Pilot Prequalification Procedure: Overview
Scope
This WHO pilot procedure for prequalification of biotherapeutic products (BTPs) or their corresponding similar biotherapeutic products (SBPs) is specifically focused on human insulin and is carried out using either full assessment or abridged assessment pathways. Full assessment includes, among other requirements WHO inspection of the relevant manufacturing facilities and clinical research sites, based on information submitted by the manufacturer of such products. Evaluation and inspection is based on WHO-recommended technical standards and guidance including those mentioned above. This document addresses technical, communication, policy and other aspects of the WHO pilot procedure for the prequalification of human insulin BTPs and corresponding SBPs. Based on the experience gained during the pilot process, WHO reserves the right to revise the prequalification procedure accordingly.
Steps of the pilot procedure
The steps of the full assessment pathway include, but are not limited to:
- The publication of an invitation to submit an expression of interest for product evaluation(EOI) by WHO.
- A presubmission meeting with WHO before the submission by the applicant of an EOI.
- Submission by the applicant to WHO of an EOI to participate in this pilot procedure.
- A screening procedure to ensure that the dossier(s) submitted by the applicant as part of its EOI is complete.
- Assessment of product dossier, which must include product data and information as specified in the applicable guidelines for submission.
- Inspection of manufacturing sites of drug substances and drug products, if applicable, to assess compliance with current good manufacturing practices and current good distribution practices.
- Inspection of clinical sites (if applicable) to assess compliance with current good clinical practice and current good laboratory practice, as appropriate.
The steps of the abridged assessment pathway include, but are not limited to:
- The publication of an EOI by WHO.
- Submission by the applicant to WHO of an EOI to participate in this pilot procedure.
- A screening procedure to ensure that the dossier(s) submitted by the applicant as part of its EOI is complete.
- Assessment of prequalification-specific data and information as specified in the applicable guidelines for submission.
Reliance on the assessment of the product dossier, inspection of manufacturing sites and/or clinical sites conducted by the SRAs. However, WHO reserves the right to conduct inspections of manufacturing sites and/or clinical sites in connection with an abridged assessment if, in WHO’s discretion, such inspections are necessary or required.
Note: By submitting an EOI, the applicant undertakes to share information with WHO on all relevant aspects of manufacture and control of the specified products along with changes made and/or planned. Applicants must provide the necessary information to WHO by submitting a product dossier, in the prescribed format, and other information as requested by WHO.
WHO reserves the right to terminate the prequalification assessment of a specific product if the applicant is not able or not willing to provide the required information or to implement corrective actions which WHO may require within a specified time period, or if the information supplied is inadequate to conduct this procedure.
Applicant's responsibilites – abridged and/or full assessment pathway
- It is the applicant's responsibility to source and purchase the RBP, used to conduct the similarity exercise (quality characteristics, non-clinical and clinical data set), from an SRA market.
- It is the applicant's responsibility to promptly communicate to WHO any safety concerns arising from the RBP on which its prequalification application is based, in the case of similar biotherapeutic products (SBPs).
- WHO relies on information supplied by or originated from SRAs, which may result in WHO determining (in its sole discretion) to waive one or more of the requirements listed below.
- It is the applicant's responsibility to demonstrate that the selected RBP has been licensed and approved by an SRA based on a product dossier containing comprehensive data on nonclinical and clinical studies / full quality, safety and efficacy data.
- It is the applicant's responsibility to conduct a similarity exercise(s), starting with comparison of quality characteristics, of the SBP and RBP that represents the prerequisite for the reduction of the non-clinical and clinical data set required for licensure of the SBP and prequalification.
- It is the applicant’s responsibility to provide evidence of the similarity of the SBP with a suitable RBP based on evaluation of the whole data package for each of the quality, nonclinical, and clinical parameters, i.e. the totality of evidence.
Applicant's responsibilites – full assessment pathway
- This consists of WHO assessment of the required product dossier submitted by the applicant, which must include product data and information on quality, non-clinical and clinical aspects, including product formulation, manufacture and test data and results. Product data and information should meet the requirements described in the WHO guidelines on the evaluation of BTPs or of SBPs.
