Validation: Validation is a documented program that provides high degree of assurance that a specific process, method or system consistently produces a result meeting pre-determined acceptance criteria.
It is process of “Establishing documentary evidence that provide a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes”.
In the pharmaceutical industry, it is very important that in addition to final testing and compliance of products, it is also assured that the process will consistently produce the expected results.
Validation is action of proving in accordance with the principles of good manufacturing practices, that any procedure, process, equipment, material, activity or system actually leads to expected results.
Cleaning validation is documented evidence with a high degree assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits.
The primary regulatory concern driving the need for cleaning validation is cross contamination of the desired drug substance either by other API from previous batch runs or by residues from the cleaning agents used.
The prime purpose of validating a cleaning process is to ensure compliance with federal and other standard regulations
1. Cross contamination with active ingredients
Contamination of one batch of product with significant levels of residual active ingredients from previous batch cannot be tolerated.
In addition to the obvious problems posed by subjecting consumers or patients to unintended contaminants, potential clinically significant synergistic interactions between pharmacologically active chemicals are a real concern.
2. Contamination with unintended materials or compounds
While inert ingredients used in drug products are generally recognized as safe for human consumption, the routine use, maintenance and cleaning of equipment's provide the potential contamination with such items as equipment parts, lubricants and chemical cleaning agents3. Microbiological contamination
Maintenance , cleaning and storage conditions may provide adventitious microorganisms with the opportunity to proliferate within the processing equipment.
Validation: Validation is a documented program that provides high degree of assurance that a specific process, method or system consistently produces a result meeting pre-determined acceptance criteria.
It is process of “Establishing documentary evidence that provide a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes”.
In the pharmaceutical industry, it is very important that in addition to final testing and compliance of products, it is also assured that the process will consistently produce the expected results.
Validation is action of proving in accordance with the principles of good manufacturing practices, that any procedure, process, equipment, material, activity or system actually leads to expected results.
Cleaning validation is documented evidence with a high degree assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits.
The primary regulatory concern driving the need for cleaning validation is cross contamination of the desired drug substance either by other API from previous batch runs or by residues from the cleaning agents used.
The prime purpose of validating a cleaning process is to ensure compliance with federal and other standard regulations
1. Cross contamination with active ingredients
Contamination of one batch of product with significant levels of residual active ingredients from previous batch cannot be tolerated.
In addition to the obvious problems posed by subjecting consumers or patients to unintended contaminants, potential clinically significant synergistic interactions between pharmacologically active chemicals are a real concern.
2. Contamination with unintended materials or compounds
While inert ingredients used in drug products are generally recognized as safe for human consumption, the routine use, maintenance and cleaning of equipment's provide the potential contamination with such items as equipment parts, lubricants and chemical cleaning agents3. Microbiological contamination
Maintenance , cleaning and storage conditions may provide adventitious microorganisms with the opportunity to proliferate within the processing equipment.
In this slide contains introduction, qualification, preventive maintenance, requalification method.
Presented by: Malarvannan M (Department of pharmaceutical analysis).RIPER, anantapur
This presentation explains about qualifications of HPTLC, types of qualifications, design qualification , installation qualification ,operational qualification, performance qualification ,documentation of qualification .
The presentation was an overview of the GMP regulations specific to cleaning validation for medicine manufacturers. New guidelines for Health Based Exposure Limits were discussed along with common GMP deficiencies observed during TGA inspections.
This presentation includes detail about cleaning levels,equipments for cleaning validation , steps for cleaning method validation and analytical method validation used for cleaning.
Aseptic / sterile- “ A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product”
In this slide contains introduction, qualification, preventive maintenance, requalification method.
Presented by: Malarvannan M (Department of pharmaceutical analysis).RIPER, anantapur
This presentation explains about qualifications of HPTLC, types of qualifications, design qualification , installation qualification ,operational qualification, performance qualification ,documentation of qualification .
The presentation was an overview of the GMP regulations specific to cleaning validation for medicine manufacturers. New guidelines for Health Based Exposure Limits were discussed along with common GMP deficiencies observed during TGA inspections.
This presentation includes detail about cleaning levels,equipments for cleaning validation , steps for cleaning method validation and analytical method validation used for cleaning.
Aseptic / sterile- “ A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product”
Previously certain classes of active substances were required to be manufactured in dedicated or segregated self-contained facilities Certain antibiotics, Certain hormones, Certain cytotoxic ,Certain highly active drugs .This was due to the perceived risk of these active substances.
Pharmaceuticals not covered under these criteria were addressed by a cleaning validation process This involved reduction of the concentration of residual active substance to a level where the maximum carryover from the total equipment train would result in no greater than 1/1000th of the lowest clinical dose of the contaminating substance in the maximum daily dosage of the next product to be manufactured.
