Post on 26-Aug-2020
Distribution: General
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Meeting Report
WHO Workshop on Implementation of Guidelines for procedures and data
requirements for changes to approved vaccines
Green One UN House, Hanoi, Viet Nam
7-9 August 2019
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Executive summary
Regulation of changes to approved vaccines is one of the most important elements in ensuring that
the vaccines of consistent quality, are distributed after they receive authorization or licensure. In
response to the request from National Regulatory Authorities (NRAs) of the World Health
Organization (WHO) Member States on the data needed to support changes to approved vaccines to
ensure the comparability with respect to quality, safety and efficacy of vaccines manufactured with
the change, WHO have developed Guidelines for procedures and data requirements for changes to
approved vaccines. These guidelines were adopted by Expert Committee on Biological
Standardization (ECBS) in its meeting 2014 and published in the WHO Technical Report Series 993.
The Guidelines provide guidance to NRAs and manufacturers on the essential data required to
support the change, which does not negatively impact on the quality, safety and efficacy of the
vaccines and also provide regulatory procedures to review and approve the changes submitted by
manufacturers.
To facilitate the implementation of these guidelines, a three-day workshop was organized by the
WHO Headquarters with assistance from the WHO country office in Viet Nam, NRA and vaccine
manufacturers who are responsible for regulation of post-approval changes in their institution, at
Green One UN House in Hanoi, from 7-8 August 2019. This workshop was attended by the
representatives of Egypt, India, Ghana, Pakistan, Poland, Senegal, Tanzania and Viet Nam. Vaccine
manufacturers representing International Federation of Pharmaceutical Manufacturers &
Associations (IFPMA) and Developing Country Vaccine Manufacturers Network (DCVMN), from US,
India, Indonesia and Vietnam such as MSD, BioFarma and Bharat Biotech etc. were present. The
workshop was facilitated by experts from regulators with rich experience on regulation of post-
approval changes. In the workshop the principles on categorization of quality changes and efficacy,
safety and labelling information changes were presented by the facilitators. Case-studies regarding
different types of changes were studied by the participants. The participants used the WHO
guidelines to classify the category of each change and identify the necessary supporting data needed
to demonstrate that there is no impact on the quality, safety and efficacy of the product after
change. The case studies were the most welcomed sessions in the workshop and the cases helped
the participants to understand how to use WHO guidelines on post-approval changes. It was
suggested by the participants that if more complicated cases with a set of supporting data to be
reviewed by the participants would be more interesting and useful for the workshop.
It was recognized that the WHO guidelines on post-approval changes is a very practical and useful
document. Participants of the workshop expressed that they will implement WHO Guidelines in the
regulation of changes in the future. Those countries where national guidelines are already in place,
will refer to the WHO Guidelines and update or align their guidelines with the procedures and data
requirement of WHO guidelines and those without guidelines will develop them based on or adopt
the WHO guidelines.
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Introduction
Changes to the vaccine manufacturing process or product labelling information often need to be
implemented after a new vaccine has been approved. Changes may be made for a variety of
reasons, such as to maintain the routine production of vaccines, to improve the quality attributes of
the vaccine or the efficiency of manufacture or to update product labelling information. It is
recognized that: any change to a vaccine may impact upon the quality, safety and efficacy of that
vaccine and any change to the information associated with the vaccine (that is, product labelling
information) may impact on the safe and effective use of that vaccine. The regulation of changes to
approved vaccines is one of the most important elements in ensuring that vaccines of consistent
quality, safety and efficacy are distributed after they receive authorization or licensure. In response
to the request from NRAs of WHO Member States on the data needed to support changes to
approved vaccines to ensure the comparability with respect to quality, safety and efficacy of
vaccines manufactured with the change. WHO have developed Guidelines for procedures and data
requirements for changes to approved vaccines. These guidelines were adopted by ECBS in its
meeting 2014 and published in WHO Technical Report Series 993. The Guidelines provide guidance
to NRAs and manufacturers on the essential data required to support the change, which does not
negatively impact on the quality, safety and efficacy of the vaccines and also provide regulatory
procedures to review and approve the changes submitted by manufacturers.
To facilitate the implementation of the Guidelines into national regulatory practices, WHO organized
the first implementation workshop in Thailand in 2015 with participants of NRAs from Bangladesh,
China, Indonesia, Malaysia, Myanmar, Nepal, Republic of Korea, Singapore, Sri Lanka, Thailand and
Viet Nam and representatives from vaccines manufacturers. The workshop was highly appreciated
by the participants and it was recommended to organize more workshops to provide more detailed
information on regulation of post-approval changes by regulators. To follow the request, the second
workshop to implement the Guidelines was organized by WHO Headquarters with the assistance of
the WHO Country office in Vietnam at Green One UN House in Hanoi, from 7-8 August 2019. The
workshop was facilitated by Dr Heidi Meyer from PEI Germany, Mrs Teeranart Jivapaisarnpong from
Thailand, Dr Lorenzo Tesolin from Sciensano Belgium and Dr Dianliang Lei from WHO.
