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National Agency for Food and Drug Administration and Control (NAFDAC)

Guidance Document for the Registration of Biosimilars in Nigeria

VISION

To safeguard public health.

MISSION

To safeguard public health by ensuring that only the right quality products are manufactured, imported, exported, advertised, distributed, sold and used.

Our goal is to eradicate fake drugs and other substandard regulated products.

Foreword

This Guidance document is meant to clearly outline the registration requirements and/or process to effect the registration of biosimilars in Nigeria. It will also elaborate the policy decisions, regulatory approach and position on interchangeability and substitutability with the reference product.

It is important to note that NAFDAC reserves the right to request information or material, or define conditions not specifically described in this document, in order to ensure the safety, efficacy or quality of a therapeutic biologic product. NAFDAC is committed to ensure that such requests are justifiable and that decisions are clearly documented.

A variety of terms, such as Biosimilar Medicinal Products, follow-on protein products, subsequent-entry biologics or biogenerics have been used by different jurisdictions.

For the purpose of this document, a biosimilar is a product that demonstrates similarity in terms of quality, safety and efficacy to a named reference biotherapeutic product (RBP) that is licenced on the basis of a full registration dossier in Nigeria and/or by astringent regulatory authority.

The purpose of this guidance document is:

  • To introduce the concept of biosimilars;
  • To outline the basic principles to be applied;
  • To provide applicants with a user guide for the relevant scientific information, in order to substantiate the claim of similarity.
ACKNOWLEDGEMENT

The Regulatory and Registration Directorate wishes to thank all who have contributed and made the production of this document possible.

Special thanks go to Dr. Kwashi A. Nyarko of Health Canada, members of the NAFDAC Committee on Biosimilars.

We are also especially grateful for the support and encouragement we have received from Dr. Paul Orhii O.O.N., Director General, (NAFDAC).

Copies of this document are available and can be requested from:
The Director,
Regulatory and Registration Directorate.
445, Herbert Macauley Street, Yaba, Lagos.
Tel: 01- 8929418, 4772452, 4728627
Dr. Monica Hemben Eimunjeze
Director
R&R, NAFDAC
DECEMBER, 2012
NAFDAC Committee on Biosimilars
1. Pharm. O.M. Alabi – Deputy Director
2. Pharm. E. Ogbeide – Deputy Director
3. Dr. N.Y. Beno – Chief Regulatory Officer
4. Mrs. I.E. Adegoke – Asst. Chief Regulatory Officer
5. Pharm. E.P. Anto – Asst. Chief Regulatory Officer
6. Dr. C.C. Ilonze – Asst. Chief Regulatory Officer
7. Pharm. D.D. Daniel – Asst. Chief Regulatory Officer
8. Pharm. O.O. Sopein-Mann – Asst. Chief Regulatory Officer
9. Mrs. C.I. Ekwealor – Senior Regulatory Officer

 

Abbreviations
API – Active Pharmaceutical Ingredient
BMP – Biosimilar Medicinal Product
CMC – Chemistry, Manufacturing and Control
cGMP – Current Good Manufacturing Practice
DMF – Drug Master File (dossiers and applications)
ICH – International Conference on Harmonization (of Technical Requirements for Registration of Pharmaceuticals for Human Use)
IM – Intramuscular route of administration
INN – International Non-proprietary Name
IV – Intravenous route of administration
MCB – Master Cell Bank
NRA – National Regulatory Authority
PD – Pharmacodynamics
PK – Pharmacokinetics
PV – Pharmacovigilance
rDNA – Recombinant Deoxyribo-Nucleic Aci
SC – Subcutaneous route of administration
SmPCs – Summary of Product Characteristics
T1/2 – Half-life
WCB – Working Cell Bank
WHO – World Health Organization
RBP – Reference Biotechnology Product
RMP – Risk Management Plan
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Chapter 1 : Introduction and Important Considerations

Biotechnological products are protein molecules derived from biotechnology methods or other cutting-edge technologies. They were introduced on the market in the early 1980s, setting new milestones in modern pharmaceutical therapy that improve the quality of life for many patients with life-threatening, serious, chronic and debilitating diseases. Today, the so-called similar biotechnological products (also known as biosimilars), their first-generation successors, have gone into medical application.

Biologics are large, highly complex molecular entities manufactured using living cells and are inherently variable. Their manufacturing process is highly complex and critical to defining the characteristics of the final product. Maintaining batch-to-batch consistency is a challenge. Subtle variations in the production, or even transport or storage conditions, may potentially result in an altered quality, safety and efficacy profile of the final product. Hence, the phrase, “process is the product” is often used in reference to biologics.

Biotherapeutic products have a successful record in treating many life threatening and chronic diseases. However, their cost has often been high, thereby limiting their access to patients, particularly in developing countries. Recently, the expiration of patents and/or data protection for the first major group of originator‟s biotherapeutics has ushered in an era of products that are designed to be „similar‟ to a licensed originator product. These products rely, in part, for their registration on prior information regarding quality, safety and efficacy obtained with the originator products. The clinical experience and established safety profile of the originator products should contribute to the development of Biosimilars. A variety of terms, such as „similar biotherapeutic products, ‘follow-on protein products’, ‘follow-on biologics’ and ‘subsequent-entry biologics’ have been used by different jurisdictions to describe these products.

As part of its mandate for assuring quality, safety and efficacy of regulated products in Nigeria, the National Agency for Food and Drug Administration and Control (NAFDAC) sets nationally accepted norms and standards for the evaluation of these products. Written standards established through the Expert Committee on Biological Standardization (ECBS) of the World Health Organization (WHO) serve as a basis for setting national requirements for the overall regulation of biosimilars.

An increasingly wide range of biosimilars are under development or are already licensed in many countries and a need for guidelines for their evaluation and overall regulation was formally recognized by the WHO in 2007. This document is intended to provide guidance for the development and evaluation of such products.

It is essential that the standard of evidence supporting the decisions to license biosimilars be sufficient to ensure that the product meets acceptable levels of quality, safety and efficacy to ensure public health. Also, it is expected that the elaboration of the data requirements and considerations for the registration of these products will facilitate development of and increased access to biosimilars of assured quality, safety and efficacy at more affordable prices. In most cases, their authorization will be evaluated on a case-by-case basis, and the amount of data required by NAFDAC may vary.

It is important to note that biosimilars which are not shown to be similar to a Reference Biotherapeutic Product (RBP) as indicated in this guideline should not be described as ‘similar’, nor called a biosimilar. Such products could be licensed through the usual processes using a more extensive non-clinical and clinical data set before full registration application.

It was recognized that some important issues associated with the use of biosimilars shall be defined by NAFDAC. They include but are not limited to the following:

  •  Intellectual property issues;
  • Interchangeability and substitution of biosimilar with RBP; and biosimilar with another Biosimilar;
  • Labeling and prescribing information.
1.1 Aim

The intention of this document is to provide acceptable principles for registration of biosimilar products that are claimed to be similar to RBP of assured quality, safety, and efficacy that have been licensed based on a full registration dossier by a stringent

Regulatory Authority. On the basis of proven similarity, the registration of a biosimilar will rely, in part, on non-clinical and clinical data generated with an already licensed RBP.

