” a quantitative measure called the
Cleaning Effectiveness Factor (CEF) is derived from the study data.
(CEF) ‫محاسبه فاکتور اثربخشی تمیزکاری‬
𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑐𝑜𝑢𝑝𝑜𝑛 𝑎𝑓𝑒𝑡𝑟 𝑐𝑙𝑒𝑎𝑛𝑖𝑛𝑔 − 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑐𝑜𝑢𝑝𝑜𝑛

𝐶𝐸𝐹𝑟𝑒𝑚𝑎𝑖𝑛𝑖𝑛𝑔 =
𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑐𝑜𝑢𝑝𝑜𝑛 + 𝑃𝑟𝑜𝑑𝑢𝑐𝑡 − 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑐𝑜𝑢𝑝𝑜𝑛
(𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑐𝑜𝑢𝑝𝑜𝑛 + 𝑃𝑟𝑜𝑑𝑢𝑐𝑡) − 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑐𝑜𝑢𝑝𝑜𝑛 𝑎𝑓𝑒𝑡𝑟 𝑐𝑙𝑒𝑎𝑛𝑖𝑛𝑔

𝐶𝐸𝐹𝑟𝑒𝑚𝑜𝑣𝑒𝑑 =
𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑐𝑜𝑢𝑝𝑜𝑛 + 𝑃𝑟𝑜𝑑𝑢𝑐𝑡 − 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑐𝑜𝑢𝑝𝑜𝑛
24
‫کاهش بار میکروبی‬
Activities Reducing Bio-Burden
A. Shah Miri
Regulatory Basis
 The earliest guidance document (the 1993 FDA guidance) states

“This guide is intended to cover equipment cleaning for chemical
residues only”
 In the PIC/S guidance document, there’re explicit statements that
“removal of potential microbial contaminants” is a part of cleaning
validation. (PIC/S PI 006-3, #7.2.1)
 The risk presented by microbial and endotoxin contamination
should be considered during the development of cleaning validation
protocols. (PIC/S GMP PE 009, Annex 15)
25
Activities Reducing the Bio-burden (BB)
 Control measures to limit the BB in the manufactured product:

• Limiting BB in raw materials
• Limiting BB in packaging materials
• Limiting BB in the manufacturing environment
• Limiting BB on manufacturing equipment product-contact
surface area. (Cleaning validation!)
 Control measures to reduce the BB on process equipment product-

contact surface area:
• The cleaning process itself
• A separate sanitization step
• Drying the equipment following cleaning
• Preventing equipment recontamination in controlled environment
The Cleaning Process
 Many of the factors in a typical cleaning process, such as the

followings, are hostile to survival of MOs:
• A high temperature ( ≥ 60ºC)
• The pH extremes (pH ≥ 11 or ≤ 4)
• The presence of oxidizing agents such as sodium hypochlorite
which in addition to producing smaller, more water soluble
residues, is a well-known biocide. (disinfection!)
• The presence of surfactants which can assist in good physical
removal of MOs including bacterial spores. (sanitization!)
 An effective cleaning process also reduces potential nutrients,
which if left on surfaces following cleaning, can lead to more
significant BB proliferation if equipment is stored in a wet state.
26
A Separate Sanitization Step (1/3)
 Separate sanitization steps (thermal or chemical) are more common

in situations where the cleaning process:
• involves a neutral pH cleaner
• occurs at ambient temperature,
• includes manual cleaning of disassembled parts.
 Suitable chemical sanitizers for process equipment include:
• sodium hypochlorite (chlorine bleach),
• quaternary ammonium compounds,
• alcohol (ethyl or isopropyl),
• hydrogen peroxide, and
• peracetic acid.
 With the exception of (isopropyl)alcohol and hydrogen peroxide,

additional rinses would be necessary to remove any chemical
residues of the sanitizer from the equipment.
 Additional advantages of IPA as a sanitizer:
• serves as a final “polishing” rinse to further reduce residues of
drug product.
• may serve to dry the equipment, which reduces the possibility
of BB proliferation on storage of cleaned equipment.
 Those sanitizer residues may also have to be evaluated as residues
to be measured in the cleaning validation protocol.
27
 For such chemical treatments, it is not an expectation that the

equipment be sterile.
 Unless the final rinse is with sterile water, MOs will be reintroduced
into the equipment from the use of WFI or PW as the final rinse.
 An alternative to sanitizing immediately after cleaning usually
involves sanitizing after storage and immediately before use.
 This may be used in situations where it is difficult to control
microbial recontamination or proliferation during storage.
 It should be noted that control of storage conditions, if possible, is
preferable (GMP environment !)
Holding Times
A. Shah Miri
28
Equipment Holding Times
 There are two aspects of “hold times” generally evaluated for

validated cleaning processes in pharmaceutical manufacturing:
• Dirty Hold Times (DHT):
The time elapsed from the end of manufacturing until the
beginning of the cleaning process.
• Clean Hold Times (CHT):

