Who MHP RPQ Lpa 2022.1 Eng

Virtual cGMP
Training Marathon
for Vaccine
Manufacturing
Questions & Answers
05 OCTOBER – 11 NOVEMBER 2021
Virtual cGMP
Training Marathon
for Vaccine
Manufacturing
Questions & Answers
05 OCTOBER – 11 NOVEMBER 2021
WHO/MHP/RPQ/LPA/2022.1 – © WHO 2022. Some rights reserved.
This work is available under the CC BY-NC-SA 3.0 IGO licence.
All reasonable precautions have been taken by WHO to verify the information contained in this publication.
However, the published material is being distributed without warranty of any kind, either expressed or
implied. The responsibility for the interpretation and use of the material lies with the reader. In no event
shall WHO be liable for damages arising from its use.
CONTENTS
Abbreviations iv
Introduction 1
Session 1: Vaccine lifecycle and technology platforms 2

Session 2: Quality management system principles 7
Session 3: Quality risk management principles and implementation 13
Session 4: Good manufacturing practice for sterile manufacturing 18
Session 5: Quality control overview 23
Session 6: Equipment qualification 30
Session 7: Premises and plant design 36
Session 8: Cold chain management through the vaccine lifecycle 41
Session 9: Process validation and cleaning validation 45
Session 10: Data integrity 51
Session 11: Documentation for regulatory submission - cGMP related matters to be 55
included in common technical document (CTD) and site master file (SMF)
Session 12: Common cGMP deficiencies for vaccine manufacturing 59
iii
ABBREVIATIONS
AEFI adverse events following immunization LAF laminar air flow
AQL acceptable quality level LOEL lowest-observed-effect level
ALARP as low as reasonably practicable LIMS laboratory information management system
APS aseptic process simulation LNP lipid nanoparticle
BI biological indicator MAH marketing authorization holder
BMS building management system MCB master cell bank
BPR batch production record MKT mean kinetic temperature
BSC biosafety cabinet MSC maximum safe carryover
BSL biosafety level mRNA messenger ribonucleic acid
CAPA corrective action and preventive action NCL National Control Laboratory
CCS contamination control strategy NDA new drug application
CE computerized equipment NMRA National Medicines Regulatory Authority
CEHT clean equipment hold time NOAEL no-observed-adverse-effect level
cGMP current good manufacturing practice NRA National Regulatory Authority
CIS computerized information system OP operational qualification
CIP clean-in-place PIC/S Pharmaceutical Inspection Co-operation Scheme
CMO contract manufacturing organization QA quality assurance
CMC chemistry, manufacturing and control QbD quality by design
CNC controlled not classified QC quality control
COA certificate of analysis QM quality manual
CTD common technical document QSE quality, safety and efficacy
CV cleaning validation OOS out of specification
CpK process capability index OOT out of trend
CPP critical process parameter OPV oral poliomyelitis vaccine
CMA critical material attribute OQ operational qualification
CQA critical quality attribute PDE permitted daily exposure
CTD common technical dossiers PHA preliminary hazard analysis
DEHT dirty equipment hold time PLC programmable logic controller
DI data integrity PPM parts per million
DNA deoxyribonucleic acid PQ pre-qualification
DQ design qualification PQMS Pharmaceutical Quality Management System
DS drug substance PQR product quality review
ECTC extended controlled temperature condition PUPSIT pre-use post sterilization integrity testing
EBI electronic bottle inspector QP qualification plan
ELISA enzyme-linked immunosorbent assay QA quality assurance
EM environmental monitoring QbD quality by design
EMS environmental monitoring system QRM quality risk management
EUA emergency use authorization Ra surface roughness
FAT factory acceptance test RABS restricted access barrier system
FMEA failure modes effects analysis RCA root cause analysis
GC gas chromatograph RPN risk priority number
GCP good clinical practice RRF risk ranking and filtering
GDocP good documentation practice SAR sterility assurance report
GEP good engineering practice SAT site acceptance test
GMO genetically modified organism SME subject matter expert
GMP good manufacturing practice SMF site master file
GPT growth promotion test SOP standard operating procedure
HACCP hazard analysis and critical control point SUS single-use system
HBEL health-based exposure limit TOC total organic carbon
HEPA high-efficiency particulate air TOR time-out-of-refrigeration
HPLC high-performance liquid chromatography UNICEF United Nations Children’s Fund
HVAC heating, ventilation, and air conditioning URS user requirement specification
IQ installation qualification UV ultraviolet
IMP investigational medicinal product VLP virus-like particle
IND investigational new drug VMP validation master plan
IPC in-process control VVM vaccine vial monitor
IQ installation qualification WCB working cell bank
JIT just-in-time WFI water for injection
KNAPP Hartung-Knapp
iv
INTRODUCTION
The World Health Organization (WHO) Local Production and
Assistance (LPA) Unit in the Regulation and Prequalification
World Health Organization | Virtual cGMP Training Marathon for Vaccine Manufacturing | Questions & Answers
Department, Access to Medicines and Health Products Division,
supports Member States, particularly low- and middle-income
countries (LMICs), to strengthen local production toward quality
assurance and sustainability to improve access to essential health
products.
In response to Member States’ requests for capacity building in the

local production of quality-assured vaccines, the LPA Unit organized
the Virtual cGMP Training Marathon for Vaccine Manufacturing (5
October to 11 November 2021) for vaccine and biopharmaceutical
manufacturers, regulators, and government officials from the six
WHO regions. Over 800 participants from more than 60 Member
States in the six regions attended each of the 12 sessions in the
training marathon to improve their knowledge, understanding and
capacity to comply with WHO/international cGMP standards and
requirements.
This document collates the questions raised during the 12 sessions

and the answers from the good manufacturing practice (GMP)
experts who delivered the training as a continuous learning resource
for participants and other relevant stakeholders.
1
1
SESSION
5 October 2021
2
Vaccine lifecycle and
technology platforms
1 | Vaccine lifecycle and technology platforms | 5 October 2021
1. Should the phase 3 clinical trial batch 3. Where in the vaccine life cycle should
size be pilot-scale or commercial-scale? the National Regulatory Authority (NRA)
be involved?
It could be produced in either pilot scale or
commercial scale. The NRA can be involved at all stages of
However, for prequalification vaccines, a vaccine life cycle, from pharmaceutical
WHO recommends that phase 3 clinical development to product discontinuation.
trial batches be similar to commercial Normally, the NRA will grant approvals
batches. Expectations from the WHO for clinical trials execution and then, for
prequalification programme are that during marketing authorization. It will approve
the manufacturing of phase 3 clinical material, GMP facilities, and will inspect IMP GMP
consistency lots (i.e. process validation lots) compliance, good clinical practices (GCPs),
should be produced as part of adequate and routine GMP compliance (commercial
validation studies. production).
Therefore, phase 3 batches should be Once marketing authorization has been
produced on an industrial scale using the granted, the NRA has the regulatory
same manufacturing process/scale for oversight of the vaccine for its entire life cycle.
commercialization to ensure the same quality For changes to manufacturing processes/
for clinical phase 3 batches as for commercial specifications, the NRA should be notified
batches. In addition, consistency between or approve the change to the marketing
the batches for the clinical studies should be authorization.
demonstrated.
Please refer to Validation of Production 4. What makes protein subunit particularly
Processes for Vaccines for WHO desirable as a vaccine technology
Prequalification Compliance Expectations: platform, given that it commands the
A note for guidance for the manufacture of largest percentage of Covid-19 vaccine in
prequalified vaccines for supply to United development?
Nations agencies, July 2013.
The advantages of protein subunit are safety,
2. What are the principal differences safe handling, and low biosafety concerns.
between good manufacturing practice Therefore, it does not require a high level of
(GMP) for investigational medicinal biosafety facilities and operations.
products (IMP) and GMP for commercial
production? 5. Given the difference in doses, is there a
significant difference in the immunogenic
In clinical trials, there may be added risk to capacity between DNA and messenger
participating subjects compared to patients RNA (mRNA) vaccines?
treated with marketed products. The
application of GMP to the manufacturing of Both DNA and mRNA vaccines will let our
IMP is intended to ensure that trial subjects body express protein antigen to stimulate
are not placed at risk, and that the results of the immune responses to that antigen. The
clinical trials are unaffected by inadequate differences between immunogenicity induced
safety, quality or efficacy arising from by DNA and mRNA vaccines could come
unsatisfactory manufacture. from the encoded gene optimization and
Please refer to Pharmaceutical Inspection efficiency of gene delivery system used which
Co-operation Scheme (PIC/S) GMP Annex 13 can impact the level of gene expression.
which applies to IMP.
3
6. Why is sterility required for orally biological products such as Type I borosilicate
administered vaccines? glass can be used. If plastic is chosen, USP
Class VI plastic should be used. However,
Taking the example of oral poliomyelitis compatibility studies, as well as leachable and
vaccine (OPV), the vaccine contains live extractable studies should be performed. Risk
attenuated virus in culture mediIf there is assessment should also be undertaken.
any contamination, other viruses, bacteria or
fungi can grow, and the contaminated vaccine 11. What is the technique used for
cannot be used. encapsulating lipid nanoparticles (LNPs)
with mRNA?
7. How to manage the toxicity issues of the
formaldehyde used in the process? LNPs can readily encapsulate nucleic
acids due to the ionizable lipid presence,
The concentration of formaldehyde used as which at low pH is cationic and allows for
well as time and temperature conditions are complexation with negatively charged
critical process parameters which must be RNLNPs are formed by encapsulating mRNA
optimized, validated and controlled. using rapid mixing of the lipid components
in an organic phase and the nucleic acid
8. Are dedicated facilities required for the component in an aqueous phase. This mixing
manufacture of adenoviral vaccines? is performed using a precise microfluidic
mixing platform, allowing for nanoparticle
An evaluation should be made based on risk self-assembly.
assessment considering different factors such
as types of vaccines to be produced, cleaning 12. Is there a process to discard the
processes and cleaning validation (CV) results, vaccine in cases where the vaccines are
and if single-use systems (SUSs) are applied, considered rejected?
etc. before making a decision.
A destruction procedure of the vaccine must
9. Usually, stainless steel is preferable for be in place and should be evaluated based
manufacturing. When we use the SUS, is on knowledge management and quality risk
there any compatibility issue that we need management (QRM). For almost all types of
to study? vaccines (such as whole microbe vaccines,
toxoids and other subunit vaccines), autoclave
Compatibility between the contact surface would be applicable. After autoclaving, the
of the SUS with the product/materials should vials should be destroyed before disposal.
be considered. Studies could be initiated to
verify compatibility. 13. How do we differentiate live virus in
Additionally, stainless steel is a good material, an attenuated vaccine pool if it did not get
but there are several types of SUS currently attenuated during processing?
available that are also useful in preventing
cross contamination and reducing the need The seed must be qualified to ensure
for CV. stable attenuation before it can be used for
vaccine production. If needed during the
10. Are there any principles for selecting manufacturing process, there can be some
packaging materials? in-process testing and/or release testing to
verify attenuation of the virus.
There are compendial requirements for
primary packaging materials. Conventional
materials for containers of pharmaceutical/
4
14. Is it necessary to maintain any specific 18. Is filtration required immediately before
temperature during mRNA-based drug filling to produce the vaccine?
product filling?
Yes, if the product can be filter sterilized,
Generally, it can be filled at room the final sterile filtration step must be as
temperature, but the fill/finish time must be close as possible to the filling point. This
minimized. is a requirement for sterile manufacturing
products. However, some vaccines cannot be
15. What is the impact/efficacy and safety filter sterilized just before filling, such as those
of plant-based vaccine in comparison with containing aluminium adjuvant. Therefore,
the mammalian expression technology aseptic processing must be applied from the
platform? formulation step.
There may be impurities 19. For a technology transfer of vaccine

from the plant (such as production from one plant to another
nicotine from tobacco plant, will this require clinical trials before a
plant, plant glycans), post- marketing authorization can be provided to
translational modification of the receiving plant?
protein after gene
expression in plants may be different from This issue has to be discussed with the NRFor
mammalian cells, etc. example, if there is a good technology
transfer with supportive data such as process
16. What should be the consideration validation and comparability studies (process
of novel excipients? Because during and analytical comparability), clinical trials may
development, manufacturers incorporate not be necessary. However, the regulators may
new excipients which are not covered in ask for a clinical bridging study, if they deem it
any pharmacopeia. necessary.
Several novel excipients have advantages for 20. Is egg-based vaccine classified as
vaccine formulation. However, when using inactivated or activated?
novel excipients, there is a need to have
safety/toxicity studies of those excipients in It depends. Egg-based vaccine is not always
addition to those of the formulated vaccine. necessarily regarded as an inactivated vaccine
if there is no inactivation process.
17. Is it difficult to manufacture DNA There is an egg-based Newcastle disease
vaccines? virus vectored COVID-19 vaccine (under
development) which is a live-attenuated
Manufacturing DNA vaccines is not vaccine for intranasal administration.
considered difficult/sophisticated because
it is mostly produced in Escherichia coli. 21. What steps need to be critically
However, the yield and the purification inspected from the lifecycle of vaccine
process must be carefully considered. The manufacturing?
difficult part of DNA vaccines is the delivery
system/device. This is mainly related to the manufacturing
process and technology platform of each
vaccine. However, the critical process
parameters (CPPs) and critical quality attributes
(CQAs) of each vaccine must be continuously
monitored through its lifecycle.
5
22. What will be the most difficult of recombinant vaccine. However, viral
task during inactivation of the vaccine vectored vaccine is considered a genetically
manufacturing stage and how can one modified organism (GMO) while some other
ensure that these steps are well done? recombinant proteins, such as virus-like
particle (VLP), DNA, mRNA vaccines are not
The most crucial and difficult GMO.
task for the inactivation
process is to control all critical
material attributes (CMAs)
and the CPPs of the
inactivation process such as
concentration of bulk antigen before
inactivation, concentration of inactivating
agent(s), buffer, excipients, temperature, time,
agitation, etc., which must be validated and
monitored for process performance and
product quality. In-process control and in-
process testing should be done. For some
vaccines, the manufacturer will take samples
during the inactivation process to determine
the kinetic energy of inactivation. The
inactivated product should be tested for live
virus to verify if the inactivation process is
complete or not.
23. What is the difference between Stage