This criterion was applied concurrently with a maximum permitted contamination of 10 ppm of the previous active substance in the next product manufactured. Whichever of these criteria resulted in the lowest carryover, constituted the limit applied for cleaning validation. However, these limits did not take account of the available pharmacological and toxicological data They may have been too restrictive or not restrictive enough. EMA therefore felt for a more scientific case by case approach for all classes of pharmaceutical substances.
The subject of cleaning validation in active pharmaceutical ingredient manufacturing plants has continued to receive a large amount of attention from regulators, companies and customers alike.
The integration of Cleaning Validation within an effective Quality System supported by Quality Risk Management Processes should give assurance that API Manufacturing Operations are performed in such a way that Risks to patients related to cleaning validation are understood, assessed for impact and are mitigated as necessary.
It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place at this stage.
This presentation covers the requirements of Cleaning Validation for a Multipurpose API Manufactuirng Plant
Process Validation is Key important factor for the Pharmaceutical Industry to maintain Consistent Quality in product which claimed by the manufacturer.
Bioburden Validation Strategy for Cleaning Validationangelsalaman
This presentation is based on the article published by Pharmaceutical Technology (USA) entitled “BIOBURDEN METHOD SUITABILITY FOR CLEANING AND SANITATION MONITORING: HOW FAR WE HAVE TO GO?”, Aug 2010. by Angel L. Salaman-Byron
In the last year or so the FDA and the EMA have issued new guidance/ draft guidance on "Process Validation".These align process validation activities with a product lifecycle concept and the International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. The earlier guidelines were developed before the elaboration of the new ICH guidelines.With these new guidelines, additional opportunities are available to verify the control of the process by alternative means to the manufacture of traditional process validation batches. The main objective of process validation remains that a process design yields a product meeting its pre-defined quality criteria. ICH Q8, Q9 and Q10 provide a structured way to define product critical quality attributes, design space, the manufacturing process and the control strategy. ICH Q8 refers to an ‘enhanced’ approach to pharmaceutical development which includes an alternative to the traditional process validation.
Continuous process verification [see definition in ICH Q8(R2) glossary] can be utilised in process validation protocols for the initial commercial production and for manufacturing process changes for the continual improvement throughout the remainder of the product lifecycle.
There is now a new paradigm in process validation. This presentation has been prepared from material available from FDA , EMA and ICH for beginners to have an overview of the new paradigm.
In this presentation from CPhi 2014, Elise Gallais outlines the guidelines for cleaning validation: and focuses on analytical methods and their validation.
Aseptic / sterile - “ A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product”
Validation of aseptic process should be designed to provide assurance through appropriate testing that all phases and activities of the process remain sterile and it is controlled within the predetermined parameters.
Drug product, container, and closure are subject to sterilization separately, and then brought together.
This presentation describes approaches for software validation used to automate laboratory research procedures, consolidate data collection and analysis and/or run sophisticated QC or manufacturing operations.
Several approaches to software validation exist and may be appropriate for a specific project.
The scope of any validation effort depends upon a number of factors
Size and complexity of the software,
Origin of the software (custom vs. off-the-shelf) and
Whether the functions are critical or non-critical in nature.
By effectively planning the process, validation time and resources can be reduced while meeting regulatory requirements.
Cleaning validation is a procedure of establishing evidence that cleaning processes for
manufacturing equipment prevents product contamination. Cleaning validation should be
properly documented to demonstrate Current Good Manufacturing Practice (CGMP) for
finished pharmaceuticals.
◦ Cleaning procedures should normally be validated. In general, cleaning validation should be
directed to situations or process steps where contamination or carryover of materials poses the
greatest risk to API quality.
◦ For example, in early production it may be unnecessary to validate equipment cleaning
procedures where residues are removed by subsequent purification steps.
◦ Validation of cleaning procedures should reflect actual equipment usage patterns. If various
APIs or intermediates are manufactured in the same equipment and the equipment is cleaned
by the same process, a representative intermediate or API can be selected for cleaning
validation.
◦ This selection should be based on the solubility and difficulty of cleaning and the calculation
of residue limits based on potency, toxicity, and stability.
Cleaning is much important step in pharmaceutical production and delivering high quality products to the system .
Cleaning is done by multiple step approach and all that have necessary role in production of high quality accepted product.
To minimise the times , money and inventory we discovered the concept of CIP - i.e. Clean In Place
System.
By this system we clean and sterilize all the pharmaceutical equipment on working site , without any loss and dissemble that's the advantages of CIP .
