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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

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.

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

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-

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

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

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,

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

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

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.

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.

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.

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

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.

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

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


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


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

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


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

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