3 and Stage 4 of vaccine development?
Vaccine development Stage 3 is the clinical

trials phase, and Stage 4 is post-marketing
pharmacovigilance. The main difference is
that Stage 3 is undertaken before obtaining
marketing authorization and Stage 4
is undertaken after getting marketing
authorization.
24. Should the three phases of lot release

be documented?
Yes, the manufacturer should have a standard

operating procedure (SOP) describing the lot
release process.
25. Is a vector vaccine a special case of

recombinant vaccine?
The recombinant DNA technology is often

used in new generation vaccines, and
a vectored vaccine is not a special case
6
2
SESSION
7 October 2021
7
system principles
Quality management
2 | Quality Management System Principles | 7 October 2021
1. Can protocols replace batch production 4. Is it possible to start drug substance

records (BPRs) during product registration (DS) production if the facilities have not yet
application? received GMP?
This should be discussed with the National The manufacturing may need to be
Regulatory Authority (NRA). Both documents done before receiving GMP because the
serve different purposes and can be manufacturer would need the information
considered supplementary to each other to prove that the process is robust and
during product registration. For example, validated. For example, process validation
process validation batches need a protocol to lots.
perform the process validation and also need
BPRs for operators to record parameters/ 5. What is the procedure to follow to
operations carried out as defined in the correct an approved standard operating
protocol. procedure (SOP) or batch record during
the execution of a task?
2. How long should a manufacturer retain
relevant documentation after product The best way is to revise such a document.
discontinuation? However, in case it cannot be done
immediately, the revision of a portion of
The WHO good manufacturing practice the document should follow the document
(GMP) requirements state that related approval route. For example, signed and
documents such as batch records and dated by the same people who approved the
material records should be retained for at document plus the reason for alteration.
least one year after the expiry date. However, However, if such correction is a change that
it is beneficial to keep them longer as it requires a change control, it should not be
can be useful for the purpose of adverse corrected until a change control is approved.
event following immunization (AEFI) and
investigation. In some vaccine companies, 6. Why are third parties common in vaccine
they never destroy any important product production?
related records. With the increasing use of
electronic systems for document retention, Third parties are common for vaccine
the problem of physical space is significantly production and quality control (QC),
reduced. mainly due to the complex technological
requirement of vaccines. For large-scale
3. How long should a manufacturer retain production, it is common to see companies
critical documents such as validation, subcontract some parts of production and/or
clinical data, stability data, etc.? QC to specific plants/laboratories.
These critical documents should be kept until 7. What are the procedures to do
the end of the product’s life cycle, or one year requalification of QC personnel? And what
after the expiry date, whichever is longer. is the right frequency to do the personnel
Please see the previous answer for additional requalification?
detail.
The requalification requirements of QC
personnel should be considered based on the
test activities. However, it is more common
to see an analyst’s qualifications review done
every 6–12 months depending on the test.
8
8. In order to maintain QC personnel’s is also important in justifying in scope and

qualifications, is it feasible to check an out of scope. However, whenever a supplier
analyst’s QC qualifications on the basis of of material is out of scope of the SOP on
test results that they have carried out to management of supplier, there should be
confirm that they are still qualified to carry another procedure to control these materials
out the test? (e.g., chemical grade, supplier, manufacturer,
etc.).
It depends on the test and the requirement
for qualification of such a test. However, in 12. If auditing of the supplier is not
general, there should be some indicators possible, for example, if the supplier is in a
that can be used to review an analyst’s remote country and resources are limited, is
performance before extending the it acceptable to rely on history and in-house
qualification. For example, training, frequency testing of incoming materials only?
of testing, invalidity rate, out of specification
(OOS), out of trend (OOT) from analyst’s error, Relying on in-house testing history means
etc. These indicators and staff responsibilities we rely on QC, but such information cannot
should be justified and documented. replace the requirement to ensure quality
management of the supplier. The adequate
9. When to a perform quality audit? Should resources to ensure quality management of
it be done before the batch is released? third parties should be considered.
Quality audit of third parties, 13. Is it a requirement to audit the suppliers

when required, should be of raw materials for bulk production or
done before starting a suppliers of packaging materials?
commercial business with a
third party, which means Initially, all starting material/packaging material
before the batch that is involved with the suppliers should be approved/qualified based
third party is released. Additional audits may on criteria documented in the SOP and from a
be required after starting a commercial risk-based approach before use. An audit may
business, depending on the activity of such a form part of such approval/qualification, as
third party. needed.
10. How much can we trust the data 14. Is it a requirement to audit the suppliers
obtained through questionnaires from the of bulk vaccine?
supplier?
According to GMP, a bulk vaccine is one of the
The quality questionnaire sent to the supplier critical materials and so initially the supplier
should be used as a basic information to should be approved/qualified following the
increase the knowledge about the supplier. procedure. If the on-site audit is evaluated
However, it cannot totally replace the on-site to be necessary, it should be carried out
audit. accordingly.
11. Do we need supplier qualification 15. Do we need a change control to change

of non-critical chemicals used in a QC a certified supplier?
laboratory?
Yes, a change control is needed to change an
What is in scope and out of scope should approved/certified supplier.
be defined in the SOP on management of
supplier. The definition of “non-critical”
9
16. What is the situation that virtual Having a document in the local language is
audit of the subcontractor cannot be better for their own workforce. For quality
acceptable? audit purposes, the language of audit and
major documentation should be detailed in
Virtual audit has its limitations and so cannot the quality agreement.
be used to fully replace the on-site audit.
One of the examples that the virtual audit 20. What is a quality unit?
may not be enough is the initial qualification
audit of a production subcontractor. However, According to WHO GMP,
this should be documented in the company’s quality unit(s) is an
document. organizational unit
independent of production
17. What is the difference between the which fulfils both quality
desk GMP review and the virtual audit? assurance (QA) and QC
responsibilities. This can be in the form of
The processes involved should be similar separate QA and QC units or a single
to on-site audit with the exception that the individual or group, depending upon the size
auditor is not on site. Thus, the virtual audit and structure of the organization.
includes opening the meeting, a virtual site
tour, an interview with an auditee, as well as 21. What are the administrative changes
closing the meeting via an online meeting to GMP documents that do not need a
platform. change control?
18. A planned deviation is usually a The administrative changes to GMP

temporary thing and not permanent. documents are changes that do not have an
How can I issue a change control for a impact on GMP. For example, corrections to
temporary planned deviation, especially typographical errors, document formatting,
when there is not enough time to update etc.
the document? Are planned deviations
non-GMP compliant? 22. Are changes affecting key production
and quality personnel required to follow
The change control system should be change-management procedures?
designed to process temporary changes and
emergency changes. Yes, a change control should be used to
Change control procedures and action plans handle changes affecting key personnel,
should be responsive to these temporary and including key production and quality
emergency changes. personnel.
Treating a planned deviation as a deviation
is not GMP compliant since deviation is an 23. What are major and minor changes in
unexpected event. change control?
19. In some countries, the documents Major and minor changes are part of a
are prepared in local languages, which change category that is evaluated based on
is very difficult for foreign auditors and the risk of each change control request.
even translators. Is it mandatory for
companies to have English or other widely
spoken languages in addition to their local
language?
10
24. What happens if change controls 28. Which is a good trend analysis for a
are not completed or closed within the PQR?
timeframe?
Choosing a trend analysis tool depends on
The change proposed cannot be the type of data available. It is also possible
implemented for routine implementation. to have different tools for different sets of
This includes the related batches that cannot datExamples of trend analysis tools are
be released for sale. control charts, and process capability index.
25. If we manufacture more than one 29. Is it possible to perform root cause
finished product batch using the same analysis (RCA) using 5 whys techniques in a
batch of bulk vaccine, do all the finished fishbone diagram?
product batches need to be released from
the NRA/National Control Laboratory It is possible to use a mixture of investigation
(NCL)? tools depending on the nature and extent of
a deviation.
Lot release of vaccines by regulatory
authorities depends on the specific 30. Is it mandatory for a NCL to analyse all
requirements in each country. However, in the lots of vaccine?
general, a lot release certificate provided by
NRA/NCL will be for a lot of vaccine in the Not unless it is a specific requirement for the
final container. For additional information, country. For WHO’s requirement, please refer
please refer to WHO Technical Report Series to WHO technical Report Series 978, Annex
978, Annex 2, “Guidelines for independent lot 2: “Guidelines for independent lot release of
release of vaccines by regulatory authorities”. vaccines by regulatory authorities”.
26. Is it mandatory for the product quality 31. How many product batches are
review (PQR) to be initialled on every page recommended for a PQR to be conducted?
or can it be approved on either the first or
last page? GMP guideline expects PQR to be done on
an annual basis.
A PQR is a quality document, and it should be
approved by the quality unit. The review and 32. In preventive maintenance, if some
approval route of a PQR should be written parts of the equipment were found not to
in the SOP. The WHO GMP does not specify be functioning, should they be changed
how the PQR is approved. through change procedure? Similarly, if
there were a change to machine parts as
27. Should a blank (unfilled) BPR have an a corrective action for a deviation, is a
effective date and a review due date? change control required?
There must be a system detailing how a For both cases, if it is a like-for-like

blank (unfilled) BPR is prepared, reviewed, replacement, there is no need to do a change
approved, trained, effected, revised, and control. However, the like-for-like spare parts
archived. Therefore, an effective date is should be written clearly in the SOP. The
compulsory. replacement should be documented and
The blank (unfilled) BPR is a living document traceable.
and a periodic review of such a document
is beneficial for identifying any potential
improvement.
11
33. For inactive vendors, how many years A SAR contains all sterility assurance
should they be kept on the approved list information related to the batch. For
before being disqualified? example, environmental monitoring results,
latest media fill status, related water
Inactive vendor management should be monitoring results, etc.
evaluated regularly, possibly during the third-
party performance review. There should be 37. Considering the effectiveness of virtual
a documented process for keeping inactive inspection, can we assume that virtual
vendors on the approved vendor list. inspection is not generally encouraged for
GMP assessment of facilities?
34. For the PQR of a vaccine product
where the final bulk for filling and Implementing virtual inspection depends on
packaging is sent to several contract each country’s regulation and NRHowever, in
manufacturing organizations (CMOs), which general, virtual inspection has its limitations
also have filling and packaging activities, is and so may not be used to fully replace the
it necessary to include their activities in the on-site inspection. One example of when
PQR of the product? virtual inspection may not be enough is the
initial assessment of GMP.
It would depend on the quality agreement.
Each CMO may perform their own PQR on
their activities and pass it to the contract
giver; or provide information to the contract
giver to perform PQR. Ultimately, as
marketing authorization holder (MAH), the
PQR of the whole manufacturing process
should be available and be compliant with
GMP.
Please refer to WHO Technical Report
Series 986, 2014, Annex 2, for additional
requirements on PQR.
35. What is the minimum frequency for

self-inspection of a vaccine production
facility?
What is the minimum frequency for third-
party quality audit?
According to WHO GMP, self-inspection

should be done at least annually. Third-party
audit is not considered as self-inspection.
The interval for a quality audit of third parties
should be determined based on quality risk
management (QRM).
36. What is the content that should be

included in the sterility assurance report
(SAR)?
12
3
SESSION
12 October 2021
Quality risk
13
and implementation
management principles
3 | Quality Risk Management Principles and implementation | 12 October 2021
1. What is meant by “Quality Risk questions to identify and analyse the risks and
Management (QRM) cannot be used evaluate the outcome against predetermined
to be non-compliant from regulatory criteriQuestions include “What might
requirements”? go wrong?”, “What is the probability of
occurrence?” and “What is the severity?”. A
This refers to an intent by an organization/ single or a combination of QRM tools can be
manufacturer to avoid regulatory compliance selected to aid the execution of QRM.
using QRM in favour of a particular situation
or to justify actions already taken. A good 4. When analysing risk, would it be
QRM is one that uses science-backed data/ correct to say severity of risk remains
facts that can withstand regulatory scrutiny. constant irrespective of the probability of
occurrence?
2. Some pharmaceutical manufacturers
try to justify non-compliance of good The severity of risk is not a constant. It is a
manufacturing practice (GMP) on the basic score derived from the analysis of the risk
principle of QRM although the regulatory on “How bad is the harm?”. Organizations
guidelines do not allow such practice. Is assessing the same problem, or a person
this acceptable? assessing the same problem in a different
organizational setting, may arrive at different
WHO guidelines on QRM require that severity scores. This is largely dependent on
its implementation should not obviate a the background data, past experience and
manufacturer’s obligation to comply with trends observed/monitored that affect the
regulatory expectations (for example, score for the individually identified failure
regulatory requirements, regulatory modes.
filings and inspection commitments). In
that respect, regulators do recognize the 5. In practical terms, is it possible to
inappropriate practices in the industry. It is eliminate risk?
for the organization/manufacturers to provide
evidence in the form of science knowledge/ Risk is unlikely to be
data/facts, to justify and demonstrate to the eliminated entirely even when
regulators that the QRM process is effective the best QRM is applied. In
and facilitate informed decision-making in most instances, “as low as
order to avoid citation of deficiencies by reasonably practicable”
regulators. (ALARP) is applied to indicate that no further
controls can be applied to reduce its risk
3. How do we carry out a risk assessment further and that the risk is acceptable. In
for a preventive maintenance system? addition, for every decision made, there is a
need to reassess whether any new risk has
Preventive maintenance can be performed arisen to impact the risk control.
proactively and prospectively prior to
potential problems. A clear risk problem 6. In this QRM context do we need
with defined scope and boundaries of the to develop a QRM protocol before
risk assessment will enable the focus to implementation, or is a standard operating
be on a particular department/process/ procedure (SOP) enough?
system, e.g., production, quality control (QC)
or utilities system. Using the background The quality system governing documentation
information and outputs gathered from in an organization should describe the
the brainstorming at the initiation phase, distinction and function of the different
risk assessment can proceed by asking key critical documents for its optimal operation.
14
It depends on the level of detail on the leads to the decision-making step of, “What
steps and instructions in the SOP. If the can be done?” in order to mitigate and/or
SOP outlines the basic rules of QRM and its accept the risks.
conduct, a protocol may complement the
SOP to describe the required steps in depth 9. What is a matrix system for risk rating?
and outline the prerequisites/guidance in
initiation, risk assessment, risk control, risk It is a measurement system developed by an
review, risk communication, tool selection and organization to describe the standards and
documentation. corresponding definitions/actions to these
risk scores/numbers in order to rate and/or
7. What is the meaning of an “acceptable prioritize the available resources.
risk”? How is it decided? How does one
convince decision-makers or regulators? 10. How can risk levels in a manufacturing
process be prioritized to maximize
“Acceptable risk” indicates how the risk to effective controls in ensuring quality and
product/process/patient is managed and safety?
kept at reasonably low levels with appropriate
controls in place. Decision-makers and Knowledge of QRM tools and how to use
interested stakeholders should be a part them are essential in aiding the selection of
of the commitment to risk communication the appropriate tool to perform prioritization
across all stages of the QRM process. The of risks/controls/activities. Amongst plausible
output/result of the QRM process ought tools that can be considered are preliminary
to be communicated to the organization hazard analysis (PHA), risk ranking and
and interested stakeholders to increase filtering (RRF) and failure modes effects
awareness, coordinate understanding and analysis (FMEA).
priorities, and ensure acceptance of known
residual risks. This residual risk, however, 11. Which is the most useful/common QRM
may change over time with changes/new tool in vaccine manufacturing?
information and has to be reviewed/verified
accordingly. A robust and scientifically sound All QRM tools are useful in a QRM process
QRM based on a thorough understanding of with its set of strengths and weaknesses.
the QRM decisions involved will be able to As the tools are not equal, the selection of
withstand the regulator’s scrutiny. tool should be appropriate to facilitate the
intent of QRM and the risk problem. FMEA is
8. If we accept a risk, what should we do to regarded as a commonly used tool in vaccine
document it and what should we do about manufacturing due to its capability to risk
the related possibility of deviation? assess a complex problem and break it down
into smaller segments. Also, FMEA can be
Acceptance of residual risk is part of the scaled back to accommodate qualitative
risk control component. Prerequisites and or more simple assessments. However, the
criteria for risk deemed as ALARP and the emphasis of an effective QRM is that no one
resulting required actions, if any, should tool is appropriate for all risk problems and
be appropriately defined. Communication the selected tool can be combined with other
of the output/result of the QRM process, tools to complement the weakness of tools
including risk acceptance decisions, should used.
be documented. Any related possibility of
deviations identified from the QRM should
be appropriately evaluated to determine if
risk control measures need to be taken, which
15
12. When deciding on the probability and 16. Why is the risk priority number (RPN) a
severity of occurrence, do we need to relative risk score?
review historical data to determine how
frequently a hazard occurs or base it on RPN is not an absolute risk number. Instead,
literature? it is a relative risk score for each failure mode
and is further used to rank the failure modes
There is no distinction between the on a relative risk basis.
type of data/information that is suitable
for evaluating severity, occurrence and 17. Should decisions be based solely on
detectability. Background information should RPN scores? What happens when you have
be gathered and can range from historical similar RPNs?
data, past performances of the product/
process/system, experience, scientific For FMEA, the RPN score guides the
knowledge, and literature. relative priority for actions and should be
considered with other factors that influence
13. In QRM, is severity defined in relation the risk of failure mode. From the already
to product quality or patient safety? And agreed terms for the corresponding risk
how do we give a sound severity score? index, the importance of actions will take
precedence from big RPN numbers to the
Severity can be defined as impact to process, small numbers. When two RPN numbers are
product quality or patient safety. Once the equal and are taken to the next step of risk
definitions of the level and severity scores control, a new RPN number may be derived
are predetermined, severity of a failure mode from reassessment to estimate the impact of
can be assessed by asking, “How bad is the the changes to be made. Other factors that
harm?”. have important considerations are available
resources, ease of control measure, short-
14. For the criticality in FMEA, do we and long-term plans, etc.
multiply or add severity and occurrence?
18. When assigning numbers to the
Criticality is a product of severity and degrees of occurrence and severity,
occurrence. To derive a criticality score, the numbers were in the order 1 3 5 7 9, what
two numbers are multiplied. informed their selection of numbers?
15. Are manufacturers required to justify Consecutive numbers (e.g. 1,

