IPhVC recommendations & monitoring requirement of biosimilars, Worldwide & Iraq control of Bioproducts & biosimiliars, as well as references enlisted adverse reactions to common products used in our hospital Lecture presented at the 31st Jan 2024 in our hospital

1. Pharmacovigilance:
Biosimilars & Bioproducts
Alaa Fadhel Hassan
(Specialist pharmacist, MSc. Pharmacology)
Al-Mahmoudiya General Hospital

2. What to monitor?
According to IPhvC instructions
• Any medical event to be diagnosed after administration of
therapy.
• Any medical event caused pt. hospitalization/looking for
health assistance.
• An un-expected change in health state/un-responsiveness to
therapy.
• Significant change in laboratory results with clinical
importance.
• An expected adverse drug reaction (ADRs) to therapy.

3. Wait!
what are the expected ADRs to
biosimilars,
What are biosimilars &
bioproducts already?

4. Entrance to biosimilars & bioproducts
! (
‫عليكم‬ ‫للسالم‬ ‫طأطأ‬ ‫من‬
)
• The term biotechnology refer to any technique that
produce/modify therapies utilizing microorganisms, tissue culture,
living cells, & cell enzymes.
• These products are either proteins/peptide like molecules or
product of recombinant DNA/controlled gene expression, that serve
to diagnose, cure & prevent diseases.
• Such products have unpredictable medical, scientific & regulatory
status, nevertheless efficacy & risks whether expected or real,
thus require careful handling, administration, & patient education
since [quietly sensitive to change in the manufacturing processes &
show highly complex molecular structure].

5. Originator Vs Biosimilar
• The term originator/reference refers to “a single product of the innovating
company (innovator) & approved by regulatory authorities based on a full
complement of safety and effectiveness data” till the expiry of its patent when
similar biological product; aka the biosimilar, can be authorized as an identical
biologic product(s) to the originator.
• Then both originator & biosimilar should be equivalents in their chemical
structure, quality, clinical safety profile & effectiveness but not in their generic
small molecule & immunogenicity, why?!!!
• Check

6. Originator Vs Biosimilar
I. “Biologicals can never be reproduced as identical molecules and the concept
of identity does not apply, At minimum, there are unknown risks between
various lots and active ingredients considered to be the same”.
II. “Some countries/regulators have biosimilar products that were never
compared to a fully developed originator, Indications and uses have been
copied from class indications in benchmarking countries”.
III. “Switching among these products can elicit immune phenomena that were
not foreseen, their clinical safety must be monitored closely on an ongoing
basis during the post-approval phase including continued risk-benefit
assessment, even if the efficacy is shown to be comparable, the biosimilar
product can exhibit a different safety profile in terms of nature, seriousness,
or incidence of adverse reactions”.

7. THE FDA Office of
Biotechnology Products
• It was established in 1989 to serve as a main “coordinating, problem-
solving, and advisory role” contact center within the Office of the
Commissioner for issues related to new biotechnology, their mission is:
• Advise and assist biotechnologic associated scientific issues (policy,
direction, and long-range goals) providing guidance on cross-
cutting/controversial biotechnology programs.
• Representing the FDA worldwide, leading & directing biotechnologic
scientific & regulatory issues.
• Solving problems associated with concerns, questions, or complaints
about biotechnology policies/procedures or product regulation.
• Thus protecting public health via ensuring quality, safety, efficacy,
availability, and security of bioproducts.

8. THE FDA Office of
Biotechnology Products
• Includes the “Division of Therapeutic Proteins” & “the Division
of Monoclonal Antibodies”.
• Furthermore its supported by the Biological Products Facility
Staff in the Center for Drug Evaluation and Research Office of
Compliance.
• Its main activities involve revision of chemistry,
manufacturing, and controls (CMC), facilitating “Prior Approval
Inspections and biannual Good Manufacturing Practices”,
supporting biotechnology policy researches, guidance &
document development besides training .

