1. Overview of Biosimilars: How Do They Differ From Generics?
MMRP-NOM – Approved through 12/31/16 for Policy and SGA Teams. Also approved as a pre-read and a doc that can be left behind.
Thomas Felix, MD
Director, R&D Policy
Global Regulatory Affairs and Safety
MMRP-BIO

2. The Value of Biotechnology
Worldwide, nearly 200 biologics have transformed the lives of over 800 million patients with serious illnesses1
Key Point(s):
Small molecule drugs, such as acetyl salicylic acid, have been available for many years and successfully treat a wide range of diseases. However, since the 1970s, a revolution in biotechnology has resulted in a new class of drug: the biologic.
Worldwide nearly 200 biologic medicines have transformed the lives of over 800 million patients.1
A biologic is a substance that is made from a living organism or its products2 and is produced in living systems, including bacterial3, yeast4,5 and mammalian cells6,7.
The scientific understanding of underlying disease pathways has led to the discovery and development of biologic medicines for disease diagnosis, treatment and prevention.
References
Essential Action: Saving Billions: The Case for Effective Biogenerics Legislation. Last accessed on 17th March 2014
National Cancer Institute: Dictionary of Cancer Terms Last accessed on 17th March 2014
Baneyx. Recombinant protein expression in Eschericha coli. Curr Opin Biotechnol ;10:
Cregg et al. Recombinant protein expression in Pichia pastoris. Mol Biotechnol ;16:23-52.
Malys et al. Protein Production in Saccharomyces cerevisiae for systems biology studies. Methods in Enzymology ;500:
Lackner et al. A bicistronic baculovirus vector for transient and stable protein expression in mammalian cells. Anal Biochem. 2008;380:
Rosser et al. Transient transfection of CHO-K1-S using serum-free medium in suspension: a rapid mammalian protein expression system. Protein Express Purif. 2005;40:
A biologic is a substance that is made from a living organism or its products2 and is produced in living systems, including bacterial3, yeast4,5, and mammalian6,7 cells.
1. Essential Action: Saving Billions: The Case for Effective Biogenerics Legislation. Available at: Last accessed March 17, National Cancer Institute: Dictionary of Cancer Terms Accessed on March 17, Baneyx. Curr Opin Biotechnol ;10: Cregg et al. Mol Biotechnol ;16: Malys et al. Methods in Enzymology ;500: Lackner et al. Anal Biochem. 2008;380: Rosser et al. Protein Express Purif. 2005;40:

3. Immune system disorders1,2
Biologics Are Approved for the Treatment of Various Conditions Including the Following
Cancers1
Immune system disorders1,2
Neurologic disorders1
Hematologic conditions1,2
Key Point
Biologic medicines are currently prescribed to treat a wide variety of conditions, including
Cancers such as colon, breast, and lung cancer1
Immune system disorders such as rheumatoid arthritis and Crohn’s disease1-2
Neurological disorders such as multiple sclerosis1
Hematologic conditions such as low levels of red or white blood cells or platelets1-2
Transition
Many different types of biologics have been approved by the FDA to treat these various conditions.2
References
Biotechnology Industry Organization. Guilford-Blake R, Strickland D, eds. Guide to Biotechnology Accessed February 2, 2012.
Kozlowski S, Woodcock J, Midthun K, Sherman RB. Developing the nation's biosimilars program. N Engl J Med. 2011;365:
1. Biotechnology Industry Organization. Guilford-Blake R, Strickland D, eds. Guide to Biotechnology BiotechGuide2008.pdf. Accessed February 2, 2012; 2. Kozlowski S, et al. N Engl J Med. 2011:365:

4. What Is a Biologic?
Biologic is a substance that is made from a living organism or its products.1
Biologics are developed in living systems, including bacterial2, yeast3,4, and mammalian5,6 cells.
Main Points:
A biologic is a substance that is made from a living organism or its products.1
Many biologics are produced using host cells such as bacterial2, yeast3,4, insect5, plant6, or mammalian7,8 cells grown in culture.
Simple proteins can be produced using rDNA technology in bacterial cell cultures. Mammalian cell lines are used to make more complex biologics.4
Because biologics are developed in living systems, there is a potential for variability in protein composition and structure. This process contributes to the complexities of biologic manufacturing.9
References:
1. National Cancer Institute. Biological drug. Dictionary of Cancer Terms. Available at: Accessed January 18, 2013.
2. Baneyx F. Recombinatn protein expression in Escherichi coli. Curr Opin Biotechnol ;10:
3. Cregg JM, Cereghino JL, Shi J, Higgins DR. Recombinant protein expression in Pichia pastoris. Mol Biotechnol ;16:23-52.
4. Malys N, Wishart JA, Oliver SG, McCarthy JEG. Protein production in Saccharmoyces cerevisiae for systems biology studies. Methods in Enzymology ;500:
5. Kost TA, Condreay JP, Jarvis DL. Baculovirus as versatile vectors for protein expression in insect and mammalian cells. Nature Biotechnol ;23(5):
6. Fischer R, Stoger E, Schillberg S, Christou P, Twyman RM. Plant-based production of biopharmaceuticals. Curr Opin Plant Biol. 2004;7:
7. Lackner A, Genta K, Koppensteiner H, et al. A bicistronic baculovirus vector for transient and stable protein expression in mammalian cells. Anal Biochem. 2008;380:
8. Rosser MP, Xia W, Hartsell S, et al. Transient transfection of CHO-K1-S using serum-free medium in suspension: a rapid mammalian protein expression system. Protein Expr Purif ;40:
9. Gottlieb S. Biosimilars: policy, clinical, and regulatory considerations. Am J Health Syst Pharm. 2008;65(suppl 6):S2-S8.
1. National Cancer Institute: Dictionary of Cancer Terms. Available at: Accessed January, 18, Baneyx F, Curr Opin Biotechnol. 1999;10: Cregg JM, et al. Mol Biotechnol. 2000;16: Malys N, et al. Methods in Enzymology. 2011;500: Lackner A, et al. Anal Biochem. 2008;380: Rosser MP, et al. Protein Expr Purif. 2005;40: 4

5. A Vector Containing the Relevant Gene Is Inserted into Host Cells Which Then Produce the Protein
(eg, hamster, rabbit, or bacteria)
Nucleus
The recombinant DNA sequence is inserted into a host cell1,3
The host cell is grown in culture to reproduce the desired protein1
Gene for Protein of interest +
Vector (eg, plasmid or virus)
Gene for a desired protein is combined with a DNA sequence1,2
Main Points:
A first step in the development of a biologic involves identifying the protein of interest and isolating the gene that encodes the desired protein.1
Once this is done, an appropriate vector is chosen (eg, a plasmid or viral vector) and the gene sequence is spliced into the vector to create the DNA vector.1,2
A host cell line is selected (eg, hamster, rabbit, or bacterial cells) and these cells are transfected with the DNA vector.1,3
The host cell is then grown in culture to reproduce the desired protein.1
References:
Gottlieb S. Biosimilars: policy, clinical, and regulatory considerations. Am J Health Syst Pharm ;65(suppl 6):S2-S8.
Sharma BG. Manufacturing challenges for biosimilars—the process defines the product. EJHP Pract ;13:54-56.
Kresse GB. Biosimilars—science, status, and strategic perspective. Eur J Pharm Biopharm. 2009;72:
1. Gottlieb S. Am J Health Syst Pharm. 2008;65(suppl 6):S2-S8. 2. Sharma BG. EJHP Practice. 2007;13: Kresse GB, et al. Eur J Pharm Biopharm. 2009;72: 5