And also other method of cleaning are explained here .
Visual Inspection of Parentetal Drug Products in Pharmaceutical Quality testingKarishmaRK
This presentation aims to elaborate the regulatory & compendial requirements of Visual inspection in Pharmaceutical parenteral manufacturing and the methodology of carrying out the testing.
The cleaning methodology and validation process play pivotal roles in ensuring pharmaceutical manufacturing meets stringent quality standards, safeguarding against contaminants and ensuring product purity. Rigorous adherence to cleaning methodology and validation protocols is imperative to uphold the integrity of pharmaceutical production and regulatory compliance. Checkout the complete pdf here- https://www.ipa-india.org/wp-content/uploads/2021/12/ipa-cleaning-methodology-and-valodation.pdf
Francesca Gottschalk - How can education support child empowerment.pptxEduSkills OECD
Francesca Gottschalk from the OECD’s Centre for Educational Research and Innovation presents at the Ask an Expert Webinar: How can education support child empowerment?
Instructions for Submissions thorugh G- Classroom.pptxJheel Barad
This presentation provides a briefing on how to upload submissions and documents in Google Classroom. It was prepared as part of an orientation for new Sainik School in-service teacher trainees. As a training officer, my goal is to ensure that you are comfortable and proficient with this essential tool for managing assignments and fostering student engagement.
Embracing GenAI - A Strategic ImperativePeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
Synthetic Fiber Construction in lab .pptxPavel ( NSTU)
Synthetic fiber production is a fascinating and complex field that blends chemistry, engineering, and environmental science. By understanding these aspects, students can gain a comprehensive view of synthetic fiber production, its impact on society and the environment, and the potential for future innovations. Synthetic fibers play a crucial role in modern society, impacting various aspects of daily life, industry, and the environment. ynthetic fibers are integral to modern life, offering a range of benefits from cost-effectiveness and versatility to innovative applications and performance characteristics. While they pose environmental challenges, ongoing research and development aim to create more sustainable and eco-friendly alternatives. Understanding the importance of synthetic fibers helps in appreciating their role in the economy, industry, and daily life, while also emphasizing the need for sustainable practices and innovation.
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
For more information, visit-www.vavaclasses.com
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
Read| The latest issue of The Challenger is here! We are thrilled to announce that our school paper has qualified for the NATIONAL SCHOOLS PRESS CONFERENCE (NSPC) 2024. Thank you for your unwavering support and trust. Dive into the stories that made us stand out!
Palestine last event orientationfvgnh .pptxRaedMohamed3
An EFL lesson about the current events in Palestine. It is intended to be for intermediate students who wish to increase their listening skills through a short lesson in power point.
2. CLEANING VALIDATION
Background
Through its regulatory activities, FDA became aware in the
early 1960's of the potential health hazards of product residues
FDA inspections revealed manufacturing practices leading to
contamination of certain drug preparations with penicillin
Amendments to drug regulations for current good
manufacturing practices (GMPs) were published January 29,
1965 for the control of cross contamination by penicillin.
In October 1965 the Division of Antibiotics and Insulin
Certification, now the National Center for Antibiotics Analysis
(NCAA), published methods for penicillin analysis, titled
“Procedures for Detecting and Measuring Penicillin
Contaminants in Drugs”.
ABHISHEK MORRIS
3. CLEANING VALIDATION
Background
In 1963 The FDA published a Guide to Inspections
”Validation of Cleaning Processes”, intended to cover
equipment cleaning for chemical residues only. In this
document FDA outlines what is expected:
a) Expects firms to have written procedures (SOPs)
detailing the cleaning processes.
b) Expects firms to have written general procedures on
how cleaning processes will be validated.
c) Expects firms to conduct the validation studies in
accordance with the protocols and to document the
results of studies.
3
ABHISHEK MORRIS
4. CLEANING VALIDATION
Definition
EU and Australian Code of GMP
“Cleaning validation is documented evidence that an
approved cleaning procedure will provide equipment which is
suitable for processing medicinal products”.
21 CFR 211.176, Penicillin contamination, states:
“If a reasonable possibility exists that a non-penicillin
drug product has been exposed to cross-contamination
with penicillin, the non-penicillin drug product shall be
tested for the presence of penicillin. Such drug product
shall not be marketed if detectable levels are found
when tested according to procedures specified in
‘Procedures for Detecting and Measuring Penicillin
Contamination in Drugs”.
4
ABHISHEK MORRIS
5. CLEANING VALIDATION
Examples of cGMP requirements
21 CFR 211.67 (a)
“Equipment and utensils shall be cleaned,
maintained, and sanitized at appropriate
intervals to prevent malfunctions or
contamination that would alter the safety,
identity, strength, quality, or purity of the
drug product beyond the official or other
established requirements”.
