Biopharmaceutical Production

Introduction to Biological Medicines and Biosimilars

• A biosimilar is an approved version of a biological medicine.
• It has an identical primary amino acid sequence to the originator.
• It is developed with the intention to be as close to the originator as possible.
• Biosimilars are like biological medicines, complex protein molecules produced by living organisms.
• Biological medicines have had a profound impact on healthcare in the past 15 years.
• Biological medicines have primarily impacted rheumatology and oncology.
• They have also impacted endocrinology, cardiology, dermatology, gastroenterology, and neurology.
• Many of the world's top-selling medicines are biological medicines.
• Biological medicines are expensive, sometimes by several orders of magnitude more than small-molecule chemical drugs, limiting patient access.
• There is great interest in developing biosimilars, which are likely to be more affordable, as many biological medicines come off patent globally

Development of Biosimilars

• 31 different companies were developing biosimilar monoclonal antibodies as of March 2012.
• 18 companies were developing them as of September 2011, reflecting a 67% increase in a 6-month period.
• Patent expiries for biological medicines were expected to be 99 in 2010-2015.
• Patent expiries are expected to be 91 in 2016-2020.
• Post-2020, patent expiries are expected to be 46.

Biological Medicines Coming Off Patent

• Nutropin contains the active ingredient somatropin.
• Neupogen contains the active ingredient filgrastim.
• Enbrel contains the active ingredient etanercept.
• Remicade contains the active ingredient infliximab.
• Herceptin contains the active ingredient trastuzumab.
• Tysabri contains the active ingredient natalizumab.

Approved Biosimilar Products

• Abseamed contains epoetin alfa and is sponsored by Medice Arzneimittel Pütter (Germany); the reference product is Eprex (Janssen).
• Biograstim contains filgrastim (G-CSF) and is sponsored by CT Arzneimittel; the reference product is Neupogen (Amgen).
• Binocrit contains epoetin alfa and is sponsored by Sandoz; the reference product is Eprex (Janssen).
• Epoetin alfa Hexal contains epoetin alfa and is sponsored by Hexal Biotech; the reference product is Eprex/Erypo (Janssen).
• Filgrastim Hexal contains filgrastim (G-CSF) and is sponsored by Hexal Biotech; the reference product is Neupogen (Amgen).
• Nivestim contains filgrastim (G-CSF) and is sponsored by Hospira Enterprises; the reference product is Neupogen (Amgen).
• Omnitrope contains somatropin (human growth hormone) and is sponsored by Sandoz; the reference product is Genotropin (Pfizer).
• Ratiograstim contains filgrastim (G-CSF) and is sponsored by Ratiopharm; the reference product is Neupogen (Amgen).
• Filgrastim Ratiopharm contains filgrastim (G-CSF) and is sponsored by Ratiopharm; the reference product is Neupogen (Amgen).
• Retacrit contains epoetin zeta and is sponsored by Hospira; the reference product is Eprex (Janssen).
• Silapo contains epoetin zeta and is sponsored by Stada; the reference product is Eprex (Janssen).
• Tevagrastim contains filgrastim (G-CSF) and is sponsored by Teva Pharma Industries; the reference product is Neupogen (Amgen).
• Valtropin contains somatropin (HGH) and is sponsored by BioPartners Gmbh; the reference product is Humatrope (Eli Lilly).

Differences Between Biosimilars and Small-Molecule Generic Drugs

• Small-molecule generic drugs have low molecular weight and complexity, while biosimilars have high molecular weight and complex 3-D structure.
• Small-molecule generic drugs are produced synthetically; biosimilars are produced by living organisms.
• The manufacturing process for small-molecule generic drugs is easy to reverse-engineer, but the process cannot be replicated for biosimilars.
• Small-molecule generic drugs are identical copies of the active ingredient.
• Biosimilars are not identical to the originator, but rather highly similar despite containing the same primary amino acid sequence.
• Even if a biosimilar uses the same human gene as its originator, the manufacturing process is different leading to a different product

Process Development

• Scientists/engineers figure out how to "scale up" production of a drug even before it receives approval.
• Manufacturing processes can differ significantly from small-scale lab procedures.