The time elapsed from the end of the cleaning process until the
beginning of the use of the cleaned equipment for manufacture
of the next product.
Dirty Holding Time, DHT
 The cleaning process is designed to adequately clean the equipment

under worst case of normal operating conditions.
 A demonstration of effectiveness under worst-case, usually the
longest DHT should be conducted.
 For the maximum DHT ask the manufacturing department about the
longest time the equipment would be dirty before the leaning
process would be started.
 For the sake of conservancy, some extra time will be added to what
manufacturing and production department have specified.
 Considering these durations a practical duration of DHT is
proposed which is to be validated.
29
Clean Holding Time, CHT
 A professional judgment based on an analysis of storage situation

will justify a CHT by considering and documenting the following
issues:
• The characteristics of the cleaned equipment
‒ Kept drained and dried.
‒ Possible route of entry for external contamination identified
and adequately protected.
• The storage conditions of the equipment
‒ Wrapped or covered and kept in restricted access area.
‒ Storage conditions including temperature, humidity and air
quality (i.e. viable and non-viable particles) adequately
controlled and documented.
Good luck!
30

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“‫طراحی و توسعه روشهای پاکسازی و شستشو با رویکرد "کیفیت منتج از طراحی‬

Quality by Design (QbD)

Nov 2023 QbD in Development of Cleaning Procedures 1

Nov 2023 QbD in Development of Cleaning Procedures 2

‫اثبات مستند صحت ادعا !!!‬

‫مراحل پاکسازی و شستشوی )‪(Cleaning steps‬‬

Nov 2023 QbD in Development of Cleaning Procedures 5

Cleaning Approaches (1/4)

 There are different approaches to performing cleaning steps.

Nov 2023 QbD in Development of Cleaning Procedures 6

Detailed cleaning SOP!

Nov 2023 QbD in Development of Cleaning Procedures 7

Cleaning Approaches (2/4)

Nov 2023 QbD in Development of Cleaning Procedures 8

Nov 2023 QbD in Development of Cleaning Procedures 9

Cleaning Approaches (4/4)

Very consistent and reproducible cleaning method.

Nov 2023 QbD in Development of Cleaning Procedures 10

 The principal objective is to achieve the desired cleanliness without

Simplified scheme of a CIP skid Simplified scheme of a CIP system

Nov 2023 QbD in Development of Cleaning Procedures 11

A Typical CIP Program

 In the high flow, low pressure system, a cascading action serves to

Rinse with water to remove caustic residues

Nov 2023 QbD in Development of Cleaning Procedures 12

 Conductivity can be used to monitor the various cleaning steps.

Nov 2023 QbD in Development of Cleaning Procedures 13

“‫طراحی و توسعه روشهای پاکسازی و شستشو با رویکرد "کیفیت منتج از طراحی‬

Water quality for cleaning ‫کیفیت آب برای تمیزکاری و پاکسازی‬

Nov 2023 QbD in Development of Cleaning Procedures 14

 This includes the water quality for:

 Water quality includes:

Nov 2023 QbD in Development of Cleaning Procedures 15

Water Quality for Cleaning (2/4)

 Quality of water for pre-washing:

(Not water from initial rinse because these will be highly

Nov 2023 QbD in Development of Cleaning Procedures 16

 Quality of water for washing:

• If alkaline cleaning agents are used (e.g. NaOH or KOH),

Water Quality for Cleaning (4/4)

 Quality of water for rinsing:

Cleaning Mechanism ‫مکانیسم تمیزکاری‬

Nov 2023 QbD in Development of Cleaning Procedures 19

Cleaning Mechanisms (1/2)

 Several basic mechanisms exist to remove residues from equipment,

 Several basic mechanisms exist to remove residues from equipment,

“‫طراحی و توسعه روشهای پاکسازی و شستشو با رویکرد "کیفیت منتج از طراحی‬

Cleaning Parameters ‫پارامترهای تمیزکاری‬

Nov 2023 QbD in Development of Cleaning Procedures 22

 During developing of the cleaning procedure it should be noted that

• Chemistry )‫شیمی (بقایا و شوینده‬

 The following checklist summarizes shortly all the aspects to be

Nov 2023 QbD in Development of Cleaning Procedures 23

Cleaning Parameters (2/6)

 Chemistry ‫ بقایا (محصول ناخلف) و شوینده‬/ ‫شیمی مواد‬

 Rule of thumb: as much as necessary, as little as possible.

 Rule of thumb: as high as possible.

Cleaning Parameters (4/6)

 Mechanics ‫ مکانیکی‬/ ‫عملیات فیزیکی‬