9. Biosimilars & bioproducts risk
minimization action plan
• The FDA authorised a risk minimization action plan (RiskMAP)
for those products since they targets complex process in the
body, increasing their likelihood to cause ADRs.
“Nearly one-third of boxed warnings for biological
pharmaceuticals between Jan. 1995 and 2007 have been
added within 2 years of the products’ approval by the FDA”.
• Here comes our responsibility to participate in the extensive
ADR monitoring for those product.

10. Steps of risk minimization plan

11. Iraqi bioproducts/biosimilars
management plan
• Iraqi plan involves authorization of product by the Ministry of
Health, Technical Deputy, the Medicines Policy Committee, the
State Company for Marketing Drugs & Medical Appliances (Kimadia)
& the Directorate of Technical Affairs, including the National Board
for the Drug Selection (NSBD), the National Centre for Drug Control
& Research (NCDRC), the Registration Department, & the Pharmacy
Department.
• Drug evaluation & approval was held by the Drug Registration
Committee till 2018, when a new committee (the Biologics &
Biosimilars Registration Committee) was established to approve the
1st bases & guidelines of these products at 2019 depending on the
European Medicines Agency (EMA) guidelines and ending with the
Iraqi National Regulatory Authority (NRA).

12. Iraqi bioproducts/biosimilars
management plan

13. References issues’ specific to protein
pharmaceuticals/products
• Their high molecular wt. potential for
aggregation (small change in structure
can result in a change in activity).
• Their immunogenic potential, (some are
produced by fermentation-type process
and proteins can copurify with proteins).
• The assignment of potency to the
reference standards (when traditional
pharmaceuticals are about 98% pure,
these products may be only 0.1-1%
active, with their activity assigned by
potentially variable assays).
• The use of micropipettes, which can
require frequent calibration.
• Concern that constituted products can
be less stable than lyophilized products.
• The effect of agitation on a product’s
stability.
• Possible interaction of the product with
the inner wall of the glass vial and with
the elastomeric closure.
• The effectiveness of the preservative if
a multidose product is mixed with other
products.

14. Things you need to
focus on, working
with bioproducts
• Active drug constituent & the total drug delivery
system/carrier [extremely potent-used in quite low
conc.].
• Excipients, vehicle, buffers, & stabilizers [including
surfactants, amino acids, polyhydric alcohols, polyols
1%-10%., fatty acids, proteins, antioxidants, reducing
agents, & metal ions].
• Appropriate buffer for optimal pH range [maintain
product stability- usually, conc. in the range of 0.01-0.1
M; so a higher conc. = painful injection site].
• Chelating agents to bind trace metals as Cu, Fe, Ca &
Mn [ ex. EDTA ¬ 0.01%-0.05%].
• Antioxidants [oxidation = protein degradation, ex. Vit
C, sodium disulfide, monothioglycerol,& α-tocopherol
¬ 0.05% - 0.1%].
• Preservatives [phenol 0.3% - 0.5%, chlorobutanol 0.3%-
0.5%, & benzyl alcohol 1.0%-3.0%].
• Tonicity-adjusting agent [NaCl & glucose water ¬290
mOsm/L solution].

15. Do you
remember/recall
any preservative
related to ADRs in
special group of
patients?
Need a refreshment?!!
Okay, that’s one what do
you think about the others

16. Points of view:
Bioproducts related ADRs from Iraq
• Pharmacists assumed that bioproducts are safe & well tolerated medicines with
no serious ADRs with cautious, proper handling & clinical follow up, also
reported that reference products have manageable ADRs ex. allergic reactions
and injection site rash.
• Pharmacists recommended that it’s the physicians responsibility to track
bioproducts safety since physicians who follow up the targeted pt. via ordering
lab investing pre/post management for ex. “Physicians should follow-up with a
patient after each [biopharmaceutical] dose, and it is preferable to have a
physician present during treatment, especially the 1st dose".
• Pharmacist agreed that “The patient medical records in the hospitals cannot
give enough information to measure the effectiveness and safety of biological
or biosimilar medicines“.
• Reported ADRs led to different levels of consequences: Medically important
conditions (34.8%), prolonged hospitalization (29.5%), life-threatening
conditions (22.0%), disabling (7.6%), and death (6.1%).