Dr Jinho Shin and Dr Momoe Takeuchi from WHO WPRO and the WHO Country Office in Viet Nam
participated as well. The workshop was chaired by Dr Meyer and Mrs Jivapaisarnpong and
Dr Tesolin were the Rapporteurs.
Session I: Welcome and Introduction
The workshop was opened by Dr Kidong Park, WHO Representative of Vietnam. He welcomed all
participants from regulatory authorities and manufacturers. He stated that being able to access the
good quality, safe, efficacious, and affordable vaccines was one of the important mechanisms to
support the WHO policies on “One Health”. He also mentioned that in order to have access to good
quality, safety and efficacious vaccines the regulatory authorities shall evaluate the quality of the
vaccines appropriately, not only for registration but also for changes occurring after MA approval
that might impact the quality, safety and efficacy of the vaccine. To assist the regulatory authorities
and vaccine manufacturers on these matters, WHO had developed the Guidelines on procedures
and data requirements for changes to approved vaccines in 2014 and organized the first and
successful guidelines implementation workshop in Thailand in 2015. He hoped that this workshop
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would help all participants to have a better understanding on the key principles and expectation on
the evaluation of the post approval changes of vaccines. He wished all participants three fruitful days
of discussion in this workshop and to enjoy the time in Hanoi.
Dr Dianliang Lei, Scientist of Technology, Standard and Norm, WHO, and the organizer of the
implementation workshop, provided the update on WHO’s position on post-approval changes in the
context of WHO biological standardization and objectives of the workshop. He reminded the
participants that the mission of WHO is to promote health, keep the world safe and serve the
vulnerable. To achieve the primary health coverage, one of the most important part is access to
medicines with assured quality, safety and efficacy. Regulation of post-approval changes of vaccines
is essential to ensure the quality and safety of vaccines used in immunization.
Dr Dianliang Lei highlighted that changes are always made by manufacturers in production process,
testing methods or labelling information to improve the quality, safety and efficacy of the product or
to improve the safety and efficiency of the manufacturing process. Regulation of post-approval
changes (PAC) is one of the most important key elements of vaccine regulation post marketing
authorization to ensure the comparability of the product made with changes to the licensed one. In
response to requests, WHO developed Guidelines on procedures and data requirements of changes
to approved vaccines in 2014 through a consultation procedure with input from regulators and
industry. The Guidelines were published in the WHO Technical Report Series No. 993.
Implementation of these Guidelines will assist NRAs with the evaluation of the data and provide
basic information to the authorities in the development of their own national guidelines and timely
access to the vaccines needed for their immunization programmes. He also emphasized that WHO
recommends that each country should establish its national guidelines for procedures and criteria
for the evaluation of changes to a marketing authorization to ensure that vaccines of constant
quality, safety and efficacy are distributed post authorization, but regulatory reliance and
recognition were encouraged. Dr Dianliang Lei reminded the participants the objectives of the
workshop were:
1) to better understand the current practices of regulation of PAC in participating countries; 2) to
familiarize NRAs/NCLs and vaccine manufacturers with the contents of WHO guidelines and to clarify
any issues that may interfere with the implementation of the principles of WHO guidelines; and 3) to
identify any potential needs for further guidance on regulation of PAC or any other relevant
regulatory activity.
He also said that he expected that by the end of the workshop, participants will have a better
understanding of the key principles and expectations of regulation of post-approval changes and will
identify the current gaps in their regulation of post-approval changes and how to move forward with
improvement. He also expected that the workshop would provide a forum for NRAs and vaccine
manufacturers to build confidence on better communication in future.
