Docsity
Log inSign up
Docsity
Prepare for your exams
Prepare for your exams

Study with the several resources on Docsity

Earn points to download
Earn points to download

Earn points by helping other students or get them with a premium plan

Guidelines and tips
Guidelines and tips
Sell on Docsity
Sell on Docsity
Log inSign up

Prepare for your exams

Study with the several resources on Docsity

Find documents

Prepare for your exams with the study notes shared by other students like you on Docsity

Search Store documents

The best documents sold by students who completed their studies

Search through all study resources
Docsity AINEW

Summarize your documents, ask them questions, convert them into quizzes and concept maps

Explore questions

Clear up your doubts by reading the answers to questions asked by your fellow students

Earn points to download

Earn points by helping other students or get them with a premium plan

Share documents
download point icon20 Points

For each uploaded document

Answer questions
download point icon5 Points

For each given answer (max 1 per day)

All the ways to get free points
Get points immediately

Choose a premium plan with all the points you need

Study Opportunities

Choose your next study program

Get in touch with the best universities in the world. Search through thousands of universities and official partners

Community

Ask the community

Ask the community for help and clear up your study doubts

University Rankings

Discover the best universities in your country according to Docsity users

Free resources

Our save-the-student-ebooks!

Download our free guides on studying techniques, anxiety management strategies, and thesis advice from Docsity tutors

From our blog

Exams and Study
Go to the blog

Guidelines for Development, Manufacturing, & Regulation of Biologics and Biosimilar- india, Study notes of Pharmacy

Marwadi UniversityPharmacy

Title: Guidelines for Development, Manufacturing, and Regulation of Biologics and Biosimilars in India Subject Area: Pharmaceutical Sciences / Biotechnology / Regulatory Affairs Year of Publication: 2024 (assumed recent unless specified otherwise) Course/Module: Pharmacology / Pharmaceutical Biotechnology / Regulatory Guidelines for Biologics (suitable for B.Pharm, M.Pharm, M.Sc. Biotechnology, or Regulatory Affairs specialization) Unit 1: Biologics and Biosimilars – India This document provides a comprehensive guide to the regulatory framework, scientific principles, and procedural requirements related to biologics and biosimilars in the Indian context. It aligns with guidelines issued by CDSCO and other international standards (ICH, EMA, WHO).

Typology: Study notes

2024/2025

Available from 04/13/2025

heli-patel-6
heli-patel-6 🇮🇳

5 documents

1 / 15

Toggle sidebar

This page cannot be seen from the preview

Don't miss anything!

bg1
Unit: 1 Biologics and Biosimilars- India
➢ Principles for development of similar biologics
1. Selection of Reference Biologics:
The Reference Biologic has to be used in all the comparability exercises with respect to
quality, preclinical and clinical considerations. The following factors should be considered
for selection of the Reference Biologic:
• The Reference Biologic should be licensed / approved in India or ICH countries and should
be the innovator's product. The Reference Biologic should be licensed based on a full
safety, efficacy and quality data. Therefore another Similar Biologic cannot be considered
as a choice for Reference Biologic.
• In case the Reference Biologic is not marketed in India, the Reference Biologic should
have been licensed in any ICH countries. The Reference Biologic product can be imported
for developing the Similar Biologic for quality, pre-clinical and clinical comparability.
• The same Reference Biologic should be used throughout the studies supporting the safety,
efficacy and quality of the product (i.e. in the development Programme for the Similar
Biologic).
• The dosage form, strength and route of administration of the Similar Biologic should be
the same as that of the Reference Biologic.
• The active drug substance (active ingredient) of the reference biologic and that of Similar
Biologic must shown to be similar.
• The acceptance of an innovator product as a Reference Biologic for evaluation of Similar
Biologic does not imply approval for its use in India.
2. Manufacturing Process:
The manufacturing process for Similar Biologics should be validated and demonstrated to
be highly consistent and robust.
If the host cell line used for the production of Reference Biologic is disclosed, it is desired
to use the same host cell line for manufacturing Similar Biologics. Alternatively any cell
line that is adequately characterized and appropriate for intended use can be used to develop
a Similar Biologic, with appropriate justification in order to minimize the potential for
significant changes in quality attributes (QAs) of the product and to avoid introduction of
pf3
pf4
pf5
pf8
pf9
pfa
pfd
pfe
pff

Partial preview of the text

Download Guidelines for Development, Manufacturing, & Regulation of Biologics and Biosimilar- india and more Study notes Pharmacy in PDF only on Docsity!

