Islamic Republic of Iran
Ministry of Health and Medical Education
Food and Drug Organization
Title: Guideline to Definition and Specification of Biologic Products
Type:
Finalized
√
Draft
No.:
Date of Issue:
Document No.: BP-ST-07-04
Name of Office: Biologic,Deputy for Drug
TABLE OF CONTENTS
1. INTRODUCTION…………………………………………………………………………………………………………………………. 1
1.1 Objective……………………………………………………………………………………………………………………………………… 1
1.2 Background…………………………………………………………………………………………………………………………………… 1
1.3 Scope……………………………………………………………………………………………………………………………………………. 1
2. DEFINITIONS OF BIOTHECHNOLOGICAL AND BIOLOGICAL PRODUCTS……………………………………….. 1
2.1 Biological products………………………………………………………………………………………………………………………… 1
2.1.1 Therapeutic serum……………………………………………………………………………………………………………………… 1
2.1.2 Toxin…………………………………………………………………………………………………………………………………………… 2
2.1.3 Antitoxin…………………………………………………………………………………………………………………………………….. 2
2.1.4 Vaccine……………………………………………………………………………………………………………………………………….. 2
2.1.5 Blood, Blood component and derivative…………………………………………………………………………………….. 2
2.1.6 Allergenic product………………………………………………………………………………………………………………………. 2
2.1.7 Antibody, monoclonal and polyclonal…………………………………………………………………………………………. 2
2.1.8 Hormone…………………………………………………………………………………………………………………………………….. 2
2.1.9 Enzyme……………………………………………………………………………………………………………………………………….. 3
2.1.10 Cytokine……………………………………………………………………………………………………………………………………. 3
2.1.11 Immunoglobulin……………………………………………………………………………………………………………………….. 3
2.1.12 Recombinant product……………………………………………………………………………………………………………….. 3
2.1.13 Cell therapy product…………………………………………………………………………………………………………………. 3
2.1.14 Gene therapy product………………………………………………………………………………………………………………. 3
3. MAIN CHARACHTERISTICS FOR BIOLOGICAL PRODUCTS…………………………………………………………….. 4
3.1 Biological activity……………………………………………………………………………………………………………………………. 4
3.1.1 Immunochemical properties……………………………………………………………………………………………………….. 4
3.2 Purity, Impurities and contaminants………………………………………………………………………………………………. 5
3.3 Quantity…………………………………………………………………………………………………………………………………………. 6
3.4 Other Product Characteristics………………………………………………………………………………………………………... 6
4. BIOLOGICAL PRODUCTS ELIGIBLE FOR REVIEWING IN BIOLOGIC DIVISION…………………………………... 6
4.1 Biological product eligible for reviewing in biologic division…………………………………………………………….. 6
5. REFRENCES……………………………………………………………………………………………………………………………………. 7
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1. INTRODUCTION
1.1 Objective
This guideline provides definitions of biotechnological and biological products and general principles on the setting and justification, to
the extent possible, of a uniform set of national specifications for new in use biotechnological and biological products to
support marketing applications by local and foreigner manufacturers.
1.2 Background
Biotechnological and biological products have been defined legally in drug act by Undersecretary of adopted by Biological Division and
based on these definitions and National Regulatory Authority decision; a product can be reviewed by biologic division or other part of
Undersecretary of Food and Drug Affair. Biologic products must have been special characteristics which specifies by a list of tests,
references to analytical procedures, and appropriate criteria which will be mentioned briefly in this guideline and with more detail in
Quality, Safety and Efficacy guidelines.
1.3 Scope
The definitions adopted in this document apply to biotechnological and biological products applicable in Islamic Republic of Iran such
as protein and polypeptides, their derivatives, and products of which they are components (e.g., conjugates) are produced from
recombinant or nonrecombinant cell-culture expression systems and or isolated from tissues and body fluids, synthetic peptides and
polypeptides, heparins, cell metabolites, DNA products, allergenic extracts, conventional vaccines, cells, whole blood, and cellular
blood components.
2. DEFINITIONS OF BIOTECHNOLOGICALS AND BIOLOGICAL PRODUCTS
2.1Biological products
National regulatory authority defines biotechnological and biological products as a term “biological products”. A biologic product is
defined as: “a therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product or analogous
product, monoclonal antibody, hormone, enzyme, cytokine, immunoglobulin, recombinant product, and cell and gene therapy
product, applicable to the prevention, treatment, or cure of a disease or condition of human being”.