the choice of risk management tools 2, 3, 4, 5), non-consecutive
deployed? numbers (e.g. 1, 3, 5, 7, 9) and
non-linear numbers (e.g. 1, 4,
It is necessary for an organization/ 9, 16, 25) are common scales
manufacturer to be able to support their used to establish definitions for severity,
choice of QRM tool for the risk problem occurrence and detectability in FMEPiloting
in question. As each tool has its unique to validate these scales will give clarity on the
characteristics and serves its purpose in suitability of these numbers and ensure that
different areas of implementation, pre- the resulting number is distinct, clear, and not
selection of the right tool will yield quality skewed.
approaches and deliverables.
16
19. What if the regulatory inspector did 22. How can we integrate QRM in
not find any proactive risk studies? Are deviation handling?
retrospective risk studies acceptable?
QRM can be applied to identify, evaluate
Pro-active conduct of QRM is an early and communicate the potential impact of the
process implemented by an organization/ deviation and make appropriate informed
manufacturer to identify potential failure decisions with respect to the deviation.
modes and causes, hazard controls to put Investigation into the root cause of deviations
in place, and/or design risks of the product/ can be performed with the right tool and can
process/system to ensure informed decision- ensure that the causal factors are addressed
making. Its implementation is diverse adequately to resolve the failure.
across many areas in integrated quality
management, development, facilities/ 23. How can regulators utilize QRM in their
equipment/utilities, materials management, function?
production, QC, etc., for both new and
existing facilities. Therefore, if the risk studies Regulators can utilize QRM in a range of
are only retrospective to justify an action regulatory functions from inspection planning,
that has already been carried out and have a review of CAPA, complaint handling and
biased intent, they are not acceptable. dossier review.
20. For every critical change and major

deviation, is QRM required?
Change management and deviation are

among the many areas where QRM can be
deployed. However, outlines for prerequisites
of QRM conduct should be in place in the
respective systems to assess the next steps.
For example, the definition of critical change
and the applicable scope is predetermined
for identification. It is the same for major
deviation.
21. Is it possible to use the QRM approach

for a corrective action and preventive
action (CAPA) effectiveness check?
CAPA can be developed by incorporating

QRM to identify failure modes, effects, root
causes, controls, and actions to undertake.
In this manner, a more effective CAPA can
be deployed to tackle the root causes. CAPA
effectiveness can be explored at the risk
review step to monitor the specific risk control
measure relative to its acceptance limits.
17
4
SESSION
14 October 2021
18
manufacturing
practice for sterile
Good manufacturing
4 | Good manufacturing practice for sterile manufacturing | 14 October 2021
1. Are antibiotics used in all vaccine 4. What should be an acceptable

manufacturing processes? bioburden level prior to the sterile
filtration?
Certain antibiotics may be used in vaccine
production to help prevent bacterial Prior to final sterilizing filtration, products
contamination during manufacturing. As a must show a bioburden lower than 10
result, small amounts of antibiotics may be CFU/100 ml.
present in some of the vaccines, either in
very small amounts, or even in undetectable 5. What is the meaning of integrity testing
quantities. of sterilizing filters?
Some antibiotics can cause severe allergic
reactions in some children, such as hives, Integrity testing means to test if the filter is
swelling at the back of the throat, and low intact, normally before and certainly after
blood pressure. However, antibiotics most filtration.
likely to cause severe allergic reactions, e.g.
penicillins, cephalosporins and sulfonamide 6. When is the right time to test the
drugs, are not used in vaccine production integrity of the filter before use or before
and, therefore, are not contained in vaccines. or after sterilization?
Examples of antibiotics used during vaccine
manufacture include neomycin, polymyxin B, For final filtration, the integrity
streptomycin and gentamicin. testing should be done after
sterilization as filter properties
2. Does vaccine manufacturing require a may have been impacted by
dedicated facility? sterilization. However, there
may be some flexibility for early-stage sterile
There are requirements for specific vaccines filtration.
(tetanus, BCG – since they are spore formers)
to have dedicated facilities, but not for 7. Should pre-use post-sterilization
others. WHO Technical Report Series 986, integrity testing (PUPSIT) be tested before
Annex 2, and WHO Technical Report Series use after a certain holding time or tested
999, Annex 2, mention the possibility of then used after 5 days, for example?
manufacturing multiple products in the same
facilities. It is acceptable to test after a certain holding
However, considerations should include time (e.g., 5 days), if you can validate that the
the specificity of the installations, the long filter is still sterile after 5 days. However, it is
processing times, and the extremely high recommended to sterilize, cool down and test
validation requirements when thinking about immediately.
multi-purpose facilities, especially when there
is an alternance between live and inactivated 8. What is the recommendation for wetting
vaccines. agent for PUPSIT?
3. In addition to temperature and time, When the integrity test is done before the
is pressure also a part of the sterilization filtration, it is recommended to use the
condition? product itself.
There is a correlation between temperature 9. What is the function of flush bags?

and pressure, for example, in an autoclave.
However, pressure is equally distributed, but Flush bags are there to collect fluid used to
the temperature may not be. wet the filter before the test.
19
10. How do we maintain sterility of the 15. Is it possible to use restricted access
filter if we do integrity testing prior to barrier systems (RABSs) installed in Class D
use? rooms to fill aseptic products?
The integrity testing is done from the Aseptic filling takes place in Class A under
unsterile side (upstream) of the filter. The air Class B background. The Class D environment
used is sterile filtered, and the solution used is only possible when there is an isolator.
to wet the filter also comes from the upstream
side of the filter. 16. Are non-viable and viable counts
required during the transfer of working cell
11. Is hydrogen peroxide bio- expansion in flasks when we do it under
decontamination process validation Laminar Air Flow (LAF)?
required?
Both non-viable and viable counts are
Yes, there should be validation runs with required if the process is done under Grade
bioindicators to test if micro-organisms have A.
been effectively killed.
17. What should we do when monitoring
12. What are the room classification shows deviations in critical control
requirements for activities in the parameters like particles and microbial
manufacturing of sterile products? loads in aseptic facilities?
Room grades and allowed/prescribed Consider stopping operations, evaluate the

operations are presented in GMP guidelines criticality (excursions or massive deviations)
such as WHO good manufacturing practice and investigate the cause, and identify the
(GMP) for sterile products, Annex 1 of EU germs.
GMP, and Annex 1 of PIC/S GMP.
18. What is the link between closed system
13. How acceptable is it if the area and quality by design (QbD)?
classification is based on an International
Organization for Standardization (ISO) Closed systems are certainly a part of QbD, as
standard only without consideration they reduce greatly the risk of contamination.
for viable/microbial quality of the
environment? 19. What is the purpose of the smoke test?
It is not acceptable. For pharmaceuticals, The smoke test can be used to visualize
there is a need to consider viable and non- airflows (e.g. show laminarity).
viable particles.
20. Can sterilization of vials and stoppers
14. Can the isolator for filling sterile be done together in one step?
products (class A) be installed in a class C
room? It cannot be done in one step since
procedures are essentially different: dry
Yes, that is the advantage of isolators; class heat depyrogenation for vials; and steam
D is also possible, but considerations should sterilization for stoppers.
also be on the number of ancillary isolator-
compatible accessories.
20
21. What are the requirements in terms 25. Does biosafety level (BSL) decrease
of monitoring/testing for the release of after inactivation?
sterile gowns to be used in a controlled
environment (grades A or B) when those Yes, because the product does not contain
are obtained from a supplier? any bio-active agent anymore.
For sterile gowns from a supplier, the 26. Should media fill be based on the
requirement should include audits of the product with the largest batch size?
supplier, and focus on packaging and
sterilization procedures, as well as leak testing It is not so much related to the batch size, but
on packaging. the number of filled units. If the batch size
is smaller than 5000 units, a complete batch
22. How to manage breakdowns or is filled. Otherwise, the minimum number
stoppages in the sterilization area where is 5000, although many companies opt for
the production is running? larger numbers. The minimum numbers are
defined in GMP guidelines such as Annex 1
Stops and breakdowns of the EU GMP, PIC/S GMP, WHO guidelines,
should be simulated during and the United States guideline on aseptic
media fill tests. To prevent processing.
stoppages, preventive
maintenance, an 27. Is it necessary to do media fills for the
uninterruptible power last step of bulk manufacturing such as
supply, and good equipment should be sterile filtration of bulk?
considered. However, when breakdowns or
stoppages occur, the following actions The media fill should reflect all steps of the
include: recording it in the batch bulk where sterility is at risk. For example,
manufacturing records; considering media fill filtration of sterile media.
simulation; removing and discarding part of
the batch left open during the stoppage time, 28. If there is a deviation that causes the
etc. holding time between formulation and
filling to be longer than the usual process,
23. Which water type do we use for should it be simulated on the next period
vaccine production – water for injection of media fill?
(WFI) or purified water (PW)?
When holding times are validated, it is
Water type depends on the process step, but important to plan a worst-case scenario to
at the final stage, it will be WFI. avoid deviations at a later stage. However, if
the situation exists, the longer holding time
24. Does a manufacturer have to wait for would be considered at the next media fill as
inactivated test results for the product to a validation exercise.
go to the next step in the inactivated area,
or can they be based on historical data? 29. Is a fumigation schedule necessary in
vaccine manufacturing?
If the process is properly validated, the
process can continue, taking into account that Generally, there is no need for scheduled
there is a risk; it depends on how long it takes fumigation. Good householding practices
to verify the inactivation. should be sufficient.
21
30. When a single-use system (SUS) is used 34. What are the most critical steps
for fill and finish products, do we have to for inspection for fill and finish vaccine
do the assembling under laminar flow? And manufacturers?
is one filter before filling (close to the point
of fill) enough? Of particular importance is quality assurance
(QA), and the manufacture of sterile products
The use of a laminar flow for connections must strictly follow carefully established
depends on whether there are conventional and validated methods of manufacture and
aseptic connections or connectors. Sterile control. A contamination control strategy
filtration near the point of fill is necessary. (CCS) should be implemented across the
However, the filling itself (including facility in order to define all critical control
assembly of the filling elements) is prone to points and assess the effectiveness of all the
contamination as well; thus, the filtration is controls (design, procedural, technical and
not a guarantee of sterility. organizational) and monitoring measures
employed to manage risks associated with
31. Is it necessary to do aseptic process contamination.
validation for seed preparation? The CCS should be actively updated and
should drive continuous improvement of
Yes, because the purity of the seed is critical; manufacturing and control methods.
a contaminated seed will negatively affect all
subsequent process steps.
32. Is there any guideline specifying

whether we need isolator systems for
product filling, or is a RABS acceptable?
Or is it based on quality risk management
(QRM)?
The decision is both QRM-based and cost-

based, as isolators are expensive as are their
ancillary features, e.g., Realtime Transport
Protocol (RTP) ports, transfer systems, etc.
33. For replication-incompetent vectors of

COVID-19 vaccine, what are the suggested
containment strategies for the whole
production process starting from cell
culture up to formulation and filling?
According to the current requirement, the

manufacturer has to make their own safety
risk assessment (see WHO Laboratory
Biosafety Manual, 4th edition).
22
5
SESSION
19 October 2021
overview
23
Quality control
5 | Quality control overview | 19 October 2021
1. Are microbiology and virology 4. Is it acceptable, from a GMP point of

laboratories required independently, or view to contract QC services to another
can the virology laboratory be operated as independent firm?
part of microbiology?
It is acceptable. Please follow GMP for
Organizationally, not necessary. However, contract analysis. The contracting laboratory
function/responsibility of each laboratory must be qualified, and a quality technical
should be well defined. Additionally, agreement should be available.
laboratory conditions and biosafety levels
(BSLs) of the microbiology laboratory and the 5. What is the difference between safety
virology laboratory are different and should and impurity specifications?
be appropriately managed.
Impurities could be process-related or
2. Which department is in charge of product-related and may not be directly
assigning an authorized person? And who related to safety.
should be designated as an authorized Safety specifications are related to product
person? safety, for example, endotoxins, sterility, etc.,
and may not be process-related or product-
Top management should assign the related substances.
authorized/qualified person responsible
for batch release. The authorized/qualified 6. Many raw materials are not yet
person must have qualifications in line with standardized in pharmacopeia, how can a
good manufacturing practice (GMP) and the company establish their specifications?
regulatory requirements of each country. In
several countries, they must be a pharmacist The company can establish an in-house
who has work experience in the vaccine or specification based on a supplier’s
sterile manufacturing industry. In other several specification, their risk assessment, and prior
countries, qualification requirements may be knowledge of the material.
different and may require a certification of
“qualified person”. 7. Why is it the case that for some
parameters, such as potency or
3. What is the difference in quality control quantification of active ingredients,
(QC) between sterile product and vaccine manufacturers establish only lower limits
manufacturer premises? but no upper limits.
QC premises depend on the tests to be It depends on the vaccine platforms and

done for the drug substance (DS) and drug safety profiles. Inactivated vaccines usually
product (DP). Most DS and DP vaccines have only lower acceptance limits. Live
require biological, immunological tests attenuated vaccines generally have both
(identity, potency, impurities); some may upper and lower limits to ensure their safety,
require animal tests. Viral vaccine will require so they do not receive too much live antigen.
virological testing. Newer vaccines may
require molecular biology laboratories. These 8. How can we set the limit for the
tests are generally not required for chemical, microbial limits of utility (i.e. compressed
sterile product. air and nitrogen)?
Microbial limits should be the same as the

requirement for the room classification in
which the compressed air/gas is used.
24
9. Is it obligatory to control the inactivation 13. Should samples taken for QC be

