The document presents an overview of biologics in the EU, covering their stability, safety, labelling, packaging, and advertising regulations. It emphasizes the importance of stability testing, preclinical and clinical trials for ensuring safety, and distinct regulatory requirements between the EU and the USA. Key differences in advertising strategies and labelling practices are also highlighted, along with essential reference materials.

1. STABILITY, SAFETY, ADVERTISING,
LABELLING & PACKAGING OF
BIOLOGICS IN EU
Presented By:
Tanisha Jain
2308212170005
Guided By:
Dr. Hiral Dave
Associate Professor

2. TABLE OF
CONTENTS:
ABBREVIATIONS
INTRODUCTION
STABILITY OF BIOLOGICS
SAFETY OF BIOLOGICS
LABELLING OF BIOLOGICS
PACKAGING OF BIOLOGICS
COMPARISON OF BIOLOGICS (EU &USA)
REFERENCES
ADVERTISING OF BIOLOGICS
2

3. PK- Pharmacokinetics
PD- Pharmacodynamics
ADME- (Absorption, Distribution, Metabolism, Elimination)
EFD- Embryo Fetal Development
NHP- Non-Human Primates
GCP- Good Clinical Practice
EMA- European Medical Agency
EU- European Union
CTD- Common Technical Document
ABBREVIATIONS:
3

4. INTRODUCTION
BIOLOGICS:
They are medical products. Many biologics are
made from a variety of natural sources (human,
animal or microorganism).Like drugs, some
biologics are intended to treat disease & medical
conditions. Other biologics are used to prevent or
diagnose diseases.
Example – Vaccines, Blood & Blood Products, gene
therapies, cellular therapies.
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5. STABILITY OF BIOLOGICS
 Stability: Ability of a pharmaceutical product to retain
its chemical, physical, microbiological and
biopharmaceutical properties within specified limits
throughout its shelf-life.
• Manufacturers should provide- stability indicating
profile which helps to detect changes in the product.
• Applicants should provide sufficient validated data of
stability and review it properly.
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6. STABILITY OF BIOLOGICS:
Protocol: It includes all the necessary information which
depicts the stability of the biological product also about
the expiration date of the product.
Also describes specifications of the product.
Potency: Ability or capacity of the product to achieve its
intended effect.
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7. STABILITY OF BIOLOGICS
Product’s Characteristics:
• Visual Appearance (colour/opacity of
solutions/suspensions
• PH
• Moisture Levels (powders, lyophilised products)
• Sterility testing of the container closure – to get the
proper shelf life of the product.
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8. STABILITY OF BIOLOGICS:
Storage Conditions:
• Temperature: Most biologics need defined storage
temperatures.
• Humidity: Biologics are distributed in containers
protecting against humidity. Stability data is
mandatory if container are not protecting against
humidity.
• Light: Depends on type of the product.
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9. TYPES OF STABILITY
STUDIES:
1. Long term Testing: Known as Real Time Testing.
performed for longer duration.
Test period depends upon the stability of the product
which is long and can indicate that no degradation occurs.
2. Accelerated Testing: Helps to predict shelf-life or used
to compare stability of alternative formulation.
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10. TYPES OF STABILITY
STUDIES:
3. Intermediate Testing: This test is performed when
accelerated test fails at 25°C for a longer duration.
4. Stress Testing: Helps to identify the degradation of the
product.
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11. STABILITY TESTING
REQUIREMENTS
Sr.No Parameters Drug Substance Drug Product
1. Stress Testing  Temperature: 50°C,
60°C,70°C
 Humidity: 25°C/75%RH &
25°C/90% RH
 Oxidation: Required
according to the condition.
 Photo stability: Should be
carried out on a single
batch.
 Temperature: 50°C, 60°C
for 1 month.
 Humidity: 40°C/75%RH &
25°C/80% RH
 Photo stability should be
carried out.
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12. STABILITY TESTING
REQUIREMENTS
Sr.No Parameters Drug Substance Drug Product
2. Selection of batches Data should be provided
on at least 3 primary
pilot scale batch.
 Data should be provided
on at least 3 primary
batches.
 2 should be at least pilot
scale batches.
3. Container Closure System Stability testing should be
carried out in the same
container closure system
as that proposed for
storage & distribution.
Container closure system for
testing should be same as that
proposed for marketing including
any secondary packaging.
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13. 4. Specification It is the list of tests &
proposed acceptance
criteria which the drug
substance should meet.
It is the list of tests & proposed acceptance
criteria which the drug product should
meet.
5. Testing
Frequency:
 Long Term studies: 0,
3, 6, 9,12,18,24 months
& annually through the
proposed re-test period.
 Accelerated : 0, 3, 6
months
 Intermediate : 0, 6, 9,
12 months
 Long Term studies: 0, 3, 6, 9,12,18,24
months & annually through the proposed
re-test period.
 Accelerated : 0,3,6 months
 Intermediate : 0,6,9,12 months
STABILITY TESTING
REQUIREMENTS
13