2.1.1 Therapeutic serum
Therapeutic serum is the clear portion of any body fluid which has very different types with special therapeutic uses such as
anticompelementary serum antilymphocyte serum, antipnemococcus serum, antitetanic serum, blood serum and etc.
2.1.2Toxin
The term toxin generally refers to toxic substances which are produced naturally. Some of medicines are originally toxin. Botulinum
toxin is typical.
2.1.3 Antitoxin
A purified antiserum from animals immunized by injections of a toxin or toxoid, administered as a passive immunizing agent to
neutralize a specific toxin or toxoid such as Clostridium antitoxin, Diphtheria antitoxin, Botulinum antitoxin, tetanus antitoxin.
2.1.4 Vaccine
A suspension of attenuated or killed microorganisms (bacteria, viruses, or rickettsiae), or of antigenic proteins derived from them,
administrated for the prevention, amelioration, or treatment of infectious disease such as Anthrax vaccine, BCG vaccine and Hepatitis
vaccine.
2.1.5 Blood, Blood component and derivate
Blood is the fluid that circulates through the heart, arteries, capillaries and veins carrying nutrient and oxygen to the body cells.
Basically it consists of the plasma, a pale yellow liquid containing the microscopically visible formed elements of the blood: the
erythrocytes, the leukocytes and the platelets.
Any product is prepared from blood is a blood products. Blood products are consisted of: Whole blood; Components of blood such as
concentrated red blood cell, suspension of red blood cell and concentrated platelets; blood and plasma derivatives such as albumin,
immunoglobulin and coagulation factors.
2.1.6 Allergenic product
An antigenic substance capable of producing immediate- type hypersensitivity (allergy). It can be used in immunotherapy. Histamine
is the most typical allergenic product.
2.1.7 Antibody, monoclonal and polyclonal
An immunoglobulin molecule that has a specific amino acid sequence by virtue of which it interacts only with the antigen that induced
its synthesis in cells of the lymphoid series or with antigen closely related to it.
Antibodies that are produced by immortalized cell lines (hybridomas) derived from single B cells are referred to as monoclonal
antibodies. LymphoCide, Alemtuzumab, Vitaxin, Bevacizumab and Abciximab are some examples of monoclonal antibodies use as
drugs.
Antibodies that are produced in immunized animals are formed from many different clones of B lymphocytes; hence, the name
polyclonal antibodies.
Amphiregulin, Anti- Human BAFF and Amylase, Alpha- Concentrated are some of examples of polyclonal Antibodies use as drugs.
2.1.8 Hormone
A chemical substance produced in the body by an organ, cells of an organ, or scattered cells, having a specific regulatory effect on
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the activity of an organ or organs. The term was originally applied to substances secreted by endocrine glands and transported in the
bloodstream to distant target organs, but later it was applied to various substances having similar actions. Gonadotropic, corticotropic
and hypolthalamic hormones are some of typical hormones.
2.1.9 Enzyme
A protein molecule that catalyzes chemical reactions of other substances without itself being destroyed or altered upon completion of
the reactions.
L- asparaginase is an example of enzyme drug.
2.1.10 Cytokine
A generic term for nonantibody protein released by one cell population (e.g primed T lymphocytes) on contact with the specific
antigen, which act as intercellular mediators, as in the generation of an immune response. Cytokine includes lymphokines and
monokines. Some interleukins are examples of cytokines use as drugs.
2.1.11 Immunoglobulin
Any of the structurally related glycoproteins that function as antibodies, derived into five classes (IgM, IgG, IgA, IgD, and IgE) on the
basis of structure and biologic activity. As an example, IVIG is typical.
2.1.12 Recombinant product
Recombinant product are protein that are produced by recombining the genetic material of two different organisms (hence the term
recombinant). A number of medications and vaccines contain recombinant proteins such as Insulin, Interferon, and Hepatitis B
vaccine.