agent in the final vaccine? subject to an acceptable quality level (AQL)
table? If so, how would we manage this
It is not an obligation. However, the huge number of samples for QC testing?
specification of the final vaccine lot is
established based on critical quality attributes AQL sampling (special level sampling plans
(CQAs), the manufacturing process, non- described in ANSI/ASQ Z1.4–2008 or ISO
clinical and clinical development data, and 2859) are appropriate for selection of sample
on risk assessment. Therefore, residue of size and acceptance criteria for testing visible
inactivating agent is usually included in the particulates in injections according to USP
final vaccine lot specification. <790>. But this sampling plan is not applied
for QC of drug substances and intermediates
10. Can the supplier of a material provide a and may not be applied for other QC tests of
separate container that can be considered the drug products.
as a sample for testing, obviating QC from For sampling of vaccines, the sample size is
performing supplementary sampling? usually based on the number and quantity
required to complete all the tests stipulated
It is an exceptional case as such sampling in the specifications +2 times that quantity as
of the bulk antigen or ready-to-fill bulk a reference sample.
(final bulk vaccine) could introduce a risk of For drug substances and intermediates,
contamination in the bulk or final bulk. In only one or a few sample containers (to be
such a case, the supplier could take a sample aliquoted later for several laboratories) may
for the vaccine manufacturer. However, be required and are taken based on risk
the sampling procedure would have to be assessment.
validated and the responsibility for sampling For drug products, other statistical sampling
defined in the quality technical agreement. plans (random sampling or fixed-tray
sampling) may be applied, but the principle
11. How long is the retention period for that samples must be representative of the
the retention samples? batch must be achieved. Sterility test and
endotoxin test samples will have special
Reference and retention samples from each requirements.
batch of finished product should be retained The sampling plan used should be
for at least one year after the expiry date. appropriately justified and based on a risk
management approach (PIC/S GMP Part I,
12. Do vaccine sampling activities have to Chapter 6, par6.12).
be performed by QC personnel?
14. Should the company wait for the
In principle, sampling is results of the in-process testing of samples
QC’s responsibility. In some before starting the next step of the
cases, sampling may be process?
done by production, but
the sampler must be Ideally, yes. However, in practice not waiting
trained and qualified to for the in-process testing results could put the
follow the QC sampling procedure and the next step at risk. Nevertheless, the finished
sampling should have quality unit oversight. product cannot be released until all in-
process controls (IPCs) and release test results
are available.
25
15. How are variations in bioassay/in vivo 18. How can a manufacturer identify out of
testing results managed? trend (OOT) for test results with high result
variation?
They need to be evaluated on a case-by-
case basis since it depends on the test. The company needs to carry out a trend
Animal challenge tests normally have higher analysis before they can determine if the test
variabilities than animal immunization result is OOT. Validity of the test should be
before taking serum for enzyme-linked verified to ensure that the result really is OOT.
immunosorbent assay (ELISA) testing.
In general, you need to have all parameters 19. Regarding OOS and OOT results in
under controlled and validated conditions, microbiological tests, should the same
taking into considerations the Man (analysts) procedures as those for analytical tests be
trained and qualified; Machine (equipment, used?
instruments) qualified and calibrated;
Materials (Reagents, Reference standards, Yes, but the investigation checklist could be
Animals (age, sex, weight, strain, etc.); cells designed to fit microbiological tests. There
(passage number, seed lot system); Method is a requirement that sterility tests cannot be
validated; and Environment (clean room retested except where there is supportive
conditions, animal house air changes, etc.). evidence that the tests are invalid.
In some tests, more than one replication of
the test (e.g., duplicate, triplicate) can be 20. In QC, what standard tools should we
useful. In some animal tests, the increasing follow for trend analysis?
numbers of animals used in each test vaccine
and reference vaccine dilution will be helpful. Standard deviation: +/- 2 and 3 SDs.
Also, for some animal potency assays, two
test determinations may be required, and the 21. What is the difference between
geometric/arithmetic mean calculated. atypical results and OOT?
16. What would be the condition for OOT is determined from trend analysis;
resampling during out of specification atypical results are not.
(OOS) investigation?
22. Is analytical method validation required
1. If OOS investigation phase 1b shows that for both compendial methods and in-house
there is sample error. methods?
2. If OOS investigation phase 2 (and/or phase
3) requires resampling/additional sampling Non-compendial analytical procedure (such
according to the approved protocol. as in-house method) should be fully validated
according to ICH Q2 (R1) Validation of
17. Should we document an OOS analytical procedures: text and methodology.
investigation even when its invalidity may For compendial methods (such as those in
be an analytical error? pharmacopeial monographs, WHO Technical
Report Series, etc.), only analytical method
Yes, it should be documented in the OOS verification is required.
investigation record form according to the
approved standard operating procedure
(SOP).
26
23. If minor changes have been made 27. Given the heat sensitivity of vaccines,
to a compendial method, can it then be what is the purpose of performing an
considered as an in-house method, and accelerated stability study of them?
does it require full validation?
An accelerated stability study provides
It depends on the change(s). Please proceed useful support data in: establishing the
through the change control process and do expiration date; providing product stability
risk assessment to determine if a method information for future product development
validation or method verification is needed. (e.g. preliminary assessment of proposed
manufacturing changes such as change
24. What is the difference between in formulation, scale-up); assisting in the
method verification and method transfer? validation of analytical methods for the
stability programme; and generating
Method transfer is the transfer of an analytical information which may help elucidate the
procedure from a sending laboratory to a degradation profile of the drug substance
receiving laboratory. Comparability between or drug product. Studies under stress
the sending laboratory and the receiving conditions may be useful in determining
laboratory should be demonstrated. whether accidental exposure to conditions
Method verification is an assessment that other than those proposed (e.g. during
the compendial procedure can apply in the transportation) are deleterious to the product
laboratory to yield acceptable results utilizing and also in evaluating which specific test
the personnel, equipment and reagents parameters may be the best indicators
available. Only some of the validation of product stability (ICH Q5C Quality of
characteristics can be evaluated to verify biotechnological products: Stability testing of
the suitability of the procedure. There is no biotechnological/biological products).
comparison with other laboratories. Accelerated stability studies may provide
useful support data to establish the shelf-
25. Is checking the requirements of system life or release specifications but should not
suitability parameters on the monograph be used to forecast real-time, real-condition
enough for method verification? stability of a vaccine. They could also provide
preliminary information on vaccine stability
It is not enough. For more detail, please refer at early developmental stages and assist in
to the USP <1226>. assessing the stability profile of a vaccine
after manufacturing changes (WHO Technical
26. Is method validation required for all Report Series 962, 2011, Annex 3: “Guidelines
in-process and drug product specification on stability evaluation of vaccines”.)
tests? For example, how do we to perform
validation for the visible particle test? 28. Is it enough to include only one batch
for evidence of the photostability of the
All analytical procedures applied to drug product?
substances and products, and in-process tests
should be validated/verified. Yes. Please refer to ICH Topic Q1B:
The Visible Particulates in Injections Photostability testing of new active
(USP<790>) test is the simplest instrumental substances and medicinal products.
method. Method verification may not be However, please note that photostability is
necessary, but the equipment/instrument not mandatory for vaccine stability studies
must be qualified, and analysts must be (WHO Technical Report Series 962, 2011,
trained and qualified using the visual Annex 3).
inspection defects kit.
27
29. What is the purpose/use of real-time dataset for statistical evaluation would be
stability and ongoing stability? required.
(See ISO GUIDE 35: Reference materials
Real-time stability studies will be required for – general and statistical principles for
clinical trial approval, licensing, and shelf-life certification.)
determination.
Ongoing stability study is required after 32. Should samples submitted to stability
marketing to monitor the product over its studies in the climate chamber include
shelf life and to determine that the product a secondary package or is the primary
remains, and can be expected to remain, package sufficient?
within specifications under the labelled
storage conditions (see PIC/S GMP Part I, Samples in the primary package are used
Chapter 6, paras. 6.26–6.36). for stability studies for clinical approval and
registration.
30. Is stability evaluation necessary for For ongoing stability studies, products in the
vaccines that have undergone extended package in which they are sold should be
controlled temperature conditions (ECTC)? used.
Yes. It is important to have enough supportive 33. What is the Inspector’s position on the
stability data to ensure that a vaccine exhibits use of loose worksheets as opposed to
a stability profile suitable for the ECTC prior bound notebooks for recording laboratory
to administration, while remaining compliant data?
with the approved vaccine specifications.
Stability evaluation of a specific vaccine The laboratory test record worksheets are
planned for use under ECTC must generate compiled as “batch testing records” and
sufficient scientifically valid data to support combined into the batch record for batch
regulatory approval of labelling for such use release decision.
(see WHO Technical Report Series 999, 2016, There must be evidence that data are not
Annex 5). altered. Loose worksheets are not considered
appropriate. Laboratory notebooks may be
31. What is the minimum stability that used to record other laboratory activities such
needs to be demonstrated before using as reagent preparation, standardization of
internal reference standards or working reagents, equipment/instrument usage.
standards?
34. In vaccine-importing countries, how
Stability data are not required before does the regulator monitor the quality of
using the reference material. But a stability incoming vaccines without duplicating re-
monitoring programme must be in place to testing?
monitor quality/stability of the material.
It is important that the reference material The National Regulatory
must be qualified before use. For some Authority (NRA) may
in-house reference vaccines, qualification choose to review the
includes testing of that material (as summary protocol of an
specification) and testing some parameters imported batch of vaccine
(e.g. potency) in many replicates so as to have or may take a sample to
enough data for a statistical evaluation to test some parameters to confirm the quality
assign the reference value with limits. of the batch or may use a data logger to
For working standards, calibration against verify if there have been any deviations/
international standards with an appropriate temperature excursions during transportation.
28
The recipient country will usually receive

the lot release certificate from the NRA and
may rely on the already performed release
and testing. See also the WHO guidelines
for independent lot release of vaccines
by regulatory authorities and the WHO
operational tool for efficient and effective lot
release of SARS-CoV-2 (Covid-19) vaccines.
35. Should the NRA perform the

same vaccine control validation as a
manufacturer?
The NRA should follow the same rule:

• in-house/non-compendial method – full
validation
• compendial method – verification
• analytical transfer – partial validation/
verification.
29
6
SESSION
21 October 2021
Equipment
30
qualification
6 | Equipment qualification | 21 October 2021
1. What is the meaning of the statement the company needs to develop scientific data
“quality cannot be tested into the and rationale to demonstrate that the number
product”? of batches produced are sufficient to cover all
the possible process variability.
That statement refers to the limitation of
quality control (QC) testing to assure overall 5. Equipment qualification appears at the
quality. In-process, intermediate and final QC level of process qualification, does it mean
testing is a minimum good manufacturing that unqualified equipment can be used at
practice (GMP) and a regulatory requirement, the process design stage?
but it is not sufficient. All other aspects of
GMP and quality systems including validation During development, a minimum degree of
requirements, starting with raw materials, qualification needs to be documented, but
controlled upstream and downstream there is no need to use formal protocols as
processes, etc., are also necessary. needed in the commercial phase.
2. What is the difference between 6. How do we evaluate whether

equipment and instrument? parameters and tests written in a validation
protocol are correct for new equipment?
Equipment will usually include instruments
(e.g., fermenter with instruments such as Validation protocols should be prepared
pH meter). However, instruments may be by subject matter experts (SMEs), with the
considered individually (e.g., pH meter). support of the vendor, and based on the
equipment specifications, and approved by
3. What is the difference between quality assurance (QA). Equipment used for
qualification and validation? producing clinical phases material for humans
must be proven/qualified (at least) to be safe.
Validation may be used as a broad term Basically, this means to prove materials of
encompassing all related activities, including construction are sanitary, calibrated, sterile,
qualification. Also, validation is usually with no cross-contamination risk.
used for processes, and qualification for
equipment. However, there is no strict 7. Should validation master plans (VMPs)
difference. be updated regularly? What is the trigger
for re-validation?
4. The majority of pharmaceutical
companies follows the traditional “at least Yes, VMPs should be reviewed periodically,
three batches validation” concept and as any other GxP regulatory validation
is submitting this evidence to National document.
Regulatory Agencies (NRAs) during Revalidation may be triggered by time (e.g.,
dossier submission. However, the 2011 autoclave), or by changes/deviations/product
U.S. Food & Drug Administration process quality review/continued process verification.
validation guidance does not prescribe
how many batches are necessary to ensure 8. At what stage during a new product
compliance. What is the recommendation project does a VMP need to be
for NRAs? developed?
The recommendation is that at least three The VMP is a “living document” and is
successful consecutive batches should always adapted to the stage of the project.
be considered as part of process/product Therefore, it needs to be developed at a very
validation. However, the expectation is that early stage.
31
9. Should factory acceptance tests (FATs) 12. If a company is in the phase of IQ

and site acceptance tests (SATs) be carried and OQ without a user requirements
out on all equipment? specification (URS) or functional
specification, should they be produced
No, usually they are performed on large retrospectively?
complex equipment (e.g., filling machine,
water systems, steam generators, tank Although there are less advantages, URS and
reactors, fermenters, etc.). design qualification (DQ) should be prepared
retrospectively.
10. Many regulations do not require FAT
and SAT as a mandatory requirement. 13. Does off-the-shelf equipment need to
Therefore, how important is to execute start from URS?
these tests, and is it necessary to demand
its execution from a regulatory point of Yes, URS is always needed for equipment
view? and/or instruments considered critical based
on intended use and risk, but not necessarily
FAT and SAT are not mandatory, but they for accessories.
are clear regulatory expectation as it is very
unlikely that the pharmaceutical company 14. Is DQ a comparative review of an
will be able to start up complex systems equipment manual/brochure with a URS?
without these activities which are driven by
the manufacturer of the equipment. If not Yes, but DQ should also consider the
performed, this should be justified, and in technical and functional specifications
that case, the inspectors would most likely which are usually not included in manuals/
verify the installation qualification (IQ)/ brochures.
operational qualification (OQ) in great depth.
15. At what point in the cycle of DQ, IQ,
11. Are SATs and commissioning OQ and performance qualification (PQ) is
considered equivalent? equipment commissioning done?
Commissioning is defined as “a well-planned, Usually, commissioning will be performed

documented and managed engineering at the customer’s site, after DQ and factory
approach to the start-up and turnover of acceptance testing.
facilities, systems and equipment to the
end user that results in a safe and functional 16. How does one qualify the
environment that meets established computerized system of equipment?
design requirements and stakeholders’
expectations”. Thus, it focuses on good The computerized system
engineering practices (GEPs) applied to the will be validated as part of
equipment, rather than on the product. In IQ and OQ, which includes
some cases, FAT and SAT documents may testing of all routine
include most of the commissioning testing/ operations, sequences,
inspection. SAT may also be considered alarms, data recording and
a pre-commissioning activity. The scope storage, interfaces with other systems, and
and boundaries may vary according to the input/output programmable logic controller
equipment, system or facility involved, and (PLC) verifications.
should be clearly described and documented
in the VMP/project plan.
32
17. The PQ should mimic the routine quality risk management (QRM) and by the
process. So, for the filling machine, do we change control system.
have to do PQ using the same number
of vials as during the routine production 22. How often do equipment qualifications
process? need to be re-done if there are no major
changes? Is there a typical timeframe?
Yes, PQ studies need to prove that, at
commercial scale, the equipment is capable of Requalification criteria needs to be
performing reliably throughout the expected established as per the VMP and specific
routine conditions, maintaining the required validation protocols, but it is a decision made
critical process parameters and critical quality on a case-by-case basis. Some critical pieces
attributes of the product. Any other approach of equipment, such as autoclaves and ovens,
should be fully justified and proven to be need to be performed at least annually. All the
representative of the planned routine process rest, in general, should be verified regularly,
conditions. as required in Stage 3 of the current validation
approach.
18. Can a placebo be used instead of the
product for PQ? 23. What should be done if after
equipment PQ is finished, it is observed
The approach taken should be justified in a that the performance of equipment is not
documented manner. A placebo may be used consistent?
if there is no evidence that the drug substance
might influence the performance of the A deviation should be opened to investigate
equipment. If not, the actual product should the causes of the failure and assess the need
be used. to revalidate, with the required depth, on a
case-by-case basis.
19. Is it true that PQ focuses on equipment
and utilities and not on materials, personnel, 24. If there is a change of process, does the
etc.? manufacturer have to perform a new PQ
study to fit the change?
It is not true. At every qualification stage, all
related aspects and prerequisites, such as Depending on the extent of the change,
training, should be checked. PQ and process validation studies may be
required.
20. Is there an example of when it is
acceptable for PQ to be executed with 25. Do we need a requalification for change
process validation? of like-for-like components?
A typical example would be the PQ of an It depends on the component being changed.