6. The Host Cell That Most Effectively Produces the Protein Is Mass Produced
The cell that most effectively produces the protein is grown and replicated to create a “bank” of identical master cells1,2
A few cells from this master cell bank are used to create a working cell bank1,2
This working cell bank is used to make many identical copies of the desired protein1,2
Main Points:
Following transfection with the DNA vector, unique clones are screened for the desired characteristics or attributes, selected for expansion, and then preserved in a cell bank system that includes a master and working cell bank.1,2
The master cell bank houses primary cell strains that are not used for production purposes. A working cell bank is established from the master cell bank so that stability and uniformity of the cell line is well characterized. Cells from the working cell bank are used for production purposes.1,2
Extensive work and careful screening go into engineering and preserving an appropriate cell line for producing the protein of interest. The resulting cell line will be unique for each manufacturer.1,3-4
References:
1. Kresse GB. Biosimilars—science, status, and strategic perspective. Eur J Pharm Biopharm. 2009;72:
2. Amgen Inc. An Introduction to Biotechnology Available at: Accessed January, 2013.
3. Sharma BG. Manufacturing challenges for biosimilars—the process defines the product. EJHP Pract. 2007;13:54-56.
4. Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19:
Each biologic starts with a cell bank that will produce the protein into perpetuity3
Kresse GB, et al. Eur J Pharm Biopharm. 2009;72: Amgen Inc. An Introduction to Biotechnology. Available at: Accessed January, Chuck AS, et al. In: Elliot SG, et al, eds. Erythropoietins, erythropoietic factors, and erythropoiesis: molecular, cellular, preclinical, and clinical biology. 2nd ed. Basel, Switzerland: Birkhäuser Basel; 2009:87-104 6

7. Biologics Are Made by Living Cells Using Complex Manufacturing Processes1
Scale-Up1
Cells are multiplied in vessels of increasing size: bioreactors can hold up to 10,000-20,000 liters 2
Product Recovery and Purification1
The protein is extracted and purified 3
Cell Culture1
Cells from the working cell bank are thawed
Quality Assurance1,2
Tests and controls are performed to demonstrate identity, strength, quality, potency, and purity 4
Fill and Finish1
The product is purified and the final product is packaged 5
Refrigerate, Store, Transport3
Tightly controlled environmental conditions are required for transportation and storage 6
Main Point:
Scientific development and manufacturing of biologics requires many steps and is complex. This slide reviews key components and steps in the manufacture of biologics.
Background:
Upstream processing begins with the cells that scientists create or engineer to make the protein product. Once the desired cell line is made, it is cryopreserved: scientists freeze a large number of vials of the cells to create a cell bank. To begin a manufacturing process for a product batch, scientists remove and thaw a vial of cells from the cell bank and initiate a cell culture in a flask containing a small volume of growth media. The initial volume of media can be as little as 5 mL. The media provides the nutrients and the optimum environment for cells to survive.1
Scale-up is done by gradually transferring the growing cells into successively larger growth vessels containing larger media volumes. The cells are constantly dividing as long as the growth environment remains favorable. Therefore, more and more cells are present with each step. The greater the number of cells, the more protein product is generated. The average bioreactor holds between 10,000 and 20,000 liters.1
In the downstream phase of manufacturing, the protein product is isolated from the cells that produced it. Proteins found inside the cell (intracellular proteins) require special protocols to extract them for purification. Usually this involves bursting the cells open to release the protein product, which then has to be purified away from the other components that were inside the cell. Researchers verify the isolation and purification of the protein product through confirmed testing protocols.1
Quality control (QC) and quality assurance (QA) departments are responsible for all of the monitoring that is crucial to the success of the scale-up and manufacturing stages of product development. The QC department assures product quality and testing during the product development stages well before the product is at the stage of marketing, ensuring that the scale-up and manufacturing processes meet certain standards. The QA department is usually responsible for meeting and reporting quality objectives.1 Potency tests, along with a number of other tests, are performed as part of product conformance testing, comparability studies, and stability testing. These tests are used to measure product attributes associated with product quality and manufacturing controls, and are performed to assure identity, purity, strength (potency), and stability of products.2
The protein product is then formulated according to specifications and packaged for use by physicians and patients.1
Biopharmaceuticals are highly sensitive to environmental influences, such as temperature, agitation, and exposure to light. Improper storage and handling can lead to protein degradation.3
References:
1. Amgen Inc. An Introduction to Biotechnology Available at: Accessed January, 2013
2. Food and Drug Administration. Guidance for industry: potency tests for cellular and gene therapy products. Available at: Accessed June 1, 2013.
3. Sharma BG. Manufacturing challenges for biosimilars—the process defines the product. EJHP Pract. 2007;13:54-56.
Amgen Inc. An Introduction to Biotechnology Available at: Accessed January, Food and Drug Administration. Guidance for industry: potency tests for cellular and gene therapy products. Available at: Accessed June 1, Sharma BG. EJHP Pract. 2007;13:54-56.