5
ABHISHEK MORRIS
6. CLEANING VALIDATION
Examples of cGMP requirements
EU and Australian CMP, 5.18
“Contamination of a starting material or of a product by
another material or product must
be avoided….... The significance of this risk varies with
the type of contaminant and of product being
contaminated. Amongst the most hazardous contaminants
are highly sensitizing materials, biological preparations
containing living organisms, certain hormones, cytotoxics,
and other highly active materials”.
6
ABHISHEK MORRIS
7. CLEANING VALIDATION
Examples of cGMP requirements
WHO, Annex 4, 4.11
“It is of critical importance that particular attention is
paid to the validation of analytical test methods,
automated systems and cleaning procedures”.
7
ABHISHEK MORRIS
8. CLEANING VALIDATION
Principle
Pharmaceutical products and active pharmaceutical
ingredients (APIs) can be contaminated by other
pharmaceutical products or APIs, by cleaning agents, by
micro-organisms or by other material (e.g. air-borne
particles, dust, lubricants, raw materials, intermediates).
In many cases, the same equipment may be used for
processing different products. To avoid contamination
of the following pharmaceutical product, adequate
cleaning procedures are essential.
Cleaning procedures must strictly follow carefully
established and validated methods of execution. This
applies equally to the manufacture of pharmaceutical
products and active pharmaceutical ingredients (APIs).
8
ABHISHEK MORRIS
9. CLEANING VALIDATION
General requirements
Normally only cleaning procedures for product contact
surfaces of the equipment need to be validated.
Consideration should be given to noncontact parts into
which product may migrate. For example, seals,
flanges, mixing shaft, fans of ovens, heating elements
etc.
Cleaning procedures for product changeover in the case
of marketed products should be fully validated.
Cleaning procedures for products and processes which
are very similar, do not need to be individually
validated.”.
Generally in case of batch-to-batch production it is not
necessary to clean after each batch. However, cleaning
intervals and methods should be determined.
9
ABHISHEK MORRIS
10. CLEANING VALIDATION
General requirements
It is considered acceptable to select a representative
range of similar products and processes concerned and
to justify a validation program which addresses the
critical issues relating to the selected products and
processes. A single validation study under consideration
of the “worst case” can then be carried out which takes
account of the relevant criteria. This practice is termed
"Bracketing” or “grouping
10
ABHISHEK MORRIS
11. CLEANING VALIDATION
General requirements
At least three consecutive applications of the cleaning
procedure should be performed and shown to be successful
in order to prove that the method is validated.
Raw materials sourced from different suppliers may have
different physical properties and impurity profiles. Such
differences should be considered when designing cleaning
procedures, as the materials may behave differently.
It is usually not considered acceptable to "test until clean".
This concept involves cleaning, sampling and testing, with
repetition of this sequence until an acceptable residue limit
is attained. For the system or equipment with a validated
cleaning process, this practice of "test until clean" should
not be required. The practice of "test until clean" is not
considered to replace the need to validate cleaning
procedures.
11
ABHISHEK MORRIS
12. CLEANING VALIDATION
General requirements
Products which simulate the physicochemical
properties of the substance to be removed may be used
instead of the substances themselves, where such
substances are either toxic or hazardous.
12
ABHISHEK MORRIS
13. CLEANING VALIDATION
Some general questions
Several questions should be addressed when evaluating the cleaning
process. For example:
a) At what point does a piece of equipment or system become clean?
b) What does visually clean mean?
c) Does the equipment need to be scrubbed by hand?
d) What is accomplished by hand scrubbing rather than just a solvent
wash?
13
ABHISHEK MORRIS
14. CLEANING VALIDATION
Some general questions
e) How variable are manual cleaning processes from batch
to
batch and product to product?
f) What is the most appropriate solvent or detergent?
g) Are different cleaning processes required for different
products in contact with a piece of equipment?
h) How many times need a cleaning process be applied to
ensure adequate cleaning of each piece of equipment?
14
ABHISHEK MORRIS
15. CLEANING VALIDATION
Equipment cleaning strategies
Dedicated
Campaign
Common
Cleaning of processing areas also requires validation.
The general principles outlined in this presentation are
applicable. Sampling methods and limits should be
appropriate to the material be processed.