1.2 Guiding Principles

Our primary objective is public health protection and patient safety. Biosimilars should meet the same standards of quality, safety and efficacy as any other registered biotechnological product. The regulatory paradigm for biosimilars is not intended to be too onerous, too stringent or too loose rather we undertake a cautious and balanced approach.

Our experience demonstrates that transparent and open dialogue with all relevant stakeholders is key to put in place a robust and responsive regulatory framework in this emerging field whilst creating and promoting a patient-oriented, innovative and favourable regulatory environment. In corollary this will further enhance and promote a dynamic and competitive knowledge-based economy for healthcare biotechnology in Nigeria.

1.3 Scope and Application

The concept of biosimilarity applies to biotechnology drug licensing submissions in which the manufacturer would, based on demonstrated similarity to a RBP, rely in part on publicly available information from a previously approved biotechnological product in
order to present a reduced non-clinical and clinical package as part of submission. The demonstration of similarity depends upon detailed and comprehensive product characterization, therefore, information requirements outlined within this document apply to biotechnological product that contain, as the active substances, well characterized proteins derived through modern biotechnological methods such as recombinant DNA, into microbial or cell culture.

The rationale for creating the new regulatory paradigm for biosimilars is that biotherapeutics / biologics similar to a reference product do not usually meet all the conditions to be considered as a generic. The term “generic medicine” refers to chemically-derived products which are identical and therapeutically equivalent to the originator product, For such generics, demonstration of bioequivalence with the originator product is usually appropriate to infer therapeutic equivalence.

However, it is unlikely that biotherapeutics can generally follow this standard approach for generics because of their large and complex molecular structures, which are more difficult to adequately characterize in the laboratory.

Based on the current analytical techniques, two biotherapeutics produced by different manufacturing processes cannot be shown to be totally identical, but similar at best.

For these reasons, the standard generic approach is scientifically not applicable to development of biosimilar products and additional non-clinical and clinical data are usually required.

Based on the comparability approach and when supported by analytical systems, the comparability exercise at the quality level may allow a reduction of the non-clinical and clinical data requirements compared to a full dossier. This in turn, depends on the clinical experience with the substance class and will be a case by case approach.

The biosimilar approach does not cover complex biologics such as blood-derived products, vaccines, immunologicals and gene and cell therapy products.

Whether a product would be acceptable using the biosimilar paradigm depends on the analytical procedures, the manufacturing process employed, as well as clinical and regulatory experiences.

1.4 Policy Statements

The following policy statements outline the fundamental concepts and principles constituting the basis of the regulatory framework for biosimilars:

1.4.1 In implementing this guidance document, the Guidelines on biosimilars, will be used as the basis for defining the registration requirements and / or process for registration of biosimilars in Nigeria.

1.4.2 Biosimilars are not generic biologics / biogenerics. Thus, the classic generic paradigm (i.e demonstration of bioequivalence of the generic drug with the reference product is usually appropriate to infer therapeutic equivalence) and many characteristics associated with approval process used for generic drugs do not apply to biosimilars.

1.4.3 Approval of a product through the biosimilar pathway is not an indication that the biosimilar may be automatically substituted with its reference product or other biosimilar. The decision for substitutability with the reference product shall be based on science and clinical data.

1.4.4 A biosimilar product cannot be used as a reference product by another manufacturer because a reference product has to be approved on the basis of a complete/full quality and clinical data package.

1.4.5 Eligibility for a biosimilar pathway hinges on the ability to demonstrate similarity to a reference product. Product employing clearly different approaches to manufacture from the reference product (for example use of transgenic organisms versus cell culture) will not be eligible for the regulatory pathway for biosimilars.

1.4.6 The manufacturer must conduct a direct and extensive comparability exercise between its product and the reference product, in order to demonstrate that the two products have a similar profile in terms of quality, safety and efficacy. Only one reference product is allowed throughout this exercise. The rationale for the choice of reference product should be provided by the manufacturer to the NRA.

1.4.7 Non-clinical and clinical requirements outlined for biosimilar submission in this guidance document must demonstrate similarity to the reference product, based on results of the comparability exercises from Chemistry, Manufacturing and control (CMC) perspectives. When similarity of a biosimilar cannot be adequately established, the submission of such a product should be as a ‘Stand-alone’ biotechnological product with complete non-clinical and clinical data.

1.4.8 It should be recognized that there may be subtle differences between biosimilars from different manufacturers or compared with reference products, which may not be fully apparent until greater experience in their use have been established.

Therefore, in order to support Pharmacovigilance monitoring, the specific biosimilar given to patient should be clearly identified.

1.4.9 It was acknowledged that although International Non-proprietary Names (INNs) served as a useful tool in worldwide Pharmacovigilance, for biologicals they could not be relied upon as the only means neither of product identification, nor as an indicator of the interchangeability of biologicals in particular biosimilars.

1.4.10 A biosimilar manufacturer that is not from a jurisdiction that formally adopts International Conference on Harmonization (ICH) guidelines, a current Good Manufacturing Practice (cGMP) audit of the manufacturing facilities is required.

1.5 Scientific considerations and Concept for Registration of Biosimilars

For the registration of generic medicines, the regulatory framework is well-established in most countries. Demonstration of structural similarity and bioequivalence of the generic medicine with the reference product is usually appropriate to infer (conclude) therapeutic equivalence between the generic and the reference product. However, the generic approach is not suitable for the registration of biosimilars since biotherapeutic products usually consist of relatively large and complex entities that are difficult to characterize. In addition, biosimilars are manufactured and controlled according to their own development since the manufacturer of a biosimilar normally does not have access to all the necessary manufacturing information on the originator product. However, even minor differences in the manufacturing process may affect the pharmacokinetics, pharmacodynamics, efficacy and/or safety of biotherapeutic products. As a result, it has been agreed that the normal method for registration of generic medicines through bioequivalence studies alone is not scientifically appropriate for biosimilars.

Decision making regarding the registration of biosimilars should be based on scientific evidence. The onus is on a manufacturer of a biosimilar to provide the necessary evidence to support all aspects of an application for registration. As with any drug development program, the development of a biosimilar involves a stepwise approach starting with characterization and evaluation of quality attributes of the product and followed by non-clinical and clinical studies. Comprehensive characterization and comparison at the quality level are the basis for possible data reduction in the non-clinical and clinical development. If differences between the biosimilars and the RBP are found at any step, the underlying reasons for the differences should be investigated. Differences should always be explained and justified and may lead to the requirement of additional data (e.g. safety data).

In addition to the quality data, biosimilars require non-clinical and clinical data  generated with the product itself. The amount of non-clinical and clinical data  considered necessary will depend on the product or class of products, the  extent of characterization possibly done using analytical methods, on  observed or potential differences between the biosimilar and the RBP, and on  the clinical experience with the product class (e.g. safety/immunogenicity  concerns in a specific indication).

