pharmacist rana musa al-ali (malkawi) msc (pharmaceutical

Pharmacist Rana Musa Al-ali (Malkawi)

MSc (Pharmaceutical Quality Assurance) Registration Department/JFDA

2ND MENA Regulatory Conference On Bioequivalence, Biowaivers, Bioanalysis, Dissolution & Biosimilars Amman (15th-17th September/2015)

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1-Biologicals Vs small molecule

drugs 2- Regulatory

Pathway In Jordan

3-Biosimilars general

considerations 4-Conclusions

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Biologicals Vs Small Molecule Drugs

• Biological products: They include a wide range of products either synthezised or extracted from a biologic system, such as vaccines, blood & blood components, allergenics, somatic cells, gene therapy, tissues, & recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells & tissues. Biologics are isolated from a variety of natural sources - human, animal, or microorganism - & may be produced by biotechnology methods & other cutting-edge technologies. They often are at the forefront of biomedical research & may be used to treat a variety of medical conditions for which no other treatments are available

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Sm

all m

olec

ule

drug

s • Made by chemical synthesis

• Low molecular weight

• Well defined structure

• Process independent

• Easily characterized

• Stable • Mostly non-

immunogenic

Bio

logi

cal d

rugs

• Made by living cells

• High molecular weight

• Complex & heterogeneous structure

• Strongly process dependent

• Difficult to characterize

• Unstable, sensitive to external conditions

• Immunogenic 7

Biologicals key points:

• There is a strong relationship between the manufacturing process & the characteristics of the final product.

• The safety & efficacy of the final product is very sensitive to small changes in the manufacturing process (the effect of these changes are difficult to predict)

• This could lead to a negative health consequences on patients

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• The only official body that is responsible for regulating all aspects related to medicines throughout their full lifecycle ,starting from active ingredients until it’s ready for patient’s use as finished product.

• Works on providing & maintaining proper public health through allocating all possible means & tools to obtain medicines within a reasonable period of time after ensuring safety, quality & efficacy.

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Drug registration Division

Pharmacovigilance Unit

Drug Registration

Unit

Herbal registration unit

Files archiving

Unit

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History of Biopharmaceutical Regulatory system

• In 2004 : issuance of the criteria for Registration

& Re-registration of all drugs. • Since 2009, all drug applications submitted to

JFDA followed the CTD format. • In 7/5/2015 the guideline for Biosimilars

registration in Jordan was released & published in the official gazette.

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The guideline for Biosimilars registration in Jordan

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The purpose of the Biosimilar registration guideline:

• Provide assistance to applicants (industry) on how to comply with the regulations.

• Introduce the concept of biosimilars. • Require a baseline scientific comparison of the Biosimilar with the

Reference drug (the comparability requirements) with regards to quality, safety & efficacy.

• Identify the level of clinical data needed to evaluate & approve the Biosimilar.

• Focus on the Quality assessment, with head-to-head comparison to the Reference drug with full characterization of quality parameters using state of the art techniques & analytical methods or procedures.

• Focus on-marketing safety studies to monitor any potential differences in safety including immunogenicity between the Biosimilar & Reference drug that become apparent once a Biosimilar enters the market.

• Specify details to ensure traceability with regards to Pharmacovigilance for biosimilars.

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Major Articles in the guideline:

Article (2), Definitions:

• RBP (Reference Biological Product): Innovator biological medicinal product either already approved/registered in the reference countries in the EU (via the centralized procedure) , USA, Australia, Canada, Japan, &/or Jordan, this product should be registered on the basis of a complete dossier (full quality, safety & efficacy). The reference product is used in demonstrating the comparability of a biosimilar product through quality, non-clinical & clinical studies .

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• Biosimilar Product: a biological medicinal product that is similar to the reference product in terms of quality, safety & efficacy, contains a version of the active substance that is similar, in molecular & biological terms, to the active substance of the reference product. The posology & route of administration of the biosimilar must be the same as those of the reference medicinal product. Deviations from the reference product as regards strength, pharmaceutical form, formulation, excipients or presentation require justification. If needed, additional data should be provided. Any difference should not compromise safety. 16

Reference Biological Product VS

Biosimilar Product

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Manufacturing site: • Site/s responsible for any step in the manufacturing

of the active ingredient/s, starting from the storage & use of the Working Cell Bank.