15
ABHISHEK MORRIS
16. CLEANING VALIDATION
Some points to consider
Required written procedures that are standardized
Required written protocols
Justification for limits set
Equipment and product mix for common and dedicated
equipment
Use of manual verses automatic cleaning procedures,
such as CIP
Ongoing program of monitoring effectiveness
16
ABHISHEK MORRIS
17. CLEANING VALIDATION
Some equipment & product considerations
Use of “worst case” (e.g. smallest batch size, smallest number of
maximum daily doses, hardest to clean) product as a marker for
easier other products
Grouping of products
For example grouping based on; those products capable of causing
the largest possible problems if contaminated, or if they contaminate
other products; drug solubility and; equipment.
Identification of items of equipment that contribute most to cross
contamination of the next product
Identification of “worst case” locations in equipment , i.e. the design
of the equipment should be carefully examined.
Critical areas (those hardest to clean) should be identified,
particularly in large systems that employ semi-automatic or fully
automatic clean-in-place (CIP) systems.
17
ABHISHEK MORRIS
18. CLEANING VALIDATION
Some equipment & product considerations
Dedicated equipment should be used for products which
are difficult to remove (e.g. tarry or gummy residues in
the bulk manufacturing), for equipment which is
difficult to clean (e.g. bags for fluid bed dryers), or for
products with a high safety risk (e.g. biologicals or
products of high potency which may be difficult to
detect below an acceptable limit).
18
ABHISHEK MORRIS
19. CLEANING VALIDATION
Residue detection
Visual checking
- Suitable for dedicated equipment
- Include in all protocols and routine monitoring
Chemical tests
- Specific methods such as; high performance liquid
chromatography (HPLC), ion selective electrodes, flame
photometry, derivative UV spectroscopy, enzymatic detection
and titration
19
ABHISHEK MORRIS
20. CLEANING VALIDATION
Residue detection
Methods validation and recovery studies
Involves the use of the sampling and detection method on known
spiked surfaces at representative levels, typically spiked at 50%,
100% and 150% of the acceptable limit and at lower expected
actual levels to show linearity with documented % recovery as
analyzed and to determine the limit of detection and limit of
quantitation. Ideally the expected
values and limits should be multiples of the limits of
quantization.
20
ABHISHEK MORRIS
21. CLEANING VALIDATION
Residue detection
Chemical tests
a) Non-specific methods that detect the presence of a blend of
ingredients such as: total organic carbon, pH, and conductivity.
b) Specific methods. The FDA prefers specific methods, but
will accept non-specific methods with adequate rationales for
their use.
c) Chemical limits can be expressed as a maximum
concentration in the next product (ug/ml), amount per surface
area (ug/cm2), amount in a swab sample (ug or ug/ml),
maximum carryover in a train (mg or g), or concentration in
rinse water (ug/ml). There can be a calculated safety based
acceptance limit, a lower internal action level, and a lower
process control level based on actual manufacturing and
measuring experience.
21
ABHISHEK MORRIS
22. CLEANING VALIDATION
Residue detection
c) Chemical limits can be expressed as a maximum
concentration in the next product (ug/ml), amount per surface
area (ug/cm2), amount in a swab sample (ug or ug/ml),
maximum carryover in a train (mg or g), or concentration in
rinse water (ug/ml). There can be a calculated safety based
acceptance limit, a lower internal action level, and a lower
process control level based on actual manufacturing and
measuring experience.
22
ABHISHEK MORRIS
23. CLEANING VALIDATION
Microbial considerations
a) Endotoxins
b) TAMC
c) The existence of conditions favourable to reproduction of
microorganisms (e.g. moisture, temperature, crevices and rough
surfaces) and
the time of storage should be considered. The aim should be to
prevent excessive microbial contamination.
23
ABHISHEK MORRIS
24. CLEANING VALIDATION
Microbial considerations
d) The period and when appropriate, conditions of
storage of equipment before cleaning and the time
between cleaning and equipment reuse, should form
part of the validation of cleaning procedures. This is
to provide confidence that routine cleaning and
storage of equipment does not allow microbial
proliferation.
e) In general, equipment should be stored dry, and
under no circumstances should stagnant water be
allowed to remain in
equipment subsequent to cleaning operations.
24
ABHISHEK MORRIS
25. CLEANING VALIDATION
Detergent considerations
The efficiency of cleaning procedures for the removal of
detergent residues should be evaluated. Acceptable limits
should be defined for levels of detergent after cleaning. Ideally,
there should be no residues detected. The possibility of
detergent breakdown should be considered when validating
cleaning procedures.
25
ABHISHEK MORRIS
26. CLEANING VALIDATION
Detergent considerations
The composition of detergents should be known.
If such information is not available, alternative detergents
should be selected whose composition can be defined. As a
guide, food regulations may be consulted. The manufacturer
should ensure that he is notified by the detergent supplier of
any critical changes in the formulation of the
detergent.