Unit: 1 Biologics and Biosimilars- India

➢ Principles for development of similar biologics

  1. Selection of Reference Biologics: The Reference Biologic has to be used in all the comparability exercises with respect to quality, preclinical and clinical considerations. The following factors should be considered for selection of the Reference Biologic:
  • The Reference Biologic should be licensed / approved in India or ICH countries and should be the innovator's product. The Reference Biologic should be licensed based on a full safety, efficacy and quality data. Therefore another Similar Biologic cannot be considered as a choice for Reference Biologic.
  • In case the Reference Biologic is not marketed in India, the Reference Biologic should have been licensed in any ICH countries. The Reference Biologic product can be imported for developing the Similar Biologic for quality, pre-clinical and clinical comparability.
  • The same Reference Biologic should be used throughout the studies supporting the safety, efficacy and quality of the product (i.e. in the development Programme for the Similar Biologic).
  • The dosage form, strength and route of administration of the Similar Biologic should be the same as that of the Reference Biologic.
  • The active drug substance (active ingredient) of the reference biologic and that of Similar Biologic must shown to be similar.
  • The acceptance of an innovator product as a Reference Biologic for evaluation of Similar Biologic does not imply approval for its use in India.
  1. Manufacturing Process: The manufacturing process for Similar Biologics should be validated and demonstrated to be highly consistent and robust. If the host cell line used for the production of Reference Biologic is disclosed, it is desired to use the same host cell line for manufacturing Similar Biologics. Alternatively any cell line that is adequately characterized and appropriate for intended use can be used to develop a Similar Biologic, with appropriate justification in order to minimize the potential for significant changes in quality attributes (QAs) of the product and to avoid introduction of

certain types of process related impurities that could impact clinical outcomes and immunogenicity. 2.1 Molecular Biology Considerations The details regarding host cell cultures (including viral clearance), vectors, gene sequences, promoters etc. used in the production of Similar Biologics should be provided with appropriate drawings/figures. The detail of post-translational modifications (glycosylation, oxidation, deamidation, phosphorylation etc.), if any should be explained.

  1. Upstream Process Development
    • Upstream process should be described in detail including media components used for cell growth.
    • At least three batches of reproducible fermentation data at pilot scale (batch size adequate to give enough purified product to generate preclinical data).
    • Upstream process should be well controlled and monitored.
    • Details of upstream process kinetics data from consistency batches indicating cell growth, product formation, pH, temperature, dissolved oxygen, major nutrient consumption pattern and agitation rate.
    • Concentration to be defined in terms of product/litre, yield and volumetric productivity.
    • Data to verify that the specific protein yield (amount of protein per unit cell mass) remains constant for all upstream batches.
    • Demonstrate that the overall productivity is reproducible and scalable. 2.3. Downstream Process Development
  • Detail description of the methods followed for the cell harvesting and extraction of the protein.
  • Steps involved in purification of protein.
  • Batch size for protein purification.
  • Description of each unit operation step during purification and recovery of protein along with quantitative recovery of product at each stage.
  • Describe the quality of the refolded protein if the starting material is aggregated or from inclusion bodies and include details of the refolding process, specific activity at different doses, dose response curve, stability data and confirmation of solubility and absence of aggregation.