2.1.13 Cell therapy product
Cell therapy products are products with live cells that replace, augment, or modify the function of a patient’s cells that are diseased,
dysfunctional, or missing. Transplantation of bone marrow to replace marrow that has been destroyed by chemotherapy and radiation
is an example of a cell- therapy product. These products are also referred to as somatic cell therapy products because nongerm- line
cells are used in the product. In addition, cells may be combined with biomematerials. For example, dermal or epidermal cells can be
grown on a collagen substrate to produce a sheet of cells for wound and burn therapy. Other examples of cell therapy products are
cells secreting endorphins or catecholamines (encapsulated in a hollow fiber) and encapsulated β- islet cells secreting insulin in
response to glucose levels.
2.1.14 Gene therapy product
Gene therapy products are products in which nucleic acids are used to modify the genetic materials of cells. These nucleic acids are
usually delivered by viral vectors. A retroviral vector used to deliver the gene for factor IX to cells of patients with hemophilia B is an
example of a gene therapy products. Another example is growth factor vector on a biocompatible scaffold for cardiovascular disease
(this product promotes formation of new blood vessels.
3. MAIN CHARECHTERISTICS FOR BIOLOGICAL PRODUCTS
3.1 Biological activity
Assessment of the biological properties constitutes an equally essential step in establishing a complete characterization profile. An
important property is the biological activity that describes the specific ability or capacity of a product to achieve a defined biological
effect.
A valid biological assay to measure the biological activity should be provided by the manufacturer. Examples of procedures used to
measure biological activity include:
•Animal – based biological assays, which measure an organism’s biological response to the product;
•Cell culture- based biological assays, which measure biochemical or physiological response at the cellular level;
•Biochemical assays, which measure biological activities such as enzymatic reaction rates or biological responses induced by
immunological interactions.
Other procedures such as ligand and receptor binding assays may be acceptable. Potency (usually expressed in units) is the
quantitative measure of biological activity based on the attribute of the product which is linked to the relevant biological properties,
whereas, quantity (usually expressed in mass) is a physiochemical measure of active substance content. Potency is the specific ability
of capacity of a product to achieve its intended effect. It is based on the measurement of some attribute of the product and is
determined by a suitable quantitative method. In general, potencies of biotechnological/ biological products tested by different
laboratories can be compared in a meaningful way only if expressed in relation to that of an appropriate reference material. For that
purpose, a reference material calibrated directly or indirectly against the corresponding national or international reference material
should be included in the assay. In some case, in vitro tests for biological activity and physiochemical characterizations are impractical
or provide inaccurate results. Appropriate strategies (e.g. testing the product prior to conjugation/ binding, assessing the release of
the active compound from the second moiety, in vivo assays) or the use of an appropriate surrogate test should be considered to
overcome the inadequacies of in vitro testing. In some cases, a biological assay, with wider confidence limits, may be acceptable
when combined with a specific quantitative measure. Importantly, a biological assay to measure the biological activity of proteins may
be replaced by physiochemical tests only in those instances where:
•Sufficient physiochemical information about the drug, including higher order structure, can be thoroughly established by such
physiochemical methods, and relevant correlation to biological activity demonstrated; and
•there exists a well- established manufacturing history.
Where physiochemical tests alone are used to quantities the biological activity (based on appropriate correlation), results should be
expressed in mass.
3.1.1 Immunochemical properties
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When an antibody is the desired product, its immunological properties should be fully characterized. Binding assays of the antibody to
purified antigens and defined regions of antigens should be performed, as feasible, to determine affinity, avidity and immunoreactivity
(including cross- reactivity). In addition the target molecule bearing the relevant epitope should be biochemically defined and the
epitope itself defined, when feasible.
For some drug substances or drug products, the protein molecule may need to be examined using immunochemical procedures (e.g.
ELISA, Western – blot) utilizing antibodies which recognize different epitopes of the protein molecule. Immunochemical properties of
a protein may serve to establish its identity, homogeneity or purity, or serve to quantify it. If immunochemical properties constitute
lot release criteria, all relevant information pertaining to the antibody should be made available.
3.2 Purity, impurities and contaminants
•Purity
Historically, the relative purity of a biological product has been expressed in terms of specific activity (units of biological activity per
mg of product). Due to the effect of glycosylation, dilapidation, or other heterogeities, the absolute purity of a biotechnological/
biological product is extremely difficult to determine. Thus, the purity of a biotechnological/ biological product should be typically
assessed by more than one method and the purity value derived is method- dependent. In other word, the purity of the drug
substance and drug product is assessed by a combination of analytical procedures.
