This document contains questions and answers related to pharmaceutical quality and manufacturing. It discusses topics like clean hold time, dirty hold time, contamination control strategies, particles in injections, the differences between CMC, GMP, and continuous manufacturing. It also addresses questions about PIC/S, such as whether they issue membership, if inspections by one country are accepted by others, and that GMP certificates are issued by individual regulatory authorities rather than PIC/S.

1. 22nd
September 2022 Q & A - P a g e | 1/6
WWW.ORCQS.COM
Your Questions & Our Answers
(June 2022 – Sept 2022)
Expand Clarity with Centre for Quality Sciences
On the road to embrace knowledge & moral economy in the field of Pharmaceutical Sciences

2. 22nd
September 2022 Q & A - P a g e | 2/6
WWW.ORCQS.COM
Your Questions & Our Answers
(June 2022 – Sept 2022)
Expand Clarity with Centre for Quality Sciences
Question: What is Clean Hold Time and
what is Dirty Hold Time? Is it mandatory to
perform?
Answer: Clean Hold Time (CHT) is a
duration when a clean equipment (or room or
any object) is considered clean. Dirty Hold
Time (DHT) is a duration when a used
equipment can be left unclean. Both holding
times are scientifically studied through valid
methods.
Every equipment is required to be clean before
its use. Cleaning means removal of all traces
of previous materials and demonstration of
cleanliness level. This cleanliness level is
predefined in terms of its attributes and their
permissible operational boundary. Similarly,
every equipment may not be left unattended
after its use. A validated cleaning method may
not clean if dirty equipment is kept for longer
period and study is not available for that
extended period. It means stay period of dirty
equipment is also required to be studied in
order to see effectiveness and validity of the
cleaning process. Yes, both studies CHT and
DHT are mandatory to perform under
contamination control strategy and cleaning
validation.
Let’s unfold to understand why CHT is
important. Cleaning of equipment etc. is
required to remove all residues of previous
batches in order to prevent potential of
contamination. Detergents (chemicals) are
used to clean and cleaning certainly requires
removal of detergent too. Environmental
conditions such as particle count in air,
temperature, humidity etc. have an impact on
cleanliness level of cleaned equipment etc.
Nothing is considered zero but permissible
limits are established for every attribute and
assessment of corresponding potential risk.
Under certain defined environmental
conditions, CHT is determined through
cleaning validation study. This is a critical step
but does not mean to delay manufacturing
processes conclusively in the account of
availability of the CHT. Breaking down of
process without justifying reason, to me it is
deviation and requires management. Similarly
study of DHT is critical and one can
understand difficulty of cleaning after every
passing moment. Holding of dirty equipment
etc. increase potential of microbial growth
that is not certain to calculate on
mathematical scale every time due to multiple
inherent reasons. Again holding of dirty
equipment etc. without convincing reason for
the period of studied holding time may not be
considered as a good practice but otherwise.
To me, it is critical question on culture of
quality that is developed to adhere the system
and practices with GMP standards.
The bottom line is that these are critical
segments of cleaning validation. Cleaning
validation is critical element to demonstrate
prevention of contamination. Contamination
prevention is the fundamental intent of GMP.
GMP is the heart of Quality System. Science is