- It is the applicant's responsibility to source and purchase the comparator used for clinical studies from an SRA market.
- It is the applicant's responsibility to provide WHO with all results of pharmaceutical (physico-chemical, biological andmicrobiological) tests, pre-clinical (toxicological and pharmacological) tests and clinical trials related to the product to be prequalified.
- It is the applicant's responsibility to document that the manufacturer is authorized in their country to produce medicinal products for human use.
- It is the applicant's responsibility to provide WHO with the details of any decision to refuse authorization in any country and the reasons for such a decision.
- It is the applicant's responsibility — after the product has been listed in the prequalification list and with respect to the methods of manufacture and control provided in the prequalified dossier — to take into account technical progress and introduce any changes that may be required to enable the prequalified product to be manufactured and checked by means of generally accepted scientific methods. Those changes shall be subject to WHO evaluation.
- It is the applicant's responsibility to ensure that the product information is kept up to date with the current scientific knowledge. The proposed changes shall be subject to WHO evaluation the applicant is encouraged, if a product has been prequalified by WHO via the full assessment route, to apply for the collaborative procedure which facilitates the assessment and accelerated national registration of a WHO-prequalified product.
Furthermore, WHO may collaborate with NRAs regarding the product dossier assessments and site inspections. Subject to the terms described in the section below (Steps of the pilot procedure), WHO'sprequalification of human insulin BTPs, or corresponding SBPs as applicable, may also be based on approval of such products by SRAs. WHO recommends that applicants expressing interest in participating in the prequalification procedure:
- inform the NRAs in the country of manufacture and/or the country where an application for registration has been submitted of their intention to do so
- request such NRAs to collaborate with WHO in the prequalification process including, in particular, the quality assessment process.
Applicants should provide the NRAs with the necessary authorization to discuss the relevant product files with WHO representatives during the product dossier assessment and site inspections (subject to appropriate confidentiality provisions, if necessary).
Invitation for submission of expressions of interest
The products listed in any invitation for submission of EOIs are considered by WHO to be vital for the effective diagnostic, treatment or prevention of specified diseases. Invitations are open and transparent, inviting all relevant parties to submit an EOI for the products listed.
Such invitations are published on this WHO website and possibly also through other media, such as the international press.
For each product for which prequalification under this pilot procedure is sought, the applicant should send a product dossier in the common technical document (CTD) format, together with the other data required, as per the relevant guidelines, to the WHO Team Lead for Medicine Assessment.
The definitions given below apply to the terms used in this pilot procedure and should be read in conjunction with the WHO Guidelines on submission of documentation for the pilot procedure for prequalification of biotherapeutic products for human insulin – full assessment pathway. Preparation of product dossiers in common technical document format and the WHO Guidelines on submission of documentation for the pilot procedure for prequalification of human insulin approved by stringent regulatory authorities – abridged assessment pathway. Terms may have different meanings in other contexts.
applicant
The person or entity who, by the deadline mentioned in an invitation for expressions of interest (EOI), submits an EOI to participate in the WHO pilot procedure for prequalification of: (i) human insulin BTPs, or corresponding SBPs, that have been approved by stringent regulatory authorities (SRAs) and marketed in the country of registration, or (ii) human insulin BTPs, or corresponding SBPs, that have not been registered by SRAs (in case the product is claimed to be a human insulin SBP the approval should have been based on a RBP approved by an SRA), together with the required documentation on such product(s).
comparability exercise or similarity exercise
Head-to-head comparison of a biotherapeutic product with a licensed reference biotherapeutic product (RBP) with the goal of establishing similarity in quality, safety and efficacy. Products should be compared in the same study using the same procedures.
comparator for clinical studies
A comparator for clinical studies for BTPs is an established human insulin product approved by an SRA with a pharmacological profile similar to that of the product to be prequalified.
contract research organization (CRO)
An organization (commercial, academic or other) to which an applicant may have transferred some of its tasks and obligations in relation to the conduct of clinical studies with the product submitted to WHO for assessment under the above-mentioned procedure.