Session II: WHO Guidelines for post-approval changes
WHO Guidelines for procedures and data requirements for changes to approved vaccines: purpose
and general principles:
Dr Dianliang Lei presented the general principles on the WHO Guidelines on Post Approval Change
(PAC). He stated that WHO had developed two guidelines on PAC, one for vaccines and the other for
biotherapeutic products separately. He outlined the key principles regarding regulation of post-
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approval changes to vaccines. The purpose of the WHO Guidelines for post-approval changes is to
serve as a guide for establishing national requirements and to assist NRAs in establishing regulatory
procedures for post-approval changes to vaccines. It provides guidance on the procedures and
criteria for the appropriate categorization and reporting of changes and data required to enable
NRAs to evaluate the impact of the change on the quality, safety and efficacy of the vaccine. In
general, no change should be implemented without the approval of the NRA unless otherwise
defined in this guideline (e.g. minor change). Prior to implementing the change, the MA holder
should assess the effects of the change and demonstrate through appropriate studies the absence of
any negative effect of the change on the quality, safety and efficacy of the vaccine. He emphasized
that changes are categorized using a risk-based approach. Some changes need approval of NRA prior
to implementation, some changes do not need approval from the NRA prior to implementation, but
the need to retain information for audit and some changes require a new marketing authorization
application. Based on the potential effect of the quality change on the quality attributes of the
vaccine, and the potential impact of this on the safety or efficacy of the vaccine, a change is
categorized and identified as either a major quality change, a moderate quality change or a minor
quality change. Safety, efficacy and product labelling information changes, are classified as the
following categories: a safety and efficacy change; a product labelling information change; an urgent
product labelling information change; or an administrative product labelling information change. He
highlighted that certain major changes, such as changes in the vaccine antigen composition (for
example, addition of virus or bacterial types), use of new cell substrates (for example, use of cells
unrelated to the established master cell bank (MCB) or pre-MCB material) or changes in the
composition of vaccine adjuvants are generally considered to be a new product and as such require
the submission of a product licence. Different regulatory pathways for assessing post-approval
change submission can be applied by regulators which include full review of supporting data,
recognition of decision of a competent NRA and review of the decision of the NRA from producing
countries. Finally, he reminded the participants that implementation of any new regulation should
not affect vaccine supply and access by the public to vaccines. Therefore, NRAs are strongly
encouraged to establish requirements that are commensurate with public health priorities and with
their own regulatory capacity and resources to ensure the vaccine supply in their country.
How to use WHO Guidelines on post-approval change:
Dr Heidi Meyer gave a presentation on how to use WHO Guidelines on post-approval changes. She
outlined the principles laid down in the guidelines including the outline of the document, the
categorization and reporting of post-approval changes. With regards to quality changes to approved
vaccines, the marketing authorization (MA) holders are expected to perform a risk assessment to
evaluate the potential effect of the intended change to the quality, safety and/or efficacy of the
vaccine. Depending on the risk level identified, the change needs to be categorized. In order to
facilitate risk assessment and to provide assistance to NRAs to allow judgement of the proper
classification comprehensive lists of major, moderate and minor quality changes are provided in
Appendices 2 and 3 of the WHO Guidelines on post-approval changes. Appendices 2 and 3 give clear
guidance on the categorization of quality changes, the conditions to be fulfilled for each change, the
data sets required to support the respective changes to the manufacture or quality control of
antigen, final product or its intermediates and the reporting category of the change. Implementation
of major or moderate changes requires reporting to the NRA and must be reviewed and approved by
the NRA prior to the implementation of the change. Minor quality changes may be implemented by
the MA holder without prior review and approval by the NRA. Changes related to the clinical use or
to the product labelling information on the safe and effective use of a vaccine, should be classified
by MA holders according to the categories given in Appendix 4 of the WHO Guidelines. In general, it
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is advised that NRAs establish a mechanism that allows for the updating of its guidelines to address
technological changes that require new regulatory classifications. In addition, it should be
considered to allow submission of multiple changes to an approved vaccine which are related to
each other to reduce the administrative burden.
Session III: Current approaches of regulation of post-approval changes
Current practices of regulation of post approval changes to vaccines, biologicals in selected
participating countries:
Representatives of NRA from nine countries presented their practices of regulation of post approval
changes as following:
Egypt:
The guideline is aligned with WHO guidelines in terms of classification (minor, moderate and major)
and technical assessment. However, in certain circumstances, technical assessment might be
conducted according to EMA, FDA, etc. The assessment was divided into two parts, which were 20%
administrative and 80% technical assessment conducted in CAPA and NORCB. The timeline for
approval are 30 working days in a normal case. Another 30 working days may be added for further
requirements.
Ghana:
A guideline to provide guidance to applicants to effectively prepare submissions of the variations
exists. Reporting categories are major and minor (same as notifications). The applicants have to
submit a cover letter (addressed to the CEO), a completed variation application form, and needs to
add the relevant documents/parts of the dossier where the changes are made (e.g. labels, package
inserts, etc.). Timelines for approval of minor variations are 30 days and 90 days for major variations.
Challenges mentioned were that the current variation guideline does not address non-clinical and
clinical variations and that there are no standardized regulatory tools with the MA Department to
provide guidance to evaluate non-clinical and clinical part of post- approval changes. It is planned to
review the current national variation guidelines to incorporate the moderate change category, and
to expand the existing guidelines to include the non-clinical and clinical parts.
India:
A presentation describing role, vision and function of the CDSCO was given. A guidance for industry
exists and it assists in classification of changes and provides support. Three categories of variations
are defined which are level 1 (major), 2 (minor) and 3 (notification). A cover letter, relevant data, e-
copy or hard copy are required for post approval change submissions. Supporting data for the Level
3 changes should be submitted on an annual basis. However, upon request the data should be
available to DCGI within fifteen (15) calendar days. The timelines for approval of level 1 and 2 are 6
months and 3 months, respectively. For level 3, there is no evaluation except for shelf-life changes.