autoclave, where it is also a sterilization If it is critical, some degree of requalification
process validation. is required. For example, in an autoclave, one
to three OQ empty chamber runs to verify
21. Is it mandatory to revalidate the whole temperature uniformity may be needed.
process in cases where a single piece of
qualified equipment is changed?
It is not mandatory. The company would need

to treat the situation discretely based on
33
26. If a company were to upgrade the 30. Is it enough to perform water for
equipment controller software, which injection (WFI) validation initially or are
qualification stages should be repeated? there more requirements for validation?
All the necessary IQ and OQ should be In general, WFI systems will be validated
performed focusing on the functions affected initially (up to one year), and will be verified at
by the change. Usually, such change would least annually (continued process verification),
not require a PQ, unless it would change a unless there is a change, adverse trend, series
critical process step. of deviations, etc.
27. How do we undertake the PQ of a 31. Is it necessary to perform annual

single-use bioreactor? heating, ventilation, and air conditioning
(HVAC) requalification or is an annual
The PQ of a bioreactor will include at environmental data monitoring review
least three consecutive successful runs sufficient?
at commercial scale using the actual
product or a representative placebo. If the There is no need to perform an annual
actual product is used, these runs may be requalification of the HVAC system, but
considered as process validation runs of a it is necessary to carry out the required
unit operation. maintenance, calibration, air grade
reclassification, and continued process
28. For autoclave, do we need to validate verification.
the minimum, maximum, and in between
loads? 32. Which equipment should be used for
measuring the volume of emulsion vaccine,
Maximum and minimum loads need to be especially during in-process control (IPC)?
validated. There is no need to validate a load
that is between a maximum and minimum For IPC, consider using the standard
load configuration, unless there is a specific procedure for weighing a representative
reason, which should be justified. number of units at a certain frequency, and
then calculate the volume based on the
29. If a qualified load of 800L liquid has density of the product.
been sterilized in an autoclave, does it
need to be requalified if it is reduced to 33. Should qualification of the bioreactor
600L liquid? include testing its capability to operate for
a maximum number of days?
In general, a certain range may be
established where no requalification is Yes, qualification studies should, as far
necessary (e.g., +/- 10% of the validated as possible, mimic the actual production
volume). If the change were outside this conditions.
range, a revalidation would be necessary,
including a potential change in the
sterilization time, in order to avoid a possible
overcooking in the case of culture mediAlso,
consideration would be necessary of whether
the case were related to production or QC
testing.
34
34. Is it necessary to do a test run after a 38. How do we handle validation or

change of parts on a filling machine? How qualification of old equipment which does
many vials are considered sufficient for a not have prior data or information from
test run and what parameters should be previous manufacturers?
tested to justify the routine use of the
machine after the change of parts? To qualify old equipment
with no previous data, you
Usually, a test run will be performed after need to consider:
changing machine parts. The degree of a. collecting flow
testing depends on the part/s changed and diagrams and matrixes that
should be treated on a case-by-case basis can be useful in providing
considering the impact on the process and an overview;
the risk to the product. The number of vials b. preparing a VMP and/or qualification plan;
to be tested should be sufficient to allow any c. collecting, reviewing and updating
possible variation, and this should be justified procedures, changes, historical production
and documented. If there were a possibility data, process deviations;
that the change might influence the aseptic d. applying QRM to identify which items of
processing, one or more media fills would be equipment require qualification, and to
warranted. what degree;
e. updating the plant detailed line diagram
35. What is the surface roughness (Ra) by checking it against the physical plant;
required for stainless tubing used for f. preparing a qualification matrix to identify
product transfer and cleaning utilities for items requiring OQ and PQ;
vaccines and sterile products? g. performing OQ and PQ to complete the
qualification;
A typical GMP required Ra is not greater than h. using change management.
0.8 microns, as per WHO Technical Report
Series 970, 2012, Annex 2.
36. Is it necessary to do routine passivation

of stainless-steel piping and equipment?
Yes, passivation is done for stainless steel

piping and equipment. It is done during FAT,
SAT or commissioning and, if required, during
the lifecycle of the equipment.
37. What approach to equipment

qualification should be applied to legacy
equipment?
For legacy equipment, an assessment

needs to be done in order to identify which
qualification activities need to be (and may
be) performed, in order to detect the gaps
and act accordingly based on risk assessment.
35
SESSION
Premises and
plant design
26 October 2021
Introduction: It is important to make a difference between

“risk group” of organisms and biosafety level (BSL) of
practice/equipment/facility. These two terms are not
directly interchangeable, while interrelated.
36
7 | Premises and plant design | 26 October 2021
1. How is the BSL of a microorganism 5. Can we have different BSL-level

determined? classifications among the different unit
operations of vaccine manufacturing?
The BSL is mainly set from the pathogenicity
of the microorganism and, partly from the It would be difficult to justify different
exposure (infectivity and available treatment). BSL classifications for the same organism.
Ebola is really lethal (>50%) and no approved However, a killed pathogenic organism (killed
standard treatment exist. Therefore, it is of a with a validated methodology) is most often
higher BSL than influenza which has lethality no longer considered a “BSL” classified
of less than 5% and which can be treated with germ.
approved antiviral products.
6. Can the filtered air from the high-
2. Based on an understanding of efficiency particulate air (HEPA) filter be
pathogenicity and treatment options, recycled in BSL-4?
can the BSL level for an organism be re-
classified? According to most guidance, no recirculation
of air is allowed for BSL-4 facilities.
There is a possibility to re-classify the BSL Additionally, there should be HEPA filters on
level of a pathogenic organism (and WHO the exhausted air.
Laboratory Safety Manual, 4th edition, is this
trend) and for precautions to be taken, but 7. Can an autoclave be used for both
the classification will remain until there is an purposes (import of sterile materials and
official corrective statement. sterilization of waste) in BSL-3?
3. Can SARS-CoV-2 be reclassified as BSL-2 Where the layout does not permit the
since there are a lot of vaccines available? installation of two autoclaves, it may be
possible to use the same equipment for entry
The classification is currently based more on and exit but it should be explicitly accepted
the “risk” (pathogenicity) rather than on a by the competent authority. Empty autoclave
combination of pathogenicity X infectivity X sterilization may be needed. A higher F0
detectability. Infectivity is close to the classic (adapted to the risk) should be developed for
“exposure” term of the usual risk equation. exit cycles.
Therefore, the number of organisms In fact, a decontamination autoclave
manipulated should be considered: for BSL-3 requires bio-seal and effluent
manufacturing manipulations generally decontamination treatment before disposal.
represent a higher risk than laboratory. Besides, it is a double door with a specified
One other important consideration for the loading side (inside the BSL-3 area) and
SARS-CoV-2 is the long and seemingly unloading side (outside of the BSL-3). It
undetectable incubation period. is, therefore, difficult to use it for both
sterilization and decontamination without a
4. According to BSL requirements, is it specific logic embedded in the software – it
better to have a water shower or an air would be a good practice to have a software
shower? preventing misuse of this autoclave.
The cleaning efficiency of an air shower is very

low due to the “attachment” phenomenon.
A water or detergent shower is much more
effective.
37
8. What are the heating, ventilation, and of microorganisms and the number of people
air conditioning (HVAC) requirements for working in the same place.
BSL-3 and BSL-4?
12. Is it possible to work in the same R&D
These requirements are relatively easy to set laboratory with BSL-2 and BSL-3 agents,
up. The WHO Biosafety Manual, 3rd edition, dividing the work by time, and taking into
mentions that HVAC filtration should be account that the laboratory is equipped
made with HEPA filters at both air entry and according to the requirements for working
air exit (today, the state-of-the-art is to use with BSL-3?
HEPA H14). Pressure cascade will depend on
the general layout and on the equipment, It is possible, provided that all the BSL-
biosafety cabinet (BSC) or isolator. 3 constraints will also be applicable
when working with a BSL-2 organism. No
9. Is there any relation between BSLs and operational difference should exist.
good manufacturing practice (GMP) air
cleanliness classifications (e.g. PIC/S)? 13. What is the difference between an
isolator and a biosafety cabinet (BSC)?
Because BSLs and PIC/S air cleanliness
classifications do not have the same objective An isolator is fully closed (contained) and is
(BSLs are to protect the operator, GMPs are operated with specially connected gloves.
to protect the product), there cannot be a A BSC is partly open for manipulations.
fixed correlation between the two scales.
14. How are materials decontaminated
10. How do we design a manufacturing and transferred to the waste management
facility considering the concept of area?
biosafety and GMP especially for a HVAC
system bearing in mind that GMP and Most viruses can be killed/inactivated with
biosafety have a slightly different flow heat, detergent, chemical, pH, etc. The risk
direction? is when the inactivation method cannot be
applied to all viruses present in each location.
The most important point is the stage (step)
of manufacturing and the corresponding 15. When using a BSC, is it necessary
infectivity of the microorganisms that for the environment in the room to be
could be present. At this point, the GMP classified, for example A in B or A in C?
problematic and the BSL problematic are
the same. In the GMP/BSL logic, one should The logic to establish a classified environment
not be able to return from a “contaminated” around a BSC goes with the nature of the
to a “non-contaminated” area or from an operation. If the “living organism” were to be
“inactivated area” to a “virulent area”. put into a vaccine or immunological injectable
preparation, the BSC should be placed in a
11. How are manufacturing facilities class B environment. If the preparation were
designed, taking into account the an oral one, the environment should be
differences between BSLs and GMP classified C or D.
requirements?
As a general rule, the requirements for

industrial BSL are stronger than for laboratory
BSL. This is due to the fact that the risk is
augmented because of the increased volume
38
16. Can the upstream and downstream 19. What are the personnel
processes, fill and finish, be in the same decontamination requirements for the
building or do they need dedicated different BSLs on factory exit?
facilities/buildings?
In general, remove the BSL area’s protective
In theory, it would not be prohibited if the garments. Then, with increasing BSLs, the
different steps were clearly separated and requirements are augmented.
isolated. However, because the operations For BSL-1, it is good practice to keep the coat
are very different, there would be few inside the laboratory area and to hand wash
advantages to having them in one building. before exiting.
It also depends on whether the activity is BSL-2, with gowning more complete, the
laboratory scale or industrial scale. Usually gowns should be kept inside the areHand
upstream and downstream are located in a washing and disinfecting is required. No
same building (with a pre-/post- inactivation shower is mandatory in BSL-2 except for
barrier) and fill and finish is in different manipulation of incidents.
building(s) or site(s). Again, BSL-3 with gowning is more complete,
but the principle is the same. Showers are
17. Is it acceptable to have sample flow encouraged and even requested in certain
and deactivated solid waste flow from the companies. For the BSL-4, a decontamination
same airlock, considering time separation shower of the suits is absolutely mandatory
and airlock disinfection between both before de-gowning. Consequently, high-level
activities? hygiene is requested (soap shower, hand
washing, etc.).
Solid and liquid wastes should be inactivated
before disposal. Alternatively, they can be 20. Can ultraviolet (UV) ray be used for
placed in bio-secure tight containers that decontamination of facilities, particularly in
can be treated remotely. Time separation the case of aerosol pathogens?
is a rather theoretical solution but is not
encouraged because it is not guaranteed in UV can kill microbial populations exposed
practice. Physical separation is always a better in close proximity to the lamp(s). However,
option. decontamination of facilities cannot be
ensured with UV because it is a challenge to
18. For a BSL-2 facility, is it acceptable to ensure that the full air volume is passing in
have one entry for personnel going into close proximity. Hence, providing shadow
the gowning area in the upstream and areas are avoided, UV can be additional but
downstream processing areas? not the only decontamination tool.
The BSL-2 facility has to 21. According to GMP, can two or more
follow the containment/ cell banks be stored in a same nitrogen
separation principles. container, and different virus banks be
Typically, in a BSL facility there stored in a same ultra-freezer?
are living organisms upstream
and inactivated/killed In theory, it depends on the packaging of the
organisms downstream. Therefore, it is cell or the virus bank aliquots. However, such
neither a good “BSL practice” nor a good a practice is not recommended.
GMP practice to have only one entry for
upstream and downstream processing areas.
39
22. Is a double corridor design

(unidirectional flow of personnel
and material) essential for a vaccine
manufacturing facility?
A double corridor design in a facility

normally involves the transfer of personnel
or material susceptible to contamination by
the microorganism of interest. For example,
in one corridor the transit is “upstream”
while in the second corridor the transit in
“downstream”.
23. Do quality control (QC) laboratories

need a BSL facility to perform lot release
analysis for vaccines (for example, SARS
COV-2)?
In the industry, the BSL of laboratories should

be consistent with the nature and BSL level
of the tested microorganisms. Thus, where
SARS-COV-2 is killed, no specific BSL is
required (unless the inactivation status is
uncertain).
Where the SARS-COV-2 is living or
attenuated, BSL-3 laboratories are required.
24. Do finished product QC laboratories

need the same biosafety requirements as
manufacturing areas?
An authorized finished pharmaceutical

product (vaccine or other immunological
product) is “QSE” meaning of the required
Quality, of the required Safety and of the
required Efficacy for the patient (human or
animal). Therefore, it can be handled out of
the BSL environment. By definition a vaccine
(finished product) is not infectious, so, it is
not subjected to BSL requirements. However,
some laboratory tests of finished products
require the use of live virus and animal cell
culture such as virus titration. In this case and
based on risk assessment, a relevant BSL
practice/equipment/facility may be required
for testing the bulk product.
40
8
SESSION
28 October 2021
Cold chain
41
the vaccine lifecycle
management through
8 | Cold chain management through the vaccine lifecycle | 28 October 2021
1. What is the difference between time- 3. How is the TOR determined?

out-of-refrigeration (TOR) and holding
time? The TOR is most often imposed by the
industrial operation. For example, filling
TOR is the total time that a cold-chain 50000 vials with 2 ml of liquid will require at
product spends at ambient temperature least 3 to 4 hours on most high-performance
(industrial conditions) due to the necessary laboratory equipment. There is no practical
production sequences. solution to ensuring that the liquid will be
For example: filled in a shorter time. Therefore, in this case,
• a frozen product should be defrosted and the company can state that a 4-hour TOR
should be in a liquid state to be filled with is required in the process. Then, it will be
accuracy in vials; verified that the stability of the product is not
• after filling, the product is generally affected.
returned to a fridge or freezer until further
manufacturing steps, such as labelling; 4. Should cold storage consider seasonal
• since it is almost impossible to label a cold changes in temperature?
vial, the product will have to come out of
the fridge/freezer to avoid condensation Cold storage conditions should be the same
on the external wall of the vials; (example: +2°C/+8°C) during the shelf life
• then, the final packaging is often of the product, whether it is winter, spring,
performed at ambient temperature; summer or autumn. To maintain these
• after that, the product will be put back in a conditions, the performance of the storage
fridge/freezer. premises should be varied to compensate for
In this example, the time taken to fill, label, external temperature variations.
and package the product is the TOR. Holding
time is generally used for the time elapsed in 5. Is relative humidity monitoring necessary
between two steps. for vaccines at positive temperatures?
2. Is time-out-of-refrigeration (TOR) critical If vaccine vials have rubber elastomer

in the quality control (QC) department stoppers, humidity cannot penetrate them,
when testing these products? and they cannot leak. Also, the wall of the
glass vials is a barrier to humidity. Therefore,
The TOR may be critical in a QC the need for relative humidity monitoring is
laboratory if the stability of the not key in storing the finished vaccine.
product is poor at +15/+25°C. However, in certain manufacturing/
However, some tests are not purification steps, humidity could affect the
affected by the temperature of product or the working environment.
the product. The sample
conditions should normally be described in 6. Is it necessary to initiate a change
the analytical (biological) validation report. control for requalifying a cold room?
Therefore, tracking samples during their
sampling, manipulation, transport and Requalifying a cold room is not changing the
storage is important. The logging of the storage conditions that are ensured in that
samples when received at the laboratory, room. Where there is no temperature range
logging of the time of retrieval from the QC change, and where no temperature regulation
fridge, and the time of testing are necessary. change has been adopted, there is no need
to apply for a change control. Requalification
should be performed according to a
procedure.
42
7. Is it acceptable to remove vaccines from 11. What should be done if it is discovered

their original packaging to save space that vaccines have been stored at
during storage? inappropriate temperatures?
The product stability data First, a deviation and an in-depth