8. Small Molecules and Biologics Differ in Structure
Small molecules (chemically based drugs)1
Biologics (protein-based drugs)1
Key Points
Small molecules are less structurally complex than biologics.1
Because the molecular structure of chemical medicines is relatively simple, it is easier to analyze and compare them in order to determine whether they are identical.2
In contrast, protein molecules can be larger and more complex than chemical drugs. Proteins consist of one or more chains of amino acids with a complex three-dimensional structure.3 This factor complicates determination of the differences between two protein molecules.2,3
A biologic molecule could be 800 times larger than a small molecule one.1 This complexity has key implications for the manufacture of biologics.3
Transition
Let’s review some of the key differences in the properties of small molecules and biologics.
References
Kozlowski S, Woodcock J, Midthun K, Sherman RB. Developing the nation's biosimilars program. N Engl J Med. 2011;365:
Genazzani AA, Biggio G, Caputi AP, et al. Biosimilar drugs: concerns and opportunities. BioDrugs. 2007;21:
Roger SD. Biosimilars: how similar or dissimilar are they? Nephrology. 2006;11:
Example
Aspirin2
MW = 180 Da
Biologic monoclonal antibody3
MW = ~ 150,000 Da
Images are for illustrative purposes and are not to scale.
MW = molecular weight; Da = dalton.
1. Kozlowski S, et al. N Engl J Med. 2011;365: ; 2. Aspirin comprehensive prescribing information, ac/03/briefing/4012B1_03_Appd%201-Professional%20Labeling.pdf. Accessed February 15, 2012; 3. Davies DR, et al. Ann Rev Biochem. 1975;44:

9. Differences Between Small Molecules and Biologics
Small Molecules (chemically based drugs)
Biologics (protein-based drugs)
Differences Between Small Molecules and Biologics
Example
Acetyl salicylic acid1
MW = 180 Da
Biologic monoclonal antibody
MW = ~ 150,000 Da6
Size
Small2
Large2
Structure
Simple3 and well defined2,4
Complex with many options for post-translational modification7
Manufacturing
Predictable chemical process;
Identical copy can be made2
Each manufactured in a unique living cell line2
Similar but not identical copy can be made2
Properties
Key Point(s):
This slide illustrates some key differences in the properties of biologics (protein-based drugs) and small molecules (chemically based drugs). Biologics, which are protein-based, differ from chemically based, small molecule drugs in a number of important ways.1 By reviewing the properties of these two types of molecules, one can appreciate that developing and manufacturing protein-based drugs is more complex.
Background:
Size: The size of a biologic may be measured to be thousands of daltons, while the size of a small molecule is typically in the tens of daltons.2
Structure: Biologics typically have a complex and heterogeneous structure, while small molecule or chemically based drugs typically have a simple and defined structure.1,3
Modification and characterization: Proteins are dynamic entities with many options for modification and are difficult to fully characterize. In contrast, modification of small molecule drugs can be well defined and small molecule drugs are easy to fully characterize based on structural and computational models.4,5
Stability and immunogenicity: Biologics are sensitive to storage and handling conditions, including the temperature and other characteristics of the environment, while small molecules are relatively stable. Biologics have a higher potential for immunogenicity, while small molecules have a lower potential to be immunogenic.2
Manufacturing: Biologics are derived from a unique line of living cells, and it is difficult to ensure an identical copy. Small molecule drugs are manufactured based on a predictable chemical processes and identical copies can be readily made.2
References:
Roger SD. Biosimilars: How similar or dissimilar are they? Nephrology. 2006;11:
Genazzani AA, Biggio G, Caputi AP, et al. Biosimilar drugs: concerns and opportunities. Biodrugs. 2007;21:
Prugnaud JL. Similarity of biotechnology-derived medicinal products: specific problems and new regulatory framework. Br J Clin Pharmacol. 2007;65:
Gottlieb S. Biosimilars: policy, clinical, and regulatory considerations. Am J Health Syst Pharm. 2008;65(suppl 6):S2-S8.
Crommelin DJ, Storm G, Verrijk R, et al. Shifting paradigms: biopharmaceuticals versus low molecular weight drugs. Int J Pharm. 2003;266:3-16.
Characterizations
Easy to fully characterize5
Difficult to characterize fully due to a mixture of related molecules2
Stability
Relatively stable2
Sensitive to storage and handling conditions2
Immunogenicity
Lower potential2
Higher potential2
Images are for illustrative purposes and are not to scale.
1. Aspirin comprehensive prescribing information.
Accessed January 24, 2013; 2. Genazzani AA, et al. Biodrugs. 2007;21: ; 3. Prugnaud JL. Br J Clin Pharmacol. 2007;65: ; 4. Crommelin DJ, Storm G, Verrijk R, et al. Int J Pharm. 2003;266:3-16; 5. Gottlieb S. Am J Health Syst Pharm. 2008;65(suppl 6):S2-S8; 6. Davies DR, et al. Ann Rev Biochem. 1975;44: ;
7. Roger SD. Nephrology. 2006;11:

10. What are Biosimilars?
Biosimilars are copies of existing biologic products, which are similar but not identical1
The Public Health Service Act defines biosimilar or biosimilarity as:
“the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components,”2 and
“there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”2
Key Point(s):
Unlike generic drugs, biosimilars are not identical to the innovator biologic. They are “similar” but not the “same.”1,2
Biosimilars are not the same as the reference or innovator biologic because they are developed from different cell lines, and undergo different manufacturing, and purification processes.1,2
Reference:
Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19:
Lee JF et al. Curr Med Res Opin. 2012;28:
Biosimilars are not generics; there is neither an expectation nor requirement for sameness. They are “similar” but not the “same.”1
Original Biologic
Biosimilars
1Mellstedt H, et al. Ann Oncol. 2008;19:
2Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2) of the PHS Act.