The ability for the biosimilar to be approved based on reduced non-clinical and clinical  data depends on proof of its similarity to an appropriate named RBP through the  comparability exercise. Manufacturers should demonstrate a full understanding of their  product, consistent and robust manufacture of their product, and submit a full quality  dossier that includes a complete characterization of the product. The comparability  exercise between the biosimilar and the RBP in the quality part represents an additional  element to the „traditional‟ full quality dossier. The reduction in data requirements is  therefore only possible for the non-clinical and/or clinical parts of the development  program. The dosage form and route of administration of the biosimilar should be the  same as for the RBP.

Studies must be comparative in nature employing analytical strategies (methods) that  are sensitive to detect potential differences between the biosimilar and the RBP. The  main clinical studies should use the final formulation derived from the final process  material of the biosimilar. Otherwise, additional evidence of comparability will be  required to demonstrate that the biosimilar to be marketed is comparable to that used  in the main clinical studies.

If similarity between the biosimilar and the RBP has been convincingly demonstrated,  the biosimilar may be approved for use in other clinical indications of the RBP that have  not directly been tested in clinical trials if appropriate scientific (clinical & non-clinical)  justification for such extrapolation is provided by the manufacturer. Significant  differences between the biosimilars and the RBP detected during the comparability  exercise would be an indication that the products are not similar and more extensive,  non-clinical and clinical data may be required to support the application for registration.

1.6 Comparability Exercise

The comparability exercise for a biosimilar is designed to show that the product has  highly similar quality attributes when compared to the RBP. However, it also includes  the non-clinical and clinical studies to provide an integrated set of comparative data.  The comparability data for safety, efficacy and quality can be considered to be an  additional set of data over that which is normally required for an originator product  developed as a new and independent product. This is the basis for reducing the non- clinical and clinical data requirements.

Although the quality comparisons are undertaken at various points throughout the quality application / dossier, a distinction should be made between usual quality data requirements and those presented as part of the comparability exercises. It may be useful to present these as a separate section in the quality module.

1.7 Key Principles for the Registration of Biosimilars

a. The development of a biosimilar product involves stepwise comparability exercise(s) starting with comparison of the quality characteristics of the biosimilar and RBP. Demonstration of similarity of a biosimilar product to a RBP in terms of quality is a prerequisite for the reduction of the non-clinical and clinical data set required for registration. After each step of the comparability exercise, the decision to proceed further with the development of the biosimilar should be evaluated.

b. The basis for registering a product as a Biosimilar product depends on its demonstrated similarity to a suitable RBP in quality, non-clinical, and clinical parameters. The decision to register a product as a biosimilar should be based on evaluation of the whole data package for each of these parameters.

c. If relevant differences are found in the quality, non-clinical, or clinical studies, the product will not likely qualify as a biosimilar and a more extensive non-clinical and clinical data set will likely be required to support its application for registration. Such a product should not qualify as a biosimilar as defined in this guideline.

d. If comparability exercises and/or studies with the RBP are not performed throughout the development process as outlined in this guidance document, the final product should not be referred to as a biosimilar.

e. Biosimilas are not “generic medicines” and many characteristics associated with the authorization process generally do not apply.

f. Biosimilars, like other biotherapeutic products, require effective regulatory oversight for the management of their potential risks and in order to maximize their benefits.

1.8 Reference Biotherapeutic Product

Comprehensive information on the RBP provides the basis for establishing the safety,  quality, and effectiveness profile to which the biosimilar is compared. The RBP also  provides the basis for dose selection and route of administration, and is utilized in the  comparability studies required to support the registration application. The  demonstration of an acceptable level of similarity between the biosimilar and RBP  provides the rationale for utilizing a reduced non-clinical and clinical data set to support  the application for market authorization of the biosimilar. Hence the RBP is central to  the registration of a biosimilar.

To support registration of the biosimlars, similarity of the product to the RBP should be  demonstrated through head-to-head comparability with the RBP. The same RBP should  be used throughout the entire comparability exercise.

The choice of a RBP is of critical importance for the evaluation of biosimilars. The  rationale for the choice of the RBP should be provided by the manufacturer of the  biosimilars in the submission to NAFDAC.  NAFDAC has criteria to guide their acceptability of registering of biosimilars. The use of  reference products with proven efficacy and safety in a given population will be one of  the factors to consider. Another parameter will be post marketing safety experience in  addition to the duration and marketed indication.

1.9 Considerations for Choice of Reference Biotherapeutic Product (RBP).

1) The RBP should have been registered on the basis of a full registration dossier in Nigeria and / or by a stringent Regulatory Authority for a suitable duration and have been used such that the demonstration of similarity to it brings into relevance a substantial body of acceptable data regarding the safety and efficacy.

2) The manufacturer needs to demonstrate that the chosen RBP is suitable to support the application for registration / marketing authorization of a biosimilar.

3) The RBP should be registered based on a full quality, safety, and efficacy data.

Therefore a biosimilar should not be considered as a choice for RBP.

4) The same RBP should be used throughout the development of the biosimilar (i.e. for the comparative quality, non-clinical, and clinical studies).

5) The drug substance of the RBP and the biosimilar must be shown to be similar.

6) The dosage form and route of administration of the biosimilar should be the same as that of the RBP.

Note: Appropriate Circumstances for the Use of a Reference Biotechnology Product (RBP) not licensed in Nigeria

In instances where the RBP used is not licensed in Nigeria, the following should be considered:

a. The applicant is responsible for showing that the RBP not licensed in Nigeria, used for the purposes of demonstrating similarity is registered in a jurisdiction that formally adopts International Conference on Harmonization (ICH) guidelines and has regulatory standards and principles for evaluation of medicines, post-market surveillance activities, and approach to comparability that are similar to Nigeria;

b. The applicant has the responsibility of ensuring that the chosen RBP not licensed in Nigeria has associated with it sufficient information and data to support the submission;

c. The RBP not licensed in Nigeria is from a jurisdiction that has an established relationship with Nigeria; and

1.10 Extrapolation of Efficacy and Safety Data to other Clinical Indications

If similar efficacy and safety of the biosimilar and RBP have been demonstrated for a particular clinical indication, extrapolation of these data to other indications of the RBP (not studied in independent clinical studies with the biosimilar) may be possible if all of the following conditions are fulfilled:

i. A sensitive clinical test model has been used that is able to detect potential differences between the biosimilar and the RBP;

ii. The clinically relevant mechanism of action and/or involved receptor(s) are the same; e.g. Growth Hormone (GH) action in different conditions of short stature in children; erythropoiesis-stimulating action of epoetins in different conditions associated with anaemia or for the purpose of autologous blood donation. If the mechanism of action is different or not known a strong scientific rationale and additional clinical data will be needed;

iii. Safety and immunogenicity of the biosimilar have been sufficiently characterized and there are no unique/additional safety issues expected for the extrapolated indication(s), for which clinical data on the biosimilar are not being provided; e.g. immunogenicity data in immunosuppressed patients would not allow extrapolation to an indication in healthy subjects or patients with autoimmune diseases while the reverse would be valid.

iv. If the efficacy trial used a non-inferiority study design and demonstrated acceptable safety and efficacy of the biosimilar compared to the RBP, the applicant should provide convincing arguments that this finding can be applied to the extrapolated indications; e.g. results from a non-inferiority trial in an indication where a low dose is used may be difficult to extrapolate to an indication where a higher dose is used, from both efficacy and safety point of view.