• Site/s responsible for any step in the manufacture of the finished product.

• The batch release site.

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• Article (4): -This guideline is applicable to similar biological products

that contain, as the active substances, well characterized proteins derived through modern biotechnological methods such as recombinant DNA, into microbial or eukaryotic cell culture.

- It does not cover complex biologics such as blood-derived products, vaccines, immunologicals/allergens ,and tissue , gene and cell therapy products.

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• Article (5): It is prohibited to register a biosimilar drug

except after approving its manufacturing sites in accordance with the approved principles thereof.

• Article (6): It is prohibited to market a biosimilar drug

except after its registration, pricing & the issuance of a registration number for it.

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• Article (7): JFDA reserves the right to request further information not specifically described in the guideline, to ensure safety, efficacy & quality of biosimilar products on justifiable scientific bases. • Article (9): An application for registration for every pharmaceutical form & concentration must be submitted separately. • Article (10): All Biosimilar drugs registered before the issuance of this guideline will be reviewed on a case by case bases upon the re-registration process .

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• Article (11): When conducting a post approval change on a registered biosimilar product , a variation application must be submitted with all the required documents to support this change. • Article (12): This guideline follows the EMA guidelines on biosimilar drugs & all the relevant Guidelines on biological products containing biotechnology-derived proteins as active substance, & any further updates on the EMA guidelines are subsequently adopted by default. 22

Application submission

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• All biosimilars should be submitted as new DRUGS & should take NDA

number. • Biosimilars are evaluated by New

drugs registration Committee.

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Standing Committees Director General

Drug Directorate Higher Drug Committee

Originator Drug Registration Generic Drug Registration

Vitamins and Minerals Bio-equivalence

Pharmaceutical Manufacturing Site Accreditation

Baby Formula PAC

RE-Registration Cosmetics

Pricing

Clinical Research

Sera & Vaccines 25

General considerations for application submission

• It is required to submit a separate copy of the technical file for analysis purposes at the Drug Control Laboratory enclosing:

• Samples of the finished product (the number of which will be determined in accordance with the drug testing system).

• An adequate quantity for analysis of the reference primary

active substance(s) & degradation products.

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Major contents of Biosimilars

file - Files should be on CTD format

-CTD Format consists of 5 modules

module 1: Regional requirements.

module 2: Summaries of the other 3 modules

module 3: Quality module 4: Non clinical data

module 5: Clinical data

For Biosimilars :Comparability studies with the Reference Product should be submitted.

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Major contents of

Biosimilars file (cont.) :

CTD Module 2

of Summariesmodu. 3 other

Quality Overall Summary Non clinical summary & overview. Clinical summary & overview .

CDER Forum /Jordan FDA Oct.25-29 2010

Application forms Certificates :CPP(WHO format), prices, TSE/BSE Product Information: Labeling, outer & inner package, leaflet legalized SmPC, sample, registration status, list of registered similar products. Letter of accreditation of manufacturing site by JFDA.

approval certificate PMFTechnical Contract, Specific requirements:from the health authority . Pharmacovigilance system description: provide description of the system & presence of a qualified person for the notification of any adverse rxns Risk management plan (RMP)

CTD Module 1

Administrative Documents Country

specific

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Major contents of


CTD Module 3

Comparability starting with the API

to the finished product

(Quality)

CDER Forum /Jordan FDA Oct.25-29 2010

: Substance (API) Part

Technical data : characteristics (impurities, purity, immunogenicity), manufacturers, manufacturing process, specifications, analytical methods, validation, containers, stability studies, batch analysis ……..) Drug Product part: composition, excipients, formulation development, manufacturers, manufacturing process & validation, specifications, analytical methods, validation, containers, stability studies, batch analysis……. for intermediates + Final intermediates +finished product

Batch record for 3 consecutive production batches (consistency). Batch numbering system . Plasma Master File (PMF) if needed.