11. FDA Perspective: A “Totality of the Evidence” Approach will be Applied to Assess Biosimilarity
Generics
Biosimilars
Establish same active ingredient, strength, dosage form, route of administration, and condition of use
Extensive structural and functional characterization
Consider need for animal data to assess toxicity
Demonstration of bioequivalence
Clinical studies to compare clinical immunogenicity and PK/PD
Key Point(s):
Given the complex nature of biologics, it is unlikely that a “one size fits all” assessment of biosimilarity can be developed and FDA scientist will need to integrate various types of information to provide an overall assessment that a biologic is biosimilar to an approved reference product.1
In a 2011 publication in the New England Journal of Medicine in 2011, members of CDER and CBER, published the FDA’s perspective on developing the approval pathway for biosimilars. They discussed a “risk-based totality of the evidence approach” to the evaluation of biosimilarity.1
In February, 2012, the FDA issued draft guidance on biosimilar product development to assist industry in developing such products in the United States.2 The guidance documents provide the FDA's current thinking on key scientific and regulatory factors involved in submitting applications for biosimilar products to the agency. 2
The FDA suggested a step-wise approach to evaluate attributes of biosimilar products using multiple complementary methods and advanced analytic techniques to target additional studies needed.3
Start with extensive structural and functional characterization
Consider need for animal data to assess toxicity
Conduct comparative human PK and PD studies
Compare clinical immunogenicity
If “residual uncertainties” exist, comparative safety and effectiveness data will be needed
In all cases, FDA has discretion under BPCIA to determine that certain studies are not required
The FDA noted that demonstrating comparability following changes by the same manufacturer is not the same as a biosimilar comparability exercise.3
Reference:
Kozlowski S, Woodcock J, Midthun K, Sherman RB. Developing the nation's biosimilars program. N Engl J Med. 2011;365:
FDA. Guidance for industry on biosimilars: Q & As regarding implementation of the BPCI Act of Accessed January 24, 2013.
FDA. Guidance for Industry. Scientific considerations in demonstrating biosimilarity to a reference product. Accessed January 24, 2013.
Sufficient to demonstrate that the product is “highly similar” to the reference product and safe, pure, and potent for one or more approved conditions of use
FDA has discretion to determine that certain studies not required
Food and Drug Administration. Accessed January 24, 2013.

12. Determination of Interchangeability Requires Evidence Beyond That Needed to Demonstrate Biosimilarity
Interchangeability
Approved as a biosimilar, AND:
Expectation of same clinical result in any given patient
AND
For a product that is administered more than once, no additional risk to safety or efficacy as a result of switching
Biosimilarity
Highly similar notwithstanding minor differences in clinically inactive components
AND
No clinically meaningful differences in safety, purity, and potency of the product
Key Point(s)
Section 351(k) of the BPCIA was added to the PHSA to describe an approval pathway for biologics that are “highly similar” (biosimilar) to or “interchangeable” with an FDA-licensed biologic.
Biosimilars are highly similar but not the same as the reference biologic.1
- Biosimilars are highly similar not withstanding minor differences in clinically inactive components and there are no clinically meaningful differences in terms of safety, purity, and potency.1
An interchangeability designation will be considered for a biosimilar that can be expected to provide the same clinical result in any given patient. An interchangeable biological product should pose no additional risk to safety or efficacy as a result of switching.1
Background
The evaluation and approval of a proposed biologic as “biosimilar” to the reference product will be based upon data derived from analytical studies, animal studies, and a clinical study or studies sufficient to demonstrate the safety, purity, and potency in one or more appropriate conditions of use for which the reference biologic is licensed.2
To meet the higher standard of “interchangeability,” a product must demonstrate that it can be expected to produce the same clinical result as the reference product in any given patient.1
- For products administered more than once, the safety and/or diminished efficacy risks of alternating or switching between the biosimilar and the reference biologic cannot be higher than the risks associated with using the reference product alone.1
As outlined in the draft guidance documents on the biosimilar approval pathway, the FDA is considering the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product.2
References
Patient Protection and Affordable Care Act. frwebgate.access.gpo.gov/cgi-bin/ getdoc.cgi?dbname=111_cong_bills&docid=f:h3590pp.txt.pdf. Accessed January 24, 2013.
Food and Drug Administration. Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. Draft guidance. January 24, Accessed January 24, 2013.
Patient Protection and Affordable Care Act. f:h3590pp.txt.pdf.

13. Interchangeable biologic
FDA Determines Interchangeability, While Automatic Substitution Is Governed at the State Level
FDA designation1
Automatic substitution with reference product is not allowed2
Biosimilar
Automatic substitution with reference product may be allowed2
Subject to limitations of state laws3
Interchangeable biologic
FDA policy on approval standards for biosimilars does not address automatic substitution
There is ongoing legislative activity in multiple states with regard to automatic substitution of interchangeable biologics with the reference product3
1. Patient Protection and Affordable Care Act Accessed April 30, FDA. ucm htm. Accessed February 18, NCSL. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars Accessed April 4, 2015.