26
ABHISHEK MORRIS
27. CLEANING VALIDATION
Sampling methods principle
There are two methods of sampling that are considered to be
acceptable, direct surface sampling (swab method) and indirect
sampling (use of rinse solutions). A combination of the two
methods is generally the most desirable, particularly in
circumstances where accessibility of equipment parts can
mitigate against direct surface sampling.
27
ABHISHEK MORRIS
28. CLEANING VALIDATION
Sampling methods principle
Direct Surface Sampling (swabbing)
The suitability of the material to be used for sampling and of the
sampling medium should be determined. The ability to recover
samples accurately may be affected by the choice of sampling
material. It is important to ensure that the sampling medium and
solvent are satisfactory and can be readily used.
Rinse Samples
Rinse samples allow sampling of a large surface area. In
addition, inaccessible areas of equipment that cannot be
routinely disassembled can be evaluated. However,
consideration should be given to the
solubility of the contaminant.
28
ABHISHEK MORRIS
29. CLEANING VALIDATION
Sampling methods considerations
Swab samples
a) Reliable determination of residue
b) Locations must be carefully defined (use difficult to clean
locations).
c) Extrapolate sample area to whole area
d) Method recovery must be validated (e.g. spiking studies, recovery
target, LOD and LOQ, precision, linearity and selectivity)
Rinse samples
a) May be helpful where sites are inaccessible to swabs
b) Useful for cleaning agent residues
c) Must define volumes of rinse agent used
d) Method recovery must be validated
29
ABHISHEK MORRIS
30. CLEANING VALIDATION
Sampling method considerations
e) The choice of containers used in the analysis of samples is
very important. It has been shown that, in very dilute solutions,
surfactants can adsorb onto the surfaces of sample vials. This
will produce artificially low results in the analysis. Appropriate
spiking studies should be performed to ensure that this
phenomenon is not occurring and will not interfere with the
analytical method.
30
ABHISHEK MORRIS
31. CLEANING VALIDATION
Selection of limits - principle
Establishment of Limits
a) The pharmaceutical company's rationale for selecting limits
for product residues should be logically based on a consideration
of the materials involved and their therapeutic dose. The limits
should be practical, achievable and verifiable.
b) The approach for setting limits can be:
i) Product specific Cleaning Validation for all products, or
ii) Grouping into product families and choosing a "worst case"
product
iii) Grouping into groups of risk (e.g. very soluble products,
similar potency, highly toxic products, difficult to detect etc.).
31
ABHISHEK MORRIS
32. CLEANING VALIDATION
Selection of limits - principle
Carry-over of product residues should meet defined
criteria, for example the most stringent of the
following three criteria:
(a) No more than 0.001 (0.01%)of the normal
therapeutic dose of any product (or minimum dose if
there are number formulations with different
strengths) will appear in the maximum daily dose of
the following product
(b) No more than 10 ppm of any product will appear
in another
product,
32
ABHISHEK MORRIS
33. CLEANING VALIDATION
Selection of limits - principle
(c) No quantity of residue should be visible on the equipment
after cleaning procedures are performed. Spiking studies should
determine the concentration at which most active ingredients
are visible
(d) For certain allergenic ingredients, penicillins,
cephalosporins or potent steroids and cytotoxics, the limit
should be below the limit of detection by best available
analytical methods. In practice this may mean that dedicated
plants are used for these
products.
33
ABHISHEK MORRIS
34. CLEANING VALIDATION
Selection of limits - principle
e) It should not be assumed that the contaminant will be uniformly
distributed throughout a system. The assumption that a residual
contaminant would be worn off the equipment surface uniformly,
or that the contamination might only occur at the beginning of the
batch, should not be made.
f) In establishing residual limits, it may not be adequate to focus
only on the principal reactant since chemical variations (active
decomposition materials) may be more difficult to remove.
34
ABHISHEK MORRIS
35. CLEANING VALIDATION
Selection of limits
Some points to consider:
General
a) Regulatory agencies do not set limits
b) Use of dedicated equipment wherever possible, e.g.
scoops, FBP, blenders, compression machines etc.
c) Total surface areas of all common equipment used
d) Validation data should support a conclusion that
residues have been reduced to an acceptable level
35
ABHISHEK MORRIS
36. CLEANING VALIDATION
Selection of limits
Some points to consider:.
Visually clean
a) Accepted by FDA for cleaning between batches of
the same product or different lots of the same
intermediate in a bulk process
b) Useful for both equipment and walls, floors etc. of
processing areas
c) Note that for many residues the visual detection limit
is in the order of 1-4 ug/cm2. It is possible that the
visually clean criteria will be the most stringent criteria.