The GMP inspection is possible after PAC. Conditions and supporting data are listed in the guideline.
Some examples of changes, conditions, and supporting data were presented. For the imported
vaccine, the country of origin approval is required prior to approval. Problems identified in post
approval changes were no uniformity with respect to categorization of PAC variations and that the
supporting documentation was not the same along with country of origin approval. Cases where
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discrepancies were found in the documentation when compared to routine practices were shown.
Plan to revise the national guidelines was also presented.
Pakistan:
It was presented that the Drug Regulatory Authority of Pakistan (DRAP) had established the list of
Reference Regulatory Authority approved by registration board such as EMA, USFDA, Health Canada,
TGA (Australia), PMDA (Japan), Denmark etc. Any vaccine imported from countries of these
regulatory authorities listed was exempted from GMP Inspection by DRAP and relied upon the
inspection conducted by the NRA of that country. For post approval changes, the national guidelines
had not yet been established, it is currently under development by following the reference countries
and WHO guidelines. As the vaccines used in Pakistan are imported, for some changes related to
safety and efficacy, the justification relied on the Reference Regulatory Authorities as specified by
Registration Board. Changes related to quality, evaluation of applications were performed by DRAP
according to recent developments and considering the current state of scientific knowledge,
manufacturing, and validation in assured cGMP environment. The document required for approval
of changes includes a cover letter stating subject or type of change, supporting documents, evidence
of approval of applied change by NRA in the country of origin. The major difficulty Pakistan is facing
was the lack of opportunities for networking. Therefore, the opportunities to attend training,
seminars, and workshops would be very useful in developing the national guidelines.
Poland:
A presentation of the different units and structure responsible for assessment of variations and
renewal following the national procedures as well as European procedures was given. The post-
approval changes or variations are defined as any amendment to the contents
of the documentation which was the legal basis for the marketing authorization of the medicinal
product and submitted to the competent authority. In general, changes are categorized into three
types which were administrative, quality, and safety & efficacy changes. As Poland is a member state
of the European Union, the same rules and requirements as European Commission regulation apply
for the authorization and post-approval changes.
Senegal:
It was presented that the division of homologation under the Direction of Pharmacy and Drugs, the
Ministry of Health and Social Action, is responsible for registration, variation or renewal of
pharmaceutical products. To obtain approval of a variation, it is currently necessary beforehand to
have the approval letter of the authority of the producing country. The difficulties Senegal is
currently facing include the lack of experts at the level of authority and use of external experts to
evaluate applications of the changes. The support of WHO in capacity building of the national
regulatory authorities, as well as establishment of an evaluator network to overcome these
difficulties were also mentioned. The implementation of WHO Guidelines for procedures and data
requirements for changes to approved vaccines is planned.
Tanzania:
The structure of Tanzania Food and Drug Authority was presented. A guideline on changes on
registered human medicinal products is in place and was developed based on WHO guidelines on
changes to prequalified products. The national guidelines on post approval changes exist but is
applicable only to APIs and excipients manufactured by chemical synthesis, classical fermentation, or
semi-synthetic processes and FPPs containing such API’s and excipients. APIs from fermentation,
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biological, biotechnological or herbal origin are treated as special cases. Changes are classified as
major changes, minor changes, notifications and changes that make a new application necessary.
Major changes and changes that need new application require prior approval from the authority.
The other changes can be reported as Annual Notification, Immediate Notification or Minor
Changes.
Viet Nam:
Legal documents related to post approval changes were presented. Three categories of changes are
defined including major changes, minor changes that need to be approved by the authority before
implementation and minor changes that do not need prior approval but have to be notified to the
authority. Timelines and approval fees were also presented. Detailed types of changes of approved
vaccines, requirements of document for each type of change to be submitted, and conditions for
each change are described in Annex II of circular 32/2018/TT-BYT. The technical guidelines for
assessor on quality, safety and efficacy evaluation, Quality manual for biological products, and SOP
for handling change dossier are in place. The difficulties identified by Viet Nam were: the
information in the current guidelines is not as detailed as in the WHO guidelines; high workload;
limited human resources; fee for approval of changes by the NRA is too low; and the ASEAN
guideline on changes to approved vaccines has not been harmonized. The amendment of the
national guidelines according to the WHO guidelines on post approval changes for vaccines is
planned to be conducted in 2019. Training of vaccine assessors on evaluating vaccine dossiers by
experts from EMA and TGA is also planned.
