The document discusses regulations regarding stability, safety, and advertising of biologicals in the European Union. It provides details on stability testing requirements, including selecting representative batches, defining a stability-indicating profile, and testing frequencies. Safety aspects addressed include risk management plans, post-marketing studies, adverse event reporting, and additional monitoring. Advertising laws aim to prevent misleading promotions and define such advertising as likely to deceive or affect economic behavior.

1. Department of Pharmaceutical Sciences,
Maharshi Dayanand University
Presented By…
Garima Saini
M.Pharm. (SEM-II)
Guided By…
Ms. Poonam Yadav
BIOLOGICALS REGULATIONS
EUROPEAN UNION : STABILITY,SAFETY, ADVERTISING

2. STABILITY

3. INTRODUCTION
The products are particularly sensitive to environmental factors such as
temperature changes, oxidation, light, ionic content, and shear. In order to
ensure maintenance of biological activity and to avoid degradation, stringent
conditions for their storage are usually necessary.
Appropriate physicochemical, biochemical and immunochemical methods
for the analysis of the molecular entity and the quantitative detection of
degradation products should also be part of the stability program.

4. SELECTION OF
BATCHES

5. Drug Substance (Bulk Material)
Where bulk material is to be stored after manufacture but prior to formulation
and final manufacturing, stability data should be provided on at least three
batches for which manufacture and storage are representative of the
manufacturing scale of production.
A minimum of six months stability data, in cases where storage periods
greater than six months are requested.
For drug substances with storage periods of less than six months, the minimum
amount of stability data in the initial submission should be determined on a case-
by-case basis.

6. Drug Product (Final Container Product)
Stability information should be provided on at least three batches of final
container product. Derived from different batches of bulk material.
Product expiration dating will be based upon the actual data submitted in
support of the application.
Data from pilot-plant scale batches of drug product may be provided at the
time the dossier is submitted to the regulatory agencies with a commitment
to place the first three manufacturing scale batches into the long-term
stability program after approval.

7. Sample selection criteria
Product is distributed in batches differing in fill volume (e.g., 1 milliliter (ml), 2ml,
or 10 ml), unitage (e.g., 10 units, 20 units, or 50 units), or mass (e.g., 1 milligram
(mg), 2mg, or 5 mg) samples to be entered into the stability program may be
selected on the basis of a matrix system and/or by bracketing.
Matrixing, i.e., the statistical design of a stability study in which different
fractions of samples are tested at different sampling points, should only be
applied when appropriate documentation is provided that confirms that the
stability of the samples tested represents the stability of all samples.
Where the same strength and exact container/closure system is used for three
or more fill contents, the manufacturer may elect to place only the smallest and
largest container size into the stability program, i.e., bracketing.

8. STABILITY-INDICATING PROFILE
On the whole, there is no single stability-indicating assay or parameter that
profiles the stability characteristics of a biotechnological/biological product.
Consequently, the manufacturer should propose a stability-indicating
profile that provides assurance that changes in the identity, purity and
potency of the product will be detected

9. Protocol
Include all necessary information which demonstrates the stability of the
biotechnological/biological product throughout the proposed expiration
dating period.
Potency
potency is the specific ability or capacity of a product to achieve its
intended effect.
Potency studies should be performed at appropriate intervals
potency is dependent upon the conjugation of the active ingredient(s) to a
second moiety or binding to an adjuvant.

10. Purity and Molecular Characterisation
The purity of a biotechnological/biological product should be typically
assessed by more than one method
The use of relevant physicochemical, biochemical and immunochemical
analytical methodologies should permit a comprehensive characterisation of
the drug substance and/or drug product
The accurate detection of degradation changes that may result from
deamidation, oxidation, sulfoxidation, aggregation or fragmentation
during storage.

11. Other Product Characteristics
• Visual appearance of the product
• 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.
• Additives (e.g., stabilisers, preservatives) or excipients may degrade during the
dating period of the drug product
• The container/closure has the potential to adversely affect the product and should
be carefully evaluated.

12. STORAGE CONDITIONS
Temperature
the storage conditions for the real-time/real-temperature stability studies
may be confined to the proposed storage temperature.
Humidity
Biotechnological/biological products are generally distributed in
containers protecting them against humidity.
afford sufficient protection against high and low humidity,
Where humidity-protecting containers are not used, appropriate stability
data should be provided.