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Major contents of


-For biosimilars: comparability studies are required according to EMA guidelines

CTD Module 4

clinical)–on N(

CTD Module 5

(Clinical)

-Clinical studies, -Published literature (peer reviewed Journals) -PSUR & Risk Management Plan -For biosimilars: comparability studies are required according to EMA guidelines

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Comparability exercise considerations :

• Biosimilars can be approved based on an exercise to demonstrate proof of similarity in terms of quality, safety & efficacy of an already approved reference product.

• Comparability with the chosen reference product should be addressed for both the active substance & drug product.

• Applicants should note that the comparability exercise for a biosimilar versus the reference product is an additional element to the requirements of the quality dossier & should be dealt with separately when presenting the data. 31

• Representative number of batches produced according to a manufacturing process with proven consistency intended for commercial use should be used to cover all comparability studies.

• Quality differences may impact the amount of non-clinical & clinical data needed, & will be dealt with on a case by case approach

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Pharmacovigilance Plan/Risk Management Plan (RMP)

• Any post-market Risk Management Plan (RMP) should include detailed information of a systematic testing plan for monitoring immunogenicity of the biosimilar post-market.

• The RMP may be maintained & implemented throughout the life-cycle of the product.

• Risk minimization activities may differ from region to another so it’s very important that the manufacturers should take the region specifications into consideration while setting the RMP.

• RMP should take into account identified & potential risks associated with the use of the reference product &, if applicable, additional potential risks identified during the development program of the biosimilar & should detail how these issues will be addressed in post-marketing follow-up 33

• The Pharmacovigilance plan must be submitted in the registration file.

• The Pharmacovigilance plan should be designed to

monitor & detect both known inherent safety concerns & potentially unknown safety problems that may have resulted from the impurity profiles of a biosimilar, or may have been undetected in pre-market testing or otherwise not expected.

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Discovery RBP

General development pathway difference

Development Pre-

Clinical Phase I Phase II Phase III

Biosimilar Development Pre-

Clinical Phase I Phase III

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Differences in the manufacturing process between RBP & Biosimilar arises from:

• Cloning the gene sequence on a different DNA

Vector. • Using a different host cell for expression. • Using different fermentation process (different

growth media for cell expansion). • Using different purification protocol (different elution

conditions)

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Complex manufacturing process lead to:

• Heterogeneity of Biopharmaceuticals. • Different cell lines producing the proteins could alter

the 3D structure of the protein. • Impact the receptor binding, stability , PK & safety. • Immunogenic potential in patients. 38

POST-MARKET REQUIREMENTS • Since limited clinical data are submitted at the time of

approval, this requires a vigorous, comprehensive & well structured PV plan (to monitor immunogenicity & adverse drug reactions, ..) .

• Traceability . • Periodic Safety Update Reports (PSURs). • Reports should be continuously submitted to the

authority (where appropriate ) and SmPC should be updated whenever new findings .

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INTERCHANGEABILITY & SUBSTITUTION

• Biosimilars are not generic products & cannot be identical, but similar to their reference products, further biosimilar do not necessarily have the same indications or clinical use as the reference product; thus, the decision to treat a new patient with either a reference product or its biosimilar medicine, or switch in an already treated patient, between a reference product & its biosimilar should only be taken following the opinion of a qualified health professional

• Automatic substitution & active substance-based prescription cannot apply to biologicals, including biosimilars.

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Summary & Conclusions

• Biologics are one of the fastest growing sectors of the

pharmaceutical industry, that introduced many new treatments to life-threatening and rare illnesses.

• A biosimilar is not identical to the RB. • Complexicity of biosimilar products in all aspects needs

to be considered critically. • Pharmacovigilance is a key pillar & very essential in

tracking down any safety and efficacy problems that may arise from the use of biosimilars.

• There is a need for a regulatory framework to control the post approval changes of Biosimilars.

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