Industry’s experiences and perspectives:
IFPMA- industry perspectives and experience:
Industry’s experiences and perspectives were presented by representative of IFPMA,
Mr Mic McGoldrick. He mentioned there were several challenges with getting approval of changes
worldwide. A large company with a large portfolio might file 6000 to 8000 variations per year
globally. Each change was classified differently in different countries and led to different supporting
data requirements as well as different timelines for approval. The outcome of approval of a specific
change is sometimes different between different countries. More and more variations are delayed
for approval and this delay impacts the supply. Harmonization by following the international
standards such as WHO guidelines and ICH guidelines, recognition of the other regulatory
authorities’ decision, work-sharing and mutual recognition could help in solving these challenges. He
showed the list of challenges and solutions. Introduction to comparability Protocols/PACMPs, the
novel regulatory mechanisms as per ICH Q12 (Drafted), which was one of the solutions described.
Potential opportunities for comparability protocols such as site changes, new source of diluent, shelf
life extension, etc., were shown. Practical solutions including expedited reviews and adoption of risk-
based approaches for expediting the implementation of PACs were described. Implementation of
WHO guidelines on PACs for vaccines on a global and harmonized basis was also elaborated as one
of the practical solutions. He mentioned the willingness of IFPMA to work together with WHO and
NRAs in order to improve the situation for ensuring timely supply of vaccines to populations who
need them.
DCVMN point of view:
Representatives DCVMN, presented the challenges faced for changes to approved vaccines. Several
changes were listed including manufacturing process, quality control, change from in vivo to in vitro
assays because of 3R’s principles, labelling information (such as shelf life, indication), and change of
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seed/cell banks. The challenges included submission with different classification categories of
changes and requirements of supporting documents, varying timelines, and implementation on site
were mentioned. The use of one referred guideline or reliance of regulators on the decision of a
stringent NRA were suggested in order to accelerate implementation of changes and minimize the
confusion in the field. A comparison between CDSCO (India) and WHO guidelines (prequalified
products) with some examples were made including categorization, composition changes (change in
fill volume of prequalified product, addition of new strength), manufacturing site changes, batch size
changes, manufacturing process changes, container closure system changes, specifications changes,
stability changes, administrative changes. Examples on changes categorized in one guideline but not
in the other were presented. A suggestion to use the risk-based approach mention in the draft ICH
Q12 documents was made. Difficulties raised were in getting approval from each NRA on the
recommended deletion of abnormal toxicity test as well as appropriate use of WHO guidelines.
Discussion and feedback on day one:
A summary of day one was made. Some questions were raised and discussed. The major topics of
concern were timelines for NRA approval for post approval changes, addition of manufacturing site
during licensing, reliance/recognition system on other NRAs’ decision, what should be justified in
case the NRA of country of origin had not yet approved the changes, how to manage in case of
temperature excursion during shipment, criteria for selection of the external experts.
Session IV: Recommendations in WHO Guidelines for post-approval changes
Reporting procedures and data requirements for quality changes – Changes to antigens and final
products:
Dr Lorenzo Tesolin and Dr Heidi Meyer provided the key information on common principles of WHO
Guidelines for procedures and data requirements for changes to approved vaccines as well as quality
changes to comply with updated compendia and/or pharmacopoeia. Specific considerations need to
be given to quality changes affecting lot release as the institution responsible for reviewing the
release of vaccine lots (NCL) needs to be informed about any change that affects the lot release
protocol or the official lot release process. It was highlighted that in general it is acceptable that a
pre-change batch is used until depletion unless a quality change is introduced for a reason directly
linked to safety or efficacy of a specific vaccine. Furthermore, principle observations on quality
changes including the requirements for batch stability data were discussed. Specific considerations
should be given to the annual strain update of influenza vaccines due to the extensive experience
with such changes and in order to maximize the flexibility and brevity of the review process. It was
emphasized that the need for clinical data to support a quality change should be limited to very
specific cases, i.e., when comparability can’t be established by quality data only. Examples of such
changes include changes to the composition or to the pharmaceutical form of a vaccine or changes
due to the removal or replacement of a biological component used in the manufacture and resulting
in new residuals present in the final vaccine product. Finally, it was elaborated how to interpret the
requirements for the classification of a quality change, the conditions to be fulfilled, supporting data,
and reporting category as given in Appendices 2 and 3.
Working group on case studies related to the quality changes and labelling information changes:
The participants were randomly separated into 5 groups, approximately 6 persons in each group.
Five case studies which were examples of quality change and labelling information changes to
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vaccines were used for the working group discussion. The cases were A) change in the specification
used to release the final product, B) final product manufacturing site change, C) replacement of an in
vivo test by an in vitro test, D) change of a reference standard, and E) change of the labelled storage
conditions for the final product.
Each group was assigned to work on two case studies and the same case was studied by two groups.
Each group presented the outcome of one case in the plenary session as well as commented on
outcome of the second case presented by another group. The facilitators and all participants
provided comments on the outcomes for conclusions as well as for the future improvement.
The points raised during the discussion were modification of some case studies to provide clearer
descriptions, justification on selecting only potency and sterility assays for stability studies VS using
the same test as for product release, and format of testing procedure as supporting data SOP VS test
description.