If these prerequisites for extrapolation of efficacy and safety data of the biosimilar to other indication(s) of the RBP are not fulfilled, the manufacturer will need to submit their own clinical data to support the desired indication(s).

If extrapolation of results from clinical studies for one indication to one or more different indications is intended, a detailed scientific discussion on the benefit/ risk of such a proposal should be provided based on the above criteria.

1.11 Interchangeability and Substitution

This remains a controversial issue among different regulators worldwide and all concerned parties. Biosimilars are protein therapies, similar to indigenous human mediators, given in microgram quantities, not exact copies of an original medicine, with limited clinical experience at approval. Although interchangeability and substitution are not encouraged and can be detrimental to pharmacovigilance and risk management, there could be situations (financial, availability, intolerability, hospital or country necessities) when they are needed. It is generally viewed that changing or substituting a protein medicine produced by rDNA technology, whether original (innovator) or a biosimilar, is the decision of the physician and the patient when the physician explains to the patient the possibility of such substitution and examines the risks versus benefits. Physicians and pharmacist should discuss the issue before talking to the patient to prevent inappropriate substitution. Pharmacists cannot substitute biosimilars without such consultations with physicians.However, NAFDAC strongly recommends the followings:(1) Changing from an innovator drug to a biosimilar which used the same innovator drug as its RBP for comparability can be accepted after physician and patient discussion.

(2) Changing from a biosimilar to another same biosimilar drug from a different manufacturer can be accepted after physician and patient discussion only if they both used the same RBP for comparability purposes.

(3) Changing from an innovator drug to another innovator drug for the same indication, or from a biosimilar drug to another biosimilar drug which did not use the same innovator drug as a RBP for comparability is not acceptable in ordinary situation. In extreme situations, physician and patient discussion, as well as hospital administration involvement in the decision for change are mandatory.

In all cases, close monitoring of the patient‟s responses should be performed when interchangeability or substitution is warranted, if possible on a daily basis until results are satisfactory and stable. Dosage and route of administration should be studied and adjusted when necessary. Minute differences among biosimilars and between a biosimilar and the innovator may affect the clinical outcome. In addition, and for obvious reasons, substitutions negatively affect the pharmacovigilance exercise.

1.12 Storage conditions

1.12.1 Temperature

Most finished biosimilar products need precisely defined storage temperatures.

For this reason, it is mandatory that they be transported in thermal bags to maintain the cold chain. The storage conditions for the real-time/real-temperature stability studies may be confined to the proposed storage temperature.

1.12.2 Humidity

Biosimilars are generally stored in containers protecting them from humidity. Where it can be demonstrated that the proposed containers (and conditions of storage) provides sufficient protection against high and low humidity, stability tests at different relative humidities can be omitted.

1.12.3 Accelerated and Stress Conditions

As previously noted, the shelf life should be based on real-time/real-temperature data. However, it is strongly suggested that studies be conducted on the drug substance and drug product under accelerated and stress conditions. Studies under accelerated conditions may provide useful support data for establishing the expiration date, provide product stability information for future product development (e.g., preliminary assessment of proposed manufacturing changes such as change in formulation, scale-up), assist in validation of analytical methods for the stability program, or generate information which may help elucidate the degradation profile of the drug substance or drug product. Studies under stress conditions may be useful in determining whether accidental exposures to conditions other than those proposed (e.g., during transportation) are deleterious to the product and also for evaluating which specific test parameters may be the best indicators of product stability. Studies of the exposure of the drug substance or drug product to extreme conditions may help to reveal patterns of degradation; if so, such changes should be monitored under proposed storage conditions. While the tripartite ICH guideline on stability  describes the conditions of the accelerated and stress study, the applicant  should note that those conditions may not be appropriate for  biotechnological/biological products. Conditions should be carefully  selected on a case-by-case basis.

1.12.4 Light

Sensitivity to light as stated by the manufacturer should be indicated on the label.

1.12.5 Container/Closure

Changes in the quality of the product may occur due to the interactions  between the formulated biosimilars and container/closure. Where the lack  of interactions cannot be excluded in liquid products (other than sealed  ampoules), stability studies should include samples maintained in the  inverted or horizontal position (i.e., in contact with the closure), as well as  in the upright position, to determine the effects of the closure on product  quality.

Data should be supplied for all different container/closure combinations that will be marketed.
In addition to the standard data necessary for a conventional single-use vial, the  manufacturer should demonstrate that the closure used with a multiple-dose vial  is capable of withstanding the conditions of repeated insertions and withdrawals  so that the product retains its full potency, purity, and quality for the maximum  period specified in the instructions-for-use on containers, packages, and/or  package inserts. Such labeling should be in accordance with relevant NAFDAC  labeling requirements.

1.12.6 Stability after Reconstitution of Freeze-dried ProductThe stability of freeze-dried products, after their reconstitution, should be  demonstrated for the conditions and the maximum storage period specified on  containers, packages, and/or package inserts. Such labeling should be in  accordance with relevant NAFDAC Drug Labeling Regulations 2005 at  www.nafdac.gov.ng.

1.13 Labeling

This issue deals with the information shown on the primary or secondary  package label and the inside leaflet of biosimilar. In both, the name of the  product must be clearly written, with the scientific name of the product  [international Non-proprietary Name, INN, if there is any designated by WHO]  with the company‟s name and logo clearly demonstrated. For further information  refer to NAFDAC Drug Labeling Regulations 2005 on www.nafdac.gov.ng.1. The minimum labeling requirements on the primary and secondary package labels are;

(a) Name of product- INN/scientific name and brand name (where applicable). The INN/scientific name must be written directly under the brand name and in same character.

(b) Manufacturer‟s name and factory location address.

(c) Provision for NAFDAC Registration Number.

(d) Batch Number/Lot Number.

(e) Manufacturing and Expiry dates.

(f) Quantitative listing of all the active ingredients per unit dose.

(g) Precisely defined storage conditions.

2. The minimum requirements on the leaflet insert are:

(a) Name of product- INN/scientific name and brand name (where applicable). The INN/scientific name must be written directly under the brand name and in same character.

(b) A statement indicating that the product is a biosimilar.

(c) The leaflet shall carry advice / caution stating that interchangeability or substitution of a biosimilar with another biosimilar or a reference biotechnology product with a biosimilar, is not advisable.

(d) Manufacturer‟s name and factory location address.

(e) Dosage regimen.

(f) Indications, frequency, route and conditions of administration.

(g) Quantitative listing of all the active ingredients per unit dose.

(h) Precisely defined storage conditions.

(i) Adequate warnings where necessary.

3. Any Biosimilar product whose name, package or label bears close resemblance to an already registered product or is likely to be mistaken for such registered product, shall not be considered for registration.

4. Any Biosimilar product which is labeled in a foreign language shall NOT be considered for registration unless an English translation is included on the label and package insert (where applicable).

5. Information on indication carried on packages and leaflet insert of product shall not differ from that in other countries, and in particular the country of origin of the product.