14. 6. Storage
Conditions:
a. General Case:
 Long Term- 25°C/60%RH or 30°C/
65%RH
 Intermediate- 30°C/65%RH
 Accelerated -40°C/ 75% RH
a. Freeze condition:
 Long Term- 5°C
 Accelerated Term- 25°C/ 60% RH
a. Freezer: -20°C
Storage condition for general case for the
product intended to be stored in refrigerator &
freezer is same as for drug product.
7. Stability
Commitment
If the data does not cover the proposed
retest period granted at the time of
approval a committed should be made to
continue the stability testing.
If the data does not cover the proposed shelf-
life granted at the time of approval committed
should be made to continue the long term
studies through proposed shelf-life, the
accelerated studies for 6 months.
STABILITY TESTING
REQUIREMENTS
14

15. 8. Evaluation Based on evaluation of data
re-test period should be
established.
Based on evaluation of data shelf- life should
be established.
9. Labelling A storage statement should be
established based on stability
evaluation of drug substance.
A storage statement should be established
based on stability evaluation of drug product.
STABILITY TESTING
REQUIREMENTS
15

16. SAFETY OF BIOLOGICS:
For evaluating safety of biologics preclinical and clinical
studies are done.
A) Preclinical Studies:
It is also known as non-clinical studies. It is conducted
prior clinical trials It contains following of the
parameters.
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17. A) PRECLINICAL STUDIES:
. 1. Study Design
2. Pharmacology Studies
3. Selection of Species
4. Number/Gender of Animals
5. Dose Selection
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18. A) PRECLINICAL STUDIES:
6. Immunogenicity
7. Single Dose Toxicity
8. Immunotoxicity Studies
9. Local Tolerance Studies
10. Reproductive and Developmental
toxicity
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19. A)PRECLINICAL STUDIES:
1. Study Design:
• For conducting any kind of study , study design plays
an important role.
• Helps for easy evaluation and assessment of the
results.
• While designing study , PK-PD approaches should
be considered.
• Clinical Trials should be conducted easily using the
study design.
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20. A) PRECLINICAL STUDIES:
2. Pharmacology Studies:
• Evaluates the biologics potential adverse effects on vital
functions of the body.
• Special assays and biomarkers are used to access safety
concerns of biologics.
• Helps identify potential risk and gives guidance for
selecting a proper dose for clinical trials.
• Pharmacokinetic properties are also evaluated of the
biologics (ADME) data.
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21. A) PRECLINICAL STUDIES:
3. Animal Species/Model Selection:
• Sponsor should select relevant species for preclinical
trials.
• A relevant species is one in which the test material is
pharmacologically active.
• A variety of techniques (e.g., immunochemical or
functional tests) can be used to identify a relevant
species.
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22. A) PRECLINICAL STUDIES:
4. Number/Gender of the animal:
• The number of animal used per dose should have the
ability to detect toxicity.
• Small sample size – failure to observe toxicity.
• Both genders should be used and if not justification
should be provided.
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23. A) PRECLINICAL STUDIES:
5. Dose Selection:
• Dosage levels – To provide information on dose-
response relationship.
• Ideal dosage range for further trials is based on
preclinical evaluation.
• Optimal dose selection is crucial to ensure more
therapeutic efficacy while minimizing potential
adverse events.
• All PK-PD characteristics are also considered.
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24. A) PRECLINICAL STUDIES:
6. Immunogenicity:
• Many biologics intended for human are immunogenic in
animals.
• Evaluations of immunogenicity determine whether a
biologics has a capacity to induce into the immune system