Special considerations on multiple changes application, expedited review procedures in special or
urgent circumstances, seed virus changes for seasonal influenza vaccines:
Mrs Teeranart Jivapaisarnpong provided the information stated in WHO guidelines on special
consideration on applications of multiple changes, expedited review procedures in special or urgent
circumstances, and seed virus changes for seasonal influenza vaccines. General principle and
examples of multiple changes and multiple change application were presented. Procedures for
expedited review in special or urgent circumstances including the recognition of other NRAs’
decision or inspection were elaborated. Example of change of production site of Inactivated
Influenza Vaccine and consideration of supporting data requirement in case of emergency were
provided. Annual change of seed virus for seasonal influenza vaccine production and required
supporting data were also presented.
Discussion and feedback on day two:
Some questions were raised and discussed. The questions and answers were as following:
1) Question: What is the justification if the diluent was deleted because the product was
changed from freeze-dried to liquid form?
Answer: In many countries, this is justified as the new product.
2) Question: For scaling up, stability data 1 lot is acceptable or not?
Answer: In general, at least 3 lots are required for stability study. In some circumstances,
less than 3 lots may be accepted. Accelerated stability study can be used to compare the
stability profile of the product before and after changes.
3) Question: If the minor changes found later that it related to the quality, safety, efficacy of
the vaccine what to do?
Answer: Justification should be done following WHO guidelines. In addition, for changes
related to safety, the good system for causality assessment should be in place and risk
benefit assessment might be used for stopping the supply of the vaccines.
Appropriate timelines for approval were also discussed.
Reporting procedures and data requirements for efficacy, safety and labelling information
changes:
Dr Heidi Meyer summarized the reporting procedures and data requirements for efficacy, safety and
labelling information as specified in Appendix 4 of the WHO Guidelines on post-approval changes.
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Due to the varying amount of safety and efficacy data needed to support a change to the safe and
efficacious use of a vaccine there is no ‘one-size-fits-all’ approach feasible. The examples of changes
given in Appendix 4 are provided for clarification only, they are not limited, however, to those
included to the guidelines. In general, there are three categories of clinical changes, i.e. safety and
efficacy changes, product labelling information changes and administrative product labelling
information changes. Examples of clinical changes for the different categories were provided. All
clinical changes except for solely administrative changes need approval by the NRA prior to
implementation of these changes.
Working group on case studies related to safety and efficacy changes and product labelling
information changes:
Five case studies related to efficacy, safety and product labelling information were used for the
working group discussion. The cases were A) change to add information on co-administration with
other vaccines, B) change to add AEFI identified as consistent with a causal association with
immunization, C) multiple changes of Flu vaccine including change of the vaccine formulation,
change of the finished product container, and extending the use of the vaccine in another age group,
D) change of vaccine composition for Human Papilloma Virus vaccine, E) change of the vaccine
composition by replacing polygeline with sucrose in the final vaccine product.
Each working group composed of 6 participants and was assigned to work on two case studies and
the same case was studied by two groups. Each group presented the outcome of one case in the
plenary session as well as commented on outcome of the second case presented by another group.
The facilitators and all participants provided comments on the outcomes for conclusions as well as
for the future improvement.
Considerations on time frame of evaluation of post-approval changes:
Dr Lorenzo Tesolin provided an overview on the proposed timetables for review and approval of the
various change categories (e.g. major and moderate quality changes, safety and efficacy changes
etc.) and the data package to be submitted to the NRA for changes to approved vaccines.
Considerations should be given to implement mechanisms of reliance specifically in resource limited
settings.
Session V: Networking for participating countries Encouraging networking, work-sharing and reliance in the context of regulation of post-approval
changes:
Dr Dianliang Lei inform the participants how important networking and work-sharing are in the
context of global vaccine supply.
During this presentation, it was agreed that reliance and mutual recognition were important.
It was needed to build capacity and better utilize available resources to be able to assess a dossier
when there was an urgent need of vaccine supply and an assessment had been received by the country
of origin/NRA of reliance. It was proposed that development of database on regulatory activities such
as lot release, MA, or PAC and sharing the country’s experience with the others should be encouraged.
It was also agreed that ICH Q5E and EMA guidelines can be a source of information for PAC.
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A question was raised about harmonization of the prequalification procedure and the PAC guidelines.
This will be raised to the concerned parties at WHO.
Round table discussion on the regulation of post-approval changes:
All participants were requested to provide their opinions on identification of area for improvements,
needs from the countries, and implementation plan for the regulation of vaccine post-approval
changes as well as feedback on the workshop.
All participants agreed that this workshop was very useful and WHO guidelines provided clear
guidance for the users. However, the categories of changes and approval timelines in some countries
were different from WHO guidelines. Some countries had only two categories, major and minor.