In addition to the above, the following specific information are also required:

i. A statement indicating that the product is a biosimilar.

ii. Key data on which the decision for market authorization will be made.

iii. The results of the comparisons between the biosimilar and RBP information on the indications approved for use should be shown.

iv. There should be no claims for bioequivalence between the biosimilar and RBP.

v. There should be no claims for clinical equivalence between the biosimilar and the RBP.

vi. Interchangeability and substitution advice should clearly and prominently stated.

vii. The brand name and the scientific name / INN of a biosimilar should be clearly stated.

viii. For all biosimilar products, precise defined storage conditions are should be clearly stated.

ix. Leaflet should include all Adverse Drug Reactions that may be associated with the use of the biosimilar.

Note: It is the duty of the Marketing Authorization Holder to inform NAFDAC of any changes to the prescribing information.

Chapter 2 : Manufacturing and Quality Consideration

The biosimilars development process, followed by a validated manufacturing process, is the start of the long pathway towards a beneficial product. Expression system, fermentation or cell culture, purification, sterilization, drug substance e.g. batch definition, pooling strategy, formulation and filling, and general parameters affecting all manufacturing steps e.g., water quality, temperature, personnel are all important elements of the process. Any manufacturing change, even among batches, can produce  process-related impurities, culture/fermentation-derived impurities, purification-derived impurities, and final product-related impurities. Thus, any deviation from the RMP  manufacturing (the innovator’s) process may have a minor or major impact on product  quality, safety, and/or efficacy. Comparing results of in-process controls of  intermediates can give the first hint of such product changes. However, such  comparisons will be possible only for innovators because follow-on manufacturers will  not have access to the innovator’s process intermediates. Deviant conformations, altered post-translational modifications, and different selections of subtype isoforms are  potential consequences of process deviations that could result in altered  microheterogeneity. Substitution of a single amino acid will alter biological activity.  Patterns of absorption may be influenced by formulation. Finally, the batch-to-batch  variability is inevitable with biologic products and contributes to comparability  difficulties.

2.1 Manufacturing Process

The biosimilar product is in part defined by its own specific manufacturing process for  both the drug substance and the final drug product. For a biosimilar registration in  Nigeria, it would be expected that the relevant international guidelines of ICH have  been considered by the manufacturer through each stage of drug development and  production.2.1.1 Comparability Consideration

The comparability exercise for a biosimilar is designed to show that the biosimilar has  highly similar quality attributes when compared to the RBP. However, it also includes  the non-clinical and clinical studies to provide an integrated set of comparative data.  The comparability data for safety, efficacy and quality can be considered to be an additional set of data over that which is normally required for an originator product developed as a new and independent product. This is the basis for reducing the non- clinical and clinical data requirements.

Although the quality comparisons are undertaken at various points throughout the  quality application/dossier, a distinction should be made between usual quality data  requirements and those presented as part of the comparability exercises. It may be useful to present these as a separate section in the quality module.  Comparability studies should be performed during the manufacturing stage comparing the biosimilar under development to the RMP in all aspects including, but not limited to, qualitative and quantitative composition of the final preparation, strength and  concentration, and formulation.

2.2 Quality Aspects

2.2.1 Specifications

Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval to ensure product quality and consistency. They should focus on those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product.

The selection of tests to be included in the specifications is product specific and should be defined according to ICH Q6B. The rationale used to establish the proposed range of acceptance criteria should be described by the manufacturer. Each acceptance criterion should be established and justified based on data obtained from lots used in preclinical and/or clinical studies, and by data from lots used for the manufacturing process validation, data from stability studies, relevant development data and data obtained from the quality, safety and efficacy studies.

2.2.2 Analytical Characterization

Extensive characterization studies should be applied to the biosimilar and RMP, in parallel, at both the active substance and the final medicinal product levels, to demonstrate with a high level of assurance that the quality of the biosimilar is comparable to the RMP. The direct comparison of the drug substance in the biosimilar product to a publicly available standard as a reference is not appropriate to demonstrate comparability of the drug substance. This is because the manufacturer generally does not have access to the drug substance of the RMP and since drug substance of biosimilar may not have existing and defined safety and efficacy profiles.

However, the use of these standards plays an important role during development. In cases where the required analyses of quality attributes of the drug substance of the biosimilar can be made at the initial and intermediate product stages, testing of the drug product may not be needed.

2.2.3 Physicochemical Properties

A physicochemical characterization program should include determination of the composition, physical properties, and primary and higher order structures of the drug substance of the biosimilar product.

The manufacturer should consider the concept of the desired product (and its variants) as defined in ICH Q6B when designing and conducting a comparability exercise. The complexity of the molecular entity with respect to the degree of molecular heterogeneity should also be considered.

2.2.4 Biological Activity and Properties

Biological activity is the specific ability or capacity of the product to achieve a defined biological effect. It serves multiple purposes in the assessment of product quality and is required for characterization, and batch analysis. Ideally, the biological assay will reflect the existing mechanism of action of the protein and will thus serve as a link to clinical activity.

Thus, the use of a relevant biological assay(s) with appropriate precision and accuracy provides an important means of confirming that a significant functional difference does not exist between the biosimilar and the RBP.

For a product with multiple biological activities, manufacturers should perform, as part of product characterization, a set of relevant functional assays designed to evaluate the range of activities of the product. For example, certain proteins possess multiple functional domains that express enzymatic and receptor-binding activities. In such situations, manufacturers should evaluate and compare all relevant functional activities of the Biosimilar and RBP.

2.2.5 Purity, Impurities, and Contaminants

The purity and impurity profiles of the active substance and the final medicinal product should be assessed both qualitatively and quantitatively by a combination of analytical procedures for the biosimilar product.

2.2.5.1 The combination of analytical procedures selected should provide data to evaluate whether a change in purity profile has occurred in terms of the desired product. Where the change results in the appearance of new impurities, the new impurities should be identified and characterized when possible. Depending on the impurity type and amount, it might be appropriate to conduct preclinical studies to confirm that there is no adverse impact on quality, safety or efficacy of the drug product.

2.2.6 Changes Introduced during Development and Post Registration

Manufacturers of biosimilar products frequently make changes to manufacturing processes of products, both during development and after approval. Reasons for such changes include but are not limited to improving the manufacturing process, increasing scale, improving product stability, and complying with changes in regulatory requirements. When changes are made to the  manufacturing process, the manufacturer generally evaluates the relevant quality  attributes of the product to demonstrate that modifications did not occur that  would adversely impact the quality, safety and efficacy of the drug product. Such  an evaluation should indicate whether or not confirmatory preclinical or clinical  studies are appropriate.  When these changes are made to a process, the manufacturer should  demonstrate that the associated process controls, including any new ones,  provide assurance that the modified process will also be capable of providing a  comparable product.

For approved products, an appropriate number of post-change batches should be  analysed to demonstrate consistent performance of the process.  To support the analysis of the changes and the control strategy, the manufacturer should prepare a description of the change that summarises the pre-change and the post-change manufacturing process and that clearly highlights modifications of the process and changes in controls in a side-by-side  format.