17. Points of view:
Bioproducts related ADRs from Iraq

18. Points of view:
Bioproducts related ADRs from Iraq

19. Always remember
We are still in our “learning phase” but are taking a pragmatic
and operational approach to resolve these until we have learned
a sufficient amount to update our guidelines

20. ADRs/Side effects
of products commonly available
in our hospital

21. Human Albumin
• Chills, fever, skin rash &/hives.
• Headache, hypotension &/tachycardia.
• Nausea, vomiting & salivation.
• Major effect with congestive heart failure pt.: decreased
myocardial contractility, hypersensitivity reactions
(anaphylaxis & precipitous hypotension).
• Pulmonary oedema salt & water retention.

22. rDNA Glucagon
• Hyperglycemia in diabetic pt.
• Hypersensitivity reactions: dyspnea, hypotension & rash.
• Hypoglycaemia & hypoglycaemic coma.
• Hypotension.
• Overdose symptoms including: increased blood pressure &
heart rate (greater effect in pt. treated with beta blockers),
nausea, vomiting, inhibition of gastrointestinal motility &
hypokalaemia.

23. Recombinant human erythropoietin
• Response to treatment is achieved within 10 days of increment in
reticulocyte count, subsequent increment in RBCs count,
hemoglobin & hematocrit (suggested target range 30-36%) within 2
to 6 weeks; otherwise, we can report nonresponsive pt.?
• It is available in preservative free single dose vial which contains
human albumin to prevent adsorptive losses, may be admixture
with benzyl alcohol & bacteriostatic water for inj. To prevent S.C.
related pain. It should not be shaken to avoid glycoprotein
denaturation render product inactivity, all these procedures could
render ADRs.
• “In early 2003, a counterfeit version of erythropoietin, was
discovered. It posed a serious health threat because it contained a
concentration of the active ingredient one twentieth of the
expected and was contaminated with two types of bacteria”.

24. Recombinant human erythropoietin
• Hypertension, hypertensive encephalopathy & seizure, cerebrovascular
accidents/transient ischemic attack, chest pain, myocardial infarction,
tachycardia, deep vein thrombosis, both hyperkalaemia & hypokalaemia
(increased risk of death, shortened time to tumor progression & decreased
survival observed when its used to target hemoglobin conc. over 11g/dl).
• Clotted vascular access (AV shunt) & clotting of artificial kidney may occur
during dialysis.
• Chills, cough, fever, diarrhoea, dysphagia, stomatitis, nausea, vomiting,
decreased weight, fatigue, headache, dizziness, insomnia & depression.
• Allergic reactions, pruritus, rash, injection site irritations, muscle spasm,
arthralgia, asthenia, bone marrow fibrosis & bone pain.
• Polycythaemia, pure red cells aplasia (PRCA) & severe anaemia ± cytopenia’s
neutralizing antibodies.
• Respiratory congestion, shortness of breath, upper respiratory tract infections &
oedema.

25. Enoxaparin sodium
• This product; which is not a small molecule drug, became a
source of confusion for the Iraqi NRA & the US FDA designated
enoxaparin sodium as a generic product for the originator
product while the EMA treated its copies proposed biosimilars.
• “It is worth mentioning that enoxaparin sodium is quite
heterogeneous product of alkaline depolymerization of
heparin benzyl ester derived from porcine intestinal mucosa”.

26. Enoxaparin sodium
• Excessive bleeding, heparin induced thrombocytopenia (cross
sensitivity with heparin), thrombocytopenia with thrombosis,
anemia, eosinophilia, ecchymosis, epidural/spinal hematoma (when
adm. With anaesthesia &/spinal puncture).
• Antigenicity, chills, fever, urticaria & anaphylaxis shock, local site
reactions (nodules inflammation & oozing), vesiculobullous rash,
cutaneous vasculitis purpura, skin necrosis (anywhere), alopecia
• Osteoporosis after long term therapy.
• Elevation of serum AST, hepatocellular & cholestatic liver injury,
nausea & headache.
• Atrial fibrillation, heart failure, pulmonary oedema, pneumonia &
hyperkalaemia.