were acquired when the investigation should be launched in order to
vaccines were in their original determine the extent of the excursion and the
packaging. Removing that stability data available. Then, the outcome
packaging risks decreasing the depends on the stability of each product.
vaccine stability by exposing it to augmented But a precise knowledge of the storage
degradation conditions, such as light, shocks, conditions (during excursion) is needed.
vibrations, etc. It is not uncommon for manufacturers to
have expanded data on the stability of their
8. Can a shortage of vaccines be a good products. In case of any doubt, the vaccines
reason for redistribution of vaccines from should not be used, and their destruction
one international client to another? should be recorded.
Where the cold chain is respected and 12. In case of electrical outage, how can
recorded, and where other conditions are we determine if the vaccine is still safe for
defined and kept under control, there is consumption?
no reason to oppose the redistribution
of vaccines from one to another client. Only continuous temperature records can
However, the temperature records should be deliver the necessary information. It should
continuous, not partial. be noted that most data loggers operate on
batteries and, therefore, are not impacted by
9. Why are most vaccine manufacturing an electrical disruption.
companies not using the vaccine vial
monitor (VVM)? 13. Is mean kinetic temperature (MKT) a
temperature monitoring method?
VVM is a device that is essentially used for
“unit” distribution to trace temperature The MKT is not a temperature monitoring
deviations. It is a United Nations Children’s method but rather an approach to determine
Fund (UNICEF) requirement but not an the impact of temperature excursion(s) with
absolute good manufacturing practice (GMP) regards of the demonstrated stability of the
requirement. When the distribution is made product (proven data).
in boxes of several vaccines that are kept
together up to the final storage point, the 14. What is the applicability of MKT for
VVM is usually “replaced” with data loggers vaccines? Can it be used for vaccines that
put into the boxes and/or in the shippers. are stored at 2–8°C?
10. Could VVM be used to redistribute a To keep the concept simple most of the
returned product? stakeholders will consider that MKT cannot
be used for vaccines. However, where the
VVM are devices that trace temperature manufacturer has stability data out of the
excursions and even sometimes temperature- standard cold-chain range (e.g., 0°C to +2°C
time excursions. However, in the absence and/or + 8°C to +12°C), MKT can be used to
of continuous records of the (cold) storage assess the impact of temperature excursions
conditions, no returned products should be between 0°C and +12°C.
redistributed.
43
15. Can we apply MKT in fill-and-finish

vaccine manufacturing facilities?
MKT is for storage conditions, not for

manufacturing. Manufacturing facilities have
a regulated temperature, so TOR should be
used.
16. What kind of stability data could give
support to temperature excursions?
Temperature excursions can be examined in

light of the stability datTo consider whether
an excursion has had a predictable impact,
the maximum temperature should be less
than the accelerated temperature as recorded
during the stability data.
17. When will inspectors consider

temperature excursions acceptable?
Auditors will only consider and may accept

temperature excursions that are within the
known stability space, if available.
44
9
SESSION
2 November 2021
45
cleaning validation
Process validation and
9 | Process validation and cleaning validation | 2 November 2021
1. How does the lifecycle concept of 5. What is the difference between in-line,
process validation apply to product online, and at-line monitoring?
discontinuation?
Online example: An online total organic
Product discontinuation must be considered carbon (TOC) analyser which is built into the
a critical change and, thus, needs to be system in a water-for-injection (WFI) loop, and
managed in terms of the impact on other automatically takes and periodically analyses
products. For example, if a product is a sample.
discontinued, the cleaning validation (CV) In-line example: A conductivity meter in the
matrix must be revised in order to evaluate WFI loop, with the sensor that is inside the
the need for a cleaning process revalidation. tubing and in the stream of the water; the
Also, it is very important to understand that measurement can be continuous.
the product may be discontinued, but the At-line: Is equivalent to the typical
associated process knowledge should be manual sampling and testing performed
preserved. at a laboratory, meaning that at-line is
discontinuous monitoring.
2. At what time or stage should we
perform the pre-validation studies? 6. What is the minimum number of batches
to derive a meaningful process capability
This is part of Process Validation Stage I and index (Cpk) value?
the initial part of Stage II.
First, before calculating the Cpk, the process
3. Should the manufacturer perform must be under control and shown to meet
process validation on all volumes and a normal distribution. Then, normally, a
strengths of a product? minimum of 17–20 measurements are
required, and the process repeated at least
If adequately justified in a documented three times.
manner, the company could group different
presentations, volumes and strengths in one 7. What is the difference between
product family, and thus reduce the level of continued process verification (CPV) and
validation testing. annual product quality review (PQR)?
4. What is the difference between a critical Annual PQR will focus on product-related
process parameter (CPP) and a critical data, and the CPV will focus on equipment
quality attribute (CQA)? (e.g., fermenter) and systems (e.g., water
system) qualification, regardless of the
A CPP is a process parameter with variability product involved. CPV is continuous, so it
that has an impact on a critical quality does not need to wait a year to obtain trends.
attribute. It should, therefore, be monitored PQR may cross-reference a CPV document.
or controlled to ensure that the process All in all, annual PQR and CPV complement
produces the desired quality. each other.
A CQA is a physical, chemical, biological or
microbiological property or characteristic that 8. Does change of supplier of the
should be within an appropriate limit, range, vaccine drug substance require a process
or distribution to ensure the desired product validation?
quality.
The product release specifications are based All changes must be managed and analysed
on the CQAs. through the change control system in place,
in order to define the need and depth
46
of the validation studies required. In the to health. The presence of degradants

case of a change of a key critical supplier, may shorten the dirty equipment hold time
a comprehensive revalidation should be (DEHT).
considered.
13. If the worst-case product in a CV study
9. In cases where new equipment is is no longer manufactured, should the
added to the upstream process, is process study be repeated?
validation required if the equipment has
the same operating principle and same Yes, the study should be repeated to prove
contact material? that the cleaning procedure is adapted to
the new family. Anyway, immediate CV is not
In such cases, a complete process revalidation required but a new “worst-case product”
would not be necessary. However, all the should be identified and used for the next
qualification stages should be carried out. periodic validation exercise.
Regarding the cleaning process, a series of
cleaning verifications would be advisable. 14. Which are the recommended testing
methods used for CV?
10. Do we need to verify specific
pathogens during CV? WHO recommendation: TOC, protein
content, conductivity and pH are normally
Specific objectionable organisms, such as used for upstream/downstream processes.
certain pathogens, must be considered. In the
case of biologicals which are filter sterilized, 15. What is the meaning of a recovery
bacterial endotoxins and endotoxin- study?
producing bacteria should be monitored.
Recovery studies aim to prove that the
11. In CV, what is the difference between sampling method chosen is capable of
the acceptance criteria of bioburden after recovering the actual substance (residue)
cleaning for small-scale and larger scale selected, at a certain level. For example,
manufacturing (ex. <10 cfu/10mL)? coupons (i.e., small pieces of the same
material used for production which need to
The bioburden specification should be be cleaned) are prepared, cleaned, dried,
justified in a documented manner and should and spiked with the substance of interest
normally be the same in small scale as in (e.g., protein), at TOC concentrations similar
a proportional value. However, during the to those in the CV acceptance criteria limit.
scale up, if there is an increase in the time Recovery studies should prove there is no
before sampling, a higher bioburden can be interference of the sampling method (e.g.,
expected. swab) that could alter the recovery rate.
12. Is it mandatory to check degradation 16. What should be the approach in CV if

residue during CV? And how is it going to we use single-use systems (SUSs)?
impact hold time study?
In the case of SUSs, the concern is the
If there is a product which is known to interaction of the product with the
generate degradation by-products, then, composition of the container (e.g., disposable
it needs to be considered as part of the bag) in terms of leachables and extractables.
possible residues left after the cleaning,
especially if these degradants are hazardous
47
17. What is the common DEHT in the CV of that the outer surfaces of equipment will
critical equipment? eventually get dirty with dust, particles or
other substances. Therefore, it is necessary
It is a case-by-case decision which needs to to have procedures in place to address that,
be justified and documented. However, a including a situation where the equipment
general recommendation is that equipment is stored outside the working area, and is
should be cleaned as soon as possible, and moved.
never left dirty overnight or for a period
greater thar 8 hours. Usually, the DEHT 21. Is it acceptable to have equipment that
is shorter when dealing with a difficult to is used with multiple products?
remove material/product.
Yes, multipurpose is acceptable if proven
18. Is DEHT necessary if a company to be safe and validated, except in some
decides to clean immediately after situations (e.g., tetanus toxin production
manufacturing? requires dedicated equipment and facility).
The term “immediately” may vary for 22. For dedicated machine parts, can
different companies and different products. we test only general tests, such as total
In the case of automated equipment, such organic carbon (TOC)?
as clean-in-place (CIP), the cleaning is usually
done after the process is finished (e.g., within If justified in a documented manner, the
the hour). However, companies will choose to approach would be acceptable. Possible
validate an extended period in case there is products of degradation should be
an unexpected delay in the cleaning process, considered and proven that the TOC
to avoid opening a deviation. For manual acceptance criteria (i.e., 500 ppb) is below the
processes, this approach would be even toxicity level.
more advisable, considering the difficulties in
managing personnel. 23. Would you compare CV specific to
residues in pharmaceuticals and live
19. Can it become a finding if, during vaccines?
inspection, DEHT is longer than that during
the CV exercise? Especially in the initial
stages of
Yes, that would be a deviation from the biopharmaceutical
procedures and validation requirements. The processes (e.g., upstream
cleaning procedure would not be reliable. If processes), the cleaning of
the exceeded DEHT has not been identified manufacturing equipment
by the manufacturer and if it is found during is typically performed under conditions which
inspection, then it could be a serious finding. expose equipment surfaces to pH extremes
and/or heat, which would lead to the
20. What is the implication of long cleaned degradation and inactivation of protein-
equipment hold time (CEHT) and what risk based products. In view of this, the
mitigation strategies are applied in case of determination of health-based exposure
long CEHT? limits (HBELs) using permitted daily exposure
(PDE) limits of the active and intact product
Long CEHT has the impact of possible may not be required, as mentioned in WHO
microbial growth, especially if equipment is regulations. As such, this would be one of the
left with some degree of moisture, or even differences with non-biologics production.
wet. Also, the company needs to consider
48
24. Should the CV be repeated annually if 28. If the vaccine is not based on a daily
no changes occurred? dose, how do we calculate the PDE?
A reasonable frequency for revalidation (e.g., To calculate the PDE, the no-observed-
one to three years) should be established adverse-effect level (NOAEL) is considered,
based on the risk of the cleaning process which is defined as mg/kg/day. Therefore, the
(e.g., automated vs. manual cleaning PDE is based on a daily dose.
procedure, age and state of repair of the
equipment, high rotation of personnel, etc.). 29. What approach would you recommend
However, on an annual basis (at least), always in setting CV limits, e.g., the PDE
a review of all cleaning-related matters approach?
(maintenance, deviations, results and trends
from the cleaning verification routine tests), The initial steps are usually the difficult parts
should be conducted as part of the continued for calculating the PDE where a thorough
process verification (Process Validation Stage investigation of the available information
III). As a result of this review, a revalidation on toxicity is needed. Where resources are
may be decided. Also, an adverse trend of limited, the formulas should calculate such
cleaning verification results may trigger a situations, and there are factors to be used in
revalidation. such cases:
25. Is routine verification of TOC sufficient NOAEL x Wieght Adjustment

PDE (mg/day)=
for CV? F1 x F2 x F3 x F4 x F5
No, routine cleaning verification comes after F5: A variable factor that may be applied
CV. if the no-observed-adverse-effect level
(NOAEL) was not established.
26. Are direct sampling methods necessary In addition, if the NOAEL was not calculable,
for transfer lines or other inaccessible the lowest-observed-effect level (LOEL) may
equipment parts, considering that they be used.
can neither be tested visually nor via
swab testing. Would final rinse testing be 30. What is the maximum allowable
sufficient? carryover (MACO) value for vaccine CV and
how can we define the MACO values from
Typically, piping and product transfer lines PDE?
are sampled by final rinse water, which is
an appropriate method for smooth uniform The MACO is the calculated quantity of
surfaces. However, if piping is made with residue from a previous product when
some removable parts attached with clamps, carried over into a different product that can
swabbing should be considered. represent potential harm to the patient. It is
based on:
27. Is PDE applicable for vaccine - toxicity/pharmacology
manufacturing? - mode of administration
- batch size
PDE calculation is required for all - shared equipment surface area plus a safety
pharmaceutical products. In the case of factor.
vaccines, this would be applied to the final
formulation-fill finish production stage.
49
The following is a formula using PDE: 34. If CV or process validation (PV) fail, is
it necessary to raise an out of specification
PDE x MBSnext (OOS)?
MACO (mg)=
SF x TDDnext
OOS is mandatory for intermediate or
PDE: Obtained in Step 4 finished product release. However, an OOS
may be initiated if considered appropriate for
MBSnext: Min. Batch Size
SF: Safety Factor other situations, such as in validation studies.
TDDnext: Standard Therapeutic Daily Dose (mg/day) The reason for the failed CV or PV should be
identified and documented.
31. What is the maximum safe carryover

(MSC) we can apply in vaccines, such as
pentavalent and hexavalent vaccines,
where the specification is usually not less
than specific value, with no upper limit?
MSC of residue from product “a” to product

“b”.
In this case, the MSC of most difficult to
clean and more toxic residue of Hexavalent
vaccine (product “a”) that may go to the next
most vulnerable (e.g., larger daily dose, large
product contact equipment surface) product
“b”.
32. Are HBELs) mandatory in quality

control (QC) laboratories of National
Regulatory Authorities (NRAs)/National
Control Laboratories (NCLs) when
handling/testing biologicals?
No. As part of CV, HBEL is used for

manufacturing processes where there is a risk
to the patient.
33. Can the extension of linearity of the

analytical method be used as proof that
the method is reliable?
Yes, the extension of linearity is one of the

studies that should be performed to validate
analytical methods used for CV. In addition,
specificity should also be considered.
50
SESSION
10
4 November 2021
51
Data integrity
10 | Data integrity | 4 November 2021
1. What is the difference between ALCOA 5. In a situation where a video is the only
and ALCOA+? data record of an investigation, how can it
be transformed into hard copy data to be
ALCOA stands for “Attributable, Legible, presented in a setting where there is no
Contemporaneous, Original & Accurate” electronic device?
while the “+” goes with “available, complete,
consistent and enduring”. A typical example could be the visualization
ALCOA is general, and ALCOA+ points of air flows, using a fogger. By using the
have been added with computer-based capture function during the projection of
documentation in mind. the video, relevant typical pictures could be
saved.
2. Who should be the lead for data
integrity (DI) in the company? 6. Generally, batch records are kept for
shelf-life plus one year of the product.
DI includes all good manufacturing practice If the company decides to keep them,
(GMP) relevant data, so the lead should for example, for 7–10 years, how can
be quality assurance (QA). However, DI a company cope with the huge space
responsibilities are shared with others – required?
please refer to WHO Technical Report
Series986, Annex 2, paragraph 9.8(j). Yes, significant space is required, but
documents can be scanned or microfilmed.
3. If the dynamic records are prone to There is no formal requirement to keep
manipulation, does it mean that the static records beyond their GMP shelf-life (shelf-life
records are better? plus one year of the product). If it is decided
to keep them longer (such as 7–10 years),
Manipulation of dynamic records depends then the company has to ensure that it has
mainly on how the access rights are managed. the capacity to do so.
The fact that a company has static or dynamic
records depends on the type of instrument/ 7. How to comply with DI if we have to
equipment used, not about which one is record backdated data?
better.
Backdating is considered a breach of DI.
4. How can training records kept only in an If these data have to be used, then there
Excel worksheet be controlled to make it should be an explanation for the backdating
an acceptable practice according to data and a risk analysis carried out on the possible
integrity? consequences of backdating.
Excel worksheets are made for calculation, 8. If true copies of paper records are kept
not for database uses. By exception, a frozen as photocopies, do they need to be signed
dated Excel file (e.g., in pdf format) can be again with a signature on the copy?
accepted. Training records include data
on trainers, training topics (questionnaires, No, but the photocopying has to be certified.
presentations), exam results, individuals, etc.
The Excel worksheet may not be the right 9. Who should have the authority
tool for the job. to manipulate or delete data in a
computerized data acquisition system?
Data should not be deleted, but a

manipulation of data, e.g., change of baseline
52
in high-performance liquid chromatograph vulnerable functions used in applications,