3. 22nd
September 2022 Q & A - P a g e | 3/6
WWW.ORCQS.COM
the way of thinking and one should
understand difference between good and bad,
valid or invalid approaches.
08 August 2022
Question: What is Contamination Control
Strategy (CCS) and why it is important?
Answer: Before responding the question, let’s
allow to explain first why it is required now?
Progress and advancement in technology,
process controls and contamination controls
have enhanced the regulatory expectations for
quality of product manufactured. This is more
concerned with sterile products. As a bottom
line limitation, we know if contamination
occurs in sterile product there is no alternative
to opt reworking or reprocessing for removal
of contamination.
Back to the question now what CCS is? It is a
structured plan across the facility to assess the
effectiveness of monitoring and controls
placed to manage risk of contamination, it is
therefore defined as all Critical Control
Points in design, procedures, technical and
organizational frame.
Just to share understanding on the subject to
keep clarity that CCS is not the facility layout
design, but the design to identify vulnerable
areas for efficient risk management. It
certainly speaks about science of decisions
impacting on quality during the entire
manufacturing process for any particular
product.
Smart use of quality risk management for
Critical Control Points having potential for
viable contamination and contamination of
nonviable particles that may or may not carry
viable particles is the first line for designing
and planning controls for particles in CCS.
Critical Control Points and in-process
controls are not same. CCS are certainly the
process phases where risks are identified that
have to go for mitigation.
Let’s try to wrap up, CCS is a predictive
roadmap that provides opportunity to identify
and assess risk, develop plan to respond and
tells about preventive measures to deal
potential of contamination.
24 July 2022
Question: Particles in injections are the
reason of major recalls. Why particles are a
matter of extreme concern and why
injections are required to be free from
particles?
Answer: Injections are administered to the
critically ill patient directly into his or her
blood stream that circulates freely all around
the body and reaches to the vital organs.
Instead of discussing “why” let’s understand
what is particle, what it can do and from
where it comes in. Any particulate of defined
size in an injection is certainly a mobile
undissolved substance unintentionally
present in an injectable product. Gas bubble
may not be considered as particle. Viable
particle use support of non-viable particles for
its migration. This migration of viable particle
becomes reason of microbial contamination
of product. Particulate in an injection may
end up with adverse event that may be
infection or emboli in vein or artery as well as
micro-emboli, abscesses and granulomas

4. 22nd
September 2022 Q & A - P a g e | 4/6
WWW.ORCQS.COM
within visceral organs. Patients may also
experience phlebitis and localized infections
upon administration of particulate containing
injections. Particles are sometimes introduced
as inherent to the product itself. Some
particles that come from manufacturing
processes or from the formulation are
recognized as intrinsic ones. Environmental
particles of the manufacturing suits are called
as extrinsic particles if found in the injection.
Since injections are usually administered in
tertiary care, therefore, extreme cautions are
inevitable. Particles in injections may not be
allowed in any case because of potential
damage to the patient at a high scale.
31 August 2022
Question: The word “Manufacturing” is
common both in CMC & GMP. Are both
the names of same thing? If not same, what
is the difference between two terminologies?
Answer: It looks an interesting innocent
question. Both cross roads and share common
objectives that enhance protection and
promotion of health by and large.
Chemistry, Manufacturing and Controls
(CMC) are designed and developed to see
strength in delivering the promise. The same
CMC helps to bridge every dose with the dose
used in clinical studies. Clinical studies define
therapeutic benefits of the drug and provide
reason for its use. Every dose may not be
subject to clinical testing and the same way
every batch or every manufacturing site cannot
be tested for clinical response. It is the CMC
that assures placement of controls in
manufacturing to maintain identity, strength,
quality, purity or potency of the product for its
desired safety and effectiveness. Chemistry of
drug substance and drug product are
thoroughly studied for their quality attributes
and stability in CMC as primary block.
Manufacturing processes, their processing
parameters and operating validity for effective
performance are examined to understand the
reasons for consistent manufacturing are kept
under microscope as essential block.
Designing of strategy to place static and
dynamic controls for maintaining the
operating conditions within the studied frame
are covered under critical block.
Good Manufacturing Practices (GMP) are
designed and practiced to prevent
contamination, to block potential of mix up
and to maintain consistency within each dose
of entire batch, batch after batch, time after
time throughout the shelf life. GMP has
nothing to do directly with the inherent safety
profile of drug substance or product
subsequently manufactured. GMP tells about
state of control from approval of vendors till
the supply of drug to the patient and
processing of complaint. GMP generates
knowledge and enhance deep understanding
about the material and product behavior. This
way GMP plays a vital role to pass on the
promise securely and contribute in promotion
of health. Similarly, GMP prevents any
potential error that may cause harm and
contributes in protection of health.
CMC and GMP both have different objectives
and interdependent on each other whenever
it is a matter of passing therapeutic benefit to
the patient.
06 September 2022