2.2.7 Stability

The stability of a product is generally highly dependent on its storage conditions, which must be clearly defined according to the product’s characteristics.  Biosimilars are rather unstable structures. Most biosimilars have to be stored at 4oC, and never shaken or heated.

ICH Q5C should be consulted for details on stability studies for product to product comparison.

Chapter 3 : Non-Clinical Evaluation

3.1 Introduction

This addresses the general principles for the Pre-clinical (non-clinical)  development and assessment of registration applications for biosimilars  containing recombinant proteins as active substance(s).  The studies to be carried out should be comparative in nature and designed to  detect differences in response between the biosimilar product and the RBP. The  focus will be on issues regarding biological activity, pharmacokinetics,  comparability, efficacy, safety, and immunogenicity.  Pre-clinical studies may be used to highlight differences between the biosimilar  product and the RMP. Such studies may have a useful role in the preliminary  assessment of safety at one or more points in the development process, thus  enabling clinical studies to be undertaken with greater confidence.

The applicant should justify, in the Drug Master File (DMF), the approach chosen  during the development of the biosimilar and note the following:

(1) The manufacturer should demonstrate that Biosimilar is similar in terms of quality, safety and efficacy to the RMP. It may not be necessary to repeat all safety and efficacy studies if the manufacturer can demonstrate that:

(a) It is possible to characterize the product in detail with respect to physico-chemical properties and biological in vitro activity.

(b) Comparability can be shown from a chemical-pharmaceutical perspective. During the whole comparability exercise, the same RMP should be used.

(2) In case the RMP has more than one indication, the efficacy and safety of the biosimilar medicinal product claimed to be similar has to be justified or, if necessary, demonstrated separately for each of the claimed indications. Justification will depend on the clinical experience, the available literature data for the RBP, irrespective of the receptor(s) involved in all indications, the pre-clinical data, and the immunogenicity profile.

(3) Safety data will be needed prior to marketing authorization, as well as a Plan for Period Safety Update Report, as possible differences might become evident later, though comparability with regard to efficacy has been shown.

3.2 Issues Regarding Biological Activity (In Vitro and In Vivo Studies)

The combined results from in vitro and in vivo studies assist in the extrapolation of the findings to humans. (See ICH S6).

3.3 Issues Regarding Immunogenicity

Many biosimilars intended for human are immunogenic in animals. Therefore, measurement of antibodies associated with administration of these types of products should be performed when conducting repeated dose toxicity studies, in order to aid in the interpretation of these studies.

The detection of antibodies should not be the sole criterion for the early  termination of a pre-clinical safety study or modification in the duration of the  study design, unless the immune response neutralizes the pharmacological  and/or toxicological effects of the biosimilar in a large proportion of the animals.

In most cases, the immune response to biosimilars (and all biopharmaceuticals) is variable, like that observed in humans. If the interpretation of the data from  the safety study is not compromised by these issues, then no special significance should be ascribed to the antibody response.  The induction of antibody formation in animals is not predictive of a potential for antibody formation in humans. Humans may develop serum antibodies against  humanized proteins, and frequently the therapeutic response persists in their  presence.

3.4 Issues Regarding Comparability

Two situations are indicated in which comparability becomes necessary:

(1) When a product is claimed to be similar to the RMP after the expiry of the data protection period (new application procedure).

(2) When a change is introduced in the manufacturing process of the biosimilar product (either before or after the granting of a marketing authorization [variation procedure]).

In either case the applicant will have to demonstrate or justify that the  biosimilar product and RBP have similar profiles in terms of quality, safety  and efficacy. This might be a sequential process, beginning with quality  studies (partial or comprehensive) and supported, as necessary, by pre- clinical and/or clinical bridging studies to provide useful signals of  potential therapeutic differences.

Chapter 4 : Clinical Studies

4.1 Introduction

The requirements for the clinical studies depend on the existing knowledge about the RBP and the claimed therapeutic indication(s). A comparability exercise must be conducted.

It is recommended to generate the required clinical data for the comparability study  with the test product as produced with the final manufacturing process and, therefore,  representing the quality profile of the batches to become commercialized. Any deviation  from this recommendation should be justified and supported by adequate additional  data.

4.2 Pharmacokinetic (PK) Studies

The PK profile is an essential part of the basic description of a medicinal product and should always be investigated. PK studies should generally be performed for the routes applied for and using doses within the therapeutic dose range recommended for the

RBP. PK studies must be comparative in nature and should be designed to enable detection of potential differences between the biosimilar and the chosen RBP.

4.3 Pharmacodynamic (PD) Studies

The pharmacodynamic effect should be compared in a population where the possible differences can best be observed. The design and duration of the studies must be justified. Pharmacodynamics should preferably be evaluated as part of the comparative pharmacokinetic study, since alterations in pharmacodynamics can sometimes be explained by altered kinetics and such design may provide useful information on the relationship between exposure and effect.

The selected dose should be in the steep part of the dose-response curve. Studies at more than one dose level may be useful. Again, studies should be comparative in nature and not merely show the pharmacodynamics of the product.

General guidance for conducting clinical trials can be obtained from the Guidelines for Clinical Trials in Nigeria.

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) website (www.ich.gov) provides more general considerations for clinical trials regarding the objectives, design, conduct, analysis and reporting.

4.4 Efficacy studies

Dose finding studies are not required for a biosimilar. Demonstration of comparable potency, PK and PD profiles provide the basis for the use of the posology of the RBP in the confirmatory clinical trial(s). Similar efficacy of the biosimilar and the chosen RBP will usually have to be demonstrated in adequately powered, randomized, and controlled clinical trial(s). The principles of such trials are laid down in relevant ICH guidelines 8, 9.

In principle, equivalence designs (requiring lower and upper comparability margins) are clearly preferred for the comparison of efficacy and safety of the biosimilars with the RBP. Non-inferiority designs (requiring only one margin) may be considered if appropriately justified.

Equivalence/ non-inferiority margins have to be pre-specified and justified based on clinical relevance; i.e. the selected margin should represent the largest difference in efficacy that would not matter in clinical practice. Treatment differences within this margin would thus, by definition, be acceptable because they have no clinical relevance.

Generally, equivalence trials are clearly preferable to ensure that the biosimilar is not clinically less or more effective than the RBP when used at the same dosage(s). For biosimilar with a wide safety margin, non-inferiority trials may also be acceptable. It should, however, be considered that non-inferior efficacy, by definition, does not exclude the possibility of superior efficacy of the biosimilar compared to the RBP which, if clinically relevant, would contradict the principle of similarity.

4.6 Immunogenicity

This is the most important aspect of safety of biosimilars. For many proteins and peptides, a number of patients develop clinically relevant anti-drug antibodies. The immune response against therapeutic proteins differs between products since the immunogenic potential is influenced by many factors. For further information, please refer to ICH S8.