14. Scientifically Sound Policy Protects Patients
Principle
Substitution based on an FDA determination
The prescribing physician should be able to specify ‘dispense as written’
The patient should be informed of the substitution
Pharmacy records should be maintained
Only after dispensing, the patient’s medical record should be updated (e.g., through direct entry into a shared electronic record, communication via fax)
Prevailing Generic Requirements
Suggested Biosimilar Requirements
Yes – Therapeutic Equivalence
Yes –
Interchangeable
Yes No

15. Summary
Biologics are developed in living systems1,2, using complex processes involving many highly regulated and unique steps3-6
Biosimilars are highly similar, but not identical to the innovator biologic2
The US pathway for approval of biosimilars was signed into law along with the Patient Protection and Affordable Care Act7
A totality of evidence will be considered when evaluating a biosimilar product for approval8
Determination of interchangeability requires a higher standard of evidence7,9
Key Point(s):
The key takeaways conveyed in this presentation are:
Biologics are engineered utilizing living cells and the basic building blocks of proteins to develop natural biologic therapies to treat various diseases.1,2
Manufacturing and development of biologics is a complex process involving many highly regulated and unique steps.3-6
The pathway for approval of biosimilars was signed into law along with the Patient Protection and Affordable Care Act.7
- A totality of evidence will be considered when evaluating a biosimilar product for approval8
- Determination of interchangeability requires a higher standard of evidence7,9
Distinguishable names and clear labeling may help facilitate accurate and timely AE reporting and assist with informed decision making10
Ensuring consistent product supply requires a commitment to manufacturing excellence and risk management
References:
Biotechnology Industry Organization. Guilford-Blake R, Strickland D, eds. Guide to Biotechnology Accessed January 24, 2013.
Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19:
Amgen Inc. An Introduction to Biotechnology Accessed January 24, 2013.
Kresse GB. Biosimilars—science, status, and strategic perspective. Eur J Pharm Biopharm. 2009;72:
Sharma BG. Manufacturing challenges for biosimilars—the process defines the product. EJHP Pract. 2007;13:54-56.
Roger SD. Biosimilars: How similar or dissimilar are they? Nephrology. 2006;11:
Patient Protection and Affordable Care Act. frwebgate.access.gpo.gov/cgi-bin/ getdoc.cgi?dbname=111_cong_bills&docid=f:h3590pp.txt.pdf. Accessed January 24, 2013.
Food and Drug Administration. FDA issues draft guidance on biosimilar product development. Accessed January 24, 2013.
Kozlowski S, Woodcock J, Midthun K, Sherman RB. Developing the nation's biosimilars program. N Engl J Med. 2011;365:
Amgen Inc. response to FDA draft guidance documents on the implementation of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) as presented in the February 15, 2012 Federal Register Notices [Docket Nos. FDA-2011-D-0602, FDA-2011-D-0605, and FDA D Available at
1. Biotechnology Industry Organization. Guilford-Blake R, Strickland D, eds. Guide to Biotechnology BiotechGuide2008.pdf. Accessed January 24, 2013; 2. Mellstedt H, et al. Ann Oncol. 2008;19: ; 3. Amgen Inc. An Introduction to Biotechnology Accessed January 24, 2013; 4. Kresse GB, et al. Eur J Pharm Biopharm. 2009;72: ; 5. Sharma BG. EJHP Practice. 2007;13:54-56; 6. Roger SD. Nephrology. 2006;11: ; 7. Patient Protection and Affordable Care Act. frwebgate.access.gpo.gov/cgibin/getdoc.cgi?dbname=111_cong_bills&docid=f:h3590pp.txt. pdf. Accessed January 24, 2013; 8. Food and Drug Administration. Accessed January 24, 2013; 9. Kozlowski S, et al. N Engl J Med. 2011:365: ;