13. Accelerated and stress conditions
The expiration dating should be based on real-time/real-temperature data.
Studies under accelerated conditions may provide useful support data for :
• establishing the expiration date,
• assist in validation of analytical methods for the stability program,
• 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.

14. Container/Closure
Changes in the quality of the product may occur due to the interactions
between the formulated biotechnological/biological product and
container/closure.
LABELLING
precisely defined storage temperatures are recommended.
recommendations for protection against light and/or humidity, should
appear on containers, packages, and/or package inserts.

15. TESTING FREQUENCY
shelf-lives may vary from days to several years. (range of 0.5 to 5 years.)
shelf-lives of one year or less, the real-time stability studies should be
conducted monthly for the first three months and at three-month intervals
thereafter.
For products with proposed shelf-lives of greater than one year, the studies
should be conducted every three months during the first year of storage,
every six months during the second year, and annually thereafter.

16. SAFETY

17. General considerations on safety for
biosimilars
Apart from reactions of an immunological nature, most adverse drug reactions
(ADRs) can be predicted from the pharmacological action, and occur with both
the reference medicine and the biosimilar

18. Safety monitoring for biological medicines,
The EU has a well-established system for monitoring, reporting, assessing
and preventing adverse drug reactions for all medicines, including all
biological medicines.
Authorities continuously evaluate the benefit-risk balance of all medicines
and take necessary regulatory action (e.g. introducing new warnings in the
product information or restricting use) to safeguard public health.

19. A plan to manage risks
Companies applying for marketing authorisation in the EU must submit a risk
management plan (RMP).
The RMP, includes a pharmacovigilance plan and risk minimisation measures
to identify, characterise and minimise a medicine’s important risks.
The RMP of a biosimilar is based on knowledge and experience gained with
the reference medicine.

20. Safety studies after marketing
Post-marketing studies allow monitoring of known risks and also permit
detection of rare adverse drug reactions that emerge only when large
numbers of patients have been treated for a long period.

21. Collecting spontaneous adverse drug reactions
and submitting PSURs
Companies marketing biosimilars must collect all reports of suspected adverse
drug reactions and submit periodic safety update reports (PSURs) to
regulators.
Regulatory authorities review reports for any signal suggestive of a possible
unwanted effect. If a signal is suspected, it is evaluated by EMA’s scientific
committees, which will determine if any action is needed.

22. Additional monitoring and black triangle
All new medicines are closely monitored after being introduced to the market.
Biological medicines approved after 1 January 2011 are subject to so-called
‘additional monitoring’ and are included in a list of medicines under ‘additional
monitoring’.
The black triangle symbol identifies medicines under additional monitoring.

23. Traceability: importance of identifying biological
medicines by tradename and batch number
An important requirement for the safety monitoring of all biological medicines
is the need for product and batch traceability during clinical use and at all
levels in the supply chain.
This covers the time from release by the manufacturer and progress through
the entire distribution chain until the medicine is administered to the patient.

24. ADVERTISEMENT

25. European Union -Trade Promotion and Advertising
General Legislation
• Laws against misleading advertisements differ widely from member state to
member state within the EU.
• the Commission adopted a directive, in October 1986, to establish minimum
and objective criteria regarding truth in advertising.(amended in October
1997 )
• Under the Directive, misleading advertising is defined as any "advertising
which in any way, including its presentation, deceives or is likely to deceive
the persons to whom it is addressed or whom it reaches and which, by
reason of its deceptive nature, is likely to affect their economic behavior or
which for those reasons, injures or is likely to injure a competitor."
• Member States can authorize even more extensive protection under their
national laws.

26. REFERENCES
• https://www.ema.europa.eu/en/documents/scientific-guideline/ich-topic-q-
5-c-quality-biotechnological-products-stability-testing-
biotechnological/biological-products_en.pdf
• https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
similar-biological-medicinal-products-containing-biotechnology-derived-
proteins-active_en-2.pdf
• https://www.privacyshield.gov/article?id=European-union-Trade-
Promotion-and-Advertising

27. THANK YOU