of the species or not (preclinical trial).
• Assessments are done in accordance with regulatory
guidelines.
• Techniques like ELISA, cell based are used for the same.
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25. A) PRECLINICAL STUDIES:
7. Single Dose Toxicity :
• Single dose studies may generate useful data to
describe the relationship of dose to systemic and/or
local toxicity.
• These data can be used to select doses for repeated
dose toxicity studies.
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26. A) PRECLINICAL STUDIES:
8. Immunotoxicity Studies :
• Many biologics are intended to stimulate or supress the
immune system.
• Toxic effects can be caused by formulation vehicle
which may result in the toxic changes at the site of
infection.
• Immunotoxicological Testing strategies are required to
clarify issues.
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27. A) PRECLINICAL STUDIES:
9. Local Tolerance Studies :
• Studies are done to check the local tolerance of the drug.
• Data of single dose and repeated dose can also be used to
evaluate the study.
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28. A) PRECLINICAL STUDIES:
10. Reproductive and Developmental toxicity :
• Provides general advice on reproductive toxicity.
• Fertility Studies
• Embryo- Fetal Developmental Studies (EFD)
• Pre and post natal developmental studies
• Non-human primates studies (NHP)
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29. SAFETY OF BIOLOGICS:
For evaluating safety of biologics preclinical and clinical tests
are done.
B) Clinical Studies:
Biologics need to undergo clinical trials before a marketing
authorization application.
Following are the considerations:
29

30. B) CLINICAL STUDIES:
1. Clinical Trial Authorization
2. GCP and other aspects
3. Study Design Considerations
4. Consultation with EMA
30

31. B) CLINICAL STUDIES:
1. Clinical Trial Authorization:
• Trials begins when:
• Subjects understands the objective and risk of the trial
and give their informed consent.
• The physical and mental integrity of the subjects
should be maintained.
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32. B) CLINICAL STUDIES:
2. GCP and other aspects of trials:
• Clinical trials of biologics must comply with GCP and
the ICH E6.
• Clinical trial information must be handled, recorded
and stored with all the privacy rules.
• Trials must comply ethical principles (benefits & risk
ratio) ensuring safety of subjects.
• Investigators must obtain freely given consent from
every subject before the trial.
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33. B) CLINICAL STUDIES:
3. Study Design Considerations :
• Phase I - involves the initial safety and PK studies.
• Phase II study is a therapeutic exploratory study that
explores efficacy.
• Phase III - involves therapeutic confirmatory studies.
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34. B) CLINICAL STUDIES:
4. Consultation with EMA:
• A sponsor may obtain scientific advice regarding
clinical trial protocols from the EMA
• The agency remarks will only address scientific issues
and will focus on matters such as selection of endpoints,
comparator, duration of treatment or follow-up.
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35. C) MARKETING AUTHORIZATION
APPLICATION:
1. The requirements of EU centralised procedure:
• The approval standards for biotechnology products are
the same as for chemically synthesized medicines.
• Both types of products must be safe and effective and
have appropriate quality.
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36. C) MARKETING AUTHORIZATION
APPLICATION:
2. MAA for biologics must meet the standard dossier
submission requirements:
 MAA must comply with CTD format
• Module 1(Administrative info, including labelling).
• Module 2 (various summaries)
• Module 3 (chemical, pharmaceutical and biological
information)
• Module 4 (non-clinical reports)
• Module 5 (clinical study reports) 36