drug product (DP)
A pharmaceutical product type that contains a drug substance, generally in association with excipients. This refers to a dosage form in the final immediate packaging intended for marketing.
drug substance (DS)
The active pharmaceutical ingredient and associated molecules that may be subsequently formulated, with excipients, to produce the drug product. Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
head-to-head comparison
Direct comparison of the properties of the SBP with the RBP in the same study.
immunogenicity
The ability of a substance to trigger an immune response or reaction (e.g. development of specific antibodies, T cell response, allergic or anaphylactic reaction).
impurity
Any component present in the drug substance or drug product that is not the desired product, a product-related substance, or excipient including buffer components. It may be either process- or product-related.
invitation for submission of an expression of interest (EOI)
Invitation calling upon interested parties (e.g. manufacturers or other applicants) to submit an expression of interest (EOI) to WHO by a specified deadline for the purpose of participating in the WHO prequalification procedure in respect of the product(s) listed in the invitation. Such an EOI should be accompanied by the required documentation on the product(s) in question.
manufacturer
Any person or legal entity engaged in the manufacture of a product subject to marketing authorization or licensure. The term “manufacturer” also includes any person or legal entity that is an applicant or holder of a marketing authorization or product licence where the applicant assumes responsibility for compliance with the applicable product and other established standards.
originator product
BTP licensed and approved by an SRA on the basis of a full dossier with comprehensive data on non-clinical and clinical studies.
prequalification
Standardized prequalification procedure of WHO to assess, in principle, whether candidate products: (a) meet WHO technical guidance on quality, safety and efficacy, including compliance with WHO’s recommended standards for good clinical practice (GCP), good manufacturing practices (GMP), good laboratory practices (GLP) and good distribution practices (GDP); (b) adhere to the principles laid out in the WHO guidelines on the international packaging and shipping of vaccines (1); and (c) meet relevant operational packaging and presentation specifications, for the purpose of providing guidance to interested United Nations agencies and WHO Member States in their procurement decisions. United Nations agencies and WHO Member States using information resulting from the WHO prequalification should perform additional steps of qualification prior to purchasing such products, including ensuring financial stability and standing of the supplier, ability to supply the required quantities, security of the supply chain, preshipment quality control and other related aspects, including the registration status of the products to be procured.
reference biotherapeutic product (RBP)
A reference biotherapeutic product that: (a) has been licensed and approved by an SRA on the basis of a full dossier with comprehensive data on non-clinical and clinical studies; and (b) is used as the comparator for head-to-head comparability studies with the SBP in order to show similarity in terms of quality, safety and efficacy. This definition does not refer to measurement standards such as international, pharmacopoeial, or national standards or reference standards.
risk management plan
A detailed description of the activities that continuously ensure patients' safety and their benefit from a medicinal ingredient. A risk management plan includes:
- safety specifications, which summarize the known and potential safety issues and missing information about the rDNA-derived biotherapeutic
- a pharmacovigilance plan to further evaluate important known or potential safety concerns and to provide post-marketing data where relevant information is missing
- a risk minimization plan, which provides proposals on how to minimize any identified or potential safety risk.
similarity
Absence of a relevant difference in the parameter of interest. A difference that is expected to induce a difference in clinical effect, such as better impurity profile, could be accepted. No differences exist that are expected to induce impact on clinical activities based on a comparability or similarity exercise.
similar biotherapeutic product (SBP)
A biotherapeutic product that is similar in terms of quality, safety and efficacy to a reference biotherapeutic product.
stringent regulatory authority (SRA)
A regulatory authority which is: a. a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), being the European Commission, the US Food and Drug Administration and the Ministry of Health, Labour and Welfare of Japan also represented by the Pharmaceuticals and Medical Devices Agency; or b. an ICH observer, being the European Free Trade Association, as represented by Swissmedic, and Health Canada (as before 23 October 2015); or c. a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement, including Australia, Iceland, Liechtenstein and Norway (as before 23 October 2015).
Note: For the purpose of WHO pilot procedure, this interim definition is taken from the WHO Technical Report Series No. 1003, Fifty-first Report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. This interim definition is currently being revised.