36
ABHISHEK MORRIS
37. CLEANING VALIDATION
Selection of limits
Some points to consider:.
Medical dosage level is probably the most common basis for
limits calculations in the pharmaceutical industry. It is based
on allowing a certain fraction of a daily dose to carry over to a
daily dose of a following product. The fraction that reduces the
dosage is referred to as a safety factor or a risk assessment
factor and takes the form of a fraction such as 1/100th,
1/1000th, or 10,000th of the original daily dose.
37
ABHISHEK MORRIS
38. CLEANING VALIDATION
Selection of limits
Some points to consider:.
A commonly used limit is no more than one thousandth
(0.001) of the minimum daily dose of a current product will
appear in the maximum daily dose of a subsequent
Product
Where a there is a large product range, to reduce swabbing
work load, one approach is to identify which product is a
worst case (e.g. based on the smallest number of maximum
daily doses, i.e. batch size divided by maximum daily dose).
38
ABHISHEK MORRIS
39. CLEANING VALIDATION
Selection of limits
Some points to consider:.
a) No more than 10ppm of any product will appear in another
product
i) This has its origins in the regulations that apply to food products
in
the US.
ii) Also used in the USP for hazardous substances, such as heavy
metals and impurities.
iii) Assumes that residue is as harmful as a hazardous substance
iv) Useful for materials for which no toxicological data is available,
e.g. cleaning agents
39
ABHISHEK MORRIS
40. CLEANING VALIDATION
Selection of limits
b) In the case of small final filling equipment such as filling needles
for vials or tablet punches and dies, it may be necessary to do
separate residue studies on the filling needles or punches and dies to
be sure that there was not enough residue just on that equipment to
contaminate the first few bottles or tablets of the next batch with the
maximum allowable carryover limit (MACO) of the previous
product.
40
ABHISHEK MORRIS
41. CLEANING VALIDATION
Protocol
The Cleaning Validation Protocol should include, for
example, the following:
a) The objective of the validation process.
b) Responsibilities for performing and approving the
validation study
c) Description of the equipment to be used.
d) The interval between the end of production and the
beginning of the cleaning procedures.
41
ABHISHEK MORRIS
42. CLEANING VALIDATION
Protocol
e) Cleaning procedures to be used for each product, each
manufacturing system or each piece of equipment.
f) The number of cleaning cycles to be performed
consecutively.
g) Any routine monitoring requirement.
h) Sampling procedures, including the rationale for why a certain
sampling method is used.
i) Clearly defined sampling locations.
42
ABHISHEK MORRIS
43. CLEANING VALIDATION
Protocol
j) Data on recovery studies where appropriate,
k) Analytical methods including the limit of detection and the
limit of quantitation of those methods or reference to them
l) Acceptance criteria and limits
m) Details of of product “grouping”
n) When Re-validation will be required.
o) A Final Validation Report. The conclusions of this report
should state if the cleaning process has been validated
successfully.
43
ABHISHEK MORRIS
44. CLEANING VALIDATION
Equipment considerations
In the case of a product changeover, the total surface area of
equipment common to each product has to be determined.
Assuming a swab area of 10 cm2 , the total amount of residue
present is determined by dividing the equipment surface area
(cm2 ) by 10 and multiplying this result by the residue quantity.
This is repeated for all common equipment in the “train” and the
total residue calculated by
adding all results together.
44
ABHISHEK MORRIS
45. CLEANING VALIDATION
Selection of limits
We first manufacture product A and then product B, "What is
an acceptable level of product A to carry over and be present in
product B and yet not cause a medical effect in the patient
consuming product B?" The math is.
The maximum allowable carryover, MACO
= (allowable carryover into a single daily dose of next
product) x (# of daily doses in complete batch of next product)
45
ABHISHEK MORRIS
46. CLEANING VALIDATION
Selection of limits
or,
MACO = ( allowable carryover into a single daily dose of next
product) x (batch size of next product divided by daily dose of
next product)
The allowable carryover of product A into a single dose of
product would be:
(Daily dose of A) divided by (Safety Factor)
46
ABHISHEK MORRIS
47. CLEANING VALIDATION
Selection of limits
Thus, the total maximum allowable carryover depends on four
variables:
The daily dose of product A
The safety factor selected
The batch size of product B
The daily dose of product B
47
ABHISHEK MORRIS
48. CLEANING VALIDATION
Selection of limits
Example 1
Let's suppose, for the present example, that we have two orally
administered products (A and B) manufactured using the same
equipment. Product A is formulated in two strength, a 500mg
dose and a 850mg dose, each dose is given once a day. The
maximum daily dose of Product B is 8 tablets and the batch
size is 320,000 tablets.