4.7 Risk Management and Pharmacovigilance

The applicant should give a risk specification in the application DMF for the biosimilars  under review. This includes a description of possible safety issues related to tolerability  of the product that may result from a manufacturing process different from that of the  innovator. In the DMF, the applicant should present a Risk Management Plan and  Period Safety Update Report (PSUR) in accordance with current NAFDAC procedures  and guidelines. This should take into account risks identified during product  development and potential risks. Pharmacovigilance systems and procedures to achieve  this monitoring should be in place before a marketing authorization is granted. Any  specific safety monitoring imposed to the RMP or product class should be taken into  consideration in the risk management plan.

The compliance of the marketing authorization holder with commitments (where  appropriate) and their pharmacovigilance obligations will be closely monitored. The  marketing authorization holder should address reports and any other information on  tolerability of the biosimilar that the company has received. These reports or information must be evaluated and assessed by the marketing authorization holder in a  scientific manner with regard to causality of adverse events or adverse drug reactions and related frequencies.

For further information on this issue, ICH Q9 can be used. For reporting, NAFDAC  Guidelines on Pharmacovigilance should be referred to.

——————————

National Agency for Food and Drug Administration and Control (NAFDAC)

Regulatory and Registration (R&R) Directorate

Guidelines for the Registration of Biosimilars in Nigeria

A. GENERAL

▪ These guidelines are for the interest of the general public and in particular, pharmaceutical industries in Nigeria.

▪ It is necessary to emphasize that, no medicinal product shall be manufactured, imported, exported, advertised, sold or distributed in Nigeria unless it has been registered in accordance with the provisions of decree 19 of 1993 and the accompanying guidelines.

▪ Biotechnology¹ Product is any product prepared from cells cultivated from cell banks, excluding microbial metabolites such as antibiotics, amino acids, carbohydrates and other low molecular weight substances.

They may be isolated from a variety of natural sources – human, animal, or microorganism – and produced by biotechnology methods.

▪ Reference Biotechnology Product (RBP) is a product used as the comparator for head-to-head comparability studies with a Biosimilar in order to show similarity in terms of quality, safety and efficacy. Only a biotherapeutic product that was licensed on the basis of a full registration dossier in Nigeria and/or by a stringent Regulatory Authority can serve as a RBP.

¹ Reference Biotechnology Product (RBP) can also refer to Reference Biotherapeutic Product and Reference Biopharmaceutical Product

Note: See below the appropriate circumstances under which a biotherapeutic product that is not licensed in Nigeria may be used as a RBP.

Biosimilar: A product is said to be a biosimilar if it demonstrates similarity in terms of quality, safety and efficacy to a named reference biotherapeutic product licenced in Nigeria and/or a by stringent regulatory authority.

Appropriate Circumstances for the Use of a Reference Biotechnology Product (RBP) not Licensed in Nigeria.

In instances where the RBP used is not licensed in Nigeria, the following should be considered:

a. The applicant is responsible for showing that the RBP not licensed in Nigeria, used for the purposes of demonstrating similarity is registered in a jurisdiction that formally adopts International Conference on Harmonization (ICH) guidelines and has regulatory standards and principles for evaluation of medicines, post-market surveillance  activities, and approach to comparability that are similar to Nigeria;

b. The applicant has the responsibility of ensuring that the chosen RBP not licensed in Nigeria has associated with it sufficient information and data to support the submission;

c. The RBP not licensed in Nigeria is from a jurisdiction that has an established relationship with Nigeria.

B. APPLICATIONS

1. (a) The manufacturer shall be represented by an applicant – a duly registered pharmaceutical company – who must be in possession of a notarized Power of Attorney from the manufacturer authorizing him to speak for the principal on all matters relating to the product.


(b) The manufacturer must show:

I.

Manufacturer’s Licence/Certificate

This is the documentary evidence issued by Competent Health Authority of the country of manufacture that the company is licenced to manufacture biotechnological products which may be used in the country of origin and / or exported.

II.

Product License/Certificate of Registration

This is the documentary evidence of registration of such product by the competent Health Authority of the country of manufacture.

III.

Certificate of Pharmaceutical Product (COPP) in conformity with WHO format

This is the documentary evidence by the competent Health Authority that the sale of the product does not constitute a contravention of the drug laws of the country of manufacture.

IV. Valid WHO GMP Certificate

NOTE: The documents in respect of (I), (II), (III) and (IV) shall be authenticated by the Nigerian Mission in that country. In countries where no Nigerian Embassy or High Commission exists, any other Embassy or High Commission of any Commonwealth or West African country can authenticate the documents.

2.

(a)  An application for registration of a Biosimilar product shall be made by the applicant who procures the prescribed application form which must be duly completed with all required information.

This form shall be obtained from the office of the Director (R & R) upon payment of prescribed fee and submitted with a formal application letter, stating the name of the manufacturer, International Non-proprietary Name(INN)/scientific name, brand name (where applicable), strength, pack size and indication of product.

(b) A separate application form shall be submitted for each Biosimilar product. In this context, the application for registration of one dosage form with different strengths, of same formulations with different dosage forms, shall be made on different application forms.


(c)

i. The applicant shall be responsible for ensuring that the product that will be imported after licensing shall comply with the approved label, quality and other conditions of approval.

ii. The applicant shall be responsible for importation, good distribution and storage of the product.

iii. The applicant shall also be responsible for submitting a detailed Risk Management Plan (RMP) as well as provide Periodic Safety Update Report (PSUR) in line with the Guidelines for Post Marketing Surveillance (PMS).

C. PRODUCT

1. There must be evidence to demonstrate similarity to a named Reference Biotechnology Product of assured quality, safety, and efficacy in respect to the indication(s), route of administration and dosage forms that has been licensed based on a full registration dossier in Nigeria and/or by a stringent Regulatory Authority

(please see ‘A’ above, under Appropriate Circumstances…).

2. Any product that shall not comply with (c) 1 above shall not be considered for registration.

3. An applicant shall not be allowed to register a formulation in more than one brand name even where different doses of the active ingredient(s) are used.

4. The product information dossier shall be submitted in International Conference on Harmonization (ICH) Common Technical Document (CTD) format with the relevant sections duly completed and signed by both the Managing Director and Superintendent Pharmacist. The content of the dossier must be in compliance with the sections on the format. This should be submitted in 2 copies (hard and electronic copies).


D. LABELLING REQUIREMENTS

1. Labeling shall be informative and accurate.

2. The minimum labeling requirements on the primary and secondary package labels are; (a) Name of product- INN/scientific name and brand name (where applicable). The INN/scientific name must be written directly under the brand name and in same character. (b) Manufacturer’s name and factory location address. (c) Provision for NAFDAC Registration Number. (d) Batch Number/Lot Number. (e) Manufacturing and Expiry dates. (f) Quantitative listing of all the active ingredients per unit dose. (g) Precisely defined storage conditions.

3. The minimum requirements on the leaflet insert are:

(a) Name of product- INN/scientific name and brand name (where applicable). The INN/scientific name must be written directly under the brand name and in same character.

(b) A statement indicating that the product is a biosimilar.

(c) The leaflet shall carry advice / caution stating that interchangeability or substitution of a biosimilar with another biosimilar or a reference biotechnology product with a biosimilar, is not advisable.

(d) Manufacturer’s name and factory location address.

(e) Dosage regimen.

(f) Indications, frequency, route and conditions of administration.