5. 22nd
September 2022 Q & A - P a g e | 5/6
WWW.ORCQS.COM
Question: What is Continuous
Manufacturing for drug product and how do
you see it?
Answer: When any manufacturing process has
no place to stop over and is well-connected
with next steps of the process, it is a
continuous process. For example, conversion
of egg into chick without any breakage of
process, every process is well-connected to
each other within the space of time.
Continuous manufacturing (CM) in
pharmaceutical finished products is an
advance technology that pushes material
produced during each process step directly
and continuously to the next step for further
processing. All inputs, materials are
continuously fed into production line where
they are transformed and finally process
output is coming out on continuous basis.
Certainty in terms of quality will move to
higher side with the expansion of process
understanding. Placement of process analytics
and controls will remarkably enhance
efficiency in all aspects. CM has a significant
potential to enhance product quality and
confidence. By and large, it will reduce cost of
manufacturing and waste. It will also help to
maintain supply and reduce fear of shortage.
CM is now in place everywhere for upcoming
biologics and I see a rapid progress in chemical
drugs too. CM will soon contribute a lot in
shifting from import to domestic
manufacturing particularly in US.
13 September 2022
June – July 2022 on PIC/S
Question: Does PIC/S issue membership to
Pharmaceutical Companies and
Manufacturer Associations etc.?
Answer: No. PIC/S has nothing to do with
pharmaceutical companies or manufacturer
associations. It is limited to regulatory
authorities.
Question: Is PIC/S a good strategy for DRAP
Pakistan?
Answer: It is an excellent move for progress in
way to strengthen GMP inspections and
quality of drugs manufactured here. It would
be a worst trap, if blind move without
considering the strength of bond among the
chain of concerns is followed.
Question: If a facility is inspected by World
Health Organization (WHO) on behalf of
United Nations (UN) for GMP, member
countries of UN accept it as an obligation
and do not perform inspection of that site.
Answer: No. It is a wrong perception. WHO
is neither a regulatory authority nor members
are bound to.
Question: Does PIC/S tells about the PIC/S
approved facility or recalls or closure of
facility etc.
Answer: No. PIC/S approved facility is wrong
word, Don’t use it. PIC/S works in its
domain. It neither tells about the “approved”

6. 22nd
September 2022 Q & A - P a g e | 6/6
WWW.ORCQS.COM
facility or product “not approved” facility or
products etc. It is the concerned regulatory
authority of the particular country to do so.
Question: If any PIC/S member issues a
GMP certificate to a drug manufacturing
facility, Will it be acceptable for all other
PIC/S member countries.
Answer: No. GMP Certificate of one member
is not acceptable to all members. For e.g.
Malaysia and Canada both are PIC/S member
countries, if Malaysia issues a GMP certificate
to Facility “X”, it does not mean Canada will
waive GMP inspection on the basis of
Malaysia GMP Certificate. Mutual
Recognition Agreement (MRA) is respecting
others decisions on equal conditions. GMP
inspections may also be waived if MRA exist
between the countries, PIC/S has nothing to
do in this MRA. Recognition of GMP
certificate among EU/EEA is well in place.
Waiver of GMP inspection may exist in any
country as its own unilateral policy. These
countries are considered less stringent and
weak in technical knowledge.
Question: Is GMP certificate issued from
PIC/S office, Geneva, Switzerland upon
PIC/S inspection?
Answer: No. It is absolutely wrong. PIC/S
itself do not conduct any inspection and there
is no reason in their mandate till time. GMP
certificates are issued by the respective
regulatory authority of the member country.
PIC/S itself does not carry any liability of
GMP certificates issued by its member
countries.
Question: If any finished drug product is
prequalified by WHO (World Health
Organization) after application review and
inspection of the manufacturing facility, will
the same finished drug product be
considered approved in US & Europe for
their market?
Answer: No. It is absolutely incorrect. FDA
does not recognize WHO blindly.
Question: Can a drug manufactured in
facility having GMP Certificate from any
PIC/S member country be exported to all
other PIC/S member countries?
Answer: No. GMP is not the one and only
tool for Market Authorization (MA). Export
of drug requires MA of country where
someone intends to export. MA depends on
review/assessment of the particular drug
application and GMP inspections of
manufacturing facilities. Different countries
have different approaches and pathways to
grant MA. GMP Certificate of one member is
not acceptable to all members. For e.g.
Malaysia and Canada both are PIC/S member
countries, if Malaysia issues a GMP certificate
to Facility “X”, it does not mean Canada will
waive GMP inspection on the basis of
Malaysia GMP Certificate.
Footnote: Please feel free to correct and
don't be victim of ignorance and
assumptions.
Obaid Ali & Roohi B. Obaid