Pharmaceutical/Biopharmaceutical Production Steps

• Synthesis via chemical or cell culture
• Purification
• Formulation
• Final dosage form preparation

Step 1: Synthesis

• Order raw materials to make the product.
• Test raw materials to ensure they meet quality standards.
• Sterilize equipment and materials to avoid bacterial and other contamination to the cell cultures for biomanufacturing.
• The active ingredient is created through chemical processes (chemical synthesis) for pharmaceuticals, or cell culture/fermentation for biopharmaceuticals.
• For biopharmaceuticals, begin the original cell culture in small bottles.
• As cells increase, introduce cells into a small bioreactor.
• Cells are grown in large bioreactors which can be several stories tall!

Step 2: Purification

• Active ingredient synthesized must be purified.
• Purification involves removing chemicals used in the process for pharmaceuticals.
• Purification involves separating cells from cellular nutrients and byproducts for biopharmaceuticals.
• The end result of production after purification is called the bulk product.
• Bulk product can then be sold, processed further at the same plant, or shipped to another plant for more processing.

Step 3: Formulation

• Several operations get bulk product into final form.
• Formulation chemically mixes the active ingredient with other filler substances needed in the final form.
• The final product may be solid (tablet/capsule), liquid, gels/creams, or an aerosol.
• Biopharmaceuticals are often sold as sterile liquids or sterile powders.

Step 4: Final Dosage Form Preparation

• Formulated preparation is made into final form.
• Final form is dispensed into containers, then labeled and packaged.

Quality Control

• Standards of quality are high because stakes are high.
• Poor quality products can harm/kill consumers.
• Companies must adhere to Good Manufacturing Practice (GMP) regulations established by the FDA.

Ensuring Quality

• Manufacturers have three departments that ensure quality.
• These are Quality Control (QC), Quality Assurance (QA), and Validation.
• Standard Operating Procedures (SOPs) are important

Quality Control

• QC employees sample and test the raw materials and product at many stages of the manufacturing process.

Quality Assurance

• QA ensures product quality by setting up and checking systems of standard operating procedures (SOPs) and documentation.
• SOPs define each procedure in detail to be performed the same way every time.
• Companies must prepare/follow SOPs by the FDA.
• Any deviation from the SOP must be documented and approved by the QA department.
• Critical deviations that could affect product quality are investigated further.
• Documentation proves a company has done what it said, a company must have a traceable written record of all processes and checks.
• "If it isn't written down, it doesn't exist. If it isn't written down, it never happened."

Validation

• Validation proves a manufacturing process will consistently produce a product to predefined specifications.
• The operation of every part of the plant that affects quality must be validated.
• All processes and equipment affecting quality must be validated if a manufacturing process changes or a new product is introduced.
• Validation scientists and engineers have extensive experience and must be very familiar with the regulations.

Five Rules for Quality

• Understand customer needs by noting that companies have internal (fellow employees) and external customers
• A process technician's internal customer is a coworker at the next process stage.
• Say what you do (write down procedures) so standard procedures and forms are required for every step.
• Batch records define the process to manufacture the product, materials used, etc.
• Do what you say (follow procedures) as manufacturers are required to consistently and exactly follow procedures.
• SOPs are thus vital, and exist for every step.
• Prove it (keep records), companies must have traceable, written records of all processes.
• Remember that "If it isn't written down, it doesn't exist. If it isn't written down, it never happened."
• Improve it by continually evaluate the processes and procedures of companies.
• Companies should steps to make the product and process better, and be sure that new procedures must be validated

Standard Operating Procedures

• SOPs define a particular process in detail so it can be performed the same way, every time.
• Lengthy regulations related to manufacturing are found in the Code of Federal Regulations.
• Good Manufacturing Practice (GMP) regulates methods, equipment, facilities, and controls.
• SOPs include effective date, purpose, scope, safety, responsibility, references (other SOPs), materials and equipment, procedures, and approval

Questions cover biosimilars, biological medicines, and biopharmaceutical manufacturing. Topics include production steps, active ingredients, and the impact of biological medicines on healthcare. Covers cell culture and bioreactors.