Some countries had already amended their regulations following WHO Guidelines.
Regional networking with MOU to recognize was encouraged. In the African region, AVAREF
Networking had been established but there was no recognition between members because there
were different competencies. Capacity and trust needed to be built in order to be comfortable to
recognize the decision of other NRAs in the network. The question on how to approve the changes
which had not yet been approved by the NRA of country of origin was also raised.
One participant proposed the establishment of an electronic data base of post approval changes
would be useful for information sharing among the members of the network.
The participants encouraged WHO to harmonize the WHO guidelines for procedures and data
requirements for changes to approved vaccines with the one developed by the prequalification
team.
The request to organize more of such workshops at the regional level (e.g. African Region) was
emphasized by the participants as it would be helpful for the member countries to implement their
regulatory system for post approval changes.
Some areas for improvement of the workshop were also raised including clearer background
information in some case studies should be provided, such as the quality of supporting data
submitted as well as examples of supporting data and how to assess them should be added in the
case studies. Capacity building in good review practice for the supporting data was also requested.
Authors:
Mrs Teeranart Jivapaisarnpong, Thailand, Dr Lorenzo Tesolin, Sciensano, Belgium, Dr Heidi Meyer,
PEI, Germany and Dr Dianliang Lei, WHO, Geneva, Switzerland on behalf of the WHO Workshop to
implement WHO Guidelines for procedures and data requirements for changes to approved
vaccines.
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Appendix 1. Meeting participants
The implementation workshop was participated by Mr Marcin KOLAKOWSKI, Office for Registration
of Medicinal Products, Medical Devices and Biocidal Products, MOH, Poland; Mr Lukasz MONTEWKA,
Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, MOH, Poland;
Mr Khurram KHALID, Biologicals, Evaluation & Research, Drug Regulatory Authority of Pakistan,
MOH, Pakistan; Miss Noor-ul-Ain ARSHIA, Pharmaceutical, Evaluation & Registration, Drug
Regulatory of Pakistan, MOH, Pakistan; Mr Rajesh Kumar VERMA, CDSCO, MOH&FW, New Delhi,
India; Ms Tejaswini KOPPULA, CDSCO, MOH&FW, New Delhi, India; Dr Osidai Solomon KIVUYO,
Tanzania Food and Drug Authority, Tanzania; Ms Kulsum REHEMTULLA, Tanzania Food and Drug
Authority, Tanzania; Dr Madické DIAGNE, Pharmacien Inspecteur en charge de la liberation des
vaccins, Ministère de la Santé et de l'Action sociale, Senegal; Dr El Hadji Ibrahima TOURE, Evaluatrue
des dossiers de demande d’autorisation de mise sur le marché (AMM), Ministère de la Santé et de
l'Action sociale, Senegal; Mr Mawunya AKPEKE, Regulatory Officer, Food and Drugs Authority, Accra,
Ghana; Ms Irene Koramah FREMPONG, Regulatory Officer, Food and Drugs Authority, Accra, Ghana;
Mr Ngoc Anh NGUYEN, Drug Registration division of Drug Administration of Vietnam, Hanoi,
Vietnam; Mr Hoang Phuong HA, Drug Quality management division of Drug Administration of
Vietnam, Hanoi, Vietnam; Dr Akram Mohamed ElSayed Mahmoud ELHABAB, Quality Control
Specialist and Quality Manager of VCU (NORCB), MOHP, Egypt; Dr Shaimaa Hamdy Sheded
MOHAMED, Variation Department Manager & Quality Manager in Lot Release (NORCB), MOHP,
Egypt.
The following participants attended the workshop as Observers: Ms Thi Thao DO, Expert on quality
aspect of DAV, Hanoi, Vietnam; Ms Anh Thu LUU; QMS department of NICVB, Hanoi Vietnam; Ms Thi
Dung LUU, Lot release and Post marketing control department of NICVB, Hanoi, Vietnam; Mr Phuong
Thanh NGUYEN, Chemical Pharmacology Center of Hanoi Medical University, Hanoi, Vietnam; Ms
Thuy Duong DAU, Chemical Pharmacology Center of Hanoi Medical University, Hanoi, Vietnam; Ms
Thi Tuyet Lan LE, Drug Registration division of Drug Administration of Vietnam, Hanoi, Vietnam; Mr
Duc Manh TRUONG, Drug Registration division of Drug Administration of Vietnam, Hanoi, Vietnam;
Ms Thi Huyen NGUYEN, Drug Registration division of Drug Administration of Vietnam, Hanoi,
Vietnam; Mr Xuan Hoanh LE, Drug Quality management division of Drug Administration of Vietnam
(GMP inspector), Hanoi, Vietnam.