48
ABHISHEK MORRIS
49. CLEANING VALIDATION
Selection of limits
Example 1
The minimum daily dose of Product A, which is 500mg, is
used in the following calculation.
MACO= (Minimum daily dose of Product A/safety factor of
1000) x (# of daily doses in complete batch of next product)
MACO = 500/1000 x 320,000/8 = 20g
49
ABHISHEK MORRIS
50. CLEANING VALIDATION
Selection of limits
Example 2
Let's suppose, for the present example, that we have five
products (A, B, C, D, and E) in the current product grouping,
and they are all products given by the oral route of
administration. Let's further assume that the group of five all
has different dosages and batch sizes as represented in the next
slide.
50
ABHISHEK MORRIS
51. CLEANING VALIDATION
Selection of limits
Example 2
PRODUCT
BATCH
SIZE Kg
A
B
C
D
E
MAX
DAILY DOSE mg
100
150
200
250
300
50
100
100
10
150
51
ABHISHEK MORRIS
52. CLEANING VALIDATION
Selection of limits
Example 2
The limits calculated will depend upon the specific
sequence of products manufactured, thus there are
20 different combinations and permutations of
possible manufacturing sequences for only a fiveproduct group. Even if the initial product is
specified, then there could be four other products
manufactured subsequently, thus four different
limits. For this reason, many companies use an
equation which takes into account the "worst case"
situations for all products in the same
group.
52
ABHISHEK MORRIS
53. CLEANING VALIDATION
Selection of limits
Example 2
If Product A is selected as the initial product. In
order to calculate a limit for carryover of product A
into any other product, we could use the following
equation:
MACO= (DTDA) x (WC#D)/SF
MACO = Maximum allowable carryover
DTDA = Daily therapeutic dose of product A
WC#D = Worst case # doses
SF = Safety factor (usually 1,000)
53
ABHISHEK MORRIS
54. CLEANING VALIDATION
Selection of limits
Example 2
The worst case number of doses in the following
product would be determined by a combination of
the largest daily dose (active plus excipients) of any
of the other product in the group and the smallest
batch size of any other product in the
group by the relationship:
Worst case = Smallest batch size*
Largest daily dose*
* of any other product in group
54
ABHISHEK MORRIS
55. CLEANING VALIDATION
Selection of limits
Example 2
The data show in Slide 60 for the current group of five
products shows that Product E has the largest Daily Dose
Weight (300 mg) and Product D has the Smallest Batch Size
(10 Kg) of the product group. Thus the Worst Case Number of
Doses would be:
Worst case # doses = 10,000,000 mg = 33,333 doses
300 mg/dose
55
ABHISHEK MORRIS
56. CLEANING VALIDATION
Selection of limits
Example 2
The 10 Kg was converted to mg so that the units would agree.
This value would now be substituted back into the MACO
calculation with the following results:
MACO = DTDA x WC#D in following product
SF
MACO = 10 mg x 33,333 = 333 mg
1000
We can now perform a 'worst case' calculation for each of the
five products in the group and this would reduce the number of
calculations from twenty down to five. The resulting
calculations for the group of five products are shown in the
next slide.
56
ABHISHEK MORRIS
57. CLEANING VALIDATION
Selection of limits
Example 2
PRODUCT
A
B
C
D
E
MACO for all products in group mg
333
990
3330
6660
16650
The MACO for Product A, shown in slide 55, is the maximum
residue that can be present on the surfaces of all common
equipment in the train. This is regardless of which product is
being produced and which product is produced next.
57
ABHISHEK MORRIS
58. CLEANING VALIDATION
Selection of limits
Example 3
The limit of Product A (which contains the most potent active)
in Product B (which contains the least number of maximum
daily doses per batch)
MACO = D x E mg
where:
D = The minimum daily dose of the smallest strength of
Product A
E = The maximum number of daily doses per batch of Product
B
58
ABHISHEK MORRIS
59. CLEANING VALIDATION
Selection of limits
Example 3
In a tablet product grouping product A is the most potent. One
thousandth of the minimum daily dose is 0.0006 mg.
Product D has the least number of maximum daily doses per
batch, 50,000.
The MACO limit is 0.0006 x 50,000 = 30mg
59
ABHISHEK MORRIS
60. CLEANING VALIDATION
Selection of limits
Example 3
From swabbing, the total residue found on all common
equipment is 0.600 mg.
Based on the data, the cleaning procedure is acceptable
regardless of which product is being produced and which
product is produced next.
60
ABHISHEK MORRIS