27. Recombinant Alteplase
• Mild to serious hypersensitivity & anaphylactoid reactions:
angioedema (when comb with angiotensin converting enzyme
inhibitors), laryngeal-/orolaringual- oedema, hypotension, rash&
urticaria.
• Bleeding: internal (gastrointestinal, genitourinary, retroperitoneal
intracranial) & superficial/external (ecchymosis, epistaxis, gingival
bleeding, venous cutdown & arterial puncture site of recent
surgical intervention).
• Heart &/ renal [acute] failure, bowel infarction, myocardial
infarction, retinal artery occlusion, gangrenous digits, purple toe
syndrome, livedo reticularis & pancreatitis.
• Cerebral/spinal cord infarction, seizures, pleural effusion,
pulmonary oedema & re-embolization, rhabdomyolysis & fatalities
have been reported.

28. Rho (D) Immunoglobulin
• Abdominal & back pain, arthralgia, asthenia, shaking, chills,
diarrhoea, fever, sweating, dizziness, headache, hyperkinesia,
hypertension, hypotension, increased LDH level, somnolence
Hypersensitivity reactions, anaphylaxis, rash & pruritus
• In pregnant women, few treatment failures results in developing
Rho (D) antibodies.
• In immune thrombocytopenic purpura pt. decreased haemoglobin
range 0.4-6.1 gm/dl (destruction of (D) carrier RBCs),
intraventricular haemorrhage, haemoglobinuria, acute onset &
exacerbation of anaemia.
• Renal insufficiency in Rho (D) positive pt. rarely resulted in death.

29. References
• Iraqi Ministry of heath/ Directory of technical affairs/ Department of pharmacy/ Section of pharmacovigilance & medication-risk
management. Biosimilar follow up instructions no. (5629/12/8) at 17th. Sep. 2023
• Loyed V. Allen Jr. & Howard C. Ansel. Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, chapter 19:Product of
Biotechnology. 10th Ed 2014. Lippincott Williams & Wilkins, a Wolters Kluwer.
• Agnes V. Klein. Challenges when implementing guidelines for biosimilars. Centre for Evaluation of Radiopharmaceuticals and
Biotherapeutics, Pan American Health Organization, 2013, Ottawa, Ontario.
https://www3.paho.org/hq/index.php?option=com_docman&task=doc_view&gid=23989&Itemid=270&lang=en
• Calvo B, Zuig L. Risk Management Plan and Pharmacovigilance System. Biopharmaceuticals: Biosimilars [Internet]. Risk Management
Trends. InTech; 2011. Available from: http://dx.doi.org/10.5772/16246
• Khalid K. Al-Kinani, Mazin J. Ibrahim, Ruaa F. Al-Zubaidi, Manal M. Younus, Samir H. Ramadhan, Hussein J. Kadhim, Rodeina Challand,
Iraqi regulatory authority current system and experience with biosimilars, Regulatory Toxicology and Pharmacology, Volume 117, 2020,
104768, ISSN 0273-2300. https://doi.org/10.1016/j.yrtph.2020.104768
• Al Ani NA, Gorial FI, Al-Sulaitti S, Humadi JA, Awadh NI, Mounir M, Dershaby YE, Jones H, Sunna N. Review of biologics, biosimilars, and
intended copies in rheumatology, and current practice in Iraq. Open Access Rheumatol. 2018 Dec 24;11:1-9. doi:
https://doi.org/10.2147/OARRR.S176965 PMID: 30613169; PMCID: PMC6307490.
• Hiba Leith Fahmi, and Ali Azeez Al-Jumaili. Understanding the Experience of Hospital Pharmacists with the Effectiveness, Safety,
Adverse Drug Reaction Reporting and Interchangeability of Biopharmaceutical Medicines. Iraqi J Pharm Sci, Vol.31(1) 2022 DOI:
https://doi.org/10.31351/vol31iss1pp72-86
• Karen Whalen. Lippincott Illustrated Reviews Pharmacology. Wolters KluwerHeath. 8th Ed. 2023 [International Edition]
• Shelly Rainforth Collins. Elseviers’ Intravenous Medications: A Handbook for Nurses & Health Professionals. Elsevier. 40th Ed. 2024
• Medscape mobile application 2024. v11.9.2 drug ref v1140.0