(HPLC), may be allowed, if a QA-approved outdated application versions, plugins,
procedure is in place (detailing what can themes, templates, bugs in system
be manipulated, and by whom). More backdoors, applications from the untrusted
importantly, data “manipulation” is not the sources which come with preloaded outdoors,
same as data falsification. hardware failure, network issues where there
are chances of data loss.
10. What is the difference between archive Cloud service providers may try to hide these
and backup? details from users to their own benefits as
well as to maintain industry reputation.
Archive is the storage of documents. This is why cloud users cannot completely
Backup is the creation of a copy of the trust the cloud service provider. With the help
same documents for emergency purposes of auditing procedures, users can gain trust as
(computer crash/cyberattack, for instance). well as audit these data more efficiently.
Archived documents should be secured and Thus, regular auditing by specialists is the
should never be damaged. solution.
11. Is manual monitoring acceptable for 14. What is the difference between
temperature and humidity monitoring? computerized information system (CIS) and
Or should it be done through the computerized equipment (CE)? Do they
building management system (BMS) or have the same data criticality?
environmental monitoring system (EMS)?
A CIS can include different equipment, e.g., a
Manual monitoring/verification is acceptable, laboratory information management system
but thermometers/hygrometers should not (LIMS) where all gas chromatographs (GCs)
be a located in a place that is difficult to and HPLCs are attached.
access, such as close to the ceiling. CE is a piece of equipment that is part of a
system
12. How to ensure that data are safe when
stored by a third party? 15. Which parameters should be reviewed
during an audit trail review? Please give
The technical agreement with the third party an example of a computerized system.
should include periodic auditing.
Audit trails are required when users create,
13. What are the pros and cons of the modify or delete regulated records during
cloud storage of GMP data (through normal operations. Audit trails are considered
commercial cloud providers)? How to part of the history of associated records.
ensure the security and integrity of data if Personnel responsible for reviewing regulated
cloud storage is used? records should assess the audit trails that
capture changes to critical data associated
Cloud storage is attractive, with the record. Audit trails that capture
but users’ data are not kept changes to critical data should be reviewed
under their full control. The with each record and before final approval of
data could be hacked, the record.
changed or modified by Decisions on which items to include in the
internal or external entities. data audit trail, if configuration is available,
Cloud servers always should be based on risk assessment and
provide better security but due to different specific GxP requirements. The inclusion of
integrity threats towards data such as unnecessary information should be avoided
53
because it can increase, rather than decrease,

compliance risk.
With the exception of entering a reason for a
change, audit trails should be automated, i.e.
all audit trail functions should be executed
without user intervention, and should be
secure. Also, audit trails should be secure
from unauthorized change.
As an example, audit trail review for HPLC
will consist of reading the file to look if any
new line has been automatically created
meaning that change(s) have been made
on the chromatography parameters. Not all
changes are prohibited but any change has to
be justified and approved.
16. When printing a record sheet from

the system for operation, what is the
recommended time that the record is pre-
printed to ensure that it is ready for use by
the operator?
It is sufficient to use the just-in-time (JIT)

concept.
54
SESSION
11
Documentation for regulatory
submission - cGMP related
matters to be included in
common technical document
(CTD) and site master file (SMF)
9 November 2021
55
11 | Documentation for regulatory submission | 9 November 2021
1. How to determine whether the 4. Should all the documents be translated

manufacturer’s electronically signed and into English?
approved documents are acceptable or
not? It depends on where the company is seeking
registration. For example, if the goal is WHO
They are acceptable if the manufacturer prequalification (PQ), key documents should
uses document management systems with be in English.
electronic signature capacity. The system
needs an audit trail and a verified source of 5. Is there any difference between common
signature. technical dossiers (CTDs) for investigation
of new drugs (INDs), emergency use
2. Is it acceptable to have methods of authorizations (EUAs) or new drug
analysis and blank forms available to the application (NDAs)?
quality control (QC) laboratory on an online
system with no live stamps and all versions IND: The dossier for investigational medicinal
are available, and the user is responsible products (IMPs or INDs) (= Investigational
for making the correct choice of version? medicinal product dossier – IMPD) is not
required to have full information as for
It is acceptable to have access to standard product registration CTDs (for NDAs). The
operating procedures (SOPs) on methods of requirement for IMPDs to support clinical
analysis online, provided there is a system trials should be commensurate with the stage
in place to ensure SOPs are secure from of product development. Therefore, the IMPD
unauthorized change. The document should for a phase 3 trial batch would contain more
also indicate effective data and review date. data/information than those for phases 2 and
It is reasonable to archive previous versions, 1 batch.
but they should not be accessible to routine EUA: The dossier for EUA would contain
users. information up to phase 3 clinical trial batches
but would not be required to have full
3. Should document analyses from test process validation as for NDAs. Clinical data
equipment be printed out and saved as for phase 3 trials may not be fully obtained
part of good documentation practice when applying for EUA.
(GDocP) or can they be kept and secured It is recommended to check the National
in the application software itself? Regulatory Authority (NRA) guidelines on the
documentary requirements for the different
If the test equipment is a pathways.
validated computerized
system, data could be kept 6. Is there any relationship between
electronically. If not, the chemistry, manufacturing and controls
test results must be printed (CMC) and CTD?
out and the hard copy
should be reviewed, signed, approved, and The CMC of a medicinal product is the body
archived. of information that defines not only the
Test results could also be printed out and manufacturing process itself but also the QC
compiled with the batch test records even if release testing, specifications, and stability of
the equipment is a validated computerized the product together with the manufacturing
system. facility and all of its support utilities.
The CTD is in dossier format. In the CTD
format, CMC data are presented in Module 3
and in Module 2 Quality Overall summary.
56
7. Where does a company put information With regards to regulatory review, the
on the manufacturing processes of the inspector will decide whether all sites need to
master cell bank (MCB) used to prepare be visited and may request SMFs prior to the
the working cell bank (WCB) in the CTD? inspection.
The relevant section is 3.2.S.2.3 Control of 12. What properties of the seed banks
Materials. should be trended?
8. Where in the CTD should the According to section 8.7 of WHO Technical
information for novel adjuvants and novel Report Series 999, Annex 2:
carriers-lipid nanoparticles (LNPs) be Thereafter, the viability, purity and other
provided? stability-indicating attributes of seed lots
and cell banks should be checked regularly
The CMC data are presented in 3.2.P.4 according to justified criteriEvidence of the
Control of Excipients [name]; animal safety stability and recovery of the seed lots and
and toxicity data are presented in Module 4; banks should be documented and records
clinical studies are presented in Module 5. should be kept in a manner that permits trend
evaluation.
9. In case of manufacturing change, how
can the company submit the information 13. Is it allowed to skip sterility testing
according to the common technical dossier in vaccine manufacture provided there is
(CTD) format? Is Module 2 submission trend analysis and risk study?
mandatory?
No, each batch of vaccine requires sterility
If the manufacturing change impacts on testing.
information in modules 2 and 3, then updated
dossier sections should be prepared and 14. Is it enough to present a certificate of
submitted. analysis (COA) to support the requirement
for animal origin adventitious agents’
10. Is a summary of validation report, safety of vaccines?
tables, and related documents in the
CTD sufficient for review? Are complete No. A company should follow guidance on
documents necessary for the evaluation of minimizing the risk of transmitting animal
the dossier? spongiform encephalopathy agents via
human and veterinary medicinal products.
The company should provide a summary
of validations performed. Key validation 15. What should be the condition for real-
reports are also expected to be included time and accelerated stability studies for
(for example, for an inactivated viral vaccine, vaccines stored in a freezer?
a reviewer would expect a complete virus
inactivation validation report to be in the Real-time condition is the normal condition
dossier). for storage.
For WHO PQ, for example, a company should
11. What should be done about the demonstrate at least six-month accelerated
site master file (SMF) if the product is stability at 2–8°C for a product that is
manufactured at two or more places under normally stored at -20°C.
contract manufacturing?
57
16. Is it possible to hire a third party to do

the audit of a supplier if they are overseas?
If so, how would we qualify them?
Yes. The third party would be qualified

as described in the quality system for
qualification of suppliers.
17. How to determine a product recall
effectiveness? Is it mandatory to do a real-
product recall?
Testing the recall system does not require

a physical recall of material. What is being
tested are the systems of communication
to ensure they are timely and complete for
reconciliation of a number of units released,
used and remaining.
58
SESSION
12
11 November 2021
59
manufacturing
Common cGMP
deficiencies for vaccine
12 | Common cGMP deficiencies for vaccine manufacturing | 11 November 2021
1. Why is good manufacturing practice Categorization should be based upon risk