Individual and/ or collective acceptance criteria for product- related substances should be set, as appropriate. For the purpose of lot
release, an appropriate subset of methods should be selected and justified for determination of purity.
•Impurities
In addition to evaluating the purity of the drug substance and drug product, which may be composed of the desired product and
multiple product- related substances, the manufacturer should also assess impurities which may be present. Impurities may be either
processor product- related. They can be of known structure, partially characterized, or unidentified. When adequate quantities of
impurities can be generated, these materials should be characterized to the extent possible and, where possible, their biological
activity should be evaluated.
Process- related impurities encompass those that are derived from the manufacturing process, i.e. cell substrates (e.g. host cell
protein, host cell DNA), cell culture, or downstream processing.
Product- related impurities are molecular variants arising during manufacture and/ or storage, which do not have properties
comparable to those of the desired product with respect to activity, efficacy, and safety.
Further, the acceptance criteria for impurities should be based on data obtained from lots used in acceptance criteria for impurities
(product- related and process- related) should be set, as appropriate.
New analytical technology and modifications to existing technology are continually being developed and should be utilized when
appropriate.
•Contaminants
Contaminant in a product include all adventitiously introduced materials not intended to be part of the manufacturing process, such
as chemical and biochemical materials (e.g. microbial proteases), and /or microbial species. Contaminant should be strictly avoided
and/ or suitably controlled.
For the special case of adventitious viral or mycoplasma contamination, the concept of action limits is not applicable, and the
strategies proposed in quality Used for Production of Biotechnological/ Bio logical Products should be considered.
3.3 Quantity
Quantity is critical for a biotechnological assay, usually physiochemical in nature. In some cases, it may be demonstrated that the
quantity values obtained may be directly related to those found using the biological assay.
When this correlation exists, it may be appropriate to use measurement of quantity rather than the measurement of biological activity
in manufacturing processes such as filling.
3.4 Other Product Characteristics
The following product characteristics, though not specifically relating to biotechnological/ biological products, should be mentioned
and reported for the drug product in its final container: 1) Visual appearance of the product (color and opacity for solution/
suspensions; color, texture and dissolution time for powders), visible particulars in solution or after the reconstitution of powders or
lyophilized cakes, pH, and moisture level of powders and lyophilized products. 2) Sterility testing or alternatives (e.g. container/
closure integrity testing) should be performed at a minimum initially and at the end of the proposed shelf- life. 3) Additives (e.g.
stabilizer. Preservatives) or excipients may degrade during the dating period of the drug product. If there is any indication during
preliminary stability studies that reaction or degradation of such materials adversely affects the quality of the drug product, these
items may need to be monitored during the stability program. 40 The container/ closure has the potential to adversely affect the
product and should be carefully evaluated (see below).
4. BIOLOGICAL PRODUCTS ELIGIBLE FOR REVIWING IN BIOLOGIC DIVISION.
4.1 Biologic product eligible for reviewing in biologic division
He NRA has different division and biologic division is responsible for reviewing of eligible biologic products. For the purpose of the
marketing authorization procedure, a biological medicinal product should be in one of following categories:
1) Recombinant DNA product
2) Vaccines (all types)
3) Blood derivatives
Recombinant DNA technology essentially involves the cutting and rejoining of the host genome with an exogenous gene sequence,
which contains the genetic information required to produce the desired protein under certain conditions. As a result, the category of
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recombinant proteins, but also gene- based therapeutics and prophylactics such as gene transfer medicinal products and DNA
vaccines. Whole blood, plasma and blood components are responsibilities of Iran Blood Transfusion Organization (IBTO). The other
items have been mentioned in biological product definition are reviewing in other divisions of NRA. This classification is current issue
of NRA and it can be changed in special cases or in future.
5. REFRENCES
1) USP NF 2004
2) Anderson, M; 2005. Dorland’s illustrated medical dictionary.
3) Plotkin, S.A.; Orenstein, W.A; 2005. Vaccines (third edition)
4) Q6B: ICH HARMONISED TRIPARTITEGUIDLINE SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR
BIOTECHNOLOGICAL/ BIOLOGICAL PRODUCTS
5) Tsang, L.; Beers, D.; LLP, A. &p.: 2005. Follow- on biological products: the regulatory minefield
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