drug substance and the product along with other significant physicochemical properties. The target amino acid sequence of the Similar Biologic should be confirmed and is expected to be the same as for the Reference Biologic. Analytical methods that are used should have acceptable precision and accuracy. In case any significant differences are found, these should be scientifically justified and critically examined in preclinical studies and clinical trials. ii. Biological Activity: Biological products may have multiple biological activities. Biological assays should be validated against an international or national Reference standard, where available and appropriate. If no such standards are available, an internal Reference standard must be established as per the ICH guidelines. If the methods of bioassay(s) are documented in the specification, test(s) can be conducted accordingly. iii. Immunological Properties: The manufacturing process of Similar Biologics is known to affect the level of process related impurities and post translational modifications of the product. These characteristics may affect the immunogenicity of the product. iv. Purity and Impurities: Characterization of a Similar Biologic requires evaluation of the following via a combination of analytical procedures:

  • Product related variants (e.g., glycoforms, isomers etc.)
  • Product related impurities (e.g., aggregated, oxidized or deamidated product)
  • Host cell related impurities (e.g., host cell protein, host cell DNA etc.)
  • Process related impurities (residual media components, resin leachates etc.) 3.3 Specifications Specifications of Similar Biologics are established around quality attributes (QAs) with the intent of ensuring consistency in product quality and comparability to Reference Biologic. Methods used for setting specifications may or may not be the same as the analytical methods used for product characterization. Acceptance limits should be set based on Reference Biologic data. 3.4. Stability The shelf-life and storage condition of drug substance and drug product should be assigned based on real-time stability studies.

Stability studies on drug substance and drug product should be carried out using containers and conditions that are representative of the actual storage containers and conditions.

  1. Quality Comparability Study The quality comparison between Similar Biologic and Reference Biologic is essential. The applicant should submit a full quality dossier as per CDSCO guidance for industry. First three consecutive standardized batches which have been used to demonstrate consistency of the manufacturing process should be used. characterization studies are required to compare the Similar Biologic and the Reference Biologic at active drug product level. It is required to assure that the molecular structure of active drug substance present in the Similar Biologic is comparable to active drug substance present in Reference Biologic. Quality Attributes of a Similar Biologic may be considered in two categories; Critical Quality Attributes (CQA) and Key Quality Attributes (KQA):
    1. Critical Quality Attributes (CQA) are those Quality Attributes which have direct impact on the clinical safety or efficacy. All attributes that directly impact the known mechanism(s) of action of the molecule fall in this category.
    2. Key Quality Attributes (KQA) are those Quality Attributes which are not known to impact clinical safety and efficacy but are considered relevant from a product and process consistency perspective. Attributes that do not impact the known mechanism(s) of action of the molecule fall in this category.

➢ Data Requirements for Pre-clinical studies

  1. Prerequisite before Conducting Preclinical Studies: The applicant has to comply with the RCGM requirements. The applicant should submit the data generated along with the following basic clinical information and preclinical study protocols to RCGM for obtaining permission. The basic information about the Reference Biologic and Similar Biologic may include the following: Basic information about the Reference Biologic - Information about the drug, route of administration, absorption and elimination rate, therapeutic index, dose, vehicle, mode of administration, dose response etc.

ii. In vivo studies: In vivo evaluation of Biological/ pharmacodynamic activity may be dispensable if in vitro assays are available, In cases where the in-vitro assays do not reflect the pharmacodynamics, In vivo studies should be performed, as applicable. Toxicological Studies: In case of in vivo toxicity studies, at least one repeat dose toxicity study in a pharmacologically relevant species is required to be conducted with an intended route of administration. Regarding the animal models to be used, the applicant should provide the scientific justification for the choice of animal model(s). toxicity studies need to be undertaken either in rodent or non- rodent species as per requirements of Schedule Y. The duration of the study would be generally not less than 28 days with 14 days recovery period. However the duration may vary depending on the dosage and other parameters on case by case basis. The protocols and the study reports should provide complete details of various steps in the toxicity testing as indicated below:

  • Procedures prior to euthanasia e.g. blood drawing, body weight, etc.
  • Events immediately after euthanasia, necropsy, gross – description, organ weights and organs sampled for histopathology.
  • Biochemical parameters – Equipment and methods used - units of measurement and expression.
  • Haematology procedures and parameters – method to be used (automated or manual).
  • Statistical methods used.
  • Bone marrow either examined as an aspirate /smear or on histopathology section. In case of histopathological observations, the applicants should consider the following points:
  • Every observation considered as deviation from described normal histology needs to be documented and the incidence of each of these in the different groups should be denoted.
  • Whether such a feature is significant or not can be decided on review of statistical significance or dose response or if it is within or outside the normal range of values in case of biochemical and haematological observations.
  • If all organs from all animals were not examined e.g. in 5 animals only 4 livers were examined, the reason for the 1 liver not being examined should be documented.
  • In case of premature death or morbidity the proposed course of action is to be included in the protocol. The final report of the study should reflect all the aspects approved in the protocol and the following additional sections/documents:
  • RCGM approval of protocol and test center
  • IBSC approval of report
  • IAEC approval for animal use and for the procedures
  • QA statement
  • Signatures of study director and all investigators who were involved in the study
  • All quality analytical reports on the test material and vehicle
  • Animal feed and animal health certifications. Protocol deviations if any
  • Discussion on the results.
  • Individual animal data, summary data and any other data like computer analysis outputs etc.
  • Conclusion.
  1. Immune Responses in Animals Antibody response to the Similar Biologic should be compared to that generated by the reference Biologic in suitable animal model. For evaluating immune toxicity of the Similar Biologic under study, the results of local tolerance (part of repeat dose or standalone test) should be analyzed with the observations regarding immunogenicity in sub-chronic study.

➢ Data Requirement for clinical Trial Application

The information submitted in the preclinical application, the applicant has to submit application for conduct of clinical trial. The quality data submitted should indicate that there are no differences in Critical Quality Attributes (CQAs), and that all Key Quality Attributes (KQAs) are well controlled in order to allow the initiation of clinical evaluation.

  1. PK Studies

PD studies may be combined with PK studies, in which case the PK/PD relationship should be characterized. If PD marker is not available and the PK can be done in patients then the PK study can be combined with phase III clinical study. The PD study can also be a part of Phase III clinical trials wherever applicable.

  1. Confirmatory Safety and Efficacy Study Information to establish comparative safety and efficacy in relevant patient population is mandatory for all Similar Biologics. Comparative clinical trials are critical to demonstrate the similarity in safety and efficacy profiles between the Similar Biologic and Reference Biologic with few exceptions. The study should be conducted in a sensitive and homogenous patient population with appropriate sensitive primary end points as per requirement of a Phase III clinical trial. 3.1 Waiver of safety and efficacy study The confirmatory clinical safety and efficacy study can be waived if all the below mentioned conditions are met: i. Structural and functional comparability of Similar Biologic and Reference Biologic can be characterized to a high degree of confidence by physicochemical and in vitro techniques. ii. The Similar Biologic is comparable to Reference Biologic in all preclinical evaluations conducted. iii. PK / PD study has demonstrated comparability of PD markers validated for clinical outcome and has preferentially been done in an in-patient setting with safety measurement (including meaningful immunogenicity assessment) for adequate period justified by the applicant and efficacy/PD measurements. iv. A comprehensive post-marketing risk management plan has been presented that will gather additional safety data with a specific emphasis on gathering immunogenicity data. The confirmatory clinical safety and efficacy study cannot be waived if there is no reliable PD marker validated for clinical outcome.
    1. Safety and Immunogenicity Data
    2. Extrapolation of Efficacy and Safety Data to Other Indications

Post-Market Data for Similar Biologics

It is important to establish a formal Risk Management Plan to monitor and detect both known inherent safety concerns and potential unknown safety signals that may arise from the Similar Biologic since authorization is based on a reduced preclinical and clinical data package. The risk management plan should consist of the following: 10.1 Pharmacovigilance Plan The clinical studies done on Similar Biologics prior to market authorization are limited in nature so the rare adverse events are unlikely to be encountered. Hence comprehensive pharmacovigilance plan should be prepared by manufacturer to further evaluate the clinical safety in all the approved indications in the post marketing phase. The pharmacovigilance plan should include the submission of periodic safety update reports (PSURs). The PSURs shall be submitted every six months for the first two years after approval of the Similar Biologic is granted to the applicant. For subsequent two years the PSURs need to be submitted annually to DCGI office as per the Schedule Y. 10.2 Adverse Drug Reaction (ADR) Reporting All cases involving serious unexpected adverse reactions must be reported to the licensing authority as per Schedule Y. 10.3 Post Marketing Studies (Phase IV Study) Finally, in order to further reduce the residual risk of the Similar Biologics, additional safety data may need to be collected after market approval through a pre-defined single arm study of generally, more than 200 evaluable patients and compared to historical data of the Reference Biologic. The study should be completed preferably within 2 years of the marketing permission / manufacturing license unless otherwise justified. The primary aim of the post marketing phase IV study is safety and hence following parameters should be considered for the post marketing phase IV study protocol:

  • Primary endpoint: Safety
  • Secondary endpoint: Efficacy and Immunogenicity The phase IV protocol should be submitted along with marketing authorization application for approval. The clinical studies done on Similar Biologics prior to market authorization are limited in nature so post marketing studies should be conducted and the reports be submitted to

➢ Why Need to Regulate Herbal Products

1. Safety - Toxicity and Side Effects : Herbal products can contain substances that are toxic or cause adverse reactions. Without regulation, harmful products could reach consumers. - Interactions with Medications : Many herbs can interact with prescription and over-the- counter medications, leading to reduced efficacy or harmful side effects. 2. Efficacy - Health Claims : Unregulated products may make unverified health claims, misleading consumers about their effectiveness. - Evidence-Based Use : Regulation ensures that products are supported by scientific evidence regarding their benefits and appropriate usage. 3. Quality Control - Consistency and Purity : Regulations ensure that products contain the ingredients in the amounts stated on the label, and are free from contaminants like heavy metals, pesticides, or microorganisms. - Manufacturing Standards : Good manufacturing practices (GMP) must be followed to maintain product quality and consistency. 4. Consumer Protection - Misleading Information : Regulation helps prevent false advertising and misleading labels, ensuring consumers receive accurate information. - Recalls and Accountability : Regulatory bodies can recall harmful or defective products and hold manufacturers accountable. 5. Public Health - Preventing Public Health Crises : By ensuring safety and efficacy, regulations help prevent public health crises caused by unsafe or ineffective herbal products. - Educating Consumers : Regulatory frameworks often include educational efforts to inform the public about safe and effective use of herbal products. 6. Market Integrity - Fair Competition : Regulations help create a level playing field where companies compete based on product quality and efficacy, rather than deceptive practices. - Consumer Trust : A regulated market builds trust among consumers, knowing that the products they use meet certain standards. 7. International Trade

  • Harmonization of Standards : Regulations align with international standards, facilitating trade and ensuring products meet the safety requirements of various countries. Overall, regulation of herbal products is essential to protect public health, ensure product quality, and maintain consumer confidence in the market.

➢ Which Countries Regulates

1. United States

  • Regulatory Body : Food and Drug Administration (FDA)
  • Regulations : Herbal products are regulated under the Dietary Supplement Health and Education Act (DSHEA) of 1994. They are considered dietary supplements and must meet specific labeling requirements, but do not require pre-market approval.

2. European Union

  • Regulatory Body : European Medicines Agency (EMA)
  • Regulations : The Traditional Herbal Medicinal Products Directive (THMPD) 2004/24/EC governs the sale of herbal products. Products must be registered and proven to be safe based on traditional use over at least 30 years, including 15 years within the EU.

3. Canada

  • Regulatory Body : Health Canada
  • Regulations : Herbal products are regulated under the Natural Health Products Regulations. They must be licensed before being sold, requiring evidence of safety, efficacy, and quality.

4. Australia

  • Regulatory Body : Therapeutic Goods Administration (TGA)
  • Regulations : Herbal products are categorized as complementary medicines and must be listed or registered with the TGA. Listed products must meet safety and quality standards, while registered products require evidence of efficacy.

5. China

  • Regulatory Body : National Medical Products Administration (NMPA)
  • Regulations : Traditional Chinese Medicine (TCM) products are regulated similarly to pharmaceutical products, requiring rigorous testing for safety and efficacy.

6. India