The following participants attended the workshop as representatives of vaccine manufacturers: Mr
Mic MCGOLDRICK, CMC Vaccines and Biologicals, MERCK, USA; Le Thu NGA, POLYVAC, Hanoi,
Vietnam; Do Tuan DAT, VABIOTECH, Hanoi, Vietnam; Dr Dilip KUMAR, Bharat Biotech, Hyderabad,
India; IDA Nurnaeni, PT Biofarma (Persero), Indonesia;
The following participants are from WHO Regional Office for Western Pacific (WPRO):
Dr Jinho SHIN, Regulatory Systems Strengthening, Essential Medicines and Health Technologies,
Division of Health Systems, Regional Office for the Western Pacific, World Health Organization,
Manila, Philippines; Dr Momoe TAKEUCHI, Health Systems Group Coordinator, World Health
Organization Vietnam, Hanoi Viet Nam; Ms Sheau Wen Choo, Health Systems team World Health
Organization Vietnam, Hanoi Viet Nam; and Nihal Singh, EPI team, World Health Organization
Vietnam, Hanoi Viet Nam.
The workshop was facilitated by: Mrs Teeranart JIVAPAISARNPONG, National Pharmaceutical
Facility, King Mongkut’s University of Technology Thonburi, Bangkok, Thailand; Dr Heidi MEYER,
Section Viral Vaccines, Paul-Ehrlich-Institut, Langen, Germany; Dr Lorenzo TESOLIN, Batch release of
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vaccines, In vivo & Immunology Unit, Sciensano (former IPH), Belgium and Dr Dianliang Lei,
Technologies, Standards and Norms (TSN), Regulation of Health Products and Technologies, Access
to Medicines, Vaccines and Pharmaceuticals, World Health Organization, Geneva, Switzerland.
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Appendix 2. Agenda
WHO Workshop on Implementation of Guidelines for procedures and data requirements for
changes to approved vaccines
7-9 August 2019
Venue: Green One UN House, Hanoi, Viet Nam
Day 1, (7 August)
Session I Opening of the meeting
8.300-9.00 Registration
9.00-9.30 Opening Remarks
& Welcome Speech K Park CO/HQ WHO
Self-introduction All participants
Group Photo
9.30-9.50 Update on WHO position on post-approval changes in the context of WHO biological
standardization and objectives of the workshop
D Lei, WHO
9.50-10.00 Discussion
10.00-10.30 Coffee break
Session II WHO Guidelines for post-approval changes
10.30-11.00 WHO Guidelines for procedures and data requirements for changes to approved vaccines: purpose and general principles
D Lei
11.00-11.30 How to use WHO Guidelines on post-approval changes
H Meyer
11.30-12.00 Discussion
12.00-13.00 Lunch Break
Session III: Current approaches of regulation of post-approval changes
13.00-15.00 Current practices of regulation of post approval changes to vaccines, biologicals in selected participating countries
Ghana, India, Pakistan, Poland, Senegal, Tanzania and Viet Nam
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15.00-15.30 Coffee Break
15.30-16.10 Industry’s experiences and perspectives
IFPMA (Mic McGoldrick)
DCVMN
16.10-17.00 A round table discussion and feedback on day one
all participants
facilitators
Day 2,
Session IV Recommendations in WHO Guidelines for post-approval changes
9.00-10.30 Reporting procedures and data requirements for quality changes – Changes to
antigens and final products
L Tesolin, H Meyer
10.30-11.00 Coffee break
11.00-11.10 Presentation on case studies
L Tesolin, H Meyer
11.10-12.30 Case study 1-5 – examples of quality change and labelling information changes to
vaccines
Participants
facilitators
12.30-13.30 Lunch break
13.30-14.00 Preparation of the outcomes of the group discussion
Group work
14.00-15.30 Reporting of the outcomes of group and discussion
Groups 1- 5
15.30-16.00 Coffee break
16.00-16.30 Special considerations on:
multiple changes application
expedited review procedures in special or urgent circumstances
seed virus changes for seasonal influenza vaccines
T Jivapaisarnpong
16.30-17.00 discussion and feedback on day two
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Participants
facilitators
17.00 Closure of the day
Day 3,
9.00-9.30 Reporting procedures and data requirements for efficacy, safety and
labelling information changes
H. Meyer
9.00-10.30 Group on Case studies
5 Case studies (efficacy, labelling info focused
Preparation of the outcomes of the group discussion
Group work
10.30-11.00 Coffee break
11.00-12.30 Preparation and Reporting of the outcomes of group and discussion
Group 1- 5
12.30-13.30 Lunch break
13.30-13.45 Considerations on time frame of evaluation of post-approval changes
L Tesolin
Session V Networking for participating countries
15.15-15.45 Encouraging networking, work-sharing and reliance in the context of regulation of
post-approval changes
D Lei
Round table discussion on the regulation of post-approval changes:
identification of area for improvements
needs from the countries
Implementation plan
Feedback on the workshop
Participants and Facilitators
15.45-16.00 Closing of the meeting