(GMP) inspection required by regulatory principles. Further information, explanation,
agencies in addition to final batch analysis examples of guidance can be found in several
of pharmaceutical or biological products? publications, such as the PIC/S Guidance on
Classification of GMP Deficiencies (PI 040),
There are many examples of products that and the Canadian Health Products and Food
have killed or severely injured patients Branch Inspectorate: Risk Classification of
even though they passed all their end- Good Manufacturing Practices Observations
product specifications satisfactorily. No (GUI-0023).
testing will detect every impurity and even
sterility testing is unlikely to detect sporadic 3. How many minor or major deficiencies
contamination with microorganisms during sum up to be of a critical deficiency?
aseptic manufacture unless a very high
proportion of the batch is contaminated. There is no simple rule to this question. A
It is one of the basic principles of quality, single observation can be critical in isolation.
that “you cannot test quality into a batch”. More likely, however, critical observations
In other words, any end product testing is concerning the Pharmaceutical Quality
just one element in the suite of regulatory Management System (PQMS) are likely to be
controls that together assure safe and composed of multiple major failings in several
effective, quality medicines. elements of the PQMS, such as change
GMP inspection is a critical part of the management, deviations, investigations,
supervisory regulatory system, which corrective actions and preventative actions
collectively provides evidence that what has (CAPA), out of specification (OOS) and out of
been declared in a product dossier is actually trend (OOT). In these cases, there is a strong
being done in practice on a daily basis, and likelihood that quality risk management
that these inspections together with the (QRM) will also be significantly deficient.
results of sampling and testing form a reliable Further information and guidance can be
basis for decision-making. found in the PIC/S Guidance on Classification
An example of this principle is that GMP of GMP Deficiencies.
states that “The manufacturer should take all
steps and precautions necessary to assure the 4. What should be done if, during an
sterility of the products manufactured within audit, it was found that most of the quality
its facilities. Sole reliance for sterility or other control (QC) members and managers
quality aspects should not be placed on any themselves were newly hired and could not
terminal process or finished product test.” explain or justify many of the findings?
Unfortunately, not all companies are well run
and sometimes also not always honest. On- This situation rarely arises in well prepared
site investigations and inspections are also companies, but not every company is well
a safeguard against poor practices. Recent prepared and there are instances during the
history has seen many examples of major pandemic where companies have grown
breaches of data integrity and poor practices rapidly, and it has been a challenge to ensure
resulting in huge fines and restrictions on the new personnel are fully up to speed.
business, these issues would never have However, even in these operations, there
been fully uncovered without robust on-site should be some subject matter experts
inspection. (SMEs) who can answer those questions.
If on auditing a site, it was found that the
2. Is there any reference for deficiency personnel are unable to answer technical
rating? How are deficiencies rated as questions due to their being new employees
critical/major/minor? and inadequately trained and experienced in
60
the operations on the site, then the auditor products manufactured on site.
has no alternative than to declare the site Confirmation of serious non-compliance
GMP non-compliant at the time of the audit. with the principles and guidelines of GMP
It is a core GMP requirement that at all by definition requires regulatory action to
times, all necessary resources are provided, be taken. Depending upon the nature of
including sufficient and appropriately the observations and risk, further possible
qualified, knowledgeable and trained QC sanctions include: recall, caution in use
personnel – WHO Technical Report Series notifications, suspension or revocation of
986, Annex 2, Para 2.1 (C). marketing or manufacturing authorizations,
importation bans, prohibition on further
5. If there is an absence of quality distribution, sanctions against the qualified
assurance (QA) and/or QC during the person(s) (QPs) and/or other named officials
production of vaccines, is it classified as of the company in those countries where they
deficient? practice, injunctions, warning letters, and
import alerts. Most authorities will put the
There must be a suitably publication of the regulatory sanctions taken
designed QA system on the Internet for public viewing.
throughout all vaccine In coming to their decision, NMRAs may
operations. If QA is not take into consideration possible shortages
present at all in the of products critical to public health. In these
production operations and cases, the risk of shortage will be a national
all samples are taken by production operators matter as alternatives may be available in
without periodic audits by QA, then this will some markets but not in others.
be reported as a deficiency.
However, the number of personnel present 7. How do we integrate the contamination
in critical areas should be minimized, e.g., control strategy (CCS) into the routine
aseptic fill operations and bio-positive quality system, and how do we prepare an
areas. In these cases, suitably trained and evidence-based justification?
authorized production operators can perform
tasks under QA supervision. This routine QA A CCS should be implemented across the
supervision and audit can be performed by facility in order to define all critical control
visual checks from outside the critical areas points and assess the effectiveness of all the
including by closed circuit television (CCTV) controls (design, procedural, technical and
if the systems are of sufficient quality, and if organizational) and monitoring measures
the cameras are located so that they provide employed to manage risks associated
for visual checks for such audits. It is, however, with contamination. The CCS should be
expected that authorized QA staff will still actively updated and should drive continual
enter the core areas for periodic audit and improvement of the manufacturing and
supervision although this will be infrequent. control methods. Its effectiveness should
form part of the periodic management
6. What will be a regulatory decision, if a review. Where existing control systems are in
final product fails the GMP inspection? place and are appropriately managed, these
may not require replacement but should be
Action following the notification of any referenced in the CCS and the associated
non-compliance should be commensurate interactions between systems should be
with the level of risk. If a site fails a GMP understood.
inspection, the National Medicines The CCS should be a living assessment and
Regulatory Authority (NMRA) will typically periodically reviewed in light of any new
demand an urgent risk assessment of all information discovered in operations that was
61
not foreseen in the original risk assessments 9. Is it acceptable to indicate the CCS in
and creation of the CCS. This means that other forms of documentation such as the
whenever there is a change, an OOS result or quality manual (QM), site master file (SMF)
deviation which might lead to contamination, and validation master plan (VMP)?
the CCS will need to be reviewed and
possibly updated. The same would go for any The GMP does not specifically prohibit this
change in key starting or packaging materials. approach but, because of the specificity and
On a daily basis, for example, interventions detail that must be in the CCS inspection,
in the restricted access barrier system experience suggests that a comprehensive
(RABS) should be trended for frequency and CCS normally extends to at least 100+ pages.
time, and these trends compared to the It is, therefore, highly unlikely that a QM,
estimates made in the risk assessments on SMF or VMP would adequately document all
which the control strategy is based. Similarly, this necessary detail. Also, as the CCS for a
any deviations or adverse trends in any liquid product will be different from that for a
environmental microbiology or container lyophilized product so the QM and SMF are
particle rejects outside normal ranges would not the place for this necessary detail.
also precipitate a revaluation of certain
elements of the CCS. 10. What is the meaning of “process can
be a source of contamination”?
8. Should the CCS be product specific?
Contamination can be either intrinsic
The CCS must always be sufficiently or extrinsic to the process. Extrinsic
comprehensive to be capable of supporting contamination could include adventitious
and demonstrating the control of risks for viral or bacterial contamination, chemicals
an individual product, but this does not that leach from plastic single-use systems
necessarily mean that every product needs (SUSs) and/or filters as well as most
to have a separate CCS document. The CCS particulate matter. Intrinsic sources would
should be particularly robust for any aseptic include, for example, host cell DNA or RNA
process especially those such as whole-cell that purification systems do not completely
pertussis and adjuvanted vaccines where 0.22 remove. Other process related contaminants
micron filtration is impossible. might include residual inactivation agents
Many companies have prepared their CCS(s) such as formaldehyde or propiolactone, that
based upon matrixes for groups of similar should be limited in downstream processing.
products such as liquids, suspensions, freeze
dried products as well as different CCS for 11. Visual inspection is often a regulatory
bacterial and viral vaccines. Other approaches requirement in vaccine/biopharmaceutical
have included breaking down the drug manufacturing especially at secondary
substance (bulk antigen) and drug product packaging. Can this be automated with the
(formulated bulk) manufacture and filled drug use of qualified electronic bottle inspectors
product into separate documents. Whatever (EBIs)?
the approach, it is important that the CCS
should be holistic, logical and any grouping Most companies today making vaccines
should have robust documented scientific are already using automated vial inspection
rationales. It should also be considered how machinery for their liquid products. Some
the CCS is to be maintained as a life-cycle also use automated inspection for freeze-
document, so some grouping makes good dried products though this is technically much
management sense where this is possible. more challenging. Processes must, of course,
62
be validated and it is usual to have daily 13. What are the requirements for the use
performance testing of the machines using of video in GMP?
known defective vials or syringes, in addition
to annual requalification. Automated testing GMP recommends the use
should always be followed by manual checks of video for several
on an “Acceptable Quality Level (AQL) activities, and video is a
sample” (the exact number being statistically common feature of
selected depending upon batch size, and effective GMP training
sampling plan selected). Initial qualification of materials. Any video used
the inspection machinery normally follows the for training or validation evidence, e.g.,
so-called Hartung-Knapp (KNAPP) approach videos of media fill studies, smoke direction
and involves establishing a “quality factor” studies) should be maintained and archived in
for each defective vial utilized to decide the the same manner and to the same policies as
probability of the unit being detected by any other quality record, i.e., they must be
both automated and manual methods. In complete and attributable, be securely stored
the case of lyophilized products and some and recoverable. Normal ALCOA+
suspensions, such as some adjuvanted requirements exist as per any other electronic
vaccines, companies use both automated record. The same applies to any CCTV record
inspections followed by manual 100% that is used in an investigation or audit of a
inspection. deviation or other problem. The latter applies
irrespective of whether the video turns out to
12. What are the acceptable applications be useful or not. As soon as it is observed as
of a laminar air flow (class A) in a room part of an investigation it ceases to be a
with class C? security video and becomes a quality record.
The use of a LAF and the background 14. Are there any justifications for a
environment are only part of the controls company to deny the inspector access to
necessary for aseptic operations to be their camera footage?
reliable. Other factors are also important,
such as how items being used are sterilized No, not only will the refusal be viewed as the
and transferred to the workstation. It company hiding something, but failure to
is sometimes possible to use an open provide access to any record (including video
unidirectional air flow cabinet in a Grade C footage) may be considered to be obstruction
area for certain upstream aseptic operations, of an official in the course of their legal
depending upon risk and the likelihood of duties. Depending upon the circumstances,
subsequent detection of contamination obstruction may result in a warning letter and
or whether there are sterilization steps in import alerts or other measures in the case of
subsequent steps. If the workstation is an overseas inspections. Intentionally deleting
isolator or the connections are all using records so as to avoid inspectors viewing the
closed secure aseptic connection devices, footage, will also most likely result in critical
then a Grade C area (or perhaps even a or major data integrity (DI) deficiencies.
Grade D area) may be satisfactory. For In domestic inspections, it will depend
further information see WHO environmental upon how the local law is written. In many
monitoring of clean rooms in vaccine countries, obstruction of an official and failure
manufacturing facilities points to consider for to produce records when requested may even
manufacturers of human vaccines, 2012. be considered an arrestable, criminal offence.
63
15. During the inspection, should an throughout processing under the intended
inspector ask to perform the performance operational conditions.
test of important equipment (e.g., Attention to the structural integrity of the
autoclave) to identify defects or should single-use components is necessary and
the inspection be based on a review of particularly important where these may be
important documents? exposed to more extreme conditions (e.g.,
freezing and thawing processes) either
Usually inspection of any critical equipment during routine processing or transportation.
involves review of multiple source materials Checks should include verification that
including but not limited to: detailed intrinsic sterile connection devices (both
standards operating procedures (SOPs), sealed and mechanically sealed) remain
validations and confirmation that the tests integral under these conditions. In addition to
in validation are consistent with routine integrity, qualification needs to take account
operations, log books, loading consistency of the migration of bag plastic and label
controls, cycle records, review of the number constituents as well as the intrinsic stability of
and reasons for any aborted cycles or failures the product being stored. In general, it is not
such as vacuum leak tests and Bowie Dick recommended to label the body of a storage
tests (in the case of steam sterilizers), or bag due to migration of adhesive and ink
high-efficiency particulate air (HEPA) filters components during long-term storage.
in the case isolators, restricted access barrier There is no standard maximum hold time.
systems (RABS) or sterilizing tunnels. That Every set of circumstances must be qualified
said, if the inspector has some doubts according to the specific application. Some
remaining, e.g., DI concerns, a confirmatory, bags of antigen have qualified deep frozen
witnessed test may be appropriate and can hold times of up to 12 months or longer.
be requested.
18. How to maintain the cold chain
16. Concerning the use of SUSs, what is requirement for the bulk product if we
the best way to check the proper waste do not install a cold room facility for
disposal of the used materials? the allowable retention period during
production?
After all necessary checks have been
performed, e.g., integrity checks on Sometimes, it will be
SUS, waste exiting the production areas necessary to have facilities
including used SUS materials should for cold storage of process
be decontaminated using appropriate materials and intermediates
technical measures, e.g., autoclaving in a such as bulk antigen or bulk
decontamination-specific chamber, or other formulated product as well as resins used in
treatment according to the nature of the risk purification steps. Storage will require cold
to be controlled, prior to incineration. This is rooms or local chilled vessels and GMP
particularly important for materials originating demands there are adequate well-designed
from bio-secure areas, but secure disposal facilities. It is always necessary to balance the
should be part of any pharmaceutical waste various risks involved in the process.
management plan. One key question to consider is: does the
bulk really need to be stored cold to maintain
17. What is the permissible holding time of adequate stability at all steps in production.
storage bags? If so, it will be necessary to have cold storage
facilities for the storage of SUS bags or
SUSs should be designed to maintain both vessels.
the integrity and stability of its contents Cold storage rooms should always be
64
outside of the critical areas especially Grade possible, adopt other mitigating measures,
B areas. It is also best to avoid storage in e.g., using sterile aseptic connection devices
cold rooms in Class C areas. This is because and minimizing any aseptic connections, for
the interior of the cold rooms should be the example, by using pre-connected pumps
same as the room in which the cold room is and tubing sets, pumps that can be sterilized
located. Cold rooms are also often a source assembled or by using peristaltic pumps
of contamination and should be monitored to reduce as far as possible the number of
especially for moulds. The nature of the connections made. The overall approach and
risk will depend upon how the bulks are rationale should be documented in the CCS.
stored and for how long, and also how the
bulks have to enter the fill areas. Wheeled 20. What tool is best suited for the risk
vessels are always a problem to disinfect, and assessment for determining environmental
normally the bulk is supplied from adjacent monitoring (EM) sampling locations?
areas using intrinsically safe sterile connection
technologies. It is most important to design any line from
In general, if possible, refrigeration should the beginning to avoid difficult to clean
be avoided during the actual filling due to and monitor areas. Generally speaking,
the complexity of the cooling equipment L-shaped lines installed against a wall will be
normally necessary, and the fact that typically considered seriously deficient as it creates
this equipment will probably be very difficult zones that are extremely difficult to clean and
to clean and sterilize. Also, cooled surfaces maintain. During line design qualification
will cause considerable condensation with (DQ) and in site acceptance testing, start
possible contamination hazards due to water by process mapping to identify activities
on equipment. and possible failure points, and perhaps
use an Ishikawa assessment and hazard
19. Is it mandatory to carry out double analysis and critical control points (HACCPs)
filtration before filling? tools. Evidence would include records of
interventions, identifying positions of high
Normally, it is recommended that a company human activity or other critical activities.
should consider and implement double Machine and room smoke studies in the
filtration, whenever and wherever, it is dynamic condition would also be critically
technically feasible, to mitigate aseptic risks. useful tools to help identify or confirm higher
Documentary evidence should be available risk areas and locations. Reviews of both
to support any position the company has locations, and action and alert levels should
adopted. include a critical review of trend data and
In many cases, however, authorities recognize data from any ad hoc and investigational
that multiple filtrations present technical testing.
challenges for many vaccines and may even
be impossible. Importantly, the filtration 21. How to initially set alert and action
should always be as close as possible to the limits for an EM programme for live
point of fill as technically feasible. In all cases, trending?
it is important that the location of filtration
points are considered robustly, particularly It is recommended to start performing the
a single filtration as close as possible to EM as early as possible for site acceptance
the point which will best mitigate risk. tests (SATs), engineering runs and initial
Sometimes, a combination of 0.45 followed validations including aseptic process
by 0.22 micron filters may be possible and simulations (APSs), so as to build a body
should be considered. of data as quickly as possible. Once trial
In addition, a company should, where
65
manufacture commences, e.g., water fills 24. What type of environmental monitoring
used for training can also provide additional should be performed in a controlled not
useful information. Nevertheless, initial classified (CNC) area?
datasets will still probably be limited, so
initial monitoring should be performed more The company should monitor these areas
frequently than the expected normal intervals initially and establish alert levels. The
until a rich dataset is established, and any company should use critical thinking and
possible trends identified in these datAn risk management in the establishment of
early review of real-world data should be action and alert levels. Key risks will be
performed after three months and six months, moulds and bacterial spore formers that may
and alert levels adapted as necessary. Data evade disinfection procedures. Moulds are a
from other facilities on the campus or within particular risk that may need special attention
the company may also be used to inform in the monitoring of cold storage.
decision-making on initial alert levels.
25. Is it mandatory to perform integrity
22. Do we need to monitor the testing of the gloves in RABS?
temperature, humidity and pressure
difference and conduct trend analysis of The materials used for glove systems
items in environmental monitoring? (for both isolators and RABS) should be
demonstrated to have good mechanical
Yes. The frequency of monitoring will depend and chemical resistance. The frequency of
upon the grade of area and the risk presented glove replacement should be defined within
by the operations performed in that area. the contamination control strategy (CCS).
For RABS, gloves used in the Grade A area
23. Must every batch of the media be should be sterilized before installation and
tested for growth promotion before use? sterilized or effectively bio-decontaminated
by a validated method prior to each
Yes. Every batch of liquid media delivered manufacturing campaign. If exposed to the
should be growth promotion tested (GPT) background class B environment during
the first time each batch (after sterilization, operation, disinfection using an approved
where appropriate) is used, if it has been methodology following each exposure should
accepted on a supplier certificate of analysis be completed. Gloves should be visually
(CoA). Where media is prepared in-house examined with each use, and integrity testing
from, for example purchased powdered should be performed at periodic intervals.
media, then each batch prepared should be
formally released by QIt is also important 26. How do we establish the bioburden
that pre-purchased media be selected with acceptance criteria for components, such
care and, where necessary, include in its as equipment parts, assuming that the
formulation neutralizers and inactivators as loads to be sterilized have predictable
required for its intended usage, e.g., media bioburden?
used for surface monitoring should include
neutralisers for any disinfectant residues that The allowable bioburden will depend
may remain on working surfaces. Specialized upon the nature of the sterilization or
studies for media used in gassed enclosures decontamination process being used. When
should be performed to ensure that the using a high vacuum-high pressure steam
decontamination gases, e.g. hydrogen process, the capability of the properly
peroxide vapour used in isolators, do not designed process will be substantial for
penetrate the media wrapping materials. most typical organisms found in lower grade
clean rooms. Decontamination processes
66
such as vapour phase hydrogen peroxide block steam penetration when placed in
are very useful but are not considered pipework so often will be unsuitable for
sterilizing methods and these processes this type of location and other BI types
are more fragile. Companies using this will, therefore, be required. In these cases,
technology need to take particular care that alternatives such as using a spore strip or
items being decontaminated are clean and even spore suspensions offer preferred
free from soilage where microorganisms options, but these also bring their own
may be protected, when designing their challenges and will require experienced
processes. The presence of highly resistant microbiologists to design protocols for their
organisms should always be well controlled use. The use of suspensions significantly
by pre-sterilization washing and drying. complicates the design of the study due
The standardization of washing/drying to the necessity to perform positive and
processing is a key control measure and, negative controls, and recovery studies to
therefore, automated washing and drying is ensure that the intended inoculum has been
strongly preferred. Where items are manually exposed.
washed then there should be checks to
ensure that items are clean, well drained
and well dried before wrapping for steam
sterilization. Items should have a short
qualified clean hold time prior to sterilization
or for rewashing and sterilization for items
not needed immediately. Bioburden studies
of pre-sterilized items may be performed by
swabbing of complex surfaces or the use of
contact plates on smooth surfaces and testing
the fluid path of tubing, etc.
27. Why can biological indicators (BIs) be

problematic?
BIs require good knowledge and experience

to use effectively, unfortunately they are
often used by companies lacking in adequate
experience and may be misused and
erroneous conclusions may be made. One
challenge in using BIs is that they should be
placed in locations where the penetration of
the sterilizing agent might be inhibited. In
many cases this means locations where the
physical size of a self-contained indicator will
mean that it is impossible to place. The failure
to place the BIs in the difficult-to-penetrate
zones of the load may lead to a false sense of
security that the cycle performance is better
than it really is.
BIs that are self-contained devices are
straightforward to use but have technical
limitations on placement due to their physical
size. Self-contained units may also partially
67

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Virtual cGMP

Session 1: Vaccine lifecycle and technology platforms 2

In response to Member States’ requests for capacity building in the

This document collates the questions raised during the 12 sessions

There may be impurities 19. For a technology transfer of vaccine

23. What is the difference between Stage

Vaccine development Stage 3 is the clinical

24. Should the three phases of lot release

Yes, the manufacturer should have a standard

25. Is a vector vaccine a special case of

The recombinant DNA technology is often

1. Can protocols replace batch production 4. Is it possible to start drug substance

8. In order to maintain QC personnel’s is also important in justifying in scope and

Quality audit of third parties, 13. Is it a requirement to audit the suppliers

11. Do we need supplier qualification 15. Do we need a change control to change

18. A planned deviation is usually a The administrative changes to GMP

There must be a system detailing how a For both cases, if it is a like-for-like

35. What is the minimum frequency for

According to WHO GMP, self-inspection

36. What is the content that should be

15. Are manufacturers required to justify Consecutive numbers (e.g. 1,

20. For every critical change and major

Change management and deviation are

21. Is it possible to use the QRM approach

CAPA can be developed by incorporating

1. Are antibiotics used in all vaccine 4. What should be an acceptable

There is a correlation between temperature 9. What is the function of flush bags?

Room grades and allowed/prescribed Consider stopping operations, evaluate the

32. Is there any guideline specifying

The decision is both QRM-based and cost-

33. For replication-incompetent vectors of

According to the current requirement, the

1. Are microbiology and virology 4. Is it acceptable, from a GMP point of

QC premises depend on the tests to be It depends on the vaccine platforms and

Microbial limits should be the same as the

9. Is it obligatory to control the inactivation 13. Should samples taken for QC be

The recipient country will usually receive

35. Should the NRA perform the

The NRA should follow the same rule:

2. What is the difference between 6. How do we evaluate whether

9. Should factory acceptance tests (FATs) 12. If a company is in the phase of IQ

Commissioning is defined as “a well-planned, Usually, commissioning will be performed

A typical example would be the PQ of an It depends on the component being changed.

It is not mandatory. The company would need

27. How do we undertake the PQ of a 31. Is it necessary to perform annual

34. Is it necessary to do a test run after a 38. How do we handle validation or

36. Is it necessary to do routine passivation

Yes, passivation is done for stainless steel

37. What approach to equipment

For legacy equipment, an assessment

Introduction: It is important to make a difference between

1. How is the BSL of a microorganism 5. Can we have different BSL-level

The cleaning efficiency of an air shower is very

As a general rule, the requirements for

22. Is a double corridor design

A double corridor design in a facility

23. Do quality control (QC) laboratories

In the industry, the BSL of laboratories should