37. ADVERTISING OF BIOLOGICS:
Advertising of medicinal products shall include any
information which is designed to promote the prescription,
supply, sale or consumption of medicinal products.
• Advertising is done for general public.
• Done for qualified personnel which helps them to
prescribe or supply the product.
• Member States prohibits the product which is not
according to the regulation.
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38. ADVERTISING OF BIOLOGICS:
• All parts of the advertising of a medicinal product must
comply with product’s characteristics.
• Advertising shall encourage the rational use of the
product.
• It should not be misleading.
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39. ADVERTISING OF BIOLOGICS:
 Advertisement which include therapeutic indications
should be prohibited for example disease like:
1. Tuberculosis
2. Sexually Transmitted Diseases
3. Other serious infectious diseases
4. Cancer and other tumoral diseases
5. Chronic Insomnia
6. Diabetes and many others.
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40. LABELLING AND PACKAGING OF
BIOLOGICS:
The following particulars shall appear on the outer packaging
of medicinal products or on immediate packaging.
1. Name of the medicinal product.
2. Type of dosage form, weight, volume and dose of the
product.
3. List of excipients used in the product.
4. Route of Administration
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41. LABELLING AND PACKAGING OF
BIOLOGICS:
5. Special Warnings about the product
6. Expiry date in clear terms (month/year)
7. Special Storage Conditions
8. Special Precautions for disposal of unused or waste
products from the product.
9. Name and address of the Market Holder for placing
product in the market.
10. Manufacturer’s Batch Number
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42. LABELLING AND PACKAGING
OF BIOLOGICS:
11. The price of the medicinal product.
12. Information about contra-indications.
13. Information about interactions that can cause
adverse drug reaction.
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43. LABELLING AND PACKAGING
OF BIOLOGICS:
• Warning against using the product after the expiry date.
• Warning against certain visible signs of deterioration
• The date on which the package leaflet was last revised.
• Package leaflet must be written in clear and understandable
terms for the users and all the regulatory laws should be
followed.
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44. Comparison of Biologics in EU & USA
Information About: EU USA
Advertising Direct to consumer advertising is prohibited. Direct to consumer advertising is
permitted.
EU prioritizes healthcare professionals as the
primary audience for drug promotion.
FDA require advertisements
include fair balance, risks and
benefits, along with specific safety
standard.
Done through conferences, publications and
educational materials
Done through Television, print,
media, social media etc.
44

45. Comparison of Biologics in EU & USA
Information About: EU USA
Labelling EU labelling requirements focus on providing
comprehensive information for healthcare
professionals and patients.
FDA approved labelling for
biologics must adhere to specific
regulations outlined in CFR
Title 21.
EU labels may include information on storage
conditions, shelf-life, specific handling
instructions.
US labels may contain boxed
warnings, medication guides
for patients , administration,
dosage etc.
Packaging Involves product details , strength , dosage form,
storage form along with Patient Information
Leaflet(PIL)
Must comply with CFR 21
including details about product
along with warnings and
storage conditions.
PIL gives information about use of medicine,
side effects, precautions etc.
Packaging involves barcodes for
inventory control, tamper-seal
and other information about
packaging. 45

46. REFERENCES:
1. ICH Topic Q 5 C Quality of Biotechnological Products: Stability Testing of
Biotechnological/Biological Products Step 5 note for guidance on quality of
biotechnolo-gical products: stability testing of biotechnological/biological
products final approval by cpmp december 1995 proposed date for coming into
operation
2. International conference on harmonisation of technical requirements for
registration of pharmaceuticals for human use preclinical safety evaluation of
biotechnology-derived pharmaceuticals s6(r1)
3. Requirements for quality documentation concerning biological investigational
medicinal products in clinical trials - Scientific guideline | European Medicines
Agency
46

47. REFERENCES:
4. Non-clinical guidelines | european medicines agency
5. DIRECTIVE 2001/83/EC OF THE EUROPEAN
PARLIAMENT AND OF THE COUNCIL of 6
novemeber 2001 on the community code relating to
medicinal products for human use.
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