(g) Quantitative listing of all the active ingredients per unit dose.

(h) Precisely defined storage conditions.

(i) Adequate warnings where necessary.

4. Any Biosimilar product whose name, package or label bears close resemblance to an already registered product or is likely to be mistaken for such registered product, shall not be considered for registration.


5. Any Biosimilar product which is labeled in a foreign language shall NOT be considered for registration unless an English translation is included on the label and package insert (where applicable).

6. Information on indication carried on packages and leaflet insert of product shall not differ from that in other countries, and in particular the country of origin of the product.

E. DOCUMENTATION

Applicants shall be required to submit the following documents (original and two (2) copies) along with the duly completed application form(s) to the Liaison Office of Director (LOD):

(1) Power of Attorney or Contract Manufacturing Agreement: Power of Attorney shall be:

a) Notarized by a Notary public in the country of manufacture.

b) Issued by the manufacturer of the product.

c) Signed by the MD, GM, Chairman or President of the Company.

d) Stating the names of the products to be registered.

e) Stating the name and address of the applicant

f) Stating the owner of the trademark (where applicable).

Contract Manufacturing Agreement shall be:

a) Notarized by a notary public in the country of manufacture.

b) Signed by both parties- the manufacturer and the applicant stating names and designations of the signatories.

c) Stating the names of all the products to be registered and other relevant clauses clearly explained in an unambiguous language.

(2) Manufacturer’s License / Certificate indicating: a) The name of products to be registered. b) The name and address of manufacturer. (3) Certificate of Pharmaceutical Products (COPP – WHO FORMAT)


(4) Valid WHO Good Manufacturing Practice (GMP) Certificate

NOTE: The documents in respect of (2), (3) and (4) shall be issued by the relevant health/regulatory body and authenticated by the Nigerian Mission in that country. In countries where no Nigerian Embassy or High Commission exists, any other Embassy or High Commission of any Commonwealth or West African country can authenticate.

(5) Evidence of Trademark approval from Federal Ministry of Commerce & Tourism / Certificate of Registration of Brand Name with the trademark Registry in the Ministry of Commerce in Nigeria. This shall be done in favor of the trademark owner (manufacturer or applicant), as the case may be.

(6) Comprehensive Certificate of Analysis, issued by the manufacturer indicating the name, designation and signature of the analyst.

(7) Evidence of membership of approved sectoral group.

(8) Certificate of Business Incorporation of the importing company with the Corporate Affairs Commission in Nigeria.

(9) Current Superintendent Pharmacists License to practice issued by the Pharmacists Council of Nigeria.

(10) Valid Pharmaceutical Premises License Issued by the Pharmacists Council of Nigeria.

(11) Application letter for Import Permit by the applicant.

(12) An Invitation Letter for GMP inspection of manufacturing facility written by manufacturer which shall state;

a) The name and full location address of the manufacturer.

b) Name, e-mail address, current phone number & fax number of contact person in the country of origin of product.

c) Guide map (illustrating the shortest land/air route to the manufacturing factory).


d) Name(s) of product(s) intended for registration).

e) The applicant’s information (Name of company, full location address, functional telephone number, fax number, e-mail address.

(13) Proposed distribution channels for the product intended for registration.

(14) Name(s) and location address(es) of cold chain storage facility(s) (where applicable).

Note: Failure to comply with these requirements may result in the disqualification of the application or lead to considerable delays in processing of registration.

F. FEES SCHEDULE

Total payment for registration of Biosimilar is N350,000 plus 5% VAT. Breakdown as follows:

a. N10,000 for Import Permit

b. N240,000 for Processing Fee

c. N100,000 for Product License

Please note that every fee is subject to review and attracts 5% VAT.

G. ISSUANCE OF CERTIFICATE OF REGISTRATION

Upon registration, the applicant shall be issued a Notification of Product Registration with the registration number which shall subsequently be used to obtain the registration certificate.

H. VALIDITY OF APPROVAL

The Certificate of Registration for a Biosimilar shall be valid for a period of five (5) years.

However the Agency may suspend, withdraw or cancel the certificate of registration of Biosimilar product if found to have any of the following flaws:

i. Data/document with which the product was registered was found to be false or falsified.

ii. The circumstance under which the product was registered no longer exists.


iii Any of the conditions under which the Biosimilar product was registered has been contravened.

iv. The standard of quality, safety or efficacy as prescribed in the documentation for registration is not being complied with.

v. The premises, in which the product is processed, manufactured or stored on behalf of the holder of the certificate of registration is found to be unsuitable.

Note:

1. Procurement and submission of an application form or payment of processing fees does not confer registration status on product.

2. NAFDAC reserves the right to revoke, suspend or vary the certificate during its validity period.

3. Failure to respond promptly to queries on enquiries raised by NAFDAC on the application, will automatically lead to suspension of further processing of the application.

4. Registration of a product does not automatically confer Advertising permit. A separate approval by the Agency shall be required if the product is to be advertised.

5. NAFDAC may withdraw the Certificate of Registration in the event that the product is advertised without express approval from Agency.

6. All applicants are required to submit functional e-mail address(es) and telephone number(s).


STEPS TO PRODUCT REGISTRATION

STEP I: DOCUMENTATION

All documents (originals and two (2) copies) as stated in E above except document No. 13, are to be submitted to the Liaison Office of Director (LOD), Regulatory and Registration Directorate.

STEP II: IMPORT PERMIT

Upon satisfactory documentation,

i. Import Permit (i.e permit to import samples for registration) shall be issued by the Drug Registration Division on payment of ten thousand five hundred naira (N10, 500) only, 5% VAT inclusive.

ii. A letter for cold chain inspection shall also be issued to the company (if applicable).

STEP III: PRODUCT VETTING: 

The following shall be submitted:

i. One (1) well labeled sample.

ii. Two (2) packaging materials of the product(s) or artwork.

iii. Hard & electronic copies (CD-ROM) of Common Technical Document (CTD).

iv. Hard & electronic copies (CD-ROM) of Risk Management Plan (RMP)

v. An invitation Letter for GMP inspection.

vi. A copy of the import permit.

vii. The receipt of payment for the import permit.

STEP IV: DOSSIER REVIEW:

STEP V: LABORATORY ANALYSIS

Upon satisfactory review and payment of two hundred and forty (N240,000:00) naira only plus 5% VAT for processing, samples shall be sent to the laboratory for analysis.


STEP VI: ISSUANCE OF NOTIFICATION OF REGISTRATION
The company(s) shall be issued a Notification of Product Registration following satisfactory laboratory analysis; satisfactory cold chain inspection report (where applicable) and approval by various levels of Products Approval Committees.

All correspondence in respect of the Guidelines should be addressed to:

The Director-General
National Agency for Food and Drug Administration and Control (NAFDAC)
Plot 2032, Olusegun Obasanjo Way,
Zone 7, Wuse, Abuja
Tel: 09-5240996
Fax: 09-5240994

Attention:

Director,
Regulatory and Registration Directorate.
445, Herbert Macauley Street, Yaba, Lagos.
Tel: 01- 8929418, 4772452, 4728627

Dated: December, 2012

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