12. Personal point of view
based on education, training and
rich experience of regulating
pharmaceutical industry
Disclaimer
Constructed from the
US-FDA & Scientific
Review Articles
Reference
14. Cleaning of equipment is the requirement to prevent:
• Mix up
• Cross-contamination
• Microbial growth
• Inconsistency
• All of above
Tick √ the correct and cross “X” the wrong.
Define at least one line reason for each to justify your option.
?
16. Cross-contamination means: Contamination of batch
a. “X” into “Y” & essentially “Y” into “X” (X & Y are one product of same strength)
b. “X” into “Y” & not essentially “Y” into “X” (X & Y are one product of same strength)
c. “X” into “Y” & essentially “Y” into “X” (X & Y are two different products)
d. “X” into “Y” & not essentially “Y” into “X” (X & Y are two different products)
?
Tick √ the correct and cross “X” the wrong.
33. If we are manufacturing hhxxxxxxxxxxxxxxx ProductSame
34. Why do we need to clean between 2 batches
If we are manufacturing xxxxxxxxxxxxxxxx ProductSameIf we are manufacturing hhxxxxxxxxxxxxxxx ProductSame
35. Why do we need to clean between 2 batches
If we are manufacturing xxxxxxxxxxxxxxxx Product
?
SameIf we are manufacturing hhxxxxxxxxxxxxxxx ProductSame
38. 1
2
3
Preservance of purity & Reduction of Uncertainty
Control of Process & Control of Impurities
Isolation & Traceability of manufacturing process
40. Risk
two batches of different product
of same therapeutic class
two batches of same product
Ciprofloxacin & Ofloxacin
41. Risk
two batches of different product
of different therapeutic class
two batches of different product
of same therapeutic class
two batches of same product
Risperidone & Glimipride
42. Let us see, how do we know that
Our Clean is Clean ?
53. Equipment should be ………... to clean and
maintain.
a. Friendly
b. Easy
c. Softly
d. Perfectly
?
Please fill the blank from the given word. You may choose
more than one if you have reason.
54. Cleaning validation is required for:
• Manufacturing Equipment
• Testing Equipment
• Balance
• Floor
• HVAC Duct
Tick √ the correct and cross “X” the wrong.
Define at least one line reason for each to justify your selection.
?
57. Surface that contact
components, in process
materials or drug products
are not reactive, additive or
absorptive
Constructed inert
Why
Constructed inert
Why
58. To prevent contact with
substances required for
operations such as
lubricants and coolants
Constructed inert
Why
71. From Regulator’s Eye
Documentary evidences that
The equipment is consistently
cleaned of product, microbial and
cleaning agent residues to
predetermined, acceptable levels
87. Is some equipment more
difficult to clean
(e.g. mills, fluid bed dryers, piping,
rubber gaskets, etc.)?
88. Identify types of products
manufactured
e.g.
drug products
industrial chemicals
89. Cleaning validation is required to demonstrate
effectiveness of cleaning process and its consistency.
Please explain these two underline words or correct
if it is wrong.
?
90. Were there any OOS results
or trends during cleaning
validation studies?
92. Be Alert
to auxiliary equipment or containers that
may be re-used and/or not included in the
cleaning validation
93. Identify critical pieces of equipment for
evaluation of cleaning validation based on
previously gathered information,
It includes past difficulty in achieving
cleaning status, observed adverse trends,
hazard to intended patient population,
potency or toxicity of drug product,
degradants, excipients etc.
97. Instructions for disassembling &
assembling of equipment or parts
Types of valves, gasket & seal used
How residue will be removed
Must be Specific
CP
98. Use of dedicated versus multi
product equipment
Must be Specific
CP
106. Instructions to perform at least a
visual inspection after every
cleaning
Must be Specific
CP
107. (Dirty Hold Times)
Time b/w processing & cleaning
• Residue may dry out become more
difficult to clean
• May also increase microbial burden
Must be Specific
CP
109. Rinse sampling
• Greater surface coverage
• Inaccessible area can be sampled
• Should be direct measurement of
residue
• Insoluble residues are not tested
Sampling
110. Recovery studies
It should be representative
of all major
Product contact surfaces
For e.g.
Stainless steel, teflon, etc. &
Sampling methods (rinse or swab)Analytical Method
111. Challenge the analytical method in
combination with the sampling
Specificity
Sensitivity
Recovery
Analytical Method
113. Specific test such as
Total Organic Carbon (TOC)
Advantage – less analysis time
Disadvantage – lack of specificity
Can be used if TOC is sensitive to the
compounds being cleaned away
Analytical Method
114. Specific test such as
Total Organic Carbon (TOC)
Advantage – less analysis time
Disadvantage – lack of specificity
Can be used if TOC is sensitive to the
compounds being cleaned away
Analytical Method
115. Specific test such as
Total Organic Carbon (TOC)
Advantage – less analysis time
Disadvantage – lack of specificity
Can be used if TOC is sensitive to the
compounds being cleaned away
Analytical Method
116. Specific test such as
Total Organic Carbon (TOC)
Advantage – less analysis time
Disadvantage – lack of specificity
Can be used if TOC is sensitive to the
compounds being cleaned away
Analytical Method
117. Limit should be based on
scientific rationale
A good scientific rationale should be
logical, practical, verifiable, safe &
achievableEstablishment of Limits
118. If flexibility of rational offered,
please remember
A good scientific rationale should
be logical, practical, verifiable, safe
& achievableFreedom to establish limits
GMP Zone
119. How clean is clean?
There is no clean answer but simple
Use water for washing floor, for washing
pots, for cooking foods, for drinking, for
use of syrup, for injectionLets resolve cleanliness
120. Let’s use logic to decide
boundary of digit
• Therapeutic dosage levels
• Toxicity Profile
• Solubility of the residue (detergent)
• Batch size & nature of other
products made in the same
equipment
Moving upward ..
121. Nature of the Dosage Form
• Parenteral
• Opthalmic
• Topicals
• Liquids
• Solid oral
Establishment of Limits
122. Who is responsible for doing
cleaning validation
Who for what …
Validation Protocol
Inspection
Approach
137. Re-cleaning, re-sampling &
retesting of equipment
(“test until clean”)
without investigating the root cause
for the OOS resultsIssues & Concerns
Significant
139. Failure to properly disassemble
equipment for cleaning
Issues & Concerns
Significant
140. Failure to specify & validate
dirty hold time, or equipment
remains dirty for extended periods
exceeding those validated
Issues & Concerns
Significant
141. Interview of operators disclosed
that cleaning procedures are
not always followed
Issues & Concerns
Significant